FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Bhalla, K Liu, WJ Thompson, K Anders, L Devarakonda, S Dewi, R Buckley, S Hwang, BJ Polster, B Dorsey, SG Sun, YZ Sicinski, P Girnun, GD AF Bhalla, Kavita Liu, Wan-Ju Thompson, Keyata Anders, Lars Devarakonda, Srikripa Dewi, Ruby Buckley, Stephanie Hwang, Bor-Jang Polster, Brian Dorsey, Susan G. Sun, Yezhou Sicinski, Piotr Girnun, Geoffrey D. TI Cyclin D1 Represses Gluconeogenesis via Inhibition of the Transcriptional Coactivator PGC1 alpha SO DIABETES LA English DT Article ID NUCLEAR FACTOR 4-ALPHA; GENE-EXPRESSION; OXIDATIVE-PHOSPHORYLATION; HEPATOCELLULAR-CARCINOMA; HEPATIC GLUCONEOGENESIS; MITOCHONDRIAL-FUNCTION; INSULIN-RESISTANCE; ESTROGEN-RECEPTOR; PPAR-GAMMA; IN-VIVO AB Hepatic gluconeogenesis is crucial to maintain normal blood glucose during periods of nutrient deprivation. Gluconeogenesis is controlled at multiple levels by a variety of signal transduction and transcriptional pathways. However, dysregulation of these pathways leads to hyperglycemia and type 2 diabetes. While the effects of various signaling pathways on gluconeogenesis are well established, the downstream signaling events repressing gluconeogenic gene expression are not as well understood. The cell-cycle regulator cyclin D1 is expressed in the liver, despite the liver being a quiescent tissue. The most well-studied function of cyclin D1 is activation of cyclin-dependent kinase 4 (CDK4), promoting progression of the cell cycle. We show here a novel role for cyclin D1 as a regulator of gluconeogenic and oxidative phosphorylation (OxPhos) gene expression. In mice, fasting decreases liver cyclin 131 expression, while refeeding induces cyclin D1 expression. Inhibition of CDK4 enhances the gluconeogenic gene expression, whereas cyclin D1-mediated activation of CDK4 represses the gluconeogenic gene-expression program in vitro and in vivo. Importantly, we show that cyclin D1 represses gluconeogenesis and OxPhos in part via inhibition of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1 alpha) activity in a CDK4-dependent manner. Indeed, we demonstrate that PGC-1 alpha is novel cyclin D1/CDK4 substrate. These studies reveal a novel role for cyclin D1 on metabolism via PGC1 alpha and reveal a potential link between cell-cycle regulation and metabolic control of glucose homeostasis. C1 [Bhalla, Kavita; Liu, Wan-Ju; Thompson, Keyata; Dewi, Ruby; Buckley, Stephanie; Hwang, Bor-Jang; Dorsey, Susan G.; Girnun, Geoffrey D.] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Anders, Lars; Devarakonda, Srikripa; Sicinski, Piotr] Dana Farber Canc Inst, Boston, MA 02115 USA. [Polster, Brian] Univ Maryland, Sch Med, Dept Anesthesiol, Baltimore, MD 21201 USA. [Dorsey, Susan G.] Univ Maryland, Sch Nursing, Dept Anesthesiol, Baltimore, MD 21201 USA. [Sun, Yezhou] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Sicinski, Piotr] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Girnun, Geoffrey D.] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Girnun, Geoffrey D.] Stony Brook Sch Med, Dept Pathol, Stony Brook, NY USA. RP Girnun, GD (reprint author), Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. EM geoffrey.girnun@stonybrookmedicine.edu FU Maryland Cigarette Restitution Fund; [CA169919]; [DK064685] FX This work was funded in part by CA169919 and DK064685 and the Maryland Cigarette Restitution Fund to the Greenebaum Cancer Center (G.D.G.). NR 47 TC 9 Z9 9 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD OCT PY 2014 VL 63 IS 10 BP 3266 EP 3278 DI 10.2337/db13-1283 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AQ1FM UT WOS:000342527300015 PM 24947365 ER PT J AU Hatanaka, M Maier, B Sims, EK Templin, AT Kulkarni, RN Evans-Molina, C Mirmira, RG AF Hatanaka, Masayuki Maier, Bernhard Sims, Emily K. Templin, Andrew T. Kulkarni, Rohit N. Evans-Molina, Carmella Mirmira, Raghavendra G. TI Palmitate Induces mRNA Translation and Increases ER Protein Load in Islet beta-Cells via Activation of the Mammalian Target of Rapamycin Pathway SO DIABETES LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; PANCREATIC TRANSCRIPTION FACTOR; SATURATED FATTY-ACID; INSULIN-SECRETION; PROLIFERATION; MICE; EXPRESSION; APOPTOSIS; SURVIVAL; KINASE AB Saturated free fatty acids (FFAs) have complex effects on the islet beta-cell, acutely promoting adaptive hyperplasia but chronically impairing insulin release. The acute effects of FFAs remain incompletely defined. To elucidate these early molecular events, we incubated mouse p-cells and islets with palmitate and then studied mRNA translation by polyribosomal profiling and analyzed signaling pathways by immunoblot analysis. We found that palmitate acutely increases polyribosome occupancy of total RNA, consistent with an increase in mRNA translation. This effect on translation was attributable to activation of mammalian target of rapamycin (mTOR) pathways via L-type Ca2+ channels but was independent of insulin signaling. Longer incubations led to depletion of polyribosome-associated RNA, consistent with activation of the unfolded protein response (UPR). Pharmacologic inhibition of mTOR suppressed both the acute effects of palmitate on mRNA translation and the chronic effects on the UPR. Islets from mice fed a high-fat diet for 7 days showed increases in polyribosome-associated RNA and phosphorylation of S6K, both consistent with activation of mTOR. Our results suggest that palmitate acutely activates mRNA translation and that this increase in protein load contributes to the later UPR. C1 [Hatanaka, Masayuki; Maier, Bernhard; Sims, Emily K.; Mirmira, Raghavendra G.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Hatanaka, Masayuki; Maier, Bernhard; Sims, Emily K.; Evans-Molina, Carmella; Mirmira, Raghavendra G.] Indiana Univ Sch Med, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA. [Templin, Andrew T.; Evans-Molina, Carmella; Mirmira, Raghavendra G.] Indiana Univ Sch Med, Dept Cellular & Integrat Physiol, Indianapolis, IN 46202 USA. [Kulkarni, Rohit N.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol,Dept Med, Boston, MA 02115 USA. [Evans-Molina, Carmella; Mirmira, Raghavendra G.] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Evans-Molina, Carmella; Mirmira, Raghavendra G.] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. RP Mirmira, RG (reprint author), Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. EM rmirmira@iu.edu FU National Institutes of Health (NIH) [R01-DK-060581, R01-DK-083583, T32-DK-065549, R01-DK-67536, R01-DK-093954]; Manpei Suzuki Diabetes Foundation; American Heart Association; VA Merit Award [I01 BX001733]; George and Frances Ball Foundation; Ball Brothers Foundation FX This work was supported by National Institutes of Health (NIH) grants R01-DK-060581 and R01-DK-083583 (to R.G.M.), a grant from the Manpei Suzuki Diabetes Foundation (to M.H.), NIH grant T32-DK-065549 (to E.K.S.), a fellowship grant from the American Heart Association (to A.T.T.), NIH grant R01-DK-67536 (to R.N.K.), NIH grant R01-DK-093954 (to C.E.-M.), VA Merit Award I01 BX001733 (to C.E.-M.), and grants from the George and Frances Ball Foundation and the Ball Brothers Foundation (both to R.G.M. and C.E.-M.). NR 51 TC 7 Z9 7 U1 0 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD OCT PY 2014 VL 63 IS 10 BP 3404 EP 3415 DI 10.2337/db14-0105 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AQ1FM UT WOS:000342527300027 PM 24834975 ER PT J AU Orban, T Beam, CA Xu, P Moore, K Jiang, Q Deng, J Muller, S Gottlieb, P Spain, L Peakman, M AF Orban, Tihamer Beam, Craig A. Xu, Ping Moore, Keith Jiang, Qi Deng, Jun Muller, Sarah Gottlieb, Peter Spain, Lisa Peakman, Mark CA Type 1 Diabet TrialNet Abatacept S TI Reduction in CD4 Central Memory T-Cell Subset in Costimulation Modulator Abatacept-Treated Patients With Recent-Onset Type 1 Diabetes Is Associated With Slower C-Peptide Decline SO DIABETES LA English DT Article ID DOUBLE-BLIND; THERAPY; MELLITUS; TRIAL AB We previously reported that continuous 24-month costimulation blockade by abatacept significantly slows the decline of beta-cell function after diagnosis of type 1 diabetes. In a mechanistic extension of that study, we evaluated peripheral blood immune cell subsets (CD4, CD8-naive, memory and activated subsets, myeloid and plasmacytoid dendritic cells, monocytes, B lymphocytes, CD4(+)CD25(high) regulatory T cells, and invariant NK T cells) by flow cytometry at baseline and 3, 6, 12, 24, and 30 months after treatment initiation to discover biomarkers of therapeutic effect. Using multivariable analysis and lagging of longitudinally measured variables, we made the novel observation in the placebo group that an increase in central memory (CM) CD4 T cells (CD4(+)CD45R0(+)CD62L(+)) during a preceding visit was significantly associated with C-peptide decline at the subsequent visit. These changes were significantly affected by abatacept treatment, which drove the peripheral contraction of CM CD4 T cells and the expansion of naive (CD45R0(-)CD62L(+)) CD4 T cells in association with a significantly slower rate of C-peptide decline. The findings show that the quantification of CM CD4 T cells can provide a surrogate immune marker for C-peptide decline after the diagnosis of type 1 diabetes and that costimulation blockade may exert its beneficial therapeutic effect via modulation of this subset. C1 [Orban, Tihamer] Joslin Diabet Ctr, Boston, MA 02215 USA. [Beam, Craig A.; Xu, Ping; Muller, Sarah] Univ S Florida, Dept Pediat, Div Informat & Biostat, Tampa, FL 33620 USA. [Moore, Keith; Jiang, Qi; Deng, Jun] David H Murdock Res Inst, Kannapolis, NC USA. [Gottlieb, Peter] Univ Colorado, Barbara Davis Ctr Childhood Diabet, Aurora, CO USA. [Spain, Lisa] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD USA. [Peakman, Mark] Kings Coll London, Sch Med, Peter Gorer Dept Immunobiol, London WC2R 2LS, England. RP Orban, T (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA. EM tihamer.orban@gmail.com RI Krammel, Vera/N-4826-2014 OI Krammel, Vera/0000-0002-8273-8396 FU Type 1 Diabetes Trial Net Study Group; National Institutes of Health through National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; The Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01-DK-061010, U01-DK-061016, U01-DK-061034, U01-DK-061036, U01-DK-061040, U01-DK-061041, U01-DK-061042, U01-DK-061055, U01-DK-061058, U01-DK-084565, U01-DK-085453, U01-DK-085461, U01-DK-085463, U01-DK-085466, U01-DK-085499, U01-DK-085505, U01-DK-085509, HHSN267200800019C]; National Center for Research Resources [UL1-RR-024131, UL1-RR-024139, UL1-RR-024153, UL1-RR-024975, UL1-RR-024982, UL1-RR-025744, UL1-RR-025761, UL1-RR-025780, UL1-RR-029890, UL1-RR-031986]; General Clinical Research Center Award [M01-RR-00400]; Juvenile Diabetes Research Foundation International; American Diabetes Association FX The sponsor of the trial was the Type 1 Diabetes Trial Net Study Group. The Type 1 Diabetes Trial Net Study Group is a clinical trials network funded by the National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development through cooperative agreements U01-DK-061010, U01-DK-061016, U01-DK-061034, U01-DK-061036, U01-DK-061040, U01-DK-061041, U01-DK-061042, U01-DK-061055, U01-DK-061058, U01-DK-084565, U01-DK-085453, U01-DK-085461, U01-DK-085463, U01-DK-085466, U01-DK-085499, U01-DK-085505, and U01-DK-085509 and contract HHSN267200800019C; the National Center for Research Resources through Clinical Translational Science Awards UL1-RR-024131, UL1-RR-024139, UL1-RR-024153, UL1-RR-024975, UL1-RR-024982, UL1-RR-025744, UL1-RR-025761, UL1-RR-025780, UL1-RR-029890, and UL1-RR-031986 and General Clinical Research Center Award M01-RR-00400; the Juvenile Diabetes Research Foundation International; and the American Diabetes Association. NR 20 TC 13 Z9 13 U1 0 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD OCT PY 2014 VL 63 IS 10 BP 3449 EP 3457 DI 10.2337/db14-0047 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AQ1FM UT WOS:000342527300031 PM 24834977 ER PT J AU Abdo, S Shi, YX Otoukesh, A Ghosh, A Lo, CS Chenier, I Filep, JG Ingelfinger, JR Zhang, SL Chan, JSD AF Abdo, Shaaban Shi, Yixuan Otoukesh, Abouzar Ghosh, Anindya Lo, Chao-Sheng Chenier, Isabelle Filep, Janos G. Ingelfinger, Julie R. Zhang, Shao Ling Chan, John S. D. TI Catalase Overexpression Prevents Nuclear Factor Erythroid 2-Related Factor 2 Stimulation of Renal Angiotensinogen Gene Expression, Hypertension, and Kidney Injury in Diabetic Mice SO DIABETES LA English DT Article ID PROXIMAL TUBULAR CELLS; CONVERTING ENZYME-2 EXPRESSION; TRANSGENIC MICE; BARDOXOLONE METHYL; TUBULOINTERSTITIAL FIBROSIS; URINARY ANGIOTENSINOGEN; TRANSCRIPTION FACTOR; BLOOD-PRESSURE; CANCER CELLS; APOPTOSIS AB This study investigated the impact of catalase (Cat) overexpression in renal proximal tubule cells (RPTCs) on nuclear factor erythroid 2-related factor 2 (Nrf2) stimulation of angiotensinogen (Agt) gene expression and the development of hypertension and renal injury in diabetic Akita transgenic mice. Additionally, adult male mice were treated with the Nrf2 activator oltipraz with or without the inhibitor trigonelline. Rat RPTCs, stably transfected with plasmid containing either rat Agt or Nrf2 gene promoter, were also studied. Cat overexpression normalized systolic BP, attenuated renal injury, and inhibited RPTC Nrf2, Agt, and heme oxygenase-1 (HO-1) gene expression in Akita Cat transgenic mice compared with Akita mice. In vitro, high glucose level, hydrogen peroxide, and oltipraz stimulated Nrf2 and Agt gene expression; these changes were blocked by trigonelline, small interfering RNAs of Nrf2, antioxidants, or pharmacological inhibitors of nuclear factor-kappa B and p38 mitogen-activated protein kinase. The deletion of Nrf2-responsive elements in the rat Agt gene promoter abolished the stimulatory effect of oltipraz. Oltipraz administration also augmented Agt, HO-1, and Nrf2 gene expression in mouse RPTCs and was reversed by trigonelline. These data identify a novel mechanism, Nrf2-mediated stimulation of intrarenal Agt gene expression and activation of the renin-angiotensin system, by which hyperglycemia induces hypertension and renal injury in diabetic mice. C1 [Abdo, Shaaban; Shi, Yixuan; Otoukesh, Abouzar; Ghosh, Anindya; Lo, Chao-Sheng; Chenier, Isabelle; Zhang, Shao Ling; Chan, John S. D.] Univ Montreal, Res Ctr, Ctr Hosp Univ Montreal, Montreal, PQ, Canada. [Filep, Janos G.] Univ Montreal, Res Ctr, Hop Maisonneuve Rosemont, Montreal, PQ, Canada. [Ingelfinger, Julie R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Nephrol Unit, Boston, MA USA. RP Chan, JSD (reprint author), Univ Montreal, Res Ctr, Ctr Hosp Univ Montreal, Montreal, PQ, Canada. EM john.chan@umontreal.ca FU Canadian Institutes of Health Research [MOP-97742, MOP-86450, MOP-84363, MOP 93650, MOP 16088]; National Institutes of Health [HL-48455]; Heart and Stroke Foundation of Canada FX This work was supported by grants from the Canadian Institutes of Health Research (MOP-97742 to J.G.F.; MOP-86450 to S.L.Z.; and MOP-84363, MOP 93650, and MOP 16088 to J.S.D.C.), the National Institutes of Health (HL-48455 to J.R.I.), and the Heart and Stroke Foundation of Canada (to J.S.D.C.). Editorial assistance was provided by the Centre Hospitalier de l'Universite de Montreal Research Support Office and Ovid M. Da Silva. NR 48 TC 6 Z9 6 U1 2 U2 11 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD OCT PY 2014 VL 63 IS 10 BP 3483 EP 3496 DI 10.2337/db13-1830 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AQ1FM UT WOS:000342527300034 PM 24812425 ER PT J AU Wei, D Loeken, MR AF Wei, Dan Loeken, Mary R. TI Increased DNA Methyltransferase 3b (Dnmt3b)-Mediated CpG Island Methylation Stimulated by Oxidative Stress Inhibits Expression of a Gene Required for Neural Tube and Neural Crest Development in Diabetic Pregnancy SO DIABETES LA English DT Article ID ACTIVATED PROTEIN-KINASE; VITAMIN-E; CARDIOVASCULAR MALFORMATIONS; MAMMALIAN DEVELOPMENT; DEFECTS; EMBRYOS; CELLS; MOUSE; INFANTS; RISK AB Previous studies have shown that diabetic embryopathy results from impaired expression of genes that are required for formation of embryonic structures. We have focused on Pax3, a gene that is expressed in embryonic neuroepithelium and is required for neural tube closure. Pax3 expression is inhibited in embryos of diabetic mice due to hyperglycemia-induced oxidative stress. DNA methylation silences developmentally expressed genes before differentiation. We hypothesized that hypomethylation of Pax3 upon neuroepithelial differentiation may be inhibited by hyperglycemia-induced oxidative stress. We tested this using embryos of pregnant hyperglycemic mice and mouse embryonic stem cells (ESC). Methylation of a Pax3 CpG island decreased upon neurulation of embryos and formation of neuronal precursors from ESC. In ESC, this was inhibited by oxidative stress. Use of short hairpin RNA in ESC demonstrated that DNA methyltransferase 3b (Dnmt3b) was responsible for methylation and silencing of Pax3 before differentiation and by oxidative stress. Although expression of Dnmt3b was not affected by oxidative stress, DNA methyltransferase activity was increased. These results indicate that hyperglycemia-induced oxidative stress stimulates Dnmt3b activity, thereby inhibiting chromatin modifications necessary for induction of Pax3 expression during neurulation and thus providing a molecular mechanism for defects caused by Pax3 insufficiency in diabetic pregnancy. C1 [Loeken, Mary R.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Loeken, MR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02115 USA. EM mary.loeken@joslin.harvard.edu OI Loeken, Mary/0000-0002-8056-9816 FU National Institute of Diabetes and Digestive and Kidney Diseases [RO1DK058300]; Diabetes Endocrine Research Center [PO1DK036836] FX M.R.L. was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases under award number RO1DK058300 and was assisted by core facilities supported by a Diabetes Endocrine Research Center grant, PO1DK036836, to the Joslin Diabetes Center and by the DNA Resource Core provided by the Dana-Farber/Harvard Cancer Center. NR 50 TC 11 Z9 11 U1 2 U2 16 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD OCT PY 2014 VL 63 IS 10 BP 3512 EP 3522 DI 10.2337/db14-0231 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AQ1FM UT WOS:000342527300036 PM 24834974 ER PT J AU Iezzoni, LI Kurtz, SG Rao, SR AF Iezzoni, Lisa I. Kurtz, Stephen G. Rao, Sowmya R. TI Trends in U.S. adult chronic disability rates over time SO DISABILITY AND HEALTH JOURNAL LA English DT Article DE Disability; Prevalence rates; Movement difficulties; National health interview survey ID UNITED-STATES; OLDER AMERICANS; US POPULATION; HEALTH; OBESITY; DISPARITIES; LIMITATIONS; DECLINES; LIFE AB Background: Trends in the patterns and prevalence of chronic disability among U.S. residents carry important implications for public health and public policies across multiple societal sectors. Objectives: To examine trends in U.S. adult population rates of chronic disability from 1998 to 2011 using 7 different disability measures and examining the implications of trends in population age, race and ethnicity, and body mass index (BMI). Methods: We used National Health Interview Survey data on civilian, non-institutionalized U.S. residents ages >= 18 from selected years between 1998 and 2011. We used self-reported information on functional impairments, activity/participation limitations, and expected duration to create 7 chronic disability measures. We used direct standardization to account for changes in age, race/ethnicity, and BMI distributions over time. Multivariable logistic regression models identified associations of disability with sociodemographic characteristics. Results: Without adjustment, population rates of all 7 disabilities increased significantly (p < 0.0001) from 1998 to 2011. The absolute percentage change was greatest for movement difficulties: 19.3% in 1998 and 23.3% in 2011. After separate adjustments for trends in age, race/ethnicity, and BMI distributions, 6 disability types continued to show increased rates over time (p < 0.01), except for sensory disabilities. Over time, poor education, poverty, and unemployment remained significantly associated with disability. Conclusions: If these trends continue, the numbers and proportions of U.S. residents with various disabilities will continue rising in coming years. In particular, the prevalence of movement difficulties and work limitations will increase. Furthermore, disability will remain strongly associated with low levels of education, employment, and income. (C) 2014 Elsevier Inc. All rights reserved. C1 [Iezzoni, Lisa I.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Iezzoni, Lisa I.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Kurtz, Stephen G.; Rao, Sowmya R.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. [Rao, Sowmya R.] Bedford Veteran Affairs Med Ctr, CHOIR, Bedford, MA USA. RP Iezzoni, LI (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Staniford St,Room 901B, Boston, MA 02114 USA. EM liezzoni@mgh.harvard.edu FU National Cancer Institute [5R01CA160286-02] FX This work was funded by the National Cancer Institute, 5R01CA160286-02. NR 30 TC 7 Z9 7 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-6574 EI 1876-7583 J9 DISABIL HEALTH J JI Disabil. Health J. PD OCT PY 2014 VL 7 IS 4 BP 402 EP 412 DI 10.1016/j.dhjo.2014.05.007 PG 11 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Rehabilitation SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Rehabilitation GA AP8LW UT WOS:000342331500006 PM 25224980 ER PT J AU Miles, WO Korenjak, M Griffiths, LM Dyer, MA Provero, P Dyson, NJ AF Miles, Wayne O. Korenjak, Michael Griffiths, Lyra M. Dyer, Michael A. Provero, Paolo Dyson, Nicholas J. TI Post-transcriptional gene expression control by NANOS is up-regulated and functionally important in pRb-deficient cells SO EMBO JOURNAL LA English DT Article DE Nanos; post-transcriptional gene regulation; pRb; Pumilio; stress response ID RETINOBLASTOMA GENE; TRANSLATIONAL REGULATOR; TUMOR-SUPPRESSOR; MESSENGER-RNAS; CYCLE CONTROL; PUMILIO; DROSOPHILA; PROTEINS; CANCER; E2F AB Inactivation of the retinoblastoma tumor suppressor (pRb) is a common oncogenic event that alters the expression of genes important for cell cycle progression, senescence, and apoptosis. However, in many contexts, the properties of pRb-deficient cells are similar to wild-type cells suggesting there may be processes that counterbalance the transcriptional changes associated with pRb inactivation. Therefore, we have looked for sets of evolutionary conserved, functionally related genes that are direct targets of pRb/E2F proteins. We show that the expression of NANOS, a key facilitator of the Pumilio (PUM) post-transcriptional repressor complex, is directly repressed by pRb/E2F in flies and humans. In both species, NANOS expression increases following inactivation of pRb/RBF1 and becomes important for tissue homeostasis. By analyzing datasets from normal retinal tissue and pRb-null retinoblastomas, we find a strong enrichment for putative PUM substrates among genes de-regulated in tumors. These include pro-apoptotic genes that are transcriptionally down-regulated upon pRb loss, and we characterize two such candidates, MAP2K3 and MAP3K1, as direct PUM substrates. Our data suggest that NANOS increases in importance in pRb-deficient cells and helps to maintain homeostasis by repressing the translation of transcripts containing PUM Regulatory Elements (PRE). C1 [Miles, Wayne O.; Korenjak, Michael; Dyson, Nicholas J.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Miles, Wayne O.; Korenjak, Michael; Dyson, Nicholas J.] Harvard Univ, Sch Med, Mol Oncol Lab, Charlestown, MA USA. [Griffiths, Lyra M.; Dyer, Michael A.] St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA. [Provero, Paolo] Univ Turin, Dept Mol Biotechnol & Hlth Sci, Turin, Italy. [Provero, Paolo] Ist Sci San Raffaele, Ctr Translat Genom & Bioinformat, I-20132 Milan, Italy. RP Dyson, NJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. EM dyson@helix.mgh.harvard.edu FU National Institutes of Health Public Health Service [R01 CA163698, R01 CA64402] FX We would like to acknowledge Brandon Nicoloy and Katrin Tschoep for their critical reading and helpful reading of the manuscript. We would additionally like to thank the laboratories of James Rocco, Anders Naar, Lee Zou, Jonathon Whetstine, and Mo Motamedi for their helpful suggestions and support during this work. This work was supported by National Institutes of Health Public Health Service grants R01 CA163698 and R01 CA64402 to N.J.D. N.J.D. is the James and Shirley Curvey MGH Research Scholar. NR 55 TC 7 Z9 7 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD OCT 1 PY 2014 VL 33 IS 19 BP 2201 EP 2215 DI 10.15252/embj.201488057 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AQ0WL UT WOS:000342503300008 PM 25100735 ER PT J AU Liu, ES Zalutskaya, A Chae, BT Zhu, ED Gori, F Demay, MB AF Liu, Eva S. Zalutskaya, Alena Chae, Byongsoo Timothy Zhu, Eric D. Gori, Francesca Demay, Marie B. TI Phosphate Interacts With PTHrP to Regulate Endochondral Bone Formation SO ENDOCRINOLOGY LA English DT Article ID HORMONE-RELATED PEPTIDE; PROGRAMMED CELL-DEATH; PARATHYROID-HORMONE; HYPERTROPHIC CHONDROCYTES; GROWTH-PLATE; TGF-BETA; RECEPTOR; APOPTOSIS; PHOSPHORYLATION; MICE AB Phosphate and parathyroid hormone related peptide (PTHrP) are required for normal growth plate maturation. Hypophosphatemia impairs hypertrophic chondrocyte apoptosis leading to rachitic expansion of the growth plate; however, the effect of phosphate restriction on chondrocyte differentiation during endochondral bone formation has not been examined. Investigations were, therefore, undertaken to address whether phosphate restriction alters the maturation of embryonic d15.5 murine metatarsal elements. Metatarsals cultured in low phosphate media exhibited impaired chondrocyte differentiation, analogous to that seen with PTHrP-treatment of metatarsals cultured in control media. Because phosphate restriction acutely increases PTHrP expression in cultured metatarsals, studies were undertaken to determine if this increase in PTHrP plays a pathogenic role in the impaired chondrocyte differentiation observed under low phosphate conditions. In contrast to what was observed with wild-type metatarsal elements, phosphate restriction did not impair the differentiation of metatarsals isolated from PTHrP heterozygous or PTHrP knockout mice. In vivo studies in postnatal mice demonstrated that PTHrP haploinsufficiency also prevents the impaired hypertrophic chondrocyte apoptosis observed with phosphate restriction. To determine how signaling through the PTH/PTHrP receptor antagonizes the pro-apoptotic effects of phosphate, investigations were performed in primary murine hypertrophic chondrocytes. Receptor activation impaired phosphate-induced Erk1/2 phosphorylation specifically in the mitochondrial fraction and decreased levels of mitochondrial Bad, while increasing cytosolic phospho-Bad. Thus, these data demonstrate that phosphate restriction attenuates chondrocyte differentiation as well as impairing hypertrophic chondrocyte apoptosis and implicate a functional role for the PTH/PTHrP signaling pathway in the abnormalities in chondrocyte differentiation and hypertrophic chondrocyte apoptosis observed under phosphate restricted conditions. C1 [Liu, Eva S.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Liu, Eva S.; Zalutskaya, Alena; Chae, Byongsoo Timothy; Zhu, Eric D.; Gori, Francesca; Demay, Marie B.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Liu, Eva S.; Zalutskaya, Alena; Gori, Francesca; Demay, Marie B.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Demay, MB (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier11, Boston, MA 02114 USA. EM demay@helix.mgh.harvard.edu FU National Institutes of Health [R01 AR061376, T32 DK007529, F32 AR065386] FX This work was supported by Grants R01 AR061376, T32 DK007529, and F32 AR065386 from the National Institutes of Health. NR 30 TC 3 Z9 3 U1 0 U2 8 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2014 VL 155 IS 10 BP 3750 EP 3756 DI 10.1210/en.2014-1315 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8QX UT WOS:000342345000005 PM 25057796 ER PT J AU Castroneves, LA Jugo, RH Maynard, MA Lee, JS Wassner, AJ Dorfman, D Bronson, RT Ukomadu, C Agoston, AT Ding, L Luongo, C Guo, CC Song, HD Demchev, V Lee, NY Feldman, HA Vella, KR Peake, RW Hartigan, C Kellogg, MD Desai, A Salvatore, D Dentice, M Huang, SA AF Castroneves, Luciana A. Jugo, Rebecca H. Maynard, Michelle A. Lee, Jennifer S. Wassner, Ari J. Dorfman, David Bronson, Roderick T. Ukomadu, Chinweike Agoston, Agoston T. Ding, Lai Luongo, Cristina Guo, Cuicui Song, Huaidong Demchev, Valeriy Lee, Nicholas Y. Feldman, Henry A. Vella, Kristen R. Peake, Roy W. Hartigan, Christina Kellogg, Mark D. Desai, Anal Salvatore, Domenico Dentice, Monica Huang, Stephen A. TI Mice With Hepatocyte-Specific Deficiency of Type 3 Deiodinase Have Intact Liver Regeneration and Accelerated Recovery From Nonthyroidal Illness After Toxin-Induced Hepatonecrosis SO ENDOCRINOLOGY LA English DT Article ID THYROID-HORMONE; IODOTHYRONINE DEIODINASE; PARTIAL-HEPATECTOMY; RAT-LIVER; REQUIRES; GROWTH; CELLS; DIFFERENTIATION; PROLIFERATION; INACTIVATION AB Type 3 deiodinase (D3), the physiologic inactivator of thyroid hormones, is induced during tissue injury and regeneration. This has led to the hypotheses that D3 impacts injury tolerance by reducing local T3 signaling and contributes to the fall in serum triiodothyronine (T3) observed in up to 75% of sick patients (termed the low T3 syndrome). Here we show that a novel mutant mouse with hepatocyte-specific D3 deficiency has normal local responses to toxin-induced hepatonecrosis, including normal degrees of tissue necrosis and intact regeneration, but accelerated systemic recovery from illness-induced hypothyroxinemia and hypotriiodothyroninemia, demonstrating that peripheral D3 expression is a key modulator of the low T3 syndrome. C1 [Castroneves, Luciana A.; Jugo, Rebecca H.; Maynard, Michelle A.; Lee, Jennifer S.; Wassner, Ari J.; Guo, Cuicui; Song, Huaidong; Lee, Nicholas Y.; Huang, Stephen A.] Childrens Hosp Boston, Div Endocrinol, Thyroid Program, Boston, MA 02115 USA. [Feldman, Henry A.] Childrens Hosp Boston, Clin Res Ctr, Boston, MA 02115 USA. [Peake, Roy W.; Hartigan, Christina; Kellogg, Mark D.] Childrens Hosp Boston, Dept Lab Med, Boston, MA 02115 USA. [Huang, Stephen A.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Thyroid Sect, Boston, MA 02115 USA. [Dorfman, David; Agoston, Agoston T.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ukomadu, Chinweike; Demchev, Valeriy; Desai, Anal] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Ding, Lai] Harvard Univ, Neurodiscovery Ctr, Boston, MA 02115 USA. [Bronson, Roderick T.; Huang, Stephen A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Vella, Kristen R.] Beth Israel Deaconess Med Ctr, Div Endocrinol, Boston, MA 02115 USA. [Luongo, Cristina; Salvatore, Domenico; Dentice, Monica] Univ Naples Federico II, Dept Mol & Clin Endocrinol & Oncol, I-80131 Naples, Italy. RP Huang, SA (reprint author), Childrens Hosp Boston, 300 Longwood Ave, Boston, MA 02115 USA. EM stephen.huang@childrens.harvard.edu OI SALVATORE, DOMENICO/0000-0002-4556-7620; Wassner, Ari/0000-0003-0894-9301 FU Murray Family; William F. Milton Foundation; National Institutes of Health [DK76099, HD052896] FX This work was supported by a donation from the Murray Family, the William F. Milton Foundation Award, and the National Institutes of Health Grants DK76099 and HD052896. NR 32 TC 0 Z9 0 U1 0 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2014 VL 155 IS 10 BP 4061 EP 4068 DI 10.1210/en.2013-2028 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8QX UT WOS:000342345000032 PM 25004090 ER PT J AU Guo, CC Chen, X Song, HD Maynard, MA Zhou, Y Lobanov, AV Gladyshev, VN Ganis, JJ Wiley, D Jugo, RH Lee, NY Castroneves, LA Zon, LI Scanlan, TS Feldman, HA Huang, SA AF Guo, Cuicui Chen, Xia Song, Huaidong Maynard, Michelle A. Zhou, Yi Lobanov, Alexei V. Gladyshev, Vadim N. Ganis, Jared J. Wiley, David Jugo, Rebecca H. Lee, Nicholas Y. Castroneves, Luciana A. Zon, Leonard I. Scanlan, Thomas S. Feldman, Henry A. Huang, Stephen A. TI Intrinsic Expression of a Multiexon Type 3 Deiodinase Gene Controls Zebrafish Embryo Size SO ENDOCRINOLOGY LA English DT Article ID I IODOTHYRONINE DEIODINASE; THYROID-HORMONE; RING DEIODINATION; METAMORPHOSIS; VITRO; INACTIVATION; METABOLISM; KNOCKDOWN; THYROXINE; DISEASE AB Thyroid hormone is a master regulator of differentiation and growth, and its action is terminated by the enzymatic removal of an inner-ring iodine catalyzed by the selenoenzyme type 3 deiodinase (dio3). Our studies of the zebrafish reveal that the dio3 gene is duplicated in this species and that embryonic deiodination is an important determinant of embryo size. Although both dio3 paralogs encode enzymatically active proteins with high affinity for thyroid hormones, their anatomic patterns of expression are markedly divergent and only embryos with knockdown of dio3b, a biallelically expressed selenoenzyme expressed in the developing central nervous system, manifest severe thyroid hormone-dependent growth restriction at 72 hours post fertilization. This indicates that the embryonic deficiency of dio3, once considered only a placental enzyme, causes microsomia independently of placental physiology and raises the intriguing possibility that fetal abnormalities in human deiodination may present as intrauterine growth retardation. By mapping the gene structures and enzymatic properties of all four zebrafish deiodinases, we also identify dio3b as the first multiexon dio3 gene, containing a large intron separating its open reading frame from its selenocysteine insertion sequence (SECIS) element. C1 [Guo, Cuicui; Chen, Xia; Song, Huaidong] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, State Key Lab Med Genom, Shanghai 200025, Peoples R China. [Guo, Cuicui; Chen, Xia; Song, Huaidong; Maynard, Michelle A.; Jugo, Rebecca H.; Lee, Nicholas Y.; Castroneves, Luciana A.; Huang, Stephen A.] Boston Childrens Hosp, Div Endocrinol, Thyroid Program, Boston, MA 02115 USA. [Feldman, Henry A.] Boston Childrens Hosp, Clin Res Ctr, Boston, MA 02115 USA. [Zhou, Yi; Ganis, Jared J.; Wiley, David; Zon, Leonard I.] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston Childrens Hosp,Stem Cell Program, Boston, MA 02115 USA. [Zhou, Yi; Ganis, Jared J.; Wiley, David; Zon, Leonard I.] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston Childrens Hosp,Div Hematol Oncol, Boston, MA 02115 USA. [Zhou, Yi; Ganis, Jared J.; Wiley, David; Zon, Leonard I.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Lobanov, Alexei V.; Gladyshev, Vadim N.; Huang, Stephen A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Gladyshev, Vadim N.; Zon, Leonard I.; Huang, Stephen A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Scanlan, Thomas S.] Oregon Hlth & Sci Univ, Dept Physiol, Portland, OR 97239 USA. [Scanlan, Thomas S.] Oregon Hlth & Sci Univ, Dept Pharmacol, Portland, OR 97239 USA. RP Huang, SA (reprint author), Childrens Hosp Boston, 300 Longwood Ave, Boston, MA 02115 USA. EM stephen.huang@childrens.harvard.edu FU Murray Family; National Institutes of Health [DK076099, GM061603, DK53298]; William F. Milton Foundation Award; People's Republic of China National Natural Science Foundation Program [30900503]; PhD Student Visiting Program of Shanghai Jiaotong University School of Medicine; Howard Hughes Medical Institute FX This work was supported by a donation from the Murray Family; by Grants DK076099, GM061603, and DK53298 from the National Institutes of Health; the William F. Milton Foundation Award; Grant 30900503 from the People's Republic of China National Natural Science Foundation Program; the PhD Student Visiting Program of Shanghai Jiaotong University School of Medicine; and the Howard Hughes Medical Institute (to L.I.Z.). NR 47 TC 6 Z9 6 U1 0 U2 11 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2014 VL 155 IS 10 BP 4069 EP 4080 DI 10.1210/en.2013-2029 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8QX UT WOS:000342345000033 PM 25004091 ER PT J AU Radmanesh, F Devan, WJ Anderson, CD Rosand, J Falcone, GJ AF Radmanesh, Farid Devan, William J. Anderson, Christopher D. Rosand, Jonathan Falcone, Guido J. CA ADNI TI Accuracy of imputation to infer unobserved APOE epsilon alleles in genorne-wide genotyping data SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE apolipoprotein E; APOE; epsilon alleles; GWAS; imputation ID ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; ASSOCIATION; ONSET; RISK; GENE AB Apolipoprotein E, encoded by APOE, is the main apoprotein for catabolism of chylomicrons and very low density lipoprotein. Two common single-nucleotide polymorphisms (SNPs) in APOE, rs429358 and rs7412, determine the three epsilon-alleles that are established genetic risk factors for late-onset Alzheimer's disease (AD), cerebral amyloid angiopathy, and intracerebral hemorrhage (ICH). These two SNPs are not present in most commercially available genome-wide genotyping arrays and cannot be inferred through imputation using HapMap reference panels. Therefore, these SNPs are often separately genotyped. Introduction of reference panels compiled from the 1000 Genomes project has made imputation of these variants possible. We compared the directly genotyped and imputed SNPs that define the APOE epsilon alleles to. determine the accuracy of imputation for inference of unobserved epsilon alleles. We utilized genome-wide genotype data obtained from two cohorts of ICH and AD constituting subjects of European ancestry. Our data suggest that imputation is highly accurate, yields an acceptable proportion of missing data that is non-differentially distributed across case and control groups, and generates comparable results to genotyped data for hypothesis testing. Further, we explored the effect of imputation algorithm parameters and demonstrated that customization of these parameters yields an improved balance between accuracy and missing data for inferred genotypes. C1 [Radmanesh, Farid; Devan, William J.; Anderson, Christopher D.; Rosand, Jonathan; Falcone, Guido J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Radmanesh, Farid; Devan, William J.; Anderson, Christopher D.; Rosand, Jonathan; Falcone, Guido J.] Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Dept Neurol, Boston, MA 02114 USA. [Radmanesh, Farid; Devan, William J.; Anderson, Christopher D.; Rosand, Jonathan; Falcone, Guido J.] Massachusetts Gen Hosp, Dept Neurol, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA. [Radmanesh, Farid; Devan, William J.; Anderson, Christopher D.; Rosand, Jonathan; Falcone, Guido J.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. RP Anderson, CD (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Simches Res Bldg,185 Cambridge St,CPZN 5820, Boston, MA 02114 USA. EM cdanderson@partners.org RI Falcone, Guido/L-2287-2016 OI Falcone, Guido/0000-0002-6407-0302 FU NIH-NINDS [R01NS059727]; Keane Stroke Genetics Research Fund; Edward and Maybeth Sonn Research Fund; University of Michigan General Clinical Research Center [M01 RR000042]; National Center for Research Resources; NIH-NINDS SPOTRIAS fellowship [P50NS061343]; American Brain Foundation; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc; Biogen Idec Inc; Bristol-Myers Squibb Company; Eisai Inc; Elan Pharmaceuticals, Inc; Eli Lilly and Company; F Hoffmann-La Roche Ltd; Genentech, Inc; GE Healthcare; Irmogenetics, NV; IXECO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC; Medpace, Inc; Merck Co, Inc; Meso Scale Diagnostics, LLC; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc; Piramal Imaging; Servier; Synarc Inc; Takeda Pharmaceutical Company; Canadian Institutes of Health Research; Foundation for the National Institutes of Health; Northern California Institute for Research and Education; NIH [P30 AG010129, K01 AG030514] FX The Genetics of Cerebral Hemorrhage with Anticoagulation study was funded by NIH-NINDS grant R01NS059727, the Keane Stroke Genetics Research Fund, the Edward and Maybeth Sonn Research Fund, by the University of Michigan General Clinical Research Center (M01 RR000042), and by a grant from the National Center for Research Resources. GJF was supported by the NIH-NINDS SPOTRIAS fellowship grant P50NS061343. CDA was supported by a Clinical Research Training Fellowship from the American Brain Foundation. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc; Biogen Idec Inc; Bristol-Myers Squibb Company; Eisai Inc; Elan Pharmaceuticals, Inc; Eli Lilly and Company; F Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc; GE Healthcare; Irmogenetics, NV; IXECO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC; Medpace, Inc; Merck & Co, Inc; Meso Scale Diagnostics, LLC; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc; Piramal Imaging; Servier; Synarc Inc; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, Rev October 16, 2012 San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514. The investigators within the ADNI contributed to the design and implementation of the ADNI and/or provided data, but did not participate in analysis or writing of this report. NR 17 TC 5 Z9 5 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD OCT PY 2014 VL 22 IS 10 BP 1239 EP 1242 DI 10.1038/ejhg.2013.308 PG 4 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AQ0LZ UT WOS:000342476100015 PM 24448547 ER PT J AU Deyo, RA Dworkin, SF Amtmann, D Andersson, G Borenstein, D Carragee, E Carrino, J Chou, R Cook, K DeLitto, A Goertz, C Khalsa, P Loeser, J Mackey, S Panagis, J Rainville, J Tosteson, T Turk, D Von Korff, M Weiner, DK AF Deyo, Richard A. Dworkin, Samuel F. Amtmann, Dagmar Andersson, Gunnar Borenstein, David Carragee, Eugene Carrino, John Chou, Roger Cook, Karon DeLitto, Anthony Goertz, Christine Khalsa, Partap Loeser, John Mackey, Sean Panagis, James Rainville, James Tosteson, Tor Turk, Dennis Von Korff, Michael Weiner, Debra K. TI Focus article: report of the NIH task force on research standards for chronic low back pain SO EUROPEAN SPINE JOURNAL LA English DT Article DE Low back pain; Chronic low back pain; Research standards; Minimum dataset; NIH Task Force ID CLINICAL-PRACTICE GUIDELINE; DEFINING CHRONIC PAIN; INFORMATION-SYSTEM PROMIS; FUNCTION ITEM BANK; QUALITY-OF-LIFE; PRIMARY-CARE; PROGNOSTIC APPROACH; SCREENING TOOL; START BACK; OUTCOME MEASURES AB Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement. A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. C1 [Deyo, Richard A.; Chou, Roger] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Dworkin, Samuel F.; Amtmann, Dagmar; Loeser, John; Turk, Dennis] Univ Washington, Seattle, WA 98195 USA. [Andersson, Gunnar] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Borenstein, David] George Washington Univ, Washington, DC USA. [Carragee, Eugene; Mackey, Sean] Stanford Univ, Stanford, CA 94305 USA. [Carrino, John] Johns Hopkins Univ, Baltimore, MD USA. [Cook, Karon] Northwestern Univ, Evanston, IL USA. [DeLitto, Anthony; Weiner, Debra K.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [DeLitto, Anthony; Weiner, Debra K.] Univ Pittsburgh, Pittsburgh, PA USA. [Goertz, Christine] Palmer Coll Chiropract, Davenport, IA USA. [Khalsa, Partap] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. [Panagis, James] NIAMSD, Bethesda, MD 20892 USA. [Rainville, James] New England Baptist Hosp, Roxbury Crossing, MA USA. [Tosteson, Tor] Dartmouth Coll, Hanover, NH USA. [Von Korff, Michael] Grp Hlth Res Inst, Seattle, WA USA. RP Deyo, RA (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd,Mail Code FM, Portland, OR 97239 USA. EM deyor@ohsu.edu FU National Center for Complementary and Alternative Medicine; National Institute for Arthritis, Musculoskeletal, and Skin Diseases FX This study was supported by the National Center for Complementary and Alternative Medicine and the National Institute for Arthritis, Musculoskeletal, and Skin Diseases. NR 123 TC 13 Z9 13 U1 8 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0940-6719 EI 1432-0932 J9 EUR SPINE J JI Eur. Spine J. PD OCT PY 2014 VL 23 IS 10 BP 2028 EP 2045 DI 10.1007/s00586-014-3540-3 PG 18 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA AQ0EI UT WOS:000342455200002 PM 25212440 ER PT J AU Vernochet, C Damilano, F Mourier, A Bezy, O Mori, MA Smyth, G Rosenzweig, A Larsson, NG Kahn, CR AF Vernochet, Cecile Damilano, Federico Mourier, Arnaud Bezy, Olivier Mori, Marcelo A. Smyth, Graham Rosenzweig, Anthony Larsson, Nils-Goeran Kahn, C. Ronald TI Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications SO FASEB JOURNAL LA English DT Article DE TFAM; WAT; BAT; diabetes; hypertension; cardiomegaly ID TRANSCRIPTION-FACTOR; HIV-INFECTION; GENERALIZED LIPODYSTROPHY; COPY NUMBER; MICE; OBESITY; DNA; ADIPONECTIN; MAINTENANCE; INSIGHTS AB Mitochondrial dysfunction in adipose tissue occurs in obesity, type 2 diabetes, and some forms of lipodystrophy, but whether this dysfunction contributes to or is the result of these disorders is unknown. To investigate the physiological consequences of severe mitochondrial impairment in adipose tissue, we generated mice deficient in mitochondrial transcription factor A (TFAM) in adipocytes by using mice carrying adiponectin-Cre and TFAM floxed alleles. These adiponectin TFAM-knockout (adipo-TFAM-KO) mice had a 75-81% reduction in TFAM in the subcutaneous and intra-abdominal white adipose tissue (WAT) and interscapular brown adipose tissue (BAT), causing decreased expression and enzymatic activity of proteins in complexes I, III, and IV of the electron transport chain (ETC). This mitochondrial dysfunction led to adipocyte death and inflammation in WAT and a whitening of BAT. As a result, adipo-TFAM-KO mice were resistant to weight gain, but exhibited insulin resistance on both normal chow and high-fat diets. These lipodystrophic mice also developed hypertension, cardiac hypertrophy, and cardiac dysfunction. Thus, isolated mitochondrial dysfunction in adipose tissue can lead a syndrome of lipodystrophy with metabolic syndrome and cardiovascular complications.-Vernochet, C., Damilano, F., Mourier, A., Bezy, O., Mori, M. A., Smyth, G., Rosenzweig, A., Larsson, N.-G., Kahn, C. R. Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications. C1 [Vernochet, Cecile; Bezy, Olivier; Mori, Marcelo A.; Smyth, Graham; Kahn, C. Ronald] Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. [Vernochet, Cecile; Damilano, Federico; Bezy, Olivier; Mori, Marcelo A.; Smyth, Graham; Rosenzweig, Anthony; Kahn, C. Ronald] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Damilano, Federico; Rosenzweig, Anthony] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. [Mourier, Arnaud; Larsson, Nils-Goeran] Max Planck Inst Biol Ageing, Dept Mitochondrial Biol, Cologne, Germany. RP Kahn, CR (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu RI MOURIER, Arnaud/I-8117-2012 OI MOURIER, Arnaud/0000-0002-5413-611X FU U.S. National Institutes of Health (NIH) [R01-DK082659]; Eli Lilly Foundation; Joslin Diabetes Research Center (NIH) [P30-DK036836]; Mary K. Iacocca Professorship; NIH [R01-HL094677] FX This work was supported by U.S. National Institutes of Health (NIH) grant R01-DK082659 (C.R.K.), a grant from the Eli Lilly Foundation, Joslin Diabetes Research Center (NIH grant P30-DK036836), the Mary K. Iacocca Professorship, and NIH grant R01-HL094677 (A.R.). NR 41 TC 17 Z9 17 U1 0 U2 7 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD OCT PY 2014 VL 28 IS 10 BP 4408 EP 4419 DI 10.1096/fj.14-253971 PG 12 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AP6XU UT WOS:000342222700019 PM 25005176 ER PT J AU Barcelo, C Etchin, J Mansour, MR Sanda, T Ginesta, MM Lobo, VJSA Real, FX Capella, G Estanyol, JM Jaumot, M Look, AT Agell, N AF Barcelo, Carles Etchin, Julia Mansour, Marc R. Sanda, Takaomi Ginesta, Mireia M. Sanchez-Arevalo Lobo, Victor J. Real, Francisco X. Capella, Gabriel Estanyol, Josep M. Jaumot, Montserrat Look, A. Thomas Agell, Neus TI Ribonucleoprotein HNRNPA2B1 Interacts With and Regulates Oncogenic KRAS in Pancreatic Ductal Adenocarcinoma Cells SO GASTROENTEROLOGY LA English DT Article DE Signal Transduction; Carcinogenesis; Oncogene; Mouse Model ID K-RAS; BINDING-PROTEIN; CANCER-CELLS; HEPATOCELLULAR-CARCINOMA; TUMOR-DEVELOPMENT; GENE-EXPRESSION; EGF RECEPTOR; LUNG-CANCER; IN-VIVO; N-RAS AB BACKGROUND & AIMS: Development of pancreatic ductal adenocarcinoma (PDAC) involves activation of c-Ki-ras2 Kirsten rat sarcoma oncogene homolog (KRAS) signaling, but little is known about the roles of proteins that regulate the activity of oncogenic KRAS. We investigated the activities of proteins that interact with KRAS in PDAC cells. METHODS: We used mass spectrometry to demonstrate that heterogeneous nuclear ribonucleoproteins (HNRNP) A2 and B1 (encoded by the gene HNRNPA2B1) interact with KRAS G12V. We used co-immunoprecipitation analyses to study interactions between HNRNPA2B1 and KRAS in KRAS-dependent and KRAS-independent PDAC cell lines. We knocked down HNRNPA2B1 using small hairpin RNAs and measured viability, anchorage-independent proliferation, and growth of xenograft tumors in mice. We studied KRAS phosphorylation using the Phos-tag system. RESULTS: We found that interactions between HRNPA2B1 and KRAS correlated with KRAS-dependency of some human PDAC cell lines. Knock down of HNRNPA2B1 significantly reduced viability, anchorage-independent proliferation, and formation of xenograft tumors by KRAS-dependent PDAC cells. HNRNPA2B1 knock down also increased apoptosis of KRAS-dependent PDAC cells, inactivated c-akt murine thymoma oncogene homolog 1 signaling via mammalian target of rapamycin, and reduced interaction between KRAS and phosphatidylinositide 3-kinase. Interaction between HNRNPA2B1 and KRAS required KRAS phosphorylation at serine 181. CONCLUSIONS: In KRAS-dependent PDAC cell lines, HNRNPA2B1 interacts with and regulates the activity of KRAS G12V and G12D. HNRNPA2B1 is required for KRAS activation of c-akt murine thymoma oncogene homolog 1-mammalian target of rapamycin signaling, interaction with phosphatidylinositide 3-kinase, and PDAC cell survival and tumor formation in mice. HNRNPA2B1 might be a target for treatment of pancreatic cancer. C1 [Barcelo, Carles; Jaumot, Montserrat; Agell, Neus] Univ Barcelona, Fac Med, Dept Biol Cellular Immunol & Neurociencies, IDIBAPS, Barcelona 08036, Spain. [Etchin, Julia; Mansour, Marc R.; Sanda, Takaomi; Look, A. Thomas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Sanda, Takaomi] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore. [Ginesta, Mireia M.; Capella, Gabriel] ICO IDIBELL, Catalan Inst Oncol, Translat Res Lab, Hereditary Canc Program, Barcelona, Spain. [Sanchez-Arevalo Lobo, Victor J.; Real, Francisco X.] CNIO Spanish Natl Canc Res Ctr, Programa Patol Mol, Grp Carcinogenesis Epitelial, Madrid, Spain. [Estanyol, Josep M.] Univ Barcelona, CCiTUB, E-08036 Barcelona, Spain. RP Agell, N (reprint author), Univ Barcelona, Fac Med, Dept Biol Cellular Immunol & Neurociencies, C Casanova 143, Barcelona 08036, Spain. EM neusagell@ub.edu RI Real Arribas, Francisco/H-5275-2015; Agell, Neus/E-9640-2016; Estanyol, Josep M/I-1039-2015; OI Real Arribas, Francisco/0000-0001-9501-498X; Sanchez-Arevalo Lobo, Victor Javier/0000-0002-4561-1505; Agell, Neus/0000-0002-1205-6074 FU MICINN-Spain [SAF2010-20712]; RTICC (MINECO-Spain) [RD12/0036/0049, RD12/0036/0031, RD12/0036/0034]; Spanish Government FX This study was supported by MICINN-Spain (SAF2010-20712) and RTICC (MINECO-Spain; groups RD12/0036/0049, RD12/0036/0031, and RD12/0036/0034). C. Barcelo is recipient of a predoctoral fellowship "FPU" from the Spanish Government. NR 70 TC 6 Z9 8 U1 1 U2 12 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD OCT PY 2014 VL 147 IS 4 BP 882 EP U280 DI 10.1053/j.gastro.2014.06.041 PG 19 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AQ0SO UT WOS:000342493200031 PM 24998203 ER PT J AU Johnson, DA Barkun, AN Cohen, LB Dominitz, JA Kaltenbach, T Martel, M Robertson, DJ Boland, CR Giardello, FM Lieberman, DA Levin, TR Rex, DK AF Johnson, David A. Barkun, Alan N. Cohen, Larry B. Dominitz, Jason A. Kaltenbach, Tonya Martel, Myriam Robertson, Douglas J. Boland, C. Richard Giardello, Frances M. Lieberman, David A. Levin, Theodore R. Rex, Douglas K. TI Optimizing Adequacy of Bowel Cleansing for Colonoscopy: Recommendations From the US Multi-Society Task Force on Colorectal Cancer SO GASTROENTEROLOGY LA English DT Article DE Colonoscopy Preparation; Colonoscopy Quality; Colonoscopy; Colon Cancer Screening; Colon Polyp Detection; Bowel Preparations ID ORAL SODIUM-PHOSPHATE; RANDOMIZED CONTROLLED-TRIAL; POLYETHYLENE-GLYCOL SOLUTION; ELECTROLYTE LAVAGE SOLUTION; PLUS ASCORBIC-ACID; INVESTIGATOR-BLINDED TRIAL; HIGH-DOSE SENNA; INCREASE SCREENING COLONOSCOPY; ADENOMA DETECTION RATE; CLEAR LIQUID DIET C1 [Johnson, David A.] Eastern VA Med Sch, Norfolk, VA 23507 USA. [Barkun, Alan N.; Martel, Myriam] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Cohen, Larry B.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Dominitz, Jason A.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Dominitz, Jason A.] Univ Washington, Seattle, WA 98195 USA. [Kaltenbach, Tonya] Stanford Univ, Sch Med, Vet Affairs Palo Alto, Palo Alto, CA 94304 USA. [Robertson, Douglas J.] VA Med Ctr, Portland, VA USA. [Robertson, Douglas J.] Geisel Sch Med Dartmouth, White River Jct, VT USA. [Boland, C. Richard] Baylor Univ, Med Ctr, Dallas, TX USA. [Giardello, Frances M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Lieberman, David A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Levin, Theodore R.] Kaiser Permanente Med Ctr, Walnut Creek, CA USA. [Rex, Douglas K.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. RP Johnson, DA (reprint author), Eastern VA Med Sch, Norfolk, VA 23507 USA. EM dajevms@aol.com OI Dominitz, Jason/0000-0002-8070-7086 FU Boston Scientific; Cook; Salix; Olympus America, Inc; Braintree Laboratories; Ferring Pharmaceuticals FX These authors disclose the following: David Johnson has served as a consultant and clinical investigator for Epigenomics, as a consultant for Given Imaging, and as a clinical investigator for Exact Sciences; A. Barkun has served as a consultant for Olympus, Inc, and Pendopharm, Inc, and has received clinical research support from Boston Scientific and Cook; L. B. Cohen has served as a consultant and on the speaker's bureau and received research support from Salix, and as a consultant for Braintree; T. Kaltenbach has been a research grant recipient and consultant for Olympus America, Inc, D. J. Robertson has served as a consultant for Given Imaging; D. A. Lieberman has served on the scientific advisory boards for Exact Sciences, Given Imaging, and Roche, and as a consultant for MOTUS; and D. K. Rex has received research support and served as a consultant for Braintree Laboratories and Ferring Pharmaceuticals, Given Imaging, and Olympus America Corp, has served as a consultant for Epigenomics and Exact Sciences, and has served on the speaker's bureau for Boston Scientific, Inc. The remaining authors disclose no conflicts. NR 252 TC 49 Z9 51 U1 0 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD OCT PY 2014 VL 147 IS 4 BP 903 EP 924 DI 10.1053/j.gastro.2014.07.002 PG 22 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AQ0SO UT WOS:000342493200033 PM 25239068 ER PT J AU Cleary, JM Lima, CMSR Hurwitz, HI Montero, AJ Franklin, C Yang, JN Graham, A Busman, T Mabry, M Holen, K Shapiro, GI Uronis, H AF Cleary, James M. Lima, Caio Max S. Rocha Hurwitz, Herbert I. Montero, Alberto J. Franklin, Catherine Yang, Jianning Graham, Alison Busman, Todd Mabry, Mack Holen, Kyle Shapiro, Geoffrey I. Uronis, Hope TI A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE ABT-263; Apoptosis; Bcl-2; Bcl-xL; Gemcitabine; Navitoclax ID PANCREATIC-CANCER CELLS; RESISTANCE; CRITERIA; THERAPY; ABT-737; ABT-263; MODELS; MCL-1 AB Purpose: To investigate the safety, optimal dosing, pharmacokinetics and clinical activity of a regimen of navitoclax (ABT-263) combined with gemcitabine in patients with solid tumors. Experimental Design: Patients with solid tumors for which gemcitabine was deemed an appropriate therapy were enrolled into one of two different dosing schedules (21-day dosing schedule: navitoclax administered orally on days 1-3 and 8-10,; and gemcitabine 1,000 mg/m(2) on days 1 and 8; 28-day dosing schedule: navitoclax administrated orally on days 1-3, 8-10, and 15-17; and gemcitabine 1,000 mg/m(2) on days 1, 8 and 15). Navitoclax doses were escalated from 150 to 425 mg. An expanded safety cohort was conducted for the 21-day dosing schedule at the maximum tolerated dose (MTD) of navitoclax. Results: Forty-six patients were enrolled at three U.S. centers. The most common adverse events included: hematologic abnormalities (thrombocytopenia, neutropenia, and anemia), liver enzyme elevations (ALT and AST), and gastrointestinal disturbances (diarrhea, nausea, and vomiting). Dose-limiting toxicities (DLTs) observed in cycle 1 were grade 4 thrombocytopenia (2 patients), grade 4 neutropenia (1 patient), and grade 3 AST elevation (2 patients). The MTD of navitoclax was 325 mg co-administered with gemcitabine 1,000 mg/m(2) for the 21-day schedule. No clinically significant pharmacokinetic drug-drug interactions were observed. There were no objective responses. Stable disease, reported at the end of cycle 2, was the best response in 54 % of evaluable patients (n = 39). Conclusions: The combination of navitoclax 325 mg with gemcitabine 1,000 mg/m(2) was generally well tolerated and exhibited a favorable safety profile in patients with advanced solid tumors. C1 [Cleary, James M.; Shapiro, Geoffrey I.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med Oncol,Dana Farber Canc Inst, Boston, MA 02115 USA. [Cleary, James M.; Shapiro, Geoffrey I.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Lima, Caio Max S. Rocha] Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL USA. [Hurwitz, Herbert I.; Uronis, Hope] Duke Univ, Med Ctr, Div Med Oncol, Durham, NC USA. [Montero, Alberto J.] Cleveland Clin, Taussig Canc Inst, Dept Solid Tumor Oncol, Cleveland, OH 44106 USA. [Franklin, Catherine; Yang, Jianning; Graham, Alison; Busman, Todd; Mabry, Mack; Holen, Kyle] AbbVie Inc, N Chicago, IL USA. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Early Drug Dev Ctr, Boston, MA 02215 USA. RP Shapiro, GI (reprint author), Dana Farber Canc Inst, Early Drug Dev Ctr, 450 Brookline Ave,Mayer 446, Boston, MA 02215 USA. EM geoffrey_shapiro@dfci.harvard.edu FU AbbVie Inc. FX AbbVie Inc. NR 22 TC 9 Z9 11 U1 1 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD OCT PY 2014 VL 32 IS 5 BP 937 EP 945 DI 10.1007/s10637-014-0110-9 PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA AP9PK UT WOS:000342411500015 PM 24916770 ER PT J AU Ciombor, KK Feng, Y Benson, A Su, YJ Horton, L Short, SP Kauh, JSW Staley, C Mulcahy, M Powell, M Amiri, KI Richmond, A Berlin, J AF Ciombor, Kristen K. Feng, Yang Benson, Al Bowen, III Su, Yingjun Horton, Linda Short, Sarah P. Kauh, John Sae Wook Staley, Charles Mulcahy, Mary Powell, Mark Amiri, Katayoun I. Richmond, Ann Berlin, Jordan TI Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202): a trial of the Eastern Cooperative Oncology Group SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Hepatocellular carcinoma; Bortezomib; Doxorubicin; Proteasome inhibition ID NF-KAPPA-B; PROTEASOME INHIBITOR PS-341; ENDOTHELIAL GROWTH-FACTOR; MULTIPLE-MYELOMA CELLS; CHEMOTHERAPEUTIC-AGENTS; PROMOTER ACTIVITY; LIVER METASTASIS; TUMOR-GROWTH; ACTIVATION; EXPRESSION AB Purpose To evaluate the efficacy and tolerability of bortezomib in combination with doxorubicin in patients with advanced hepatocellular carcinoma, and to correlate pharmacodynamic markers of proteasome inhibition with response and survival. Experimental Design This phase II, open-label, multicenter study examined the efficacy of bortezomib (1.3 mg/m(2) IV on d1, 4, 8, 11) and doxorubicin (15 mg/m(2) IV on d1, 8) in 21-day cycles. The primary endpoint was objective response rate. Results Best responses in 38 treated patients were 1 partial response (2.6 %), 10 (26.3 %) stable disease, and 17 (44.7 %) progressive disease; 10 patients were unevaluable. Median PFS was 2.2 months. Median OS was 6.1 months. The most common grade 3 to 4 toxicities were hypertension, glucose intolerance, ascites, ALT elevation, hyperglycemia and thrombosis/embolism. Worse PFS was seen in patients with elevated IL-6, IL-8, MIP-1 alpha and EMSA for NF-kappa B at the start of treatment. Worse OS was seen in patients with elevated IL-8 and VEGF at the start of treatment. Patients had improved OS if a change in the natural log of serum MIP-1 alpha/CCL3 was seen after treatment. RANTES/CCL5 levels decreased significantly with treatment. Conclusions The combination of doxorubicin and bortezomib was well-tolerated in patients with hepatocellular carcinoma, but the primary endpoint was not met. Exploratory analyses of markers of proteasome inhibition suggest a possible prognostic and predictive role and should be explored further in tumor types for which bortezomib is efficacious. C1 [Ciombor, Kristen K.] Ohio State Univ, Arthur G James Canc Hosp, Div Med Oncol, Dept Internal Med, Columbus, OH 43212 USA. [Ciombor, Kristen K.] Ohio State Univ, Richard J Solove Res Inst, Columbus, OH 43212 USA. [Feng, Yang] Dana Farber Canc Inst, Boston, MA 02115 USA. [Benson, Al Bowen, III; Mulcahy, Mary] Northwestern Univ, Chicago, IL 60611 USA. [Su, Yingjun] Fourth Mil Med Univ, Xijing Hosp, Xian 710032, Shaanxi Provinc, Peoples R China. [Horton, Linda; Short, Sarah P.; Richmond, Ann; Berlin, Jordan] Vanderbilt Univ, Nashville, TN 37235 USA. [Horton, Linda; Richmond, Ann] Tennessee Valley Healthcare Syst, Dept Vet Affairs, Nashville, TN USA. [Kauh, John Sae Wook; Staley, Charles] Emory Univ, Atlanta, GA 30322 USA. [Amiri, Katayoun I.] Celgene Corp, Summit, NJ USA. RP Ciombor, KK (reprint author), Ohio State Univ, Arthur G James Canc Hosp, Div Med Oncol, Dept Internal Med, A445A Starling Loving Hall,320 West 10th Ave, Columbus, OH 43212 USA. EM kristen.ciombor@osumc.edu FU Public Health Service [CA23318, CA66636, CA21115, CA49957, CA17145, CA116021, CA9060625]; SRCS award from the Department of Veterans Affairs; National Cancer Institute, National Institutes of Health; Department of Health and Human Services; Public Health Service from the National Cancer Institute [5R21 CA099269-02] FX This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis), and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA49957, CA17145, CA116021, CA9060625, an SRCS award from the Department of Veterans Affairs, and from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Laboratory correlatives were supported by Public Health Service Grant 5R21 CA099269-02 from the National Cancer Institute. NR 49 TC 7 Z9 7 U1 2 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD OCT PY 2014 VL 32 IS 5 BP 1017 EP 1027 DI 10.1007/s10637-014-0111-8 PG 11 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA AP9PK UT WOS:000342411500023 PM 24890858 ER PT J AU Banerjee, T Scherzer, R Powe, NR Steffick, D Shahinian, V Saran, R Pavkov, ME Saydah, S Shlipak, MG AF Banerjee, Tanushree Scherzer, Rebecca Powe, Neil R. Steffick, Diane Shahinian, Vahakn Saran, Rajiv Pavkov, Meda E. Saydah, Sharon Shlipak, Michael G. CA Ctr Dis Control Prevention Chronic TI Race and Other Risk Factors for Incident Proteinuria in a National Cohort of HIV-Infected Veterans SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; proteinuria; race ID CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; ACTIVE ANTIRETROVIRAL THERAPY; ASSOCIATION; PREVALENCE; MANAGEMENT; OUTCOMES; WOMEN; INDIVIDUALS; GUIDELINES AB Background: Proteinuria in human immunodeficiency virus (HIV)-infected individuals has been associated with poorer outcomes. We examined risk factors associated with the development of proteinuria in a national registry of HIV-infected veterans. Methods: A total of 21,129 HIV-infected veterans of black and white race without preexisting kidney disease were receiving health care in the Veterans' Health Administration (VHA) medical system between 1997 and 2011. Using the VHA electronic record system, we identified kidney-related risk factors (hypertension, diabetes, and cardiovascular disease) and HIV-related risk factors (CD4 lymphocyte count, HIV RNA level, hepatitis C virus, and hepatitis B virus) for developing proteinuria. Proteinuria was defined by 2 consecutive dipstick measures of 1(+) or higher. The Fine-Gray competing risk model was used to estimate association between clinical variables and incident proteinuria, while accounting for intervening mortality events. Results: During follow-up (median = 5.3 years), 7031 patients developed proteinuria. Overall, black race compared with white race was associated with a higher risk of proteinuria {hazard ratio [95% confidence interval (CI)] = 1.51 [1.43 to 1.59]}, but the association was stronger at younger ages (P interaction <0.001). Age-stratified risk of proteinuria for blacks relative to whites was greatest among veterans,30 years [2.19 (1.66 to 2.89)] and the risk diminished with increasing age [1.14 (0.97 to 1.34) for >60 years]. We found the race difference to be stronger for the outcome of 2(+) or higher proteinuria [2.13 (1.89 to 2.39)]. Both HIV-related and traditional risk factors were also associated with incident proteinuria (P < 0.05). Conclusions: Compared with whites, risk of proteinuria was higher in black veterans with HIV infection, particularly at younger ages. In both races, HIV- and kidney-related risk factors were associated with higher proteinuria risk. C1 [Banerjee, Tanushree; Powe, Neil R.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Banerjee, Tanushree; Powe, Neil R.] San Francisco Gen Hosp, San Francisco, CA 94110 USA. [Scherzer, Rebecca; Shlipak, Michael G.] San Francisco VA Med Ctr, Div Gen Internal Med, San Francisco, CA 94121 USA. [Steffick, Diane; Shahinian, Vahakn; Saran, Rajiv] Univ Michigan, Kidney Epidemiol & Cost Ctr, Ann Arbor, MI 48109 USA. [Pavkov, Meda E.; Saydah, Sharon] Ctr Dis Prevent & Control, Div Diabet Translat, Atlanta, GA USA. RP Shlipak, MG (reprint author), San Francisco VA Med Ctr, Div Gen Internal Med, San Francisco, CA 94121 USA. EM michael.shlipak@ucsf.edu FU Centers for Disease Control and Prevention, Atlanta, GA [1U58DP003839] FX Supported by the Cooperative Agreement No. 1U58DP003839 from The Centers for Disease Control and Prevention, Atlanta, GA. NR 35 TC 3 Z9 4 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2014 VL 67 IS 2 BP 145 EP 152 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AP4NT UT WOS:000342055000012 PM 25072613 ER PT J AU Zheng, L Taiwo, B Gandhi, RT Hunt, PW Collier, AC Flexner, C Bosch, RJ AF Zheng, Lu Taiwo, Babafemi Gandhi, Rajesh T. Hunt, Peter W. Collier, Ann C. Flexner, Charles Bosch, Ronald J. TI Factors Associated With CD8(+) T-Cell Activation in HIV-1-Infected Patients on Long-term Antiretroviral Therapy SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE CD8(+) T-cell activation; viral suppression; age; HCV; CD4(+) T-cell count ID HEPATITIS-C VIRUS; LOW-LEVEL VIREMIA; IMMUNE ACTIVATION; HIV-INFECTION; VIRAL SUPPRESSION; RNA LEVELS; RECOVERY; REPLICATION; REGIMENS; DISEASE AB Background: Abnormal levels of CD8(+) T-cell activation persist in HIV-1-infected patients on suppressive antiretroviral therapy (ART) and may be deleterious. Methods: CD8+ T-cell activation (% coexpressing CD38/HLA-DR) was analyzed on blood specimens from 833 HIV-1-infected patients on ART for >= 96 weeks with concurrent plasma HIV RNA (vRNA) <= 200 copies per milliliter. Factors associated with CD8(+) T-cell activation were assessed using generalized estimating equations to incorporate longitudinal measurements (median 4/participant). Results: Participants were 84% men, 47% white, 28% black, and 22% Hispanic, with median pre-ART age 38 years and median ART exposure 144 weeks. CD8(+) T-cell activation was higher at time-points when vRNA was 51-200 versus <= 50 copies per milliliter [mean CD8(+) T-cell activation 23.4% vs. 19.7%; adjusted difference: 1.7% (95% confidence interval: 0.1 to 3.4), P = 0.042]. Restricting to vRNA <= 50 copies per milliliter, multivariable models showed the following factors associated with higher CD8(+) T-cell activation: older age [>= 45 vs. <= 30 years: 3.6% (1.4 to 5.7), P = 0.004], hepatitis C virus antibody positivity [3.6% (0.9 to 6.2), P = 0.032], Hispanic vs. white [7.2% (5.3 to 9.0), P < 0.001], lower concurrent CD4 count [<= 200 vs. >500 cells/mm(3): 2.2% (0.7 to 3.7), P < 0.001], lower concurrent CD4/CD8 ratio [-2.6% (-3.7 to -1.5) per 0.5 unit increase, P < 0.001], and higher pre-ART CD8+ T-cell activation [2.0% (1.6 to 2.5) per 10% higher, P < 0.001]. Conclusions: In participants included in our analysis, residual low-level viremia between 51 and 200 copies per milliliter during ART was shown to be associated with greater CD8(+) T-cell activation than full suppression to <50 copies per milliliter. Older age, hepatitis C virus antibody positivity, race/ethnicity, higher pre-ART CD8(+) T-cell activation, and lower concurrent CD4/CD8 ratio and CD4(+) T-cell count also contribute to greater CD8(+) T-cell activation during suppressive ART. C1 [Zheng, Lu; Bosch, Ronald J.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Taiwo, Babafemi] Northwestern Univ, Div Infect Dis, Chicago, IL 60611 USA. [Gandhi, Rajesh T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Gandhi, Rajesh T.] MIT, Ragon Inst MGH, Cambridge, MA 02139 USA. [Gandhi, Rajesh T.] Harvard, Cambridge, MA USA. [Hunt, Peter W.] Univ Calif San Francisco, San Francisco Gen Hosp, Div HIV AIDS, San Francisco, CA USA. [Collier, Ann C.] Univ Washington, Dept Med, Div Infect Dis, Seattle, WA USA. [Flexner, Charles] Johns Hopkins Univ, Sch Med, Div Clin Pharmacol, Baltimore, MD USA. RP Zheng, L (reprint author), Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, FXB Bldg,Room 613,651 Huntington Ave, Boston, MA 02115 USA. EM szheng@sdac.harvard.edu FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [AI-68636, AI-68634, AI-38858, AI-38855, AI-69434]; Janssen; Pfizer; GlaxoSmithKline; ViiV; Abbott; Merck; Roche Molecular Systems; Schering-Plough; Boehringer-Ingelheim FX Supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (AI-68636, AI-68634, AI-38858, AI-38855, and AI-69434).; B.T. has served as an advisor and/or received research support (to Northwestern University) from Janssen, Pfizer, GlaxoSmithKline, and ViiV. R. T. G. has received institutional research grant support from Abbott, ViiV, and Janssen. A. C. C. received research support (to University of Washington) from Merck, Roche Molecular Systems, and Schering-Plough, previously owned stock in Abbott, Bristol-Myers Squibb, Johnson and Johnson, and Pfizer, and was a DSMB member for a Merck-sponsored study. C. F. reports receiving research grant support from Boehringer-Ingelheim and GlaxoSmithKline for research unrelated to this study and serving as a consultant to Bristol-Myers Squibb, Boehringer-Ingelheim, GlaxoSmithKline, Merck, Roche, Schering-Plough, Tobira Therapeutics, Tibotec, Vertex, Virostatics, and ViiV Healthcare. The remaining authors have no conflicts of interest to disclose. NR 37 TC 7 Z9 7 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2014 VL 67 IS 2 BP 153 EP 160 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AP4NT UT WOS:000342055000013 PM 25072610 ER PT J AU Grannan, BL Yanamadala, V Venteicher, AS Walcott, BP Barr, JC AF Grannan, Benjamin L. Yanamadala, Vijay Venteicher, Andrew S. Walcott, Brian P. Barr, John C. TI Use of external ventriculostomy and intrathecal anti-fungal treatment in cerebral mucormycotic abscess SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Amphotericin; External ventricular drain; Intrathecal; Mucormycosis; Neurocritical care ID AMPHOTERICIN; EPIDEMIOLOGY; ZYGOMYCOSIS; MANAGEMENT; THERAPY AB Mucormycosis is an invasive fungal infection associated with a high mortality. Cerebral mucor abscesses can result secondary to rhinocerebral or hematogenous spread. Amphotericin B, posaconazole, and aggressive surgical resection are the hallmarks of treatment. While amphotericin is typically administered intravenously, less is known about the use of intrathecal amphotericin B. We describe a 42-year-old man who developed a cerebellar mucor abscess after undergoing hematopoietic stem cell transplant for the treatment of myelodysplastic syndrome. In the post-operative period he was admitted to the neurocritical care unit and received liposomal amphotericin B intravenously and through an external ventricular drain. This patient demonstrates that utilization of an external ventricular drain for intrathecal antifungal therapy in the post-operative period may warrant further study in patients with difficult to treat intracranial fungal abscesses. (C) 2014 Published by Elsevier Ltd. C1 [Walcott, Brian P.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Walcott, BP (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,WACC 745, Boston, MA 02115 USA. EM walcott.brian@mgh.harvard.edu NR 11 TC 0 Z9 2 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD OCT PY 2014 VL 21 IS 10 BP 1819 EP 1821 DI 10.1016/j.jocn.2014.01.008 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AQ0ML UT WOS:000342477300032 PM 24852901 ER PT J AU King, MW Resick, PA AF King, Matthew W. Resick, Patricia A. TI Data Mining in Psychological Treatment Research: A Primer on Classification and Regression Trees SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE classification and regression trees; CART; exploratory data analysis; data mining ID SELECTION; PTSD AB Data mining of treatment study results can reveal unforeseen but critical insights, such as who receives the most benefit from treatment and under what circumstances. The usefulness and legitimacy of exploratory data analysis have received relatively little recognition, however, and analytic methods well suited to the task are not widely known in psychology. With roots in computer science and statistics, statistical learning approaches offer a credible option: These methods take a more inductive approach to building a model than is done in traditional regression, allowing the data greater role in suggesting the correct relationships between variables rather than imposing them a priori. Classification and regression trees are presented as a powerful, flexible exemplar of statistical learning methods. Trees allow researchers to efficiently identify useful predictors of an outcome and discover interactions between predictors without the need to anticipate and specify these in advance, making them ideal for revealing patterns that inform hypotheses about treatment effects. Trees can also provide a predictive model for forecasting outcomes as an aid to clinical decision making. This primer describes how tree models are constructed, how the results are interpreted and evaluated, and how trees overcome some of the complexities of traditional regression. Examples are drawn from randomized clinical trial data and highlight some interpretations of particular interest to treatment researchers. The limitations of tree models are discussed, and suggestions for further reading and choices in software are offered. C1 [King, Matthew W.; Resick, Patricia A.] VA Boston Healthcare Syst, Womens Hlth Sci Div, Natl Ctr PTSD, Boston, MA USA. [Resick, Patricia A.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. RP King, MW (reprint author), VA Boston Healthcare Syst 116B 3, Natl Ctr PTSD, Womens Hlth Sci Div, 150 South Huntington Ave, Boston, MA 02130 USA. EM matthew.king2@va.gov NR 30 TC 9 Z9 9 U1 2 U2 17 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X EI 1939-2117 J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD OCT PY 2014 VL 82 IS 5 SI SI BP 895 EP 905 DI 10.1037/a0035886 PG 11 WC Psychology, Clinical SC Psychology GA AQ0VZ UT WOS:000342502100014 PM 24588404 ER PT J AU Pais, VM Chew, B Shaw, O Hyams, ES Matlaga, B Venkatesh, R Page, J Paterson, RF Arsovska, O Kurtz, M Eisner, BH AF Pais, Vernon M., Jr. Chew, Ben Shaw, Ojas Hyams, Elias S. Matlaga, Brian Venkatesh, Ramakrishna Page, Jay Paterson, Ryan F. Arsovska, Olga Kurtz, Michael Eisner, Brian H. TI Percutaneous Nephrolithotomy for Removal of Encrusted Ureteral Stents: A Multicenter Study SO JOURNAL OF ENDOUROLOGY LA English DT Article ID MANAGEMENT AB Purpose: Encrusted ureteral stents are a challenging endourologic problem. We performed a multi-institutional review of percutaneous nephrolithotomy (PCNL) as primary treatment for encrusted stents. Materials and Methods: We identified 36 patients who underwent PCNL for treatment of an encrusted stent. A retrospective review was performed to compile details of procedures and outcomes for these patients. Results: In 36 patients, 38 renal units underwent PCNL for encrusted ureteral stents. The mean patient age was 47.1 years (+/- 16.7), and the female:male ratio was 15:21. Mean stent indwelling time before removal was 28.2 months (+/- 27.8). The reason for long indwelling time was reported in 25 cases; these reasons included "patient unaware stent needed to be removed" (17 cases), pregnancy (2 cases), other comorbidities (3 cases), and patient incarceration (3 cases). In 3 cases, the stent had become encrusted within 3 months of placement. Mean operative time was 162 minutes (+/- 71). There were no major intraoperative complications, and no patients required blood transfusion. Litholapaxy was required for bladder coil encrustations in 22 cases (58%), and ureteroscopy with lithotripsy was required for encrustation of the ureteral portion of the stent in 13 cases (34.2%). Second look percutaneous procedures were required in 13 cases (34.2%). The stent was removed at the time of PCNL without need for concomitant or delayed ureteroscopy and/or cystolitholapaxy in 8 cases (21%). Ultimately, all stents were removed successfully. Patients were rendered stone free according to radiographs in 24 cases (63%). Conclusions: In this multicenter review, PCNL is confirmed to be a safe and effective means of addressing the retained and encrusted ureteral stent. PCNL without ureteroscopy or litholapaxy was sufficient in a minority of cases (21%). Adjunctive endourologic modalities are often required, and the surgeon should anticipate the need for concomitant antegrade ureteroscopic laser lithotripsy and/or cystolitholapaxy. Although complete stent removal can be anticipated, residual fragments are not uncommon. C1 [Pais, Vernon M., Jr.; Hyams, Elias S.] Dartmouth Hitchcock Med Ctr, Urol Sect, Lebanon, NH 03756 USA. [Chew, Ben; Paterson, Ryan F.; Arsovska, Olga] Univ British Columbia, Dept Urol Sci, Vancouver, BC V5Z 1M9, Canada. [Shaw, Ojas] NYU, Dept Urol, New York, NY USA. [Matlaga, Brian] Johns Hopkins Univ, Brady Urol Inst, Baltimore, MD USA. [Venkatesh, Ramakrishna; Page, Jay] Univ Kentucky, Dept Urol, Lexington, KY USA. [Kurtz, Michael; Eisner, Brian H.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. RP Pais, VM (reprint author), Dartmouth Hitchcock Med Ctr, Urol Sect, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM vmp@hitchcock.org NR 13 TC 4 Z9 5 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0892-7790 EI 1557-900X J9 J ENDOUROL JI J. Endourol. PD OCT 1 PY 2014 VL 28 IS 10 BP 1188 EP 1191 DI 10.1089/end.2014.0004 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA AQ1SP UT WOS:000342561600011 PM 24745371 ER PT J AU Lee, GC Fong, ZV Ferrone, CR Thayer, SP Warshaw, AL Lillemoe, KD Fernandez-del Castillo, C AF Lee, Grace C. Fong, Zhi Ven Ferrone, Cristina R. Thayer, Sarah P. Warshaw, Andrew L. Lillemoe, Keith D. Fernandez-del Castillo, Carlos TI High Performing Whipple Patients: Factors Associated with Short Length of Stay after Open Pancreaticoduodenectomy SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Length of stay; Pancreaticoduodenectomy; Cost; Epidural analgesia; Weekday ID INTERNATIONAL STUDY-GROUP; PANCREATIC RESECTION; OF-STAY; ROBOTIC PANCREATICODUODENECTOMY; CLINICAL PATHWAY; HOSPITAL VOLUME; UNITED-STATES; SURGERY; READMISSION; INSTITUTION AB Despite the decreasing mortality of pancreaticoduodenectomy (PD), it continues to be associated with prolonged length of postoperative hospital stay (LOS). This study aimed to determine factors that could predict short LOS after PD. Additionally, as preliminary data of minimally invasive PD emerges, we sought to determine the average LOS after open PD at a high-volume center to set a standard to which minimally invasive PD can be compared. A total of 634 consecutive patients who underwent open PD between January 2007 and December 2012 at the Massachusetts General Hospital comprised the study cohort. "High performers" were defined as patients with postoperative LOS a parts per thousand currency sign5 days. Median LOS was 7 days. A total of 61 patients (9.6 %) had LOS a parts per thousand currency sign5 days and were deemed "high performing." In multivariate logistic regression analysis, male gender (p = 0.032), neoadjuvant chemoradiation (p = 0.001), epidural success (p = 0.019), epidural duration a parts per thousand currency sign3 days (p = 0.001), lack of complications (p < 0.001), surgery on Thursday or Friday (p = 0.001), and discharge on Monday through Wednesday (p < 0.001) were independently associated with LOS a parts per thousand currency sign5 days. Readmission rate, time to readmission, and mortality were not different between the two groups. The proportion of patients with pancreatic ductal adenocarcinoma who went on to receive adjuvant therapy was no different if LOS was a parts per thousand currency sign5 or > 5 days, but high performance was predictive of beginning therapy < 8 weeks after surgery (p = 0.010). In our experience, median LOS was 7 days, and early discharge (a parts per thousand currency sign5 days) after open PD is safe and feasible in about 10 % of patients. These high performers are more likely to be male, have received neoadjuvant therapy, and had successful epidural analgesia. High performers with cancer are more likely to start chemotherapy < 8 weeks after surgery. Minimally invasive PD should be compared to this high standard for median LOS, among other quality metrics, to justify its increased cost, operative duration, and learning curve. C1 [Lee, Grace C.; Fong, Zhi Ven; Ferrone, Cristina R.; Thayer, Sarah P.; Warshaw, Andrew L.; Lillemoe, Keith D.; Fernandez-del Castillo, Carlos] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. RP Fernandez-del Castillo, C (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, 15 Parkman St, Boston, MA 02114 USA. EM cfernandez@partners.org NR 46 TC 9 Z9 9 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD OCT PY 2014 VL 18 IS 10 BP 1760 EP 1769 DI 10.1007/s11605-014-2604-3 PG 10 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA AQ0CQ UT WOS:000342450000006 PM 25091843 ER PT J AU Spiegel, BMR Kaneshiro, M Russell, MM Lin, A Patel, A Tashjian, VC Zegarski, V Singh, D Cohen, SE Reid, MW Whitman, CB Talley, J Martinez, BM Kaiser, W AF Spiegel, Brennan M. R. Kaneshiro, Marc Russell, Marcia M. Lin, Anne Patel, Anish Tashjian, Vartan C. Zegarski, Vincent Singh, Digvijay Cohen, Samuel E. Reid, Mark W. Whitman, Cynthia B. Talley, Jennifer Martinez, Bibiana M. Kaiser, William TI Validation of an Acoustic Gastrointestinal Surveillance Biosensor for Postoperative Ileus SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Postoperative Ileus; Biosensor; Health technology ID SURGERY; METAANALYSIS; RECOVERY; PATTERNS; TRIALS; SOUNDS AB Postoperative ileus (POI) can worsen outcomes, increase cost, and prolong hospitalization. An objective marker could help identify POI patients who should not be prematurely fed. We developed a disposable, non-invasive acoustic gastro-intestinal surveillance (AGIS) biosensor. We tested whether AGIS can distinguish healthy controls from patients recovering from abdominal surgery. AGIS is a disposable plastic device embedded with a microphone that adheres to the abdominal wall and connects to a computer that measures acoustic event rates. We compared intestinal rates of healthy subjects using AGIS for 60 min after a standardized meal to recordings of two postoperative groups: (1) patients tolerating standardized feeding and (2) POI patients. We compared intestinal rates among groups using ANOVA and t tests. There were 8 healthy controls, 7 patients tolerating feeding, and 25 with POI; mean intestinal rates were 0.14, 0.03, and 0.016 events per second, respectively (ANOVA p < 0.001). AGIS separated patients from controls with 100 % sensitivity and 97 % specificity. Among patients, rates were higher in fed versus POI subjects (p = 0.017). Non-invasive, abdominal acoustic monitoring distinguishes POI from non-POI subjects. Future research will test whether AGIS can identify patients at risk for development of POI and assist with postoperative feeding decisions. C1 [Russell, Marcia M.] VA Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA USA. [Spiegel, Brennan M. R.; Kaneshiro, Marc; Patel, Anish; Cohen, Samuel E.; Reid, Mark W.; Talley, Jennifer] VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Zegarski, Vincent; Singh, Digvijay; Kaiser, William] UCLA Wireless Hlth Inst, Henry Samueli Sch Engn & Appl Sci, Los Angeles, CA USA. [Russell, Marcia M.; Lin, Anne] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Spiegel, Brennan M. R.; Kaneshiro, Marc; Tashjian, Vartan C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Digest Dis, Los Angeles, CA 90095 USA. [Spiegel, Brennan M. R.; Patel, Anish; Cohen, Samuel E.] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA. [Spiegel, Brennan M. R.] UCLA Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. [Spiegel, Brennan M. R.; Reid, Mark W.; Whitman, Cynthia B.; Talley, Jennifer; Martinez, Bibiana M.] UCLA VA Ctr Outcomes Res & Educ CORE, Los Angeles, CA USA. [Spiegel, Brennan M. R.] West Los Angeles VA Med Ctr, Div Gastroenterol, Los Angeles, CA 90073 USA. [Kaiser, William] Univ Calif Los Angeles, Dept Elect Engn, Los Angeles, CA 90024 USA. RP Spiegel, BMR (reprint author), West Los Angeles VA Med Ctr, Div Gastroenterol, Los Angeles, CA 90073 USA. EM bspiegel@mednet.ucla.edu; kaiser@ee.ucla.edu NR 21 TC 3 Z9 3 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD OCT PY 2014 VL 18 IS 10 BP 1795 EP 1803 DI 10.1007/s11605-014-2597-y PG 9 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA AQ0CQ UT WOS:000342450000010 PM 25091837 ER PT J AU Fisichella, PM Patti, MG AF Fisichella, P. Marco Patti, Marco G. TI From Heller to POEM (1914-2014): A 100-Year History of Surgery for Achalasia SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Review DE Achalasia; Heller myotomy; Laparoscopic myotomy; Thoracoscopic myotomy; Dor fundoplication; Toupet fundoplication; Surgical treatment of achalasia; POEM ID ENDOSCOPIC MYOTOMY POEM; LONG-TERM OUTCOMES; ESOPHAGEAL ACHALASIA; DOR FUNDOPLICATION; SURGICAL-TREATMENT; CARDIOSPASM; ESOPHAGOMYOTOMY; OPERATION AB The year 2014 marks the 100th anniversary of Dr. Heller's description of the surgical treatment of patients with achalasia with a cardiomyotomy. This 100-year-old operation, which is today performed laparoscopically with the addition of a partial fundoplication, is considered the treatment of choice for patients with achalasia. Our goals are to revisit the accounts from the beginning of the twentieth century in which surgeons tried to identify the pathophysiology of achalasia and proposed several operative techniques and to follow the evolution of the surgical treatment until modern days. C1 [Fisichella, P. Marco] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Dept Surg, Boston, MA 02132 USA. [Patti, Marco G.] Univ Chicago, Pritzker Sch Med, Dept Surg, Ctr Esophageal Dis, Chicago, IL 60637 USA. RP Fisichella, PM (reprint author), Harvard Univ, Sch Med, Boston VA Healthcare Syst, Dept Surg, 1400 VFW Pkwy, Boston, MA 02132 USA. EM piero.fisichella@va.gov NR 44 TC 7 Z9 7 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD OCT PY 2014 VL 18 IS 10 BP 1870 EP 1875 DI 10.1007/s11605-014-2547-8 PG 6 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA AQ0CQ UT WOS:000342450000020 PM 24878993 ER PT J AU Fisichella, PM AF Fisichella, P. Marco TI The Importance of Evidence to Validate Clinical Practice and Its Significance in Making Recommendations SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Letter C1 Harvard Univ, Sch Med, Boston VA Healthcare Syst, Dept Surg, Boston, MA 02132 USA. RP Fisichella, PM (reprint author), Harvard Univ, Sch Med, Boston VA Healthcare Syst, Dept Surg, 1400 VFW Pkwy, Boston, MA 02132 USA. EM piero.fisichella@va.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD OCT PY 2014 VL 18 IS 10 BP 1882 EP 1882 DI 10.1007/s11605-014-2595-0 PG 1 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA AQ0CQ UT WOS:000342450000024 PM 25091836 ER PT J AU Horn, DM Sequist, TD AF Horn, Daniel M. Sequist, Thomas D. TI The Impact of Cost Displays on Ordering SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Letter C1 [Horn, Daniel M.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Sequist, Thomas D.] Partners Healthcare Syst, Boston, MA USA. RP Horn, DM (reprint author), Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD OCT PY 2014 VL 29 IS 10 BP 1332 EP 1332 DI 10.1007/s11606-014-2945-3 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AQ0DV UT WOS:000342453900007 PM 24990245 ER PT J AU Steinman, MA Miao, YH Boscardin, WJ Komaiko, KDR Schwartz, JB AF Steinman, Michael A. Miao, Yinghui Boscardin, W. John Komaiko, Kiya D. R. Schwartz, Janice B. TI Prescribing Quality in Older Veterans: A Multifocal Approach SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE quality assessment; pharmacoepidemiology; veterans; geriatrics ID ADVERSE DRUG-REACTIONS; POTENTIALLY INAPPROPRIATE MEDICATION; DISEASE INTERACTIONS; ELDERLY VETERANS; ADULTS; RISK; PEOPLE; FRAIL; CARE; POLYPHARMACY AB Quality prescribing for older adults involves multiple considerations. We evaluated multiple aspects of prescribing quality in older veterans to develop an integrated view of prescribing problems and to understand how the prevalence of these problems varies across clinically important subgroups of older adults. Cross-sectional observational study of veterans age 65 years and older who received medications from Department of Veterans Affairs (VA) pharmacies in 2007. Using VA pharmacy data linked with encounter, laboratory and other data, we assessed five types of prescribing problems. Among 462,405 patients age 65 and older, mean age was 75 years, 98 % were male, and patients were prescribed a median of five medications. Half of patients (50 %) had one or more prescribing problems, including 12 % taking one or more medications at an inappropriately high dose, 30 % with drug-drug interactions, 3 % with drug-disease interactions, and 26 % taking one or more Beers criteria drugs. In addition, 16 % were taking a high-risk drug (warfarin, insulin, and/or digoxin). On multivariable analysis, age was not strongly associated with four of the five types of prescribing issues assessed (relative risk < 1.3 across age groups), and comorbid burden conferred substantially increased risk only for drug-disease interactions and use of high-risk drugs. In contrast, the number of drugs used was consistently the strongest predictor of prescribing problems. Patients in the highest quartile of medication use had 6.6-fold to12.5-fold greater risk of each type of prescribing problem compared to patients in the lowest quartile (P < 0.001 for each). The number of medications used is by far the strongest risk factor for each of five types of prescribing problems. Efforts to improve prescribing should especially target patients taking multiple medications. C1 [Steinman, Michael A.; Miao, Yinghui; Boscardin, W. John; Komaiko, Kiya D. R.; Schwartz, Janice B.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94141 USA. [Steinman, Michael A.; Miao, Yinghui; Boscardin, W. John; Komaiko, Kiya D. R.] San Francisco VA Med Ctr, San Francisco, CA USA. [Boscardin, W. John] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94141 USA. [Schwartz, Janice B.] Jewish Home San Francisco, San Francisco, CA USA. RP Steinman, MA (reprint author), Univ Calif San Francisco, Div Geriatr, 4150 Clement St,VA Box 181G, San Francisco, CA 94141 USA. EM Mike.steinman@ucsf.edu FU NIA NIH HHS [K23 AG030999, RC1-AG036377, RC1 AG036377, P30 AG044281, 1 K23-AG030999] NR 44 TC 9 Z9 9 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD OCT PY 2014 VL 29 IS 10 BP 1379 EP 1386 DI 10.1007/s11606-014-2924-8 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AQ0DV UT WOS:000342453900014 PM 25002159 ER PT J AU Jena, AB DePasse, JW Prasad, V AF Jena, Anupam B. DePasse, Jacqueline W. Prasad, Vinay TI The Declining Demand for Hospital Care as a Rationale for Duty Hour Reform SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article ID INTERNS; TIME AB The regulation of duty hours of physicians in training remains among the most hotly debated subjects in medical education. Although recent duty hour reforms have been chiefly motivated by concerns about resident well-being and medical errors attributable to resident fatigue, the debate surrounding duty hour reform has infrequently involved discussion of one of the most important secular changes in hospital care that has affected nearly all developed countries over the last 3 decades: the declining demand for hospital care. For example, in 1980, we show that resident physicians in US teaching hospitals provided, on average, 1,302 inpatient days of care per resident physician compared to 593 inpatient days in 2011, a decline of 54 %. This decline in the demand for hospital care by residents provides an under-recognized economic rationale for reducing residency duty hours, a rationale based solely on supply and demand considerations. Work hour reductions and growing requirements for outpatient training can be seen as an appropriate response to the shrinking demand for hospital care across the health-care sector. C1 [Jena, Anupam B.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Jena, Anupam B.] NBER, Cambridge, MA 02138 USA. [Jena, Anupam B.; DePasse, Jacqueline W.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Jena, Anupam B.; DePasse, Jacqueline W.; Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Jena, AB (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM jena@hcp.med.harvard.edu OI Prasad, Vinay/0000-0002-6110-8221 FU NIH HHS [DP5 OD017897, 1DP5OD017897-01] NR 9 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD OCT PY 2014 VL 29 IS 10 BP 1400 EP 1403 DI 10.1007/s11606-014-2901-2 PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AQ0DV UT WOS:000342453900021 PM 24866469 ER PT J AU Edwards, ST Abrams, MK Baron, RJ Berenson, RA Rich, EC Rosenthal, GE Rosenthal, MB Landon, BE AF Edwards, Samuel T. Abrams, Melinda K. Baron, Richard J. Berenson, Robert A. Rich, Eugene C. Rosenthal, Gary E. Rosenthal, Meredith B. Landon, Bruce E. TI Structuring Payment to Medical Homes After the Affordable Care Act SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article ID ACCOUNTABLE CARE; INNOVATION PROFILE; SYSTEM REFORM; HEALTH; SAVINGS; ORGANIZATION; MODEL; COST AB The Patient-Centered Medical Home (PCMH) is a leading model of primary care reform, a critical element of which is payment reform for primary care services. With the passage of the Affordable Care Act, the Accountable Care Organization (ACO) has emerged as a model of delivery system reform, and while there is theoretical alignment between the PCMH and ACOs, the discussion of physician payment within each model has remained distinct. Here we compare payment for medical homes with that for accountable care organizations, consider opportunities for integration, and discuss implications for policy makers and payers considering ACO models. The PCMH and ACO are complementary approaches to reformed care delivery: the PCMH ultimately requires strong integration with specialists and hospitals as seen under ACOs, and ACOs likely will require a high functioning primary care system as embodied by the PCMH. Aligning payment incentives within the ACO will be critical to achieving this integration and enhancing the care coordination role of primary care in these settings. C1 [Edwards, Samuel T.] Vet Affairs VA Boston Healthcare Syst, Gen Internal Med Sect, Boston, MA USA. [Edwards, Samuel T.] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Edwards, Samuel T.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Abrams, Melinda K.] Commonwealth Fund, New York, NY USA. [Baron, Richard J.] Amer Board Internal Med, Philadelphia, PA USA. [Berenson, Robert A.] Urban Inst, Washington, DC 20037 USA. [Rich, Eugene C.] Mathemat Policy Res, Washington, DC USA. [Rosenthal, Gary E.] Univ Iowa, Carver Coll Med, Iowa City, IA USA. [Rosenthal, Gary E.] Iowa City VA Hlth Care Syst, Iowa City, IA USA. [Rosenthal, Meredith B.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Landon, Bruce E.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Landon, Bruce E.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Landon, BE (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM landon@hcp.med.harvard.edu OI Rosenthal, Meredith/0000-0003-3410-0184 NR 25 TC 16 Z9 16 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD OCT PY 2014 VL 29 IS 10 BP 1410 EP 1413 DI 10.1007/s11606-014-2848-3 PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AQ0DV UT WOS:000342453900023 PM 24687292 ER PT J AU Pober, BR AF Pober, B. R. TI OVERVIEW OF WILLIAMS SYNDROME SO JOURNAL OF INTELLECTUAL DISABILITY RESEARCH LA English DT Meeting Abstract DE microdeletion; intellectual disability; anxiety; diabetes; vascular stenosis C1 [Pober, B. R.] Quinnipiac Univ, Netter Sch Med, Dept Med Sci, North Haven, CT USA. [Pober, B. R.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Pober, B. R.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0964-2633 EI 1365-2788 J9 J INTELL DISABIL RES JI J. Intell. Disabil. Res. PD OCT PY 2014 VL 58 IS 10 BP 890 EP 891 PG 2 WC Education, Special; Genetics & Heredity; Clinical Neurology; Psychiatry; Rehabilitation SC Education & Educational Research; Genetics & Heredity; Neurosciences & Neurology; Psychiatry; Rehabilitation GA AP5YA UT WOS:000342153400032 ER PT J AU Luo, S Tsao, H AF Luo, Su Tsao, Hensin TI Epidermal, Sebaceous, and Melanocytic Nevoid Proliferations Are Spectrums of Mosaic RASopathies SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID ACTIVATING HRAS MUTATION; NEVUS SEBACEUS; PHAKOMATOSIS PIGMENTOKERATOTICA; POSTZYGOTIC HRAS; RAS MUTATIONS; SPILUS; KRAS AB Growing evidence demonstrates that various nevoid proliferations such as keratinocytic epidermal nevi and nevus sebaceous result from somatic mosaicism. Many of the mutations identified have been within the RAF/RAS/MAPK pathway, hence supporting the previously introduced term "mosaic RASopathy" for these nevi. In this issue, Kinsler et al. were among the first to characterize certain pigmented melanocytic nevi that may also fit this paradigm. To better frame these findings, we provide a summary of the analogous genotypic profiles for epidermal and melanocytic nevi from recent studies. C1 [Luo, Su; Tsao, Hensin] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Tsao, Hensin] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Tsao, Hensin] Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA 02114 USA. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 55 Fruit St,Edwards 202A, Boston, MA 02114 USA. EM htsao@partners.org NR 17 TC 7 Z9 7 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2014 VL 134 IS 10 BP 2493 EP 2496 DI 10.1038/jid.2014.244 PG 5 WC Dermatology SC Dermatology GA AP6PT UT WOS:000342200400009 PM 25219651 ER PT J AU Hess, AT van der Kouwe, AJW Mbugua, KK Laughton, B Meintjes, EM AF Hess, Aaron T. van der Kouwe, Andre J. W. Mbugua, Kenneth K. Laughton, Barbara Meintjes, Ernesta M. TI Quality of 186 Child Brain Spectra Using Motion and B0 Shim Navigated Single Voxel Spectroscopy SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE single voxel spectroscopy; motion correction; B0 correction; navigator ID MAGNETIC-RESONANCE-SPECTROSCOPY; H-1 MR SPECTROSCOPY; SIGNAL LOSS; QUANTITATION; ARTIFACTS; FREQUENCY; INFANTS AB Purpose: To evaluate B0 shim and motion navigated single voxel spectroscopy in children. Assess the repeatability of metabolite concentrations in three regions: medial frontal grey matter, peritrigonal white matter, and basal ganglia. Determine the extent of intra-and interacquisition movement in this population. Methods: Linewidth and signal to noise ratio were calculated to assess spectral quality of 186 spectra at 3 Tesla. Repeatability was assessed on 31 repeat scans. Navigator images were used to assess localization errors, while navigator motion and shim logs were used to demonstrate the efficacy of correction needed during the scans. Results: Average linewidths +/- standard deviations of N-acetyl aspartate are 3.8 +/- 0.6 Hz, 4.4 +/- 0.5 Hz, and 4.7 6 0.8 Hz in each region, respectively. Scan-to-scan measurement variance in metabolite concentrations closely resembled the expected variance. A total of 73% and 32% of children moved before and during the acquisition, causing a voxel shift of more than 10% of the voxel volume, 1.5 mm. The predominant movement directions were sliding out of the coil and nodding (up-down rotation). First-order B0 corrections were significant (>10 mT/m) in 18 % of acquisitions. Conclusion: Prospective motion and B0 correction provides high quality repeatable spectra. The study found that most children moved between acquisitions and a substantial number moved during acquisitions. C1 [Hess, Aaron T.] Univ Oxford, Oxford Ctr Clin Magnet Resonance Res OCMR, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England. [van der Kouwe, Andre J. W.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [van der Kouwe, Andre J. W.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Mbugua, Kenneth K.; Meintjes, Ernesta M.] Univ Cape Town, MRC UCT Med Imaging Res Unit, Dept Human Biol, ZA-7700 Rondebosch, South Africa. [Laughton, Barbara] Univ Stellenbosch, Childrens Infect Dis Clin Res Unit, Dept Paediat & Child Hlth, Cape Town, South Africa. [Laughton, Barbara] Tygerberg Hosp, Cape Town, South Africa. RP Hess, AT (reprint author), John Radcliffe Hosp, OCMR, Level 0,Headley Way, Oxford OX3 9DU, England. EM aaron.hess@cardiov.ox.ac.uk RI Laughton, Barbara/Q-3496-2016; OI Laughton, Barbara/0000-0001-7260-7723; Hess, Aaron/0000-0002-9289-5619 FU NIH [R21AA017410, R21MH096559, R01HD071664, U19A153217]; NRF [CPR20110614000019421] FX Contract grant sponsor: NIH; Contract grant number: R21AA017410; Contract grant number: R21MH096559; Contract grant number: R01HD071664; Contract grant number: U19A153217; Contract grant sponsor: NRF; Contract grant number: CPR20110614000019421. NR 25 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD OCT PY 2014 VL 40 IS 4 BP 958 EP 965 DI 10.1002/jmri.24436 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AP8QA UT WOS:000342342500025 PM 24924772 ER PT J AU Yoshida, T Friehs, I Mummidi, S del Nido, PJ Addulnour-Nakhoul, S Delafontaine, P Valente, AJ Chandrasekar, B AF Yoshida, Tadashi Friehs, Ingeborg Mummidi, Srinivas del Nido, Pedro J. Addulnour-Nakhoul, Solange Delafontaine, Patrice Valente, Anthony J. Chandrasekar, Bysani TI Pressure overload induces IL-18 and IL-18R expression, but markedly suppresses IL-18BP expression in a rabbit model. IL-18 potentiates TNF-alpha-induced cardiomyocyte death SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Myocardial hypertrophy; Cardiac failure; Cyclical stretch; Interleukins; Inflammation ID NF-KAPPA-B; CARDIAC FIBROBLAST MIGRATION; STRETCH-INDUCED HYPERTROPHY; HEART-FAILURE; INTERLEUKIN-18 EXPRESSION; BINDING-PROTEIN; ACTIVATION; DYSFUNCTION; INDUCTION; APOPTOSIS AB Recurrent or sustained inflammation plays a causal role in the development and progression of left ventricular hypertrophy (LVH) and its transition to failure. Interleukin (IL)-18 is a potent pro-hypertrophic inflammatory cytokine. We report that induction of pressure overload in the rabbit, by constriction of the descending thoracic aorta induces compensatory hypertrophy at 4 weeks (mass/volume ratio: 1.7 +/- 0.11) and ventricular dilatation indicative of heart failure at 6 weeks (mass/volume ratio: 0.7 +/- 0.04). In concordance with this, fractional shortening was preserved at 4 weeks, but markedly attenuated at 6 weeks. We cloned rabbit IL-18, IL-18R alpha, IL-18R beta, and IL-18 binding protein (1-18BP) cDNA, and show that pressure overload, while enhancing IL-18 and IL-18R expression in hypertrophied and failing hearts, markedly attenuated the level of expression of the endogenous IL-18 antagonist IL-18BP. Cyclical mechanical stretch (10% cyclic equibiaxial stretch, 1 Hz) induced hypertrophy of primary rabbit cardiomyocytes in vitro and enhanced ANP, IL-18, and IL-18Ra expression. Further, treatment with rhIL-18 induced its own expression and that of IL-18Ra via AP-1 activation, and induced cardiomyocyte hypertrophy in part via PI3K/Akt/GATA4 signaling. In contrast, IL-18 potentiated TNF-alpha-induced cardiomyocyte death, and by itself induced cardiac endothelial cell death. These results demonstrate that pressure overload is associated with enhanced IL-18 and its receptor expression in hypertrophied and failingrabbit hearts. Since IL-18BP expression is markedly inhibited, our results indicate a positive amplification in IL-18 proinflammatory signaling during pressure overload, and suggest IL-18 as a potential therapeutic target in pathological hypertrophy and cardiac failure. Published by Elsevier Ltd. C1 [Yoshida, Tadashi; Delafontaine, Patrice; Chandrasekar, Bysani] Tulane Univ, Sch Med, Inst Heart & Vasc, New Orleans, LA 70112 USA. [Friehs, Ingeborg; del Nido, Pedro J.; Valente, Anthony J.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Cardiac Surg, Boston, MA 02115 USA. [Mummidi, Srinivas] Univ Texas Hlth Sci Ctr San Antonio, South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Mummidi, Srinivas] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Addulnour-Nakhoul, Solange] Tulane Univ, Sch Med, Dept Med Gastroenterol, New Orleans, LA 70112 USA. [Addulnour-Nakhoul, Solange; Chandrasekar, Bysani] Southeast Louisiana Vet Hlth Care Syst, Res Serv, New Orleans, LA 70161 USA. RP Chandrasekar, B (reprint author), Tulane Univ, Sch Med, Inst Heart & Vasc, 1430 Tulane Ave,SL-48, New Orleans, LA 70112 USA. EM bchandra@tulane.edu OI Yoshida, Tadashi/0000-0002-4544-1497 FU U.S. Department of Veterans Affairs, Office of Research and Development Biomedical Laboratory Research and Development (ORD-BLRD) Service Award [1IO1BX000246]; NIH/National Heart, Lung, and Blood Institute Grant [HL-86787, HL-075430, HL-70241, HL-80682]; Veterans Affairs ORD-BLRD Service Award [I01BX000975]; NIH/NIGMS Tulane COBRE Pilot Project [P20GM103629] FX This work was supported by the U.S. Department of Veterans Affairs, Office of Research and Development Biomedical Laboratory Research and Development (ORD-BLRD) Service Award 1IO1BX000246 and the NIH/National Heart, Lung, and Blood Institute Grant HL-86787 (to BC), HL-075430 (IF), and HL-70241 and HL-80682 (PD). SM is supported by Veterans Affairs ORD-BLRD Service Award I01BX000975. TV is supported by a NIH/NIGMS Tulane COBRE Pilot Project (P20GM103629). The contents of this report do not represent the views of the Department of Veterans Affairs or the United States Government. NR 41 TC 7 Z9 8 U1 0 U2 9 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD OCT PY 2014 VL 75 BP 141 EP 151 DI 10.1016/j.yjmcc.2014.07.007 PG 11 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA AP7QL UT WOS:000342271700015 PM 25108227 ER PT J AU Vranceanu, AM Merker, VL Plotkin, SR Park, ER AF Vranceanu, Ana-Maria Merker, Vanessa L. Plotkin, Scott R. Park, Elyse R. TI The relaxation response resiliency program (3RP) in patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis: results from a pilot study SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Relaxation response; Mind-body therapies; Neurofibromatoses; Psychological resilience ID PAIN CATASTROPHIZING SCALE; EPWORTH SLEEPINESS SCALE; VALIDATION; LIFE; SUPPORT; MODEL AB NF1, NF2, and Schwannomatosis are incurable tumor suppressor syndromes associated with poor quality of life. The aim of this study was to determine the feasibility, acceptability, and preliminary efficacy of an NF adapted, 8-week group mind body skills based intervention, the relaxation response resiliency program (3RP) aimed at improving resiliency and increasing satisfaction with life. Patients seen at MGH's Neurofibromatosis Clinic were offered participation if they described difficulties coping to a treating physician. Participants completed measures of life satisfaction, resiliency, stress, mood, lifestyle, pain, post-traumatic growth and mindfulness at baseline and after completing the 3RP program. The intervention had relative feasible enrollment rate (48 % rate, 32 out of 67 of patients signing the informed consent form). However, out of the 32 patients who signed the informed consent, only 20 started the study (62.5 %) and only 16 completed it (50 %), suggesting problems with feasibility. The main reason cited for non-participation was burden of travel to the clinic. The intervention was highly acceptable, as evidenced by an 80 % completion rate (16/20). Paired t tests showed significant improvement in resiliency, satisfaction with life, depression, stress, anxiety, mindfulness and post traumatic growth, with effect sizes ranging from 0.73-1.33. There was a trend for significance for improvement in somatization and sleepiness (p = 0.06), with effect sizes of 0.54-0.92 respectively. Statistically nonsignificant improvement was observed in all other measures, with effect sizes small to medium. In sum, the 3RP was found to be relatively feasible, highly acceptable and preliminary efficacious in decreasing symptom burden in this population, supporting the need of a randomized controlled trial. C1 [Vranceanu, Ana-Maria; Park, Elyse R.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Vranceanu, Ana-Maria; Merker, Vanessa L.; Plotkin, Scott R.; Park, Elyse R.] Harvard Univ, Sch Med, Boston, MA USA. [Vranceanu, Ana-Maria; Park, Elyse R.] MGH Benson Henry Inst Mind Body Med, Boston, MA USA. [Merker, Vanessa L.; Plotkin, Scott R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Merker, Vanessa L.; Plotkin, Scott R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Vranceanu, AM (reprint author), Massachusetts Gen Hosp, Dept Psychiat, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM avranceanu@partners.org OI Merker, Vanessa/0000-0002-4542-5227 NR 25 TC 9 Z9 9 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD OCT PY 2014 VL 120 IS 1 BP 103 EP 109 DI 10.1007/s11060-014-1522-2 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AQ0EW UT WOS:000342456600011 PM 25022450 ER PT J AU Gandhi, CD Bulsara, KR Fifi, J Kass-Hout, T Grant, RA Almandoz, JED English, J Meyers, PM Abruzzo, T Prestigiacomo, CJ Powers, CJ Lee, SK Albani, B Do, HM Eskey, CJ Patsalides, A Hetts, S Hussain, MS Ansari, SA Hirsch, JA Kelly, M Rasmussen, P Mack, W Pride, GL Alexander, MJ Jayaraman, MV AF Gandhi, Chirag D. Bulsara, Ketan R. Fifi, Johanna Kass-Hout, Tareq Grant, Ryan A. Almandoz, Josser E. Delgado English, Joey Meyers, Philip M. Abruzzo, Todd Prestigiacomo, Charles J. Powers, Ciaran James Lee, Seon-Kyu Albani, Barbara Do, Huy M. Eskey, Clifford J. Patsalides, Athos Hetts, Steven Hussain, M. Shazam Ansari, Sameer A. Hirsch, Joshua A. Kelly, Michael Rasmussen, Peter Mack, William Pride, G. Lee Alexander, Michael J. Jayaraman, Mahesh V. CA SNIS Stand Guidelines Comm TI Platelet function inhibitors and platelet function testing in neurointerventional procedures SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID PIPELINE EMBOLIZATION DEVICE; PERCUTANEOUS CORONARY INTERVENTION; SINGLE-CENTER EXPERIENCE; UNRUPTURED INTRACRANIAL ANEURYSMS; LIGHT TRANSMISSION AGGREGOMETRY; GLYCOPROTEIN IIB/IIIA RECEPTOR; TRANSIENT ISCHEMIC ATTACK; DUAL ANTIPLATELET THERAPY; PLACEBO-CONTROLLED TRIAL; OF-CARE DEVICE C1 [Gandhi, Chirag D.; Kass-Hout, Tareq; Prestigiacomo, Charles J.] Rutgers State Univ, NJ Med Sch, Dept Neurosurg, Newark, NJ 07102 USA. [Bulsara, Ketan R.; Grant, Ryan A.] Yale Univ, Sch Med, Dept Neurosurg, New Haven, CT USA. [Fifi, Johanna] Columbia Univ, St Lukes Roosevelt Hosp Ctr, Hyman Newman Inst Neurol & Neurosurg New York, New York, NY USA. [Almandoz, Josser E. Delgado] Abbott NW Hosp, Dept Intervent Neuroradiol, Minneapolis, MN 55407 USA. [English, Joey] UCSF, Dept Neurol & Radiol, San Francisco, CA USA. [Meyers, Philip M.] Columbia Presbyterian Med Ctr, Dept Neurointervent Surg, New York, NY USA. [Abruzzo, Todd] Univ Cincinnati, Dept Neurosurg, Cincinnati, OH USA. [Powers, Ciaran James] Wexner Med Ctr, Dept Neurosurg, Columbus, OH USA. [Lee, Seon-Kyu] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. [Albani, Barbara] Christiana Care Hlth Syst, Dept Neurointervent Surg, Newark, DE USA. [Do, Huy M.] Stanford Univ, Dept Neurosurg & Radiol, Stanford, CA 94305 USA. [Eskey, Clifford J.] Dartmouth Hitchcock Med Ctr, Dept Radiol Neurol & Neurosurg, Lebanon, NH 03766 USA. [Patsalides, Athos] New York Presbyterian Hosp, Weill Cornell Med Coll, Dept Neurol Surg, New York, NY USA. [Hetts, Steven] WUCSF, Dept Radiol, San Francisco, CA USA. [Hussain, M. Shazam] Cleveland Clin, Stroke Program, Cleveland Hts, OH USA. [Ansari, Sameer A.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, NeuroEndovasc Program, Boston, MA 02114 USA. [Kelly, Michael] Univ Saskatchewan, Royal Univ Hosp, Dept Neurosurg, Saskatoon, SK, Canada. [Rasmussen, Peter] Cleveland Clin, Dept Neurosurg, Cleveland, OH 44106 USA. [Mack, William] Univ So Calif, Dept Neurosurg, Los Angeles, CA USA. [Pride, G. Lee] UT Southwestern, Dept Neuroradiol, Dallas, TX USA. [Alexander, Michael J.] Cedars Sinai Med Ctr, Dept Neurosurg, Los Angeles, CA 90048 USA. [Jayaraman, Mahesh V.] Brown Univ, Warren Alpert Sch, Providence, RI 02912 USA. RP Gandhi, CD (reprint author), Rutgers State Univ, NJ Med Sch, Dept Neurosurg, Newark, NJ 07102 USA. EM gandhich@rutgers.edu RI Powers, Ciaran/E-3890-2011; OI Alexander, Michael/0000-0003-0280-809X NR 157 TC 5 Z9 5 U1 1 U2 6 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 EI 1759-8486 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD OCT PY 2014 VL 6 IS 8 BP 567 EP 577 DI 10.1136/neurintsurg-2014-011357 PG 11 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA AQ1FX UT WOS:000342528400002 PM 25056369 ER PT J AU Zaidat, OO Castonguay, AC Gupta, R Sun, CHJ Martin, C Holloway, WE Mueller-Kronast, N English, JD Linfante, I Dabus, G Malisch, TW Marden, FA Bozorgchami, H Xavier, A Rai, AT Froehler, MT Badruddin, A Nguyen, TN Taqi, MA Abraham, MG Janardhan, V Shaltoni, H Novakovic, R Yoo, AJ Abou-Chebl, A Chen, PR Britz, GW Kaushal, R Nanda, A Issa, MA Nogueira, RG AF Zaidat, Osama O. Castonguay, Alicia C. Gupta, Rishi Sun, Chung-Huan J. Martin, Coleman Holloway, William E. Mueller-Kronast, Nils English, Joey D. Linfante, Italo Dabus, Guilherme Malisch, Tim W. Marden, Franklin A. Bozorgchami, Hormozd Xavier, Andrew Rai, Ansaar T. Froehler, Michael T. Badruddin, Aamir Nguyen, Thanh N. Taqi, M. Asif Abraham, Michael G. Janardhan, Vallabh Shaltoni, Hashem Novakovic, Roberta Yoo, Albert J. Abou-Chebl, Alex Chen, Peng R. Britz, Gavin W. Kaushal, Ritesh Nanda, Ashish Issa, Mohammad A. Nogueira, Raul G. TI North American Solitaire Stent Retriever Acute Stroke registry: post-marketing revascularization and clinical outcome results SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID ACUTE ISCHEMIC-STROKE; ENDOVASCULAR TREATMENT; RETROSPECTIVE MULTICENTER; MECHANICAL THROMBECTOMY; ARTERY OCCLUSIONS; THERAPY; TRIAL; EXPERIENCE; DEVICE; SYSTEM AB Background Limited post-marketing data exist on the use of the Solitaire FR device in clinical practice. The North American Solitaire Stent Retriever Acute Stroke (NASA) registry aimed to assess the real world performance of the Solitaire FR device in contrast with the results from the SWIFT (Solitaire with the Intention for Thrombectomy) and TREVO 2 (Trevo versus Merci retrievers for thrombectomy revascularization of large vessel occlusions in acute ischemic stroke) trials. Methods The investigator initiated NASA registry recruited North American sites to submit retrospective angiographic and clinical outcome data on consecutive acute ischemic stroke (AIS) patients treated with the Solitaire FR between March 2012 and February 2013. The primary outcome was a Thrombolysis in Myocardial Ischemia (TIMI) score of >= 2 or a Treatment in Cerebral Infarction (TICI) score of >= 2a. Secondary outcomes were 90 day modified Rankin Scale (mRS) score, mortality, and symptomatic intracranial hemorrhage. Results 354 patients underwent treatment for AIS using the Solitaire FR device in 24 centers. Mean time from onset to groin puncture was 363.4 +/- 239 min, mean fluoroscopy time was 32.9 +/- 25.7 min, and mean procedure time was 100.9 +/- 57.8 min. Recanalization outcome: TIMI >= 2 rate of 83.3% (315/354) and TICI >= 2a rate of 87.5% (310/354) compared with the operator reported TIMI >= 2 rate of 83% in SWIFT and TICI >= 2a rate of 85% in TREVO 2. Clinical outcome: 42% (132/315) of NASA patients demonstrated a 90 day mRS <= 2 compared with 37% (SWIFT) and 40% (TREVO 2). 90 day mortality was 30.2% (95/315) versus 17.2% (SWIFT) and 29% (TREVO 2). Conclusions The NASA registry demonstrated that the Solitaire FR device performance in clinical practice is comparable with the SWIFT and TREVO 2 trial results. C1 [Zaidat, Osama O.; Castonguay, Alicia C.; Issa, Mohammad A.] Med Coll Wisconsin, Froedtert Mem Lutheran Hosp, Dept Neurol, Milwaukee, WI 53226 USA. [Zaidat, Osama O.] Med Coll Wisconsin, Froedtert Mem Lutheran Hosp, Dept Neurosurg, Milwaukee, WI 53226 USA. [Zaidat, Osama O.] Med Coll Wisconsin, Froedtert Mem Lutheran Hosp, Dept Radiol, Milwaukee, WI 53226 USA. [Gupta, Rishi; Sun, Chung-Huan J.; Nogueira, Raul G.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Martin, Coleman; Holloway, William E.] St Lukes Kansas City, Kansas City, MO USA. [Mueller-Kronast, Nils] Delray Med Ctr, Dept Neurol, Delray Beach, FL USA. [English, Joey D.] Calif Pacific Med Ctr, San Francisco, CA USA. [Linfante, Italo; Dabus, Guilherme] Baptist Cardiac & Vasc Inst, Div Intervent Neuroradiol, Miami, FL USA. [Malisch, Tim W.; Marden, Franklin A.] Alexian Bros Med Ctr, Elk Grove Village, IL USA. [Bozorgchami, Hormozd] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Xavier, Andrew] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48201 USA. [Rai, Ansaar T.] West Virginia Univ Hosp, Dept Radiol, Morgantown, WV USA. [Froehler, Michael T.] Vanderbilt Univ, Med Ctr, Dept Neurol, Nashville, TN USA. [Froehler, Michael T.] Vanderbilt Univ, Med Ctr, Dept Neurosurg, Nashville, TN USA. [Froehler, Michael T.] Vanderbilt Univ, Med Ctr, Dept Radiol, Nashville, TN 37232 USA. [Badruddin, Aamir] Provena St Joseph Med Ctr, Joliet, IL USA. [Nguyen, Thanh N.] Boston Med Ctr, Dept Neurol, Boston, MA USA. [Nguyen, Thanh N.] Boston Med Ctr, Dept Neurosurg, Boston, MA USA. [Nguyen, Thanh N.] Boston Med Ctr, Dept Radiol, Boston, MA USA. [Taqi, M. Asif] Desert Reg Med Ctr, Palm Springs, CA USA. [Abraham, Michael G.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Janardhan, Vallabh] Texas Stroke Inst, Plano, TX USA. [Shaltoni, Hashem] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Novakovic, Roberta] UT Southwestern Med Ctr, Dept Radiol, Dallas, TX USA. [Novakovic, Roberta] UT Southwestern Med Ctr, Dept Neurol, Dallas, TX USA. [Yoo, Albert J.] Massachusetts Gen Hosp, Dept Radiol, Div Diagnost & Intervent Neuroradiol, Boston, MA 02114 USA. [Abou-Chebl, Alex] Univ Louisville, Sch Med, Dept Neurol, Louisville, KY 40292 USA. [Chen, Peng R.] Univ Texas Houston, Houston, TX USA. [Britz, Gavin W.] Methodist Neurol Inst, Dept Neurosurg, Houston, TX USA. [Kaushal, Ritesh] St Louis Univ, St Louis, MO 63103 USA. [Nanda, Ashish] Univ Missouri, Columbia, MO USA. RP Zaidat, OO (reprint author), Med Coll Wisconsin, Froedtert Mem Lutheran Hosp, Neurointervent Div, Dept Neurol, Milwaukee, WI 53226 USA. EM szaidat@mcw.edu NR 16 TC 39 Z9 39 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 EI 1759-8486 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD OCT PY 2014 VL 6 IS 8 BP 584 EP 588 DI 10.1136/neurintsurg-2013-010895 PG 5 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA AQ1FX UT WOS:000342528400004 PM 24062252 ER PT J AU Smith, BA Jacobs, JV Horak, FB AF Smith, Beth A. Jacobs, Jesse V. Horak, Fay B. TI Effects of Amplitude Cueing on Postural Responses and Preparatory Cortical Activity of People With Parkinson Disease SO JOURNAL OF NEUROLOGIC PHYSICAL THERAPY LA English DT Article DE cueing; contingent negative variation; electroencephalography; event-related desynchronization; Parkinson disease; postural responses ID CEREBRAL-CORTEX; MOTOR; SET; INSTABILITY; SYNCHRONIZATION; INTEGRATION; POTENTIALS; DYNAMICS; STRATEGY; BALANCE AB Background and Purpose: Persons with Parkinson disease (PD) are unable to modify their postural responses, and show an associated increase in cortical preparatory activity for anticipated postural perturbations.(1) In this study we asked whether participants with PD could modify their postural responses and cortical preparatory activity when cued to focus on increasing movement amplitude before a series of predictable postural perturbations. Methods: Twelve participants with PD performed postural responses to 30 identical backward surface translations. We cued participants to focus on increasing movement amplitude, and examined the effects of cueing by measuring postural responses (center-of-pressure initial rate of change, automatic postural response stability, peak trunk flexion, peak ankle extension) and preparatory cortical activity (electroencephalographic measures of contingent negative variation, alpha and beta event-related desynchronization). Results: Participants with PD modified their postural responses during the amplitude trials by increasing trunk flexion, slowing center-of-pressure initial rate of change, and decreasing automatic postural response stability. However, no significant differences in contingent negative variation amplitude or alpha or beta event-related desynchronization were observed with versus without amplitude cueing. Discussion and Conclusions: Persons with PD were able to modify their feet-in-place postural responses with amplitude cueing. These changes were not associated with changes in cortical preparation during amplitude cue trials, suggesting that other regions or measures of brain function were responsible for changes in postural responses. Future studies are needed to determine the effects of long-term amplitude-cueing practice on cortical preparation and postural stability. Video Abstract available. See Video (Supplemental Digital Content 1, http://links.1ww.com/JNPT/A78) for more insights from the authors. C1 [Smith, Beth A.] Univ So Calif, Div Biokinesiol & Phys Therapy, Infant Neuromotor Control Lab, Los Angeles, CA 90089 USA. [Jacobs, Jesse V.] Univ Vermont, Dept Rehabil & Movement Sci, Human Mot Anal Lab, Burlington, VT USA. [Horak, Fay B.] Oregon Hlth & Sci Univ, Dept Neurol, Balance Disorders Lab, Portland, OR 97201 USA. [Horak, Fay B.] Portland VA Med Ctr, Portland, OR USA. RP Smith, BA (reprint author), Univ So Calif, Div Biokinesiol & Phys Therapy, 1540 Alcazar St,CHP 155, Los Angeles, CA 90089 USA. EM beth.smith@usc.edu RI Smith, Beth A./D-2914-2014 OI Smith, Beth A./0000-0003-2531-5394 FU National Institutes of Health, National Institute of Aging [R37 A60006457]; National Institutes of Health, National Institute of Child Health and Human Development [F32 HD070796]; Medical Research Foundation of Oregon; Foundation for Physical Therapy New Investigator Fellowship Training Initiative FX Supported by National Institutes of Health, National Institute of Aging R37 A60006457 (F.B.H.); National Institutes of Health, National Institute of Child Health and Human Development F32 HD070796 (B.A.S.), Medical Research Foundation of Oregon (B.A.S.), and the Foundation for Physical Therapy New Investigator Fellowship Training Initiative (B.A.S.). Funding sources provided funding only and did not influence the work. NR 46 TC 4 Z9 4 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1557-0576 EI 1557-0584 J9 J NEUROL PHYS THER JI J. Neurol. Phys. Ther. PD OCT PY 2014 VL 38 IS 4 BP 207 EP 215 DI 10.1097/NPT.0000000000000058 PG 9 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA AQ1PN UT WOS:000342553400002 PM 25198870 ER PT J AU Peacock, ZS Lee, CCY Klein, KP Kaban, LB AF Peacock, Zachary S. Lee, Cameron C. Y. Klein, Katherine P. Kaban, Leonard B. TI Orthognathic Surgery in Patients Over 40 Years of Age: Indications and Special Considerations SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID SAGITTAL SPLIT OSTEOTOMY; SYMPTOMATIC PLATE REMOVAL; OBSTRUCTIVE SLEEP-APNEA; ALVEOLAR NERVE FUNCTION; FOLLOW-UP; MAXILLOMANDIBULAR ADVANCEMENT; NEUROSENSORY DISTURBANCE; RAMUS OSTEOTOMY; COMPLICATIONS; SATISFACTION AB Purpose: To assess indications, incidence, patient experience, and outcomes of orthognathic surgery in patients over 40 years of age. Patients and Methods: This was a retrospective cohort study of all patients who underwent orthognathic surgical procedures at Massachusetts General Hospital from 1995 to 2012. Demographic variables, including age, gender, indications, date, and type of operation, were documented. Patients were divided into 2 groups by date of operation: 1) 1995 to 2002 and 2) 2003 to 2012. The predictor variable was age (> 40 vs < 40 yr). Outcome variables included indications for treatment, date of operation, length of hospital stay, and removal of hardware. Results: During the study period, 1,420 patients underwent 2,170 procedures; 911 patients (1,343 procedures) met the inclusion criteria. Group 1 consisted of 260 subjects (346 procedures, 35 patients >= 40 yr old, 13.5%) and group 2 consisted of 651 subjects (997 procedures, 89 patients >= 40 yr old, 13.8%). Subjects over 40 had longer hospital stays (P <=. 0001) than those under 40. Indications for men were more frequently functional problems, whereas women sought esthetic improvements (P =.0001). Subjects over 40 were 2.51, 2.44, and 2.72 times more likely to require hardware removal 6 months (P =.0245), 12 months (P =.0073), and 24 months (P =.0003) postoperatively than those younger than 40. Conclusion: Motivation to undergo orthognathic surgery varies by age and gender. Older patients, particularly men, tend to seek treatment for functional rather than esthetic reasons. Patients older than 40 years had longer hospital stays and an increased rate of postoperative hardware removal. (C) 2014 American Association of Oral and Maxillofacial Surgeons C1 Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Lee, Cameron C. Y.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. RP Peacock, ZS (reprint author), Massachusetts Gen Hosp, Warren 1201,55 Fruit St, Boston, MA 02114 USA. EM zpeacock@partners.org FU Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund; Harvard Medical School Scholars in Medicine Program FX This work was funded by the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund and the Harvard Medical School Scholars in Medicine Program. NR 37 TC 6 Z9 6 U1 0 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD OCT PY 2014 VL 72 IS 10 BP 1995 EP 2004 DI 10.1016/j.joms.2014.03.020 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AQ0IL UT WOS:000342466500020 PM 24836418 ER PT J AU Delpire, E Staley, KJ AF Delpire, Eric Staley, Kevin J. TI Novel determinants of the neuronal Cl- concentration SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Review ID CATION-CHLORIDE COTRANSPORTERS; ROOT GANGLION NEURONS; MAMMALIAN EPITHELIAL-CELLS; POSTNATAL RAT BRAINS; INTRACELLULAR CHLORIDE; NA+-K+-2CL(-) COTRANSPORTER; NA-K-2CL COTRANSPORTER; HIPPOCAMPAL-NEURONS; SYNAPTIC INHIBITION; CORTICAL-NEURONS AB It is now a well-accepted view that cation-driven Cl(-)transporters in neurons are involved in determining the intracellular Cl- concentration. In the present review, we propose that additional factors, which are often overlooked, contribute substantially to the Cl- gradient across neuronal membranes. After briefly discussing the data supporting and opposing the role of cation-chloride cotransporters in regulating Cl-, we examine the participation of the following factors in the formation of the transmembrane Cl- gradient: (i) fixed 'Donnan' charges inside and outside the cell; (ii) the properties of water (free vs. bound); and (iii) water transport through the cotransporters. We demonstrate a steep relationship between intracellular Cl- and the concentration of fixed negative charges on macromolecules. We show that in the absence of water transport through the K+-Cl- cotransporter, a large osmotic gradient builds at concentrations below or above a set value of 'Donnan' charges, and showthat at any value of these fixed charges, the reversal potential for Cl- equates that of K+. When the movement of water across the membrane is a source of free energy, it is sufficient to modify the movement of Cl- through the cotransporter. In this scenario, the reversal potential for Cl- does not closely follow that of K+. Furthermore, our simulations demonstrate that small differences in the availability of freely diffusible water between inside and outside the cell greatly affect the Cl- reversal potential, particularly when osmolar transmembrane gradients are minimized, for example by idiogenic osmoles. We also establish that the presence of extracellular charges has little effect on the chloride reversal potential, but greatly affects the effective inhibitory conductance for Cl-. In conclusion, our theoretical analysis of the presence of fixed anionic charges and water bound on macromolecules inside and outside the cell greatly impacts both Cl- gradient and Cl- conductance across neuronal membranes. C1 [Delpire, Eric] Vanderbilt Univ, Sch Med, Dept Anesthesiol, Nashville, TN 37212 USA. [Staley, Kevin J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. RP Delpire, E (reprint author), Vanderbilt Univ, Sch Med, Dept Anesthesiol, MCNT 4202,1161 21st Ave South, Nashville, TN 37212 USA. EM eric.delpire@vanderbilt.edu FU National Institutes of Health [GM074771, DK093501, NS040109, NS074772] FX Support for the authors' research comes from the National Institutes of Health grants GM074771, DK093501 to E. D. and NS040109, NS074772 to K.J.S. NR 72 TC 11 Z9 11 U1 0 U2 10 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 OCT 1 PY 2014 VL 592 IS 19 BP 4099 EP 4114 DI 10.1113/jphysiol.2014.275529 PG 16 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA AQ0ZE UT WOS:000342510400002 PM 25107928 ER PT J AU Gorrindo, T Stock, SL AF Gorrindo, Tristan Stock, Saundra L. TI Bringing Education to the Bedside: A Primer on Continuing Medical Education (CME) and Maintenance of Certification (MOC) Requirements SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Editorial Material ID BOARD C1 [Gorrindo, Tristan] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gorrindo, Tristan] Harvard Univ, Sch Med, Boston, MA USA. [Stock, Saundra L.] Univ S Florida, Tampa, FL USA. RP Gorrindo, T (reprint author), MGH Psychiat, 1 Bowdoin Sq,Ste 700, Boston, MA 02114 USA. EM Tristan.Gorrindo@mgh.harvard.edu NR 7 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD OCT PY 2014 VL 53 IS 10 BP 1042 EP 1044 DI 10.1016/j.jaac.2014.07.009 PG 3 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA AP9MO UT WOS:000342404100002 PM 25245345 ER PT J AU Groen-Blokhuis, MM Middeldorp, CM Kan, KJ Abdellaoui, A van Beijsterveldt, CEM Ehli, EA Davies, GE Scheet, PA Xiao, XJ Hudziak, JJ Hottenga, JJ Neale, B Boomsma, DI AF Groen-Blokhuis, Maria M. Middeldorp, Christel M. Kan, Kees-Jan Abdellaoui, Abdel van Beijsterveldt, Catharina E. M. Ehli, Erik A. Davies, Gareth E. Scheet, Paul A. Xiao, Xiangjun Hudziak, James J. Hottenga, Jouke-Jan Neale, Ben M. Boomsma, Dorret I. CA Psychiatric Genomics Consortium TI Attention-Deficit/Hyperactivity Disorder Polygenic Risk Scores Predict Attention Problems in a Population-Based Sample of Children SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE ADHD; attention problems; polygenic scores; genetics; dimensional models ID DEFICIT HYPERACTIVITY DISORDER; NETHERLANDS TWIN REGISTER; GENOME-WIDE ASSOCIATION; DEVELOPMENTAL PSYCHOPATHOLOGY; LATENT CLASS; ADHD; HERITABILITY; CHILDHOOD; STABILITY; SYMPTOMS AB Objective: Clinically, attention-deficit/hyperactivity disorder (ADHD) is characterized by hyperactivity, impulsivity, and inattention and is among the most common childhood disorders. These same traits that define ADHD are variable in the general population, and the clinical diagnosis may represent the extreme end of a continuous distribution of inattentive and hyperactive behaviors. This hypothesis can be tested by assessing the predictive value of polygenic risk scores derived from a discovery sample of ADHD patients in a target sample from the general population with continuous scores of inattention and hyperactivity. In addition, the genetic overlap between ADHD and continuous ADHD scores can be tested across rater and age. Method: The Psychiatric Genomics Consortium has performed the largest genome-wide analysis (GWA) study of ADHD so far, including 5,621 clinical patients and 13,589 controls. The effects sizes of single nucleotide polymorphisms (SNPs) estimated in this meta-analysis were used to obtain individual polygenic risk scores in an independent population-based cohort of 2,437 children from the Netherlands Twin Register. The variance explained in Attention Problems (AP) scale scores by the polygenic risk scores was estimated by linear mixed modeling. Results: The ADHD polygenic risk scores significantly predicted both parent and teacher ratings of AP in preschool- and school-aged children. Conclusion: These results indicate genetic overlap between a diagnosis of ADHD and AP scale scores across raters and age groups and provides evidence for a dimensional model of ADHD. Future GWA studies on ADHD can likely benefit from the inclusion of population-based cohorts and the analysis of continuous scores. C1 [Groen-Blokhuis, Maria M.; Middeldorp, Christel M.; Kan, Kees-Jan; Abdellaoui, Abdel; van Beijsterveldt, Catharina E. M.; Hottenga, Jouke-Jan; Boomsma, Dorret I.] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Groen-Blokhuis, Maria M.; Boomsma, Dorret I.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Middeldorp, Christel M.] Vrije Univ Amsterdam, Med Ctr, GGZinGeest, Amsterdam, Netherlands. [Ehli, Erik A.; Davies, Gareth E.] Avera Inst Human Genet, Sioux Falls, SD USA. [Scheet, Paul A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Xiao, Xiangjun] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Hanover, NH 03756 USA. [Hudziak, James J.] Vermont Ctr Children Youth & Families, Burlington, VT USA. [Hudziak, James J.] Univ Vermont, Coll Med, Burlington, VT USA. [Neale, Ben M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Neale, Ben M.] Harvard Univ, Sch Med, Boston, MA USA. [Neale, Ben M.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. RP Boomsma, DI (reprint author), Boechorststr 1, NL-1081 BT Amsterdam, Netherlands. EM dorret@psy.vu.nl OI Middeldorp, Christel/0000-0002-6218-0428 FU ARRA [RC2 2MH08995]; European Research Council (Genetics of Mental Illness) [ERC-230374]; Spinozapremie [NWO/SPI 56-464-14192]; Neuroscience Campus Amsterdam (NCA); EMGO+ Institution; twin-family database for behavior genetics and genomics studies [NWO 480-04-004]; Genetic influences on stability and change in psychopathology from childhood to young adulthood [ZonMW 912-10-020] FX This project was supported by ARRA RC2 2MH08995; the European Research Council (Genetics of Mental Illness, ERC-230374); Spinozapremie (NWO/SPI 56-464-14192); Neuroscience Campus Amsterdam (NCA) and the EMGO+ Institution; twin-family database for behavior genetics and genomics studies (NWO 480-04-004); Genetic influences on stability and change in psychopathology from childhood to young adulthood (ZonMW 912-10-020). NR 46 TC 9 Z9 9 U1 3 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD OCT PY 2014 VL 53 IS 10 BP 1123 EP 1129 DI 10.1016/j.jaac.2014.06.014 PG 7 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA AP9MO UT WOS:000342404100013 PM 25245356 ER PT J AU Shlyankevich, J Corey, KC Garshick, MK Roh, EK Kimball, AB AF Shlyankevich, Julia Corey, Kristen C. Garshick, Marisa K. Roh, Ellen K. Kimball, Alexandra B. TI Dermatology urgent care: Enlisting help from primary care in triage decisions SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter C1 [Shlyankevich, Julia; Kimball, Alexandra B.] Massachusetts Gen Hosp, Clin Unit Res Trials & Outcomes Skin, Boston, MA 02114 USA. [Shlyankevich, Julia; Roh, Ellen K.; Kimball, Alexandra B.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Corey, Kristen C.] Univ Massachusetts, Dept Dermatol, Worcester, MA USA. [Garshick, Marisa K.] Weill Cornell Med Coll, Dept Dermatol, New York, NY USA. [Roh, Ellen K.; Kimball, Alexandra B.] Harvard Univ, Sch Med, Boston, MA USA. RP Kimball, AB (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 50 Staniford St,Suite 240, Boston, MA 02114 USA. EM harvardskinstudies@partners.org NR 2 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD OCT PY 2014 VL 71 IS 4 BP 838 EP 839 DI 10.1016/j.jaad.2014.05.024 PG 2 WC Dermatology SC Dermatology GA AP6FJ UT WOS:000342172700072 PM 25219712 ER PT J AU Enamandram, M Schoch, K Miller, DD Horn, TD AF Enamandram, Monica Schoch, Kathryn Miller, Daniel D. Horn, Thomas D. TI Calcific elastosis in the setting of weight gain SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter C1 [Enamandram, Monica; Horn, Thomas D.] Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Miller, Daniel D.] Boston Univ, Sch Med, Dermatopathol Sect, Boston, MA 02118 USA. [Schoch, Kathryn] Boston Univ, Sch Med, Dept Dermatol, Boston, MA 02118 USA. RP Horn, TD (reprint author), MGPO Dermatopathol Associates, 2 Wells Ave, Newton, MA 02459 USA. EM THorn@partners.org NR 7 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD OCT PY 2014 VL 71 IS 4 BP E156 EP E158 DI 10.1016/j.jaad.2014.06.034 PG 4 WC Dermatology SC Dermatology GA AP6FJ UT WOS:000342172700029 PM 25219746 ER PT J AU Ryan, ME Palasis, S Saigal, G Singer, AD Karmazyn, B Dempsey, ME Dillman, JR Dory, CE Garber, M Hayes, LL Iyer, RS Mazzola, CA Raske, ME Rice, HE Rigsby, CK Sierzenski, PR Strouse, PJ Westra, SJ Wootton-Gorges, SL Coley, BD AF Ryan, Maura E. Palasis, Susan Saigal, Gaurav Singer, Adam D. Karmazyn, Boaz Dempsey, Molly E. Dillman, Jonathan R. Dory, Christopher E. Garber, Matthew Hayes, Laura L. Iyer, Ramesh S. Mazzola, Catherine A. Raske, Molly E. Rice, Henry E. Rigsby, Cynthia K. Sierzenski, Paul R. Strouse, Peter J. Westra, Sjirk J. Wootton-Gorges, Sandra L. Coley, Brian D. TI ACR Appropriateness Criteria Head Trauma-Child SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Appropriateness criteria; head trauma; nonaccidental injury; pediatric; CT; MRI ID MAGNETIC-RESONANCE SPECTROSCOPY; PEDIATRIC BRAIN-INJURY; COMPUTED-TOMOGRAPHY; CERVICAL-SPINE; NEUROBEHAVIORAL OUTCOMES; INTRACRANIAL INJURY; RADIATION-EXPOSURE; UNIQUE FEATURES; DECISION RULE; SKULL AB Head trauma is a frequent indication for cranial imaging in children. CT is considered the first line of study for suspected intracranial injury because of its wide availability and rapid detection of acute hemorrhage. However, the majority of childhood head injuries occur without neurologic complications, and particular consideration should be given to the greater risks of ionizing radiation in young patients in the decision to use CT for those with mild head trauma. MRI can detect traumatic complications without radiation, but often requires sedation in children, owing to the examination length and motion sensitivity, which limits rapid assessment and exposes the patient to potential anesthesia risks. MRI may be helpful in patients with suspected nonaccidental trauma, with which axonal shear injury and ischemia are more common and documentation is critical, as well as in those whose clinical status is discordant with CT findings. Advanced techniques, such as diffusion tensor imaging, may identify changes occult by standard imaging, but data are currently insufficient to support routine clinical use. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. C1 [Ryan, Maura E.] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Palasis, Susan] Childrens Hosp Atlanta, Atlanta, GA USA. [Saigal, Gaurav] Univ Miami Hlth Syst, Miami, FL USA. [Singer, Adam D.] Univ Miami, Jackson Mem Hosp, Miami, FL 33136 USA. [Karmazyn, Boaz] Indiana Univ, James Whitcomb Riley Hosp Children, Indianapolis, IN USA. [Dempsey, Molly E.] Texas Scottish Rite Hosp Crippled Children, Dallas, TX USA. [Dillman, Jonathan R.; Strouse, Peter J.] CS Mott Childrens Hosp, Ann Arbor, MI USA. [Dory, Christopher E.] Childrens Hosp, San Diego, CA USA. [Garber, Matthew] Div Gen & Hosp Pediat, Columbia, SC USA. [Garber, Matthew] Amer Acad Pediat, Elk Grove Village, IL USA. [Hayes, Laura L.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Iyer, Ramesh S.] Seattle Childrens Hosp, Seattle, WA USA. [Mazzola, Catherine A.] New Jersey Pediat Neurosci Inst, Morristown, NJ USA. [Mazzola, Catherine A.] Amer Assoc Neurol Surg, Rolling Meadows, IL USA. [Mazzola, Catherine A.] Illinois Congress Neurol Surg, Schaumburg, IL USA. [Raske, Molly E.] St Paul Radiol PA, St Paul, MN USA. [Rice, Henry E.] Duke Univ, Med Ctr, Durham, NC USA. [Rice, Henry E.] Amer Pediat Surg Assoc, Deerfield, IL USA. [Rigsby, Cynthia K.] Childrens Mem Hosp, Chicago, IL 60614 USA. [Sierzenski, Paul R.] Christiana Care Hlth Syst, Newark, DE USA. [Sierzenski, Paul R.] Amer Coll Emergency Phys, Irving, TX USA. [Westra, Sjirk J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wootton-Gorges, Sandra L.] Univ Calif Davis, Sacramento, CA 95817 USA. [Coley, Brian D.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. RP Ryan, ME (reprint author), Ann & Robert H Lurie Childrens Hosp Chicago, 225 E Chicago Ave, Chicago, IL 60611 USA. EM mryan@luriechildrens.org OI Coley, Brian/0000-0003-0354-4727 FU Siemens Medical FX Boaz K Karmazyn, MD, receives grant funding for research into CT dose and dose reduction techniques from Siemens Medical, but does not have any ownership in or receive any direct compensation from Siemens Medical. NR 68 TC 6 Z9 6 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD OCT PY 2014 VL 11 IS 10 BP 939 EP 947 DI 10.1016/j.jacr.2014.07.017 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AQ1FY UT WOS:000342528500008 PM 25164794 ER PT J AU Stern, EJ Adam, EJ Bettman, MA Brink, JA Dreyer, KJ Frija, G Keefer, R Mildenberger, P Remedios, D Vock, P AF Stern, Eric J. Adam, E. Jane Bettman, Michael A. Brink, James A. Dreyer, Keith J. Frija, Guy Keefer, Raina Mildenberger, Peter Remedios, Denis Vock, Peter TI Proceedings from the First Global Summit on Radiological Quality and Safety SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Quality; safety; appropriateness; clinical imaging guidelines AB The ACR, the European Society of Radiology, and the International Society of Radiology held the first joint Global Summit on Radiological Quality and Safety in May 2013. The program was divided into 3 day-long themes: appropriateness of imaging, radiation protection/infrastructure, and quality and safety. Participants came from global organizations, including the International Atomic Energy Agency, the World Health Organization, and other institutions; industry and patient advocacy groups with an interest in imaging were also represented. The goal was to exchange ideas and solutions and share concerns to arrive at a better and more uniform approach to quality and safety. Participants were asked to use the information presented to develop strategies and tactics to harmonize and promote best practices worldwide. These strategies were summarized at the conclusion of the meeting. C1 [Stern, Eric J.] Univ Washington, Seattle, WA 98195 USA. [Adam, E. Jane] St George Hosp, London, England. [Bettman, Michael A.] Wake Forest Univ, Bowman Gray Sch Med, Hanover, NH USA. [Brink, James A.; Dreyer, Keith J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Frija, Guy] European Soc Radiol, Vienna, Austria. [Keefer, Raina] Amer Coll Radiol, Reston, VA USA. [Mildenberger, Peter] Univ Med Ctr, Mainz, Germany. [Remedios, Denis] Northwick Pk Hosp & Clin Res Ctr, Harrow, Middx, England. [Vock, Peter] Univ Hosp Bern, CH-3010 Bern, Switzerland. RP Stern, EJ (reprint author), Univ Washington, 1959 NE Pacific,Box 357115, Seattle, WA 98195 USA. EM estern@u.washington.edu NR 7 TC 3 Z9 3 U1 5 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD OCT PY 2014 VL 11 IS 10 BP 959 EP 967 DI 10.1016/j.jacr.2014.03.006 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AQ1FY UT WOS:000342528500011 PM 24836270 ER PT J AU Sabbisetti, VS Waikar, SS Antoine, DJ Smiles, A Wang, C Ravisankar, A Ito, K Sharma, S Ramadesikan, S Lee, M Briskin, R De Jager, PL Ngo, TT Radlinski, M Dear, JW Park, KB Betensky, R Krolewski, AS Bonventre, JV AF Sabbisetti, Venkata. S. Waikar, Sushrut S. Antoine, Daniel J. Smiles, Adam Wang, Chang Ravisankar, Abinaya Ito, Kazumi Sharma, Sahil Ramadesikan, Swetha Lee, Michelle Briskin, Rebeccah De Jager, Philip L. Ngo, Thanh Thu Radlinski, Mark Dear, James W. Park, Kevin B. Betensky, Rebecca Krolewski, Andrzej S. Bonventre, Joseph V. TI Blood Kidney Injury Molecule-1 Is a Biomarker of Acute and Chronic Kidney Injury and Predicts Progression to ESRD in Type I Diabetes SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID PROXIMAL TUBULE INJURY; ACUTE-RENAL-FAILURE; URINARY BIOMARKERS; FIBROSIS; KIM-1; QUALIFICATION; CELLS; RISK AB Currently, no blood biomarker that specifically indicates injury to the proximal tubule of the kidney has been identified. Kidney injury molecule-1 (KIM-1) is highly upregulated in proximal tubular cells following kidney injury. The ectodomain of KIM-1 is shed into the lumen, and serves as a urinary biomarker of kidney injury. We report that shed KIM-1 also serves as a blood biomarker of kidney injury. Sensitive assays to measure plasma and serum KIM-1 in mice, rats, and humans were developed and validated in the current study. Plasma KIM-1 levels increased with increasing periods of ischemia (10, 20, or 30 minutes) in mice, as early as 3 hours after reperfusion; after unilateral ureteral obstruction (day 7) in mice; and after gentamicin treatment (50 or 200 mg/kg for 10 days) in rats. In humans, plasma KIM-1 levels were higher in patients with AKI than in healthy controls or post-cardiac surgery patients without AKI (area under the curve, 0.96). In patients undergoing cardiopulmonary bypass, plasma KIM-1 levels increased within 2 days after surgery only in patients who developed AKI (P<0.01). Blood KIM-1 levels were also elevated in patients with CKD of varous etiologies. In a cohort of patients with type 1 diabetes and proteinuria, serum KIM-1 level at baseline strongly predicted rate of eGFR loss and risk of ESRD during 5-15 years of follow-up, after adjustment for baseline urinary albumin-to-creatinine ratio, eGFR, and Hb1Ac. These results identify KIM-1 as a blood biomarker that specifically reflects acute and chronic kidney injury. C1 [Sabbisetti, Venkata. S.; Waikar, Sushrut S.; Wang, Chang; Ravisankar, Abinaya; Ito, Kazumi; Sharma, Sahil; Ramadesikan, Swetha; Ngo, Thanh Thu; Radlinski, Mark; Bonventre, Joseph V.] Harvard Univ, Sch Med, Dept Med, Div Renal, Boston, MA 02115 USA. [Lee, Michelle; Briskin, Rebeccah; De Jager, Philip L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Program Translat NeuroPsychiat Genom, Boston, MA 02115 USA. [Antoine, Daniel J.; Park, Kevin B.] Univ Liverpool, Inst Translat Med, Dept Mol & Clin Pharmacol, MRC Ctr Drug Safety Sci, Liverpool L69 3BX, Merseyside, England. [Smiles, Adam; Krolewski, Andrzej S.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. [Dear, James W.] Univ Edinburgh, British Heart Fdn Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland. [Betensky, Rebecca] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Sabbisetti, VS (reprint author), Harvard Univ, Inst Med, Brigham & Womens Hosp, Room 550 576,4 Blackfan Circle, Boston, MA 02115 USA. EM vsabbisetti@partners.org; joseph_bonventre@hms.harvard.edu FU National Institutes of Health (NIH) [DK39773, DK072381, DK075941]; Gene Expression & Regulatory Networks in Human Leukocytes at the Brigham and Women's Hospital [RC2 GM093080]; Juvenile Diabetes Research Foundation [1-2008-1018]; NIH [DK041526]; CKD Biomarker Consortium [U01-DK85660]; Medical Research Council via Centre for Drug Safety Science [G0700654]; Royal Society; Wellcome Trust FX This research was supported by National Institutes of Health (NIH) grants DK39773 and DK072381 to J.V.B., DK075941 to S.S.W. Gene Expression & Regulatory Networks in Human Leukocytes at the Brigham and Women's Hospital (RC2 GM093080) to P.L.D. and Juvenile Diabetes Research Foundation research grant 1-2008-1018 and NIH grants DK041526 to A.S.K. S.S.W., & V.S. are also supported by U01-DK85660 as members of the CKD Biomarker Consortium. D.J.A. and B.K.P. would like to acknowledge the Medical Research Council (via the Centre for Drug Safety Science, grant number G0700654). D.J.A. would also like to acknowledge financial support from the Royal Society and the Wellcome Trust. NR 26 TC 56 Z9 57 U1 1 U2 16 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD OCT PY 2014 VL 25 IS 10 BP 2177 EP 2186 DI 10.1681/ASN.2013070758 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA AP9ML UT WOS:000342403800008 PM 24904085 ER PT J AU Dasgupta, D Wee, MJ Reyes, M Li, YW Simm, PJ Sharma, A Schlingmann, KP Janner, M Biggin, A Lazier, J Gessner, M Chrysis, D Tuchman, S Baluarte, HJ Levine, MA Tiosano, D Insogna, K Hanley, DA Carpenter, TO Ichikawa, S Hoppe, B Konrad, M Savendahl, L Munns, CF Lee, H Juppner, H Bergwitz, C AF Dasgupta, Debayan Wee, Mark J. Reyes, Monica Li, Yuwen Simm, Peter J. Sharma, Amita Schlingmann, Karl-Peter Janner, Marco Biggin, Andrew Lazier, Joanna Gessner, Michaela Chrysis, Dionisios Tuchman, Shamir Baluarte, H. Jorge Levine, Michael A. Tiosano, Dov Insogna, Karl Hanley, David A. Carpenter, Thomas O. Ichikawa, Shoji Hoppe, Bernd Konrad, Martin Saevendahl, Lars Munns, Craig F. Lee, Hang Jueppner, Harald Bergwitz, Clemens TI Mutations in SLC34A3/NPT2c Are Associated with Kidney Stones and Nephrocalcinosis SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID HEREDITARY HYPOPHOSPHATEMIC RICKETS; VITAMIN-D; IDIOPATHIC HYPERCALCIURIA; PHOSPHATE HOMEOSTASIS; INTRONIC DELETIONS; GENE; BONE; NEPHROLITHIASIS; REABSORPTION; METABOLISM AB Compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na+)-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH)(2) vitamin D levels, hypercalciuria, and rickets/osteomalacia. Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH). Here, we report a review of clinical and laboratory records of 133 individuals from 27 kindreds, including 5 previously unreported HHRH kindreds and two cases with IH, in which known and novel SLC34A3 mutations (c.1357delTTC [p.F453del]; c.G1369A [p.G457S]; c.367delC) were identified. Individuals with mutations affecting both SLC34A3 alleles had a significantly increased risk of kidney stone formation or medullary nephrocalcinosis, namely 46% compared with 6% observed in healthy family members carrying only the wild-type SLC34A3 allele (P=0.005) or 5.64% in the general population (P<0.001). Renal calcifications were also more frequent in het carriers (16%; P=0.003 compared with the general population) and were more likely to occur in comp/hom and het individuals with decreased serum phosphate (odds ratio [OR], 0.75, 95% confidence interval [95% CI], 0.59 to 0.96; P=0.02), decreased tubular reabsorption of phosphate (OR, 0.41; 95% CI, 0.23 to 0.72; P=0.002), and increased serum 1,25(OH)(2) vitamin D (OR, 1.22; 95% CI, 1.05 to 1.41; P=0.008). Additional studies are needed to determine whether these biochemical parameters are independent of genotype and can guide therapy to prevent nephrocalcinosis, nephrolithiasis, and potentially, CKD. C1 [Dasgupta, Debayan; Wee, Mark J.; Reyes, Monica; Li, Yuwen; Jueppner, Harald; Bergwitz, Clemens] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Sharma, Amita; Jueppner, Harald] Massachusetts Gen Hosp, Pediat Nephrol Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Simm, Peter J.; Biggin, Andrew; Munns, Craig F.] Childrens Hosp, Inst Endocrinol & Diabet, Westmead, NSW, Australia. [Simm, Peter J.; Munns, Craig F.] Univ Sydney, Discipline Pediat & Child Hlth, Sydney, NSW 2006, Australia. [Schlingmann, Karl-Peter; Konrad, Martin] Univ Childrens Hosp, Dept Gen Pediat, Munster, Germany. [Janner, Marco] Univ Childrens Hosp, Div Pediat Endocrinol Diabetol & Metab, Bern, Germany. [Lazier, Joanna] Univ Calgary, Dept Med Genet, Calgary, AB, Canada. [Gessner, Michaela; Hoppe, Bernd] Univ Hosp, Dept Pediat, Div Pediat Nephrol, Cologne, Germany. [Chrysis, Dionisios] Univ Patras, Sch Med, Dept Pediat, Div Endocrinol, GR-26110 Patras, Greece. [Tuchman, Shamir] George Washington Univ, Sch Med, Childrens Natl Med Ctr, Div Pediat Nephrol, Washington, DC USA. [Baluarte, H. Jorge] Univ Penn, Sch Med, Div Pediat Nephrol, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Levine, Michael A.] Childrens Hosp Philadelphia, Div Endocrinol & Diabet, Philadelphia, PA 19104 USA. [Tiosano, Dov] Meyer Childrens Hosp, Div Pediat Endocrinol, Haifa, Israel. [Insogna, Karl] Yale Univ, Sch Med, Dept Med, Div Endocrinol, New Haven, CT 06510 USA. [Carpenter, Thomas O.] Yale Univ, Sch Med, Dept Pediat Endocrinol, New Haven, CT 06510 USA. [Hanley, David A.] Univ Calgary, Fac Med, Dept Med, Calgary, AB, Canada. [Hanley, David A.] Univ Calgary, Fac Med, Dept Community Hlth Sci, Calgary, AB, Canada. [Hanley, David A.] Univ Calgary, Fac Med, Dept Oncol, Calgary, AB, Canada. [Ichikawa, Shoji] Indiana Univ, Sch Med, Div Endocrinol, Indianapolis, IN USA. [Saevendahl, Lars] Karolinska Inst, Dept Womens & Childrens Hlth, Pediat Endocrinol Unit, Stockholm, Sweden. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Bergwitz, C (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier Bldg 1055, Boston, MA 02114 USA. EM cbergwitz@partners.org OI Dasgupta, Debayan/0000-0002-1064-0541; Levine, Michael/0000-0003-0036-7809 FU National Institutes of Health [R01-DK46718-20, P01-DK11794]; National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [5K08-DK078361]; National Kidney Foundation; American Association for Clinical Investigation FX This work was supported by National Institutes of Health Grants R01-DK46718-20 and P01-DK11794, project IV (to H.J.), National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases Grant 5K08-DK078361 (to C.B.), Young Investigator Awards by the National Kidney Foundation, and the American Association for Clinical Investigation (C.B.). NR 48 TC 14 Z9 16 U1 0 U2 8 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD OCT PY 2014 VL 25 IS 10 BP 2366 EP 2375 DI 10.1681/ASN.2013101085 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA AP9ML UT WOS:000342403800025 PM 24700880 ER PT J AU Bromley, B Shipp, TD Lyons, J Navathe, RS Groszmann, Y Benacerraf, BR AF Bromley, Bryann Shipp, Thomas D. Lyons, Jennifer Navathe, Reshama S. Groszmann, Yvette Benacerraf, Beryl R. TI Detection of Fetal Structural Anomalies in a Basic First-Trimester Screening Program for Aneuploidy SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE early anatomic survey; fetal anomalies; first-trimester screening; nuchal translucency scan; obstetric ultrasound; sonographer ID ULTRASOUND EXAMINATION; NUCHAL TRANSLUCENCY; ABNORMALITIES; SCAN; DIAGNOSIS; ANATOMY; US AB Objectives-The purpose of this study was to determine whether first-trimester aneuploidy screening sonographyinitiallyperformed by credentialed sonographers was useful for detecting fetal anomalies between 11 and 14 weeks' gestation. Methods-We conducted a retrospective cohort study of consecutive patients referred to a private ultrasound facility between January 1, 2008, and June 30, 2012, for measurement of the nuchal translucency (NT) and crown-rump length as part of a screening protocol for aneuploidy. Patients were included if there was at least 1 live fetus with a crown-rump length between 34 and 84 mm No specific anatomic imaging protocol was followed. The presence of anomalies was based on the sonographic report and review of the medical record. The absence of anomalies was based on the report from the anatomic survey. Anomalies were categorized as lethal, major, and minor. The anomaly category and gestational age at diagnosis (<= 14 versus >14 weeks) were compared. Results-An NT scan was performed on 9692 fetuses. Anatomic surveys were done on 9077 (93.7%) of these fetuses at a mean of 18 weeks' gestation. Anomalies were detected in 180 fetuses (1.8%): SO (0.5%) at the NT scan and 130 (1.3%) at the anatomic scan. Overall, 46 of 111 fetuses (41.4%) with major or lethal anomalies were detected at the NT scan. Two suspected abnormalities at the NT scan were not present at the anatomic scan. Conclusions-First-trimester aneuploidy screening sonography initially performed by credentialed sonographers can identify a substantial proportion of major and lethal anomalies. C1 [Bromley, Bryann; Shipp, Thomas D.; Groszmann, Yvette; Benacerraf, Beryl R.] Diagnost Ultrasound Associates PC, Boston, MA USA. [Bromley, Bryann; Benacerraf, Beryl R.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Bromley, Bryann; Shipp, Thomas D.; Navathe, Reshama S.; Groszmann, Yvette; Benacerraf, Beryl R.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Bromley, Bryann; Shipp, Thomas D.; Benacerraf, Beryl R.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Lyons, Jennifer] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Navathe, Reshama S.] Harvard Vanguard Med Associates, Boston, MA USA. RP Bromley, B (reprint author), Diagnost Ultrasound Associates PC, 1 Brookline Pl,Suite 506, Brookline, MA 02445 USA. EM bbsono@aol.com NR 26 TC 13 Z9 13 U1 0 U2 2 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 EI 1550-9613 J9 J ULTRAS MED JI J. Ultrasound Med. PD OCT PY 2014 VL 33 IS 10 BP 1737 EP 1745 DI 10.7863/tiltra.33.10.1737 PG 9 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA AQ0MP UT WOS:000342477700003 PM 25253819 ER PT J AU Bromley, B Shipp, TD Lyons, J Groszmann, Y Navathe, RS Benacerraf, BR AF Bromley, Bryann Shipp, Thomas D. Lyons, Jennifer Groszmann, Yvette Navathe, Reshama S. Benacerraf, Beryl R. TI What Is the Importance of Second-Trimester "Soft Markers" for Trisomy 21 After an 11- to 14-Week Aneuploidy Screening Scan? SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE aneuploidy; first-trimester screening; nuchal fold; obstetric ultrasound; soft markers ID DOWN-SYNDROME; GENETIC SONOGRAPHY; TRIMESTER AB Objectives-The purpose of this study was to evaluate the importance of second-trimester "soft markers" for trisomy 21 after an 11-to 14-week aneuploidy screening scan. Methods-We conducted a retrospective cohort study of consecutive patients referred for measurement of the nuchal translucency (NT) as part of a screening protocol for aneuploidy. Patients who returned for an anatomic survey between 16 and 20 weeks' gestation were evaluated. The sonographic markers and anomalies associated with the detection of trisomy 21 in the second trimester were analyzed. Results-There were 42 fetuses (0.4%) with trisomy 21 identified in the study cohort of 9692 patients. Trisomy 21 was suspected at the NT scan in 28 fetuses (67%) and at the second-trimester anatomic survey in 14 (33%). In fetuses first suspected of having trisomy 21 in the second trimester, 9 of 14 had normal anatomic survey results, and 5 of 14 had congenital malformations. All 14 fetuses had soft markers for aneuploidy. A thickened nuchal fold was identified in 5 of 9 fetuses with trisomy 21 and normal anatomic survey results, all of whom had an NT of less than 3.0 mm at the initial screening scan. Conclusions-Second-trimester soft markers, especially a thickened nuchal fold, remain important observations in the detection of trisomy 21 by sonography among fetuses who have had first-trimester sonographic screening for aneuploidy. C1 [Bromley, Bryann; Shipp, Thomas D.; Groszmann, Yvette; Benacerraf, Beryl R.] Diagnost Ultrasound Associates PC, Boston, MA USA. [Bromley, Bryann; Benacerraf, Beryl R.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Bromley, Bryann; Shipp, Thomas D.; Groszmann, Yvette; Navathe, Reshama S.; Benacerraf, Beryl R.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Bromley, Bryann; Shipp, Thomas D.; Benacerraf, Beryl R.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Lyons, Jennifer] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Navathe, Reshama S.] Harvard Vanguard Med Associates, Boston, MA USA. RP Bromley, B (reprint author), Diagnost Ultrasound Associates PC, 1 Brookline Pl,Suite 506, Brookline, MA 02445 USA. EM bbsono@aol.com NR 17 TC 5 Z9 6 U1 0 U2 5 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 EI 1550-9613 J9 J ULTRAS MED JI J. Ultrasound Med. PD OCT PY 2014 VL 33 IS 10 BP 1747 EP 1752 DI 10.7863/ultra.33.10.1747 PG 6 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA AQ0MP UT WOS:000342477700004 PM 25253820 ER PT J AU Lewiss, RE Hayden, GE Murray, A Liu, YT Panebianco, N Liteplo, AS AF Lewiss, Resa E. Hayden, Geoffrey E. Murray, Alice Liu, Yiju Teresa Panebianco, Nova Liteplo, Andrew S. TI SonoGames An Innovative Approach to Emergency Ultrasound Education SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE clinical sonography; medical education; point-of-care ultrasound; SonoGames; ultrasound education ID SIMULATION; MEDICINE AB SonoGames was created by the Academy of Emergency Ultrasound for the 2012 annual meeting of the Society for Academic Emergency Medicine. The assessment of resident knowledge and of the performance of point-of-care ultrasound examinations is an integral component of ultrasound education and is required in emergency medicine residency training. With that in mind, game organizers sought to assess and improve emergency medicine residents' point-of-care ultrasound knowledge, hands-on skills, and integration of knowledge into clinical decision making. SonoGames is an annual 4-hour competition consisting of 3 rounds. In this article, we provide a description of SonoGames and provide a blueprint for an effective and successful educational event. C1 [Lewiss, Resa E.] St Lukes Roosevelt Hosp, Dept Emergency Med, New York, NY 10025 USA. [Hayden, Geoffrey E.] Med Univ S Carolina, Div Emergency Med, Charleston, SC 29425 USA. [Murray, Alice] Boston Med Ctr, Div Pediat Emergency Med, Boston, MA USA. [Liu, Yiju Teresa] George Washington Univ, Dept Emergency Med, Washington, DC USA. [Panebianco, Nova] Hosp Univ Penn, Dept Emergency Med, Philadelphia, PA 19104 USA. [Liteplo, Andrew S.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Lewiss, RE (reprint author), St Lukes Roosevelt Hosp, Dept Emergency Med, 1111 Amsterdam Ave, New York, NY 10025 USA. NR 11 TC 1 Z9 1 U1 1 U2 2 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 EI 1550-9613 J9 J ULTRAS MED JI J. Ultrasound Med. PD OCT PY 2014 VL 33 IS 10 BP 1843 EP 1849 DI 10.7863/ultra.33.10.1843 PG 7 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA AQ0MP UT WOS:000342477700016 PM 25253832 ER PT J AU Kwan, SW Mortell, KE Hippe, DS Brunner, MC AF Kwan, Sharon W. Mortell, Kelly E. Hippe, Daniel S. Brunner, Michael C. TI An Economic Analysis of Sublobar Resection versus Thermal Ablation for Early-Stage Non-Small-Cell Lung Cancer SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID PROSTATE-CANCER; SEER-MEDICARE; COST; SURGERY; CARE; COMORBIDITY; SURVIVAL; IMPACT AB Purpose:. To compare medical costs for a matched-pair cohort of Medicare patients with early-stage non-small,cell lung cancer (NSCLC) Who underwent treatment with sublobar resection or thermal ablation. Materials and Methods: Patients at least 65 years of age with stage IA/IB NSCLC treated with sublobar resection or thermal ablation, front 2007 to 2009 were identified from Surveillance, Epidemiology, and End Results/Medicare-linked data and matched by propensity scores. The primary outcome of interest, cost from the payees perspective, was derived from Medicare claims data A partitioned inverse probability weighted estimator was used to calculate mean and Median treatment-related costs and costs at 1, 3, 12, 18, and 24 months after treatment. Baseline characteristics, Kaplan-Meier survival curie, and calculated cost variables were compared between. the two groups. Results : The final matched cohort of 128 patients had similar baseline Characteristics and overall survival (P = .52). Patients. who underwent ablation had, significantly lower treatment-related costs than those who underwent sublobar resection (P < .001). The difference in median treatment-related cost was $16,105. At 1, month, 3 months, and 12 months after treatment, cumulative costs remained significantly different (P <= .011). Lower cost associated with ablations performed in the outpatient setting was a major contributor to the differences between the two treatment modalities, although inpatient ablations maintained a small cost advantage over sublobar resections. Conclusions : Among matched Medicare patients with stage I NSCLC, thermal ablation resulted in significantly lower treatment-related costs and cumulative medical costs 1 month, 3 months, and 12 months after treatment compared with sublobar resection. C1 [Kwan, Sharon W.; Hippe, Daniel S.] Univ Washington, Med Ctr, Dept Radiol, Seattle, WA 98195 USA. [Kwan, Sharon W.] Univ Washington, Comparat Effectiveness Cost & Outcomes Res Ctr, Seattle, WA 98195 USA. [Mortell, Kelly E.] Univ Hosp Case Med Ctr, Dept Radiol, Cleveland, OH USA. [Brunner, Michael C.] William S Middleton Mem Vet Adm Med Ctr, Dept Radiol, Madison, WI USA. Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. RP Kwan, SW (reprint author), Univ Washington, Med Ctr, Dept Radiol, 1959 NE Pacific St,Suite 357115, Seattle, WA 98195 USA. EM shakwan@uw.edu FU Society of Interventional Radiology (SIR); SIR Foundation FX The authors thank William Kreuter, MPA, for his programming assistance and Robert White, MHS, for his general support. This study was partially supported by the Society of Interventional Radiology (SIR) and the SIR Foundation. This study used the linked Surveillance, Epidemiology, and End Results (SEER)/Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the Applied Research Program of the National Cancer Institute, the Office of Research, Development, and Information, Centers for Medicare and Medicaid Services, Information Management Services, and the SEER Program tumor registries in the creation of the SEER/Medicare database. NR 21 TC 6 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD OCT PY 2014 VL 25 IS 10 BP 1558 EP 1564 DI 10.1016/j.jvir.2014.07.002 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA AQ0OQ UT WOS:000342483000010 PM 25130308 ER PT J AU Deipolyi, AR Iafrate, AJ Zhu, AX Ergul, EA Ganguli, S Oklu, R AF Deipolyi, Amy R. Iafrate, A. John Zhu, Andrew X. Ergul, Emel A. Ganguli, Suvranu Oklu, Rahmi TI High Lung Shunt Fraction in Colorectal Liver Tumors Is Associated with Distant Metastasis and Decreased Survival SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID HEPATOCELLULAR-CARCINOMA; CANCER AB Purpose: To assess how intratumoral shunting relates to liver metastasis and to clinical outcome. Materials and Methods: Lung shunt fraction (LSF) was calculated from macroaggregated albumin scan after transcatheter injection of radioactive particles in 62 patients with colorectal cancer, and liver metastases evaluated for :selective internal radiation therapy (SIRT) from May 2007 to August 2012. Assessment was :performed Of how LSF, liver tumor burden, and systemic chemotherapy relate to survival and the presence of lung metastases. LSF and tumor burden were also assessed in a subset of patients who underwent genetic profiling with SNaPshot analysis. Results: Patients with higher LSF were more likely to have lung metastases and decreased survival, Whereas, tumor burden was not associated with these outcomes. Patients with genetic, mutations had significantly higher LSF than patients with no mutations. Patients who received chemotherapy before SIRT and had tow LSF had the longest Survival after SIRT. Conclusions: LSF may be a more robust marker of metastasis than tumor size. increased LSF secondary to vascular shunting within liver metastasis is an indicator of distant lesions and is associated with decreased survival after SIRT. Intratumoral shunting May provide a conduit for circulating tumor cells to access More remote organs, bypassing filtration by liver parenchyma, and may be an important factor in metastasis from colorectal Cancer. C1 [Deipolyi, Amy R.; Ergul, Emel A.; Ganguli, Suvranu; Oklu, Rahmi] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Intervent Radiol, Boston, MA 02114 USA. [Iafrate, A. John] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Mol Pathol, Boston, MA 02114 USA. [Zhu, Andrew X.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Hematol Oncol,Ctr Liver Canc, Boston, MA 02114 USA. RP Oklu, R (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Intervent Radiol, 55 Fruit St,290 Gray Bigelow, Boston, MA 02114 USA. EM roklu@mgh.harvard.edu OI Deipolyi, Amy/0000-0003-3144-386X FU National Institutes of Health [RO3 CA172738]; Department of Radiology, Massachusetts General Hospital FX This study was supported by National Institutes of Health grant RO3 CA172738 (R.O.) and the Department of Radiology, Massachusetts General Hospital. NR 15 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD OCT PY 2014 VL 25 IS 10 BP 1604 EP 1608 DI 10.1016/j.jvir.2014.06.019 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA AQ0OQ UT WOS:000342483000016 PM 25086965 ER PT J AU Aparici, CM Win, AZ AF Aparici, Carina Mari Win, Aung Zaw TI Use of Positron Emission Tomography/CT to Perform Biopsy of a Mesenteric Mass SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Editorial Material C1 [Aparici, Carina Mari] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. [Win, Aung Zaw] San Francisco VA Med Ctr, Dept Radiol, San Francisco, CA 94121 USA. RP Win, AZ (reprint author), San Francisco VA Med Ctr, Dept Radiol, 4150 Clement, San Francisco, CA 94121 USA. EM aungzwin@gmail.com 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 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD OCT PY 2014 VL 25 IS 10 BP 1609 EP 1609 DI 10.1016/j.jvir.2014.05.017 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA AQ0OQ UT WOS:000342483000017 PM 25255947 ER PT J AU Lezcano, C Kleffel, S Lee, NY Larson, AR Zhan, Q DoRosario, A Wang, LC Schatton, T Murphy, GF AF Lezcano, Cecilia Kleffel, Sonja Lee, Nayoung Larson, Allison R. Zhan, Qian DoRosario, Andrew Wang, Linda C. Schatton, Tobias Murphy, George F. TI Merkel cell carcinoma expresses vasculogenic mimicry: demonstration in patients and experimental manipulation in xenografts SO LABORATORY INVESTIGATION LA English DT Article ID HUMAN-MALIGNANT MELANOMA; STEM-LIKE CELLS; LUNG-CANCER; THERAPEUTIC IMPLICATIONS; ABERRANT EXPRESSION; TUMOR ANGIOGENESIS; COLORECTAL-CANCER; CHANNEL FORMATION; PROGNOSTIC-FACTOR; IN-VIVO AB Merkel cell carcinoma (MCC) is a highly virulent cutaneous neoplasm that, like melanoma, is a frequent cause of patient morbidity and mortality. The cellular mechanisms responsible for the aggressive behavior of MCC remain unknown. Vasculogenic mimicry (VM) is a phenomenon associated with cancer virulence, including in melanoma, whereby anastomosing laminin networks form in association with tumor cells that express certain endothelial genes. To determine whether VM is a factor in MCC, we employed a relevant xenograft model using two independent human MCC lines. Experimentally induced tumors were remarkably similar histologically to patient MCC, and both contained laminin networks associated with vascular endothelial-cadherin (CD144) and vascular endothelial growth factor receptor 1, as well as Nodal expression typical of VM in melanoma. Moreover, two established chemotherapeutic agents utilized for human MCC, etoposide and carboplatin, induced necrosis in xenografts on systemic administration while enriching for laminin networks in apparently resistant viable tumor regions that persisted. These findings for the first time establish VM-like laminin networks as a biomarker in MCC, demonstrate the experimental utility of the MCC xenograft model, and suggest that VM-rich regions of MCC may be refractory to conventional chemotherapeutic agents. C1 [Lezcano, Cecilia] Univ Pittsburgh, Med Ctr, Dept Pathol, Pittsburgh, PA USA. [Kleffel, Sonja; Lee, Nayoung; Larson, Allison R.; Schatton, Tobias] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Kleffel, Sonja; Lee, Nayoung; Larson, Allison R.; Zhan, Qian; DoRosario, Andrew; Schatton, Tobias; Murphy, George F.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Zhan, Qian; Murphy, George F.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [DoRosario, Andrew] Dana Faber Brigham & Womens Canc Ctr, Ctr Cutaneous Oncol, Boston, MA USA. [Wang, Linda C.] Inst Canc Care, Mercy Med Ctr, Baltimore, MD USA. [Schatton, Tobias] Childrens Hosp, Transplantat Res Ctr, Boston, MA 02115 USA. RP Murphy, GF (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, 221 Longwood Ave,EBRC Suite 401, Boston, MA 02115 USA. EM gmurphy@rics.bwh.harvard.edu RI Larson, Allison/N-4263-2015 OI Larson, Allison/0000-0001-8534-7078 FU Brigham and Women's Hospital Department of Dermatology; Dermatology Foundation; [NIH-P50 CA93683]; [R01 CA58467] FX NIH-P50 CA93683 and R01 CA58467 (GFM) and Brigham and Women's Hospital Department of Dermatology Funding for Young Investigators (TS) supported the present work. IS is the recipient of a Research Career Development Award from the Dermatology Foundation. NR 52 TC 6 Z9 6 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD OCT PY 2014 VL 94 IS 10 BP 1092 EP 1102 DI 10.1038/labinvest.2014.99 PG 11 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA AQ0NW UT WOS:000342481000003 PM 25111691 ER PT J AU Min, Z Baddley, JW AF Min, Zaw Baddley, John W. TI Mollaret's meningitis SO LANCET INFECTIOUS DISEASES LA English DT Editorial Material C1 [Min, Zaw] Allegheny Gen Hosp, Dept Med, Div Infect Dis, Allegheny Hlth Network, Pittsburgh, PA 15212 USA. [Baddley, John W.] Univ Alabama Birmingham, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. [Baddley, John W.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Min, Z (reprint author), Allegheny Gen Hosp, Dept Med, Div Infect Dis, Allegheny Hlth Network, 420 East North Ave,East Wing,Suite 407, Pittsburgh, PA 15212 USA. EM zmin@wpahs.org NR 0 TC 0 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD OCT PY 2014 VL 14 IS 10 BP 1022 EP 1022 PG 1 WC Infectious Diseases SC Infectious Diseases GA AP7HY UT WOS:000342249600043 PM 25253408 ER PT J AU Eichner, C Wald, LL Setsompop, K AF Eichner, Cornelius Wald, Lawrence L. Setsompop, Kawin TI A Low Power Radiofrequency Pulse for Simultaneous Multislice Excitation and Refocusing SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE SMS; blipped CAIPI; Multiband; PINS; RF pulse design ID SELECTIVE EXCITATION; SLICES PINS; ECHO; NUMBER AB PurposeSimultaneous multislice (SMS) acquisition enables increased temporal efficiency of MRI. Nonetheless, MultiBand (MB) radiofrequency (RF) pulses used for SMS can cause large energy deposition. Power independent of number of slices (PINS) pulses reduce RF power at cost of reduced bandwidth and increased off-resonance dependency. This work improves PINS design to further reduce energy deposition, off-resonance dependency and peak power. Theory and MethodsModifying the shape of MB RF-pulses allows for mixing with PINS excitation, creating a new pulse type with reduced energy deposition and SMS excitation characteristics. Bloch Simulations were used to evaluate excitation and off-resonance behavior of this MultiPINS pulse. In this work, MultiPINS was used for whole-brain MB=3 acquisition of high angular and spatial resolution diffusion MRI at 7 Tesla in 3 min. ResultsBy using MultiPINS, energy transmission and peak power for SMS imaging can be significantly reduced compared with PINS and MB pulses. For MB=3 acquisition in this work, MultiPINS reduces energy transmission by up to approximate to 50% compared with PINS pulses. The energy reduction was traded off to shorten the MultiPINS pulse, yielding higher signal at off-resonances for spin-echo acquisitions. ConclusionMB and PINS pulses can be combined to enable low energy and peak power SMS acquisition. Magn Reson Med 72:949-958, 2014. (c) 2014 Wiley Periodicals, Inc. C1 [Eichner, Cornelius; Wald, Lawrence L.; Setsompop, Kawin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr, Boston, MA USA. [Eichner, Cornelius] Max Planck Inst Human Cognit & Brain Sci, Leipzig, Germany. RP Eichner, C (reprint author), Athinoula A Martinos Ctr, 149 13th St, Charlestown, MA 02129 USA. EM ceichner@nmr.mgh.harvard.edu RI Setsompop, Kawin/P-1464-2014; Wald, Lawrence/D-4151-2009 OI Setsompop, Kawin/0000-0003-0455-7634; FU NIH Human Connectome Project [NIH U01MH093765, NIBIB R00EB012107, NIBIB R01EB006847, NCRR P41RR14075] FX Grant sponsor: NIH Human Connectome Project; Grant numbers: NIH U01MH093765, NIBIB R00EB012107, NIBIB R01EB006847, NCRR P41RR14075. NR 21 TC 12 Z9 12 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD OCT PY 2014 VL 72 IS 4 BP 949 EP 958 DI 10.1002/mrm.25389 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AP8PZ UT WOS:000342342300007 PM 25103999 ER PT J AU Muir, ER Cardenas, D Huang, SL Roby, J Li, G Duong, TQ AF Muir, Eric R. Cardenas, Damon Huang, Shiliang Roby, John Li, Guang Duong, Timothy Q. TI MRI Under Hyperbaric Air and Oxygen: Effects on Local Magnetic Field and Relaxation Times SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE oxygen therapy; BOLD; magnetic susceptibility; T1; T2; T2*; relaxation time constants ID CEREBRAL-BLOOD-FLOW; PARTIAL-PRESSURE; BRAIN; ARTIFACTS; HYPEROXIA; FMRI; SUSCEPTIBILITY; HYPERCAPNIA; HYPOXIA; TENSION AB PurposeHyperbaric oxygen therapy has shown efficacies in the treatment of a number of diseases. The goal of this study was to develop a rodent hyperbaric chamber for MRI studies and to investigate the effects of hyperbaric air and hyperbaric oxygen on local magnetic field (B-0) and MRI relaxation parameters in the rat brain. MethodsA hyperbaric chamber, constructed to fit inside an animal MRI scanner, was pressurized with air to four atmospheres, while oxygen was delivered locally via nose cone. B-0, T-2, T-2*, and T-1 maps in the rat brain were evaluated under normobaric air, hyperbaric air, and hyperbaric oxygen at 7T. ResultsUnder hyperbaric oxygen, images exhibited artifacts and temporal instability, attributable to fluctuating oxygen concentration from air and oxygen mixing near the imaging region. Physically shielding the imaging region from fluctuating oxygen concentration resolved the problems. With increasing oxygen at hyperbaric pressure, B-0 was shifted downfield with increased inhomogeneity near the ear canals and nose. Brain T-2 and T-2* were lengthened, and T-1 was shortened. ConclusionThis study establishes the means to perform MRI on rodents under hyperbaric conditions. Hyperbaric air and hyperbaric oxygen have significant effects on B-0 and tissue relaxation parameters compared with normobaric air. Magn Reson Med 72:1176-1181, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Muir, Eric R.; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Ophthalmol, San Antonio, TX 78229 USA. [Muir, Eric R.; Cardenas, Damon; Huang, Shiliang; Roby, John; Li, Guang; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Li, Guang; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Cardenas, Damon] Univ Texas Hlth Sci Ctr San Antonio, Dept Biomed Engn, San Antonio, TX 78229 USA. [Duong, Timothy Q.] Dept Vet Affairs, South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Duong, TQ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. EM duongt@uthscsa.edu FU National Institutes of Health [R01 NS45879, T32 HL007446] FX Grant sponsor: National Institutes of Health; Grant numbers: R01 NS45879 and T32 HL007446. NR 21 TC 5 Z9 5 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD OCT PY 2014 VL 72 IS 4 BP 1176 EP 1181 DI 10.1002/mrm.25027 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AP8PZ UT WOS:000342342300030 PM 24243603 ER PT J AU Harris, CT Handler, WB Araya, Y Martinez-Santiesteban, F Alford, JK Dalrymple, B Van Sas, F Chronik, BA Scholl, TJ AF Harris, Chad T. Handler, William B. Araya, Yonathan Martinez-Santiesteban, Francisco Alford, Jamu K. Dalrymple, Brian Van Sas, Frank Chronik, Blaine A. Scholl, Timothy J. TI Development and Optimization of Hardware for Delta Relaxation Enhanced MRI SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE coil; molecular imaging; MRI; relaxation; eddy-current ID CONTRAST AGENTS AB PurposeDelta relaxation enhanced magnetic resonance (dreMR) imaging requires an auxiliary B-0 electromagnet capable of shifting the main magnetic field within a clinical 1.5 Tesla (T) MR system. In this work, the main causes of interaction between an actively shielded, insertable resistive B-0 electromagnet and a 1.5T superconducting system are systematically identified and mitigated. MethodsThe effects of nonideal fabrication of the field-shifting magnet are taken into consideration through careful measurement during winding and improved accuracy in the design of the associated active shield. The shielding performance of the resultant electromagnet is compared against a previously built system in which the shield design was based on an ideal primary coil model. Hardware and software approaches implemented to eliminate residual image artifacts are presented in detail. ResultsThe eddy currents produced by the newly constructed dreMR system are shown to have a significantly smaller long-time-constant component, consistent with the hypothesis that less energy is deposited into the cryostat of the MR system. ConclusionWith active compensation, the dreMR imaging system is capable of 0.22T field shifts within a clinical 1.5T MRI with no significant residual eddy-current fields. Magn Reson Med 72:1182-1190, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Harris, Chad T.; Handler, William B.; Araya, Yonathan; Dalrymple, Brian; Van Sas, Frank; Chronik, Blaine A.; Scholl, Timothy J.] Univ Western Ontario, London, ON N6A 5C1, Canada. [Martinez-Santiesteban, Francisco; Chronik, Blaine A.; Scholl, Timothy J.] Robarts Res Inst, Imaging Res Labs, London, ON N6A 5C1, Canada. [Alford, Jamu K.] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Alford, Jamu K.] Harvard Univ, Sch Med, Charlestown, MA USA. RP Scholl, TJ (reprint author), Univ Western Ontario, Dept Med Biophys, London, ON N6A 5C1, Canada. EM scholl@uwo.ca RI Scholl, Timothy/I-6178-2012; Chronik, Blaine/M-2802-2013 OI Scholl, Timothy/0000-0002-0807-363X; FU Ontario Institute for Cancer Research, Smarter Imaging Program; Natural Sciences and Engineering Research Council FX Grant sponsor: The Ontario Institute for Cancer Research, Smarter Imaging Program; Grant sponsor: The Natural Sciences and Engineering Research Council. NR 14 TC 0 Z9 0 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD OCT PY 2014 VL 72 IS 4 BP 1182 EP 1190 DI 10.1002/mrm.25014 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AP8PZ UT WOS:000342342300031 PM 24407990 ER PT J AU Hassett, MJ Ritzwoller, DP Taback, N Carroll, N Cronin, AM Ting, GV Schrag, D Warren, JL Hornbrook, MC Weeks, JC AF Hassett, Michael J. Ritzwoller, Debra P. Taback, Nathan Carroll, Nikki Cronin, Angel M. Ting, Gladys V. Schrag, Deb Warren, Joan L. Hornbrook, Mark C. Weeks, Jane C. TI Validating Billing/Encounter Codes as Indicators of Lung, Colorectal, Breast, and Prostate Cancer Recurrence Using 2 Large Contemporary Cohorts SO MEDICAL CARE LA English DT Article DE cancer; recurrence; administrative data; applied methods ID SEER-MEDICARE DATA; RACIAL-DIFFERENCES; FREE SURVIVAL; OLDER WOMEN; STAGE; COMORBIDITY; POPULATION; OUTCOMES; SURGERY; THERAPY AB Background: A substantial proportion of cancer-related mortality is attributable to recurrent, not de novo metastatic disease, yet we know relatively little about these patients. To fill this gap, investigators often use administrative codes for secondary malignant neoplasm or chemotherapy to identify recurrent cases in population-based datasets. However, these algorithms have not been validated in large, contemporary, routine care cohorts. Objective: To evaluate the validity of secondary malignant neoplasm and chemotherapy codes as indicators of recurrence after definitive local therapy for stage I-III lung, colorectal, breast, and prostate cancer. Research Design, Subjects, and Measures: We assessed the sensitivity, specificity, and positive predictive value (PPV) of these codes 14 and 60 months after diagnosis using 2 administrative datasets linked with gold-standard recurrence status information: CanCORS/Medicare (diagnoses 2003-2005) and HMO/Cancer Research Network (diagnoses 2000-2005). Results: We identified 929 CanCORS/Medicare patients and 5298 HMO/CRN patients. Sensitivity, specificity, and PPV ranged widely depending on which codes were included and the type of cancer. For patients with lung, colorectal, and breast cancer, the combination of secondary malignant neoplasm and chemotherapy codes was the most sensitive (75%-85%); no code-set was highly sensitive and highly specific. For prostate cancer, no code-set offered even moderate sensitivity (<= 19%). Conclusions: Secondary malignant neoplasm and chemotherapy codes could not identify recurrent cancer without some risk of misclassification. Findings based on existing algorithms should be interpreted with caution. More work is needed to develop a valid algorithm that can be used to characterize outcomes and define patient cohorts for comparative effectiveness research studies. C1 [Hassett, Michael J.; Schrag, Deb; Weeks, Jane C.] Dana Farber Canc Inst, Dept Med Oncol, Ctr Outcomes & Policy Res, Boston, MA 02215 USA. [Hassett, Michael J.; Schrag, Deb; Weeks, Jane C.] Harvard Univ, Sch Med, Boston, MA USA. [Ritzwoller, Debra P.; Carroll, Nikki] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. [Taback, Nathan] Univ Toronto, Div Biostat, Toronto, ON, Canada. [Cronin, Angel M.; Ting, Gladys V.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Warren, Joan L.] NCI, Bethesda, MD 20892 USA. [Hornbrook, Mark C.] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR USA. RP Hassett, MJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Ctr Outcomes & Policy Res, 450 Brookline Ave, Boston, MA 02215 USA. EM michael_hassett@dfci.harvard.edu FU National Cancer Institute [RC2 CA148185-01]; NCI (Cancer Research Network) [U19 CA79689]; American Society of Clinical Oncology; Susan G. Komen for the Cure; National Cancer Institute (NCI) [U01 CA093344]; Dana-Farber Cancer Institute/Cancer Research Network [U01 CA093332]; Harvard Medical School/Northern California Cancer Center [U01 CA093324]; University of Iowa [U01 CA01013]; University of North Carolina [U01 CA093326]; Department of Veterans Affairs [VA HSRD CRS 02 164] FX Supported by a grant from the National Cancer Institute (RC2 CA148185-01 to J.C.W. and D. P. R.) and an NCI cooperative agreement (U19 CA79689, Cancer Research Network). The American Society of Clinical Oncology (Career Development Award) and Susan G. Komen for the Cure (Career Catalyst Award) provided salary support to M.J.H. The work of the CanCORS consortium was supported by grants from the National Cancer Institute (NCI) to the Statistical Coordinating Center (U01 CA093344) and to the Primary Data Collection and Research Centers (Dana-Farber Cancer Institute/Cancer Research Network U01 CA093332; Harvard Medical School/Northern California Cancer Center U01 CA093324; University of Iowa U01 CA01013; University of North Carolina U01 CA093326); and by a Department of Veterans Affairs grant to the Durham VA Medical Center VA HSRD CRS 02 164. NR 23 TC 14 Z9 14 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD OCT PY 2014 VL 52 IS 10 BP E65 EP E73 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AP9CK UT WOS:000342375800001 PM 23222531 ER PT J AU Rathi, Y Michailovich, O Laun, F Setsompop, K Grant, PE Westin, CF AF Rathi, Y. Michailovich, O. Laun, F. Setsompop, K. Grant, P. E. Westin, C. -F. TI Multi-shell diffusion signal recovery from sparse measurements SO MEDICAL IMAGE ANALYSIS LA English DT Article DE Diffusion MRI; Compressed sensing; Diffusion spectrum imaging; Diffusion propagator; Kurtosis ID WATER DIFFUSION; WHITE-MATTER; HUMAN BRAIN; MRI; RECONSTRUCTION; COMPUTATION; APPROXIMATION; DISTRIBUTIONS; MINIMIZATION; ARCHITECTURE AB For accurate estimation of the ensemble average diffusion propagator (EAP), traditional multi-shell diffusion imaging (MSDI) approaches require acquisition of diffusion signals for a range of b-values. However, this makes the acquisition time too long for several types of patients, making it difficult to use in a clinical setting. In this work, we propose a new method for the reconstruction of diffusion signals in the entire q-space from highly undersampled sets of MSDI data, thus reducing the scan time significantly. In particular, to sparsely represent the diffusion signal over multiple q-shells, we propose a novel extension to the framework of spherical ridgelets by accurately modeling the monotonically decreasing radial component of the diffusion signal. Further, we enforce the reconstructed signal to have smooth spatial regularity in the brain, by minimizing the total variation (TV) norm. We combine these requirements into a novel cost function and derive an optimal solution using the Alternating Directions Method of Multipliers (ADMM) algorithm. We use a physical phantom data set with known fiber crossing angle of 45 degrees to determine the optimal number of measurements (gradient directions and b-values) needed for accurate signal recovery. We compare our technique with a state-of-the-art sparse reconstruction method (i.e., the SHORE method of Cheng et al. (2010)) in terms of angular error in estimating the crossing angle, incorrect number of peaks detected, normalized mean squared error in signal recovery as well as error in estimating the return-to-origin probability (RTOP). Finally, we also demonstrate the behavior of the proposed technique on human in vivo data sets. Based on these experiments, we conclude that using the proposed algorithm, at least 60 measurements (spread over three b-value shells) are needed for proper recovery of MSDI data in the entire q-space. (C) 2014 Elsevier B.V. All rights reserved. C1 [Rathi, Y.; Westin, C. -F.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Michailovich, O.] Univ Waterloo, Dept Elect Engn, Waterloo, ON N2L 3G1, Canada. [Grant, P. E.] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA USA. [Laun, F.] German Canc Res Ctr, Dept Med Phys Radiol, Heidelberg, Germany. [Setsompop, K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Rathi, Y (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. EM yogesh@bwh.harvard.edu RI Setsompop, Kawin/P-1464-2014; Laun, Frederik/O-4810-2016 OI Setsompop, Kawin/0000-0003-0455-7634; Laun, Frederik/0000-0002-9269-5609 FU NIH [R01MH097979, R01MH074794, P41RR013218, P41EB015902]; Swedish research Grant [VR 2012-3682] FX This work has been supported by NIH Grants: R01MH097979 (Rathi), R01MH074794 (Westin), P41RR013218, P41EB015902 (Kikinis, Core PI: Westin), and Swedish research Grant VR 2012-3682 (Westin). NR 57 TC 8 Z9 8 U1 2 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1361-8415 EI 1361-8423 J9 MED IMAGE ANAL JI Med. Image Anal. PD OCT PY 2014 VL 18 IS 7 BP 1143 EP 1156 DI 10.1016/j.media.2014.06.003 PG 14 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AP7KM UT WOS:000342256200016 PM 25047866 ER PT J AU Panagiotou, G Mu, L Na, B Mukamal, KJ Mantzoros, CS AF Panagiotou, Grigorios Mu, Lin Na, Brian Mukamal, Kenneth J. Mantzoros, Christos S. TI Circulating irisin, omentin-1, and lipoprotein subparticles in adults at higher cardiovascular risk SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article DE Fibronectin type III domain containing 5; Myokine; Atherosclerosis; Metabolic syndrome; Longitudinal biomarker ID TYPE-2 DIABETES-MELLITUS; SLEEP QUALITY INDEX; ADIPOSE-TISSUE; INSULIN-RESISTANCE; ENDOTHELIAL-CELLS; SKELETAL-MUSCLE; MESSENGER-RNA; WEIGHT-LOSS; EXERCISE; DISEASE AB Objective. Muscle and fat are now recognized as metabolism-regulating endocrine organs. However, muscle and adipocyte-derived novel cytokines such as irisin and omentin-1 remain understudied in relation to metabolic biomarkers that are associated with cardiovascular risk. Subjects and methods. Thirty-nine subjects with mean (+/- SD) BMI of 29.2 +/- 5.4 kg/m(2) and either diabetes or two other cardiovascular risk factors were enrolled in a 6-month randomized trial of low-dose ethanol. We examined cross-sectional data at baseline, 3-month, and 6-month visits to assess (1) within-person stability of novel cytokines (irisin, omentin-1, visfatin, resistin, and soluble tumor necrosis factor receptor II) and (2) their associations with metabolic parameters, particularly lipoprotein subparticle profile. Results. Repeated measures of irisin and omentin-1 were highly correlated, with intra-class correlations of 0.84 (95% CI: 0.74, 0.91; P < 0.001) and 0.81 (0.70, 0.89; P < 0.001), respectively. Irisin was negatively correlated with omentin-1 (7.4% irisin decrease per a 1-SD increment in omentin-1; 95% CI: 0.5%, 13.9%; P = 0.04). In models adjusted for age, sex, and race, irisin was negatively associated with HDL cholesterol (7.3% decrease per a 10 mg/dL increment; 1.0%, 13.3%; P = 0.02) and large HDL particles (15.5% decrease per a 1-SD or 3.5-mu mol/L increment; 5.2%, 24.7%; P = 0.005). Omentin-1 Was positively associated with mean VLDL size (3.8% increase per a 1-SD increment; 0.06%, 7.8%; P = 0.05). Adjustment for alcohol intervention, BMI, and other cytokines did not materially affect these associations. Conclusions. Irisin and omentin-1 are stable within-person, inversely associated with each other, and closely related to lipoprotein profile. These molecules may be promising markers for cardiovascular risk. (C) 2014 Elsevier Inc. All rights reserved. C1 [Panagiotou, Grigorios; Mantzoros, Christos S.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Mu, Lin; Na, Brian; Mukamal, Kenneth J.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Mantzoros, Christos S.] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA 02130 USA. RP Mukamal, KJ (reprint author), Beth Israel Deaconess Med Ctr, 1309 Beacon St,2nd Floor, Brookline, MA 02446 USA. EM kmukamal@bidmc.harvard.edu OI Panagiotou, Grigorios/0000-0003-0690-1478 FU National Institute of Diabetes and Digestive and Kidney Diseases; Clinical Science Research and Development Service of the VA Office of Research and Development [1I01CX000422-01A1]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Research Resources) [8UL1TR000170-05]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [8UL1TR000170-05]; Harvard University and its affiliated academic health care centers; [R21AA016110] FX The Mantzoros Laboratory is supported by the National Institute of Diabetes and Digestive and Kidney Diseases and Award 1I01CX000422-01A1 from the Clinical Science Research and Development Service of the VA Office of Research and Development. This project was also supported with grant R21AA016110 (Mukamal) and Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health 8UL1TR000170-05 and financial contributions from Harvard University and its affiliated academic health care centers). NR 55 TC 24 Z9 25 U1 2 U2 20 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD OCT PY 2014 VL 63 IS 10 BP 1265 EP 1271 DI 10.1016/j.metabol.2014.06.001 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8LU UT WOS:000342331300006 PM 25060690 ER PT J AU Klein, RL Hammad, SM Baker, NL Hunt, KJ Al Gadban, MM Cleary, PA Virella, G Lopes-Virella, MF AF Klein, Richard L. Hammad, Samar M. Baker, Nathaniel L. Hunt, Kelly J. Al Gadban, Mohammed M. Cleary, Patricia A. Virella, Gabriel Lopes-Virella, Maria F. CA DCCT EDIC Res Grp TI Decreased plasma levels of select very long chain ceramide species Are associated with the development of nephropathy in type 1 diabetes SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article DE Sphingolipids; Sphingosine; Albuminuria; Microalbuminuria; Macroalbuminuria ID ENRICHED MEMBRANE DOMAINS; INSULIN-RESISTANCE; BIOPHYSICAL PROPERTIES; SPHINGOSINE 1-PHOSPHATE; COMPLICATIONS TRIAL; SPHINGOLIPIDS; MICROALBUMINURIA; LIPOPROTEINS; METABOLISM; PREDICTOR AB Objective. Sphingolipid metabolism is altered in diabetes and we analyzed the plasma concentrations of sphingolipid species to investigate their association with the development of albuminuria in type 1 patients with diabetes. Materials and Methods. Samples were collected from 497 type 1 diabetic patients during their enrollment into the Diabetes Control and Complications Trial (DCCT). We determined plasma concentrations of multiple ceramide species and individual sphingoid bases and their phosphates using high performance liquid chromatography-tandem mass spectrometry and investigated their association with the development of albuminuria during 14-20 years of follow-up. Results. Patients exhibited normal albumin excretion rates (AER <40 mg/24 h) at the time of plasma sampling. Although the majority of patients (N = 291; 59%) exhibited normal levels of albuminuria throughout follow-up, 141 patients (28%) progressed to microalbuminuria (40 mg/24 h <= AER < 300 mg/24 h), while 65 (13%) progressed to macroalbuminuria (AER >= 300 mg/24 h). To test the association of log transformed plasma sphingolipid level with the development of albuminuria, generalized logistic regression models were used where normal, micro- and macroalbuminuria were the outcomes of interest. Models were adjusted for DCCT treatment group, baseline retinopathy, gender, baseline HbA1c %, age, AER, lipid levels, diabetes duration, and the use of ACE/ARB drugs. Increased plasma levels of very long, but not long chain ceramide species measured at DCCT baseline were associated with decreased odds to develop macroalbuminuria during the subsequent nineteen years (DCCT Baseline to EDIC year 8). Conclusion. These studies demonstrate, prospectively, that decreased plasma levels of select ceramide species are associated with the development of macroalbuminuria in type 1 diabetes. Published by Elsevier Inc. C1 [Klein, Richard L.; Lopes-Virella, Maria F.] Med Univ S Carolina, Dept Med, Div Endocrinol Metab & Med Genet, Charleston, SC 29425 USA. [Klein, Richard L.; Hunt, Kelly J.; Lopes-Virella, Maria F.] Vet Affairs Med Ctr, Ralph H Johnson Dept, Res Serv, Charleston, SC 29403 USA. [Hammad, Samar M.; Al Gadban, Mohammed M.] Med Univ S Carolina, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA. [Baker, Nathaniel L.; Hunt, Kelly J.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Cleary, Patricia A.] George Washington Univ, Ctr Biostat, Washington, DC USA. [Virella, Gabriel] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. RP Klein, RL (reprint author), Med Univ S Carolina, 114 Doughty St,MSC 776, Charleston, SC 29425 USA. EM kleinrl@musc.edu; hammadsm@musc.edu FU National Institutes of Health [P01-HL55782, DK081352, DK088778, HL-079274, DK081352-S1]; Department of Veterans Affairs Merit Review Program; National Institute of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney diseases (NIDDK); National Institutes of Health; National Center for Research Resources through the GCRC program; Genentech, Inc. FX This work was supported by National Institutes of Health, grants P01-HL55782 & DK081352 (MLV), DK088778 (KJH), HL-079274 (SMH), DK081352-S1 (ARRA-MLV). Additional funding was obtained from the Department of Veterans Affairs Merit Review Program (MLV and RLK). The contents of this manuscript do not represent the views of the Department of Veterans Affairs or the United States Government. The DCCT/EDIC is sponsored through research contracts from the National Institute of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney diseases (NIDDK) and the National Institutes of Health. Additional support was provided by the National Center for Research Resources through the GCRC program and by Genentech, Inc. through a cooperative research and development agreement with the NIDDK. The authors gratefully acknowledge the Lipidomics Shared Resource Facility at MUSC for their continued expert analytical contributions without which this work could not have been conducted. The technical assistance of Ms. Charlyne Chassereau and Ms. Andrea Semler also is acknowledged. The authors are also grateful to the patients in the DCCT/EDIC for their long-term participation in this important trial. NR 37 TC 8 Z9 8 U1 0 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD OCT PY 2014 VL 63 IS 10 BP 1287 EP 1295 DI 10.1016/j.metabol.2014.07.001 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8LU UT WOS:000342331300009 PM 25088746 ER PT J AU Kazlauskas, A AF Kazlauskas, Andrius TI Plakophilin-2 Promotes Activation of Epidermal Growth Factor Receptor SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Editorial Material ID EGF RECEPTOR; PDGF RECEPTOR; MEMBRANE AB While growth factor-driven dimerization of receptor tyrosine kinases (RTKs) is a simple and intuitive mechanism of activating RTKs, K.-I. Arimoto et al. (Mol. Cell. Biol. 34: 3843-3854, 2014, doi: 10.1128/MCB.00758-14) describe a novel means of promoting the activity of RTKs. Namely, plakophilin-2 (PKP2) associates with the epidermal growth factor receptor (EGFR) and enhances its ligand-dependent and ligand-independent activity. This discovery suggests that antagonizing PKP2 may be a new therapeutic opportunity to combat tumors in which activation of EGFR contributes to pathogenesis. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst, Boston, MA 02138 USA. RP Kazlauskas, A (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst, Boston, MA 02138 USA. EM andrius_kazlauskas@meei.harvard.edu NR 10 TC 0 Z9 0 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2014 VL 34 IS 20 BP 3778 EP 3779 DI 10.1128/MCB.00968-14 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AP6UU UT WOS:000342214200001 PM 25113561 ER PT J AU Hill, SJ Clark, AP Silver, DP Livingston, DM AF Hill, Sarah J. Clark, Allison P. Silver, Daniel P. Livingston, David M. TI BRCA1 Pathway Function in Basal-Like Breast Cancer Cells SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PLATINUM-BASED CHEMOTHERAPY; SUSCEPTIBILITY GENE BRCA1; HOMOLOGY-DIRECTED REPAIR; DOUBLE-STRAND BREAKS; INDUCED DNA-DAMAGE; POLY(ADP-RIBOSE) POLYMERASE; TUMOR SUPPRESSION; OVARIAN-CANCER; ESTROGEN-RECEPTOR; GENOME INTEGRITY AB Sporadic basal-like cancers (BLCs) are a common subtype of breast cancer that share multiple biological properties with BRCA1-mutated breast tumors. Despite being BRCA1(+/+), sporadic BLCs are widely viewed as phenocopies of BRCA1-mutated breast cancers, because they are hypothesized to manifest a BRCA1 functional defect or breakdown of a pathway(s) in which BRCA1 plays a major role. The role of BRCA1 in the repair of double-strand DNA breaks by homologous recombination (HR) is its best understood function and the function most often implicated in BRCA1 breast cancer suppression. Therefore, it is suspected that sporadic BLCs exhibit a defect in HR. To test this hypothesis, multiple DNA damage repair assays focused on several types of repair were performed on a group of cell lines classified as sporadic BLCs and on controls. The sporadic BLC cell lines failed to exhibit an overt HR defect. Rather, they exhibited defects in the repair of stalled replication forks, another BRCA1 function. These results provide insight into why clinical trials of poly(ADP-ribose) polymerase (PARP) inhibitors, which require an HR defect for efficacy, have been unsuccessful in sporadic BLCs, unlike cisplatin, which elicits DNA damage that requires stalled fork repair and has shown efficacy in sporadic BLCs. C1 [Hill, Sarah J.; Livingston, David M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02138 USA. [Hill, Sarah J.; Clark, Allison P.; Silver, Daniel P.; Livingston, David M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Silver, Daniel P.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Livingston, DM (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02138 USA. EM david_livingston@dfci.harvard.edu FU DOD BCRP fellowship [W81XWH-08-1-0748]; NCI fellowship [1F30CA167895-01]; Susan G. Komen Foundation [SAC110022]; Breast Cancer Research Foundation; NCI SPORE grant [P50CA089393]; NCI [RO1 (R01CA136512), P01 (P01CA080111)] FX S.J.H. was initially funded by DOD BCRP fellowship W81XWH-08-1-0748 and subsequently by NCI fellowship 1F30CA167895-01. This work was supported by grants from the Susan G. Komen Foundation for the Cure (SAC110022), the Breast Cancer Research Foundation, an NCI SPORE grant (P50CA089393) in breast cancer research to the Dana-Farber/Harvard Cancer Center, and RO1 (R01CA136512) and P01 (P01CA080111) grants from NCI to D.M.L. NR 70 TC 14 Z9 15 U1 0 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2014 VL 34 IS 20 BP 3828 EP 3842 DI 10.1128/MCB.01646-13 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AP6UU UT WOS:000342214200006 PM 25092866 ER PT J AU Elvington, M Scheiber, M Yang, XF Lyons, K Jacqmin, D Wadsworth, C Marshall, D Vanek, K Tomlinson, S AF Elvington, Michelle Scheiber, Melissa Yang, Xiaofeng Lyons, Katherine Jacqmin, Dustin Wadsworth, Casey Marshall, David Vanek, Kenneth Tomlinson, Stephen TI Complement dependent modulation of anti-tumor immunity following radiation therapy SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract CT 25th International Complement Workshop CY SEP 14-18, 2014 CL Rio de Janeiro, BRAZIL C1 [Elvington, Michelle; Scheiber, Melissa; Yang, Xiaofeng; Wadsworth, Casey; Tomlinson, Stephen] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. [Lyons, Katherine; Jacqmin, Dustin; Marshall, David; Vanek, Kenneth] Med Univ S Carolina, Dept Radiat Oncol, Charleston, SC 29425 USA. [Tomlinson, Stephen] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD OCT PY 2014 VL 61 IS 2 SI SI MA 017 BP 222 EP 223 PG 2 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA AP7NZ UT WOS:000342265300036 ER PT J AU Ghosh, P Vaidya, A Sahoo, R Goldfine, A Herring, N Bry, L Chorev, M McElrath, T Halperin, J AF Ghosh, Pamela Vaidya, Anand Sahoo, Rupam Goldfine, Allison Herring, Neil Bry, Lynn Chorev, Michael McElrath, Thomas Halperin, Jose TI Blood levels of glycated CD59 (GCD59) as a novel biomarker for glucose handling in humans SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract CT 25th International Complement Workshop CY SEP 14-18, 2014 CL Rio de Janeiro, BRAZIL C1 [Ghosh, Pamela; Vaidya, Anand; Sahoo, Rupam; Chorev, Michael; Halperin, Jose] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Goldfine, Allison] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Herring, Neil; Bry, Lynn] Partners Healthcare Syst, Crimson Biospecimen Core, Boston, MA USA. [McElrath, Thomas] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Obstet & Gynecol, Boston, MA 02115 USA. RI SAHOO, RUPAM/B-3935-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD OCT PY 2014 VL 61 IS 2 SI SI MA 016 BP 222 EP 222 PG 1 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA AP7NZ UT WOS:000342265300035 ER PT J AU Takahashi, K Ohtani, K Larvie, M Moyo, P Chigweshe, L Van Cott, E Wakamiya, N AF Takahashi, Kazue Ohtani, Katsuki Larvie, Mykol Moyo, Patience Chigweshe, Lorencia Van Cott, Elizabeth Wakamiya, Nobutaka TI The new biological aspects in CL-K1 (Collectin Kidney 1) SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract CT 25th International Complement Workshop CY SEP 14-18, 2014 CL Rio de Janeiro, BRAZIL C1 [Takahashi, Kazue; Moyo, Patience; Chigweshe, Lorencia] Harvard Univ, Sch Med, Dept Pediat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Larvie, Mykol] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Van Cott, Elizabeth] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Ohtani, Katsuki; Wakamiya, Nobutaka] Asahikawa Med Univ, Dept Microbiol & Immunochem, Asahikawa, Hokkaido, Japan. NR 0 TC 0 Z9 0 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD OCT PY 2014 VL 61 IS 2 SI SI MA 060 BP 238 EP 238 PG 1 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA AP7NZ UT WOS:000342265300079 ER PT J AU Marshall, KM He, SQ Zhong, Z Atkinson, C Tomlinson, S AF Marshall, Keely M. He, Songqing Zhong, Zhi Atkinson, Carl Tomlinson, Stephen TI Dissecting the complement pathway in hepatic injury and regeneration with a novel protective strategy SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract CT 25th International Complement Workshop CY SEP 14-18, 2014 CL Rio de Janeiro, BRAZIL C1 [Marshall, Keely M.; He, Songqing; Atkinson, Carl; Tomlinson, Stephen] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. [He, Songqing] Guilin Med Univ, Affiliated Hosp, Dept Hepatobiliary Surg, Guilin 541001, Guangxi, Peoples R China. [Zhong, Zhi] Med Univ S Carolina, Dept Pharmaceut & Biomed Sci, Charleston, SC 29425 USA. [Tomlinson, Stephen] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD OCT PY 2014 VL 61 IS 2 SI SI MA 163 BP 273 EP 274 PG 2 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA AP7NZ UT WOS:000342265300182 ER PT J AU Herschhorn, A Gu, C Espy, N Richard, J Finzi, A Sodroski, JG AF Herschhorn, Alon Gu, Christopher Espy, Nicole Richard, Jonathan Finzi, Andres Sodroski, Joseph G. TI A broad HIV-1 inhibitor blocks envelope glycoprotein transitions critical for entry SO NATURE CHEMICAL BIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; NEUTRALIZING ANTIBODY PG9; HUMAN MONOCLONAL-ANTIBODY; CD4-BOUND CONFORMATION; RECEPTOR-BINDING; VARIABLE LOOPS; GP120; IDENTIFICATION; INFECTION; CD4 AB Binding to the primary receptor, CD4, triggers conformational changes in the metastable HIV-1 envelope glycoprotein (Env) trimer ((gp120-gp41)(3)) that are important for virus entry into host cells. These changes include an 'opening' of the trimer, creation of a binding site for the CCR5 co-receptor and formation and/or exposure of a gp41 coiled coil. Here we identify a new compound, 18A (1), that specifically inhibits the entry of a wide range of HIV-1 isolates. 18A does not interfere with CD4 or CCR5 binding, but it inhibits the CD4-induced disruption of quaternary structures at the trimer apex and the exposure of the gp41 HR1 coiled coil. Analysis of HIV-1 variants with increased or reduced sensitivity to 18A suggests that the inhibitor can distinguish distinct conformational states of gp120 in the unliganded Env trimer. The broad-range activity and observed hypersensitivity of resistant mutants to antibody neutralization support further investigation of 18A. C1 [Herschhorn, Alon; Gu, Christopher; Espy, Nicole; Sodroski, Joseph G.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Herschhorn, Alon; Espy, Nicole; Sodroski, Joseph G.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Richard, Jonathan; Finzi, Andres] Univ Montreal, Ctr Rech, Ctr Hosp Univ Montreal, Montreal, PQ, Canada. [Richard, Jonathan; Finzi, Andres] Univ Montreal, Dept Microbiol Infectiol & Immunol, Montreal, PQ, Canada. [Finzi, Andres] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ, Canada. [Sodroski, Joseph G.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Sodroski, JG (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM joseph_sodroski@dfci.harvard.edu FU amfAR; amfAR Mathilde Krim Fellowship in Basic Biomedical Research [108501-53-RKNT]; Canadian Institutes of Health Research operating grant [119334]; Fonds de la recherche en sante du Quebec Chercheur Boursier Junior fellowship [24639]; Canada Research Chair on Retroviral Entry; NIH [AI24755, GM56550] FX We thank Y. McLaughlin and E. Carpelan for manuscript preparation; the AIDS Research and the Reference Reagent Program, Division of AIDS, US National Institute of Allergy and Infectious Diseases, US National Institutes of Health (NIH) for providing reference panels for subtype B and C HIV-1 envelope clones, CFR01_AE.269 HIV-1 envelope clone, psPAX2 plasmid, T20, maraviroc and CEM cells. We also thank B. Keele, G. M. Shaw and the Center for HIV-AIDS Vaccine Immunology Consortium for providing transmitted/founder HIV-1 envelope clones; H.-X. Liao and B.F. Haynes (Duke University Medical Center) for providing the CRF01_AE.CM244 HIV-1 envelope clone; D. Burton (The Scripps Research Institute), J. Robinson (Tulane University) and P.D. Kwong (Vaccine Research Center, NIH) for providing the anti-gp120 monoclonal antibodies; D. Flood, J. Smith and C. Shamu (Institute of Chemistry and Cell Biology, Harvard Medical School) for assistance in the high-throughput screening campaign; and E. Pery, E. Cassol, V. Misra, N. Madani, H. Haim and A.M. Princiotto from Dana-Farber Cancer Institute for helpful discussions and for providing reagents. A.H. was supported by amfAR and is the recipient of an amfAR Mathilde Krim Fellowship in Basic Biomedical Research (108501-53-RKNT). A.F. was supported by Canadian Institutes of Health Research operating grant number 119334 and is the recipient of a Fonds de la recherche en sante du Quebec Chercheur Boursier Junior fellowship number 24639 and a Canada Research Chair on Retroviral Entry. Support for this work was also provided by grants from the NIH to J.G.S. (grant numbers AI24755 and GM56550). NR 40 TC 20 Z9 20 U1 1 U2 28 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD OCT PY 2014 VL 10 IS 10 BP 845 EP + DI 10.1038/NCHEMBIO.1623 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AQ0GV UT WOS:000342462100011 PM 25174000 ER PT J AU Chaikuad, A Tacconi, EMC Zimmer, J Liang, YK Gray, NS Tarsounas, M Knapp, S AF Chaikuad, Apirat Tacconi, Eliana M. C. Zimmer, Jutta Liang, Yanke Gray, Nathanael S. Tarsounas, Madalena Knapp, Stefan TI A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics SO NATURE CHEMICAL BIOLOGY LA English DT Article ID MAP KINASE ERK2; POLY(ADP-RIBOSE) POLYMERASE; ACQUIRED-RESISTANCE; MEK INHIBITORS; RAF INHIBITION; DNA-DAMAGE; BRAF; CONFORMATION; SELECTIVITY; DISCOVERY AB Activation of the ERK pathway is a hallmark of cancer, and targeting of upstream signaling partners led to the development of approved drugs. Recently, SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In ERK1/2, SCH772984 induces a so-far-unknown binding pocket that accommodates the piperazine-phenyl-pyrimidine decoration. This new binding pocket was created by an inactive conformation of the phosphate-binding loop and an outward tilt of helix alpha C. In contrast, structure determination of SCH772984 with the off-target haspin and JNK1 revealed two canonical but distinct type I binding modes. Notably, the new binding mode with ERK1/2 was associated with slow binding kinetics in vitro as well as in cell-based assay systems. The described binding mode of SCH772984 with ERK1/2 enables the design of a new type of specific kinase inhibitors with prolonged on-target activity. C1 [Chaikuad, Apirat; Knapp, Stefan] Univ Oxford, Struct Genom Consortium, Oxford, England. [Tacconi, Eliana M. C.; Zimmer, Jutta; Tarsounas, Madalena] Canc Res UK, Telomere & Genome Stabil Grp, Oxford, England. [Tacconi, Eliana M. C.; Zimmer, Jutta; Tarsounas, Madalena] Oxford Inst Radiat Oncol, MRC, Oxford, England. [Liang, Yanke; Gray, Nathanael S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol,Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Knapp, Stefan] George Washington Univ, Dept Biochem & Mol Med, Washington, DC USA. [Knapp, Stefan] Univ Oxford, Target Discovery Inst, Oxford, England. RP Knapp, S (reprint author), Univ Oxford, Struct Genom Consortium, Old Rd Campus,Res Bldg, Oxford, England. EM madalena.tarsounas@oncology.ox.ac.uk; stefan.knapp@ndm.ox.ac.uk OI Knapp, Stefan/0000-0001-5995-6494 FU Structural Genomics Consortium; AbbVie [1097737]; Bayer; Boehringer Ingelheim; Canada Foundation for Innovation; Canadian Institutes for Health Research; Genome Canada; GlaxoSmithKline; Janssen; Lilly Canada; Novartis Research Foundation; Ontario Ministry of Economic Development and Innovation; Pfizer; Takeda; Wellcome Trust [092809/Z/10/Z]; European Union FP7 Grant [278568]; Cancer Research UK; EMBO Young Investigator Program; Royal Society; Medical Research Council PhD Studentship FX S.K. is supported by the Structural Genomics Consortium, a registered charity (number 1097737) that receives funds from AbbVie, Bayer, Boehringer Ingelheim, the Canada Foundation for Innovation, the Canadian Institutes for Health Research, Genome Canada, GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda and the Wellcome Trust (092809/Z/10/Z). A.C. is supported by the European Union FP7 Grant No. 278568 'PRIMES' (Protein interaction machines in oncogenic EGF receptor signalling). Work in M.T.'s laboratory is supported by Cancer Research UK, the EMBO Young Investigator Program and The Royal Society, and E.T. is funded by a Medical Research Council PhD Studentship. We thank the staff at Diamond Light Source for assistance during data collection at the synchrotron and H. Lee (Seoul National University) for providing the sheep anti-BRCA2 antibody. NR 58 TC 34 Z9 34 U1 3 U2 26 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD OCT PY 2014 VL 10 IS 10 BP 853 EP + DI 10.1038/NCHEMBIO.1629 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AQ0GV UT WOS:000342462100012 PM 25195011 ER PT J AU Al Olama, AA Kote-Jarai, Z Berndt, SI Conti, DV Schumacher, F Han, Y Benlloch, S Hazelett, DJ Wang, ZM Saunders, E Leongamornlert, D Lindstrom, S Jugurnauth-Little, S Dadaev, T Tymrakiewicz, M Stram, DO Rand, K Wan, P Stram, A Sheng, X Pooler, LC Park, K Xia, L Tyrer, J Kolonel, LN Le Marchand, L Hoover, RN Machiela, MJ Yeager, M Burdette, L Chung, CC Hutchinson, A Yu, K Goh, C Ahmed, M Govindasami, K Guy, M Tammela, TLJ Auvinen, A Wahlfors, T Schleutker, J Visakorpi, T Leinonen, KA Xu, JF Aly, M Donovan, J Travis, RC Key, TJ Siddiq, A Canzian, F Khaw, KT Takahashi, A Kubo, M Pharoah, P Pashayan, N Weischer, M Nordestgaard, BG Nielsen, SF Klarskov, P Roder, MA Iversen, P Thibodeau, SN McDonnell, SK Schaid, DJ Stanford, JL Kolb, S Holt, S Knudsen, B Coll, AH Gapstur, SM Diver, WR Stevens, VL Maier, C Luedeke, M Herkommer, K Rinckleb, AE Strom, SS Pettaway, C Yeboah, ED Tettey, Y Biritwum, RB Adjei, AA Tay, E Truelove, A Niwa, S Choklcalingam, AP Cannon-Albright, L Cybulski, C Wokolorczyk, D Kluzniak, W Park, J Sellers, T Lin, HY Isaacs, WB Partin, AW Brenner, H Dieffenbach, AK Stegmaier, C Chen, C Giovannucci, EL Ma, J Stampfer, M Penney, KL Mucci, L John, EM Ingles, SA Kittles, RA Murphy, AB Pandha, H Michael, A Kierzek, AM Blot, W Signorello, LB Zheng, W Albanes, D Virtamo, J Weinstein, S Nemesure, B Carpten, J Leske, C Wu, SY Hennis, A Kibel, AS Rybicki, BA Neslund-Dudas, C Hsing, AW Chu, L Goodman, PJ Klein, EA Zheng, SL Batra, J Clements, J Spurdle, A Teixeira, MR Paulo, P Maia, S Slavov, C Kaneva, R Mitev, V Witte, JS Casey, G Gillanders, EM Seminara, D Riboli, E Hamdy, FC Coetzee, GA Li, QY Freedman, ML Hunter, DJ Muir, K Gronberg, H Nea, DE Southey, M Giles, GG Severi, G Cook, MB Nakagawa, H Wiklund, F Kraft, P Chanock, SJ Henderson, BE Easton, DF Eeles, RA Haiman, CA AF Al Olama, Ali Amin Kote-Jarai, Zsofia Berndt, Sonja I. Conti, David V. Schumacher, Fredrick Han, Ying Benlloch, Sara Hazelett, Dennis J. Wang, Zhaoming Saunders, Ed Leongamornlert, Daniel Lindstrom, Sara Jugurnauth-Little, Sara Dadaev, Tokhir Tymrakiewicz, Malgorzata Stram, Daniel O. Rand, Kristin Wan, Peggy Stram, Alex Sheng, Xin Pooler, Loreall C. Park, Karen Xia, Lucy Tyrer, Jonathan Kolonel, Laurence N. Le Marchand, Loic Hoover, Robert N. Machiela, Mitchell J. Yeager, Merideth Burdette, Laurie Chung, Charles C. Hutchinson, Amy Yu, Kai Goh, Chee Ahmed, Mahbubl Govindasami, Koveela Guy, Michelle Tammela, Teuvo L. J. Auvinen, Anssi Wahlfors, Tlina Schleutker, Johanna Visakorpi, Tapio Leinonen, Katri A. Xu, Jianfeng Aly, Markus Donovan, Jenny Travis, Ruth C. Key, Tim J. Siddiq, Afshan Canzian, Federico Khaw, Kay-Tee Takahashi, Atsushi Kubo, Michiaki Pharoah, Paul Pashayan, Nora Weischer, Maren Nordestgaard, Borge G. Nielsen, Sune F. Klarskov, Peter Roder, Martin Andreas Iversen, Peter Thibodeau, Stephen N. McDonnell, Shannon K. Schaid, Daniel J. Stanford, Janet L. Kolb, Suzanne Holt, Sarah Knudsen, Beatrice Coll, Antonio Hurtado Gapstur, Susan M. Diver, W. Ryan Stevens, Victoria L. Maier, Christiane Luedeke, Manuel Herkommer, Kathleen Rinckleb, Antje E. Strom, Sara S. Pettaway, Curtis Yeboah, Edward D. Tettey, Yao Biritwum, Richard B. Adjei, Andrew A. Tay, Evelyn Truelove, Ann Niwa, Shelley Choklcalingam, Anand P. Cannon-Albright, Lisa Cybulski, Cezary Wokolorczyk, Dominika Kluzniak, Wojciech Park, Jong Sellers, Thomas Lin, Hui-Yi Isaacs, William B. Partin, Alan W. Brenner, Hermann Dieffenbach, Aida Karina Stegmaier, Christa Chen, Constance Giovannucci, Edward L. Ma, Jing Stampfer, Meir Penney, Kathryn L. Mucci, Lorelei John, Esther M. Ingles, Sue A. Kittles, Rick A. Murphy, Adam B. Pandha, Hardev Michael, Agnieszka Kierzek, Andrzej M. Blot, William Signorello, Lisa B. Zheng, Wei Albanes, Demetrius Virtamo, Jarmo Weinstein, Stephanie Nemesure, Barbara Carpten, John Leske, Cristina Wu, Suh-Yuh Hennis, Anselm Kibel, Adam S. Rybicki, Benjamin A. Neslund-Dudas, Christine Hsing, Ann W. Chu, Lisa Goodman, Phyllis J. Klein, Eric A. Zheng, S. Lilly Batra, Jyotsna Clements, Judith Spurdle, Amanda Teixeira, Manuel R. Paulo, Paula Maia, Sofia Slavov, Chavdar Kaneva, Radka Mitev, Vanio Witte, John S. Casey, Graham Gillanders, Elizabeth M. Seminara, Daniella Riboli, Elio Hamdy, Freddie C. Coetzee, Gerhard A. Li, Qiyuan Freedman, Matthew L. Hunter, David J. Muir, Kenneth Gronberg, Henrik Nea, David E. Southey, Melissa Giles, Graham G. Severi, Gianluca Cook, Michael B. Nakagawa, Hidewaki Wiklund, Fredrik Kraft, Peter Chanock, Stephen J. Henderson, Brian E. Easton, Douglas F. Eeles, Rosalind A. Haiman, Christopher A. CA Breast Prostate Canc Cohort Consor Practical Prostate Canc Associatio COGS Consortium GAME-ON ELLIPSE Consortium TI A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; COMMON VARIANTS; MYOSIN VI; RISK; JAPANESE; GLIOMA; 22Q13; MEN AB Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of >10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 x 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease. C1 [Al Olama, Ali Amin; Benlloch, Sara; Tyrer, Jonathan; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Kote-Jarai, Zsofia; Saunders, Ed; Leongamornlert, Daniel; Jugurnauth-Little, Sara; Dadaev, Tokhir; Tymrakiewicz, Malgorzata; Goh, Chee; Ahmed, Mahbubl; Govindasami, Koveela; Guy, Michelle; Eeles, Rosalind A.] Inst Canc Res, London SW3 6JB, England. [Berndt, Sonja I.; Wang, Zhaoming; Hoover, Robert N.; Machiela, Mitchell J.; Yeager, Merideth; Burdette, Laurie; Chung, Charles C.; Hutchinson, Amy; Yu, Kai; Cook, Michael B.; Chanock, Stephen J.] Natl Canc Inst, US NIH, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Conti, David V.; Schumacher, Fredrick; Han, Ying; Hazelett, Dennis J.; Stram, Daniel O.; Rand, Kristin; Wan, Peggy; Stram, Alex; Sheng, Xin; Pooler, Loreall C.; Park, Karen; Xia, Lucy; Ingles, Sue A.; Casey, Graham; Coetzee, Gerhard A.; Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Conti, David V.; Schumacher, Fredrick; Hazelett, Dennis J.; Stram, Daniel O.; Ingles, Sue A.; Casey, Graham; Coetzee, Gerhard A.; Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Wang, Zhaoming] SAIC Frederick Inc, Natl Canc Inst, Div Canc Epidemiol & Genet, Canc Genom Res Lab, Frederick, MD USA. [Lindstrom, Sara; Chen, Constance; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Tammela, Teuvo L. J.] Univ Tampere, Tampere Univ Hosp, Dept Urol, FIN-33101 Tampere, Finland. [Tammela, Teuvo L. J.] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Auvinen, Anssi] Univ Tampere, Sch Hlth Sci, Dept Epidemiol, FIN-33101 Tampere, Finland. [Wahlfors, Tlina; Schleutker, Johanna] Univ Tampere, BioMediTech, Tampere, Finland. [Wahlfors, Tlina; Schleutker, Johanna] Univ Tampere, FimLab Labs, Tampere, Finland. [Schleutker, Johanna] Univ Turku, Inst Biomed, Dept Biochem Med, Turku, Finland. [Visakorpi, Tapio; Leinonen, Katri A.] Univ Tampere, BioMediTech, Inst Biomed Technol, Tampere, Finland. [Visakorpi, Tapio; Leinonen, Katri A.] Tampere Univ Hosp, Tampere, Finland. [Xu, Jianfeng; Zheng, S. Lilly] Wake Forest Sch Med, Ctr Canc Genom, Winston Salem, NC USA. [Aly, Markus; Gronberg, Henrik; Wiklund, Fredrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Aly, Markus] Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden. [Donovan, Jenny] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Travis, Ruth C.; Key, Tim J.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England. [Siddiq, Afshan] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London, England. [Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Khaw, Kay-Tee] Univ Cambridge, Clin Gerontol Unit, Cambridge, England. [Takahashi, Atsushi] RIKEN, Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa, Japan. [Kubo, Michiaki] RIKEN, Ctr Integrat Med Sci, Lab Genotyping Dev, Yokohama, Kanagawa, Japan. [Pharoah, Paul; Pashayan, Nora] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England. [Weischer, Maren; Nordestgaard, Borge G.; Nielsen, Sune F.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Nordestgaard, Borge G.; Nielsen, Sune F.] Univ Copenhagen, Fac Hlth & Med Sci, Herlev, Denmark. [Klarskov, Peter] Copenhagen Univ Hosp, Herlev Hosp, Dept Urol, Herlev, Denmark. [Roder, Martin Andreas; Iversen, Peter] Copenhagen Univ Hosp, Rigshosp, Copenhagen Prostate Canc Ctr, Dept Urol, Copenhagen, Denmark. [Thibodeau, Stephen N.; McDonnell, Shannon K.; Schaid, Daniel J.] Mayo Clin, Rochester, MN USA. [Stanford, Janet L.; Kolb, Suzanne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Holt, Sarah] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Knudsen, Beatrice] Cedars Sinai, Translat Pathol, Los Angeles, CA USA. [Coll, Antonio Hurtado] Prostate Ctr, Vancouver, BC, Canada. [Gapstur, Susan M.; Diver, W. Ryan] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Maier, Christiane; Luedeke, Manuel] Univ Hosp Ulm, Dept Urol, Ulm, Germany. [Herkommer, Kathleen] Tech Univ Munich, Klinikum Rechts Isar, Dept Urol, D-80290 Munich, Germany. [Rinckleb, Antje E.; Strom, Sara S.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Pettaway, Curtis] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn] Univ Ghana, Sch Med, Accra, Ghana. [Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn] Korle Bu Teaching Hosp, Accra, Ghana. [Truelove, Ann; Niwa, Shelley] Westat Corp, Rockville, MD USA. [Choklcalingam, Anand P.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Cannon-Albright, Lisa] Univ Utah, Sch Med, Dept Med, Div Genet Epidemiol, Salt Lake City, UT USA. [Cannon-Albright, Lisa] Vet Affairs Med Ctr, George E Wahlen Dept, Salt Lake City, UT 84148 USA. [Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Park, Jong; Sellers, Thomas] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Lin, Hui-Yi] H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat & Bioinformat, Tampa, FL USA. [Isaacs, William B.; Partin, Alan W.] Johns Hopkins Hosp & Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD USA. [Brenner, Hermann; Dieffenbach, Aida Karina] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann; Dieffenbach, Aida Karina] German Canc Consortium, Heidelberg, Germany. [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany. [Giovannucci, Edward L.; Stampfer, Meir; Penney, Kathryn L.; Mucci, Lorelei; Signorello, Lisa B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ma, Jing; Stampfer, Meir; Penney, Kathryn L.; Mucci, Lorelei; Signorello, Lisa B.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Channing Div Network Med, Boston, MA 02115 USA. [John, Esther M.; Hsing, Ann W.; Chu, Lisa] Cancer Prevent Inst Calif, Fremont, CA USA. [John, Esther M.; Hsing, Ann W.; Chu, Lisa] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA. [Kittles, Rick A.] Univ Illinois, Dept Med, Chicago, IL USA. [Murphy, Adam B.] Northwestern Univ, Dept Urol, Chicago, IL 60611 USA. [Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej M.] Univ Surrey, Fac Hlth & Med Sci, Guildford, Surrey, England. [Blot, William] Int Epidemiol Inst, Rockville, MD USA. [Blot, William; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Dept Med,Div Epidemiol, Nashville, TN 37235 USA. [Albanes, Demetrius; Weinstein, Stephanie] US Natl Inst Hlth, Natl Canc Inst, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Bethesda, MD USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Nemesure, Barbara; Leske, Cristina; Wu, Suh-Yuh; Hennis, Anselm] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. [Hennis, Anselm] Translat Genom Res Inst, Phoenix, AZ USA. [Kibel, Adam S.] Univ W Indies, Chron Dis Res Ctr, Bridgetown, Barbados. [Rybicki, Benjamin A.; Neslund-Dudas, Christine] Brigham & Womens Hosp, Dana Farber Canc Inst, Div Urol Surg, Boston, MA 02115 USA. [Goodman, Phyllis J.] Henry Ford Hosp, Dept Publ Hlth Sci, Detroit, MI 48202 USA. [Klein, Eric A.] Fred Hutchinson Canc Res Ctr, Ctr Stat, Southwest Oncol Grp, Seattle, WA 98104 USA. [Batra, Jyotsna; Clements, Judith] Cleveland Clin, Glickman Urol & Kidney Inst, Dept Urol, Cleveland, OH 44106 USA. [Spurdle, Amanda] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Australian Prostate Canc Res Ctr Queensland, Brisbane, Qld 4001, Australia. [Teixeira, Manuel R.; Paulo, Paula; Maia, Sofia] Queensland Univ Technol, Sch Biomed Sci, Translat Res Inst, Brisbane, Qld 4001, Australia. [Teixeira, Manuel R.] QIMR Berghofer Med Res Inst, Mol Canc Epidemiol Lab, Brisbane, Qld, Australia. [Slavov, Chavdar] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. [Kaneva, Radka; Mitev, Vanio] Univ Porto, Biomed Sci Inst, Oporto, Portugal. [Witte, John S.] Med Univ Sofia, Dept Urol, Sofia, Bulgaria. [Witte, John S.] Med Univ Sofia, Mol Med Ctr, Dept Med Chem & Biochem, Sofia, Bulgaria. [Witte, John S.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Witte, John S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Gillanders, Elizabeth M.; Seminara, Daniella] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Hamdy, Freddie C.] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England. [Li, Qiyuan; Freedman, Matthew L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Muir, Kenneth] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Nea, David E.] Canc Res UK, Li Ka Shing Ctr, Cambridge Res Inst, Cambridge, England. [Nea, David E.] Univ Cambridge, Addenbrookes Hosp, Dept Oncol, Cambridge CB2 2QQ, England. [Southey, Melissa] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic 3052, Australia. [Giles, Graham G.; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia. [Severi, Gianluca] Human Genet Fdn, Turin, Italy. [Nakagawa, Hidewaki] RIKEN, Ctr Integrat Med Sci, Lab Genome Sequencing Anal, Tokyo, Japan. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Eeles, Rosalind A.] Royal Marsden Natl Hlth Serv NHS Fdn Trust, London, England. [Eeles, Rosalind A.] Royal Marsden Natl Hlth Serv NHS Fdn Trust, Sutton, Surrey, England. RP Haiman, CA (reprint author), Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. EM rosalind.eeles@icr.ac.uk; haiman@usc.edu RI Albanes, Demetrius/B-9749-2015; Cook, Michael/A-5641-2009; Paulo, Paula/F-1441-2016; Teixeira, Manuel/E-4885-2011; Kubo, Michiaki/N-7947-2015; Batra, Jyotsna/B-4130-2011; Brenner, Hermann/B-4627-2017; Spurdle, Amanda/A-4978-2011 OI albright, lisa/0000-0003-2602-3668; Machiela, Mitchell/0000-0001-6538-9705; Giles, Graham/0000-0003-4946-9099; Clements, Judith/0000-0001-6026-1964; Leongamornlert, Daniel/0000-0002-3486-3168; Cook, Michael/0000-0002-0533-7302; Paulo, Paula/0000-0001-8387-2127; Teixeira, Manuel/0000-0002-4896-5982; Brenner, Hermann/0000-0002-6129-1572; Roder, Martin Andreas/0000-0002-0019-5333; Kierzek, Andrzej/0000-0002-2605-9057; Eeles, Rosalind/0000-0002-3698-6241; Hazelett, Dennis/0000-0003-0749-9935; Spurdle, Amanda/0000-0003-1337-7897 FU Cancer Research UK [10118, 10124, 13065, 14136]; Medical Research Council [G0401527, G0900871, G1000143]; NCI NIH HHS [R01 CA136924, P30 CA042014, P30 CA068485, P30 CA076292, P50 CA140388, R01 CA056678, R01 CA068578, R01 CA072818, R01 CA082664, R01 CA084979, R01 CA088164, R01 CA092447, R01 CA092579, R01 CA128813, R01 CA128978, R37 CA054281, RC2 CA148085, U01 CA063464, U01 CA089600, U01 CA098216, U01 CA098233, U01 CA098710, U01 CA098758, U01 CA127298, U01 CA136792, U10 CA037429, U19 CA148065, U19 CA148112, U19 CA148537, UG1 CA189974, UM1 CA182883]; NHGRI NIH HHS [U01 HG004446, U01 HG004726]; NIEHS NIH HHS [P30 ES007784, R01 ES011126]; NIGMS NIH HHS [S06 GM008016]; Prostate Cancer UK [G2011/36, G2012/48] NR 29 TC 103 Z9 103 U1 3 U2 31 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD OCT PY 2014 VL 46 IS 10 BP 1103 EP 1109 DI 10.1038/ng.3094 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA AQ1PU UT WOS:000342554100013 PM 25217961 ER PT J AU Gharahkhani, P Burdon, KP Fogarty, R Sharma, S Hewitt, AW Martin, S Law, MH Cremin, K Bailey, JNC Loomis, SJ Pasquale, LR Haines, JL Hauser, MA Viswanathan, AC McGuffin, P Topouzis, F Foster, PJ Graham, SL Casson, RJ Chehade, M White, AJ Zhou, T Souzeau, E Landers, J Fitzgerald, JT Klebe, S Ruddle, JB Goldberg, I Healey, PR Mills, RA Wang, JJ Montgomery, GW Martin, NG Radford-Smith, G Whiteman, DC Brown, MA Wiggs, JL Mackey, DA Mitchell, P MacGregor, S Craig, JE AF Gharahkhani, Puya Burdon, Kathryn P. Fogarty, Rhys Sharma, Shiwani Hewitt, Alex W. Martin, Sarah Law, Matthew H. Cremin, Katie Bailey, Jessica N. Cooke Loomis, Stephanie J. Pasquale, Louis R. Haines, Jonathan L. Hauser, Michael A. Viswanathan, Ananth C. McGuffin, Peter Topouzis, Fotis Foster, Paul J. Graham, Stuart L. Casson, Robert J. Chehade, Mark White, Andrew J. Zhou, Tiger Souzeau, Emmanuelle Landers, John Fitzgerald, Jude T. Klebe, Sonja Ruddle, Jonathan B. Goldberg, Ivan Healey, Paul R. Mills, Richard A. Wang, Jie Jin Montgomery, Grant W. Martin, Nicholas G. Radford-Smith, Graham Whiteman, David C. Brown, Matthew A. Wiggs, Janey L. Mackey, David A. Mitchell, Paul MacGregor, Stuart Craig, Jamie E. CA Wellcome Trust Case Control Consor NEIGHBORHOOD Consortium TI Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; INTRAOCULAR-PRESSURE; TRABECULAR MESHWORK; ACTIN-FILAMENTS; AQUEOUS-HUMOR; GENE; IDENTIFICATION; AFAP-110; ABILITY AB Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 x 10(-19)), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 x 10(-10)) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 x 10(-10)). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells. C1 [Gharahkhani, Puya; Law, Matthew H.; Montgomery, Grant W.; Martin, Nicholas G.; Whiteman, David C.; MacGregor, Stuart] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Burdon, Kathryn P.; Fogarty, Rhys; Sharma, Shiwani; Martin, Sarah; Zhou, Tiger; Souzeau, Emmanuelle; Landers, John; Fitzgerald, Jude T.; Mills, Richard A.; Craig, Jamie E.] Flinders Univ S Australia, Dept Ophthalmol, Adelaide, SA 5001, Australia. [Burdon, Kathryn P.; Mackey, David A.] Univ Tasmania, Menzies Res Inst Tasmania, Hobart, Tas, Australia. [Burdon, Kathryn P.; Hewitt, Alex W.; Ruddle, Jonathan B.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, CERA, Melbourne, Vic, Australia. [Cremin, Katie; Brown, Matthew A.] Univ Queensland, Diamantina Inst, Brisbane, Qld, Australia. [Bailey, Jessica N. Cooke; Haines, Jonathan L.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA. [Bailey, Jessica N. Cooke; Haines, Jonathan L.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Loomis, Stephanie J.; Pasquale, Louis R.; Wiggs, Janey L.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Loomis, Stephanie J.; Pasquale, Louis R.; Wiggs, Janey L.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Pasquale, Louis R.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Hauser, Michael A.] Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. [Hauser, Michael A.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Viswanathan, Ananth C.; Foster, Paul J.] Moorfields Eye Hosp Natl Hlth Serv NHS Fdn Trus, Biomed Res Ctr, NIHR, London, England. [Viswanathan, Ananth C.; Foster, Paul J.] UCL, Inst Ophthalmol, London, England. [McGuffin, Peter] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Res Ctr, MRC, London, England. [Topouzis, Fotis] Aristotle Univ Thessaloniki, Sch Med, AHEPA Hosp, Dept Ophthalmol, Thessaloniki, Greece. [Graham, Stuart L.] Macquarie Univ, Sydney, NSW 2109, Australia. [Casson, Robert J.; Chehade, Mark] Univ Adelaide, South Australian Inst Ophthalmol, Adelaide, SA, Australia. [White, Andrew J.; Healey, Paul R.; Wang, Jie Jin] Univ Sydney, Westmead Millennium Inst, Ctr Vis Res, Westmead, NSW 2145, Australia. [Klebe, Sonja] Flinders Univ S Australia, Flinders Med Ctr, Dept Anat Pathol, Adelaide, SA 5001, Australia. [Goldberg, Ivan] Univ Sydney, Dept Ophthalmol, Sydney, NSW 2006, Australia. [Radford-Smith, Graham] Univ Queensland, Sch Med, Brisbane, Qld, Australia. [Mackey, David A.] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia. [Craig, Jamie E.] South Australian Hlth & Med Res Inst, Adelaide, SA, Australia. RP Craig, JE (reprint author), Flinders Univ S Australia, Dept Ophthalmol, Adelaide, SA 5001, Australia. EM puya.gharahkhani@qimrberghofer.edu.au; jamie.craig@flinders.edu.au RI Montgomery, Grant/B-7148-2008; Hewitt, Alex/D-1936-2013; Whiteman, David/P-2728-2014; Mackey, David/H-5340-2014; Macgregor, Stuart/C-6442-2009; Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014 OI Montgomery, Grant/0000-0002-4140-8139; Hewitt, Alex/0000-0002-5123-5999; Whiteman, David/0000-0003-2563-9559; Mackey, David/0000-0001-7914-4709; Gharahkhani, Puya/0000-0002-4203-5952; Martin, Nicholas/0000-0003-4069-8020; Macgregor, Stuart/0000-0001-6731-8142; Wang, Jie Jin/0000-0001-9491-4898; FU Royal Australian; New Zealand College of Ophthalmology (RANZCO) Eye Foundation; National Health and Medical Research Council (NHMRC) of Australia [535074, 1023911]; NHMRC [1031362, 1037838, 1048037, 1009844, 1031920]; Alcon Research Institute grant; Allergan Unrestricted grant; BrightFocus Foundation; Ramaciotti Establishment Grant; Queensland Cancer Fund; NHMRC of Australia [199600, 552429, 241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498]; US National Cancer Institute [5 R01 CA 001833, R01 CA 136725]; NHMRC Medical Genomics Grant; US National Institutes of Health (NIH) Center for Inherited Research (CIDR), NIH/National Eye Institute (NEI) [1RO1EY018246]; Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC), Cerylid Biosciences (Melbourne); NHMRC, Canberra Australia [974159, 211069, 457349, 512423, 475604, 529912]; Centre for Clinical Research Excellence in Translational Clinical Research in Eye Diseases; NHMRC Senior Research Fellowships [358702, 632909]; Wellcome Trust, UK, Wellcome Trust Case Control Consortium 2 [085475B08Z, 08547508Z, 076113]; Medical Research Council (MRC) [G0401527]; Research Into Ageing [262]; NIHR (UK) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology funds [BRC2_009]; NEI [HG005259-01]; NIH [HHSN268200782096C, EY015543, EY006827, HL73042, HL073389, EY13315, EY023646, CA87969]; NEI through American Recovery and Reinvestment Act (ARRA) [3R01EY015872-05S1, 3R01EY019126-02S1]; Harvard Glaucoma Center for Excellence; Margolis Fund; Glaucoma Research Foundation; American Health Assistance Foundation; Glaucoma Foundation; Research to Prevent Blindness; NIH GEI (Gene Environment Initiative) [U01HG04424, U01HG004728]; GENEVA Coordinating Center [U01HG004446]; Australian Research Council (ARC); NHMRC Fellowships; Australian NHMRC Fellowships; ARC; NHMRC; [EY022305]; [CA49449]; [CA55075]; [EY009149]; [HG004608]; [EY008208]; [EY015473]; [EY012118]; [EY015682]; [EY011671]; [EY09580]; [EY013178]; [RR015574]; [EY015872]; [EY010886]; [EY009847]; [EY014104]; [EY011008]; [EY144428]; [EY144448]; [EY18660]; [T32 EY007157]; [T32 EY21453-2] FX Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG): support for recruitment of ANZRAG was provided by the Royal Australian and New Zealand College of Ophthalmology (RANZCO) Eye Foundation. Genotyping was funded by the National Health and Medical Research Council (NHMRC) of Australia (#535074 and #1023911). This work was also supported by funding from NHMRC #1031362 awarded to J.E.C., NHMRC #1037838 awarded to A.W.H., NHMRC #1048037 awarded to S.L.G., NHMRC #1009844 awarded to R.J.C. and I.G., NHMRC #1031920 and an Alcon Research Institute grant awarded to D.A.M., an Allergan Unrestricted grant awarded to A.J.W., the BrightFocus Foundation and a Ramaciotti Establishment Grant. The authors acknowledge the support of B. Usher-Ridge in patient recruitment and data collection and P. Danoy and J. Hadler for genotyping.; Controls for the ANZRAG discovery cohort were drawn from the Australian Cancer Study, the Study of Digestive Health and a study of inflammatory bowel diseases. The Australian Cancer Study was supported by the Queensland Cancer Fund and the NHMRC of Australia (program number 199600, awarded to D.C.W., A.C. Green, N.K. Hayward, P.G. Parsons, D.M. Purdie and P.M. Webb, and program number 552429, awarded to D.C.W.). The Study of Digestive Health was supported by grant number 5 R01 CA 001833 from the US National Cancer Institute (awarded to D.C.W.).; The Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study (BEAGESS) sponsored the genotyping of cases with esophageal cancer and Barrett's esophagus, which were used as unscreened controls in the ANZRAG discovery cohort. BEAGESS was funded by grant R01 CA 136725 from the US National Cancer Institute.; Genotyping for part of the Australian twin control sample included in the ANZRAG replication cohort was funded by an NHMRC Medical Genomics Grant. Genotyping for the remainder of twin controls was performed by the US National Institutes of Health (NIH) Center for Inherited Research (CIDR) as part of NIH/National Eye Institute (NEI) grant 1RO1EY018246, and we are grateful to C. Day and staff We acknowledge with appreciation all women who participated in the QIMR endometriosis study. We thank Endometriosis Associations for supporting study recruitment. We thank S. Nicolaides and the Queensland Medical Laboratory for pro bono collection and delivery of blood samples and other pathology services for assistance with blood collection. The QIMR twin and endometriosis studies were supported by grants from the NHMRC of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485 and 552498), the Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC), Cerylid Biosciences (Melbourne) and donations from N. and S. Hawkins. We thank M.J. Wright, M.J. Campbell, A. Caracella, S. Gordon, D.R. Nyholt, A.K. Henders, B. Haddon, D. Smyth, H. Beeby, O. Zheng and B. Chapman for their input into project management, databases, sample processing and genotyping. We are grateful to the many research assistants and interviewers for assistance with the studies contributing to the QIMR twin collection.; Blue Mountains Eye Study (BMES): BMES was supported by the NHMRC, Canberra Australia (974159, 211069, 457349, 512423, 475604 and 529912), the Centre for Clinical Research Excellence in Translational Clinical Research in Eye Diseases, NHMRC Senior Research Fellowships (358702 and 632909 to J.J.W.) and the Wellcome Trust, UK, as part of Wellcome Trust Case Control Consortium 2 (A.C.V., P. McGuffin, P. Mitchell, F.T. and P.J.F.) for genotyping costs of the entire BMES population (085475B08Z, 08547508Z, 076113). P.J.F. is also supported by Medical Research Council (MRC) G0401527, Research Into Ageing (Ref 262) and NIHR (UK) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology (BRC2_009) funds.; The BMES acknowledges E. Rochtchina from the Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute University of Sydney, J. Attia, R. Scott and E.G. Holliday from the University of Newcastle, J. Xie and P.N. Baird from the Centre for Eye Research Australia, University of Melbourne, M.T. Inouye, Medical Systems Biology, Department of Pathology and Department of Microbiology and Immunology, University of Melbourne and X. Sim, National University of Singapore.; NEI Glaucoma Human Genetics Collaboration (NEIGHBOR): genotyping services for the NEIGHBOR study were provided by the CIDR and were supported by the NEI through grant HG005259-01 (J.L.W.). Additionally, CIDR is funded through a federal contract from the NIH to The Johns Hopkins University, contract number HHSN268200782096C. Collecting and processing samples for the NEIGHBOR data set was supported by the NEI through American Recovery and Reinvestment Act (ARRA) grants 3R01EY015872-05S1 (J.L.W.) and 3R01EY019126-02S1 (M.A.H.). Genotype imputation and meta-analysis were supported by EY022305 (J.L.W.). Funding for the collection of cases and controls was provided by the following NIH grants: EY015543 (R.R. Allingham); EY006827 (D. Gaasterland); HL73042, HL073389, EY13315, EY023646 (M.A.H.); CA87969, CA49449, CA55075 (J.H. Kang); EY009149 (P.R. Lichter); HG004608 (C. McCarty); EY008208 (EA. Medeiros); EY015473 (L.R.P.); EY012118 (M. Pericak-Vance); EY015682 (A. Realini); EY011671, EY09580 (J.E. Richards); EY013178 (J.S. Schuman); RR015574, EY015872, EY010886, EY009847, EY014104 (J.L.W.); EY011008, EY144428, EY144448 and EY18660 (K. Zhang). J.L.W. and L.R.P. are also supported by the Harvard Glaucoma Center for Excellence and the Margolis Fund. Y. Liu is supported by the Glaucoma Research Foundation, the American Health Assistance Foundation and the Glaucoma Foundation. J.L.W., L.R.P., D.C. Musch and J.E. Richards are supported by Research to Prevent Blindness. J.N.C.B. is supported by NIH T32 EY007157 (CWRU) and T32 EY21453-2 (VUMC).; MEEI case-control sample: genotyping for the Massachusetts Eye and Ear Infirmary (MEEI) case-control sample was performed at the Broad Institute of MIT and Harvard with funding support from the NIH GEI (Gene Environment Initiative) (U01HG04424 and U01HG004728). The GENEVA Coordinating Center (U01HG004446) assisted with genotype cleaning. Imputation was supported by NIH EY022305. Collection of cases and controls was supported by NIH EY015872.; Support for molecular analysis of the associated genes was provided by the Ophthalmic Research Institute of Australia. The authors acknowledge the support of M. Philpott in collection of cadaveric human eye tissues and N. Mabarrack for initial optimization of the antibody to AFAP.; S. MacGregor is supported by Australian Research Council (ARC) and NHMRC Fellowships. G.W.M., M.A.B., K.P.B., D.C.W. and J.E.C. are supported by Australian NHMRC Fellowships. D.C.W. was funded by the ARC and G.R.-S. was funded by NHMRC during the period of this study. The authors acknowledge C. Abbot (Alcon Research Ltd.) for providing normal and glaucomatous trabecular meshwork cell lines, NTM-5 and GTM-3, respectively, as a kind gift. NR 33 TC 36 Z9 37 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD OCT PY 2014 VL 46 IS 10 BP 1120 EP 1125 DI 10.1038/ng.3079 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA AQ1PU UT WOS:000342554100016 PM 25173105 ER PT J AU Hysi, PG Cheng, CY Springelkamp, H Macgregor, S Bailey, JNC Wojciechowski, R Vitart, V Nag, A Hewitt, AW Hohn, R Venturini, C Mirshahi, A Ramdas, WD Thorleifsson, G Vithana, E Khor, CC Stefansson, AB Liao, JM Haines, JL Amin, N Wang, YX Wild, PS Ozel, AB Li, JZ Fleck, BW Zeller, T Staffieri, SE Teo, YY Cuellar-Partida, G Luo, XY Allingham, RR Richards, JE Senft, A Karssen, LC Zheng, YF Bellenguez, C Xu, L Iglesias, AI Wilson, JF Kang, JH van Leeuwen, EM Jonsson, V Thorsteinsdottir, U Despriet, DDG Ennis, S Moroi, SE Martin, NG Jansonius, NM Yazar, S Tai, ES Amouyel, P Kirwan, J van Koolwijk, LME Hauser, MA Jonasson, F Leo, P Loomis, SJ Fogarty, R Rivadeneira, F Kearns, L Lackner, KJ de Jong, PTVM Simpson, CL Pennell, CE Oostra, BA Uitterlinden, AG Saw, SM Lotery, AJ Bailey-Wilson, JE Hofman, A Vingerling, JR Maubaret, C Pfeiffer, N Wolfs, RCW Lemij, HG Young, TL Pasquale, LR Delcourt, C Spector, TD Klaver, CCW Small, KS Burdon, KP Stefansson, K Wong, TY Viswanathan, A Mackey, DA Craig, JE Wiggs, JL van Duijn, CM Hammond, CJ Aung, T AF Hysi, Pirro G. Cheng, Ching-Yu Springelkamp, Henriet Macgregor, Stuart Bailey, Jessica N. Cooke Wojciechowski, Robert Vitart, Veronique Nag, Abhishek Hewitt, Alex W. Hohn, Rene Venturini, Cristina Mirshahi, Alireza Ramdas, Wishal D. Thorleifsson, Gudmar Vithana, Eranga Khor, Chiea-Chuen Stefansson, Arni B. Liao, Jiemin Haines, Jonathan L. Amin, Najaf Wang, Ya Xing Wild, Philipp S. Ozel, Ayse B. Li, Jun Z. Fleck, Brian W. Zeller, Tanja Staffieri, Sandra E. Teo, Yik-Ying Cuellar-Partida, Gabriel Luo, Xiaoyan Allingham, R. Rand Richards, Julia E. Senft, Andrea Karssen, Lennart C. Zheng, Yingfeng Bellenguez, Celine Xu, Liang Iglesias, Adriana I. Wilson, James F. Kang, Jae H. van Leeuwen, Elisabeth M. Jonsson, Vesteinn Thorsteinsdottir, Unnur Despriet, Dominiek D. G. Ennis, Sarah Moroi, Sayoko E. Martin, Nicholas G. Jansonius, Nomdo M. Yazar, Seyhan Tai, E-Shyong Amouyel, Philippe Kirwan, James van Koolwijk, Leonieke M. E. Hauser, Michael A. Jonasson, Fridbert Leo, Paul Loomis, Stephanie J. Fogarty, Rhys Rivadeneira, Fernando Kearns, Lisa Lackner, Karl J. de Jong, Paulus T. V. M. Simpson, Claire L. Pennell, Craig E. Oostra, Ben A. Uitterlinden, Andre G. Saw, Seang-Mei Lotery, Andrew J. Bailey-Wilson, Joan E. Hofman, Albert Vingerling, Johannes R. Maubaret, Cecilia Pfeiffer, Norbert Wolfs, Roger C. W. Lemij, Hans G. Young, Terri L. Pasquale, Louis R. Delcourt, Cecile Spector, Timothy D. Klaver, Caroline C. W. Small, Kerrin S. Burdon, Kathryn P. Stefansson, Kari Wong, Tien-Yin Viswanathan, Ananth Mackey, David A. Craig, Jamie E. Wiggs, Janey L. van Duijn, Cornelia M. Hammond, Christopher J. Aung, Tin CA BMES GWAS Grp NEIGHBORHOOD Consortium Wellcome Trust Case Control Conso TI Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma SO NATURE GENETICS LA English DT Article ID OPEN-ANGLE GLAUCOMA; CENTRAL CORNEAL THICKNESS; COMMON VARIANTS; ASSOCIATION; METAANALYSIS; POPULATION; EXPRESSION; REDUCTION; TRIAL; RISK AB Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 x 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 x 10(-11) for rs2472493 near ABCA1 and P = 6.39 x 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 x 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG. C1 [Hysi, Pirro G.; Small, Kerrin S.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Cheng, Ching-Yu; Nag, Abhishek; Vithana, Eranga; Liao, Jiemin; Zheng, Yingfeng; Saw, Seang-Mei; Wong, Tien-Yin; Aung, Tin] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [Cheng, Ching-Yu; Vithana, Eranga; Khor, Chiea-Chuen; Liao, Jiemin; Wong, Tien-Yin; Aung, Tin] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore. [Cheng, Ching-Yu; Vithana, Eranga; Khor, Chiea-Chuen; Liao, Jiemin; Teo, Yik-Ying; Zheng, Yingfeng; Tai, E-Shyong; Saw, Seang-Mei; Wong, Tien-Yin; Aung, Tin] Natl Univ Hlth Syst, Singapore, Singapore. [Cheng, Ching-Yu; Teo, Yik-Ying; Zheng, Yingfeng; Tai, E-Shyong; Saw, Seang-Mei; Wong, Tien-Yin] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Cheng, Ching-Yu; Vithana, Eranga; Tai, E-Shyong; Saw, Seang-Mei] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore. [Springelkamp, Henriet; Ramdas, Wishal D.; Richards, Julia E.; Despriet, Dominiek D. G.; Vingerling, Johannes R.; Wolfs, Roger C. W.; Klaver, Caroline C. W.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Springelkamp, Henriet; Ramdas, Wishal D.; Amin, Najaf; Karssen, Lennart C.; Iglesias, Adriana I.; van Leeuwen, Elisabeth M.; van Koolwijk, Leonieke M. E.; Rivadeneira, Fernando; Uitterlinden, Andre G.; Hofman, Albert; Vingerling, Johannes R.; Klaver, Caroline C. W.; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Macgregor, Stuart; Cuellar-Partida, Gabriel; Martin, Nicholas G.] Royal Brisbane Hosp, QIMR Berghofer Med Res Inst, Brisbane, Qld 4029, Australia. [Bailey, Jessica N. Cooke; Haines, Jonathan L.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Wojciechowski, Robert] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Wojciechowski, Robert; Simpson, Claire L.; Bailey-Wilson, Joan E.] Natl Human Genome Res Inst, US Natl Inst Hlth, Baltimore, MD USA. [Vitart, Veronique] Univ Edinburgh, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh, Midlothian, Scotland. [Hewitt, Alex W.; Staffieri, Sandra E.; Kearns, Lisa; Mackey, David A.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Hohn, Rene; Mirshahi, Alireza; Pfeiffer, Norbert] Univ Med Ctr Mainz, Dept Ophthalmol, Mainz, Germany. [Venturini, Cristina] UCL, Inst Ophthalmol, London, England. [Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Stefansson, Kari] deCODE Amgen, Reykjavik, Iceland. [Khor, Chiea-Chuen] Genome Inst Singapore, Div Human Genet, Singapore, Singapore. [Stefansson, Arni B.] Eye Clin, Reykjavik, Iceland. [Wang, Ya Xing; Xu, Liang] Capital Univ Med Sci, Beijing Tongren Hosp, Beijing Inst Ophthalmol, Beijing, Peoples R China. [Wild, Philipp S.] Univ Med Ctr Mainz, Dept Internal Med 2, Mainz, Germany. [Ozel, Ayse B.; Li, Jun Z.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Fleck, Brian W.] Natl Hlth Serv NHS Princess Alexandra Eye Pavil, Edinburgh, Midlothian, Scotland. [Zeller, Tanja] Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, Hamburg, Germany. [Teo, Yik-Ying] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore. [Luo, Xiaoyan; Young, Terri L.] Duke Univ, Duke Eye Ctr, Durham, NC USA. [Allingham, R. Rand; Hauser, Michael A.] Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. [Senft, Andrea] Univ Hosp Schleswig Holstein, Inst Med Biometry & Stat, Lubeck, Germany. [Bellenguez, Celine; Amouyel, Philippe] INSERM, UMR 774, F-59045 Lille, France. [Bellenguez, Celine; Amouyel, Philippe] Univ Lille 2, Lille, France. [Bellenguez, Celine; Amouyel, Philippe] Inst Pasteur, F-59019 Lille, France. [Wilson, James F.] Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Kang, Jae H.; Pasquale, Louis R.] Harvard Univ, Sch Med, Channing Div Network Med, Boston, MA USA. [Jonsson, Vesteinn] Landspitali Natl Univ Hosp, Dept Ophthalmol, Reykjavik, Iceland. [Ennis, Sarah] Univ Southampton, Fac Med, Human Genet & Genom Med, Southampton SO9 5NH, Hants, England. [Moroi, Sayoko E.] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Jansonius, Nomdo M.] Univ Groningen, Univ Med Ctr Groningen, Dept Ophthalmol, Groningen, Netherlands. [Yazar, Seyhan; Mackey, David A.] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia. [Tai, E-Shyong] Natl Univ Singapore, Dept Med, Singapore 117548, Singapore. [Amouyel, Philippe] Univ Lille, Ctr Hosp Reg, Lille, France. [Kirwan, James] Portsmouth Hosp NHS Trust, Dept Ophthalmol, Portsmouth, Hants, England. [Hauser, Michael A.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Jonasson, Fridbert] Univ Iceland, Fac Med, Reykjavik, Iceland. [Leo, Paul] Univ Queensland, Diamantina Inst, Woollongabba, Qld, Australia. [Loomis, Stephanie J.; Pasquale, Louis R.; Wiggs, Janey L.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Loomis, Stephanie J.; Pasquale, Louis R.; Wiggs, Janey L.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Fogarty, Rhys; Burdon, Kathryn P.; Craig, Jamie E.] Flinders Univ S Australia, Dept Ophthalmol, Adelaide, SA 5001, Australia. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.; Hofman, Albert] Netherlands Consortium Healthy Ageing, Netherlands Genom Initiat, The Hague, Netherlands. [Lackner, Karl J.] Inst Clin Chem, Mainz, Germany. [Lackner, Karl J.] Lab Med, Mainz, Germany. [de Jong, Paulus T. V. M.] Netherlands Inst Neurosci, Amsterdam, Netherlands. [de Jong, Paulus T. V. M.] Leiden Univ, Med Ctr, Dept Ophthalmol, Leiden, Netherlands. [de Jong, Paulus T. V. M.] Acad Med Ctr, Dept Ophthalmol, Amsterdam, Netherlands. [Pennell, Craig E.] Univ Western Australia, Sch Womens & Infants Hlth, Perth, WA 6009, Australia. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Lotery, Andrew J.] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England. [Maubaret, Cecilia; Delcourt, Cecile] Univ Bordeaux, ISPED, Bordeaux, France. [Maubaret, Cecilia; Delcourt, Cecile] INSERM, Ctr INSERM Epidemiol Biostat Bordeaux U897, Bordeaux, France. [Lemij, Hans G.] Rotterdam Eye Hosp, Glaucoma Serv, Rotterdam, Netherlands. [Viswanathan, Ananth] Moorfields Eye Hosp NHS Fdn Trust, Biomed Res Ctr, NIHR, London, England. RP Aung, T (reprint author), Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. EM chris.hammond@kcl.ac.uk; aung_tin@yahoo.co.uk RI Delcourt, Cecile/I-2627-2013; Macgregor, Stuart/C-6442-2009; Cuellar Partida, Gabriel/P-3701-2014; Wilson, James F/A-5704-2009; Rivadeneira, Fernando/O-5385-2015; Hewitt, Alex/D-1936-2013; wang, YA XING/K-9671-2016; Mackey, David/H-5340-2014; Cuellar Partida, Gabriel/C-6686-2017; OI Delcourt, Cecile/0000-0002-2099-0481; Macgregor, Stuart/0000-0001-6731-8142; Wilson, James F/0000-0001-5751-9178; Rivadeneira, Fernando/0000-0001-9435-9441; Hewitt, Alex/0000-0002-5123-5999; Wojciechowski, Robert/0000-0002-9593-4652; wang, YA XING/0000-0003-2749-7793; Mackey, David/0000-0001-7914-4709; Cuellar Partida, Gabriel/0000-0001-7648-4097; Yazar, Seyhan/0000-0003-0994-6196; Bailey-Wilson, Joan/0000-0002-9153-2920; Hohn, Rene /0000-0003-2870-1469; Small, Kerrin/0000-0003-4566-0005; Khor, Chiea Chuen/0000-0002-1128-4729; Hammond, Christopher/0000-0002-3227-2620; Tai, E Shyong/0000-0003-2929-8966; Karssen, Lennart C./0000-0002-1959-342X; Martin, Nicholas/0000-0003-4069-8020 FU Chief Scientist Office [CZB/4/438, CZB/4/710]; Department of Health [SRF/01/010]; Medical Research Council [MC_PC_U127561128]; NEI NIH HHS [K08 EY022943, P30 EY014104, R01 EY015473, R01 EY022124, R01 EY022305, R01 EY023512]; NHGRI NIH HHS [U01 HG004728] NR 28 TC 46 Z9 47 U1 2 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD OCT PY 2014 VL 46 IS 10 BP 1126 EP 1130 DI 10.1038/ng.3087 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA AQ1PU UT WOS:000342554100017 PM 25173106 ER PT J AU Stuckey, DW Shah, K AF Stuckey, Daniel W. Shah, Khalid TI Stem cell-based therapies for cancer treatment: separating hope from hype SO NATURE REVIEWS CANCER LA English DT Review ID MESENCHYMAL STROMAL CELLS; UROKINASE PLASMINOGEN-ACTIVATOR; NEURAL STEM/PROGENITOR CELLS; LUNG METASTASIS MODEL; INHIBIT TUMOR-GROWTH; BONE-MARROW; GENE-THERAPY; MALIGNANT GLIOMA; BRAIN-TUMORS; PROGENITOR CELLS AB Stem cell-based therapies are emerging as a promising strategy to tackle cancer. Multiple stem cell types have been shown to exhibit inherent tropism towards tumours. Moreover, when engineered to express therapeutic agents, these pathotropic delivery vehicles can effectively target sites of malignancy. This perspective considers the current status of stem cell-based treatments for cancer and provides a rationale for translating the most promising preclinical studies into the clinic. C1 [Stuckey, Daniel W.; Shah, Khalid] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurotherapy & Imaging Lab, Boston, MA 02114 USA. [Stuckey, Daniel W.; Shah, Khalid] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Shah, Khalid] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. [Shah, Khalid] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Shah, K (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurotherapy & Imaging Lab, Boston, MA 02114 USA. EM kshah@mgh.harvard.edu FU James S. McDonnell Foundation; [R01CA138922]; [R01CA173077] FX The authors apologize to all colleagues whose work could not be cited owing to space limitations. This work was supported by grants R01CA138922, R01CA173077, and the James S. McDonnell Foundation. NR 126 TC 37 Z9 38 U1 4 U2 67 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD OCT PY 2014 VL 14 IS 10 BP 683 EP 691 DI 10.1038/nrc3798 PG 9 WC Oncology SC Oncology GA AQ1EU UT WOS:000342525500012 PM 25176333 ER PT J AU Kotton, CN AF Kotton, Camille N. TI Immunization after kidney transplantation-what is necessary and what is safe? SO NATURE REVIEWS NEPHROLOGY LA English DT Review ID SOLID-ORGAN TRANSPLANTATION; INFLUENZA VACCINATION; ADVISORY-COMMITTEE; UNITED-STATES; PNEUMOCOCCAL VACCINE; PRACTICES ACIP; RECIPIENTS; RECOMMENDATIONS; ADULTS; LIVER AB Many transplant recipients are not protected against vaccine-preventable illnesses, primarily because vaccination is still an underutilized tool both before and after transplantation This missed opportunity for protection can result in substantial morbidity, graft loss and mortality. Immunization strategies should be formulated early in the course of renal disease to maximize the likelihood of vaccine-induced immunity, particularly as booster or secondary antibody responses are less affected by immune compromise than are primary or de novo antibody responses in naive vaccine recipients. However, live vaccines should be avoided in immunocompromised hosts. Although some concern has been raised regarding increased HLA sensitization after vaccination, no clinical data to suggest harm currently exists; overall, non-live vaccines seem to be immunogenic, protective and safe. In organ transplant recipients, some vaccines are indicated based on specific risk factors and certain vaccines, such as hepatitis B, can protect against donor-derived infection. Vaccines given to close contacts of renal transplant recipients can provide an additional layer of protection against infectious diseases. In this article, optimal vaccination of adult transplant recipients, including safety, efficacy, indication and timing, is reviewed. C1 Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Kotton, CN (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St,Cox 5, Boston, MA 02114 USA. EM ckotton@partners.org NR 53 TC 4 Z9 4 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5061 EI 1759-507X J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD OCT PY 2014 VL 10 IS 10 BP 555 EP 562 DI 10.1038/nrneph.2014.122 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA AQ0MA UT WOS:000342476200006 PM 25072119 ER PT J AU Wang, DH Liu, HS AF Wang, Danhong Liu, Hesheng TI Functional Connectivity Architecture of the Human Brain: Not All the Same SO NEUROSCIENTIST LA English DT Article DE individual differences; functional connectivity; association cortex; lateralization; evolution; fMRI ID INDIVIDUAL VARIABILITY; PREFRONTAL CORTEX; CORPUS-CALLOSUM; NETWORKS; ASYMMETRY; EVOLUTION; COGNITION; CHILDREN; FMRI; SPECIALIZATION AB Imaging studies suggest that individual differences in cognition and behavior might relate to differences in brain connectivity, particularly in the higher order association regions. Understanding the extent to which two brains can differ is crucial in clinical and basic neuroscience research. Here we highlight two major sources of variance that contribute to intersubject variability in connectivity measurements but are often mixed: the spatial distribution variability and the connection strength variability. We then offer a hypothesis about how the cortical surface expansion during human evolution may have led to remarkable intersubject variability in brain connectivity. We propose that a series of changes in connectivity architecture occurred in response to the pressure for processing efficiency in the enlarged brain. These changes not only distinguish us from our evolutionary ancestors, but also enable each individual to develop more uniquely. This hypothesis may gain support from the significant spatial correlations among evolutionary cortical expansion, the density of long-range connections, hemispheric functional specialization, and intersubject variability in connectivity. C1 [Wang, Danhong; Liu, Hesheng] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Wang, Danhong; Liu, Hesheng] Harvard Univ, Sch Med, Charlestown, MA USA. RP Liu, HS (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Suite 2301,149 13th St, Charlestown, MA 02129 USA. EM hesheng@nmr.mgh.harvard.edu RI wang, danhong/M-2699-2014 FU NIH [K25NS069805]; NARSAD FX This work was supported by NIH grant K25NS069805, and NARSAD Young Investigator Grant. NR 51 TC 6 Z9 7 U1 2 U2 17 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 EI 1089-4098 J9 NEUROSCIENTIST JI Neuroscientist PD OCT PY 2014 VL 20 IS 5 BP 432 EP 438 DI 10.1177/1073858414543290 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AQ2TB UT WOS:000342640800006 PM 25030990 ER PT J AU Sepulcre, J AF Sepulcre, Jorge TI Functional Streams and Cortical Integration in the Human Brain SO NEUROSCIENTIST LA English DT Review DE functional streams; cortical integration; multimodal integration; multisensory; visual-motor; auditory-motor ID HUMAN PARIETAL OPERCULUM; SENSORY-MOTOR INTEGRATION; PRIMATE CEREBRAL-CORTEX; CONDUCTION APHASIA; ARCUATE-FASCICULUS; CYTOARCHITECTONIC AREAS; HUMAN CONNECTOMICS; PREMOTOR CORTEX; MIRROR NEURONS; MACAQUE MONKEY AB The processing of brain information relies on the organization of neuronal networks and circuits that in the end must provide the substrate for human cognition. However, the presence of highly complex and multirelay neuronal interactions has limited our ability to disentangle the assemblies of brain systems. The present review article focuses on the latest developments to understand the architecture of functional streams of the human brain at the large-scale level. Particularly, this article presents a comprehensive framework and recent findings about how the highly modular sensory cortex, such as the visual, somatosensory, auditory, as well as motor cortex areas, connects to more parallel-organized cortical hubs in the brain's functional connectome. C1 [Sepulcre, Jorge] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Sepulcre, Jorge] Harvard Univ, Sch Med, Boston, MA USA. [Sepulcre, Jorge] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Sepulcre, Jorge] Harvard Univ, Sch Med, Charlestown, MA USA. RP Sepulcre, J (reprint author), Harvard Univ, 52 Oxford St,Northwest Bldg,280-02, Cambridge, MA 02138 USA. EM sepulcre@nmr.mgh.harvard.edu FU Alzheimer's Association [NIRG-11-205690] FX The author disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Alzheimer's Association grant NIRG-11-205690 (J.S.). NR 88 TC 9 Z9 9 U1 1 U2 17 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 EI 1089-4098 J9 NEUROSCIENTIST JI Neuroscientist PD OCT PY 2014 VL 20 IS 5 BP 499 EP 508 DI 10.1177/1073858414531657 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AQ2TB UT WOS:000342640800011 PM 24737695 ER PT J AU Seyyedi, M Nadol, JB AF Seyyedi, Mohammad Nadol, Joseph B., Jr. TI Intracochlear Inflammatory Response to Cochlear Implant Electrodes in Humans SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Cochlear implant; Endocochlear; Foreign body; Giant cell; Labyrinthitis; Tissue response ID FOREIGN-BODY REACTION; HUMAN TEMPORAL BONES; CHRONIC ELECTRICAL-STIMULATION; AUDITORY-NERVE; RESIDUAL HEARING; TISSUE FORMATION; HISTOPATHOLOGY; BIOMATERIALS; COMPLICATIONS; GRANULOMA AB Hypothesis: This study evaluates the types and degrees of tissue response adjacent to the electrode of multichannel cochlear implants. Background: Cochlear implant electrodes have been classified as biocompatible prostheses. Nevertheless, in some reports, electrode extrusion, chronic inflammation, and even soft failure of the implant system have been attributed to a tissue response to the electrode. Methods: All celloidin-embedded temporal bones with multichannel cochlear implants from the temporal bone collection of the Massachusetts Eye and Ear Infirmary were included in the study. A total of 28 temporal bones from 21 subjects were identified and processed for histology. The severity of cellular response including eosinophil and lymphocytic infiltration, giant cell reaction, new bone formation, and fibrosis were scored on a scale from 0 to 3 at three 1-mm segments along the electrode: first 1 mm at the cochleostomy, last 1 mm from the tip of the electrode, and midway between these proximal and distal segments. The values were compared using the Wilcoxon test. Results: A granulomatous reaction to the electrode was observed in 27 (96.4%) temporal bones. Eosinophil infiltration was observed in 7 (25%) temporal bones, suggesting an allergic reaction. The Inflammatory response to the electrode was significantly greater at the basal turn of cochlea close to the cochleostomy (p < 0.05) than distal to it. Conclusion: An inflammatory response is common after cochlear implantation, and it is more robust at the cochleostomy than distal to it, suggesting the role of trauma of insertion as a contributing factor. C1 [Seyyedi, Mohammad; Nadol, Joseph B., Jr.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Seyyedi, Mohammad; Nadol, Joseph B., Jr.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Nadol, JB (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM joseph_nadol@meei.harvard.edu FU National Institute of Deafness and Other Communication Disorders [R01-DC000152] FX This study was supported by grant R01-DC000152 from the National Institute of Deafness and Other Communication Disorders. NR 44 TC 20 Z9 21 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD OCT PY 2014 VL 35 IS 9 BP 1545 EP 1551 PG 7 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA AQ0JG UT WOS:000342468700015 PM 25122600 ER PT J AU Kumarasinghe, MP Brown, I Raftopoulos, S Bourke, MJ Charlton, A de Boer, WB Eckstein, R Epari, K Gill, AJ Lam, AK Price, T Streutker, C Lauwers, GY AF Kumarasinghe, M. P. Brown, I. Raftopoulos, S. Bourke, M. J. Charlton, A. de Boer, W. B. Eckstein, R. Epari, K. Gill, A. J. Lam, A. K. Price, T. Streutker, C. Lauwers, G. Y. TI Standardised reporting protocol for endoscopic resection for Barrett oesophagus associated neoplasia: expert consensus recommendations SO PATHOLOGY LA English DT Review DE Early oesophageal neoplasia; endoscopic resections; key prognostic features; pathological assessment; standard reporting ID LYMPH-NODE METASTASIS; HIGH-GRADE DYSPLASIA; MUCOSAL RESECTION; MUSCULARIS MUCOSAE; EPITHELIAL NEOPLASMS; CRYPT DYSPLASIA; ADENOCARCINOMA; INVASION; DUPLICATION; MANAGEMENT AB Endoscopic resection (ER) is considered the therapy of choice for intraepithelial neoplasia associated with visible lesions and T1a adenocarcinoma. Pathologists are bound to encounter specimens collected via these techniques more frequently in their practice. A standardised protocol for handling, grossing, and assessing ER specimens should be adopted to ensure that all prognostic information and characteristics influencing treatment are included in reports (see Supplementary Video Abstract, http://links.lww.com/PAT/A22). The entire specimen should be appropriately oriented, processed and assessed. An ER specimen will commonly show intraepithelial neoplasia or invasive carcinoma. There are essential features that should be recorded if invasive carcinoma is found as they dictate further management and follow-up. These features are the margin status, depth of invasion, degree of differentiation and presence or absence of lymphovascular invasion. Important features such as duplication of muscularis mucosae should be recognised to avoid misinterpretation of depth of invasion. Key diagnostic and prognostic elements that are essential for optimal clinical decisions have been included in the reporting format proposed by the Structured Pathology Reporting committee of the Royal College of Pathologists of Australasia (RCPA). C1 [Kumarasinghe, M. P.; de Boer, W. B.] Queen Elizabeth II Med Ctr, PathWest, Nedlands, WA, Australia. [Kumarasinghe, M. P.; de Boer, W. B.] Univ Western Australia, Nedlands, WA 6009, Australia. [Brown, I.] Envoi Pathol, Herston, Qld, Australia. [Raftopoulos, S.] Sir Charles Gairdner Hosp, Nedlands, WA 6009, Australia. [Bourke, M. J.] Westmead Hosp, Dept Gastroenterol & Hepatol, Sydney, NSW, Australia. [Bourke, M. J.] Univ Sydney, Westmead Clin Sch, Sydney, NSW 2006, Australia. [Charlton, A.] Childrens Hosp Westmead, Dept Histopathol, Sydney, NSW, Australia. [Eckstein, R.; Gill, A. J.] Royal N Shore Hosp, Dept Anat Pathol, Sydney, NSW, Australia. [Epari, K.] St John God Hosp Murdoch, Murdoch, WA, Australia. [Epari, K.] Fremantle Hosp, Dept Surg, Fremantle, WA, Australia. [Gill, A. J.] Univ Sydney, Canc Diag & Pathol Grp, Sydney, NSW 2006, Australia. [Lam, A. K.] Griffith Univ, Griffith Med Sch, Nathan, Qld 4111, Australia. [Lam, A. K.] Griffith Univ, Griffith Hlth Inst, Nathan, Qld 4111, Australia. [Price, T.] Queen Elizabeth Hosp, Dept Med Oncol, Adelaide, SA, Australia. [Price, T.] Univ Adelaide, Adelaide, SA, Australia. [Streutker, C.] St Michaels Hosp, Toronto, ON M5B 1W8, Canada. [Lauwers, G. Y.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lauwers, G. Y.] Harvard Univ, Sch Med, Boston, MA USA. RP Kumarasinghe, MP (reprint author), PathWest, QE11,J Block Hosp Ave, Nedlands, WA 6009, Australia. EM Priyanthi.Kumarasinghe@health.wa.gov.au RI Gill, Anthony/D-4215-2015; Brown, Ian/R-7763-2016 OI Gill, Anthony/0000-0002-9447-1967; Brown, Ian/0000-0001-6329-2547 NR 36 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0031-3025 EI 1465-3931 J9 PATHOLOGY JI Pathology PD OCT PY 2014 VL 46 IS 6 BP 473 EP 480 DI 10.1097/PAT.0000000000000160 PG 8 WC Pathology SC Pathology GA AP7BB UT WOS:000342231400001 PM 25158823 ER PT J AU Vojvoda, D Stefanovics, E Rosenheck, RA AF Vojvoda, Dolores Stefanovics, Elina Rosenheck, Robert A. TI Treatment of Veterans With PTSD at a VA Medical Center: Primary Care Versus Mental Health Specialty Care SO PSYCHIATRIC SERVICES LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; COLLABORATIVE CARE; RANDOMIZED-TRIAL; RECENT TRENDS; IRAQ; INTERVENTION; AFGHANISTAN; DEPRESSION; PSYCHOTHERAPY; BARRIERS AB Objective: Recent military conflicts have generated significantly more demand for treatment of posttraumatic stress disorder (PTSD) as well as concerns about the adverse effects of stigma associated with specialty mental health care. This study examined the extent to which veterans diagnosed as having PTSD received treatment exclusively in primary care settings. Methods: Administrative data from the U.S. Department of Veterans Affairs (VA) Connecticut Healthcare System for fiscal year 2010 were used to compare the proportions and characteristics of veterans with PTSD (N=4,144) who were treated exclusively in a primary care setting or a mental health specialty clinic. Results: Most (87%) veterans were treated in specialty mental health clinics, and 13% were treated exclusively in primary care. In contrast, 24% of veterans with any mental health diagnosis received treatment exclusively in primary care. Comorbid psychiatric diagnoses were much more prevalent among those treated in mental health specialty clinics than in primary care (86% versus 14%), and psychotropic medications were far more likely to be filled in mental health specialty clinics than in primary care (80% versus 36%). The percentage of veterans with service-connected disabilities did not differ between the two treatment settings. Conclusions: Despite the VA's successful expansion of mental health services in primary care, the vast majority of patients with PTSD received treatment in mental health specialty clinics. Stigma does not seem to keep veterans with PTSD from receiving care in specialty mental health settings in spite of the availability of services in primary care. C1 [Vojvoda, Dolores] VA Connecticut Healthcare Syst, Dept Psychiat, US Dept Vet Affairs, West Haven, CT 06516 USA. [Vojvoda, Dolores; Stefanovics, Elina; Rosenheck, Robert A.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Rosenheck, Robert A.] VA New England Mental Illness Res Educ & Clin Ctr, West Haven, CT USA. RP Vojvoda, D (reprint author), VA Connecticut Healthcare Syst, Dept Psychiat, US Dept Vet Affairs, West Haven, CT 06516 USA. EM dolores.vojvoda@yale.edu NR 23 TC 1 Z9 1 U1 0 U2 9 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 OCT PY 2014 VL 65 IS 10 BP 1238 EP 1243 DI 10.1176/appi.ps.201300204 PG 6 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA AQ0MK UT WOS:000342477200010 PM 24981414 ER PT J AU Shin, HJ Greenbaum, MA Jain, S Rosen, CS AF Shin, Hana J. Greenbaum, Mark A. Jain, Shaili Rosen, Craig S. TI Associations of Psychotherapy Dose and SSRI or SNRI Refills With Mental Health Outcomes Among Veterans With PTSD SO PSYCHIATRIC SERVICES LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; AFFAIRS; ADHERENCE; THERAPY; IRAQ; CARE AB Objective: This study assessed associations between psychotherapy and pharmacotherapy for posttraumatic stress disorder (PTSD) and longitudinal changes in PTSD, depression, and mental health functioning among U.S. veterans diagnosed as having PTSD. Methods: Information about self-reported symptoms experienced from.5 to over three years was collected from 482 veterans diagnosed as having PTSD. Administrative data from the U.S. Department of Veterans Affairs (VA) were used to calculate initiation of a course of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), days of medication coverage, and number of PTSD-related psychotherapy visits during the year after a baseline survey. Hierarchical linear modeling was used to analyze the effects of psychotherapy dose, initiation of an SSRI or SNRI, and medication coverage on symptoms over one year. Results: In the year after baseline, over half of the sample (55%) received no psychotherapy for PTSD, and only 8% met the VA's proposed standard of eight PTSD-related sessions within 14 weeks. Nearly half of the participants (47%) were prescribed an SSRI or SNRI and 37% completed a 90-day trial in the year after baseline. Participants' symptoms improved slightly over time. Participants who received eight or more psychotherapy sessions in 14 weeks, completed a 90-day course of SSRIs or SNRIs, or had more days of medication coverage did not improve more than participants who received less treatment. Conclusions: These dose-of-care benchmarks were not related to symptom improvement, high-lighting the importance of directly assessing the impact of particular treatments on patient outcomes rather than solely relying on process measures. C1 [Shin, Hana J.] VA Long Beach Healthcare Syst, Psychol Serv, US Dept Vet Affairs, Long Beach, CA 90822 USA. [Greenbaum, Mark A.] VA Palo Alto Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Menlo Pk, CA USA. [Jain, Shaili; Rosen, Craig S.] VA Palo Alto Hlth Care Syst, Natl Ctr PTSD, Menlo Pk, CA USA. [Rosen, Craig S.] Stanford Sch Med, Dept Psychiat & Behav Sci, Stanford, CA USA. RP Shin, HJ (reprint author), VA Long Beach Healthcare Syst, Psychol Serv, US Dept Vet Affairs, Long Beach, CA 90822 USA. EM hana.shin@va.gov FU VA Sierra Pacific Mental Illness Research, Education and Clinical Center; VA Office of Academic Affiliations FX This work was supported by the VA Sierra Pacific Mental Illness Research, Education and Clinical Center and the VA Office of Academic Affiliations. The opinions expressed are those of the authors and do not necessarily represent the policy of the VA or the United States government. NR 21 TC 4 Z9 4 U1 1 U2 10 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 OCT PY 2014 VL 65 IS 10 BP 1244 EP 1248 DI 10.1176/appi.ps.201300234 PG 5 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA AQ0MK UT WOS:000342477200011 PM 24981643 ER PT J AU Bedoya, CA Traeger, L Trinh, NHT Chang, TE Brill, CD Hails, K Hagan, PN Flaherty, K Yeung, A AF Bedoya, C. Andres Traeger, Lara Trinh, Nhi-Ha T. Chang, Trina E. Brill, Charlotte D. Hails, Katherine Hagan, Patrick N. Flaherty, Katherine Yeung, Albert TI Impact of a Culturally Focused Psychiatric Consultation on Depressive Symptoms Among Latinos in Primary Care SO PSYCHIATRIC SERVICES LA English DT Article ID MENTAL-HEALTH-CARE; ETHNIC DISPARITIES; SELF-REPORT; AFRICAN-AMERICANS; MAJOR DEPRESSION; QUICK INVENTORY; UNITED-STATES; OLDER; SYMPTOMATOLOGY; OUTCOMES AB Objective: A culturally focused psychiatric (CFP) consultation service was implemented to increase engagement in mental health care and reduce depressive symptoms among adult Latino primary care patients. The aim of this study was to assess preliminary efficacy of the CFP consultation service to reduce depressive symptoms. Methods: In a randomized controlled study, primary care clinics were randomly selected to provide either the two-session CFP intervention or enhanced usual care. For CFP intervention participants, study clinicians (psychologists or psychiatrists) provided a psychiatric assessment, psychoeducation, cognitive-behavioral tools, and tailored treatment recommendations; primary care providers were provided a consultation summary. Depressive symptoms (as measured by the Quick Inventory of Depressive Symptomatology Self Rated [QIDS-SR]) were assessed at baseline and six-month follow-up. Multiple regression analysis was conducted to evaluate whether CFP intervention participants showed greater improvement in depressive symptoms at follow-up, with control for baseline depression, clinic site, and significant covariates. Results: Participants (N=118) were primarily Spanish-monolingual speakers (64%). Although depressive symptoms remained in the moderate range for both groups from baseline to six months, symptom reduction was greater among CFP intervention participants (mean +/- SD change in QIDS-SR score=3.46 +/- 5.48) than those in usual care (change=.09 +/- 4.43).The final multiple regression model indicated that participation in the CFP intervention predicted lower depressive symptoms at follow-up (unstandarclized beta=-3.09, p=.008), independent of baseline depressive symptoms, clinic site, age, gender, and employment status. Conclusions: Results suggest that Latinos experiencing depressive symptoms may benefit from a short-term CFP consultation. Findings also support the integration of psychiatric interventions for Latinos in the primary care setting. C1 [Bedoya, C. Andres; Traeger, Lara; Trinh, Nhi-Ha T.; Chang, Trina E.; Brill, Charlotte D.; Hails, Katherine; Hagan, Patrick N.; Yeung, Albert] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bedoya, C. Andres; Traeger, Lara; Trinh, Nhi-Ha T.; Chang, Trina E.; Yeung, Albert] Harvard Univ, Sch Med, Boston, MA USA. [Flaherty, Katherine] ABT Associates Inc, Cambridge, MA USA. RP Bedoya, CA (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM abedoya@mgh.harvard.edu FU Robert Wood Johnson Foundation's program "Finding Answers: Disparities Research for Change" [66709]; MGH Department of Psychiatry; Bristol-Myers Squibb; Pfizer FX This research project was funded through support from the Robert Wood Johnson Foundation's program "Finding Answers: Disparities Research for Change" (grant number 66709) awarded to Dr. Trinh, principal investigator, and Dr. Bedoya), with additional support from the MGH Department of Psychiatry. The authors thank the study participants, as well as professional and support staff, at the participating sites for their commitment and participation: MGH Charlestown Healthcare Center, MGH Chelsea Healthcare Center, MGH Internal Medicine Associates, and MGH Revere Healthcare Center. The authors also thank Joseph Betancourt, M.D., M.P.H., and Alexander Green, M.D., M.P.H., for their contributions to the conception and design of the study; Jerrold Rosenbaum, M.D., and Maurizio Fava, M.D., for their support of the study; and Soo Jeong Yoon and Jenny Man for their technical assistance.; Dr. Chang has received travel funds from Bristol-Myers Squibb and Pfizer and has served as an advisor to Bristol-Myers Squibb. The other authors report no competing interests. NR 45 TC 2 Z9 2 U1 3 U2 7 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 OCT PY 2014 VL 65 IS 10 BP 1256 EP 1262 DI 10.1176/appi.ps.201300088 PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA AQ0MK UT WOS:000342477200013 PM 24882225 ER PT J AU Wiechers, IR Maust, DT AF Wiechers, Ilse R. Maust, Donovan T. TI Antidepressant Prescribing in Elderly Populations SO PSYCHIATRIC SERVICES LA English DT Letter ID MEDICATION C1 [Wiechers, Ilse R.] US Dept Vet Affairs, Northeast Program, Evaluat Ctr, Off Mental Hlth Operat, West Haven, CT 06516 USA. [Wiechers, Ilse R.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Maust, Donovan T.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Maust, Donovan T.] Vet Affairs Ann Arbor Healthcare Syst, Ctr Clin Management, Ann Arbor, MI USA. RP Wiechers, IR (reprint author), US Dept Vet Affairs, Northeast Program, Evaluat Ctr, Off Mental Hlth Operat, West Haven, CT 06516 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 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 OCT PY 2014 VL 65 IS 10 BP 1285 EP 1285 PG 1 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA AQ0MK UT WOS:000342477200020 PM 25270498 ER PT J AU De Cruz, S Littner, MR Zeidler, MR AF De Cruz, Sharon Littner, Michael R. Zeidler, Michelle R. TI Home Sleep Testing for the Diagnosis of Obstructive Sleep Apnea-Indications and Limitations SO SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review DE obstructive sleep apnea; home sleep test; auto-titrating positive airway pressure; respiratory disturbance index ID POSITIVE AIRWAY PRESSURE; CPAP TITRATION; NASAL CPAP; APNOEA/HYPOPNOEA SYNDROME; APNEA/HYPOPNEA SYNDROME; HEART HEALTH; FOLLOW-UP; POLYSOMNOGRAPHY; ASSOCIATION; RISK AB The increasing prevalence and recognition of obstructive sleep apnea (OSA) coupled with an awareness of its detrimental health consequences has resulted in the need for timely and cost efficient access to diagnostic sleep testing and treatment. As a result, increased emphasis is being placed on simplified ambulatory models for the diagnosis and treatment of OSA using home sleep testing (HST). An ambulatory sleep program requires the combination of clinical assessment for identifying patients at high risk for OSA, HST for the diagnosis of OSA, and home auto-titrating positive airway pressure units for treatment. Randomized control trials evaluating the efficacy of this ambulatory approach to diagnose and treat OSA in high-risk patients without significant medical comorbidities reveal the potential for equivalent patient outcomes when compared with the use of polysomnography and in-laboratory continuous positive airway pressure titration. C1 [De Cruz, Sharon] VA Greater Los Angeles Healthcare Syst, Div Pulm Crit Care & Sleep Med, Los Angeles, CA 90073 USA. [Littner, Michael R.; Zeidler, Michelle R.] Univ Calif Los Angeles, David Geffen Sch Med, Div Pulm & Crit Care Med Clin Immunol & Allergy, Los Angeles, CA 90095 USA. [Littner, Michael R.; Zeidler, Michelle R.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Zeidler, MR (reprint author), VA Greater Los Angeles Healthcare Syst, Sleep Disorders Ctr, 11301 Wilshire Blvd 111Q, Los Angeles, CA 90073 USA. EM mzeidler@mednet.ucla.edu NR 72 TC 0 Z9 0 U1 1 U2 4 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1069-3424 EI 1098-9048 J9 SEMIN RESP CRIT CARE JI Semin. Respir. Crit. Care Med. PD OCT PY 2014 VL 35 IS 5 BP 552 EP 559 DI 10.1055/s-0034-1390066 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AP7QA UT WOS:000342270600004 ER PT J AU Winkelman, JW Schoerning, L Platt, S Jensen, JE AF Winkelman, John W. Schoerning, Laura Platt, Sam Jensen, J. Eric TI Restless legs syndrome and central nervous system gamma-aminobutyric acid: preliminary associations with periodic limb movements in sleep and restless leg syndrome symptom severity SO SLEEP MEDICINE LA English DT Article DE Restless legs syndrome; Gamma-aminobutyric acid; Glutamate; Anterior cingulate cortex; Cerebellum; Thalamus; Periodic limb movements of sleep ID ANTERIOR CINGULATE; T2 RELAXOMETRY; PAIN; SPECTRA; CORTEX; PET AB Background: Previous research has demonstrated abnormalities in glutamate and N-acetyl aspartate (NAA) in the thalamus in individuals with restless legs syndrome (RLS) compared with healthy matched controls. However, levels of these transmitters in other RLS-related brain areas and levels of the most common inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), have not been assessed. Methods: This study examined GABA, glutamate, and NAA levels in the dorsal anterior cingulate cortex (ACC), thalamus and cerebellum with the use of proton magnetic resonance spectroscopy (H-1-MRS) at 4 tesla (4 T) and Megapress difference-editing in 18 subjects with RLS and a matched control group without RLS. Actigraphy was performed on the nights before scans to assess periodic limb movements of sleep (PLMS). Results: Levels of GABA, glutamate, and NAA were no different between RLS and control subjects in any of the three voxels of interest. However, GABA levels were positively correlated with both PLM indices and RLS severity in the thalamus and negatively with both of these measures in the cerebellum in RLS subjects. In addition, NAA levels were higher in the ACC in RLS than in controls. Conclusion: Our preliminary data suggest that known cerebellar-thalamic interactions may modulate the intensity of RLS sensory and motor symptoms. In addition, anterior cingulate cortex may be associated with the affective components of the painful symptoms in this disorder. (C) 2014 Elsevier B. V. All rights reserved. C1 [Winkelman, John W.; Jensen, J. Eric] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Winkelman, John W.; Schoerning, Laura; Platt, Sam] Massachusetts Gen Hosp, Dept Psychiat, Sleep Disorders Clin Res Program, Boston, MA 02114 USA. [Winkelman, John W.; Schoerning, Laura; Platt, Sam] Massachusetts Gen Hosp, Dept Neurol, Sleep Disorders Clin Res Program, Boston, MA 02114 USA. [Jensen, J. Eric] McLean Hosp, Brain Imaging Ctr, Boston, MA USA. RP Winkelman, JW (reprint author), Massachusetts Gen Hosp, Sleep Disorders Clin Res Program, 1 Bowdoin Sq, Boston, MA 02114 USA. EM jwwinkelman@partners.org OI Platt, Samuel/0000-0003-1991-2117 FU GlaxoSmithKline FX This research was supported by an investigator-initiated research grant from GlaxoSmithKline. NR 23 TC 6 Z9 7 U1 0 U2 2 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 OCT PY 2014 VL 15 IS 10 BP 1225 EP 1230 DI 10.1016/j.sleep.2014.05.019 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA AQ0VT UT WOS:000342501500007 PM 25129262 ER PT J AU Mao, SH Sendler, E Goodrich, RJ Hauser, R Krawetz, SA AF Mao, Shihong Sendler, Edward Goodrich, Robert J. Hauser, Russ Krawetz, Stephen A. TI A comparison of sperm RNA-seq methods SO SYSTEMS BIOLOGY IN REPRODUCTIVE MEDICINE LA English DT Article DE Library preparation; reverse transcription and cDNA amplification; RNA purification ID SPERMATOZOAL RNAS; SPERMATOGENESIS; TRANSCRIPTOMICS; FERTILIZATION; AMPLIFICATION; SAMPLES AB A significant challenge to the effective application of RNA-seq to the complete transcript analysis of low quantity and/or degraded samples is the amplification of minimal input RNA to enable sequencing library construction. Several strategies have been commercialized in order to facilitate this goal. However, each strategy has its own specific protocols and methodology, and each may introduce unique bias and in some cases show specific preference for a collection of sequences. Our wider investigation of human spermatozoa! RNAs was able to reveal their complexity despite being generally characterized by low quantity and high fragmentation. In this study, the following four commercially available RNA-seq amplification and library protocols for the preparation of low quantity/highly fragmented samples, SMARTer (TM) Ultra Low RNA (SU) for Illumina (R) Sequencing, SeqPlex RNA Amplification (SP), Ovation (R) RNA-Seq System V2 (OR), and Ovation (R) RNA-Seq Formalin Fixed Paraffin Embedded System (FFPES) were assessed using human sperm RNAs. Further investigation analyzed the effects on the end results of two different library preparation methods, Encore NGS Multiplex System I (Enc) and Ovation Ultra low Library Systems (UL), that appeared best suited to this type of RNA, along with other potential confounding factors such as FFPE preservation. Our results indicate that for each library preparation protocol, the differences in the initial amount of input RNA and choice of RNA purification step do not generate marked differences in terms of RNA profiling. However, substantial disparity is introduced by individual amplification methods prior to library construction. These significant differences may be caused by the different priming methods or amplification strategies used in each of the four different protocols examined. The observation of intra-sample variation introduced by the choice of protocol highlights the role that external factors play in planning and subsequent reliable interpretation of results of any RNA-seq experiment. C1 [Mao, Shihong; Sendler, Edward; Goodrich, Robert J.; Krawetz, Stephen A.] Wayne State Univ, Ctr Mol Med & Genet, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Hauser, Russ] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Mem Obstet & Gynecol Serv, Boston, MA USA. [Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Krawetz, SA (reprint author), Wayne State Univ, Fac Med, Dept Obstet & Gynecol, 271 CS Mott Ctr,275 E Hancock Ave, Detroit, MI 48201 USA. EM steve@compbio.med.wayne.edu FU Harvard School of Public Health, National Institute of Environmental Health Sciences [ES017285]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [25PM6]; Charlotte B. Failing Professorship FX The authors declare no conflicts of interest. This work was supported in part by the Charlotte B. Failing Professorship to SAK., a grant to RH from Harvard School of Public Health, National Institute of Environmental Health Sciences (Grant Number ES017285) and in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Contract 25PM6 in collaboration with the LIFE Study Working Group, Division of Epidemiology, Statistics, and Prevention Research who provided semen samples. NR 23 TC 8 Z9 8 U1 0 U2 12 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1939-6368 EI 1939-6376 J9 SYST BIOL REPROD MED JI Syst. Biol. Reprod. Med. PD OCT PY 2014 VL 60 IS 5 BP 308 EP 315 DI 10.3109/19396368.2014.944318 PG 8 WC Andrology; Reproductive Biology SC Endocrinology & Metabolism; Reproductive Biology GA AP7QJ UT WOS:000342271500008 PM 25077492 ER PT J AU Valerio, D Raventos, H Schmeidler, J Beeri, MS Villalobos, LM Bolanos-Palmieri, P Carrion-Baralt, JR Fornaguera, J Silverman, JM AF Valerio, Daniel Raventos, Henriette Schmeidler, James Beeri, Michal S. Mora Villalobos, Lara Bolanos-Palmieri, Patricia Carrion-Baralt, Jose R. Fornaguera, Jaime Silverman, Jeremy M. TI Association of Apolipoprotein E-e4 and Dementia Declines with Age SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Successful cognitive aging; oldest-old; dementia risk factors ID RICAN NONAGENARIANS; COSTA-RICA; RISK; DISEASE; APOE AB Objective: To study the association of dementia with apolipoprotein E-e4 (APOE-e4) and its interaction with age in a nonagenarian Costa Rican group (N-sample) and a general elderly contrast group (GE-sample). Methods: In both case-control studies, participants were cognitively intact or diagnosed with dementia. The N-sample (N = 112) was at least age 90 years; the GE-sample (N = 98) was at least age 65 years. Results: Dementia and APOE-e4 were not significantly associated in the N-sample, but were in the GE-sample. There was a significant interaction of age with APOE-e4 in the N-sample, but not in the GE-sample. Descriptively dividing the N-sample at the median (age 93 years) showed a group interaction: APOE-e4 was more associated with dementia in the younger N-sample than in the older N-sample, where six of seven APOE-e4 carriers were cognitively intact. Conclusions: The results support the reduction in association of APOE-e4 with dementia in extreme old age, consistent with a survivor effect model for successful cognitive aging. C1 [Valerio, Daniel] Hosp Nacl Geriatr & Gerontol Costa Rica, San Jose, Costa Rica. [Valerio, Daniel] Univ Costa Rica, Sch Med, San Jose, Costa Rica. [Raventos, Henriette; Mora Villalobos, Lara; Bolanos-Palmieri, Patricia] Univ Costa Rica, Ctr Invest Biol Mol & Celular, San Jose, Costa Rica. [Raventos, Henriette] Univ Costa Rica, Escuela Biol, San Jose, Costa Rica. [Schmeidler, James; Beeri, Michal S.; Silverman, Jeremy M.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Beeri, Michal S.; Silverman, Jeremy M.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Beeri, Michal S.] Chaim Sheba Med Ctr, Joseph Sagol Neurosci Ctr, Tel Aviv, Israel. [Carrion-Baralt, Jose R.] Univ Puerto Rico, Gerontol Program, Dept Human Dev, Grad Sch Publ Hlth, Rio Piedras, PR 00931 USA. [Fornaguera, Jaime] Univ Costa Rica, Ctr Invest Neurociencias, San Jose, Costa Rica. [Silverman, Jeremy M.] James J Peters Vet Affairs Med Ctr, Res & Dev Serv, Bronx, NY USA. RP Silverman, JM (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, Box 1230,One Gustave L Levy Pl, New York, NY 10029 USA. EM jeremy.silverman@mssm.edu OI Raventos, Henriette/0000-0001-9423-8308 FU NIH Fogarty International Center & National Institute on Aging grant [R21TW009258]; Universidad de Costa Rica; Alzheimer's Association FX This study was funded by a NIH Fogarty International Center & National Institute on Aging grant (R21TW009258), the Universidad de Costa Rica, and the Alzheimer's Association. NR 10 TC 4 Z9 4 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD OCT PY 2014 VL 22 IS 10 BP 957 EP 960 DI 10.1016/j.jagp.2014.03.008 PG 4 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AP2VT UT WOS:000341934600002 PM 24731780 ER PT J AU West, RK Ravona-Springer, R Schmeidler, J Leroith, D Koifman, K Guerrero-Berroa, E Preiss, R Hoffman, H Silverman, JM Heymann, A Schnaider-Beeri, M AF West, Rebecca K. Ravona-Springer, Ramit Schmeidler, James Leroith, Derek Koifman, Keren Guerrero-Berroa, Elizabeth Preiss, Rachel Hoffman, Hadas Silverman, Jeremy M. Heymann, Anthony Schnaider-Beeri, Michal TI The Association of Duration of Type 2 Diabetes with Cognitive Performance is Modulated by Long-Term Glycemic Control SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Cognitive performance; diabetes; hemoglobin A1c ID ALZHEIMERS-DISEASE; MELLITUS; DECLINE; MEMORY; DYSFUNCTION; DEMENTIA; ADULTS; IMPACT; AGE AB Objectives: It is unclear why duration of type 2 diabetes (T2D) is associated with increased cognitive compromise. High hemoglobin A1c (HbA1c) has also been associated with dementia, and is the primary contributor to T2D complications. Here we investigated whether the association of duration of T2D with cognitive functioning is modulated by HbA1C levels. Methods: This study examined nondemented community-dwelling T2D elderly (N = 897) participating in the Israel Diabetes and Cognitive Decline study, who were assessed with a broad neuropsychological battery. Subjects were all from the Maccabi Healthcare Services, which has a Diabetes Registry with complete HbA1c measurements since 1998. Partial correlations were performed to examine the modulating effect of HbA1c on the relationship of duration of T2D with five cognitive measures, controlling for sociodemographic and cardiovascular risk factors. Results: An interaction of duration of T2D with HbA1c was associated with executive functioning (p = 0.006), semantic categorization (p = 0.019), attention/working memory (p = 0.011), and overall cognition (p = 0.006), such that the associations between duration of T2D and cognitive impairment increased as HbA1c levels increased-but not for episodic memory (p = 0.984). Conclusions: Because duration of T2D was associated with cognition in higher HbA1c levels and overall no associations were found in lower HbA1c levels, our results suggest that individuals with T2D may limit their risk of future cognitive decline by maintaining long-term good glycemic control. C1 [West, Rebecca K.; Schmeidler, James; Leroith, Derek; Guerrero-Berroa, Elizabeth; Silverman, Jeremy M.; Schnaider-Beeri, Michal] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Ravona-Springer, Ramit; Koifman, Keren; Preiss, Rachel; Hoffman, Hadas; Schnaider-Beeri, Michal] Chaim Sheba Med Ctr, Joseph Sagol Neurosci Ctr, Ramat Gan, Israel. [Silverman, Jeremy M.] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. [Heymann, Anthony; Schnaider-Beeri, Michal] Maccabi Healthcare Serv, Tel Aviv, Israel. RP West, RK (reprint author), Mt Sinai Sch Med, Dept Psychiat, Box 1230,One Gustave L Levy Pl,Box 1230, New York, NY 10029 USA. EM rebecca.west@mssm.edu FU NIA [R01 AG034087, P50 AG05138]; Helen Bader Foundation; Irma T. Hirschl Scholar award; American Federation for Aging Research (AFAR) Young Investigator award; Alzheimer's Association grant [NIRG-11-205083] FX This study was supported by NIA grants R01 AG034087 to Dr. Beeri and P50 AG05138 to Dr. Sano, the Helen Bader Foundation, the Irma T. Hirschl Scholar award to Dr. Beeri, the American Federation for Aging Research (AFAR) Young Investigator award, and the Alzheimer's Association grant NIRG-11-205083 to Dr. Ravona-Springer. NR 20 TC 13 Z9 13 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD OCT PY 2014 VL 22 IS 10 BP 1055 EP 1059 DI 10.1016/j.jagp.2014.01.010 PG 5 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AP2VT UT WOS:000341934600013 PM 24534521 ER PT J AU Ebert, L Malte, C Hamlett-Berry, K Beckham, J McFall, M Saxon, A AF Ebert, Lori Malte, Carol Hamlett-Berry, Kim Beckham, Jean McFall, Miles Saxon, Andrew TI Use of a Learning Collaborative to Support Implementation of Integrated Care for Smoking Cessation for Veterans With Posttraumatic Stress Disorder SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID CIGARETTE-SMOKING; PARIHS FRAMEWORK; HEALTH-SERVICES; PREVALENCE; POPULATION; DISSEMINATION; PERSPECTIVES; CHALLENGES; DEPRESSION; SCIENCE AB Objectives. We evaluated the feasibility of incorporating integrated care (IC) for smoking cessation into routine treatment for posttraumatic stress disorder (PTSD) at Department of Veterans Affairs (VA) Medical Centers and the utility of the Learning Collaborative (LC) model in facilitating implementation. Methods. We conducted 2 LCs aimed at implementing IC for smoking cessation using multidisciplinary teams comprising 70 staff members from 12 VA PTSD clinics. Using questionnaires, we evaluated providers' perceptions of the LC methodology and the effectiveness and feasibility of routine IC delivery. We assessed number of providers delivering and patients receiving IC using medical record data. Results. More than 85% of participating VA staff considered the LC to be an effective training and implementation platform. The majority thought IC effectively addressed an important need and could be delivered in routine PTSD care. All LC participants who planned to deliver IC did so (n = 52). Within 12 months of initial training, an additional 46 locally trained providers delivered IC and 395 veterans received IC. Conclusions. The LC model effectively facilitated rapid and broad implementation of IC. Facilitators and barriers to sustained use of IC are unknown and should be identified to understand how best to promote ongoing access to evidence-based treatment for smoking cessation in mental health populations. C1 [Ebert, Lori] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27701 USA. [Malte, Carol] Vet Affairs VA Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, Seattle, WA USA. [Hamlett-Berry, Kim] Dept Vet Affairs, Washington, DC USA. [Beckham, Jean] VA Midatlantic Reg Mental Illness Res Educ & Clin, Durham, NC USA. [McFall, Miles; Saxon, Andrew] VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Ebert, L (reprint author), Duke Univ, Med Ctr, Evidence Based Practice Implementat Ctr, 411 West Chapel Hill St,Suite 200, Durham, NC 27701 USA. EM lori.ebert@duke.edu FU National Center for Child Traumatic Stress is the coordinating center for the National Child Traumatic Stress Network, a collaborative network of sites across the United States FX The National Center for Child Traumatic Stress is the coordinating center for the National Child Traumatic Stress Network, a collaborative network of sites across the United States, funded to enhance services and access to care for traumatized children and their families. For more information about the National Child Traumatic Stress Network visit http://www.nctsn.org. NR 38 TC 2 Z9 2 U1 1 U2 9 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD OCT PY 2014 VL 104 IS 10 BP 1935 EP 1942 DI 10.2105/AJPH.2013.301776 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AP1XG UT WOS:000341865000039 PM 25208004 ER PT J AU Masia, R Peyton, S Lauwers, GY Brown, I AF Masia, Ricard Peyton, Stephen Lauwers, Gregory Y. Brown, Ian TI Gastrointestinal Biopsy Findings of Autoimmune Enteropathy A Review of 25 Cases SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Review DE autoimmune enteropathy; autoimmune enteritis; IPEX syndrome; celiac disease; graft-versus-host disease ID GOBLET-CELL ANTIBODIES; PROTRACTED DIARRHEA; GUT DISORDER; ADULT; COLITIS; DISEASE; IMMUNODEFICIENCY; HISTOPATHOLOGY; AUTOANTIBODIES; CHILDREN AB Autoimmune enteropathy (AIE) is a rare disorder characterized by severe diarrhea and small intestinal mucosal atrophy resulting from immune-mediated injury. It remains a challenging diagnosis because of its clinicopathologic variability. To better understand its histopathologic features, we describe the gastrointestinal biopsy findings of 25 patients, including children and adults. The most common finding on small intestinal biopsy (13/25 cases, 52%) was villous blunting, expansion of the lamina propria by mixed but predominantly mononuclear inflammation, and neutrophilic cryptitis with or without crypt microabscesses. In 5 cases (20%), the duodenum exhibited changes indistinguishable from celiac disease, with villous blunting and intraepithelial lymphocytosis. Increased crypt apoptosis with minimal inflammation, resembling acute graft-versus-host disease, was observed in 4 cases (16%). The remaining 3 cases (12%) exhibited a mixture of 2 or more of the above patterns. Mucosal abnormalities outside the small intestine were present in all 24 cases with available biopsies (100%), with the stomach most commonly affected (19/22 cases, 86%), followed by the colon (14/22, 64%) and esophagus (5/18, 28%). Findings in non-small intestinal sites were variable and included mixed active and chronic inflammation, chronic inflammation alone, intraepithelial lymphocytosis, and increased apoptosis resembling acute graft-versus-host disease. In summary, AIE most commonly presents as an active enteritis with villous blunting and expansion of the lamina propria by mixed inflammation. Mucosal abnormalities are frequently seen elsewhere in the gut. AIE may thus be better regarded as a pangastrointestinal autoimmune disorder, and biopsies from sites other than the small intestine may greatly facilitate its diagnosis. C1 [Masia, Ricard; Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol & Lab Med, Boston, MA 02114 USA. [Peyton, Stephen; Brown, Ian] Envoi Pathol, Kelvin Grove, Qld 4059, Australia. [Brown, Ian] Pathol Queensland, Anat Pathol, Brisbane, Qld, Australia. RP Brown, I (reprint author), Envoi Pathol, 5-38 Bishop St, Kelvin Grove, Qld 4059, Australia. EM ianbrown@envoi.com.au RI Brown, Ian/R-7763-2016 OI Brown, Ian/0000-0001-6329-2547 FU National Cancer Institute of the National Institutes of Health [T32CA09216] FX R.M. is supported by the National Cancer Institute of the National Institutes of Health under Award Number T32CA09216. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 33 TC 11 Z9 12 U1 2 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2014 VL 38 IS 10 BP 1319 EP 1329 PG 11 WC Pathology; Surgery SC Pathology; Surgery GA AP3TY UT WOS:000342001800003 PM 25188868 ER PT J AU Croce, S Young, RH Oliva, E AF Croce, Sabrina Young, Robert H. Oliva, Esther TI Uterine Leiomyomas With Bizarre Nuclei A Clinicopathologic Study of 59 Cases SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE uterus; leiomyoma; bizarre nuclei; prognosis ID SMOOTH-MUSCLE TUMORS; GIANT-CELL TUMOR; MITOTIC CHROMOSOME CONDENSATION; TERM-FOLLOW-UP; HISTONE H3; IMMUNOHISTOCHEMICAL ANALYSIS; SYMPLASTIC LEIOMYOMAS; ATYPICAL LEIOMYOMAS; UTERUS; LEIOMYOSARCOMA AB Leiomyoma with bizarre nuclei (LM-BN) is an uncommon tumor with histologic features (mononucleated or multinucleated bizarre cells that may have a diffuse distribution, prominent nucleoli, and karyorrhectic nuclei that may mimic atypical mitoses) that often causes confusion with leiomyosarcoma. Fifty-nine LM-BNs were collected from our consultation files over the years 2000 to 2011. Features recorded included patient age, therapy, tumor size, border, gross appearance, density and distribution of BN, mitotic count, karyorrhectic nuclei, prominent nucleoli, cells with conspicuous dense eosinophilic cytoplasm (rhabdoid-like), vascular changes and type of vasculature, and presence of necrosis and its nature. Follow-up information was obtained for all patients. Patients ranged in age from 25 to 75 (average 45) years (11 patients between 25 and 35 y, 20 between 36 and 45 y, 22 between 46 and 55 y, and 6 between 56 and 75 y). Forty-two underwent hysterectomy and 17 myomectomy. For 51 tumors gross findings were known. Forty (78%) had a solid white and whorled cut surface and 11 (22%) a yellow appearance. Five (10%) neoplasms showed prominent cystic degeneration, and hemorrhage and/or necrosis was seen in 9 (18%). Forty-five LM-BNs had a pushing margin with the surrounding myometrium, whereas 1 showed irregular borders. Margins could not be ascertained in the slides available in 13 cases. Twenty-eight (48%), 19 (32%), and 12 (20%) LM-BN showed low, intermediate, and high BN density. Eighteen (30%) tumors showed diffuse, 26 (44%) showed multifocal, and 15 (26%) had focal BN distribution. Mitotic counts ranged from 0 to 7/10 high-power fields (HPF) (average 1 to 2/10 HPF). Thirty-seven (63%) had <2/10 HPF, 19 (32%) had 2 to 5 mitoses/10 HPF, and in 3 tumors (5%) mitotic counts were 6, 7, and 7/10 HPF (2 with focal and 1 with diffuse BN). All but 4 LM-BNs showed karyorrhectic nuclei, striking in 12 neoplasms, mimicking atypical mitoses. Nineteen (32%) LMs had prominent eosinophilic nucleoli surrounded by a clear halo. Ischemic necrosis was detected in 21 (36%) LM-BN. Rhabdoid-like cells were noted in 24 (41%) tumors. All patients had no evidence of recurrence, ranging from 1 to 13 years (overall average 6 y; in patients with myomectomy 6.3 y with a range of 2.6 to 11 y). Our results corroborate that LM-BN is associated with a favorable outcome even in those patients only treated by myomectomy and highlights that a conservative approach can be undertaken in these patients, as many of them are of reproductive age. Because of the favorable outcome, the term LM-BN is preferable to alternative terminology including "atypical leiomyoma." C1 [Croce, Sabrina] Inst Bergonie, Dept Pathol, Bordeaux, France. [Young, Robert H.; Oliva, Esther] Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright Pathol Labs, Boston, MA USA. RP Oliva, E (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM eoliva@partners.org FU "Fondation" de France; ARC grants FX Supported by "Fondation" de France (Madeleine Tillier Haudebourg and Nathalie Rumaux Rambaux) and ARC grants. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 49 TC 10 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2014 VL 38 IS 10 BP 1330 EP 1339 PG 10 WC Pathology; Surgery SC Pathology; Surgery GA AP3TY UT WOS:000342001800004 PM 25140893 ER PT J AU Bledsoe, JR Kamionek, M Mino-Kenudson, M AF Bledsoe, Jacob R. Kamionek, Michal Mino-Kenudson, Mari TI BRAF V600E Immunohistochemistry Is Reliable in Primary and Metastatic Colorectal Carcinoma Regardless of Treatment Status and Shows High Intratumoral Homogeneity SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE BRAF; colorectal carcinoma; immunohistochemistry; VE1 ID BRAFV600E IMMUNOHISTOCHEMISTRY; MONOCLONAL-ANTIBODY; THYROID-CARCINOMA; LYNCH SYNDROME; POOR SURVIVAL; MUTATION; ADENOCARCINOMA; CANCER; SPECIMENS; COLON AB In colorectal carcinoma the evaluation of BRAF mutation status is increasingly being performed given its utility as a prognostic and predictive biomarker. However, there are conflicting reports of the sensitivity and specificity of BRAF V600E immunohistochemistry (IHC), and little is known about its reliability in tissues collected from metastatic sites or after chemotherapy, radiation therapy and/or targeted therapy. The degree of intratumoral staining heterogeneity is also not well established. We performed IHC for BRAF V600E (VE1) on 204 cases of colorectal carcinoma including 59 with the BRAF V600E mutation. These included primary (n = 147) and metastatic/recurrent (n = 57) tumors, collected before (n = 133) or after (n = 71) chemotherapy, radiation therapy and/or targeted therapy. Evaluation of a test cohort (39 cases) with knowledge of mutation status established a specific staining pattern for the mutation: diffuse cytoplasmic staining of near-uniform intensity, regardless of strength of staining. Using this pattern, pathologists at 3 levels of training independently performed blinded evaluation of the remaining cases. BRAF V600E staining was 96.3% sensitive and 98.5% specific for the mutation, including both pretreatment and posttreatment specimens. Fleiss kappa for interobserver agreement was 0.96. Staining of whole sections of the BRAF mutants showed diffuse staining in all cases and uniform or near-uniform intensity in 91%. In 20 cases with both pretreatment and posttreatment specimens, there was 100% accuracy and agreement in staining between samples. We conclude that BRAF V600E IHC is reliable for the evaluation of mutational status in colorectal carcinoma regardless of site or prior treatment history, and staining shows a high degree of intratumoral homogeneity. C1 [Bledsoe, Jacob R.; Kamionek, Michal; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Mino-Kenudson, M (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren Bldg 1-122,55 Fruit St, Boston, MA 02114 USA. EM mmino@partners.org FU National Cancer Institute grants [P50 CA127003, R01 CA169086] FX M.M.-K. was supported by National Cancer Institute grants P50 CA127003 and R01 CA169086. The remaining authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 29 TC 7 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2014 VL 38 IS 10 BP 1418 EP 1428 PG 11 WC Pathology; Surgery SC Pathology; Surgery GA AP3TY UT WOS:000342001800013 PM 24921639 ER PT J AU Ward, A Konya, C Mark, EJ Rosen, S AF Ward, Ashley Konya, Christine Mark, Eugene J. Rosen, Seymour TI Granulomatosis With Polyangiitis Presenting as a Renal Tumor SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE granulomatosis with polyangiitis; Wegener's granulomatosis; vasculitis; kidney tumor; antineutrophilic cytoplasmic antibody ID IMMUNE CRESCENTIC GLOMERULONEPHRITIS; WEGENERS-GRANULOMATOSIS; XANTHOGRANULOMATOUS PYELONEPHRITIS; KIDNEY; MASS; VASCULITIS; MANIFESTATION; LESION AB Inflammatory tumors of the kidney are uncommon and include primary inflammatory processes and systemic diseases such as sarcoidosis, IgG4 disease, and granulomatosis with polyangiitis (GPA). There are approximately 15 cases of the latter in the literature. Tumors in GPA are well described and have been reported in several organs including breast, orbit, mediastinum, central nervous system, and especially the lung. We report the case of a 48-year-old woman who presented with diffuse frontal headaches. Imaging showed both a cranial/sinus and renal mass. The pathology of the dura and nasal sinus biopsies were unrevealing. A nephrectomy was performed that demonstrated a discrete lesion with extensive necrosis, granulomatous inflammation, and crescentic pauci-immune glomerulonephritis, findings consistent with GPA. C1 [Ward, Ashley; Rosen, Seymour] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Konya, Christine] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Rheumatol, Boston, MA 02215 USA. [Mark, Eugene J.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Ward, A (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. EM award3@bidmc.harvard.edu NR 34 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2014 VL 38 IS 10 BP 1444 EP 1448 PG 5 WC Pathology; Surgery SC Pathology; Surgery GA AP3TY UT WOS:000342001800016 PM 25025447 ER PT J AU Swerdlow, SH Jaffe, ES Brousset, P Chan, JKC de Leval, L Gaulard, P Harris, NL Pileri, S Weiss, LM AF Swerdlow, Steven H. Jaffe, Elaine S. Brousset, Pierre Chan, John K. C. de Leval, Laurence Gaulard, Philippe Harris, Nancy Lee Pileri, Stefano Weiss, Lawrence M. CA Int Lymphoma Study Grp TI Cytotoxic T-cell and NK-cell Lymphomas Current Questions and Controversies SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE cytotoxic T-cell lymphoma; gamma delta T cells; natural killer cells; enteropathy-associated T-cell lymphoma ID EPSTEIN-BARR-VIRUS; NATURAL-KILLER-CELL; NON-HODGKINS-LYMPHOMA; DISTINCT CLINICOPATHOLOGICAL ENTITY; GAMMA-DELTA; NASAL-TYPE; ALPHA-BETA; CELIAC-DISEASE; LYMPHOPROLIFERATIVE DISORDER; GASTROINTESTINAL-TRACT AB The cytotoxic T-cell and natural killer (NK)-cell lymphomas and related disorders are important but relatively rare lymphoid neoplasms that frequently are a challenge for practicing pathologists. This selective review, based on a meeting of the International Lymphoma Study Group, briefly reviews T-cell and NK-cell development and addresses questions related to the importance of precise cell lineage (alpha beta-type T cell, gamma delta T cell, or NK cell), the implications of Epstein-Barr virus infection, the significance of anatomic location including nodal disease, and the question of further categorization of enteropathy-associated T-cell lymphomas. Finally, developments subsequent to the 2008 World Health Organization Classification, including the recognition of indolent NK-cell and T-cell disorders of the gastrointestinal tract are presented. C1 [Swerdlow, Steven H.] Univ Pittsburgh, Sch Med, Dept Pathol, Div Hematopathol, Pittsburgh, PA USA. [Jaffe, Elaine S.] NCI, Bethesda, MD 20892 USA. [Harris, Nancy Lee] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Weiss, Lawrence M.] Clarient Diagnost Serv Inc, Aliso Viejo, CA USA. [Brousset, Pierre] IUC T Oncopole, Toulouse, France. [Gaulard, Philippe] Univ Paris Est, Hop Henri Mondor, Dept Pathol, Inserm,U955, Creteil, France. [Chan, John K. C.] Queen Elizabeth Hosp, Hong Kong, Hong Kong, Peoples R China. [de Leval, Laurence] Univ Hosp Lausanne CHUV, Inst Pathol, Lausanne, Switzerland. [Pileri, Stefano] Univ Bologna, Sch Med, St Orsola Policlin, Bologna, Italy. RP Swerdlow, SH (reprint author), UPMC Hlth Syst UPMC Presbyterian, Div Hematopathol, Dept Pathol, 200 Lothrop St Room G-335, Pittsburgh, PA 15213 USA. EM swerdlowsh@upmc.edu NR 100 TC 18 Z9 18 U1 3 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2014 VL 38 IS 10 BP E60 EP E71 PG 12 WC Pathology; Surgery SC Pathology; Surgery GA AP3TY UT WOS:000342001800001 PM 25025449 ER PT J AU Rogers, DJ Collins, C Carroll, R Yager, P Cummings, B Raol, N Setlur, J Maturo, S Tremblay, S Quinones, E Noviski, N Hartnick, CJ AF Rogers, Derek J. Collins, Corey Carroll, Ryan Yager, Phoebe Cummings, Brian Raol, Nikhila Setlur, Jennifer Maturo, Stephen Tremblay, Sarah Quinones, Ernesto Noviski, Natan Hartnick, Christopher J. TI Operation Airway: The First Sustainable, Multidisciplinary, Pediatric Airway Surgical Mission SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE Operation Airway; pediatric; surgical; mission ID TRACHEOSTOMY; EXPERIENCE AB Objective: This study aimed to describe the development and implementation of the first sustainable, multidisciplinary, pediatric airway surgical mission in an underserved country. Methods: This prospective, qualitative study was conducted for the first 4 Operation Airway missions in Quito, Ecuador. The major goals of the missions were to assist children with aerodigestive abnormalities, create a sustainable program where the local team could independently provide for their own patient population, develop an educational curriculum and training program for the local team, and cultivate a collaborative approach to provide successful multidisciplinary care. Results: Twenty patients ages 4 months to 21 years were included. Twenty-three bronchoscopies, 5 salivary procedures, 2 tracheostomies, 1 T-tube placement, 1 tracheocutaneous fistula closure, 2 open granuloma excisions, and 6 laryngotracheal reconstructions (LTRs) were performed. All LTR patients were decannulated. A new type of LTR (1.5 stage) was developed to meet special mission circumstances. Two videofluoroscopic swallow studies and 40 bedside swallow evaluations were performed. One local pediatric otolaryngologist, I pediatric surgeon, 3 anesthesiologists, 7 intensivists, 16 nurses, and 2 speech-language pathologists have received training. More than 25 hours of lectures were given, and a website was created collaboratively for educational and informational dissemination (http://www.masseyeandear.org/specialties/pediatrics/pediatric-ent/airway/OperationAirway/). Conclusion: We demonstrated the successful creation of the first mission stemming from a teaching institution with the goal of developing a sustainable, autonomous surgical airway program. C1 [Rogers, Derek J.; Collins, Corey; Carroll, Ryan; Yager, Phoebe; Cummings, Brian; Raol, Nikhila; Tremblay, Sarah; Noviski, Natan; Hartnick, Christopher J.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Setlur, Jennifer] Yale New Haven Med Ctr, New Haven, CT 06504 USA. [Maturo, Stephen] Brooke Army Med Ctr, San Antonio, TX USA. [Quinones, Ernesto] Metropolitan Hosp, Quito, Ecuador. RP Hartnick, CJ (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Christopher_Hartnick@meei.harvard.edu NR 10 TC 4 Z9 4 U1 2 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0003-4894 EI 1943-572X J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD OCT PY 2014 VL 123 IS 10 BP 726 EP 733 DI 10.1177/0003489414534012 PG 8 WC Otorhinolaryngology SC Otorhinolaryngology GA AP7MQ UT WOS:000342261800008 PM 24835243 ER PT J AU Ackman, JM Lata, PF Schuna, AA Elliott, ME AF Ackman, Jamie M. Lata, Paul F. Schuna, Arthur A. Elliott, Mary E. TI Bone Health Evaluation in a Veteran Population: A Need for the Fracture Risk Assessment Tool (FRAX) SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE osteoporosis; osteoporosis treatment; osteoporosis assessment; men ID CLINICAL-PRACTICE; MALE OSTEOPOROSIS; ZOLEDRONIC ACID; OLDER MEN; ALENDRONATE; MORTALITY; DENOSUMAB; DENSITY AB Background: Approximately 2 million men in the United States have osteoporosis, but men are seldom evaluated or treated to prevent fracture. In the expanding veteran population, the fracture risk assessment tool, FRAX, could help reduce fracture risk. However, it is unknown how many veterans would meet the FRAX treatment threshold. Objective: To determine the proportion of untreated veterans who should be considered for osteoporosis treatment according to the Fracture Risk Assessment Tool (FRAX) among a randomly selected sample of older veterans receiving care at one Veterans Hospital and to determine the proportion of veterans in the sample who had received treatment. Methods: A retrospective review of 150 randomly selected charts from male veterans at least 70 years of age and female veterans at least 65 years of age receiving primary care at the William S. Middleton Memorial Veterans Hospital, Madison, WI, between January 1, 2007, and October 1, 2010. This study focused on men, but women were included per institutional review board policy. Results: Charts from 147 men and 3 women were reviewed; 25 men had received osteoporosis treatment. Of 122 untreated men, 74 (61%) met FRAY treatment criteria, including 14 who had fractured. Although bone density testing is recommended by the National Osteoporosis Foundation for men at least 70 years old, only 21 (17%) untreated men had been tested. Conclusions: Most veterans who met FRAX criteria were not treated, including some who had had fractures. The VA should consider recommending FRAX to identify veterans at high risk for fracture. C1 [Ackman, Jamie M.] La Crosse VA Outpatient Clin, La Crosse, WI USA. [Lata, Paul F.; Schuna, Arthur A.; Elliott, Mary E.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Schuna, Arthur A.; Elliott, Mary E.] Univ Wisconsin, Sch Pharm, Madison, WI 53705 USA. RP Elliott, ME (reprint author), Univ Wisconsin, Sch Pharm, 777 Highland Ave, Madison, WI 53705 USA. EM meelliott@pharmacy.wisc.edu NR 31 TC 1 Z9 1 U1 0 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1060-0280 EI 1542-6270 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD OCT PY 2014 VL 48 IS 10 BP 1288 EP 1293 DI 10.1177/1060028014542149 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AP2ZX UT WOS:000341945800005 PM 24994725 ER PT J AU Lawson, EH Zingmond, DS Stey, AM Hall, BL Ko, CY AF Lawson, Elise H. Zingmond, David S. Stey, Anne M. Hall, Bruce L. Ko, Clifford Y. TI Measuring Risk-Adjusted Value Using Medicare and ACS-NSQIP Is High-Quality, Low-Cost Surgical Care Achievable Everywhere? SO ANNALS OF SURGERY LA English DT Article DE colectomy; cost; Medicare; NSQIP; quality; surgery; value ID CLAIMS DATA; SURGERY; VOLUME; ASSOCIATION; IMPROVEMENT; MORTALITY; REGISTRY AB Objective: To evaluate the relationship between risk-adjusted cost and quality for colectomy procedures and to identify characteristics of "high value" hospitals (high quality, low cost). Background: Policymakers are currently focused on rewarding high-value health care. Hospitals will increasingly be held accountable for both quality and cost. Methods: Records (2005-2008) for all patients undergoing colectomy procedures in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) were linked to Medicare inpatient claims. Cost was derived from hospital payments by Medicare. Quality was derived from the occurrence of 30-day postoperative major complications and/or death as recorded in ACS-NSQIP. Risk-adjusted cost and quality metrics were developed using hierarchical multivariable modeling, consistent with a National Quality Forum-endorsed colectomy measure. Results: The study population included 14,745 colectomy patients in 169 hospitals. Average hospitalization cost was $21,350 (SD $20,773, median $16,092, interquartile range $14,341-$ 24,598). Thirty-four percent of patients had a postoperative complication and/or death. Higher hospital quality was significantly correlated with lower cost (correlation coefficient 0.38, P < 0.001). Among hospitals classified as high quality, 52% were found to be low cost (representing highest value hospitals) whereas 14% were high cost (P = 0.001). Forty-one percent of low-quality hospitals were high cost. Highest "value" hospitals represented a mix of teaching/nonteaching affiliation, small/large bed sizes, and regional locations. Conclusions: Using national ACS-NSQIP and Medicare data, this study reports an association between higher quality and lower cost surgical care. These results suggest that high-value surgical care is being delivered in a wide spectrum of hospitals and hospital types. C1 [Lawson, Elise H.; Ko, Clifford Y.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Lawson, Elise H.; Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Lawson, Elise H.; Hall, Bruce L.; Ko, Clifford Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL USA. [Zingmond, David S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Stey, Anne M.] Mt Sinai Med Ctr, Icahn Sch Med, New York, NY USA. [Hall, Bruce L.] Washington Univ, St Louis Sch Med, Dept Surg, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Barnes Jewish Hosp, St Louis, MO USA. [Hall, Bruce L.] St Louis Vet Affairs Med Ctr, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Ctr Hlth Policy, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Olin Business Sch, St Louis, MO USA. RP Lawson, EH (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, 10833 Le Conte Ave 72-215 CHS, Los Angeles, CA 90095 USA. EM elawson@mednet.ucla.edu FU VA Health Services Research and Development program [RWJ 65-020]; American College of Surgeons through the Robert Wood Johnson Foundation Clinical Scholars Program; Centers for Medicare and Medicaid Services FX E.H.L.'s time was supported by the VA Health Services Research and Development program (RWJ 65-020) and the American College of Surgeons through the Robert Wood Johnson Foundation Clinical Scholars Program. This study was funded by a contract from the Centers for Medicare and Medicaid Services. For the remaining authors, none were declared. NR 22 TC 5 Z9 6 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD OCT PY 2014 VL 260 IS 4 BP 668 EP 679 DI 10.1097/SLA.0000000000000931 PG 12 WC Surgery SC Surgery GA AP3LL UT WOS:000341977400013 PM 25203884 ER PT J AU Hamarneh, SR Mohamed, MMR Economopoulos, KP Morrison, SA Phupitakphol, T Tantillo, TJ Gul, SS Gharedaghi, MH Tao, QS Kaliannan, K Narisawa, S Millan, JL van der Wilden, GM Fagenholz, PJ Malo, MS Hodin, RA AF Hamarneh, Sulaiman R. Mohamed, Mussa M. Rafat Economopoulos, Konstantinos P. Morrison, Sara A. Phupitakphol, Tanit Tantillo, Tyler J. Gul, Sarah S. Gharedaghi, Mohammad Hadi Tao, Qingsong Kaliannan, Kanakaraju Narisawa, Sonoko Millan, Jose L. van der Wilden, Gwendolyn M. Fagenholz, Peter J. Malo, Madhu S. Hodin, Richard A. TI A Novel Approach to Maintain Gut Mucosal Integrity Using an Oral Enzyme Supplement SO ANNALS OF SURGERY LA English DT Article DE enteral starvation; ICU patient; intestinal alkaline phosphatase; intestinal permeability; tight junctions; total parenteral nutrition ID INTESTINAL ALKALINE-PHOSPHATASE; TIGHT JUNCTION PERMEABILITY; TOTAL PARENTERAL-NUTRITION; CRITICALLY-ILL PATIENTS; EARLY ENTERAL NUTRITION; BARRIER FUNCTION; MOUSE MODEL; BACTERIAL TRANSLOCATION; UP-REGULATION; MICE AB Objective: To determine the role of intestinal alkaline phosphatase (IAP) in enteral starvation-induced gut barrier dysfunction and to study its therapeutic effect as a supplement to prevent gut-derived sepsis. Background: Critically ill patients are at increased risk for systemic sepsis and, in some cases, multiorgan failure leading to death. Years ago, the gut was identified as a major source for this systemic sepsis syndrome. Previously, we have shown that IAP detoxifies bacterial toxins, prevents endotoxemia, and preserves intestinal microbiotal homeostasis. Methods: WT and IAP-KO mice were used to examine gut barrier function and tight junction protein levels during 48-hour starvation and fed states. Human ileal fluid samples were collected from 20 patients postileostomy and IAP levels were compared between fasted and fed states. To study the effect of IAP supplementation on starvation-induced gut barrier dysfunction, WT mice were fasted for 48 hours +/- IAP supplementation in the drinking water. Results: The loss of IAP expression is associated with decreased expression of intestinal junctional proteins and impaired barrier function. For the first time, we demonstrate that IAP expression is also decreased in humans who are deprived of enteral feeding. Finally, our data demonstrate that IAP supplementation reverses the gut barrier dysfunction and tight junction protein losses due to a lack of enteral feeding. Conclusions: IAP is a major regulator of gut mucosal permeability and is able to ameliorate starvation-induced gut barrier dysfunction. Enteral IAP supplementation may represent a novel approach to maintain bowel integrity in critically ill patients. C1 [Hamarneh, Sulaiman R.; Mohamed, Mussa M. Rafat; Economopoulos, Konstantinos P.; Morrison, Sara A.; Phupitakphol, Tanit; Tantillo, Tyler J.; Gul, Sarah S.; Gharedaghi, Mohammad Hadi; Tao, Qingsong; Kaliannan, Kanakaraju; van der Wilden, Gwendolyn M.; Fagenholz, Peter J.; Malo, Madhu S.; Hodin, Richard A.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Narisawa, Sonoko; Millan, Jose L.] Sanford Burnham Med Res Inst, Sanford Childrens Hlth Res Ctr, La Jolla, CA USA. RP Hodin, RA (reprint author), Massachusetts Gen Hosp, Dept Surg, 15 Parkman St, Boston, MA 02114 USA. EM rhodin@mgh.harvard.edu RI kaliannan, kanakaraju/P-9094-2014; OI Economopoulos, Konstantinos/0000-0003-4856-0405 FU National Institute of Health [NIH/NIDDK T32 DK007754, NIH P30-DK040561] FX The authors declare no conflicting financial interests. Funding has been received from the National Institute of Health grants: NIH/NIDDK T32 DK007754 and NIH P30-DK040561 ( R.A.H.). NR 39 TC 9 Z9 9 U1 3 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD OCT PY 2014 VL 260 IS 4 BP 706 EP 715 DI 10.1097/SLA.0000000000000916 PG 10 WC Surgery SC Surgery GA AP3LL UT WOS:000341977400017 PM 25203888 ER PT J AU Golshan, M Sagara, Y Wexelman, B Aydogan, F Desantis, S Min, HE Vosburgh, K Jagadeesan, J Caragacianu, D Gombos, E Jolesz, FA AF Golshan, Mehra Sagara, Yasuaki Wexelman, Barbara Aydogan, Fatih Desantis, Stephen Min, H. Elise Vosburgh, Kirby Jagadeesan, Jayender Caragacianu, Diana Gombos, Eva Jolesz, Ferenc Andras TI Pilot Study to Evaluate Feasibility of Image-Guided Breast-Conserving Therapy in the Advanced Multimodal Image-Guided Operating (AMIGO) Suite SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID CANCER AB Background. The rate of reexcision in breast-conserving surgery remains high, leading to delay in initiation of adjuvant therapy, increased cost, increased complications, and negative psychological impact to the patient. 1-3 We initiated a phase 1 clinical trial to determine the feasibility of the use of intraoperative magnetic resonance imaging (MRI) to assess margins in the advanced multimodal image-guided operating (AMIGO) suite. Methods. All patients received contrast-enhanced three-dimensional MRI while under general anesthesia in the supine position, followed by standard BCT with or without wire guidance and sentinel node biopsy. Additional margin reexcision was performed of suspicious margins and correlated to final pathology (Fig. 1). Feasibility was assessed via two components: demonstration of safety and sterility and acceptable duration of the operation and imaging; and adequacy of intraoperative MRI imaging for interpretation and its comparison to final pathology. Results. Eight patients (mean age 48.5 years), 4 with stage I breast cancer and 4 with stage II breast cancer, were recruited. All patients underwent successful BCT in the AMIGO suite with no AMIGO-specific complications or break in sterility during surgery. The mean operative time was 113 min (range 93-146 min). Conclusions. Our experience with AMIGO suggests that it is feasible to use intraoperative MRI imaging to evaluate margin assessment in real time. Further research is required to identify modalities that will lead to a reduction in reexcision in breast cancer therapy. C1 [Golshan, Mehra; Sagara, Yasuaki; Wexelman, Barbara; Aydogan, Fatih; Min, H. Elise; Caragacianu, Diana] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Golshan, Mehra; Sagara, Yasuaki; Wexelman, Barbara; Aydogan, Fatih; Min, H. Elise; Caragacianu, Diana] Dana Farber Canc Inst, Boston, MA 02115 USA. [Aydogan, Fatih] Istanbul Univ, Cerrahpasa Med Sch, Dept Breast Surg, Istanbul, Turkey. [Desantis, Stephen] Dana Farber Canc Inst, Breast Oncol Ctr, Boston, MA 02115 USA. [Vosburgh, Kirby; Jagadeesan, Jayender; Gombos, Eva; Jolesz, Ferenc Andras] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. RP Golshan, M (reprint author), Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. EM mgolshan@partners.org FU NIBIB NIH HHS [P41 EB015898] NR 3 TC 3 Z9 3 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD OCT PY 2014 VL 21 IS 10 BP 3356 EP 3357 DI 10.1245/s10434-014-3926-9 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA AP5UN UT WOS:000342144300032 PM 25047476 ER PT J AU Hong, TS Kwak, EL AF Hong, Theodore S. Kwak, Eunice L. TI Adjuvant Therapy for Gastric Cancers: More Answers or More Questions? SO ANNALS OF SURGICAL ONCOLOGY LA English DT Editorial Material ID CHEMOTHERAPY; SURGERY C1 [Hong, Theodore S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02138 USA. [Kwak, Eunice L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. RP Hong, TS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02138 USA. EM tshong1@partners.org NR 6 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD OCT PY 2014 VL 21 IS 11 BP 3367 EP 3368 DI 10.1245/s10434-014-3778-3 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA AP5UT UT WOS:000342144900004 PM 24841350 ER PT J AU Peterson, DJ Truong, PT Sadek, BT Alexander, CS Wiksyk, B Shenouda, M Raad, RA Taghian, AG AF Peterson, David J. Truong, Pauline T. Sadek, Betro T. Alexander, Cheryl S. Wiksyk, Bradley Shenouda, Mina Raad, Rita Abi Taghian, Alphonse G. TI Locoregional Recurrence and Survival Outcomes by Type of Local Therapy and Trastuzumab Use Among Women with Node-Negative, HER2-Positive Breast Cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; ADJUVANT CHEMOTHERAPY; CONSERVING THERAPY; PROGNOSTIC INDICATOR; RECEPTOR; RADIATION; AGE; MASTECTOMY; RADIOTHERAPY; CELLS AB While human epidermal growth factor receptor 2 (HER2) overexpression is an adverse breast cancer prognostic factor, it is unclear whether there are differences in outcomes between types of local treatment in this population. This retrospective study examined locoregional recurrence and survival in women with node-negative, HER2+ breast cancer treated with breast-conserving therapy (BCT) versus mastectomy. Subjects were 748 patients with pT1-2, N0, M0 HER2+ breast cancer, treated with BCT (n = 422) or mastectomy (n = 326). Trastuzumab was used in 54 % of subjects. The 5-year Kaplan-Meier locoregional recurrence free survival (LRRFS), breast cancer specific survival (BCSS), and overall survival (OS) were compared between cohorts treated with BCT versus mastectomy. Subgroup analyses of LRR and survival were performed separately among patients treated with BCT or mastectomy to examine the effect of trastuzumab on outcomes in each group. Median follow-up was 4.4 years. Patients treated with mastectomy had higher proportions of grade 3 histology (69 vs 60 %, p = 0.004) and lower rates of hormone therapy (51 vs 64 %, p < 0.001) and trastuzumab therapy (50 vs 57 %, p = 0.04). The 5-year outcomes in women treated with BCT compared with mastectomy were: LRRFS 98.0 versus 98.3 % (p = 0.88), BCSS 97.2 versus 96.1 % (p = 0.70), and OS 95.5 versus 93.4 % (p = 0.19). Trastuzumab was associated with similar LRRFS and improved OS in both local treatment groups. BCT is safe in the population of women with pT1-2, N0, HER2+ breast cancer, providing high rates of locoregional control and survival equivalent to mastectomy. Trastuzumab was associated with improved survival in both groups. C1 [Peterson, David J.; Truong, Pauline T.; Wiksyk, Bradley] British Columbia Canc Agcy, Vancouver Isl Ctr, Dept Radiat Oncol, Victoria, BC, Canada. [Truong, Pauline T.] British Columbia Canc Agcy, Vancouver Isl Ctr, Breast Canc Outcomes Unit, Victoria, BC, Canada. [Truong, Pauline T.] Univ British Columbia, Dept Surg, Vancouver, BC V6T 1W5, Canada. [Sadek, Betro T.; Alexander, Cheryl S.; Shenouda, Mina; Raad, Rita Abi; Taghian, Alphonse G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. RP Peterson, DJ (reprint author), British Columbia Canc Agcy, Vancouver Isl Ctr, Dept Radiat Oncol, Victoria, BC, Canada. EM ptruong@bccancer.bc.ca RI Sadek, Betro/I-7734-2013 OI Sadek, Betro/0000-0003-0119-7207 NR 37 TC 6 Z9 6 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD OCT PY 2014 VL 21 IS 11 BP 3490 EP 3496 DI 10.1245/s10434-014-3767-6 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA AP5UT UT WOS:000342144900023 PM 24841346 ER PT J AU Goodman, JH Guarino, A Chenausky, K Klein, L Prager, J Petersen, R Forget, A Freeman, M AF Goodman, Janice H. Guarino, Anthony Chenausky, Kerry Klein, Lauri Prager, Joanna Petersen, Rebecca Forget, Avery Freeman, Marlene TI CALM Pregnancy: results of a pilot study of mindfulness-based cognitive therapy for perinatal anxiety SO ARCHIVES OF WOMENS MENTAL HEALTH LA English DT Article DE Pregnancy; Anxiety; Generalized anxiety disorder; Intervention; Mindfulness; Cognitive therapy ID RANDOMIZED CONTROLLED-TRIAL; NATIONAL-COMORBIDITY-SURVEY; STATE WORRY QUESTIONNAIRE; STRESS REDUCTION PROGRAM; QUALITY-OF-LIFE; BEHAVIOR-THERAPY; MATERNAL ANXIETY; UNITED-STATES; TRANSDIAGNOSTIC TREATMENT; PSYCHIATRIC-DISORDERS AB Many women experience anxiety during pregnancy with potential negative effects on maternal, birth, and child outcomes. Because of potential risks of fetal exposure to psychotropic medications, efficacious non-pharmacologic approaches are urgently needed. However, no published studies of psychotherapeutic treatments for anxiety in pregnancy exist. Mindfulness-based cognitive therapy (MBCT) may substantially reduce anxiety and co-morbid symptoms in people with anxiety disorders. Coping with Anxiety through Living Mindfully (CALM) Pregnancy is an adaptation of MBCT designed to address anxiety in pregnant women. This study examined the feasibility, acceptability, and clinical outcomes of the CALM Pregnancy intervention in pregnant women anxiety. Twenty-four pregnant women with generalized anxiety disorder (GAD) or prominent symptoms of generalized anxiety participated in an open treatment trial of the CALM Pregnancy group intervention. Psychiatric diagnoses were determined by structured clinical interview, and self-report measures of anxiety, worry, depression, self-compassion, and mindfulness were completed at baseline and post-intervention. Qualitative feedback was elicited via questionnaire. Twenty-three participants completed the intervention with high attendance and good compliance with home practice. Completers showed statistically and clinically significant improvements in anxiety, worry, and depression, and significant increases in self-compassion and mindfulness. Of the 17 participants who met GAD criteria at baseline, only one continued to meet criteria post-intervention. Participants regarded their experience in the intervention to be overwhelmingly positive. MBCT in the form of the CALM Pregnancy intervention holds potential to provide effective, non-pharmacological treatment for pregnant women with anxiety. These promising findings warrant further testing of the intervention with a randomized controlled trial. C1 [Goodman, Janice H.; Guarino, Anthony; Chenausky, Kerry; Klein, Lauri; Prager, Joanna; Petersen, Rebecca; Forget, Avery] MGH Inst Hlth Profess, Sch Nursing, Boston, MA 02129 USA. [Freeman, Marlene] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Goodman, JH (reprint author), MGH Inst Hlth Profess, Sch Nursing, 36 1st Ave, Boston, MA 02129 USA. EM jgoodman@mghihp.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [1R21HD065156-01] FX This research was funded in part by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (1R21HD065156-01) to Dr. Goodman. We would also like to extend our gratitude to Fredda Zuckerman LICSW and the volunteer staff who facilitated recruitment at Massachusetts General Hospital Obstetrics and to the women who participated in the study. Special thanks to L. Klein for creating the CALM acronym. NR 103 TC 19 Z9 19 U1 6 U2 60 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 1434-1816 EI 1435-1102 J9 ARCH WOMEN MENT HLTH JI Arch. Womens Ment. Health PD OCT PY 2014 VL 17 IS 5 BP 373 EP 387 DI 10.1007/s00737-013-0402-7 PG 15 WC Psychiatry SC Psychiatry GA AP6TG UT WOS:000342210000004 PM 24449191 ER PT J AU Tsai, AC Tomlinson, M Dewing, S le Roux, IM Harwood, JM Chopra, M Rotheram-Borus, MJ AF Tsai, Alexander C. Tomlinson, Mark Dewing, Sarah le Roux, Ingrid M. Harwood, Jessica M. Chopra, Mickey Rotheram-Borus, Mary Jane TI Antenatal depression case finding by community health workers in South Africa: feasibility of a mobile phone application SO ARCHIVES OF WOMENS MENTAL HEALTH LA English DT Article DE Antenatal depression; Case finding; South Africa ID RANDOMIZED CONTROLLED-TRIAL; MOTHER-INFANT RELATIONSHIP; POSTNATAL DEPRESSION; MENTAL-HEALTH; POSTPARTUM DEPRESSION; MATERNAL DEPRESSION; LOW-INCOME; PERINATAL DEPRESSION; HOME VISITS; CAPE-TOWN AB Randomized controlled trials conducted in resource-limited settings have shown that once women with depressed mood are evaluated by specialists and referred for treatment, lay health workers can be trained to effectively administer psychological treatments. We sought to determine the extent to which community health workers could also be trained to conduct case finding using short and ultrashort screening instruments programmed into mobile phones. Pregnant, Xhosa-speaking women were recruited independently in two cross-sectional studies (N = 1,144 and N = 361) conducted in Khayelitsha, South Africa and assessed for antenatal depression. In the smaller study, community health workers with no training in human subject research were trained to administer the Edinburgh Postnatal Depression Scale (EPDS) during the routine course of their community-based outreach. We compared the operating characteristics of four short and ultrashort versions of the EPDS with the criterion standard of probable depression, defined as an EPDS-10 a parts per thousand yenaEuro parts per thousand 13. The prevalence of probable depression (475/1144 [42 %] and 165/361 [46 %]) was consistent across both samples. The 2-item subscale demonstrated poor internal consistency (Cronbach's alpha ranged from 0.55 to 0.58). All four subscales demonstrated excellent discrimination, with area under the receiver operating characteristic curve (AUC) values ranging from 0.91 to 0.99. Maximal discrimination was observed for the 7-item depressive symptoms subscale: at the conventional screening threshold of a parts per thousand yen10, it had 0.97 sensitivity and 0.76 specificity for detecting probable antenatal depression. The comparability of the findings across the two studies suggests that it is feasible to use community health workers to conduct case finding for antenatal depression. C1 [Tsai, Alexander C.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Tsai, Alexander C.] Massachusetts Gen Hosp, Chester M Pierce MD Div Global Psychiat, Boston, MA 02114 USA. [Tsai, Alexander C.] Harvard Univ, Sch Med, Boston, MA USA. [Tomlinson, Mark] Univ Stellenbosch, Dept Psychol, ZA-7600 Stellenbosch, South Africa. [Dewing, Sarah] Med Res Council South Africa, Hlth Syst Res Unit, Tygerberg, South Africa. [le Roux, Ingrid M.] Philani Child Hlth & Nutr Project, Cape Town, South Africa. [Harwood, Jessica M.; Rotheram-Borus, Mary Jane] Univ Calif Los Angeles, Dept Psychiat, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [Chopra, Mickey] United Nations Childrens Fund, Hlth Sect, New York, NY USA. [Rotheram-Borus, Mary Jane] Univ Calif Los Angeles, Global Ctr Child & Families, Los Angeles, CA USA. [Tsai, Alexander C.] Mbarara Univ Sci & Technol, Mbarara, Uganda. RP Tsai, AC (reprint author), Massachusetts Gen Hosp, Ctr Global Hlth, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM actsai@partners.org RI Emchi, Karma/Q-1952-2016; OI Tsai, Alexander/0000-0001-6397-7917 FU US National Institutes of Health (NIH) [R01AA017104]; NIH [P30MH058107, P30AI028697, UL1TR000124, R25MH060482, K23MH096620]; Medical Research Council of South Africa; National Research Foundation (South Africa); Department for International Development (DfID-UK); Robert Wood Johnson Health and Society Scholars Program FX Study 1 was funded by the US National Institutes of Health (NIH) R01AA017104 and supported by NIH P30MH058107, NIH P30AI028697, and NIH UL1TR000124. Study 2 was funded by the Medical Research Council of South Africa and NIH R25MH060482. MT acknowledges the support of the National Research Foundation (South Africa) and the Department for International Development (DfID-UK). ACT also acknowledges salary support from NIH K23MH096620 and the Robert Wood Johnson Health and Society Scholars Program. We thank Mary J. O'Connor, Carol M. Worthman, Nokwanele Mbweu, Jacqueline Stewart, Mary Hartley, Dallas Swendeman, W. Scott Comulada, and Robert E. Weiss for their contributions to the design and implementation of study 1 and Novakuye Sijeku and the Philani outreach workers for data collection in study 2. NR 74 TC 12 Z9 12 U1 5 U2 21 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 1434-1816 EI 1435-1102 J9 ARCH WOMEN MENT HLTH JI Arch. Womens Ment. Health PD OCT PY 2014 VL 17 IS 5 BP 423 EP 431 DI 10.1007/s00737-014-0426-7 PG 9 WC Psychiatry SC Psychiatry GA AP6TG UT WOS:000342210000008 PM 24682529 ER PT J AU Strangman, GE Sipes, W Beven, G AF Strangman, Gary E. Sipes, Walter Beven, Gary TI Human Cognitive Performance in Spaceflight and Analogue Environments SO AVIATION SPACE AND ENVIRONMENTAL MEDICINE LA English DT Review DE long-duration spaceflight; executive function; social processing; emotional processing; hippocampus ID NORMAL-PRESSURE HYDROCEPHALUS; INTERNATIONAL BIOMEDICAL EXPEDITION; PROLONGED ANTARCTIC RESIDENCE; MANUAL TRACKING PERFORMANCE; COMPLEX DECISION-MAKING; DUAL-TASK PERFORMANCE; CEREBRAL-BLOOD-FLOW; SPACE MISSION; MENTAL PERFORMANCE; CARBON-DIOXIDE AB Maintaining intact cognitive performance is a high priority for space exploration. This review seeks to summarize the cumulative results of existing studies of cognitive performance in spaceflight and analogue environments. We focused on long-duration (>21 d) studies for which no review has previously been conducted. There were 11 published studies identified for long-duration spaceflight (N = 42 subjects) as well as 21 shorter spaceflight studies (N = 70 subjects). Overall, spaceflight cognitive studies ranged from 6-438 d in duration. Some 55 spaceflight analogue studies were also identified, ranging from 6 to 520 d. The diverse nature of experimental procedures and protocols precluded formal meta-analysis. In general, the available evidence fails to strongly support or refute the existence of specific cognitive deficits in low Earth orbit during long-duration spaceflight, which may be due in large part to small numbers of subjects. The studies consistently suggest that novel environments (spaceflight or other) induce variable alterations in cognitive performance across individuals, consistent with known astronaut experiences. This highlights the need to better quantify the magnitude and scope of this interindividual variability, and understand its underlying factors, when predicting in-flight cognitive functioning for extended periods. C1 [Strangman, Gary E.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Sipes, Walter; Beven, Gary] NASA, Johnson Space Ctr, Houston, TX USA. RP Strangman, GE (reprint author), Massachusetts Gen Hosp, Neural Syst Grp, 149 13th St,Suite 2651, Charlestown, MA 02129 USA. EM strang@nmr.mgh.harvard.edu FU Wyle, Science, Technology and Engineering [T71712] FX This work was supported by Wyle, Science, Technology and Engineering, subcontract number T71712. All authors provided a professional contribution to this paper. Special thanks go to Lauren Leveton and multiple colleagues in the NASA Human Research Program's Behavioral Health and Performance element, as well as to the numerous colleagues who provided input on previous versions of this work. NR 147 TC 5 Z9 5 U1 4 U2 20 PU AEROSPACE MEDICAL ASSOC PI ALEXANDRIA PA 320 S HENRY ST, ALEXANDRIA, VA 22314-3579 USA SN 0095-6562 EI 1943-4448 J9 AVIAT SPACE ENVIR MD JI Aviat. Space Environ. Med. PD OCT PY 2014 VL 85 IS 10 BP 1033 EP 1048 DI 10.3357/ASEM.3961.2014 PG 16 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Sport Sciences SC Public, Environmental & Occupational Health; General & Internal Medicine; Sport Sciences GA AP7MM UT WOS:000342261400008 PM 25245904 ER PT J AU Koreth, J Kim, HT Nikiforow, S Milford, EL Armand, P Cutler, C Glotzbecker, B Ho, VT Antin, JH Soiffer, RJ Ritz, J Alyea, EP AF Koreth, John Kim, Haesook T. Nikiforow, Sarah Milford, Edgar L. Armand, Philippe Cutler, Corey Glotzbecker, Brett Ho, Vincent T. Antin, Joseph H. Soiffer, Robert J. Ritz, Jerome Alyea, Edwin P., III TI Donor Chimerism Early after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation Predicts Relapse and Survival SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Allogeneic transplantation; Reduced-intensity; Chimerism ID COMPETING RISK; FLUDARABINE; RECOVERY; MALIGNANCIES; BUSULFAN; KINETICS; LEUKEMIA; DISEASE; IMPACT; TESTS AB The impact of early donor cell chimerism on outcomes of T cell-replete reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) is ill defined. We evaluated day 30 (D30) and 100 (D100) total donor cell chimerism after RIC HSCT undertaken between 2002 and 2010 at our institution, excluding patients who died or relapsed before D30. When available, donor T cell chimerism was also assessed. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), relapse, and nonrelapse mortality (NRM). We evaluated 688 patients with hematologic malignancies (48% myeloid and 52% lymphoid) and a median age of 57 years (range, 18 to 74) undergoing RIC HSCT with T cell-replete donor grafts (97% peripheral blood; 92% HLA-matched), with a median follow-up of 58.2 months (range, 12.6 to 120.7). In multivariable analysis, total donor cell and T cell chimerism at D30 and D100 each predicted RIC HSCT outcomes, with D100 total donor cell chimerism most predictive. D100 total donor cell chimerism <90% was associated with increased relapse (hazard ratio [HR], 2.54; 95% confidence interval [CI], 1.83 to 3.51; P < .0001), impaired PFS (HR, 2.01; 95% CI, 1.53 to 2.65; P < .0001), and worse OS (HR, 1.50; 95% CI, 1.11 to 2.04, P = .009), but not with NRM (HR, .76; 95% CI, .44 to 2.27; P = .33). There was no additional utility of incorporating sustained D30 to D100 total donor cell chimerism or T cell chimerism. Low donor chimerism early after RIC HSCT is an independent risk factor for relapse and impaired survival. Donor chimerism assessment early after RIC HSCT can prognosticate for long-term outcomes and help identify high-risk patient cohorts who may benefit from additional therapeutic interventions. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [Koreth, John; Nikiforow, Sarah; Armand, Philippe; Cutler, Corey; Glotzbecker, Brett; Ho, Vincent T.; Antin, Joseph H.; Soiffer, Robert J.; Ritz, Jerome; Alyea, Edwin P., III] Dana Farber Canc Inst, Hematol Malignancies Div, Boston, MA 02215 USA. [Kim, Haesook T.] Dana Farber Canc Inst, Div Biostat & Computat Biol, Boston, MA 02215 USA. [Milford, Edgar L.] Brigham & Womens Hosp, Tissue Typing Lab, Boston, MA 02115 USA. RP Koreth, J (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM john_koreth@dfci.harvard.edu OI Ritz, Jerome/0000-0001-5526-4669 FU Jock and Bunny Adams Research and Education Endowment; [P01 CA142106-06A1]; [R01 CA183559-01] FX J.K. is a Scholar in Clinical Research of the Leukemia & Lymphoma Society. This study is funded in part by the Jock and Bunny Adams Research and Education Endowment and by P01 CA142106-06A1 (J.H.A.) and R01 CA183559-01 (R.J.S.). NR 23 TC 9 Z9 9 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD OCT PY 2014 VL 20 IS 10 BP 1516 EP 1521 DI 10.1016/j.bbmt.2014.05.025 PG 6 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AP5KC UT WOS:000342117100008 PM 24907627 ER PT J AU Saber, W Le Rademacher, J Sekeres, M Logan, B Lewis, M Mendizabal, A Leifer, E Appelbaum, FR Horowitz, MM Nakamura, R Cutler, CS AF Saber, Wael Le Rademacher, Jennifer Sekeres, Mikkael Logan, Brent Lewis, Moira Mendizabal, Adam Leifer, Eric Appelbaum, Frederick R. Horowitz, Mary M. Nakamura, Ryotaro Cutler, Corey S. TI Multicenter Biologic Assignment Trial Comparing Reduced-Intensity Allogeneic Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50 to 75 with Intermediate-2 and High-Risk Myelodysplastic Syndrome: Blood and Marrow Transplant Clinical Trials Network #1102 Study Rationale, Design, and Methods SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Biologic assignment; MDS; Transplantation ID ACUTE MYELOID-LEUKEMIA; PROGNOSTIC SCORING SYSTEM; ACUTE MYELOGENOUS LEUKEMIA; PHASE-III; MYELOPROLIFERATIVE DISORDERS; DECISION-ANALYSIS; OLDER PATIENTS; UNITED-STATES; 1ST REMISSION; AZACITIDINE AB The introduction of reduced-intensity conditioning (RIC) regimens made it possible to offer allogeneic hematopoietic cell transplantation (alloHCT) to older patients with myelodysplastic syndromes (MDS). However, the relative risks and benefits of alloHCT compared with novel nontransplant therapies continue to be the source of considerable uncertainty. We will perform a prospective biologic assignment trial to compare RIC alloHCT with nontransplant therapies based on donor availability. Primary outcome is 3-year overall survival. Secondary outcomes include leukemia-free survival, quality of life, and cost-effectiveness. Four hundred patients will be enrolled over roughly 3 years. Planned subgroup analyses will evaluate key biologic questions, such as the impact of age and response to hypomethylating agents on treatment effects. Findings from this study potentially may set a new standard of care for older MDS patients who are considered candidates for alloHCT. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [Saber, Wael; Le Rademacher, Jennifer; Logan, Brent; Horowitz, Mary M.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Sekeres, Mikkael] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Lewis, Moira; Mendizabal, Adam] EMMES Corp, Rockville, MD USA. [Leifer, Eric] NHLBI, Bethesda, MD 20892 USA. [Appelbaum, Frederick R.] Univ Washington, Fred Hutchinson Canc Res Ctr, Sch Med, Seattle, WA 98195 USA. [Nakamura, Ryotaro] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Cutler, Corey S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Saber, W (reprint author), Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, 9200 W Wisconsin Ave,Suite C5500, Milwaukee, WI 53226 USA. EM wsaber@mcw.edu FU National Heart, Lung, and Blood Institute [U10 HL069294]; National Cancer Institute (NCI) of the National Institutes of Health; NCI [U24 CA076518]; NHLBI; National Institute of Allergy and Infectious Diseases; Health Resources and Services Administration of the US Department of Health and Human Services [HHSH250201200016 C]; Office of Naval Research [N00014-12-1-0142, N00014-13-1-0039]; Allos Therapeutics, Inc.; Amgen, Inc.; Ariad Pharmaceuticals; Be The Match Foundation; Blue Cross and Blue Shield Association; Celgene; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Gentium SpA; Genzyme Corporation; GlaxoSmithKline; HistoGenetics, Inc.; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck Co., Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Remedy Informatics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Terumo BCT; Teva Neuroscience, Inc.; Texas Instruments Inc.; Well Point, Inc. FX Financial disclosure: The design and conduct of the BMT CTN 1102 is supported by Grant/Cooperative Agreement U10 HL069294 from the National Heart, Lung, and Blood Institute and the National Cancer Institute (NCI) of the National Institutes of Health. Data collection on alloHCT recipients will be through the CIBMTR, which is supported by Public Health Service Grant/Cooperative Agreement U24 CA076518 from the NCI, the NHLBI, and the National Institute of Allergy and Infectious Diseases; contract HHSH250201200016 C with the Health Resources and Services Administration of the US Department of Health and Human Services; grants N00014-12-1-0142 and N00014-13-1-0039 from the Office of Naval Research; and grants from Allos Therapeutics, Inc.; Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Ariad Pharmaceuticals; Be The Match Foundation; Blue Cross and Blue Shield Association; Celgene;Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Gentium SpA; Genzyme Corporation; GlaxoSmithKline; HistoGenetics, Inc.; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck & Co., Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Remedy Informatics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Terumo BCT; Teva Neuroscience, Inc.; Texas Instruments Inc.; and Well Point, Inc.. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, or any other agency of the US Government. NR 49 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD OCT PY 2014 VL 20 IS 10 BP 1566 EP 1572 DI 10.1016/j.bbmt.2014.06.010 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AP5KC UT WOS:000342117100015 PM 24972249 ER PT J AU Rajagopalan, V Vaidyanathan, M Janardhanam, VA Bradner, JE AF Rajagopalan, Vishal Vaidyanathan, Muthukumar Janardhanam, Vanisree Arambakkam Bradner, James E. TI Pre-Clinical Analysis of Changes in Intra-cellular Biochemistry of Glioblastoma Multiforme (GBM) Cells Due to c-Myc Silencing SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE Glioblastoma multiforme; c-Myc; Bcl-2; Akt; Autophagy; Lipid; Glycogen ID GENE-EXPRESSION; CYCLE ENTRY; IN-VIVO; INHIBITION; TARGET; BROMODOMAIN; GROWTH; METABOLISM; APOPTOSIS; CANCER AB Glioblastoma Multiforme (GBM) is an aggressive form of brain Tumor that has few cures. In this study, we analyze the anti-proliferative effects of a new molecule JQ1 against GBMs induced in Wistar Rats. JQ1 is essentially a Myc inhibitor. c-Myc is also known for altering the biochemistry of a tumor cell. Therefore, the study is intended to analyze certain other oncogenes associated with c-Myc and also the change in cellular biochemistry upon c-Myc inhibition. The quantitative analysis of gene expression gave a co-expressive pattern for all the three genes involved namely; c-Myc, Bcl-2, and Akt. The cellular biochemistry analysis by transmission electron microscopy revealed high glycogen and lipid aggregation in Myc inhibited cells and excessive autophagy. The study demonstrates the role of c-Myc as a central metabolic regulator and Bcl-2 and Akt assisting in extending c-Myc half-life as well as in regulation of autophagy, so as to regulate cell survival on the whole. The study also demonstrates that transient treatment by JQ1 leads to aggressive development of tumor and therefore, accelerating death, emphasizing the importance of dosage fixation, and duration for clinical use in future. C1 [Rajagopalan, Vishal; Vaidyanathan, Muthukumar; Janardhanam, Vanisree Arambakkam] Univ Madras, Dept Biochem, Chennai 600025, Tamil Nadu, India. [Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Rajagopalan, V (reprint author), Univ Madras, Dept Biochem, Guindy Campus, Chennai 600025, Tamil Nadu, India. EM dnapolren@gmail.com FU University Grants Commission, New Delhi, India FX The study was supported by University Grants Commission, New Delhi, India. We thank the Sophisticated Analytical Instrument Facility (SAIF)-Department of Anatomy, AIIMS, New Delhi, India for providing microscopes in Electron Microscopy. We thank Dr. Aparna Rajagopalan for her critical reading and editing. We also thank University of Madras for all the infrastructure support in carrying out the experiments. NR 40 TC 5 Z9 5 U1 0 U2 12 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 EI 1573-6830 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD OCT PY 2014 VL 34 IS 7 BP 1059 EP 1069 DI 10.1007/s10571-014-0083-4 PG 11 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA AP5VK UT WOS:000342146600011 PM 25056450 ER PT J AU Wang, CY Kundaria, S Fernandez-Miranda, J Duvvuri, U AF Wang, Chengyuan Kundaria, Summit Fernandez-Miranda, Juan Duvvuri, Umamaheswar TI A Description of Arterial Variants in the Transoral Approach to the Parapharyngeal Space SO CLINICAL ANATOMY LA English DT Article DE robotic surgery; TORS; parapharyngeal space; arterial variants ID ROBOTIC SURGERY AB This study demonstrates variations in the vascular anatomy of the parapharyngeal space (PPS) as seen from the transoral approach compared with the transcervical approach. The PPS was dissected in injected cadaveric specimens. Anatomical measurements, including those of branches of the external and internal carotid arteries (ECA and ICA) and the styloglossus and stylopharyngeus muscles, were recorded and analyzed. In 67% (8/12) of cases, the ascending palatine artery (APA) originated from the facial artery and crossed the styloglossus muscle. The diameter of the APA at its origin was 1.4 +/- 0.3mm. In 75% (9/12) of cases, the ascending pharyngeal artery (aPA) arose from the medial surface of the ECA near its origin. In 58% (7/12) of cases, the aPA ascended vertically between the ICA and the lateral pharynx to the skull base, along the longus capitus muscle. The aPA crossed the styloglossus muscle 12.6 +/- 3.9mm from the insertion into the tongue. In 92% (11/12) of cases, the ECA and ICA were separated by the styloid diaphragm and pharyngeal venous plexus. In 8% (1/12), the ECA bulged into the parapharyngeal fat between the styloglossus and stylopharyngeus muscles adjacent to the pharyngeal constrictors. Knowledge of the precise anatomy of the PPS is important for transoral robotic surgery (TORS). Control of the vessels that supply and traverse the PPS can help the TORS surgeon avoid those critical structures and reduce surgical morbidity and potential hemorrhage. (C) 2014 Wiley Periodicals, Inc. C1 [Wang, Chengyuan] China Japan Friendship Hosp, Dept Otolaryngol Head & Neck Surg, Beijing, Peoples R China. [Wang, Chengyuan; Fernandez-Miranda, Juan] Univ Pittsburgh, Med Ctr, Dept Neurosurg, Pittsburgh, PA 15213 USA. [Kundaria, Summit; Duvvuri, Umamaheswar] Univ Pittsburgh, Med Ctr, UPMC Dept Otolaryngol Head & Neck Surg, Vet Affairs Pittsburgh Hlth Syst,Eye & Ear Inst, Pittsburgh, PA 15213 USA. RP Duvvuri, U (reprint author), Univ Pittsburgh, Med Ctr, Dept Otolaryngol, Vet Affairs Pittsburgh Hlth Syst,Eye & Ear Inst, Suite 500,200 Lothrop St, Pittsburgh, PA 15213 USA. EM duvuriu@upmc.edu FU Department of Veterans Affairs; University of Pittsburgh School of Medicine; PNC foundation FX Grant sponsors: Department of Veterans Affairs, University of Pittsburgh School of Medicine, and PNC foundation (U.D.). NR 9 TC 4 Z9 4 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0897-3806 EI 1098-2353 J9 CLIN ANAT JI Clin. Anat. PD OCT PY 2014 VL 27 IS 7 BP 1016 EP 1022 DI 10.1002/ca.22273 PG 7 WC Anatomy & Morphology SC Anatomy & Morphology GA AP2NM UT WOS:000341909200013 PM 24510490 ER PT J AU Sonpavde, G Pond, GR Armstrong, AJ Clarke, SJ Vardy, JL Templeton, AJ Wang, SL Paolini, J Chen, I Chow-Maneval, E Lechuga, M Smith, MR Michaelson, MD AF Sonpavde, Guru Pond, Gregory R. Armstrong, Andrew J. Clarke, Stephen J. Vardy, Janette L. Templeton, Arnoud J. Wang, Shaw-Ling Paolini, Jolanda Chen, Isan Chow-Maneval, Edna Lechuga, Mariajose Smith, Matthew R. Michaelson, M. Dror TI Prognostic Impact of the Neutrophil-to-Lymphocyte Ratio in Men With Metastatic Castration-Resistant Prostate Cancer SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Advanced prostate cancer; Lymphocytes; Neutrophils; Prognosis; Survival ID RENAL-CELL CARCINOMA; CIRCULATING TUMOR-CELLS; PRETREATMENT NEUTROPHIL; PREOPERATIVE NEUTROPHIL; LEUKEMIA GROUP-B-9480; FOLLOW-UP; SURVIVAL; CHEMOTHERAPY; NOMOGRAM; MODEL AB This retrospective analysis of a phase III trial comparing prednisone combined with sunitinib or placebo following docetaxel for metastatic castration resistant prostate cancer demonstrated the prognostic impact of peripheral blood neutrophil-lymphocyte ratio (NLR) independent of known prognostic factors. NLR warrants external validation, given its ready and inexpensive availability, and the potential role of the host immune in modulating tumor biology. Background: We retrospectively evaluated the prognostic impact of neutrophil-lymphocyte ratio (NLR) as a marker for inflammatory and immune state in men with progressive metastatic castration resistant prostate cancer (mCRPC) following docetaxel. Methods: The SUN-1120 phase III trial comparing prednisone combined with sunitinib (n = 584) or placebo (n = 289) for mCRPC following docetaxel-based chemotherapy was evaluated. The arms were combined for analysis, since no difference was observed in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for survival, we used a Cox proportional hazards regression method with forward stepwise selection, stratifying for ECOG PS, progression type (prostate specific antigen [PSA] or radiographic) and treatment group. Patients were categorized into risk groups. Results: Complete data was evaluable for 784 men. The factors used in the model that remained individually significant for OS in multivariable analysis were: log-lactate dehydrogenase level (LDH) level (HR 2.86 [95% CI = 2.29, 3.56], P < .001), hemoglobin (0.80 [0.74, 0.85], P < .001), > 1 organ involved by metastatic disease (1.49 [1.21, 1.84], P < .001), log-alkaline phosphatase (1.13 [0.99, 1.28], P = .074), log-number of prior cycles of docetaxel (0.84 [0.71, 0.98], P = .031), progression on docetaxel (1.35 [1.00, 1.81], P = .049), log-PSA (1.06 [1.00, 1.12], P = .075) and log-NLR (1.55 [1.32, 1.83], P < .001). NLR increased the c-statistic of the prognostic model from 0.703 to 0.715. Conclusion: High NLR may be associated with an independent poor prognostic impact in post-docetaxel patients with mCRPC. These data warrant external validation. (C) 2014 Elsevier Inc. All rights reserved. C1 [Sonpavde, Guru] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Pond, Gregory R.] McMaster Univ, Ontario Clin Oncol Grp, Hamilton, ON, Canada. [Armstrong, Andrew J.] Duke Univ, Durham, NC USA. [Clarke, Stephen J.; Vardy, Janette L.] Univ Sydney, Sydney, NSW 2006, Australia. [Templeton, Arnoud J.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Wang, Shaw-Ling; Paolini, Jolanda; Chen, Isan; Chow-Maneval, Edna; Lechuga, Mariajose] Pfizer Inc, Bridgewater, NJ USA. [Wang, Shaw-Ling] ICON Clin Res Inc, San Diego, CA USA. [Chen, Isan; Chow-Maneval, Edna] Aragon Pharmaceut, San Diego, CA USA. [Smith, Matthew R.; Michaelson, M. Dror] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Smith, Matthew R.; Michaelson, M. Dror] Harvard Univ, Sch Med, Boston, MA USA. RP Sonpavde, G (reprint author), UAB Comprehens Canc Ctr, Dept Med, Div Hematol Oncol, 1802 6th Ave South,NP2540B, Birmingham, AL 35294 USA. EM gsonpavde@uabmc.edu OI Michaelson, Dror/0000-0001-9249-6338; Vardy, Janette/0000-0002-5739-5790 FU Pfizer FX G. Sonpavde, M.R. Smith, and M.D. Michaelson receive research support from Pfizer. S.-L. Wang, J. Paolini, I. Chen, E. Chow-Maneval, and M. Lechuga are employed by Pfizer. A.J. Armstrong receives research support and has been a speaker for Pfizer. The authors G.R. Pond, S.J. Clarke, J.L. Vardy, and A.J. Templeton have stated that they have no conflicts of interest. NR 49 TC 9 Z9 10 U1 0 U2 10 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD OCT PY 2014 VL 12 IS 5 BP 317 EP 324 DI 10.1016/j.clgc.2014.03.005 PG 8 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AP5XU UT WOS:000342152800014 PM 24806399 ER PT J AU Harshman, LC Kroeger, N Rha, SY Donskov, F Wood, L Tantravahi, SK Vaishampayan, U Rini, BI Knox, J North, S Ernst, S Yuasa, T Srinivas, S Pal, S Heng, DY Choueiri, TK AF Harshman, Lauren C. Kroeger, Nils Rha, Sun Young Donskov, Frede Wood, Lori Tantravahi, Srinivas K. Vaishampayan, Ulka Rini, Brian I. Knox, Jennifer North, Scott Ernst, Scott Yuasa, Takeshi Srinivas, Sandy Pal, Sumanta Heng, Daniel Y. Choueiri, Toni K. TI First-Line Mammalian Target of Rapamycin Inhibition in Metastatic Renal Cell Carcinoma: An Analysis of Practice Patterns From the International Metastatic Renal Cell Carcinoma Database Consortium SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Everolimus; mTOR inhibitor; Targeted therapy; Temsirolimus; Treatment-naive ID PHASE-III TRIAL; INTERFERON-ALPHA; CANCER-THERAPY; SUNITINIB; EVEROLIMUS; SORAFENIB; SURVIVAL; TEMSIROLIMUS; EFFICACY; PAZOPANIB AB Using an established international renal cell carcinoma (RCC) database, we retrospectively characterized the use and efficacy of mammalian target of rapamycin (mTOR) inhibitors in treatment-naive metastatic RCC (mRCC) patients. Front-line mTOR inhibitors are used in clinical practice mostly in select patients, who have non-clear cell histology, poor prognostic features, or as part of clinical trials. Introduction/Background: Approval of the mTOR inhibitors for the treatment of mRCC was based on efficacy in poor-risk patients in the first-line setting for temsirolimus and in vascular endothelial growth factor inhibitor-refractory patients for everolimus. We strove to characterize temsirolimus and everolimus use and effectiveness in the first-line setting. Patients and Methods: We performed a retrospective database analysis of mRCC patients who received mTOR inhibitors as first-line targeted therapy. The Kaplan-Meier product-limit method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS). Results: We identified 127 mRCC patients who had received a first-line mTOR inhibitor. Temsirolimus was administered in 93 patients (73%) and everolimus in 34 patients (27%). The main reasons for choice of temsirolimus were poor-risk disease (38%), non-clear cell histology (27%), and clinical trial availability (15%), whereas clinical trial (82%) and non-clear cell histology (6%) drove everolimus selection. Of the temsirolimus and everolimus patients, 58% and 32% were poor-risk according to the International mRCC Database Consortium criteria, respectively. The median PFS and OS were 3.4 and 12.5 months and 4.8 and 15.9 months with temsirolimus and everolimus, respectively. Although limited by small numbers, this study characterizes a real-world, international experience with the use of mTOR inhibition in treatment-naive mRCC patients. Conclusion: Poor-risk RCC, non-clear cell histology, and clinical trials were the predominant reasons for mTOR inhibitor selection in the front-line setting. Because of the different patient populations in which they were administered, direct comparisons of the front-line efficacy of temsirolimus and everolimus cannot be made. (C) 2014 Elsevier Inc. All rights reserved. C1 [Harshman, Lauren C.; Choueiri, Toni K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. [Harshman, Lauren C.; Srinivas, Sandy] Stanford Canc Inst, Stanford, CA USA. [Kroeger, Nils; Heng, Daniel Y.] Tom Baker Canc Clin, Calgary, AB, Canada. [Rha, Sun Young] Yonsei Univ, Coll Med, Yonsei Canc Ctr, Seoul, South Korea. [Donskov, Frede] Aarhus Univ Hosp, DK-8000 Aarhus, Denmark. [Wood, Lori] Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. [Tantravahi, Srinivas K.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Vaishampayan, Ulka] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Rini, Brian I.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Knox, Jennifer] Princess Margaret Canc Ctr, Toronto, ON, Canada. [North, Scott] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Ernst, Scott] London Reg Canc Program, London, ON, Canada. [Yuasa, Takeshi] JFCR, Canc Inst Hosp, Tokyo, Japan. [Pal, Sumanta] City Hope Natl Med Ctr, Duarte, CA USA. RP Harshman, LC (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Kidney Canc Ctr, 450 Brookline Ave DANA 1230, Boston, MA 02215 USA. EM LaurenC_Harshman@dfci.harvard.edu OI Donskov, Frede/0000-0002-8449-863X FU BMS; Novartis; Pfizer; Glaxo-Smith Kline; Bristol-Myers Squibb FX Lauren C. Harshman: advisory boards for Aveo, Pfizer, and Bristol-Myers Squibb, past research funding from BMS and Novartis; Frede Donskov: research funding from Novartis; Lori Wood: consultant (uncompensated) for Pfizer and Glaxo-Smith Kline, research funding from Pfizer, Glaxo-Smith Kline, and Novartis; Ulka Vaishampayan: consultant for Novartis, honoraria from Novartis and Pfizer, research support from Pfizer; Brian I. Rini: consultant and research funding from Pfizer; Jennifer Knox: consultant for Aveo, research funding from Pfizer; Scott Ernst: consultant/advisory boards for Bristol-Myers Squib, Roche, Novartis, and Glaxo-Smith Kline; Sandy Srinivas: consultant for Pfizer, Glaxo-Smith Kline, and Genentech, research funding from Bristol-Myers Squibb, Pfizer, Glaxo-Smith Kline, and Novartis; Sumanta Pal: honoraria from Novartis; Daniel Y. Heng: consultant for Pfizer, Novartis, and Bayer; Toni K. Choueiri: advisory boards for Glaxo-Smith Kline, Pfizer, Novartis, Genentech, Bayer, and AVEO, research funding from Pfizer. The remaining authors have stated that they have no conflicts of interest. NR 29 TC 5 Z9 6 U1 0 U2 6 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD OCT PY 2014 VL 12 IS 5 BP 335 EP 340 DI 10.1016/j.clgc.2014.03.003 PG 6 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AP5XU UT WOS:000342152800017 PM 24787966 ER PT J AU Khambati, HK Choueiri, TK Kollmannsberger, CK North, S Bjarnason, GA Vaishampayan, UN Wood, L Knox, JJ Tan, MH MacKenzie, MJ Donskov, F Rini, BI Heng, DYC AF Khambati, Husain K. Choueiri, Toni K. Kollmannsberger, Christian K. North, Scott Bjarnason, George A. Vaishampayan, Ulka N. Wood, Lori Knox, Jennifer J. Tan, Min-Han MacKenzie, Mary J. Donskov, Frede Rini, Brian I. Heng, Daniel Y. C. CA Int mRCC Database Consortium TI Efficacy of Targeted Therapy for Metastatic Renal Cell Carcinoma in the Elderly Patient Population SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Age; Geriatric; mRCC; Prognostic factors; Vascular endothelial growth factor ID INTERFERON-ALPHA; CANCER-PATIENTS; MANAGEMENT; SURVIVAL; IMPACT; INSUFFICIENCY; COMORBIDITY; SORAFENIB; TRIAL; OLD AB Targeted therapy has become the mainstay of treatment for metastatic renal cell carcinoma (mRCC), and the efficacy of this therapy in the older population is poorly understood. Data from 1381 patients with mRCC treated with first-line anti-vascular endothelial growth factor (VEGF) therapy were collected through the International mRCC Database Consortium from 12 centers. When adjusted for poor prognostic factors, age 75 years and older was not found to be associated with poorer overall survival or shorter treatment duration. This suggests that advanced age alone should not preclude a patient from targeted therapy. Introduction/Background: Targeted therapy has become the mainstay of treatment for mRCC. The efficacy of this therapy in the older population is poorly understood. Patients and Methods: Data from patients with mRCC treated with first-line anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. Patient characteristics, data on second-line therapy, and outcomes including treatment duration and overall survival, were evaluated using summary statistics and multivariate analysis. Results: All patients (n = 1381) were treated with front-line targeted therapy; 144 (10%) were 75 years old or older. Six patients (4%) were favorable risk, 99 patients (69%) intermediate risk, and 39 patients (27%) poor risk according to Heng Journal of Clinical Oncology 2009 prognostic factors. The initial treatment for those >= 75 years of age was sunitinib (n = 98), sorafenib (n = 35), bevacizumab (n = 7), and AZD217 (n = 4). Twenty-three percent of older patients and 39% of the younger patients went on to receive second-line therapy (P < .0001). The overall response rate, median treatment duration, and overall survival for the older versus younger group were 18% versus 25% (P = .0975), 5.5 months versus 7.5 months (P = .1388), and 16.8 months versus 19.7 months (P = .3321), respectively. When adjusted for poor prognostic factors, age 75 years and older was not found to be associated with poorer overall survival (hazard ratio [HR], 1.002; 95% confidence interval [CI], 0.781-1.285) or shorter treatment duration (HR, 1.018; 95% CI, 0.827-1.252). The retrospective study design was the primary limitation. Conclusion: The use of advanced age as a selection criterion for targeted therapy requires further study, with data suggesting no clinically meaningful differences in overall response rate, treatment duration, and overall survival between older and younger age groups. (C) 2014 Elsevier Inc. All rights reserved. C1 [Khambati, Husain K.; Heng, Daniel Y. C.] Univ Calgary, Tom Baker Canc Ctr, Calgary, AB T2N 4N2, Canada. [Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Choueiri, Toni K.] Harvard Univ, Sch Med, Boston, MA USA. [Kollmannsberger, Christian K.] British Columbia Canc Agcy, Vancouver Canc Ctr, Vancouver, BC V5Z 4E6, Canada. [North, Scott] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Bjarnason, George A.] Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Vaishampayan, Ulka N.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Wood, Lori] Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. [Knox, Jennifer J.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Tan, Min-Han] Natl Canc Ctr, Singapore, Singapore. [MacKenzie, Mary J.] London Reg Canc Program, London, ON, Canada. [Donskov, Frede] Aarhus Univ, Aarhus, Denmark. [Rini, Brian I.] Cleveland Clin, Taussig Canc Ctr, Cleveland, OH 44106 USA. RP Heng, DYC (reprint author), Univ Calgary, Tom Baker Canc Ctr, 1331 29th St NW, Calgary, AB T2N 4N2, Canada. EM daniel.heng@albertahealthservices.ca OI Bjarnason, Georg Arnold/0000-0001-6903-5357; Donskov, Frede/0000-0002-8449-863X FU Pfizer; Novartis; Bayer FX D.Y.C. Heng, J.J. Knox, G.A. Bjarnason, C.K. Kollmannsberger, and S. North have received consulting honoraria from Pfizer and Novartis. J.J. Knox, F. Donskov, G.A. Bjarnason, B.I. Rini, and T.K. Choueiri have received research funding from Pfizer and Novartis. J.J. Knox has received research funding from Bayer. The remaining authors have stated that they have no conflicts of interest. NR 25 TC 7 Z9 7 U1 0 U2 2 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD OCT PY 2014 VL 12 IS 5 BP 354 EP 358 DI 10.1016/j.clgc.2014.02.009 PG 5 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AP5XU UT WOS:000342152800020 PM 24819320 ER PT J AU Mahal, BA Aizer, AA Ziehr, DR Hyatt, AS Choueiri, TK Hu, JC Hoffman, KE Sweeney, CJ Beard, CJ D'Amico, AV Martin, NE Kim, SP Trinh, QD Nguyen, PL AF Mahal, Brandon A. Aizer, Ayal A. Ziehr, David R. Hyatt, Andrew S. Choueiri, Toni K. Hu, Jim C. Hoffman, Karen E. Sweeney, Christopher J. Beard, Clair J. D'Amico, Anthony V. Martin, Neil E. Kim, Simon P. Quoc-Dien Trinh Nguyen, Paul L. TI Racial Disparities in Prostate Cancere-Specific Mortality in Men With Low-Risk Prostate Cancer SO CLINICAL GENITOURINARY CANCER LA English DT Article DE African-American; Health Policy; Population health; Prostatic Neoplasms; SEER ID BIOCHEMICAL DISEASE RECURRENCE; AGE-BASED DISPARITIES; AFRICAN-AMERICAN MEN; ACTIVE SURVEILLANCE; RADICAL PROSTATECTOMY; CLINICAL-TRIALS; IMPACT; RACE; MANAGEMENT; OUTCOMES AB This study examined the association of race and prostate cancere-specific mortality (PCSM) in 51,315 men with low-risk prostate cancer, using the Surveillance, Epidemiology, and End Results (SEER) database. African American men were found to have a higher risk of PCSM compared with white men, suggesting that further studies are needed to determine whether guidelines for active surveillance should take race into account. Background: Men with low-risk prostate cancer (CaP) are considered unlikely to die of CaP and have the option of active surveillance. This study evaluated whether African American (AA) men who present with low-risk disease are at higher risk for death from CaP than white men. Patients and Methods: The authors identified 56,045 men with low-risk CaP (T1-T2a, Gleason score <= 6, prostate-specific antigen <= 10 ng/mL) diagnosed between 2004 and 2009 using the Surveillance, Epidemiology, and End Results (SEER) database. Fine-Gray competing-risks regression analyses were used to analyze the effect of race on prostate cancere-specific mortality (PCSM) after adjusting for known prognostic and sociodemographic factors in 51,315 men (43,792 white; 7523 AA) with clinical follow-up information available. Results: After a median follow-up of 46 months, 258 patients (209 [0.48%] white and 49 [0.65%] AA men) died from CaP. Both AA race (adjusted hazard ratio [AHR], 1.45; 95% CI, 1.03-2.05; P = .032) and noncurative management (AHR, 1.49; 95% CI, 1.15-1.95; P = .003) were significantly associated with an increased risk of PCSM. When analyzing only patients who underwent curative treatment, AA race (AHR, 1.62; 95% CI, 1.04-2.53; P = .034) remained significantly associated with increased PCSM. Conclusion: Among men with low-risk prostate cancer, AA race compared with white race was associated with a higher risk of PCSM, raising the possibility that clinicians may need to exercise caution when recommending active surveillance for AA men with low-risk disease. Further studies are needed to ultimately determine whether guidelines for active surveillance should take race into account. (C) 2014 Elsevier Inc. All rights reserved. C1 [Mahal, Brandon A.; Ziehr, David R.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Aizer, Ayal A.] Harvard Radiat Oncol Program, Boston, MA USA. [Hyatt, Andrew S.; Beard, Clair J.; D'Amico, Anthony V.; Martin, Neil E.; Nguyen, Paul L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Hyatt, Andrew S.; Choueiri, Toni K.; Sweeney, Christopher J.; Beard, Clair J.; D'Amico, Anthony V.; Martin, Neil E.; Nguyen, Paul L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Choueiri, Toni K.; Sweeney, Christopher J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hu, Jim C.] Univ Calif Los Angeles, Med Ctr, Dept Urol, Los Angeles, CA 90024 USA. [Hoffman, Karen E.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Kim, Simon P.] Yale Univ, Canc Outcomes & Publ Policy Effectiveness Res Ctr, Dept Urol, New Haven, CT USA. [Quoc-Dien Trinh] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Urol, Boston, MA 02115 USA. RP Nguyen, PL (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu RI Martin, Neil/E-2193-2014 OI Martin, Neil/0000-0002-8164-8516 FU David and Cynthia Chapin; Prostate Cancer Foundation; Fitz's Cancer Warriors; Hugh Simons in Honor of Frank; Anne Simons; anonymous family foundation FX This work was supported by David and Cynthia Chapin, the Prostate Cancer Foundation, Fitz's Cancer Warriors, Hugh Simons in Honor of Frank and Anne Simons, and a grant from an anonymous family foundation. Paul L. Nguyen served on an advisory board for Astellas Pharmaceuticals in June 2013. Quoc-Dien Trinh lectured on behalf of Intuitive Surgical. All other authors state that they have no conflicts of interest. NR 43 TC 12 Z9 12 U1 0 U2 5 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD OCT PY 2014 VL 12 IS 5 BP E189 EP E195 DI 10.1016/j.clgc.2014.04.003 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AP5XU UT WOS:000342152800004 PM 24861952 ER PT J AU Phillips, JG Aizer, AA Chen, MH Zhang, DJ Hirsch, MS Richie, JP Tempany, CM Williams, S Hegde, JV Loffredo, MJ D'Amico, AV AF Phillips, John G. Aizer, Ayal A. Chen, Ming-Hui Zhang, Danjie Hirsch, Michelle S. Richie, Jerome P. Tempany, Clare M. Williams, Stephen Hegde, John V. Loffredo, Marian J. D'Amico, Anthony V. TI The Effect of Differing Gleason Scores at Biopsy on the Odds of Upgrading and the Risk of Death From Prostate Cancer SO CLINICAL GENITOURINARY CANCER LA English DT Article DE ComboGS; Pathology; Prognostic factors; Prostate cancer-specific mortality; Radical prostatectomy ID RADICAL PROSTATECTOMY; ACTIVE SURVEILLANCE; RADIATION-THERAPY; COMPETING RISK; BRACHYTHERAPY; OUTCOMES; MODEL AB We provide evidence that differing Gleason scores (GSs) at biopsy (ComboGS) is associated with an approximately 80% decrease in the odds of upgrading and a 60% decrease in the risk of prostate cancer-specific mortality (PCSM) after definitive treatment. If validated, future randomized noninferiority studies evaluating deescalated treatment approaches in men with ComboGS could be considered. Introduction/Background: The GS is an established prostate cancer prognostic factor. Whether the presence of differing GSs at biopsy (eg, 4+3 and 3+3), which we term ComboGS, improves the prognosis that would be predicted based on the highest GS (eg, 4+3) because of decreased upgrading is unknown. Therefore, we evaluated the odds of upgrading at time of radical prostatectomy (RP) and the risk of PCSM when ComboGS was present versus absent. Patients and Methods: Logistic and competing risks regression were performed to assess the effect that ComboGS had on the odds of upgrading at time of RP in the index (n = 134) and validation cohorts (n = 356) and the risk of PCSM after definitive therapy in a long-term cohort (n = 666), adjusting for known predictors of these end points. We calculated and compared the area under the curve using a receiver operating characteristic analysis when ComboGS was included versus excluded from the upgrading models. Results: ComboGS was associated with decreased odds of upgrading (index: adjusted odds ratio [AOR], 0.14; 95% confidence interval [CI], 0.04-0.50; P = .003; validation: AOR, 0.24; 95% CI, 0.11-0.51; P < .001) and added significantly to the predictive value of upgrading for the in-sample index (P = .02), validation (P = .003), and out-of-sample prediction models (P = .002). ComboGS was also associated with a decreased risk of PCSM (adjusted hazard ratio, 0.40; 95% CI, 0.19-0.85; P = .02). Conclusion: Differing biopsy GSs are associated with a lower odds of upgrading and risk of PCSM. If validated, future randomized noninferiority studies evaluating deescalated treatment approaches in men with ComboGS could be considered. (C) 2014 Elsevier Inc. All rights reserved. C1 [Phillips, John G.; Aizer, Ayal A.] Harvard Radiat Oncol Program, Boston, MA USA. [Chen, Ming-Hui; Zhang, Danjie] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Hirsch, Michelle S.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Richie, Jerome P.; Williams, Stephen] Brigham & Womens Hosp, Dept Surg, Div Urol, Boston, MA 02115 USA. [Tempany, Clare M.] Brigham & Womens Hosp, Dept Radiol, Div MRI, Boston, MA 02115 USA. [Hegde, John V.] Harvard Univ, Sch Med, Boston, MA USA. [Loffredo, Marian J.; D'Amico, Anthony V.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Loffredo, Marian J.; D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Phillips, JG (reprint author), Brigham & Womens Hosp, Harvard Radiat Oncol Program, ASBI LL2,75 Francis St, Boston, MA 02115 USA. EM jphillips@lroc.harvard.edu FU NIH [EB 015898, CA 111288] FX This work was supported by NIH grants: EB 015898 and CA 111288. NR 31 TC 1 Z9 1 U1 0 U2 3 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD OCT PY 2014 VL 12 IS 5 BP E181 EP E187 DI 10.1016/j.clgc.2014.02.008 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AP5XU UT WOS:000342152800003 PM 24721618 ER PT J AU Rose, BS Chen, MH Zhang, DJ Hirsch, MS Richie, JP Chang, SL Hegde, JV Loffredo, MJ D'Amico, AV AF Rose, Brent S. Chen, Ming-Hui Zhang, Danjie Hirsch, Michelle S. Richie, Jerome P. Chang, Stephen L. Hegde, John V. Loffredo, Marian J. D'Amico, Anthony V. TI Maximum Tumor Diameter and the Risk of Prostate-Specific Antigen Recurrence After Radical Prostatectomy SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Adjuvant radiation therapy; Biochemical recurrence; Over treatment; Prostate cancer; Risk stratification ID RANDOMIZED CLINICAL-TRIAL; INDEPENDENT PREDICTOR; ADJUVANT RADIOTHERAPY; POSTOPERATIVE RADIOTHERAPY; BIOCHEMICAL RECURRENCE; RADIATION-THERAPY; SALVAGE RADIATION; CANCER; FAILURE; CARCINOMA AB Multiple randomized controlled trials have demonstrated that adjuvant radiation therapy (ART) for men with pT3 or margin-positive disease reduces the risk of biochemical recurrence after radical prostatectomy (RP); however, overtreatment might occur. We used multivariable Cox regression to study 354 men with clinical T1c to T2 prostate cancer who underwent RP without adjuvant therapy to investigate whether the maximum tumor diameter (MTD) could identify men at low risk of prostate-specific antigen (PSA) recurrence. We found that men with an MTD <= median (1.2 cm) appear to be at low risk of PSA recurrence (< 10% at 5 years with a median follow-up of 4 years) despite adverse features at RP and might not benefit from ART. Introduction/Background: The aim of this study was to investigate whether the MTD could identify men at low risk of PSA recurrence after RP who might not benefit from ART despite other adverse features. Patients and Methods: The study cohort consisted of 354 men with T1c to T2 prostate cancer diagnosed between September 2001 and December 2008 who underwent RP without adjuvant therapy. Multivariable Cox regression was used to assess the effect of MTD on the risk of PSA recurrence (> 0.1 ng/mL and verified), adjusting for known predictors. Results: After a median follow-up of 4.0 years, 34 men (9.6%) experienced PSA failure. In multivariable analysis, increasing MTD was significantly associated with an increased PSA recurrence risk (hazard ratio, 2.74; 95% confidence interval, 1.23-6.10; P = .01) within the interaction model. Estimates of PSA recurrence-free survival stratified around the median MTD value (1.2 cm) were significantly different in men with a pre-RP PSA > 4 ng/mL (P < .001; 5-year estimate: 74.5% vs. 99.0%) but not in men with PSA <= 4 ng/mL (P = .59; 5-year estimate: 89.6% vs. 92.6%), consistent with the significant interaction (P = .004) between PSA and MTD. Moreover, in men with a pre-RP PSA > 4 ng/mL these estimates were significantly different if at least 1 adverse feature (pT3, R1, or Gleason score >= 8) was present at RP (P = .01; 5-year estimate: 46.6% vs. 100%) versus none (P = .09; 5-year estimate: 93.4% vs. 98.9%). Conclusion: Men with a low MTD (<= 1.2 cm) appear to be at low risk of PSA recurrence despite adverse features at RP and might not benefit from ART. (C) 2014 Elsevier Inc. All rights reserved. C1 [Rose, Brent S.] Harvard Radiat Oncol Program, Boston, MA USA. [Chen, Ming-Hui; Zhang, Danjie] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Hirsch, Michelle S.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. [Richie, Jerome P.; Chang, Stephen L.] Brigham & Womens Hosp, Div Urol, Boston, MA 02215 USA. [Hegde, John V.] Harvard Univ, Sch Med, Boston, MA USA. [Rose, Brent S.; D'Amico, Anthony V.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. RP Rose, BS (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02215 USA. EM bsrose@partners.org NR 30 TC 1 Z9 1 U1 0 U2 1 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD OCT PY 2014 VL 12 IS 5 BP E173 EP E179 DI 10.1016/j.clgc.2014.03.008 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AP5XU UT WOS:000342152800002 PM 24787967 ER PT J AU Mollica, RF Chernoff, MC Berthold, SM Lavelle, J Lyoo, IK Renshaw, P AF Mollica, Richard F. Chernoff, Miriam C. Berthold, S. Megan Lavelle, James Lyoo, In Kyoon Renshaw, Perry TI The mental health sequelae of traumatic head injury in South Vietnamese ex-political detainees who survived torture SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; HOPKINS SYMPTOM CHECKLIST-25; CONCENTRATION-CAMP SURVIVORS; DOSE-EFFECT RELATIONSHIPS; OF-THE-LITERATURE; BRAIN-INJURY; MASS VIOLENCE; PSYCHOLOGICAL SEQUELAE; PSYCHIATRIC-DISORDERS; CAMBODIAN SURVIVORS AB Little is known about the relationship between traumatic head injury (THI) and psychiatric morbidity in torture survivors. We examine the relationship between THI and depression, PTSD, post-concussive syndrome (PCS), disability and poor health status in Vietnamese ex-political detainees who survived incarceration in Vietnamese re-education camps. A community sample of ex-political detainees (n = 337) and a non-THI, non-ex-detainee comparison group (n = 82) were surveyed. Seventy-eight percent of the ex-political detainees had experienced THI; 90.6% of the ex-political detainees and 3.6% of the comparison group had experienced 7 or more trauma events. Depression and PTSD were greater in ex-detainees than in the comparison group (40.9% vs 23.2% and 13.4% vs 0%). Dose-effect relationships for THI and trauma/torture in the ex-political detainee group were significant. Logistic regression in the pooled sample of ex-detainees and the comparison group confirmed the independent impact of THI from trauma/torture on psychiatric morbidity (OR for PTSD = 22.4; 95% CI: 3.0-165.8). These results demonstrate important effects of THI on depression and PTSD in Vietnamese ex-detainees who have survived torture. (C) 2014 Elsevier Inc. All rights reserved. C1 [Mollica, Richard F.; Lavelle, James] Massachusetts Gen Hosp, Dept Psychiat, Harvard Program Refugee Trauma, Boston, MA 02114 USA. [Chernoff, Miriam C.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Berthold, S. Megan] Univ Connecticut, Sch Social Work, West Harford, CT USA. [Lyoo, In Kyoon] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Seoul, South Korea. [Lyoo, In Kyoon] Ewha Womans Univ, Ewha Brain Inst, Seoul, South Korea. [Renshaw, Perry] Univ Utah, Interdept Program Neurosci, Salt Lake City, UT USA. RP Mollica, RF (reprint author), Harvard Program Refugee Trauma, 22 Putnam Ave, Cambridge, MA 02139 USA. EM rmollica@partners.org; miriam.chernoff@juno.com; megan.berthold@uconn.edu; jlavelle@partners.org; inkylyoo@ewha.ac.kr; Perry.Renshaw@hsc.utah.edu FU National Institute of Health, Bethesda, Maryland [MH R01-059559-04] FX Research for this manuscript was made possible by Grant No. MH R01-059559-04 from the National Institute of Health, Bethesda, Maryland. There are no conflicts of interest. The authors would like to acknowledge the following for their contributions to this study: (1) Vietnamese American Civic Association (VACA) and (2) Daniel H. Hovelson, BA, Harvard Program in Refugee Trauma. NR 95 TC 6 Z9 6 U1 2 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0010-440X EI 1532-8384 J9 COMPR PSYCHIAT JI Compr. Psychiat. PD OCT PY 2014 VL 55 IS 7 BP 1626 EP 1638 DI 10.1016/j.comppsych.2014.04.014 PG 13 WC Psychiatry SC Psychiatry GA AP5LX UT WOS:000342121800023 PM 24962448 ER PT J AU Grubbs, JA Baddley, JW AF Grubbs, James A. Baddley, John W. TI Pneumocystis jirovecii Pneumonia in Patients Receiving Tumor-Necrosis-Factor-Inhibitor Therapy: Implications for Chemoprophylaxis SO CURRENT RHEUMATOLOGY REPORTS LA English DT Article DE Pneumocystis jirovecii; PJP; Autoimmune disease; Biologicals; TNF inhibitor; Prophylaxis; Trimethoprim-sulfamethoxazole ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; RHEUMATOID-ARTHRITIS PATIENTS; HIV-INFECTED PATIENTS; RANDOMIZED CONTROLLED-TRIALS; SYNTHASE GENE-MUTATIONS; REAL-TIME PCR; CARINII-PNEUMONIA; SERIOUS INFECTIONS; TRIMETHOPRIM-SULFAMETHOXAZOLE; POSTMARKETING SURVEILLANCE AB Pneumocystis jirovecii pneumonia (PJP) is an important opportunistic infection that has been increasingly reported in patients with rheumatic disease. Reported incidence among patients taking TNF inhibitors (TNFi) has varied, but has usually been low. Still, disease causes significant mortality among those affected and must be considered in patients with rheumatological disease presenting with dyspnea and cough. Diagnosis can be difficult in the non-HIV population, and our understanding of the epidemiology and natural history after exposure is changing. Trimethoprim-sulfamethoxazole is believed to be the most effective agent for treatment and prophylaxis, but is associated with significant adverse effects. Given the low incidence reported in most studies of patients on TNFi, prophylaxis is probably not beneficial for this patient population as a whole. C1 [Grubbs, James A.; Baddley, John W.] Univ Alabama Birmingham, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. [Baddley, John W.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. RP Baddley, JW (reprint author), Univ Alabama Birmingham, Dept Med, Div Infect Dis, 1900 Univ Blvd,229 Tinsley Harrison Tower, Birmingham, AL 35294 USA. EM jbaddley@uab.edu FU BMS FX James A. Grubbs declares that he has no conflict of interest. John W. Baddley declares that he has served as a consultant for Pfizer, Astellas, and Merck, and that he has received a research grant from BMS. NR 87 TC 6 Z9 6 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3774 EI 1534-6307 J9 CURR RHEUMATOL REP JI Curr. Rheumatol. Rep. PD OCT PY 2014 VL 16 IS 10 AR 445 DI 10.1007/s11926-014-0445-4 PG 9 WC Rheumatology SC Rheumatology GA AP4UQ UT WOS:000342074700001 PM 25182673 ER PT J AU Wessels, D Lusche, DF Scherer, A Kuhl, S Myre, MA Soll, DR AF Wessels, Deborah Lusche, Daniel F. Scherer, Amanda Kuhl, Spencer Myre, Michael A. Soll, David R. TI Huntingtin regulates Ca2+ chemotaxis and K+-facilitated cAMP chemotaxis, in conjunction with the monovalent cation/H+ exchanger Nhe1, in a model developmental system: Insights into its possible role in Huntington's disease SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Huntingtin; Actin-myosin cytoskeleton; Myosin heavy chain kinase; Inositol 1,4,5-trisphosphate receptor; Cation/H+ exchanger; Calcium chemotaxis; Nhe1; Cell motility ID INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; HEAVY-CHAIN KINASE; SINGLE-CELL MOTILITY; CYCLIC-AMP PULSES; DICTYOSTELIUM-DISCOIDEUM; MYOSIN-II; ACTIN POLYMERIZATION; PSEUDOPOD EXTENSION; NATURAL AGGREGATION; CALCIUM AB Huntington's disease is a neurodegenerative disorder, attributable to an expanded trinucleotide repeat in the coding region of the human HIT gene, which encodes the protein huntingtin. These mutations lead to huntingtin fragment inclusions in the striatum of the brain. However, the exact function of normal huntingtin and the defect causing the disease remain obscure. Because there are indications that huntingtin plays a role in Ca2+ homeostasis, we studied the deletion mutant of the HTT ortholog in the model developmental system Dictyostelium discoideum, in which Ca2+ plays a role in receptor-regulated behavior related to the aggregation process that leads to multicellular morphogenesis. The D. discoideum tar-mutant failed to undergo both K+-facilitated chemotaxis in spatial gradients of the major chemoattractant cAMP, and chemotaxis up a spatial gradient of Ca2+, but behaved normally in Ca2+-facilitated cAMP chemotaxis and Ca2+-dependent flow-directed motility. This was the same phenotypic profile of the null mutant of Nhe1, a monovalent cation/H(+)exchanger. The htt(-)-mutant also failed to orient correctly during natural aggregation, as was the case for the Nhe1 mutant. Moreover, in a K+-based buffer the normal localization of actin was similarly defective in both htt(-) and nhe1(-) cells in a K+-based buffer, and the normal localization of Nhe1 was disrupted in the htt- mutant. These observations demonstrate that Htt and Nhe1 play roles in the same specific cation-facilitated behaviors and that Nhe1 localization is directly or indirectly regulated by Htt. Similar cation-dependent behaviors and a similar relationship between Htt and Nhe1 have not been reported for mammalian neurons and deserves investigation, especially as it may relate to Huntington's disease. (C) 2014 Elsevier Inc. All rights reserved. C1 [Wessels, Deborah; Lusche, Daniel F.; Scherer, Amanda; Kuhl, Spencer; Soll, David R.] Univ Iowa, Dept Biol, Dev Studies Hybridoma Bank, Iowa City, IA 52242 USA. [Myre, Michael A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02114 USA. RP Soll, DR (reprint author), Univ Iowa, Dept Biol, 302 BBE, Iowa City, IA 52242 USA. EM david-soll@uiowa.edu FU Developmental Studies Hybridoma Bank (DSHB) at the University of Iowa; National Resource created by the NIH; CHDI Foundation FX This research was supported by the Developmental Studies Hybridoma Bank (DSHB) at the University of Iowa, a National Resource created by the NIH, and in part by the CHDI Foundation to M.A.M. We thank Brett Hanson for assistance with the analysis of HDP. The 12E6 anti-GFP monoclonal antibody developed by Sanchez et al. (2014) was obtained from the DSHB, created by the NICHD of the NIH and maintained at the University of Iowa, Department of Biology, Iowa City, IA 52242. NR 71 TC 5 Z9 6 U1 1 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD OCT 1 PY 2014 VL 394 IS 1 BP 24 EP 38 DI 10.1016/j.ydbio.2014.08.009 PG 15 WC Developmental Biology SC Developmental Biology GA AP2ME UT WOS:000341905500004 PM 25149514 ER PT J AU Cohen, E Bolus, R Khanna, D Hays, RD Chang, L Melmed, GY Khanna, P Spiegel, B AF Cohen, Erica Bolus, Roger Khanna, Dinesh Hays, Ron D. Chang, Lin Melmed, Gil Y. Khanna, Puja Spiegel, Brennan TI GERD Symptoms in the General Population: Prevalence and Severity Versus Care-Seeking Patients SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Gastroesophageal reflux disease; Patient-reported outcomes; Symptoms ID GASTROESOPHAGEAL-REFLUX DISEASE; IRRITABLE-BOWEL-SYNDROME; QUALITY-OF-LIFE; VISCERAL SENSITIVITY INDEX; REPORTED OUTCOMES; UNITED-STATES; EPIDEMIOLOGY; DISORDERS; BURDEN; VALIDATION AB Prior estimates suggest that up to 40 % of the US general population (GP) report symptoms of gastroesophageal reflux disease (GERD). However, symptoms in the GP versus patients seeking care for gastrointestinal (GI) complaints have not been compared. We estimated the prevalence and severity of GERD symptoms in the GP versus GI patients, and identified predictors of GERD severity. We hypothesized that similar to functional GI disorders, psychosocial factors would predict symptom severity in GERD as much, or perhaps more, than care-seeking behavior alone. We compared the prevalence of heartburn and regurgitation between a sample from the US GP and patients seeking GI specialty care. We compared GERD severity between groups using the NIH PROMISA (R) GERD scale. We then performed multivariable regression to identify predictors of GERD severity. There was no difference in the prevalence of heartburn between the GP and patient groups (59 vs. 59 %), but regurgitation was more common in patients versus GP (46 vs. 39 %; p = 0.004). In multivariable regression, having high visceral anxiety (p < 0.001) and being divorced or separated (p = 0.006) were associated with higher GERD severity. More than half of a GP sample reports heartburn-higher than previous series and no different from GI patients. Although regurgitation was more prevalent in patients versus the GP, there was no difference in GERD severity between groups after adjusting for other factors; care seeking in GERD appears related to factors beyond symptoms, including visceral anxiety. C1 [Cohen, Erica; Spiegel, Brennan] VA Greater Los Angeles Healthcare Syst, Dept Gastroenterol, Los Angeles, CA 90073 USA. [Cohen, Erica; Melmed, Gil Y.] Cedars Sinai Med Ctr, Dept Gastroenterol, West Hollywood, CA USA. [Bolus, Roger; Chang, Lin; Spiegel, Brennan] Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Los Angeles, CA 90095 USA. [Bolus, Roger; Spiegel, Brennan] UCLA VA Ctr Outcomes Res & Educ, Los Angeles, CA USA. [Khanna, Dinesh; Khanna, Puja] Univ Michigan, Div Rheumatol, Ann Arbor, MI 48109 USA. [Hays, Ron D.] Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90095 USA. [Hays, Ron D.] UCLA Sch Publ Hlth, Dept Hlth Serv, Los Angeles, CA USA. [Chang, Lin] Univ Calif Los Angeles, David Geffen Sch Med, Ctr Neurobiol Stress, Los Angeles, CA 90095 USA. RP Spiegel, B (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Gastroenterol, 11301 Wilshire Blvd,Bldg 115,Room 215, Los Angeles, CA 90073 USA. EM bspiegel@mednet.ucla.edu FU National Institutes of Health through the NIH Roadmap for Medical Research Grant [AR052177]; Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grant [NIAMS 1 T32 AR053463]; ACR Research and Education Foundation Clinical Investigator Fellowship Award [2009_11]; NIAMS [K24 AR063120]; NIH/NIA [P30-AG028748, P30-AG021684]; NCMHD [2P20MD000182]; NIDDK [P50 DK64539] FX NIH/NIAMS U01 AR057936A, the National Institutes of Health through the NIH Roadmap for Medical Research Grant (AR052177). Puja Khanna was supported by Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grant NIAMS 1 T32 AR053463 and ACR Research and Education Foundation Clinical Investigator Fellowship Award 2009_11. Dinesh Khanna was also supported by NIAMS K24 AR063120. Ron Hays was also supported by NIH/NIA Grants P30-AG028748 and P30-AG021684, and NCMHD Grant 2P20MD000182. Lin Chang was also supported by NIDDK P50 DK64539. NR 33 TC 7 Z9 7 U1 1 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD OCT PY 2014 VL 59 IS 10 BP 2488 EP 2496 DI 10.1007/s10620-014-3181-8 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AP5WH UT WOS:000342148900018 PM 24811245 ER PT J AU Walter, JM Wilson, J Ware, LB AF Walter, James M. Wilson, Jennifer Ware, Lorraine B. TI Biomarkers in acute respiratory distress syndrome: from pathobiology to improving patient care SO EXPERT REVIEW OF RESPIRATORY MEDICINE LA English DT Review DE acute lung injury; acute respiratory distress syndrome; biomarkers; clinical predictor; genomics; proteomics ID ACUTE LUNG INJURY; VON-WILLEBRAND-FACTOR; ENDOTHELIAL GROWTH-FACTOR; PULMONARY-EDEMA FLUID; CLARA CELL PROTEIN; GLYCATION END-PRODUCTS; AT-RISK PATIENTS; PROGNOSTIC-SIGNIFICANCE; CLINICAL-OUTCOMES; FACTOR ANTIGEN AB Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by alveolar flooding with protein-rich pulmonary edema fluid. Despite an improved understanding of ARDS pathogenesis, our ability to predict the development of ARDS and risk-stratify patients with the disease remains limited. Biomarkers may help identify patients at highest risk of developing ARDS, assess response to therapy, predict outcome, and optimize enrollment in clinical trials. This review begins with a general description of biomarker use in clinical medicine. We then review evidence that supports the value of various ARDS biomarkers organized by the cellular injury processes central to ARDS development: endothelial injury, epithelial injury, disordered inflammation and coagulation, fibrosis, and apoptosis. Finally, we summarize the growing contributions of genomic and proteomic research and suggest ways in which the field may evolve in the coming years. C1 [Walter, James M.] Univ Calif San Francisco, Dept Internal Med, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94121 USA. [Wilson, Jennifer] Univ Calif San Francisco, Dept Internal Med, San Francisco, CA 94143 USA. [Ware, Lorraine B.] Vanderbilt Univ, Sch Med, Dept Med, Dept Pathol Microbiol & Immunol,Div Allergy Pulm, Nashville, TN 37212 USA. RP Walter, JM (reprint author), Univ Calif San Francisco, Dept Internal Med, San Francisco Vet Affairs Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM James.Walter@ucsf.edu NR 111 TC 6 Z9 7 U1 0 U2 4 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1747-6348 EI 1747-6356 J9 EXPERT REV RESP MED JI Expert Rev. Respir. Med. PD OCT PY 2014 VL 8 IS 5 BP 573 EP 586 DI 10.1586/17476348.2014.924073 PG 14 WC Respiratory System SC Respiratory System GA AP4QJ UT WOS:000342062700007 PM 24875533 ER PT J AU Restrepo, RD Nuccio, P Spratt, G Waugh, J AF Restrepo, Ruben D. Nuccio, Paul Spratt, Greg Waugh, Jonathan TI Current applications of capnography in non-intubated patients SO EXPERT REVIEW OF RESPIRATORY MEDICINE LA English DT Review DE capnography; carbon dioxide; hypoventilation; patient-controlled analgesia; procedural sedation; respiratory depression; volumetric CO2 ID MORBIDLY OBESE-PATIENTS; PROCEDURAL SEDATION; VOLUMETRIC CAPNOGRAPHY; CARBON-DIOXIDE; EMERGENCY-DEPARTMENT; PROPOFOL SEDATION; RESPIRATORY DEPRESSION; AMERICAN-SOCIETY; LUNG RECRUITMENT; CONTROLLED-TRIAL AB Current clinical guidelines recommend capnography as one of the best non-invasive methods to assess adequacy of ventilation in the non-intubated patient. Alveolar hypoventilation or respiratory depression is a serious event that occurs in a variety of clinical settings where patients receive sedatives and opioids. With the large number of procedures performed outside the operating room under the effects of sedatives and the increased use of patient-controlled analgesia, the need for capnography for monitoring has dramatically increased. Despite the succesful use of capnography to monitor ventilation in the operating room over several decades, other clinical areas have been very slow adapters of the technology and still rely heavily upon pulse oximetry to detect hypoventilation. This article reviews the most current evidence for using capnography in the non-intubated patient and summarizes the results of outcome measures reported in recent clinical trials. Capnography should be routinely used for non-intubated patients at risk for respiratory depression, in particular those receiving supplemental oxygen. C1 [Restrepo, Ruben D.] Univ Texas Hlth Sci Ctr San Antonio, Dept Resp Care, San Antonio, TX 78229 USA. [Nuccio, Paul] Brigham & Womens Hosp, Boston, MA 02115 USA. [Nuccio, Paul] Dana Farber Canc Inst, Boston, MA 02115 USA. [Spratt, Greg] Covidien Orid Capnog, St Louis, MO 63463 USA. [Waugh, Jonathan] Univ Alabama Birmingham, Birmingham, AL 35294 USA. RP Restrepo, RD (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Resp Care, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM restrepor@uthscsa.edu OI Restrepo, Ruben/0000-0003-1936-7622 NR 73 TC 0 Z9 1 U1 5 U2 14 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1747-6348 EI 1747-6356 J9 EXPERT REV RESP MED JI Expert Rev. Respir. Med. PD OCT PY 2014 VL 8 IS 5 BP 629 EP 639 DI 10.1586/17476348.2014.940321 PG 11 WC Respiratory System SC Respiratory System GA AP4QJ UT WOS:000342062700011 PM 25020234 ER PT J AU Johnson, DA Barkun, AN Cohen, LB Dominitz, JA Kaltenbach, T Martel, M Robertson, DJ Boland, CR Giardello, FM Lieberman, DA Levin, TR Rex, DK AF Johnson, David A. Barkun, Alan N. Cohen, Larry B. Dominitz, Jason A. Kaltenbach, Tonya Martel, Myriam Robertson, Douglas J. Boland, C. Richard Giardello, Frances M. Lieberman, David A. Levin, Theodore R. Rex, Douglas K. TI Optimizing adequacy of bowel cleansing for colonoscopy: recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID ORAL SODIUM-PHOSPHATE; RANDOMIZED CONTROLLED-TRIAL; POLYETHYLENE-GLYCOL SOLUTION; ELECTROLYTE LAVAGE SOLUTION; PLUS ASCORBIC-ACID; INVESTIGATOR-BLINDED TRIAL; HIGH-DOSE SENNA; INCREASE SCREENING COLONOSCOPY; ADENOMA DETECTION RATE; CLEAR LIQUID DIET AB Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States.(1) Colonoscopy can prevent CRC by the detection and removal of precancerous lesions. In addition to CRC screening and surveillance, colonoscopy is used widely for the diagnostic evaluation of symptoms and other positive CRC screening tests. Regardless of indication, the success of colonoscopy is linked closely to the adequacy of preprocedure bowel cleansing. Unfortunately, up to 20%-25% of all colonoscopies are reported to have an inadequate bowel preparation.(2,3) The reasons for this range from patient-related variables such as compliance with preparation instructions and a variety of medical conditions that make bowel cleansing more difficult to unit-specific factors (eg, extended wait times after scheduling of colonoscopy).(4) Adverse consequences of ineffective bowel preparation include lower adenoma detection rates, longer procedural time, lower cecal intubation rates, increased electrocautery risk, and shorter intervals between examinations.(3,5-7) Bowel preparation formulations intended for precolonoscopy cleansing are assessed based on their efficacy, safety, and tolerability. Lack of specific organ toxicity is considered to be a prerequisite for bowel preparations. Between cleansing efficacy and tolerability, however, the consequences of inadequate cleansing suggest that efficacy should be a higher priority than tolerability. Consequently, the choice of a bowel cleansing regimen should be based on cleansing efficacy first and patient tolerability second. However, efficacy and tolerability are closely interrelated. For example, a cleansing agent that is poorly tolerated and thus not fully ingested may not achieve an adequate cleansing. The goals of this consensus document are to provide expert, evidence-based recommendations for clinicians to optimize colonoscopy preparation quality and patient safety. Recommendations are provided using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) scoring system, which weighs the strength of the recommendation and the quality of the evidence.(8) C1 [Johnson, David A.] Eastern Vet Affairs Med Sch, Norfolk, VA 23507 USA. [Barkun, Alan N.; Martel, Myriam] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Cohen, Larry B.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Dominitz, Jason A.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Dominitz, Jason A.] Univ Washington, Seattle, WA 98195 USA. [Kaltenbach, Tonya] Stanford Univ, Sch Med, Vet Affairs Palo Alto, Palo Alto, CA 94304 USA. [Robertson, Douglas J.] White River Junct Vet Affairs Med Ctr, White River Jct, VT USA. [Robertson, Douglas J.] Dartmouth Hitchcock Med Ctr, Geisel Sch Med Dartmouth, White River Jct, VT USA. [Boland, C. Richard] Baylor Univ, Med Ctr, Dallas, TX USA. [Giardello, Frances M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Lieberman, David A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Levin, Theodore R.] Kaiser Permanente Med Ctr, Walnut Creek, CA USA. [Rex, Douglas K.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. RP Johnson, DA (reprint author), Eastern Vet Affairs Med Sch, Norfolk, VA 23507 USA. OI Dominitz, Jason/0000-0002-8070-7086 FU Veterans Health Administration FX This material is the result of work supported, in part, by resources from The Veterans Health Administration. The views expressed in this article do not necessarily represent the views of the Department of Veterans Affairs. NR 253 TC 16 Z9 16 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD OCT PY 2014 VL 80 IS 4 BP 543 EP 562 DI 10.1016/j.gie.2014.08.002 PG 20 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AP6CZ UT WOS:000342166400001 PM 25220509 ER PT J AU Das, KK Xiao, H Geng, X Fernandez-del-Castillo, C Morales-Oyarvide, V Daglilar, E Forcione, DG Bounds, BC Brugge, WR Pitman, MB Mino-Kenudson, M Das, KM AF Das, Koushik K. Xiao, Hong Geng, Xin Fernandez-del-Castillo, Carlos Morales-Oyarvide, Vicente Daglilar, Ebubekir Forcione, David G. Bounds, Brenna C. Brugge, William R. Pitman, Martha B. Mino-Kenudson, Mari Das, Kiron M. TI mAb Das-1 is specific for high-risk and malignant intraductal papillary mucinous neoplasm (IPMN) SO GUT LA English DT Article ID INTERNATIONAL CONSENSUS GUIDELINES; GASTRIC INTESTINAL METAPLASIA; MONOCLONAL-ANTIBODY; PANCREATIC CYSTS; ULCERATIVE-COLITIS; SURGICAL RESECTION; MANAGEMENT; ADENOCARCINOMA; EPITHELIUM; CANCER AB Objective Intraductal papillary mucinous neoplasm (IPMN) consists of four epithelial subtypes that correlate with histological grades and risks for malignant transformation. mAb Das-1 is a monoclonal antibody against a colonic epithelial phenotype that is reactive to premalignant conditions of the upper GI tract. We sought to assess the ability of mAb Das-1 to identify IPMN with high risk of malignant transformation. Design mAb Das-1 reactivity was evaluated in 94 patients with IPMNs by immunohistochemistry. Lesional fluid from 38 separate patients with IPMN (n=27), low-grade non-mucinous cystic neoplasms (n=7) and pseudocysts (n=4) was analysed by ELISA and western blot. Results Immunohistochemistry-Normal pancreatic ducts were non-reactive and low-grade gastric-type IPMN (IPMN-G) (1/17) and intermediate-grade IPMN-G (1/23) were minimally reactive with mAb Das-1. In contrast, mAb Das-1 reactivity was significantly higher in high-risk/malignant lesions (p<0.0001) including: intestinal-type IPMN with intermediate-grade dysplasia (9/10); high-grade dysplasia of gastric (4/7), intestinal (12/12), oncocytic (2/2) and pancreatobiliary types (2/2); and invasive tubular (8/12), colloid (7/7) and oncocytic (2/2) carcinoma. The sensitivity and specificity of mAb Das-1 for high-risk/malignant IPMNs were 85% and 95%, respectively. Lesional fluid-Samples from low-and intermediate-grade IPMN-G (n=9), and other low-grade/benign non-mucinous lesions demonstrated little reactivity with mAb Das-1. Conversely, cyst fluid from high-risk/malignant IPMNs (n=18) expressed significantly higher reactivity (p<0.0001). The sensitivity and specificity of mAbDas-1 in detecting high-risk/malignant IPMNs were 89% and 100%, respectively. Conclusions mAb Das-1 reacts with high specificity to tissue and cyst fluid from high-risk/malignant IPMNs and thus may help in preoperative clinical risk stratification. C1 [Das, Koushik K.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Das, Koushik K.; Xiao, Hong; Fernandez-del-Castillo, Carlos; Morales-Oyarvide, Vicente; Daglilar, Ebubekir; Forcione, David G.; Bounds, Brenna C.; Brugge, William R.; Pitman, Martha B.; Mino-Kenudson, Mari] Harvard Univ, Sch Med, Boston, MA USA. [Xiao, Hong; Morales-Oyarvide, Vicente; Pitman, Martha B.; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Geng, Xin; Das, Kiron M.] Rutgers Robert Wood Johnson Med Sch, Div Gastroenterol, New Brunswick, NJ USA. [Fernandez-del-Castillo, Carlos; Morales-Oyarvide, Vicente] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Daglilar, Ebubekir; Forcione, David G.; Bounds, Brenna C.; Brugge, William R.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. RP Mino-Kenudson, M (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 122, Boston, MA 02114 USA. EM koushik.das@uphs.upenn.edu; mminokenudson@partners.org FU National Institutes of Health, Bethesda, MD, USA [NIDDK, R01 DK47673, R01 DK63618]; National Cancer Institute [P50 CA127003, R01 CA169086] FX Development of mAb Das-1 was supported in part by research grants NIDDK, R01 DK47673 and R01 DK63618 to KMD from the National Institutes of Health, Bethesda, MD, USA. MMK was supported by National Cancer Institute grants P50 CA127003 and R01 CA169086. NR 44 TC 10 Z9 10 U1 1 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD OCT PY 2014 VL 63 IS 10 BP 1627 EP + DI 10.1136/gutjnl-2013-306219 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AP2TQ UT WOS:000341928300016 PM 24277729 ER PT J AU Shindo, ML Caruana, SM Kandil, E McCaffrey, JC Orloff, LA Porterfield, JR Shaha, A Shin, J Terris, D Randolph, G AF Shindo, Maisie L. Caruana, Salvatore M. Kandil, Emad McCaffrey, Judith C. Orloff, Lisa A. Porterfield, John R. Shaha, Ashok Shin, Jennifer Terris, David Randolph, Gregory TI Management of invasive well-differentiated thyroid cancer: An American Head and Neck Society Consensus Statement AHNS Consensus Statement SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE invasive thyroid cancer; tracheal invasion; recurrent laryngeal nerve invasion; locally aggressive thyroid cancer; vascular invasion ID RECURRENT LARYNGEAL NERVE; EXTERNAL-BEAM RADIOTHERAPY; JUGULAR-VEIN RECONSTRUCTION; SURGICAL-MANAGEMENT; AERODIGESTIVE TRACT; PAPILLARY CARCINOMA; TRACHEAL RESECTION; CLINICOPATHOLOGICAL FEATURES; LARYNGOTRACHEAL INVASION; ESOPHAGEAL INVOLVEMENT AB Background. Invasive differentiated thyroid cancer (DTC) is relatively frequent, yet there is a paucity of specific guidelines devoted to its management. The Endocrine Committee of the American Head and Neck Society (AHNS) convened a panel to provide clinical consensus statements based on review of the literature, synthesized with the expert opinion of the group. Methods. An expert panel, selected from membership of the AHNS, constructed the manuscript and recommendations for management of DTC with invasion of recurrent laryngeal nerve, trachea, esophagus, larynx, and major vessels based on current best evidence. A Modified Delphi survey was then constructed by another expert panelist utilizing 9 anchor points, 1=strongly disagree to 9=strongly agree. Results of the survey were utilized to determine which statements achieved consensus, near-consensus, or non-consensus. Results. After endorsement by the AHNS Endocrine Committee and Quality of Care Committee, it received final approval from the AHNS Council. (C) 2014 Wiley Periodicals, Inc. C1 [Shindo, Maisie L.] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Portland, OR 97239 USA. [Caruana, Salvatore M.] Columbia Univ, Dept Otolaryngol, New York, NY USA. [Kandil, Emad] Tulane Univ, Dept Otolaryngol, New Orleans, LA 70118 USA. [McCaffrey, Judith C.] H Lee Moffitt Canc Ctr & Res Inst, Dept Otolaryngol, Tampa, FL USA. [Orloff, Lisa A.] Stanford Univ, Stanford, CA 94305 USA. [Porterfield, John R.] Univ Alabama, Dept Otolaryngol, Tuscaloosa, AL USA. [Shaha, Ashok] Mem Sloan Kettering Canc Ctr, Dept Otolaryngol, New York, NY 10021 USA. [Shin, Jennifer] Harvard Univ, Sch Med, Dept Otolaryngol, Boston, MA 02115 USA. [Terris, David] Georgia Regents Univ, Dept Otolaryngol, Augusta, GA USA. [Randolph, Gregory] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol, Boston, MA USA. RP Shindo, ML (reprint author), Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, 3181 SW Sam Jackson Rd,PV 01, Portland, OR 97239 USA. EM shindom@ohsu.edu RI Shin, Jennifer/A-3169-2016 NR 84 TC 16 Z9 16 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 EI 1097-0347 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD OCT PY 2014 VL 36 IS 10 BP 1379 EP 1390 DI 10.1002/hed.23619 PG 12 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA AP5ZK UT WOS:000342157000004 PM 24470171 ER PT J AU Colletti, G Colombo, V Mattassi, R Frigerio, A AF Colletti, Giacomo Colombo, Valeria Mattassi, Raul Frigerio, Alice TI Strangling technique to treat large cervicofacial venous malformations: A preliminary report SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE vascular anomalies; venous malformations; head and neck; facial nerve ID VASCULAR MALFORMATIONS; NECK; HEAD; MANAGEMENT; SCLEROTHERAPY; CLASSIFICATION; DIAGNOSIS; ANOMALIES; ETHANOL AB Background. Surgical removal of large cervicofacial venous malformations might be hampered by massive intraoperative bleeding. Moreover, these lesions often insinuate within normal surrounding tissue, making complete resection impossible without causing significant morbidity. Methods. Two patients affected by facial venous malformations nonresponsive to sclerotherapy underwent surgery. Bleeding and critical branching of the facial nerve within the lesion prevented the surgeons from proceeding with the removal. The unresectable malformation was decompressed by means of a number of nonresorbable stitches from the surface of the lesion to the periosteum, tailoring a permanent pressure dressing. Results. Outcomes at 12-month follow-up were stable, with good cosmetic results and satisfaction reported by both patients. No long-term side effects related to the procedure were observed. Conclusion. Decompression of large venous malformations by means of a strangling technique might represent a safe and effective procedure for those cases where a removal cannot be accomplished. (C) 2014 Wiley Periodicals, Inc. C1 [Colletti, Giacomo; Colombo, Valeria] Univ Milan, San Paolo Hosp, Dept Biomed Surg & Dent Sci, Div Maxillofacial Surg, Milan, Italy. [Mattassi, Raul] Clin Inst Humanitas Mater Domini, Ctr Vasc Malformat Stefan Belov, Dept Vasc Surg, Castellanza, Varese, Italy. [Frigerio, Alice] Harvard Univ, Massachusetts Eye & Ear Infirm, Carolyn & Peter Lynch Ctr Laser & Reconstruct Sur, Sch Med,Dept Otol & Laryngol,Div Facial Plast & R, Boston, MA 02114 USA. RP Frigerio, A (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Carolyn & Peter Lynch Ctr Laser & Reconstruct Sur, Sch Med,Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. EM Alice_Frigerio@meei.harvard.edu OI Frigerio, Alice/0000-0001-9202-9553; Colletti, Giacomo/0000-0001-6975-495X NR 22 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 EI 1097-0347 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD OCT PY 2014 VL 36 IS 10 BP E94 EP E98 DI 10.1002/hed.23585 PG 5 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA AP5ZK UT WOS:000342157000001 PM 24375693 ER PT J AU McIntosh, N Meterko, M Burgess, JF Restuccia, JD Kartha, A Kaboli, P Charns, M AF McIntosh, Nathalie Meterko, Mark Burgess, James F., Jr. Restuccia, Joseph D. Kartha, Anand Kaboli, Peter Charns, Martin TI Organizational predictors of coordination in inpatient medicine SO HEALTH CARE MANAGEMENT REVIEW LA English DT Article DE Inpatient medicine; interprofessional coordination; intraprofessional coordination; multidisciplinary; organizational factors ID QUALITY-OF-CARE; IMPROVING-PATIENT-SAFETY; CLINICAL-OUTCOMES; SURGICAL SERVICES; JOB-SATISFACTION; TEAMWORK; PERCEPTIONS; IMPACT; COLLABORATION; PERFORMANCE AB Background: As the care of hospitalized patients becomes more complex, intraprofessional coordination among nurses and among physicians, and interprofessional coordination between these groups are likely to play an increasingly important role in the provision of hospital care. Purpose: The purpose of this study was to identify the independent effects of organizational factors on provider ratings of overall coordination in inpatient medicine (OCIM). Methodology/Approach: This was an exploratory cross-sectional, descriptive study. Primary data were collected between June 2010 and September 2011 through surveys of inpatient medicine nurse managers, physicians, and chiefs of medicine at 36 Veterans Health Administration medical centers. Secondary data from the 2011 Veterans Health Administration national survey of nurses were also used. Individual-level data were aggregated and analyzed at the facility level. Multivariate linear regression models were used to assess the relationship between 55 organizational factors and provider ratings of OCIM. C1 [McIntosh, Nathalie; Meterko, Mark; Burgess, James F., Jr.; Restuccia, Joseph D.; Charns, Martin] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA 02130 USA. [Meterko, Mark] VA Boston Healthcare Syst, Methodol & Survey Unit, Boston, MA USA. [Meterko, Mark; Burgess, James F., Jr.; Charns, Martin] Boston Univ, Dept Hlth Policy & Management, Sch Publ Hlth, Boston, MA 02215 USA. [Restuccia, Joseph D.] Boston Univ, Sch Management, Boston, MA 02215 USA. [Kartha, Anand] VA Boston Healthcare Syst Med Serv, Boston, MA USA. [Kaboli, Peter] Iowa City VA Healthcare Syst, Comprehens Access & Delivery Res & Evaluat Ctr, Iowa City, IA USA. [Kaboli, Peter] Univ Iowa, Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. RP McIntosh, N (reprint author), VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA 02130 USA. EM mcintnm@gmail.com NR 44 TC 4 Z9 4 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0361-6274 EI 1550-5030 J9 HEALTH CARE MANAGE R JI Health Care Manage. Rev. PD OCT-DEC PY 2014 VL 39 IS 4 BP 279 EP 292 DI 10.1097/HMR.0000000000000004 PG 14 WC Health Policy & Services SC Health Care Sciences & Services GA AP3HJ UT WOS:000341965900003 PM 24378402 ER PT J AU Leite, AF Costa, PHN Barbosa, LFP Tan, TC Gelape, CL Nunes, MCP AF Leite, Anderson Ferreira Nogueira Costa, Paulo Henrique Pederneiras Barbosa, Luisa Freire Tan, Timothy C. Gelape, Claudio Leo Pereira Nunes, Maria Carmo TI Echocardiography of a woman after valve intervention SO HEART LA English DT Editorial Material C1 [Leite, Anderson Ferreira; Nogueira Costa, Paulo Henrique; Pederneiras Barbosa, Luisa Freire; Gelape, Claudio Leo; Pereira Nunes, Maria Carmo] Univ Fed Minas Gerais, Hosp Clin, Sch Med, Belo Horizonte, MG, Brazil. [Tan, Timothy C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, Boston, MA USA. RP Leite, AF (reprint author), Rua Almandina 68, BR-31010080 Belo Horizonte, MG, Brazil. EM anderson_med125@yahoo.com.br NR 4 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 1355-6037 EI 1468-201X J9 HEART JI Heart PD OCT PY 2014 VL 100 IS 19 BP 1561 EP 1561 DI 10.1136/heartjnl-2014-305507 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AP2UT UT WOS:000341931800007 PM 24700562 ER PT J AU Scragg, R Slow, S Stewart, AW Jennings, LC Chambers, ST Priest, PC Florkowski, CM Camargo, CA Murdoch, DR AF Scragg, Robert Slow, Sandy Stewart, Alistair W. Jennings, Lance C. Chambers, Stephen T. Priest, Patricia C. Florkowski, Christopher M. Camargo, Carlos A., Jr. Murdoch, David R. TI Long-Term High-Dose Vitamin D-3 Supplementation and Blood Pressure in Healthy Adults A Randomized Controlled Trial SO HYPERTENSION LA English DT Article DE blood pressure; European Continental Ancestry Group; hypertension; randomized controlled trial; therapeutic use ID CARDIOVASCULAR RISK-FACTORS; PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; CHOLECALCIFEROL SUPPLEMENTATION; ENDOTHELIAL FUNCTION; PARATHYROID-HORMONE; VASCULAR HEALTH; OMRON 705IT; WEIGHT-LOSS; HYPERTENSION AB Previous randomized controlled trials of vitamin D supplementation and blood pressure (BP) mainly have given vitamin D for short periods (<6 months) or at low doses (400 IU per day). This study aims to determine whether long-term high-dose vitamin D taken for 18 months lowers BP. Adults were recruited from a healthcare organization or university into a double-blind controlled trial and randomized to receive either vitamin D 3 200 000 IU for 2 months followed by 100 000 IU monthly up to 18 months (n=161) or placebo (n=161). BP was measured at baseline, 5, and 18 months. Subjects had a mean (SD) age of 47.6 (9.7) years, 75% were women, and 94% were of European ancestry (white). Mean (SD) 25-hydroxyvitamin D 3 changed from 73 (22) nmol/L at baseline to 124 (28) nmol/L at 18 months in the vitamin D group, and from 71 (22) nmol/L to 56 (22) nmol/L in the placebo group. Mean BP was similar for the vitamin D and placebo groups at baseline (123.4/76.3 versus 122.6/75.6 mm Hg; respectively). The mean change (95% confidence interval) in BP at 18 months minus baseline in the vitamin D group compared with placebo group was -0.6 (-2.8 to 1.6) mm Hg for systolic (P=0.61) and 0.5 (-1.1, 2.2) mm Hg for diastolic (P=0.53). Long-term vitamin D supplementation, which increased mean 25-hydroxyvitamin D 3 concentration >100 nmol/L for 18 months, had no effect on systolic or diastolic BP in predominantly white, healthy adults without severe vitamin D deficiency. Beneficial effects on BP cannot be ruled out for other populations. C1 [Scragg, Robert; Stewart, Alistair W.] Univ Auckland, Sch Populat Hlth, Auckland 1, New Zealand. [Slow, Sandy; Jennings, Lance C.; Chambers, Stephen T.; Florkowski, Christopher M.; Murdoch, David R.] Univ Otago, Dept Pathol, Christchurch, New Zealand. [Priest, Patricia C.] Univ Otago, Dunedin, New Zealand. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Scragg, R (reprint author), Univ Auckland, Sch Populat Hlth, Sect Epidemiol & Biostat, Private Bag 92019,261 Morrin Rd, Auckland 1, New Zealand. EM r.scragg@auckland.ac.nz OI Scragg, Robert/0000-0003-0013-2620 FU Health Research Council of New Zealand [09-302] FX The study was funded by the Health Research Council of New Zealand (grant 09-302). NR 41 TC 18 Z9 18 U1 2 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD OCT PY 2014 VL 64 IS 4 BP 725 EP 730 DI 10.1161/HYPERTENSIONAHA.114.03466 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AP3PB UT WOS:000341988000009 PM 24980662 ER PT J AU Bai, Z Huang, GB Wang, DW Wang, H Westover, MB AF Bai, Zuo Huang, Guang-Bin Wang, Danwei Wang, Han Westover, M. Brandon TI Sparse Extreme Learning Machine for Classification SO IEEE TRANSACTIONS ON CYBERNETICS LA English DT Article DE Classification; extreme learning machine (ELM); quadratic programming (QP); sequential minimal optimization (SMO); sparse ELM; support vector machine (SVM); unified ELM ID SUPPORT VECTOR REGRESSION; FEEDFORWARD NETWORKS AB Extreme learning machine (ELM) was initially proposed for single-hidden-layer feedforward neural networks (SLFNs). In the hidden layer (feature mapping), nodes are randomly generated independently of training data. Furthermore, a unified ELM was proposed, providing a single framework to simplify and unify different learning methods, such as SLFNs, least square support vector machines, proximal support vector machines, and so on. However, the solution of unified ELM is dense, and thus, usually plenty of storage space and testing time are required for large-scale applications. In this paper, a sparse ELM is proposed as an alternative solution for classification, reducing storage space and testing time. In addition, unified ELM obtains the solution by matrix inversion, whose computational complexity is between quadratic and cubic with respect to the training size. It still requires plenty of training time for large-scale problems, even though it is much faster than many other traditional methods. In this paper, an efficient training algorithm is specifically developed for sparse ELM. The quadratic programming problem involved in sparse ELM is divided into a series of smallest possible sub-problems, each of which are solved analytically. Compared with SVM, sparse ELM obtains better generalization performance with much faster training speed. Compared with unified ELM, sparse ELM achieves similar generalization performance for binary classification applications, and when dealing with large-scale binary classification problems, sparse ELM realizes even faster training speed than unified ELM. C1 [Bai, Zuo; Huang, Guang-Bin; Wang, Danwei; Wang, Han] Nanyang Technol Univ, Sch Elect & Elect Engn, Singapore 639798, Singapore. [Westover, M. Brandon] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Westover, M. Brandon] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Bai, Z (reprint author), Nanyang Technol Univ, Sch Elect & Elect Engn, Singapore 639798, Singapore. EM zbai1@e.ntu.edu.sg; egbhuang@ntu.edu.sg; edwwang@ntu.edu.sg; hw@ntu.edu.sg; mwestover@mgh.harvard.edu RI Huang, Guang-Bin/A-5035-2011 OI Huang, Guang-Bin/0000-0002-2480-4965 FU NINDS NIH HHS [K23 NS090900] NR 33 TC 46 Z9 48 U1 8 U2 54 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2168-2267 EI 2168-2275 J9 IEEE T CYBERNETICS JI IEEE T. Cybern. PD OCT PY 2014 VL 44 IS 10 BP 1858 EP 1870 DI 10.1109/TCYB.2014.2298235 PG 13 WC Computer Science, Artificial Intelligence; Computer Science, Cybernetics SC Computer Science GA AP6ZV UT WOS:000342228100013 PM 25222727 ER PT J AU Matsui, A Jin, JO Johnston, CD Yamazaki, H Houri-Haddad, Y Rittling, SR AF Matsui, Aritsune Jin, Jun-O Johnston, Christopher D. Yamazaki, Hajime Houri-Haddad, Yael Rittling, Susan R. TI Pathogenic Bacterial Species Associated with Endodontic Infection Evade Innate Immune Control by Disabling Neutrophils SO INFECTION AND IMMUNITY LA English DT Article ID RESORPTION IN-VIVO; PORPHYROMONAS-GINGIVALIS; PREVOTELLA-INTERMEDIA; CELL-DEATH; FUSOBACTERIUM-NUCLEATUM; APICAL PERIODONTITIS; HEMOLYTIC-ACTIVITY; BONE DESTRUCTION; CHAMBER MODEL; MICE AB Endodontic infections, in which oral bacteria access the tooth pulp chamber, are common and do not resolve once established. To investigate the effects of these infections on the innate immune response, we established a mouse subcutaneous chamber model, where a mixture of four oral pathogens commonly associated with these infections (endodontic pathogens [EP]), i.e., Fusobacterium nucleatum, Streptococcus intermedius, Parvimonas micra, and Prevotella intermedia, was inoculated into subcutaneously implanted titanium chambers. Cells that infiltrated the chamber after these infections were primarily neutrophils; however, these neutrophils were unable to control the infection. Infection with a nonpathogenic oral bacterial species, Streptococcus mitis, resulted in well-controlled infection, with bacterial numbers reduced by 4 to 5 log units after 7 days. Propidium iodide (PI) staining of the chamber neutrophils identified three distinct populations: neutrophils from EP-infected chambers were intermediate in PI staining, while cells in chambers from mice infected with S. mitis were PI positive (apoptotic) or negative (live). Strikingly, neutrophils from EP-infected chambers were severely impaired in their ability to phagocytose and to generate reactive oxygen species in vitro after removal from the chamber compared to cells from S. mitis-infected chambers. The mechanism of neutrophil impairment was necrotic cell death as determined by morphological analyses. P. intermedia alone could induce a similar neutrophil phenotype. We conclude that the endodontic pathogens, particularly P. intermedia, can efficiently disable and kill infiltrating neutrophils, allowing these infections to become established. These results can help explain the persistence of endodontic infections and demonstrate a new virulence mechanism associated with P. intermedia. C1 [Matsui, Aritsune; Jin, Jun-O; Johnston, Christopher D.; Rittling, Susan R.] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA 02142 USA. [Matsui, Aritsune; Johnston, Christopher D.; Yamazaki, Hajime; Rittling, Susan R.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Yamazaki, Hajime] Forsyth Inst, Dept Appl Oral Sci, Ctr Biomineralizat, Cambridge, MA USA. [Houri-Haddad, Yael] Hebrew Univ Jerusalem Hadassah Hosp & Med Sch, Fac Med Dent, Dept Prosthodont, Jerusalem, Israel. RP Rittling, SR (reprint author), Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA 02142 USA. EM srittling@forsyth.org FU National Institute of Dental and Craniofacial Research of NIH [R01DE22380] FX This work was supported by National Institute of Dental and Craniofacial Research of NIH under award R01DE22380. NR 59 TC 4 Z9 4 U1 0 U2 6 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 OCT PY 2014 VL 82 IS 10 BP 4068 EP 4079 DI 10.1128/IAI.02256-14 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AP2VY UT WOS:000341935100008 PM 25024367 ER PT J AU Lin, J Bi, LJ Yu, XQ Kawai, T Taubman, MA Shen, BZ Han, XZ AF Lin, Jiang Bi, Liangjia Yu, Xiaoqian Kawai, Toshihisa Taubman, Martin A. Shen, Baozhong Han, Xiaozhe TI Porphyromonas gingivalis Exacerbates Ligature-Induced, RANKL-Dependent Alveolar Bone Resorption via Differential Regulation of Toll-Like Receptor 2 (TLR2) and TLR4 SO INFECTION AND IMMUNITY LA English DT Article ID NF-KAPPA-B; PERIODONTAL-DISEASE; IL-10 PRODUCTION; HEMAGGLUTININ B; DENDRITIC CELLS; INNATE IMMUNITY; HOST RESPONSE; PATHOGEN; LIPOPOLYSACCHARIDE; RECOGNITION AB Toll-like receptors (TLRs) play a key role in the innate immune responses to periodontal pathogens in periodontal disease. The present study was performed to determine the roles of TLR2 and TLR4 signaling in alveolar bone resorption, using a Porphyromonas gingivalis-associated ligature-induced periodontitis model in mice. Wild-type (WT), Tlr2(-/-), and Tlr4(-/-) mice (8 to 10 weeks old) in the C57/BL6 background were used. Silk ligatures were applied to the maxillary second molars in the presence or absence of live P. gingivalis infection. Ligatures were removed from the second molars on day 14, and mice were kept for another 2 weeks before sacrifice for final analysis (day 28). On day 14, there were no differences in alveolar bone resorption and gingival RANKL expression between mice treated with ligation plus P. gingivalis infection and mice treated with ligation alone. Gingival interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) expression was increased, whereas IL-10 expression was decreased in WT and Tlr2(-/-) mice but not in Tlr4(-/-) mice. On day 28, WT and Tlr4(-/-) mice treated with ligation plus P. gingivalis infection showed significantly increased bone loss and gingival RANKL expression compared to those treated with ligation alone, whereas such an increase was diminished in Tlr2(-/-) mice. Gingival TNF-alpha upregulation and IL-10 downregulation were observed only in WT and Tlr4(-/-) mice, not in Tlr2(-/-) mice. In all mice, bone resorption induced by ligation plus P. gingivalis infection was antagonized by local anti-RANKL antibody administration. This study suggests that P. gingivalis exacerbates ligature- induced, RANKL-dependent periodontal bone resorption via differential regulation of TLR2 and TLR4 signaling. C1 [Lin, Jiang; Yu, Xiaoqian; Kawai, Toshihisa; Taubman, Martin A.; Han, Xiaozhe] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA USA. [Lin, Jiang; Bi, Liangjia] Harbin Med Univ, Hosp 4, Dept Stomatol, Harbin, Peoples R China. [Yu, Xiaoqian] Peking Univ, Sch & Hosp Stomatol, Dept Periodontol, Beijing 100871, Peoples R China. [Shen, Baozhong] Harbin Med Univ, Dept Radiol, Hosp 4, Harbin, Peoples R China. RP Shen, BZ (reprint author), Harbin Med Univ, Hosp 4, Dept Stomatol, Harbin, Peoples R China. EM shenbzh@vip.sina.com; xhan@forsyth.org FU NIH from the National Institute of Dental and Craniofacial Research [DE-003420, DE-021837] FX This work was supported by NIH grants DE-003420 and DE-021837 from the National Institute of Dental and Craniofacial Research. NR 45 TC 12 Z9 14 U1 2 U2 12 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 OCT PY 2014 VL 82 IS 10 BP 4127 EP 4134 DI 10.1128/IAI.02084-14 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AP2VY UT WOS:000341935100013 PM 25047844 ER PT J AU Jenkins, TC Knepper, BC Moore, SJ O'Leary, ST Caldwell, B Saveli, CC Pawlowski, SW Perlman, DM McCollister, BD Burman, WJ AF Jenkins, Timothy C. Knepper, Bryan C. Moore, S. Jason O'Leary, Sean T. Caldwell, Brooke Saveli, Carla C. Pawlowski, Sean W. Perlman, Daniel M. McCollister, Bruce D. Burman, William J. TI Antibiotic Prescribing Practices in a Multicenter Cohort of Patients Hospitalized for Acute Bacterial Skin and Skin Structure Infection SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID SOFT-TISSUE INFECTIONS; RESISTANT STAPHYLOCOCCUS-AUREUS; ECONOMIC OUTCOMES; CELLULITIS; CHILDREN; EMERGENCE; THERAPY; ABSCESS; VISITS; ADULTS AB OBJECTIVE. Hospitalizations for acute bacterial skin and skin structure infection (ABSSSI) are common. Optimizing antibiotic use for ABSSSIs requires an understanding of current management. The objective of this study was to evaluate antibiotic prescribing practices and factors affecting prescribing in a diverse group of hospitals. DESIGN. Multicenter, retrospective cohort study. SETTING. Seven community and academic hospitals. METHODS. Children and adults hospitalized between June 2010 and May 2012 for cellulitis, wound infection, or cutaneous abscess were eligible. The primary endpoint was a composite of 2 prescribing practices representing potentially avoidable antibiotic exposure: (1) use of antibiotics with a broad spectrum of activity against gram-negative bacteria or (2) treatment duration greater than 10 days. RESULTS. A total of 533 cases were included: 320 with nonpurulent cellulitis, 44 with wound infection or purulent cellulitis, and 169 with abscess. Of 492 cases with complete prescribing data, the primary endpoint occurred in 394 (80%) cases and varied significantly across hospitals (64%-97%; P <.001). By logistic regression, independent predictors of the primary endpoint included wound infection or purulent cellulitis (odds ratio [OR], 5.12 [95% confidence interval (CH], 1.46-17.88), head or neck involvement (OR, 2.83 [95% CI, 1.17-6.82]), adult cases (OR, 2.20 [95% CI, 1.18-4.11]), and admission to a community hospital (OR, 1.90 [95% CI, 1.05-3.44]). CONCLUSIONS. Among patients hospitalized for ABSSSI, use of antibiotics with broad gram-negative activity or treatment courses longer than 10 days were common. There may be substantial opportunity to reduce antibiotic exposure through shorter courses of therapy targeting gram-positive bacteria. C1 [Jenkins, Timothy C.; Burman, William J.] Denver Hlth, Dept Med, Denver, CO USA. [Jenkins, Timothy C.; Burman, William J.] Denver Hlth, Div Infect Dis, Denver, CO USA. [Jenkins, Timothy C.; O'Leary, Sean T.; Saveli, Carla C.; McCollister, Bruce D.; Burman, William J.] Univ Colorado, Dept Med, Sch Med, Aurora, CO USA. [Jenkins, Timothy C.; O'Leary, Sean T.; Saveli, Carla C.; McCollister, Bruce D.; Burman, William J.] Univ Colorado, Div Infect Dis, Sch Med, Aurora, CO USA. [Knepper, Bryan C.] Denver Hlth, Dept Patient Safety & Qual, Denver, CO USA. [Moore, S. Jason] Vail Valley Med Ctr, Dept Trauma & Crit Care Serv, Vail, CO USA. [O'Leary, Sean T.; Caldwell, Brooke] Childrens Hosp Colorado, Dept Med, Aurora, CO USA. [O'Leary, Sean T.] Childrens Hosp Colorado, Div Infect Dis, Aurora, CO USA. [Pawlowski, Sean W.] Colorado Infect Dis Associates, Denver, CO USA. [Perlman, Daniel M.] Porter Adventist Med Ctr, Dept Med, Denver, CO USA. [McCollister, Bruce D.] Denver Vet Affairs Med Ctr, Dept Med, Denver, CO USA. [McCollister, Bruce D.] Denver Vet Affairs Med Ctr, Div Infect Dis, Denver, CO USA. [Burman, William J.] Denver Hlth, Denver Publ Hlth, Denver, CO USA. RP Jenkins, TC (reprint author), 660 Bannock St, Denver, CO 80204 USA. EM timothy.jenkins@dhha.org FU National Institute of Allergy and Infectious Diseases, National Institute of Health [K23 AI099082] FX This work was supported by the National Institute of Allergy and Infectious Diseases, National Institute of Health (T.C.J.: K23 AI099082). NR 24 TC 13 Z9 13 U1 1 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD OCT PY 2014 VL 35 IS 10 BP 1241 EP 1250 DI 10.1086/678056 PG 10 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA AP2XF UT WOS:000341938600004 PM 25203177 ER PT J AU Greene, MT Fakih, MG Fowler, KE Meddings, J Ratz, D Safdar, N Olmsted, RN Saint, S AF Greene, M. Todd Fakih, Mohamad G. Fowler, Karen E. Meddings, Jennifer Ratz, David Safdar, Nasia Olmsted, Russell N. Saint, Sanjay TI Regional Variation in Urinary Catheter Use and Catheter-Associated Urinary Tract Infection: Results from a National Collaborative SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID INTENSIVE-CARE UNITS; HOSPITALIZED-PATIENTS; EXTENDED USE; STATES; PREVENTION; PHYSICIANS; FEEDBACK AB OBJECTIVE. To examine regional variation in the use and appropriateness of indwelling urinary catheters and catheter-associated urinary tract infection (CAUTI). DESIGN AND SETTING. Cross-Sectional study. PARTICIPANTS. US acute care hospitals. METHODS. Hospitals were divided into 4 regions according to the US Census Bureau. Baseline data on urinary catheter use, catheter appropriateness, and CAUTI were collected from participating units. The catheter utilization ratio was calculated by dividing the number of catheter-days by the number of patient-days. We used the National Healthcare Safety Network (NHSN) definition (number of CAUTIs per 1,000 catheter-days) and a population-based definition (number of CAUTIs per 10,000 patient-days) to calculate CAUTI rates. Logistic and Poisson regression models were used to assess regional differences. RESULTS. Data on 434,207 catheter-days over 1,400,770 patient-days were collected from 1,101 units within 726 hospitals across 34 states. Overall catheter utilization was 31%. Catheter utilization was significantly higher in non intensive care units (ICUs) in the West compared with non-ICUs in all other regions. Approximately 30%-40% of catheters in non-ICUs were placed without an appropriate indication. Catheter appropriateness was the lowest in the West. A total of 1,099 CAUTIs were observed (NHSN rate of 2.5 per 1,000 catheter-days and a population-based rate of 7.8 per 10,000 patient-days). The population-based CAUTI rate was highest in the West (8.9 CAUTIs per 10,000 patient-days) and was significantly higher compared with the Midwest, even after adjusting for hospital characteristics (P =.02). CONCLUSIONS. Regional differences in catheter use, appropriateness, and CAUTI rates were detected across US hospitals. C1 [Greene, M. Todd; Meddings, Jennifer; Saint, Sanjay] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. [Greene, M. Todd; Fowler, Karen E.; Meddings, Jennifer; Ratz, David; Saint, Sanjay] Vet Affairs Univ Michigan, Patient Safety Enhancement Program, Ann Arbor, MI USA. [Fakih, Mohamad G.] St John Hosp & Med Ctr, Detroit, MI USA. [Fowler, Karen E.; Ratz, David; Saint, Sanjay] Vet Affairs Ann Arbor Healthcare Syst, Hosp Outcomes Program Excellence, Ann Arbor, MI USA. [Safdar, Nasia] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Safdar, Nasia] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. [Olmsted, Russell N.] St Joseph Mercy Hlth Syst, Ann Arbor, MI USA. RP Greene, MT (reprint author), Univ Michigan, Div Gen Med, 2800 Plymouth Rd,North Campus Res Complex Bldg 16, Ann Arbor, MI 48109 USA. EM mtgreene@med.umich.edu RI Fowler, Karen/B-5383-2015 FU Agency for Healthcare Research and Quality (AHRQ) [HHSA290201000025I, HHSA29032001T] FX This project was supported by a contract from the Agency for Healthcare Research and Quality (AHRQ; HHSA290201000025I/HHSA29032001T). NR 34 TC 11 Z9 12 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD OCT PY 2014 VL 35 SU 3 BP S99 EP S106 DI 10.1086/677825 PG 8 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA AP2XP UT WOS:000341939700015 PM 25222905 ER PT J AU Zietman, AL AF Zietman, Anthony L. TI Too Much Impact? Scientific Journals and the "Impact Factor" SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Zietman, AL (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 55 Fruit St, Boston, MA 02114 USA. EM azietman@partners.org NR 14 TC 3 Z9 4 U1 0 U2 8 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 OCT 1 PY 2014 VL 90 IS 2 BP 246 EP 248 DI 10.1016/j.ijrobp.2014.07.018 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AP3RI UT WOS:000341994400002 PM 25304783 ER PT J AU Viswanathan, AN Erickson, B Gaffney, DK Beriwal, S Bhatia, SK Burnett, OL D'Souza, DP Patil, N Haddock, MG Jhingran, A Jones, EL Kunos, CA Lee, LJ Lin, LL Mayr, NA Petersen, I Petric, P Portelance, L Small, W Strauss, JB Townamchai, K Wolfson, AH Yashar, CM Bosch, W AF Viswanathan, Akila N. Erickson, Beth Gaffney, David K. Beriwal, Sushil Bhatia, Sudershan K. Burnett, Omer Lee, III D'Souza, David P. Patil, Nikhilesh Haddock, Michael G. Jhingran, Anuja Jones, Ellen L. Kunos, Charles A. Lee, Larissa J. Lin, Lilie L. Mayr, Nina A. Petersen, Ivy Petric, Primoz Portelance, Lorraine Small, William, Jr. Strauss, Jonathan B. Townamchai, Kanokpis Wolfson, Aaron H. Yashar, Catheryn M. Bosch, Walter TI Comparison and Consensus Guidelines for Delineation of Clinical Target Volume for CT- and MR-Based Brachytherapy in Locally Advanced Cervical Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID DOSE-RATE BRACHYTHERAPY; GUIDED ADAPTIVE BRACHYTHERAPY; PDR BRACHYTHERAPY; RADIATION-THERAPY; PROSPECTIVE TRIAL; CARCINOMA; IMPACT; RECOMMENDATIONS; OPTIMIZATION; RADIOTHERAPY AB Objective: To create and compare consensus clinical target volume (CTV) contours for computed tomography (CT) and 3-Tesla (3-T) magnetic resonance (MR) image-based cervical-cancer brachytherapy. Methods and Materials: Twenty-three experts in gynecologic radiation oncology contoured the same 3 cervical cancer brachytherapy cases: 1 stage IIB near-complete response (CR) case with a tandem and ovoid, 1 stage IIB partial response (PR) case with tandem and ovoid with needles, and 1 stage IB2 CR case with a tandem and ring applicator. The CT contours were completed before the MRI contours. These were analyzed for consistency and clarity of target delineation using an expectation maximization algorithm for simultaneous truth and performance level estimation (STA-PLE), with kappa statistics as a measure of agreement between participants. The conformity index was calculated for each of the 6 data sets. Dice coefficients were generated to compare the CT and MR contours of the same case. Results: For all 3 cases, the mean tumor volume was smaller on MR than on CT (P < .001). The kappa and conformity index estimates were slightly higher for CT, indicating a higher level of agreement on CT. The Dice coefficients were 89% for the stage IB2 case with a CR, 74% for the stage IIB case with a PR, and 57% for the stage IIB case with a CR. Conclusion: In a comparison of MR-contoured with CT-contoured CTV volumes, the higher level of agreement on CT may be due to the more distinct contrast medium visible on the images at the time of brachytherapy. MR at the time of brachytherapy may be of greatest benefit in patients with large tumors with parametrial extension that have a partial or complete response to external beam. On the basis of these results, a 95% consensus volume was generated for CT and for MR. (C) 2014 Elsevier Inc. C1 [Viswanathan, Akila N.; Townamchai, Kanokpis] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Erickson, Beth] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Gaffney, David K.] Univ Utah, Huntsman Canc Hosp, Salt Lake City, UT USA. [Yashar, Catheryn M.; Bosch, Walter] Washington Univ, St Louis, MO USA. [Beriwal, Sushil] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Bhatia, Sudershan K.] Univ Iowa, Iowa City, IA USA. [Burnett, Omer Lee, III] Univ Alabama Birmingham, Birmingham, AL USA. [D'Souza, David P.; Patil, Nikhilesh] London Hlth Sci Ctr, London, ON, Canada. [D'Souza, David P.; Patil, Nikhilesh] Univ Western Ontario, London, ON, Canada. [Haddock, Michael G.; Petersen, Ivy] Mayo Med Ctr, Rochester, MN USA. [Jhingran, Anuja] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Jones, Ellen L.] Univ N Carolina, Chapel Hill, NC USA. [Kunos, Charles A.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Lin, Lilie L.] Univ Penn, Philadelphia, PA 19104 USA. [Mayr, Nina A.] Univ Washington, Seattle, WA 98195 USA. [Petric, Primoz] Inst Oncol Ljubljana, Div Radiotherapy, Ljubljana, Slovenia. [Petric, Primoz] Natl Ctr Canc Care & Res, Dept Radiat Oncol, Doha, Qatar. [Portelance, Lorraine; Wolfson, Aaron H.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Small, William, Jr.] Loyola Univ, Strich Sch Med, Chicago, IL 60611 USA. [Strauss, Jonathan B.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Yashar, Catheryn M.] Univ Calif San Diego, San Diego, CA 92103 USA. RP Viswanathan, AN (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol,Brigham & Womens Hosp, 75 Francis St,ASB 1,L2, Boston, MA 02115 USA. EM aviswanathan@lroc.harvard.edu RI Beriwal, Sushil/J-6404-2012; Patil, Nikhilesh/L-9631-2014 OI Patil, Nikhilesh/0000-0002-4391-4705 FU National Institutes of Health [R21 167800, CA81647] FX Support through National Institutes of Health R21 167800 to A. N. Viswanathan. The Advanced Technology Consortium (ATC) has received support through National Institutes of Health Grant CA81647. NR 30 TC 27 Z9 28 U1 0 U2 10 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 OCT 1 PY 2014 VL 90 IS 2 BP 320 EP 328 DI 10.1016/j.ijrobp.2014.06.005 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AP3RI UT WOS:000341994400014 PM 25304792 ER PT J AU Wattson, DA Hunink, MGM DiPiro, PJ Das, P Hodgson, DC Mauch, PM Ng, AK AF Wattson, Daniel A. Hunink, M. G. Myriam DiPiro, Pamela J. Das, Prajnan Hodgson, David C. Mauch, Peter M. Ng, Andrea K. TI Low-Dose Chest Computed Tomography for Lung Cancer Screening Among Hodgkin Lymphoma Survivors: A Cost-Effectiveness Analysis SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID COLLABORATIVE BRITISH COHORT; 2ND PRIMARY LUNG; INVOLVED-FIELD; ADULT SMOKERS; UNITED-STATES; DISEASE; RISK; RADIOTHERAPY; CHEMOTHERAPY; MORTALITY AB Purpose: Hodgkin lymphoma (HL) survivors face an increased risk of treatment-related lung cancer. Screening with low-dose computed tomography (LDCT) may allow detection of early stage, resectable cancers. We developed a Markov decision-analytic and cost-effectiveness model to estimate the merits of annual LDCT screening among HL survivors. Methods and Materials: Population databases and HL-specific literature informed key model parameters, including lung cancer rates and stage distribution, cause-specific survival estimates, and utilities. Relative risks accounted for radiation therapy (RT) technique, smoking status (> 10 pack-years or current smokers vs not), age at HL diagnosis, time from HL treatment, and excess radiation from LDCTs. LDCT assumptions, including expected stage-shift, false-positive rates, and likely additional workup were derived from the National Lung Screening Trial and preliminary results from an internal phase 2 protocol that performed annual LDCTs in 53 HL survivors. We assumed a 3% discount rate and a willingness-to-pay (WTP) threshold of $50,000 per quality-adjusted life year (QALY). Results: Annual LDCT screening was cost effective for all smokers. A male smoker treated with mantle RT at age 25 achieved maximum QALYs by initiating screening 12 years post-HL, with a life expectancy benefit of 2.1 months and an incremental cost of $34,841/QALY. Among nonsmokers, annual screening produced a QALY benefit in some cases, but the incremental cost was not below the WTP threshold for any patient subsets. As age at HL diagnosis increased, earlier initiation of screening improved outcomes. Sensitivity analyses revealed that the model was most sensitive to the lung cancer incidence and mortality rates and expected stage-shift from screening. Conclusions: HL survivors are an important high-risk population that may benefit from screening, especially those treated in the past with large radiation fields including mantle or involved-field RT. Screening may be cost effective for all smokers but possibly not for nonsmokers despite a small life expectancy benefit. (C) 2014 Elsevier Inc. C1 [Wattson, Daniel A.] Harvard Radiat Oncol Program, Boston, MA 02115 USA. [Hunink, M. G. Myriam] Erasmus MC, Dept Radiol, Rotterdam, Netherlands. [Hunink, M. G. Myriam] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Hunink, M. G. Myriam] Harvard Univ, Sch Publ Hlth, Ctr Hlth Decis Sci, Boston, MA 02115 USA. [DiPiro, Pamela J.] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. [Das, Prajnan] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Hodgson, David C.] Univ Toronto, Dept Radiat Oncol, Toronto, ON, Canada. [Mauch, Peter M.; Ng, Andrea K.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Mauch, Peter M.; Ng, Andrea K.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Wattson, DA (reprint author), Harvard Radiat Oncol Program, 75 Francis St, Boston, MA 02115 USA. EM dwattson@partners.org NR 39 TC 1 Z9 1 U1 1 U2 7 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 OCT 1 PY 2014 VL 90 IS 2 BP 344 EP 353 DI 10.1016/j.ijrobp.2014.06.013 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AP3RI UT WOS:000341994400017 PM 25104066 ER PT J AU Street, VA Kujawa, SG Manichaikul, A Broman, KW Kallman, JC Shilling, DJ Iwata, AJ Robinson, LC Robbins, CA Li, J Liberman, MC Tempel, BL AF Street, Valerie A. Kujawa, Sharon G. Manichaikul, Ani Broman, Karl W. Kallman, Jeremy C. Shilling, Dustin J. Iwata, Ayaka J. Robinson, Linda C. Robbins, Carol A. Li, Jin Liberman, M. Charles Tempel, Bruce L. TI Resistance to Noise-Induced Hearing Loss in 129S6 and MOLF Mice: Identification of Independent, Overlapping, and Interacting Chromosomal Regions SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE QTL; 129S6; MOLF; noise-induced hearing loss ID QUANTITATIVE TRAIT LOCI; ACOUSTIC INJURY; OXIDATIVE STRESS; MOUSE COCHLEA; PROTECTION; TRAUMA; INHERITANCE; STRAINS; CROSSES; DAMAGE AB Noise-induced hearing loss (NIHL) is a prevalent health risk. Inbred mouse strains 129S6/SvEvTac (129S6) and MOLF/EiJ (MOLF) show strong NIHL resistance (NR) relative to CBA/CaJ (CBACa). In this study, we developed quantitative trait locus (QTL) maps for NR. We generated F1 animals by intercrossing (129S6 x CBACa) and (MOLF x CBACa). In each intercross, NR was recessive. N2 animals were produced by backcrossing F1s to their respective parental strain. The 232 N2-129S6 and 225 N2-MOLF progenies were evaluated for NR using auditory brainstem response. In 129S6, five QTL were identified on chromosomes (Chr) 17, 18, 14, 11, and 4, referred to as loci nr1, nr2, nr3, nr4, and nr5, respectively. In MOLF, four QTL were found on Chr 4, 17, 6, and 12, referred to as nr7, nr8, nr9, and nr10, respectively. Given that NR QTL were discovered on Chr 4 and 17 in both the N2-129S6 and N2-MOLF cross, we generated two consomic strains by separately transferring 129S6-derived Chr 4 and 17 into an otherwise CBACa background and a double-consomic strain by crossing the two strains. Phenotypic analysis of the consomic strains indicated that whole 129S6 Chr 4 contributes strongly to mid-frequency NR, while whole 129S6 Chr 17 contributes markedly to high-frequency NR. Therefore, we anticipated that the double-consomic strain containing Chr 4 and 17 would demonstrate NR across the mid- and high-frequency range. However, whole 129S6 Chr 17 masks the expression of mid-frequency NR from whole 129S6 Chr 4. To further dissect NR on 129S6 Chr 4 and 17, CBACa.129S6 congenic strains were generated for each chromosome. Phenotypic analysis of the Chr 17 CBACa.129S6 congenic strains further defined the NR region on proximal Chr 17, uncovered another NR locus (nr6) on distal Chr 17, and revealed an epistatic interaction between proximal and distal 129S6 Chr 17. C1 [Street, Valerie A.; Kallman, Jeremy C.; Shilling, Dustin J.; Iwata, Ayaka J.; Robinson, Linda C.; Robbins, Carol A.; Li, Jin; Tempel, Bruce L.] Univ Washington, Dept Otolaryngol HNS, VM Bloedel Hearing Res Ctr, Seattle, WA 98195 USA. [Tempel, Bruce L.] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. [Liberman, M. Charles] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Kujawa, Sharon G.; Liberman, M. Charles] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Manichaikul, Ani] Univ Virginia, Div Biostat & Epidemiol, Dept Publ Hlth Sci, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Broman, Karl W.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Biostat & Med Informat, Madison, WI 53706 USA. RP Tempel, BL (reprint author), Univ Washington, Dept Otolaryngol HNS, VM Bloedel Hearing Res Ctr, Seattle, WA 98195 USA. EM bltempel@uw.edu OI Manichaikul, Ani/0000-0002-5998-795X; Broman, Karl/0000-0002-4914-6671 FU NIH [R21DC04983, R01DC06305, R01DC08577, R01DC02739, R01DC00188, P30DC04661, P30DC05209, R01GM074244]; DoD [DM102092]; NSF; Howard Hughes Medical Institute FX This work was supported by grants from the NIH including R21DC04983 (SGK), R01DC06305 (BLT), R01DC08577 (SGK), R01DC02739 (BLT), R01DC00188 (MCL), P30DC04661 (BLT), P30DC05209 (MCL), R01GM074244 (KWB), and DoD DM102092 (BLT). Additional support provided by an NSF Graduate Research Fellowship (AM) and a Howard Hughes Medical Institute Medical Research Fellow (AJI). NR 39 TC 2 Z9 2 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 EI 1438-7573 J9 JARO-J ASSOC RES OTO JI JARO PD OCT PY 2014 VL 15 IS 5 BP 721 EP 738 DI 10.1007/s10162-014-0472-x PG 18 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA AP6HR UT WOS:000342178800004 PM 24952082 ER PT J AU Schuth, O McLean, WJ Eatock, RA Pyott, SJ AF Schuth, Olga McLean, Will J. Eatock, Ruth Anne Pyott, Sonja J. TI Distribution of Na,K-ATPase alpha Subunits in Rat Vestibular Sensory Epithelia SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE vestibular hair cells; calyx terminals; Na,K-ATPase ID PERIPHERAL INNERVATION PATTERNS; I HAIR-CELLS; INNER-EAR; COMPARATIVE MORPHOLOGY; GLUTAMATE TRANSPORTER; CARBONIC-ANHYDRASE; NERVE CALYX; SYNAPSIN-I; K+-ATPASE; EXPRESSION AB The afferent encoding of vestibular stimuli depends on molecular mechanisms that regulate membrane potential, concentration gradients, and ion and neurotransmitter clearance at both afferent and efferent relays. In many cell types, the Na,K-ATPase (NKA) is essential for establishing hyperpolarized membrane potentials and mediating both primary and secondary active transport required for ion and neurotransmitter clearance. In vestibular sensory epithelia, a calyx nerve ending envelopes each type I hair cell, isolating it over most of its surface from support cells and posing special challenges for ion and neurotransmitter clearance. We used immunofluorescence and high-resolution confocal microscopy to examine the cellular and subcellular patterns of NKA alpha subunit expression within the sensory epithelia of semicircular canals as well as an otolith organ (the utricle). Results were similar for both kinds of vestibular organ. The neuronal NKA alpha 3 subunit was detected in all afferent endings-both the calyx afferent endings on type I hair cells and bouton afferent endings on type II hair cells-but was not detected in efferent terminals. In contrast to previous results in the cochlea, the NKA alpha 1 subunit was detected in hair cells (both type I and type II) but not in supporting cells. The expression of distinct NKA alpha subunits by vestibular hair cells and their afferent endings may be needed to support and shape the high rates of glutamatergic neurotransmission and spike initiation at the unusual type I-calyx synapse. C1 [Schuth, Olga; Pyott, Sonja J.] Univ N Carolina, Dept Biol & Marine Biol, Wilmington, NC 28403 USA. [McLean, Will J.] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. [Eatock, Ruth Anne] Univ Chicago, Dept Neurobiol, Chicago, IL 60637 USA. RP Pyott, SJ (reprint author), Univ N Carolina, Dept Biol & Marine Biol, 601 South Coll Rd, Wilmington, NC 28403 USA. EM pyotts@uncw.edu OI Eatock, Ruth Anne/0000-0001-7547-2051 FU UNC Wilmington; NIDCD [R01 DC0002290, DC0012347] FX We thank Dr. Dwayne Simmons for the original suggestion to compare profile and cross-sectional views of the vestibular sensory epithelia. We gratefully acknowledge funds from UNC Wilmington to O. S. and S. J. P. and from NIDCD R01 DC0002290 and DC0012347 to R. A. E. NR 42 TC 6 Z9 6 U1 1 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 EI 1438-7573 J9 JARO-J ASSOC RES OTO JI JARO PD OCT PY 2014 VL 15 IS 5 BP 739 EP 754 DI 10.1007/s10162-014-0479-3 PG 16 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA AP6HR UT WOS:000342178800005 PM 25091536 ER PT J AU Badour, CL Ojserkis, R McKay, D Feldner, MT AF Badour, Christal L. Ojserkis, Rachel McKay, Dean Feldner, Matthew T. TI Disgust as a unique affective predictor of mental contamination following sexual trauma SO JOURNAL OF ANXIETY DISORDERS LA English DT Article DE Disgust; Mental contamination; Sexual trauma; Posttraumatic stress disorder ID OBSESSIVE-COMPULSIVE DISORDER; POSTTRAUMATIC-STRESS-DISORDER; COGNITIVE-PROCESSING THERAPY; ADMINISTERED PTSD SCALE; PROLONGED EXPOSURE; SYMPTOMS; FEAR; POLLUTION; ASSAULT; OCD AB Mental contamination has been described as an internal experience of dirtiness that can arise and persist in the absence of contact with observable physical contaminants. Recent research has examined mental contamination specifically related to unwanted physical contact and sexual trauma. This study evaluated the degree to which disgust propensity and both self-focused and perpetrator-focused peritraumatic disgust were associated with mental contamination in a sample of women who experienced sexual trauma (n = 72). Results showed that peritraumatic self-focused disgust, but not peritraumatic perpetrator-focused disgust or fear, was significantly associated with mental contamination. Additionally, disgust propensity contributed significantly to the incremental validity of the model. These findings support the nascent literature showing that disgust plays a significant role in mental contamination, particularly following sexual trauma. Future research directions, and clinical/theoretical implications of these results are discussed. Published by Elsevier Ltd. C1 [Badour, Christal L.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Badour, Christal L.] Ralph H Johnson VA Med Ctr, Dept Psychiat, Charleston, SC 29401 USA. [Badour, Christal L.; Feldner, Matthew T.] Univ Arkansas, Dept Psychol Sci, Fayetteville, AR 72701 USA. [Ojserkis, Rachel; McKay, Dean] Fordham Univ, Dept Psychol, Bronx, NY 10458 USA. [Feldner, Matthew T.] Laureate Inst Brain Res, Tulsa, OK 74136 USA. RP Badour, CL (reprint author), Dept Psychiat & Behav Sci, 67 President St,MSC 861,2nd Floor IOP South Bldg, Charleston, SC 29425 USA. EM christalbadour@gmail.com FU NIMH NIH HHS [F31 MH092994, F31 MH092994-01] NR 55 TC 4 Z9 4 U1 2 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-6185 EI 1873-7897 J9 J ANXIETY DISORD JI J. Anxiety Disord. PD OCT PY 2014 VL 28 IS 7 BP 704 EP 711 DI 10.1016/j.janxdis.2014.07.007 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AP5LY UT WOS:000342121900010 PM 25129888 ER PT J AU Garrido, MM Boockvar, KS AF Garrido, Melissa M. Boockvar, Kenneth S. TI Perceived Symptom Targets of Antidepressants, Anxiolytics, and Sedatives: The Search for Modifiable Factors That Improve Adherence SO JOURNAL OF BEHAVIORAL HEALTH SERVICES & RESEARCH LA English DT Article ID DWELLING OLDER-ADULTS; MENTAL-HEALTH-CARE; ANXIETY DISORDERS; SELF-MANAGEMENT; DEPRESSION; ILLNESS; NONADHERENCE; MEDICATION; SERVICES; BELIEFS AB Expectations about treatment and beliefs about illness influence adherence in physical disorders, but the extent to which this occurs in mood disorders is unknown. Identifying modifiable factors, such as beliefs, may improve adherence to mood disorder medications. Data from the Collaborative Psychiatric Epidemiology Surveys were used to examine relationships among perceived symptom targets of medication (mood only, non-mood only, mood, and non-mood) and self-reported adherence to antidepressants, anxiolytics, and sedatives. The sample included 807 community-dwelling individuals with and without depression and anxiety who regularly took one of these medications in the year before the survey. Slightly over half (53.2 %) of respondents were adherent. Perceived medication purpose was only significantly related to adherence among Latino respondents. Latino respondents who viewed their symptom target as non-mood only were the most adherent. Perceived symptom targets of medications were not associated with most patients' adherence behaviors for antidepressants, anxiolytics, and sedatives. C1 [Garrido, Melissa M.; Boockvar, Kenneth S.] James J Peters VA Med Ctr, GRECC, Bronx, NY 10468 USA. [Garrido, Melissa M.; Boockvar, Kenneth S.] Icahn Sch Med Mt Sinai, Brookdale Dept Geriatr & Palliat Med, New York, NY 10029 USA. [Boockvar, Kenneth S.] Jewish Home Lifecare, New York, NY USA. RP Garrido, MM (reprint author), James J Peters VA Med Ctr, GRECC, 4A-17 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM melissa.garrido@mssm.edu OI Garrido, Melissa/0000-0002-8986-3536; Boockvar, Kenneth/0000-0003-1165-5558 FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research & Development Service [CDA 11-201/CDP 12-255, IIR 10-146]; Greenwall Foundation; National Institute of Mental Health [T32 MH16242-29]; National Palliative Care Research Center FX The authors received funding from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research & Development Service CDA 11-201/CDP 12-255 and IIR 10-146; the Greenwall Foundation; the National Institute of Mental Health T32 MH16242-29; and the National Palliative Care Research Center. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the US government. NR 27 TC 0 Z9 0 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1094-3412 EI 1556-3308 J9 J BEHAV HEALTH SER R JI J. Behav. Health Serv. Res. PD OCT PY 2014 VL 41 IS 4 BP 529 EP 538 DI 10.1007/s11414-013-9342-2 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AP2TD UT WOS:000341926800012 PM 23702612 ER PT J AU Pulliam, L Calosing, C Sun, B Grunfeld, C Rempel, H AF Pulliam, Lynn Calosing, Cyrus Sun, Bing Grunfeld, Carl Rempel, Hans TI Monocyte Activation from Interferon-alpha in HIV Infection Increases Acetylated LDL Uptake and ROS Production SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID PERSISTENT LCMV INFECTION; CORONARY-ARTERY-DISEASE; LOW-DENSITY-LIPOPROTEIN; FOAM CELL-FORMATION; SR-A EXPRESSION; ANTIRETROVIRAL THERAPY; CARDIOVASCULAR-DISEASE; CIRCULATING MONOCYTES; IMMUNE ACTIVATION; HUMAN MACROPHAGES AB Atherosclerosis is an inflammatory disease that is accelerated in human immunodeficiency virus (HIV) infection. Individuals with HIV infection have an activated type I interferon (IFN) monocyte phenotype, which may enhance uptake of modified low-density lipoprotein (LDL) thereby initiating a prefoam cell pathology and recruitment into atherosclerotic plaques. In a sampling of HIV-infected subjects, an increase in monocyte activation genes, MX1 and CXCL10, correlated with monocyte expression of the scavenger receptor A (SR-A), a major receptor for lipid uptake and foam cell formation. Monocytes from HIV-infected subjects accumulated more lipid than control uninfected subjects. We modeled increased activation in HIV infection by priming human monocytes with IFN alpha followed by exposure to acetylated LDL (acLDL). Exposure to IFN alpha increased acLDL uptake, which generated increased cellular reactive oxygen species (ROS). We posit that HIV infection augments formation of arterial plaques by triggering monocyte activation with a type I IFN profile, which induces SR-A expression, lipid uptake, and subsequent ROS production. These findings may explain in part why HIV-infected individuals with chronic immune activation have an increased risk of atherosclerosis. C1 [Pulliam, Lynn] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Lab Med, San Francisco, CA 94121 USA. [Pulliam, Lynn; Grunfeld, Carl] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Med, San Francisco, CA 94121 USA. [Calosing, Cyrus; Sun, Bing; Rempel, Hans] Vet Affairs Med Ctr, Dept Lab Med, San Francisco, CA 94121 USA. RP Pulliam, L (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Lab Med, 4150 Clement St 113A, San Francisco, CA 94121 USA. EM lynn.pulliam@ucsf.edu NR 47 TC 5 Z9 5 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 EI 1557-7465 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD OCT 1 PY 2014 VL 34 IS 10 BP 822 EP 828 DI 10.1089/jir.2013.0152 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA AQ1SR UT WOS:000342561800010 PM 24731171 ER PT J AU Olson, DM Cox, M Constable, M Britz, GW Lin, CB Zimmer, LO Fonarow, GC Schwamm, LH Peterson, ED AF Olson, DaiWai M. Cox, Margueritte Constable, Mark Britz, Gavin W. Lin, Cheryl B. Zimmer, Louise O. Fonarow, Gregg C. Schwamm, Lee H. Peterson, Eric D. TI Development and Initial Testing of the Stroke Rapid-Treatment Readiness Tool SO JOURNAL OF NEUROSCIENCE NURSING LA English DT Article DE acute stroke therapy; intervention; reperfusion; therapy; tPA; treatment ID ACUTE ISCHEMIC-STROKE; SHARED MENTAL MODELS; TEAM PERFORMANCE; EARLY MANAGEMENT; NEEDLE TIME; CARE; ASSOCIATION; THERAPY; COUNCIL; IMPROVEMENT AB No instruments are currently available to help health systems identify target areas for reducing door-to-needle times for the administration of intravenous tissue plasminogen activator to eligible patients with ischemic stroke. A 67-item Likert-scale survey was administered by telephone to stroke personnel at 252 U.S. hospitals participating in the "Get With The Guidelines-Stroke'' quality improvement program. Factor analysis was used to refine the instrument to a four-factor 29-item instrument that can be used by hospitals to assess their readiness to administer intravenous tissue plasminogen activator within 60 minutes of patient hospital arrival. C1 [Olson, DaiWai M.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Cox, Margueritte; Constable, Mark; Lin, Cheryl B.; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC USA. [Constable, Mark; Lin, Cheryl B.; Peterson, Eric D.] Duke Univ, Durham, NC USA. [Britz, Gavin W.] Methodist Hosp, Houston, TX 77030 USA. [Zimmer, Louise O.] Univ N Carolina, Chapel Hill, NC USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Los Angeles, CA USA. [Schwamm, Lee H.] Harvard Univ, Boston, MA 02115 USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Olson, DM (reprint author), Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. EM DaiWai.Olson@UTSouthwestern.edu FU Agency for Healthcare Research and Quality [U18HS016964] FX This project was supported by Cooperative Agreement Number U18HS016964 from the Agency for Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. NR 35 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0888-0395 EI 1945-2810 J9 J NEUROSCI NURS JI J. Neurosci. Nurs. PD OCT PY 2014 VL 46 IS 5 BP 267 EP 273 DI 10.1097/JNN.0000000000000082 PG 7 WC Clinical Neurology; Nursing SC Neurosciences & Neurology; Nursing GA AP3HC UT WOS:000341965200007 PM 25099063 ER PT J AU Hage, FG AF Hage, Fadi G. TI Regadenoson for myocardial perfusion imaging: Is it safe? SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Editorial Material ID HEART-RATE RESPONSE; ADENOSINE RECEPTOR AGONISTS; STRESS TEST; CORONARY VASODILATION; SUBMAXIMAL EXERCISE; GENE POLYMORPHISM; DOUBLE-BLIND; TRIAL; DISEASE; TOLERABILITY C1 [Hage, Fadi G.] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. [Hage, Fadi G.] Amer Univ Beirut, Med Ctr, Div Cardiovasc Med, Beirut, Lebanon. RP Hage, FG (reprint author), Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Lyons Harrison Res Bldg 314,1900 Univ BLVD, Birmingham, AL 35294 USA. EM fadihage@uab.edu OI Hage, Fadi/0000-0002-1397-4942 NR 38 TC 6 Z9 6 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD OCT PY 2014 VL 21 IS 5 BP 871 EP 876 DI 10.1007/s12350-014-9922-4 PG 6 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AP6UI UT WOS:000342212900004 PM 24939324 ER PT J AU Hage, FG Iskandrian, AE AF Hage, Fadi G. Iskandrian, Ami E. TI Serious complications associated with regadenoson administration for myocardial perfusion imaging: A commentary SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Editorial Material ID INFARCTION C1 [Hage, Fadi G.; Iskandrian, Ami E.] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. RP Hage, FG (reprint author), Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Lyons Harrison Res Bldg 314,1900 Univ BLVD, Birmingham, AL 35294 USA. EM fadihage@uab.edu OI Hage, Fadi/0000-0002-1397-4942 NR 11 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD OCT PY 2014 VL 21 IS 5 BP 877 EP 879 DI 10.1007/s12350-014-9985-2 PG 3 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AP6UI UT WOS:000342212900005 PM 25156654 ER PT J AU Falcone, JA Salameh, TS Yi, X Cordy, BJ Mortell, WG Kabanov, AV Banks, WA AF Falcone, Joseph A. Salameh, Therese S. Yi, Xiang Cordy, Benjamin J. Mortell, William G. Kabanov, Alexander V. Banks, William A. TI Intranasal Administration as a Route for Drug Delivery to the Brain: Evidence for a Unique Pathway for Albumin SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; PHOSPHATIDYLINOSITOL 4-KINASE; NEUROTRANSMITTER RELEASE; AXONAL-TRANSPORT; RAT-BRAIN; INSULIN; BLOOD; TRANSCYTOSIS; ENDOCYTOSIS; INHIBITION AB A variety of compounds will distribute into the brain when placed at the cribriform plate by intranasal (i.n.) administration. In this study, we investigated the ability of albumin, a protein that can act as a drug carrier but is excluded from brain by the blood-brain barrier, to distribute into the brain after i.n. administration. We labeled bovine serum albumin with [I-125] ([I-125] Alb) and studied its uptake into 11 brain regions and its entry into the blood from 5 minutes to 6 hours after i.n. administration. [I-125] Alb was present throughout the brain at 5 minutes. Several regions showed distinct peaks in uptake that ranged from 5 minutes (parietal cortex) to 60 minutes (midbrain). About 2-4% of the i.n. [I-125] Alb entered the bloodstream. The highest levels occurred in the olfactory bulb and striatum. Distribution was dose-dependent, with less taken up by whole brain, cortex, and blood at the higher dose of albumin. Uptake was selectively increased into the olfactory bulb and cortex by the fluid-phase stimulator PMA (phorbol 12-myristate 13-acetate), but inhibitors to receptor-mediated transcytosis, caveolae, and phosphoinositide 3-kinase were without effect. Albumin altered the distribution of radioactive leptin given by i.n. administration, decreasing uptake into the blood and by the cerebellum and increasing uptake by the hypothalamus. We conclude that [I-125] Alb administered i.n. reaches all parts of the brain through a dose-dependent mechanism that may involve fluid-phase transcytosis and, as illustrated by leptin, can affect the delivery of other substances to the brain after their i.n. administration. C1 [Falcone, Joseph A.; Salameh, Therese S.; Banks, William A.] Univ Washington, Sch Med, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. [Falcone, Joseph A.; Salameh, Therese S.; Yi, Xiang; Cordy, Benjamin J.; Mortell, William G.; Banks, William A.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Yi, Xiang; Kabanov, Alexander V.] Univ N Carolina, Ctr Nanotechnol Drug Delivery, Chapel Hill, NC 27515 USA. [Yi, Xiang; Kabanov, Alexander V.] Univ N Carolina, Eshelman Sch Pharm, Div Mol Pharmaceut, Chapel Hill, NC 27515 USA. [Kabanov, Alexander V.] Moscow MV Lomonosov State Univ, Fac Chem, Moscow 117234, Russia. RP Banks, WA (reprint author), 1660 S Columbian Way,810A Bldg 1, Seattle, WA 98108 USA. EM wabanks1@uw.edu FU VA merit review; National Institutes of Health National Institute of Neurological Disorders and Stroke [R01-NS051134]; National Institutes of Health National Institute on Aging [T32-AG000258]; Medical Student Training in Aging Research award - National Institute on Aging FX This work was supported by VA merit review; and the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant R01-NS051134]. T.S.S. is supported by the National Institutes of Health National Institute on Aging [Grant T32-AG000258]. J.A.F. was supported by a Medical Student Training in Aging Research award that is funded by the National Institute on Aging and administered by the American Federation for Aging Research. NR 41 TC 10 Z9 10 U1 0 U2 8 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD OCT PY 2014 VL 351 IS 1 BP 54 EP 60 DI 10.1124/jpet.114.216705 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AP2ZC UT WOS:000341943700007 PM 25027317 ER PT J AU Delaney, RA Freehill, MT Janfaza, DR Vlassakov, KV Higgins, LD Warner, JJP AF Delaney, Ruth A. Freehill, Michael T. Janfaza, David R. Vlassakov, Kamen V. Higgins, Laurence D. Warner, Jon J. P. TI 2014 Neer Award Paper: Neuromonitoring the Latarjet procedure SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Article DE Instability; Latarjet procedure; neurologic complications; axillary nerve; musculocutaneous nerve ID SHOULDER; COMPLICATIONS; DISLOCATION; NERVE; OPERATION; PALSY AB Background: We used intraoperative neuromonitoring to define the stages of the Latarjet procedure during which the nerves are at greatest risk. Methods: Thirty-four patients with a mean age of 28.4 years were included. The Latarjet procedure was divided into 9 defined stages. Bilateral median and ulnar somatosensory evoked responses and transcranial motor evoked potentials from all arm myotomes were continuously monitored. A "nerve alert'' was defined as averaged 50% amplitude attenuation or 10% latency prolongation of ipsilateral somatosensory evoked responses and transcranial motor evoked potentials. For each nerve alert, the surgeon altered retractor placement, and if there was no response to this, the position of the operative extremity was then changed. Results: Of 34 patients, 26 (76.5%) had 45 separate nerve alert episodes. The most common stages of the procedure for a nerve alert to occur were glenoid exposure and graft insertion. The axillary nerve was involved in 35 alerts; the musculocutaneous nerve, in 22. Of the 34 patients, 7 (20.6%) had a clinically detectable nerve deficit postoperatively, all correlated with an intraoperative nerve alert. All cases involved the axillary nerve, and all resolved completely from 28 to 165 days postoperatively. Prior surgery and body mass index were not predictive of a neurologic deficit postoperatively. However, total operative time (P = .042) and duration of the stage of the procedure in which the concordant nerve alert occurred (P = .010) were statistically significant predictors of a postoperative nerve deficit. Conclusions: The nerves, in particular the axillary and musculocutaneous nerves, are at risk during the Latarjet procedure, especially during glenoid exposure and graft insertion. (C) 2014 Journal of Shoulder and Elbow Surgery Board of Trustees. C1 [Delaney, Ruth A.; Freehill, Michael T.; Warner, Jon J. P.] Massachusetts Gen Hosp, Boston Shoulder Inst, Boston, MA 02114 USA. [Janfaza, David R.; Vlassakov, Kamen V.] Brigham & Womens Hosp, Dept Anesthesiol, Boston, MA 02115 USA. [Higgins, Laurence D.] Brigham & Womens Hosp, Boston Shoulder Inst, Boston, MA 02115 USA. RP Warner, JJP (reprint author), Yawkey Ctr Outpatient Care, Harvard Shoulder Serv, 55 Fruit St,Suite 3200,3G,Room 3-046, Boston, MA 02114 USA. EM jwarner@partners.org OI Vlassakov, Kamen/0000-0002-7704-3709 NR 17 TC 15 Z9 15 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 1058-2746 J9 J SHOULDER ELB SURG JI J. Shoulder Elbow Surg. PD OCT PY 2014 VL 23 IS 10 BP 1473 EP 1480 DI 10.1016/j.jse.2014.04.003 PG 8 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA AP4NO UT WOS:000342054200014 PM 24950948 ER PT J AU Russ, AL Zillich, AJ Melton, BL Russell, SA Chen, SY Spina, JR Weiner, M Johnson, EG Daggy, JK McManus, MS Hawsey, JM Puleo, AG Doebbeling, BN Saleem, JJ AF Russ, Alissa L. Zillich, Alan J. Melton, Brittany L. Russell, Scott A. Chen, Siying Spina, Jeffrey R. Weiner, Michael Johnson, Elizabette G. Daggy, Joanne K. McManus, M. Sue Hawsey, Jason M. Puleo, Anthony G. Doebbeling, Bradley N. Saleem, Jason J. TI Applying human factors principles to alert design increases efficiency and reduces prescribing errors in a scenario-based simulation SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID CLINICAL DECISION-SUPPORT; PHYSICIAN ORDER ENTRY; LABORATORY MONITORING ALERTS; DRUG INTERACTION ALERTS; SUBJECTIVE WORKLOAD; SAFETY ALERTS; MEDICATION; SYSTEMS; CARE; IMPLEMENTATION AB Objective To apply human factors engineering principles to improve alert interface design. We hypothesized that incorporating human factors principles into alerts would improve usability, reduce workload for prescribers, and reduce prescribing errors. Materials and methods We performed a scenario-based simulation study using a counterbalanced, crossover design with 20 Veterans Affairs prescribers to compare original versus redesigned alerts. We redesigned drug-allergy, drug- drug interaction, and drug- disease alerts based upon human factors principles. We assessed usability (learnability of redesign, efficiency, satisfaction, and usability errors), perceived workload, and prescribing errors. Results Although prescribers received no training on the design changes, prescribers were able to resolve redesigned alerts more efficiently (median (IQR): 56 (47) s) compared to the original alerts (85 (71) s; p=0.015). In addition, prescribers rated redesigned alerts significantly higher than original alerts across several dimensions of satisfaction. Redesigned alerts led to a modest but significant reduction in workload (p=0.042) and significantly reduced the number of prescribing errors per prescriber (median (range): 2 (1- 5) compared to original alerts: 4 (1- 7); p=0.024). Discussion Aspects of the redesigned alerts that likely contributed to better prescribing include design modifications that reduced usability- related errors, providing clinical data closer to the point of decision, and displaying alert text in a tabular format. Displaying alert text in a tabular format may help prescribers extract information quickly and thereby increase responsiveness to alerts. Conclusions This simulation study provides evidence that applying human factors design principles to medication alerts can improve usability and prescribing outcomes. C1 [Russ, Alissa L.; Zillich, Alan J.; Russell, Scott A.; Chen, Siying; Weiner, Michael; Daggy, Joanne K.; Doebbeling, Bradley N.] Richard L Roudebush VA Med Ctr, Hlth Serv Res & Dev Serv CIN 13 416, Ctr Hlth Informat & Commun, Dept Vet Affairs,Vet Hlth Adm, Indianapolis, IN 46202 USA. [Russ, Alissa L.; Zillich, Alan J.; Weiner, Michael; Doebbeling, Bradley N.] Indiana Univ, Ctr Hlth Serv & Outcomes Res, Indianapolis, IN 46204 USA. [Russ, Alissa L.; Zillich, Alan J.; Weiner, Michael; Doebbeling, Bradley N.] Regenstrief Inst Inc, Indianapolis, IN USA. [Russ, Alissa L.; Zillich, Alan J.] Purdue Univ, Coll Pharm, W Lafayette, IN 47907 USA. [Melton, Brittany L.] Univ Kansas, Sch Pharm, Lawrence, KS 66045 USA. [Spina, Jeffrey R.] VA Greater Los Angeles Healthcare Syst, Dept Vet Affairs, Los Angeles, CA USA. [Spina, Jeffrey R.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Weiner, Michael] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Johnson, Elizabette G.] Purdue Univ, Dept Psychol, W Lafayette, IN 47907 USA. [Daggy, Joanne K.] Indiana Univ Sch Med, Dept Biostat, Indianapolis, IN 46202 USA. [McManus, M. Sue] Dept Vet Affairs, Dept Nephrol Serv, Temple, TX USA. [Hawsey, Jason M.] Off Informat, Dept Vet Affairs, Bay Pines, FL USA. [Puleo, Anthony G.] Off Informat, Dept Vet Affairs, Salt Lake City, UT USA. [Doebbeling, Bradley N.] Indiana Univ Purdue Univ, Sch Informat & Comp, Dept BioHlth Informat, Indianapolis, IN 46202 USA. [Saleem, Jason J.] Vet Hlth Adm, Off Informat & Analyt, Human Factors Engn, Louisville, KY USA. RP Russ, AL (reprint author), Richard L Roudebush VA Med Ctr, 1481 W 10th St,11-H, Indianapolis, IN 46202 USA. EM alissa.russ@va.gov OI Daggy, Joanne/0000-0003-0815-1746 FU VA HSRD grant [PPO 09-298]; VA HSR&D Research Career Development Awards [CDA 11-214, CDA 09-024-1, RCD 06-304-1]; VA National Center for Patient Safety, Interprofessional Fellowship Program in Patient Safety FX This work was supported by VA HSR&D grant #PPO 09-298 (PI: Alissa L Russ) and manuscript preparation was supported by the Center for Health Information and Communication, Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service, CIN 13-416. (Work occurred under the Center of Excellence on Implementing Evidence-Based Practice, HFP 04-148.) Drs Russ, Saleem, and Zillich were supported by VA HSR&D Research Career Development Awards (CDA 11-214, CDA 09-024-1, and RCD 06-304-1, respectively). Drs Kobylinski and Chen were supported by the VA National Center for Patient Safety, Interprofessional Fellowship Program in Patient Safety. NR 46 TC 15 Z9 15 U1 4 U2 14 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD OCT PY 2014 VL 21 IS E2 BP E287 EP E296 DI 10.1136/amiajnl-2013-002045 PG 10 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA AP1UV UT WOS:000341858100016 PM 24668841 ER PT J AU Forghanifard, MM Gholamin, M Moaven, O Farshchian, M Ghahraman, M Aledavood, A Abbaszadegan, MR AF Forghanifard, Mohammad Mahdi Gholamin, Mehran Moaven, Omeed Farshchian, Moein Ghahraman, Martha Aledavood, Amir Abbaszadegan, Mohammad Reza TI Neoantigen in esophageal squamous cell carcinoma for dendritic cell-based cancer vaccine development SO MEDICAL ONCOLOGY LA English DT Article DE Esophageal squamous cell carcinoma; Immuno-gene therapy; RNA vaccine; CTAs; Dendritic cell; Chimeric construct; Cytotoxicity ID CANCER/TESTIS CT ANTIGENS; IMMUNOTHERAPY; RNA; EXPRESSION; RESPONSES; STRATEGIES; INDUCTION; MELANOMA; TARGETS; GENES AB Esophageal squamous cell carcinoma (ESCC) is a highly malignant tumor which usually is diagnosed in advanced stages due to its asymptomatic course of tumorigenesis. Current therapeutic modalities are not effective enough and the 5-year survival rate of the disease is still very low which prompts the urgent need for finding novel efficient therapeutic methods. In this study, we evaluated ex vivo immune response of ESCC patients against our newly designed chimeric construct consisting of highly immunogenic cancer-testis antigens. After confirming effective expression of the in vitro transcribed chimeric mRNA in ex vivo electroporated dendritic cells (DCs) of the ESCC patients, the patients' CTLs were primed by DCs and cytotoxicity assay was performed to evaluate how the primed CTLs can recognize and target the chimeric mRNA-loaded cells. The chimeric protein was strongly expressed relative to the housekeeping gene expression in electroporated cells. The cytotoxicity of the CTLs was significantly higher in DCs loaded with chimeric mRNAs compared to mock DCs (p < 0.05) in all of the tested ESCC patients. We are introducing a novel construct that our functional study showed can stimulate and induce an effective immune response in ESCC patients. The designed chimeric mRNA-loaded DCs are capable of priming CTLs effectively and induce cytotoxicity against tumor. Therefore, loading DCs with chimeric epitopes of highly immunogenic antigens, such as cancer-testis antigens, are potentially interesting and effective therapeutic modalities for immunotherapy of ESCC. C1 [Forghanifard, Mohammad Mahdi] Islamic Azad Univ, Damghan Branch, Dept Biol, Damghan, Iran. [Gholamin, Mehran; Abbaszadegan, Mohammad Reza] Mashhad Univ Med Sci, Avicenna Res Inst, Div Human Genet, Immunol Res Ctr, Mashhad 9196773117, Iran. [Moaven, Omeed] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Farshchian, Moein] Ferdowsi Univ Mashhad, Dept Biol, Fac Sci, Mashhad, Iran. [Ghahraman, Martha; Abbaszadegan, Mohammad Reza] Mashhad Univ Med Sci, Sch Med, Med Genet Res Ctr, Mashhad 9196773117, Iran. [Aledavood, Amir] Mashhad Univ Med Sci, Dept Radiotherapy & Oncol, Mashhad 9196773117, Iran. RP Abbaszadegan, MR (reprint author), Mashhad Univ Med Sci, Avicenna Res Inst, Div Human Genet, Immunol Res Ctr, Bu Ali Sq, Mashhad 9196773117, Iran. EM abbaszadeganmr@mums.ac.ir OI Moaven, Omeed/0000-0002-0560-0457 FU MUMS [88098] FX The authors gratefully acknowledge the colleagues at the Departments of Surgery and Pathology in Omid, Qaem and Imam Reza hospitals of MUMS, Mashhad, for samples preparation. We are grateful to Dr. Mojtaba Sankian, Dr. Mohsen Tehrani and Ms. Maliheh Moghadam at Immunobiochemistry Lab, Immunology Research Center, Avicenna Research Institute, Mashhad, as well as our colleagues at Division of Human Genetics, for their kind help and support in technical aspects. This study was supported by the grant number 88098 from the Vice Chancellor for Research at MUMS. NR 30 TC 4 Z9 4 U1 0 U2 10 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1357-0560 EI 1559-131X J9 MED ONCOL JI Med. Oncol. PD OCT PY 2014 VL 31 IS 10 AR 191 DI 10.1007/s12032-014-0191-5 PG 7 WC Oncology SC Oncology GA AP4WG UT WOS:000342079600010 PM 25178937 ER PT J AU Shalaurova, I Connelly, MA Garvey, WT Otvos, JD AF Shalaurova, Irina Connelly, Margery A. Garvey, W. Timothy Otvos, James D. TI Lipoprotein Insulin Resistance Index: A Lipoprotein Particle-Derived Measure of Insulin Resistance SO METABOLIC SYNDROME AND RELATED DISORDERS LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; NICOTINIC-ACID; GLUCOSE-TOLERANCE; SUPPRESSION TEST; LIFE-STYLE; SENSITIVITY; PREVENTION; ATHEROSCLEROSIS; SECRETION; OBESITY AB Background: Lipoprotein particle sizes and concentrations are characteristically altered in patients with insulin resistance (IR) or type 2 diabetes mellitus (T2DM). This study assessed the ability of an IR score, based on nuclear magnetic resonance (NMR)-derived lipoprotein information, to detect IR in otherwise healthy individuals. Methods: Lipoprotein subclass and size information were evaluated for strength of association with IR, as measured by homeostasis model assessment of insulin resistance (HOMA-IR) in the Multi-Ethnic Study of Atherosclerosis (MESA). To increase the likelihood of identifying subjects with IR, six lipoprotein measures were combined into a single algorithm. The resulting assay [Lipoprotein Insulin Resistance Index (LP-IR)] was developed using HOMA-IR in 4972 nondiabetic subjects from MESA and verified independently using glucose disposal rates (GDRs) measured during hyperinsulinemic-euglycemic clamps in 56 insulin-sensitive, 46 insulin-resistant, and 46 untreated subjects with T2DM. Results: LP-IR exhibited stronger associations with HOMA-IR (r = 0.51) and GDR (r = -0.53) than each of the individual lipoprotein parameters as well as the triglycerides/high-density lipoprotein cholesterol (TGs/HDL-C) ratio (r = 0.41 and -0.44, respectively). In MESA, associations between the LP-IR score and HOMA-IR were strong in men (r = 0.51), women (r = 0.52), European Americans (r = 0.58), African Americans (r = 0.48), Chinese Americans (r = 0.49), and Hispanic Americans (r = 0.45). When LP-IR was categorized by HOMA-IR and either body mass index (BMI) or fasting plasma glucose (FPG), subgroups were revealed whose LP-IR scores were high (>= 50), despite having normal BMIs (<24 kg/m(2)) or FPG (<100 mg/dL). Conclusions: LP-IR scores had strong associations with multiple measures, HOMA-IR, and GDR, the former being more reflective of hepatic and the latter of peripheral insulin sensitivity, and may represent a simple means to identify individuals with IR. C1 [Shalaurova, Irina; Connelly, Margery A.; Otvos, James D.] LipoScience Inc, Raleigh, NC 27616 USA. [Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Garvey, W. Timothy] Birmingham VA Med Ctr, Birmingham, AL USA. RP Otvos, JD (reprint author), LipoScience Inc, 2500 Sumner Blvd, Raleigh, NC 27616 USA. EM jotvos@liposcience.com FU Merit Review program of the Department of Veterans Affairs; National Institutes of Health [DK-038765, DK-083562]; UAB Diabetes Research Center [P60-DK079626] FX The authors gratefully acknowledge Drs. Deborah Winegar and Ray Pourfarzib for careful review of the manuscript and scientific comments. This work was supported in part by the Merit Review program of the Department of Veterans Affairs, the National Institutes of Health (DK-038765 and DK-083562), and the UAB Diabetes Research Center (P60-DK079626). NR 37 TC 17 Z9 17 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-4196 EI 1557-8518 J9 METAB SYNDR RELAT D JI Metab. Syndr. Relat. Disord. PD OCT PY 2014 VL 12 IS 8 BP 422 EP 429 DI 10.1089/met.2014.0050 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AP5XR UT WOS:000342152500003 PM 24959989 ER PT J AU Yoo, B Ifediba, MA Ghosh, S Medarova, Z Moore, A AF Yoo, Byunghee Ifediba, Marytheresa A. Ghosh, Subrata Medarova, Zdravka Moore, Anna TI Combination Treatment with Theranostic Nanoparticles for Glioblastoma Sensitization to TMZ SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE Theranostic; Nanoparticle; Glioblastoma multiforme; siRNA; MRI; Chlorotoxin; Targeting; Temozolomide ID IRON-OXIDE NANOPARTICLES; MGMT PROMOTER METHYLATION; MALIGNANT GLIOMA; BRAIN-TUMORS; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; PREDICTS RESPONSE; CELL INVASION; BONE-MARROW; TEMOZOLOMIDE; CHLOROTOXIN AB Tumor resistance to chemotherapeutic drugs is one of the major obstacles in the treatment of glioblastoma multiforme (GBM). In this study, we attempted to modulate tumor response to chemotherapy by combination treatment that included experimental (small interference RNA (siRNA), chlorotoxin) and conventional (temozolomide, TMZ) therapeutics. siRNA therapy was used to silence O-6-methylguanine methyltransferase (MGMT), a key factor in brain tumor resistance to TMZ. For targeting of tumor cells, we used chlorotoxin (CTX), a peptide with antitumoral properties. siRNA and CTX were conjugated to iron oxide nanoparticles (NP) that served as the drug carrier and allowed the means to monitor the changes in tumor volume by magnetic resonance imaging (MRI). Theranostic nanoparticles (termed CTX-NP-siMGMT) were internalized by T98G glioblastoma cells in vitro leading to enhancement of TMZ toxicity. Combination treatment of mice bearing orthotopic tumors with CTX-NP-siMGMT and TMZ led to significant retardation of tumor growth, which was monitored by MRI. While our results demonstrate that siRNA delivery by targeted nanoparticles resulted in modulating tumor response to chemotherapy in GBM, they also point to a significant contribution of CTX to tumor cell death. C1 [Yoo, Byunghee; Ifediba, Marytheresa A.; Ghosh, Subrata; Medarova, Zdravka; Moore, Anna] Harvard Univ, Sch Med, Massachusetts Gen Hosp,Dept Radiol, Mol Imaging Lab,MGH HST Athinoula A Martinos Ctr, Charlestown, MA 02129 USA. [Ifediba, Marytheresa A.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. RP Moore, A (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp,Dept Radiol, Mol Imaging Lab,MGH HST Athinoula A Martinos Ctr, Bldg 75,13th St, Charlestown, MA 02129 USA. EM amoore@helix.mgh.harvard.edu FU [T32CA009502] FX This work was supported in part by T32CA009502 (PI Anna Moore). NR 49 TC 10 Z9 10 U1 4 U2 25 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 EI 1860-2002 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD OCT PY 2014 VL 16 IS 5 BP 680 EP 689 DI 10.1007/s11307-014-0734-3 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AP5RG UT WOS:000342135800012 PM 24696184 ER PT J AU Hernandez-Duran, S Ogilvy, CS AF Hernandez-Duran, Silvia Ogilvy, Christopher S. TI Clinical outcomes of patients with vertebral artery dissection treated endovascularly: a meta-analysis SO NEUROSURGICAL REVIEW LA English DT Review DE Vertebral artery dissection; Cervical artery dissection; Endovascular treatment; Meta-analysis ID CONNECTIVE-TISSUE ABNORMALITIES; INFERIOR CEREBELLAR ARTERY; OF-THE-LITERATURE; SUBARACHNOID HEMORRHAGE; VERTEBROBASILAR DISSECTION; STENT PLACEMENT; INTRACRANIAL DISSECTIONS; COIL EMBOLIZATION; NATURAL-HISTORY; ACUTE STAGE AB The purpose of this study was to present a meta-analysis on the safety and efficacy of different endovascular modalities when treating vertebral artery dissections, since ideal treatment remains controversial. We performed a meta-analysis of 39 retrospective studies involving different treatment modalities for vertebral artery dissections in adults and obtained weighted pooled proportional outcome and mortality ratios with a random effects model. Overall, 75.11 % (confidence interval (CI) 68.89-80.84, I (2) 66.89 %) had excellent outcomes, 10.10 % (CI 6.83-15.56, I (2) 65.64 %) had good outcomes, and 13.70 % (CI 9.64-18.35, I (2) 60.33 %) had poor outcomes. Postoperative complications occurred in 10.52 % (CI 6.87-14.84, I (2) 62.48 %), with 2.73 % (CI 1.64-4.10, I (2) 0.0 %) exhibiting vasospasm, 3.03 % (CI 1.88-4.46, I (2) 0.0 %) experiencing postoperative rebleeding, and 6.31 % (CI 3.57-9.76, I (2) 60.92 %) showing ischemia. Overall mortality was 8.69 % (CI 6.13-11.64, I (2) 33.76 %). When compared to these overall ratios, different treatment modality subgroups did not differ significantly, except for the proximal occlusion group, with poor outcome ratio = 26.96 % (difference 13.26, CI 0.02-30.04, p = 0.0403) and mortality ratio = 21.36 % (difference 12.67, CI 0.94-28.86, p = 0.0189). Different endovascular treatment modalities are comparatively safe and effective in the management of vertebral artery dissection. Their reduced operative time, minimal invasiveness, and overall safety render them a suitable option for intervention-amenable dissections. C1 [Hernandez-Duran, Silvia; Ogilvy, Christopher S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosurg Serv, Boston, MA USA. [Hernandez-Duran, Silvia] Univ Costa Rica, Sch Med, San Jose, Costa Rica. RP Hernandez-Duran, S (reprint author), Apdo 1232-1007, San Jose, Costa Rica. EM drahernandezduran@gmail.com; cogilvy@bidmc.harvard.edu NR 65 TC 5 Z9 5 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5607 EI 1437-2320 J9 NEUROSURG REV JI Neurosurg. Rev. PD OCT PY 2014 VL 37 IS 4 BP 569 EP 577 DI 10.1007/s10143-014-0541-y PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AP6MS UT WOS:000342192500007 PM 24715276 ER PT J AU Ray, LA Courtney, KE Ghahremani, DG Miotto, K Brody, A London, ED AF Ray, Lara A. Courtney, Kelly E. Ghahremani, Dara G. Miotto, Karen Brody, Arthur London, Edythe D. TI Varenicline, low dose naltrexone, and their combination for heavy-drinking smokers: human laboratory findings SO PSYCHOPHARMACOLOGY LA English DT Article DE Naltrexone; Varenicline; Heavy drinker; Smoker; Human lab; Craving ID RANDOMIZED CONTROLLED-TRIAL; RECEPTOR PARTIAL AGONIST; PLACEBO-CONTROLLED TRIAL; NICOTINE REPLACEMENT THERAPY; SMOKING-CESSATION TREATMENT; COGNITIVE-BEHAVIORAL THERAPY; SUSTAINED-RELEASE BUPROPION; ALCOHOL-DEPENDENT SUBJECTS; DOUBLE-BLIND; WEIGHT-GAIN AB Heavy-drinking smokers constitute a sizeable and hard-to-treat subgroup of smokers, for whom tailored smoking cessation therapies are not yet available. The present study used a double-blind, randomized, 2 x 2 medication design, testing varenicline alone (VAR; 1 mg twice daily), low dose naltrexone alone (L-NTX; 25 mg once daily), varenicline plus naltrexone, and placebo for effects on cigarette craving and subjective response to alcohol and cigarettes in a sample (n = 130) of heavy-drinking daily smokers (a parts per thousand yen10 cigarettes/day). All participants were tested after a 9-day titration period designed to reach a steady state on the target medication. Testing was completed at 12 h of nicotine abstinence, after consuming a standard dose of alcohol (target breath alcohol concentration = 0.06 g/dl) and after smoking the first cigarette of the day. The combination of VAR + L-NTX was superior to placebo, and at times superior to monotherapy, in attenuating cigarette craving, cigarette and alcohol "high," and in reducing ad-lib consumption of both cigarettes and alcohol during the 9-day medication titration period. These preliminary findings indicate that clinical studies of the combination of VAR + L-NTX for heavy drinkers trying to quit smoking are warranted and may ultimately improve clinical care for this sizeable and treatment-resistant subgroup of smokers. C1 [Ray, Lara A.; Courtney, Kelly E.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Ray, Lara A.; Ghahremani, Dara G.; Miotto, Karen; Brody, Arthur; London, Edythe D.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Brody, Arthur] VA Greater Los Angeles Healthcare Syst, Dept Res, Los Angeles, CA 90095 USA. [London, Edythe D.] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. RP Ray, LA (reprint author), Univ Calif Los Angeles, Dept Psychol, 1285 Franz Hall,Box 951563, Los Angeles, CA 90095 USA. EM lararay@psych.ucla.edu RI Courtney, Kelly/L-6041-2016 OI Courtney, Kelly/0000-0002-9280-2435 FU California Tobacco Related Disease Research Program [TRDRP 18KT-0020]; National Institute on Drug Abuse [DA030898]; UCLA Clinical and Translational Science Institute (CTSI) [UL1RR033176, UL1TR000124]; UCLA Training Program in Translational Neuroscience of Drug Abuse [T32 DA024635]; GSK FX This research was supported grants from the California Tobacco Related Disease Research Program (TRDRP 18KT-0020) and from the National Institute on Drug Abuse (DA030898) to LAR. Support for this study was also provided by a grant from the UCLA Clinical and Translational Science Institute (CTSI), grants UL1RR033176 and UL1TR000124. KEC was supported by the UCLA Training Program in Translational Neuroscience of Drug Abuse (T32 DA024635). LAR is a paid consultant for GSK. None of the authors have any other conflicts of interest to disclose. NR 80 TC 10 Z9 10 U1 4 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2014 VL 231 IS 19 BP 3843 EP 3853 DI 10.1007/s00213-014-3519-0 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AP2SU UT WOS:000341925800003 PM 24733235 ER PT J AU Sanz, F Restrepo, MI Fernandez-Fabrellas, E Cervera, A Briones, ML Novella, L Aguar, MC Chiner, E Fernandez, JF Blanquer, J AF Sanz, Francisco Restrepo, Marcos I. Fernandez-Fabrellas, Estrella Cervera, Angela Luisa Briones, Maria Novella, Laura Carmen Aguar, Maria Chiner, Eusebi Fernandez, Juan F. Blanquer, Jose TI Does prolonged onset of symptoms have a prognostic significance in community-acquired pneumonia? SO RESPIROLOGY LA English DT Article DE antibiotic; community-acquired pneumonia; complication; outcome; risk factor ID PRIMARY-CARE; MANAGEMENT; MORTALITY; SEVERITY; RISK; PREDICTION; GUIDELINES; INFECTION; DATABASE; OUTCOMES AB Background and objectiveSeverity assessment is made at the time of the initial clinical presentation in patients with community-acquired pneumonia (CAP). It is unclear how the gap between time of presentation and duration of symptoms onset may impact clinical outcomes. Here we evaluate the association of prolonged onset of symptoms (POS) and the impact on clinical outcomes among hospitalized patients with CAP. MethodsThis was a prospective, multicentre study of CAP in Spain. The primary outcomes were the clinical factors associated with POS defined as days from symptoms onset to pneumonia diagnosis >7 days. The secondary outcomes were intensive care unit (ICU) admission, the presence of suppurative complications, septic shock and 30-day mortality. ResultsWe enrolled 1038 patients diagnosed of CAP: 152 (14.6%) patients had a POS. In multivariate analysis, the presence of prior corticosteroid therapy, alcohol abuse, prior antibiotic therapy, and confusion, urea, respiratory rate, blood pressure and age 65 years or older score 0-1 was independently associated with POS. Patients with POS had a higher incidence of suppurative complications, but not of 30-day mortality when compared with a shorter onset of symptoms. ConclusionsApproximately 15% of patients diagnosed with CAP had POS. Risk factors associated with POS were previous corticosteroids and antibiotic therapy, alcoholism and less severe pneumonia. POS was associated with a higher rate of suppurative complications and less need for ICU admission. Onset of symptoms for more than 7 days is found in nearly 15% of patients with CAP. Prior corticosteroid therapy, antibiotic therapy, alcohol abuse and CURB-65 score 0-1 were independently associated with prolonged symptoms onset. Those patients had a higher incidence of suppurative complications, but not of 30-day mortality. C1 [Sanz, Francisco; Fernandez-Fabrellas, Estrella; Cervera, Angela; Novella, Laura] Consorci Hosp Gen Univ Valencia, Dept Pulmonol, Valencia 46014, Spain. [Luisa Briones, Maria] Hosp Clin Univ Valencia, Dept Pulmonol, Valencia, Spain. [Carmen Aguar, Maria] Hosp Arnau Vilanova, Dept Pulmonol, Valencia, Spain. [Chiner, Eusebi; Blanquer, Jose] Hosp St Joan, Dept Pulmonol, Alacant, Spain. [Restrepo, Marcos I.; Fernandez, Juan F.] Univ Texas Hlth Sci Ctr San Antonio, Div Pulm Crit Care Med, San Antonio, TX 78229 USA. [Restrepo, Marcos I.] Vet Evidence Based Res Disseminat & Implementat C, San Antonio, TX USA. [Restrepo, Marcos I.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Sanz, F (reprint author), Consorci Hosp Gen Univ Valencia, Dept Pulmonol, Av Trescruces 2, Valencia 46014, Spain. EM sanz_fraher@gva.es NR 28 TC 4 Z9 4 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1323-7799 EI 1440-1843 J9 RESPIROLOGY JI Respirology PD OCT PY 2014 VL 19 IS 7 BP 1073 EP 1079 DI 10.1111/resp.12346 PG 7 WC Respiratory System SC Respiratory System GA AP5OZ UT WOS:000342129800021 PM 24995803 ER PT J AU Sarr, MG Warshaw, AL AF Sarr, Michael G. Warshaw, Andrew L. TI Disclosure of Funding Sources and Conflicts of Interest in Phase III Surgical Trials: Survey of 10 General Surgery Journals SO WORLD JOURNAL OF SURGERY LA English DT Editorial Material C1 [Sarr, Michael G.] Mayo Clin, Dept Surg, Rochester, MN 55905 USA. [Warshaw, Andrew L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Sarr, MG (reprint author), Mayo Clin, Dept Surg, 200 First St SW, Rochester, MN 55905 USA. EM sarr.michael@mayo.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 EI 1432-2323 J9 WORLD J SURG JI World J.Surg. PD OCT PY 2014 VL 38 IS 10 BP 2494 EP 2494 DI 10.1007/s00268-014-2648-2 PG 1 WC Surgery SC Surgery GA AP6SY UT WOS:000342209200002 ER PT J AU Kuhlthau, K Payakachat, N Delahaye, J Hurson, J Pyne, JM Kovacs, E Tilford, JM AF Kuhlthau, Karen Payakachat, Nalin Delahaye, Jennifer Hurson, Jill Pyne, Jeffrey M. Kovacs, Erica Tilford, J. Mick TI Quality of life for parents of children with autism spectrum disorders SO RESEARCH IN AUTISM SPECTRUM DISORDERS LA English DT Article DE Health-related quality of life; Parent; Parent well-being; Depression ID HEALTH-CARE NEEDS; PSYCHIATRIC-DISORDERS; ASPERGER-SYNDROME; NATIONAL-SURVEY; MEDICAL HOME; MOTHERS; EQ-5D; STRESS; FAMILY; STATES AB This project describes health-related quality of life (HRQoL) of parents of children with autism spectrum disorders (ASDs) using mixed methods. Parents of children with ASDs (N = 224) reported on their HRQoL, depression, and caregiving burden using quantitative tools. HRQoL scores were slightly worse than from those in normative populations especially related to stress and mental health. For example, parents reported average HRQoL scores from SF-6D of 0.74, which was clinically significant lower than an average normative U.S. population. 40% of parents reported having clinical depression symptoms. Married parents reported lower depression symptoms than parents who were not. In addition, families with three or more children with special health care needs (CSHCN) reported lower HRQL and higher caregiving burden than families with less CSHCN. In the qualitative study, we conducted five focus groups to gain insight as to the reasons a child's ASD might influence a parent's HRQoL. Qualitative data further supports the notion that parental HRQoL was negatively influenced by their child's ASDs. Studies that seek to quantify the influence of ASDs and to assess the effect of interventions for children with ASDs may consider measuring the effects on family members as well. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Kuhlthau, Karen; Delahaye, Jennifer; Hurson, Jill] Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Policy, Boston, MA 02114 USA. [Kuhlthau, Karen] Harvard Univ, Dept Pediat, Sch Med, Cambridge, MA 02138 USA. [Payakachat, Nalin] Univ Arkansas Med Sci, Div Pharmaceut Evaluat & Policy, Coll Pharm, Little Rock, AR 72205 USA. [Pyne, Jeffrey M.] Cent Arkansas Vet Healthcare Syst, Ctr Mental Hlth Outcomes Res, North Little Rock, AR 72114 USA. [Kovacs, Erica] Div Child & Adolescent Psychiat, Columbia Dev Neuropsychiat Program, New York, NY 10019 USA. [Tilford, J. Mick] Univ Arkansas Med Sci, Coll Publ Hlth 2226, Little Rock, AR 72205 USA. RP Kuhlthau, K (reprint author), Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Policy, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM kkuhlthau@mgh.harvard.edu NR 64 TC 6 Z9 6 U1 5 U2 46 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1750-9467 EI 1878-0237 J9 RES AUTISM SPECT DIS JI Res. Autism Spectr. Disord. PD OCT PY 2014 VL 8 IS 10 BP 1339 EP 1350 DI 10.1016/j.rasd.2014.07.002 PG 12 WC Education, Special; Psychology, Developmental; Psychiatry; Rehabilitation SC Education & Educational Research; Psychology; Psychiatry; Rehabilitation GA AO7SE UT WOS:000341552100009 ER PT J AU Kanal, KM Chung, JH Wang, J Bhargava, P Gunn, ML Shuman, WP Stewart, BK AF Kanal, Kalpana M. Chung, Jonathan H. Wang, Jin Bhargava, Puneet Gunn, Martin L. Shuman, William P. Stewart, Brent K. TI Impact of Incremental Increase in CT Image Noise on Detection of Low-contrast Hypodense Liver Lesions SO ACADEMIC RADIOLOGY LA English DT Article DE CT; image noise; radiation dose; liver lesion detection ID TUBE CURRENT MODULATION; Z-AXIS MODULATION; DOSE REDUCTION; CHEST CT; ROW CT; PHANTOM; OPTIMIZATION; QUALITY; ABDOMEN; PELVIS AB Rationale and Objectives: To determine the impact of incremental increases in computed tomography (CT) image noise on detection of low-contrast hypodense liver lesions. Material and Methods: We studied 50 CT examinations acquired at image noise index (NI) of 15 and hypodense liver lesions and 50 examinations with no lesions. Validation of a noise addition tool to be used in the evaluation of the CT examinations was performed with a liver phantom. Using this tool, three 100-image sets were assembled: an NI of 17.4 (simulating 75% of the original patient radiation dose), 21.2 (simulating 50% dose), and 29.7 (simulating 25%). Three readers scored certainty of lesion presence using a five-point Likert scale. Results: For original images (NI 15) plus images with NI of 17.4 and 21.2, sensitivity was > 90% threshold (range, 95%-98%). For images with NI of 29.7, sensitivity was-just below the threshold (89%). Reader A(z) values for receiver operating characteristic curves were good for original, NI 17.4, and NI 21.2 images (0.976, 0.973, and 0.96, respectively). For NI of 29.7, the A(z) decreased to 0.913. Detection sensitivity was < 90% for both lesion size < 10 mm (85%) and lesion-to-liver contrast < 60 Hounsfield units (85%) only at NI 29.7. Conclusions: For low-contrast lesion detection in liver CT, image noise can be increased up to NI 21.2 (a 50% patient radiation dose reduction) without substantial reduction in sensitivity. C1 [Kanal, Kalpana M.; Bhargava, Puneet; Gunn, Martin L.; Shuman, William P.; Stewart, Brent K.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Chung, Jonathan H.] Natl Jewish Hlth, Dept Radiol, Denver, CO USA. [Wang, Jin] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Bhargava, Puneet] VA Puget Sound Hlth Care Syst, Dept Radiol, Seattle, WA USA. RP Kanal, KM (reprint author), Univ Washington, Dept Radiol, 1959 NE Pacific St, Seattle, WA 98195 USA. EM kkanal@uw.edu OI Bhargava, Puneet/0000-0002-3849-9666 NR 19 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD OCT PY 2014 VL 21 IS 10 BP 1233 EP 1239 DI 10.1016/j.acra.2014.05.011 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AP1AS UT WOS:000341799400003 PM 25086952 ER PT J AU Taylor, MJ Charman, T Robinson, EB Hayiou-Thomas, ME Happe, F Dale, PS Ronald, A AF Taylor, Mark J. Charman, Tony Robinson, Elise B. Hayiou-Thomas, Marianna E. Happe, Francesca Dale, Philip S. Ronald, Angelica TI Language and Traits of Autism Spectrum Conditions: Evidence of Limited Phenotypic and Etiological Overlap SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE autism; receptive language; twin study ID CAST CHILDHOOD ASPERGER; SUSCEPTIBILITY GENE; TWIN DATA; IMPAIRMENT; DISORDERS; POPULATION; CHILDREN; ASSOCIATION; MATHEMATICS; COMORBIDITY AB Language difficulties have historically been viewed as integral to autism spectrum conditions (ASC), leading molecular genetic studies to consider whether ASC and language difficulties have overlapping genetic bases. The extent of genetic, and also environmental, overlap between ASC and language is, however, unclear. We hence conducted a twin study of the concurrent association between autistic traits and receptive language abilities. Internet-based language tests were completed by approximate to 3,000 pairs of twins, while autistic traits were assessed via parent ratings. Twin model fitting explored the association between these measures in the full sample, while DeFries-Fulker analysis tested these associations at the extremes of the sample. Phenotypic associations between language ability and autistic traits were modest and negative. The degree of genetic overlap was also negative, indicating that genetic influences on autistic traits lowered language scores in the full sample (mean genetic correlation=-0.13). Genetic overlap was also low at the extremes of the sample (mean genetic correlation=0.14), indicating that genetic influences on quantitatively defined language difficulties were largely distinct from those on extreme autistic traits. Variation in language ability and autistic traits were also associated with largely different nonshared environmental influences. Language and autistic traits are influenced by largely distinct etiological factors. This has implications for molecular genetic studies of ASC and understanding the etiology of ASC. Additionally, these findings lend support to forthcoming DSM-5 changes to ASC diagnostic criteria that will see language difficulties separated from the core ASC communication symptoms, and instead listed as a clinical specifier. (c) 2014 Wiley Periodicals, Inc. C1 [Taylor, Mark J.; Ronald, Angelica] Univ London, Genes Environm Lifespan Lab, Ctr Brain & Cognit Dev, Dept Psychol Sci, London WC1E 7JL, England. [Charman, Tony] Kings Coll London, Dept Psychol, Inst Psychiat, London WC2R 2LS, England. [Robinson, Elise B.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Robinson, Elise B.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Hayiou-Thomas, Marianna E.] Univ York, Dept Psychol, York YO10 5DD, N Yorkshire, England. [Happe, Francesca] Kings Coll London, MRC Social Genet & Dev Psychiat Ctr, Inst Psychiat, London WC2R 2LS, England. [Dale, Philip S.] Univ New Mexico, Dept Speech & Hearing Sci, Albuquerque, NM 87131 USA. RP Taylor, MJ (reprint author), Univ London, Sch Psychol Sci, Ctr Brain, Genes Environm Lifespan Lab, 32 Torrington Sq, London WC1E 7JL, England. EM mj.taylor@bbk.ac.uk RI Dale, Philip/A-2254-2009; Charman, Tony/A-2085-2014; Ronald, Angelica/C-7812-2009; Taylor, Mark/D-4853-2017; OI Dale, Philip/0000-0002-7697-8510; Charman, Tony/0000-0003-1993-6549; Ronald, Angelica/0000-0002-9576-2176; Taylor, Mark/0000-0001-5161-4182; Robinson, Elise/0000-0003-2314-2792; Happe, Francesca/0000-0001-9226-4000 FU UK Medical Research Council [G0901245 G0500079]; Medical Research Council; Economic and Social Research Council FX Grant sponsor: UK Medical Research Council; Grant number: G0901245 G0500079; Grant sponsor: Medical Research Council and Economic and Social Research Council. NR 54 TC 4 Z9 4 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD OCT PY 2014 VL 165 IS 7 BP 587 EP 595 DI 10.1002/ajmg.b.32262 PG 9 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA AP3MB UT WOS:000341979000006 PM 25088445 ER PT J AU Attaman, JA Stanic, AK Kim, M Lynch, MP Rueda, BR Styer, AK AF Attaman, Jill A. Stanic, Aleksandar K. Kim, Minji Lynch, Maureen P. Rueda, Bo R. Styer, Aaron K. TI The Anti-Inflammatory Impact of Omega-3 Polyunsaturated Fatty Acids During the Establishment of Endometriosis-Like Lesions SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article DE Cyclooxygenase-2; endometriosis; immune; interleukin-6; omega-3 fatty acids; polyunsaturated fatty acids ID TRANSGENIC MICE; ELEVATED OMEGA-3-FATTY-ACIDS; STROMAL CELLS; FAT-1 MICE; CYCLOOXYGENASE-2; TUMORIGENESIS; SUPPLEMENTATION; EXPRESSION; WOMEN; FLUID AB Problem The anti-inflammatory impact of three polyunsaturated fatty acids (3-PUFA) in endometriosis is incompletely understood. The effect of 3-PUFA on endometriosis-like lesions is evaluated as a potential anti-inflammatory treatment target. Method of StudyWild Type (WT) and transgenic Fat-1 mice (high levels of endogenous 3-PUFA) were utilized in a uterine tissue transplant endometriosis model. Experimental donorxhost pairs included: WTxWT (WW), WTxFat-1 (WF), and Fat-1xFat-1 (FF). Cytokine content (IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, IL-17A, IFN-, TNF-, MCP-1 and RANTES) and immunocellular composition in lesions was determined. ResultsIntralesion IL-6 in WF hosts was 99-fold lower than WW hosts (P=0.03). Compared to WW host lesions, Cox-2 levels were decreased in WF [1.5-fold (P=0.02)] and FF [1.2-fold (P=0.01)] host lesions, respectively, and intralesion VEGF expression was increased [1.8-fold; P=0.02 (WF) and 1.5-fold; P=0.01 (FF)]. Lesions in FF hosts demonstrated reduced phosphohistone 3 expression (70%; P=0.03) compared to WW control hosts. ConclusionsSystemic host 3-PUFA levels influence immune, angiogenic, and proliferative factors implicated in the early establishment of endometriosis. C1 [Attaman, Jill A.] Harvard Vanguard Med Associates, Dept Obstet & Gynecol, Boston, MA USA. [Attaman, Jill A.; Stanic, Aleksandar K.; Kim, Minji; Lynch, Maureen P.; Rueda, Bo R.; Styer, Aaron K.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Stanic, Aleksandar K.; Lynch, Maureen P.; Rueda, Bo R.; Styer, Aaron K.] Massachusetts Gen Hosp, Vincent Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. RP Styer, AK (reprint author), Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Thier 9, Boston, MA 02114 USA. EM astyer@partners.org OI Stanic-Kostic, Aleksandar/0000-0003-1946-6436 FU Physician Scientist Career Development Award; Executive Committee on Research and Multicultural Affairs Office; Massachusetts General Hospital; Harvard Medical School; Vincent Memorial Hospital Research Funds FX We gratefully acknowledge James H. Ware, Ph.D., Department of Biostatistics, Harvard School of Public Health. The author(s) received the following financial support for funding of this research: Physician Scientist Career Development Award, Executive Committee on Research and Multicultural Affairs Office, Massachusetts General Hospital, Harvard Medical School (to AK Styer), Vincent Memorial Hospital Research Funds (to BR Rueda and AK Styer). NR 32 TC 4 Z9 5 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1046-7408 EI 1600-0897 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD OCT PY 2014 VL 72 IS 4 BP 392 EP 402 DI 10.1111/aji.12276 PG 11 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA AP2DT UT WOS:000341883400005 PM 24898804 ER PT J AU Duffy, SA Ronis, DL Karvonen-Gutierrez, CA Ewing, LA Dalack, GW Smith, PM Carmody, TP Hicks, T Hermann, C Reeves, P Flanagan, P AF Duffy, Sonia A. Ronis, David L. Karvonen-Gutierrez, Carrie A. Ewing, Lee A. Dalack, Gregory W. Smith, Patricia M. Carmody, Timothy P. Hicks, Thomas Hermann, Christopher Reeves, Pamela Flanagan, Petra TI Effectiveness of the Tobacco Tactics Program in the Department of Veterans Affairs SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Cessation; Health services research; Tobacco control; Treatment and intervention; Veterans ID SMOKING-CESSATION INTERVENTIONS; ACUTE MYOCARDIAL-INFARCTION; NICOTINE REPLACEMENT; AFRICAN-AMERICANS; HEALTH-CARE; HOSPITALIZED SMOKERS; ETHNIC DISPARITIES; RANDOMIZED-TRIAL; GUIDELINES; QUIT AB The purpose was to determine the effectiveness of the Tobacco Tactics program in three Veterans Affairs hospitals. In this effectiveness trial, inpatient nurses were educated to provide the Tobacco Tactics intervention in Ann Arbor and Detroit, while Indianapolis was the control site (N = 1,070). Smokers were surveyed and given cotinine tests. The components of the intervention included nurse counseling, brochure, DVD, manual, pharmaceuticals, 1-800-QUIT-NOW card, and post-discharge telephone calls. There were significant improvements in 6-month quit rates in the pre- to post-intervention time periods in Ann Arbor (p = 0.004) and Detroit (p < 0.001) compared to Indianapolis. Pre- versus post-intervention quit rates were 4 % compared to 13 % in Detroit, were similar (6 %) pre- and post-intervention in Ann Arbor, and dropped from 26 % to 12 % in Indianapolis. The Tobacco Tactics program, which meets the Joint Commission standards that apply to all inpatient smokers, has the potential to significantly decrease smoking among Veterans. C1 [Duffy, Sonia A.; Karvonen-Gutierrez, Carrie A.; Ewing, Lee A.] Ann Arbor VA Ctr Clin Management Res Hlth Serv Re, Ann Arbor, MI 48105 USA. [Duffy, Sonia A.] Univ Michigan, Dept Otolaryngol, Ann Arbor, MI 48109 USA. [Duffy, Sonia A.; Dalack, Gregory W.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Smith, Patricia M.] Northern Ontario Sch Med, Greater Sudbury, ON, Canada. [Carmody, Timothy P.] San Francisco VA Med Ctr, San Francisco, CA USA. [Hicks, Thomas] Richard L Roudebush VA Med Ctr, Indianapolis, IN USA. [Hermann, Christopher; Reeves, Pamela] John D Dingell VA Med Ctr, Detroit, MI USA. [Flanagan, Petra] VA Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Duffy, Sonia A.; Ronis, David L.] Univ Michigan, Sch Nursing, Ann Arbor, MI 48109 USA. RP Duffy, SA (reprint author), Ann Arbor VA Ctr Clin Management Res Hlth Serv Re, 2215 Fuller Rd, Ann Arbor, MI 48105 USA. EM bump@umich.edu NR 48 TC 4 Z9 4 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD OCT PY 2014 VL 48 IS 2 BP 265 EP 274 DI 10.1007/s12160-014-9605-z PG 10 WC Psychology, Multidisciplinary SC Psychology GA AP1EF UT WOS:000341808600016 PM 24823842 ER PT J AU Paris, JJ Cummings, BM Moore, MP AF Paris, John J. Cummings, Brian M. Moore, M. Patrick, Jr. TI "Brain Death," "Dead," and Parental Denial The Case of Jahi McMath SO CAMBRIDGE QUARTERLY OF HEALTHCARE ETHICS LA English DT Article C1 [Paris, John J.] Boston Coll, Chestnut Hill, MA 02167 USA. [Cummings, Brian M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Moore, M. Patrick, Jr.] Boston Coll, Sch Law, Newton, MA USA. RP Paris, JJ (reprint author), Boston Coll, Chestnut Hill, MA 02167 USA. NR 35 TC 7 Z9 7 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0963-1801 EI 1469-2147 J9 CAMB Q HEALTHC ETHIC JI Camb. Q. Healthc. Ethics PD OCT PY 2014 VL 23 IS 4 BP 371 EP 382 DI 10.1017/S0963180114000048 PG 12 WC Health Care Sciences & Services; Health Policy & Services; Social Sciences, Biomedical SC Health Care Sciences & Services; Biomedical Social Sciences GA AO8VW UT WOS:000341634200001 PM 25033028 ER PT J AU Dolman, AJ Loggia, ML Edwards, RR Gollub, RL Kong, J Napadow, V Wasan, AD AF Dolman, Andrew J. Loggia, Marco L. Edwards, Robert R. Gollub, Randy L. Kong, Jian Napadow, Vitaly Wasan, Ajay D. TI Phenotype Matters The Absence of a Positive Association Between Cortical Thinning and Chronic Low Back Pain When Controlling for Salient Clinical Variables SO CLINICAL JOURNAL OF PAIN LA English DT Article DE chronic low back pain; cortical thickness; brain morphometry; clinical research methods ID LOW-BACK-PAIN; GRAY-MATTER; DEPRESSION SCALE; HOSPITAL ANXIETY; OLDER-ADULTS; BRAIN; CLASSIFICATION; QUESTIONNAIRE; INTENSITY; VALIDITY AB Aims/Objectives/Background: Studies have associated chronic low back pain (cLBP) with grey matter thinning. But these studies have not controlled for important clinical variables (such as a comorbid affective disorder, pain medication, age, or pain phenotype), which may reduce or eliminate these associations. Methods: We conducted cortical thickness and voxel-based morphometry (VBM) analyses in 14 cLBP patients with a discogenic component to their pain, not taking opioids or benzodiazepines, and not depressed or anxious. They were age and gender matched to 14 pain-free controls (PFCs). An ROI-driven analysis (regions of interest) was conducted, using 18 clusters from a previous arterial spin labeling study demonstrating greater regional cerebral blood flow (rCBF) in these cLBP subjects than the PFCs. Cortical thickness and VBM-based gray matter volume measurements were obtained from a structural MRI scan and group contrasts were calculated. Results: Multivariate analysis of variance showed a trend toward cortical thickening in the right paracentral lobule in cLBP subjects (F-1,F-17 = 3.667, P < 0.067), and significant thickening in the right rostral middle frontal gyrus (F-1,F-17 = 6.880, P < 0.014). These clusters were non-significant after including age as a covariate (P < 0.891; P < 0.279). A whole-brain cortical thickness and VBM analysis also did not identify significant clusters of thinning or thickening. Exploratory analyses identified group differences for correlations between age and cortical thickness of the right rostral middle frontal gyrus (cLBP: R = = -0.03, P = 0.9; PFCs: R = -0.81, P < 0.001), that is, PFCs demonstrated age-related thinning while cLBP patients did not. Conclusions: Our pilot results suggest that controlling for affect, age, and concurrent medications may reduce or eliminate some of the previously reported structural brain alterations in cLBP. C1 [Dolman, Andrew J.; Edwards, Robert R.; Napadow, Vitaly] Brigham & Womens Hosp, Dept Anesthesiol, Boston, MA 02115 USA. [Edwards, Robert R.] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Loggia, Marco L.; Napadow, Vitaly] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Loggia, Marco L.; Gollub, Randy L.; Kong, Jian] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Wasan, Ajay D.] Univ Pittsburgh, Sch Med, Dept Anesthesiol, Pittsburgh, PA 15261 USA. [Wasan, Ajay D.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. RP Wasan, AD (reprint author), UPMC Pain Med, 5750 Ctr Ave,Suite 400, Pittsburgh, PA 15206 USA. EM adw63@pitt.edu OI Gollub, Randy L./0000-0002-9434-4044 FU NIH/NIDA [1K23DA020681-01A1] FX Supported by NIH/NIDA 1K23DA020681-01A1. The authors declare no conflict of interest. NR 41 TC 3 Z9 3 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0749-8047 EI 1536-5409 J9 CLIN J PAIN JI Clin. J. Pain PD OCT PY 2014 VL 30 IS 10 BP 839 EP 845 DI 10.1097/AJP.0000000000000043 PG 7 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA AP1MP UT WOS:000341834800002 PM 24135900 ER PT J AU Zisook, S Iglewicz, A Avanzino, J Maglione, J Glorioso, D Zetumer, S Seay, K Vahia, I Young, I Lebowitz, B Pies, R Reynolds, C Simon, N Shear, MK AF Zisook, Sidney Iglewicz, Alana Avanzino, Julie Maglione, Jeanne Glorioso, Danielle Zetumer, Samuel Seay, Kathryn Vahia, Ipsit Young, Ilanit Lebowitz, Barry Pies, Ronald Reynolds, Charles Simon, Naomi Shear, M. Katherine TI Bereavement: Course, Consequences, and Care SO CURRENT PSYCHIATRY REPORTS LA English DT Article DE Bereavement; Grief; Mourning; Complicated grief; Persistent complex bereavement disorder; Major depressive disorder; Major depressive episode; Post-traumatic stress disorder ID COMPLICATED GRIEF; ANXIETY DISORDERS; MAJOR DEPRESSION; RISK-FACTORS; CONJUGAL BEREAVEMENT; COMMUNITY SAMPLE; DIURNAL CORTISOL; NATIONAL SAMPLE; PHYSICAL HEALTH; YOUNG-ADULTS AB This paper discusses each of several potential consequences of bereavement. First, we describe ordinary grief, followed by a discussion of grief gone awry, or complicated grief (CG). Then, we cover other potential adverse outcomes of bereavement, each of which may contribute to, but are not identical with, CG: general medical comorbidity, mood disorders, post-traumatic stress disorder, anxiety, and substance use. C1 [Zisook, Sidney; Iglewicz, Alana; Maglione, Jeanne; Seay, Kathryn; Young, Ilanit; Lebowitz, Barry] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92161 USA. [Zisook, Sidney; Iglewicz, Alana; Avanzino, Julie; Maglione, Jeanne; Zetumer, Samuel; Young, Ilanit] Vet Affairs San Diego Healthcare Syst, La Jolla, CA USA. [Zisook, Sidney; Iglewicz, Alana; Avanzino, Julie; Maglione, Jeanne; Zetumer, Samuel; Young, Ilanit] Vet Med & Res Fdn, La Jolla, CA USA. [Glorioso, Danielle; Vahia, Ipsit] Univ Calif San Diego, Ctr Hlth Aging, La Jolla, CA 92161 USA. [Seay, Kathryn] Univ Calif & San Diego State Joint Doctoral Progr, La Jolla, CA USA. [Seay, Kathryn] Vet Med Educ & Res Fdn, La Jolla, CA USA. [Lebowitz, Barry] Columbia Univ, Dept Biostat & Psychiat, New York, NY USA. [Pies, Ronald] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Pies, Ronald] Tufts Univ, Sch Med, Dept Psychiat, Boston, MA 02111 USA. [Reynolds, Charles] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Reynolds, Charles] Univ Pittsburgh, Western Psychiat Inst & Clin, Grad Sch Publ Hlth, Dept Community & Behav Hlth Sci, Pittsburgh, PA 15213 USA. [Simon, Naomi] Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Boston, MA 02114 USA. [Simon, Naomi] Massachusetts Gen Hosp, Complicated Grief Program, Boston, MA 02114 USA. [Shear, M. Katherine] Columbia Univ, Sch Social Work, Complicated Grief Treatment Res Program, New York, NY USA. [Shear, M. Katherine] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. RP Zisook, S (reprint author), Univ Calif San Diego, Dept Psychiat, 3350 La Jolla Village Dr, La Jolla, CA 92161 USA. EM szisook@ucsd.edu FU Majda Foundation; John A. Hartford Foundation; Bristol-Myers Squibb; Forest; Pfizer; Lilly; National Institute of Mental Health; National Institute on Aging; National Center for Minority Health Disparities; National Heart Lung and Blood Institute; Center for Medicare and Medicaid Services (CMS); Patient Centered Outcomes Research Institute (PCORI); Commonwealth of Pennsylvania; National Palliative Care Research Center (NPCRC); Clinical and Translational Science Institute (CTSI); American Foundation for Suicide Prevention; National Institutes of Health [P60 MD000207, P30 MH090333, UL1RR024153, UL1TR000005]; UPMC Endowment in Geriatric Psychiatry; Highland Street Foundation; NIMH; American Foundation for Suicide Prevention (AFSP); DOD; MGH Psychiatry Academy; NIMH [MH60783, MH70741]; NIH; [NIMH-5R01MH085297]; [AFSP-LSRG-S-172-12] FX Sidney Zisook has received the following grants: NIMH-5R01MH085297, AFSP-LSRG-S-172-12, and a grant from The Majda Foundation.; Alana Iglewicz received an unrestricted travel grant from John A. Hartford Foundation.; Charles Reynolds reports receiving pharmaceutical support for NIH-sponsored research studies from Bristol-Myers Squibb, Forest, Pfizer, and Lilly; receiving grants from the National Institute of Mental Health, National Institute on Aging, National Center for Minority Health Disparities, National Heart Lung and Blood Institute, Center for Medicare and Medicaid Services (CMS), Patient Centered Outcomes Research Institute (PCORI), the Commonwealth of Pennsylvania, the John A Hartford Foundation, National Palliative Care Research Center (NPCRC), Clinical and Translational Science Institute (CTSI), and the American Foundation for Suicide Prevention; and serving on the American Association for Geriatric Psychiatry editorial review board. He has received an honorarium as a speaker from MedScape/WEB MD. He is the co-inventor (Licensed Intellectual Property) of Psychometric analysis of the Pittsburgh Sleep Quality Index (PSQI) PRO10050447 (PI: Buysse). Supported by the National Institutes of Health through Grant Numbers P60 MD000207; P30 MH090333; UL1RR024153, UL1TR000005; and the UPMC Endowment in Geriatric Psychiatry; Naomi Simon has received grants from the Highland Street Foundation, NIMH, American Foundation for Suicide Prevention (AFSP) and DOD. She has received honoraria/consultation fees from the MGH Psychiatry Academy.; M. Katherine Shear has received the following grants: NIMH (MH60783 and MH70741) and AFSP. NR 109 TC 7 Z9 7 U1 9 U2 35 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 EI 1535-1645 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD OCT PY 2014 VL 16 IS 10 AR 482 DI 10.1007/s11920-014-0482-8 PG 10 WC Psychiatry SC Psychiatry GA AP1KG UT WOS:000341827500010 PM 25135781 ER PT J AU Kelley, MJ Shi, JX Ballew, B Hyland, PL Li, WQ Rotunno, M Alcorta, DA Liebsch, NJ Mitchell, J Bass, S Roberson, D Boland, J Cullen, M He, J Burdette, L Yeager, M Chanock, SJ Parry, DM Goldstein, AM Yang, XHR AF Kelley, Michael J. Shi, Jianxin Ballew, Bari Hyland, Paula L. Li, Wen-Qing Rotunno, Melissa Alcorta, David A. Liebsch, Norbert J. Mitchell, Jason Bass, Sara Roberson, David Boland, Joseph Cullen, Michael He, Ji Burdette, Laurie Yeager, Meredith Chanock, Stephen J. Parry, Dilys M. Goldstein, Alisa M. Yang, Xiaohong R. TI Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma SO HUMAN GENETICS LA English DT Article ID TRANSCRIPTION FACTOR; BRACHYURY; PROTEIN; POPULATION; SURVIVAL; COMPLEX AB Chordoma is a rare bone cancer that is believed to originate from notochordal remnants. We previously identified germline T duplication as a major susceptibility mechanism in several chordoma families. Recently, a common genetic variant in T (rs2305089) was significantly associated with the risk of sporadic chordoma. We sequenced all T exons in 24 familial cases and 54 unaffected family members from eight chordoma families (three with T duplications), 103 sporadic cases, and 160 unrelated controls. We also measured T copy number variation in all sporadic cases. We confirmed the association between the previously reported variant rs2305089 and risk of familial [odds ratio (OR) = 2.6, 95 % confidence interval (CI) = 0.93, 7.25, P = 0.067] and sporadic chordoma (OR = 2.85, 95 % CI = 1.89, 4.29, P < 0.0001). We also identified a second common variant, rs1056048, that was strongly associated with chordoma in families (OR = 4.14, 95 % CI = 1.43, 11.92, P = 0.0086). Among sporadic cases, another common variant (rs3816300) was significantly associated with risk when jointly analyzed with rs2305089. The association with rs3816300 was significantly stronger in cases with early age onset. In addition, we identified three rare variants that were only observed among sporadic chordoma cases, all of which have potential functional relevance based on in silico predictions. Finally, we did not observe T duplication in any sporadic chordoma case. Our findings further highlight the importance of the T gene in the pathogenesis of both familial and sporadic chordoma and suggest a complex susceptibility related to T. C1 [Kelley, Michael J.; Alcorta, David A.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27705 USA. [Kelley, Michael J.] Durham Vet Affairs Med Ctr, Durham, NC 27705 USA. [Shi, Jianxin; Ballew, Bari; Hyland, Paula L.; Li, Wen-Qing; Rotunno, Melissa; Mitchell, Jason; Bass, Sara; Roberson, David; Boland, Joseph; Cullen, Michael; He, Ji; Burdette, Laurie; Yeager, Meredith; Chanock, Stephen J.; Parry, Dilys M.; Goldstein, Alisa M.; Yang, Xiaohong R.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Liebsch, Norbert J.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Mitchell, Jason; Bass, Sara; Roberson, David; Boland, Joseph; Cullen, Michael; He, Ji; Burdette, Laurie; Yeager, Meredith] SAIC Frederick Inc, Canc Genom Res Lab, Bethesda, MD 20892 USA. RP Yang, XHR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. EM royang@mail.nih.gov RI Li, Wenqing/N-2293-2014 OI Li, Wenqing/0000-0002-1283-4091 FU National Cancer Institute, Division of Cancer Epidemiology and Genetics, National Institutes of Health; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development program; Chordoma Foundation FX We thank Deborah Zametkin for her outstanding skills as a research nurse; Drs. Gladys M. Glenn and Mary L. McMaster for their careful clinical evaluations of patients and family members; Dr. Nicholas J. Patronas for reviewing the MR images; Cancer Genomics Research Laboratory for sequencing and bioinformatic analyses; and, especially, the patients and their families for their participation. This work was supported by the Intramural Research Program of the National Cancer Institute, Division of Cancer Epidemiology and Genetics, National Institutes of Health, and by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development program, and a grant from the Chordoma Foundation (M.J.K.). NR 21 TC 10 Z9 10 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD OCT PY 2014 VL 133 IS 10 BP 1289 EP 1297 DI 10.1007/s00439-014-1463-z PG 9 WC Genetics & Heredity SC Genetics & Heredity GA AP1KP UT WOS:000341828900006 PM 24990759 ER PT J AU Bailey, JNC Yaspan, BL Pasquale, LR Hauser, MA Kang, JH Loomis, SJ Brilliant, M Budenz, DL Christen, WG Fingert, J Gaasterland, D Gaasterland, T Kraft, P Lee, RK Lichter, PR Liu, YT McCarty, CA Moroi, SE Richards, JE Realini, T Schuman, JS Scott, WK Singh, K Sit, AJ Vollrath, D Wollstein, G Zack, DJ Zhang, K Pericak-Vance, MA Allingham, RR Weinreb, RN Haines, JL Wiggs, JL AF Bailey, Jessica N. Cooke Yaspan, Brian L. Pasquale, Louis R. Hauser, Michael A. Kang, Jae H. Loomis, Stephanie J. Brilliant, Murray Budenz, Donald L. Christen, William G. Fingert, John Gaasterland, Douglas Gaasterland, Terry Kraft, Peter Lee, Richard K. Lichter, Paul R. Liu, Yutao McCarty, Catherine A. Moroi, Sayoko E. Richards, Julia E. Realini, Tony Schuman, Joel S. Scott, William K. Singh, Kuldev Sit, Arthur J. Vollrath, Douglas Wollstein, Gadi Zack, Donald J. Zhang, Kang Pericak-Vance, Margaret A. Allingham, R. Rand Weinreb, Robert N. Haines, Jonathan L. Wiggs, Janey L. TI Hypothesis-independent pathway analysis implicates GABA and Acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma SO HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; OXIDATIVE STRESS; COMMON VARIANTS; VIGABATRIN; THERAPY; GENES; SUSCEPTIBILITY; MUTATIONS; RATIONALE; PATTERNS AB Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. Using genome-wide association single-nucleotide polymorphism data from the Glaucoma Genes and Environment study and National Eye Institute Glaucoma Human Genetics Collaboration comprising 3,108 cases and 3,430 controls, we assessed biologic pathways as annotated in the KEGG database for association with risk of POAG. After correction for genic overlap among pathways, we found 4 pathways, butanoate metabolism (hsa00650), hematopoietic cell lineage (hsa04640), lysine degradation (hsa00310) and basal transcription factors (hsa03022) related to POAG with permuted p < 0.001. In addition, the human leukocyte antigen (HLA) gene family was significantly associated with POAG (p < 0.001). In the POAG subset with normal-pressure glaucoma (NPG), the butanoate metabolism pathway was also significantly associated (p < 0.001) as well as the MAPK and Hedgehog signaling pathways (hsa04010 and hsa04340), glycosaminoglycan biosynthesis-heparan sulfate pathway (hsa00534) and the phenylalanine, tyrosine and tryptophan biosynthesis pathway (hsa0400). The butanoate metabolism pathway overall, and specifically the aspects of the pathway that contribute to GABA and acetyl-CoA metabolism, was the only pathway significantly associated with both POAG and NPG. Collectively these results implicate GABA and acetyl-CoA metabolism in glaucoma pathogenesis, and suggest new potential therapeutic targets. C1 [Bailey, Jessica N. Cooke; Yaspan, Brian L.; Haines, Jonathan L.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37235 USA. [Pasquale, Louis R.; Loomis, Stephanie J.; Wiggs, Janey L.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02138 USA. [Pasquale, Louis R.; Kang, Jae H.; Loomis, Stephanie J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Hauser, Michael A.; Liu, Yutao; Allingham, R. Rand] Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. [Hauser, Michael A.; Liu, Yutao] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Brilliant, Murray] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA. [Budenz, Donald L.] Univ N Carolina, Dept Ophthalmol, Chapel Hill, NC USA. [Christen, William G.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Fingert, John] Univ Iowa, Coll Med, Dept Ophthalmol, Iowa City, IA 52242 USA. [Fingert, John] Univ Iowa, Coll Med, Dept Anat Cell Biol, Iowa City, IA USA. [Gaasterland, Douglas] Eye Doctors Washington, Chevy Chase, MD USA. [Gaasterland, Terry] Univ Calif San Diego, Scripps Genome Ctr, San Diego, CA 92103 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Lee, Richard K.] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Miami, FL 33136 USA. [Lichter, Paul R.; Moroi, Sayoko E.; Richards, Julia E.] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [McCarty, Catherine A.] Essentia Inst Rural Hlth, Duluth, MN USA. [Realini, Tony] WVU Eye Inst, Dept Ophthalmol, Morgantown, WV USA. [Schuman, Joel S.; Wollstein, Gadi] Univ Pittsburgh, Dept Ophthalmol, UPMC Eye Ctr, Pittsburgh, PA 15260 USA. [Scott, William K.; Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, Inst Human Genom, Miami, FL 33136 USA. [Singh, Kuldev] Stanford Univ, Dept Ophthalmol, Palo Alto, CA 94304 USA. [Sit, Arthur J.] Mayo Clin, Dept Ophthalmol, Rochester, MN USA. [Vollrath, Douglas] Stanford Univ, Dept Genet, Palo Alto, CA 94304 USA. [Zack, Donald J.] Johns Hopkins Univ Hosp, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Zhang, Kang; Weinreb, Robert N.] Univ Calif San Diego, Hamilton Eye Ctr, Dept Ophthalmol, San Diego, CA 92103 USA. RP Wiggs, JL (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02138 USA. EM janey_wiggs@meei.harvard.edu OI Zack, Don/0000-0002-7966-1973 FU Harvard Glaucoma Center of Excellence and Margolis fund (Boston, MA); Research to Prevent Blindness, Inc. (New York, NY); Arthur Ashley Foundation; Glaucoma Research Foundation (San Francisco, CA); American Health Assistance Foundation (Clarksburg, MD); Glaucoma Foundation (New York, NY); National Human Genome Research Institute (Bethesda, MD) [GLAUGEN: HG004728, HG004424, HG004446]; National Eye Institute [HG005259-01]; National Institutes of Health [HHSN268200782096C]; National Eye Institute (Bethesda, MD) through ARA [EY015872, EY019126]; National Institutes of Health (Bethesda, MD) [EY015872, EY015543, EY006827, HL073389, EY13315, EY09611, EY009149, HG004608, EY008208, EY015473, EY012118, EY015682, EY011671, EY09580, EY013178, EY010886, EY009847, EY011008, EY144428, EY144448, EY18660]; NIH [T32EY021453] FX The Harvard Glaucoma Center of Excellence and Margolis fund (Boston, MA) support LRP and JLW. LRP, JER and JLW are also supported by Research to Prevent Blindness, Inc. (New York, NY). The Arthur Ashley Foundation also supports Dr. Pasquale. The Glaucoma Research Foundation (San Francisco, CA), American Health Assistance Foundation (Clarksburg, MD), and the Glaucoma Foundation (New York, NY) support YL. The following National Institutes of Health Grants support the maintenance of the Nurses Health Study and Health Professionals Follow-up, allowing these health professionals to contribute to this analysis: CA87969, CA49449, UM1 CA167552, and HL35464. The following Grants from the National Human Genome Research Institute (Bethesda, MD) supported GLAUGEN: HG004728 (LRP), HG004424 (Broad Institute to support genotyping), HG004446 (C. Laurie, U. Washington, to support genotype data cleaning and analysis). Genotyping services for the NEIGHBOR study were provided by the Center for Inherited Disease Research (CIDR) and were supported by the National Eye Institute through Grant HG005259-01 (JLW). In addition, CIDR is funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. The National Eye Institute (Bethesda, MD) through ARA Grants EY015872 (JLW) and EY019126 (MAH) supported the collection and processing of samples for the NEIGHBOR dataset. Funding for the collection of cases and controls was provided by National Institutes of Health (Bethesda, MD) Grants: EY015543 (RRA), EY006827 (DG), HL073389 (Hauser, E), EY13315 (MAH), EY09611 (Hankinson, S), EY015473 (LRP), EY009149 (PRL), HG004608 (CAM), EY008208 (Medeiros, P.), EY015473 (LRP), EY012118 (MAP-V), EY015682 (TR), EY011671 (JER), EY09580 (JER), EY013178 (JSS), EY015872 (JLW), EY010886 (JLW), EY009847 (JLW), EY011008 (Zangwill, L), EY144428 (KZ), EY144448 (KZ), EY18660 (KZ). None of the authors have any commercial interests in the subject of the manuscript or in entities discussed in the manuscript. BL Yaspan and JN Cooke Bailey were supported in part by NIH Grant T32EY021453. NR 47 TC 6 Z9 6 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD OCT PY 2014 VL 133 IS 10 BP 1319 EP 1330 DI 10.1007/s00439-014-1468-7 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA AP1KP UT WOS:000341828900009 PM 25037249 ER PT J AU Morasco, BJ Lovejoy, TI Turk, DC Crain, A Hauser, P Dobscha, SK AF Morasco, Benjamin J. Lovejoy, Travis I. Turk, Dennis C. Crain, Aysha Hauser, Peter Dobscha, Steven K. TI Biopsychosocial factors associated with pain in veterans with the hepatitis C virus SO JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article DE Chronic pain; Biopsychosocial model; Hepatitis C ID UNITED-STATES; PSYCHOSOCIAL FACTORS; RISK-FACTORS; PREVALENCE; INFECTION; VALIDATION; FIBROMYALGIA; POPULATION; FIBROSIS; INTERFERENCE AB Little research has examined etiological factors associated with pain in patients with the hepatitis C virus (HCV). The purpose of this study was to evaluate the relationship between biopsychosocial factors and pain among patients with HCV. Patients with HCV and pain (n = 119) completed self-report measures of pain, mental health functioning, pain-specific psychosocial variables (pain catastrophizing, self-efficacy for managing pain, social support), prescription opioid use, and demographic characteristics. In multivariate models, biopsychosocial factors accounted for 37 % of the variance in pain severity and 56 % of the variance in pain interference. In adjusted models, factors associated with pain severity include pain catastrophizing and social support, whereas variables associated with pain interference were age, pain intensity, prescription opioid use, and chronic pain self-efficacy (all p values < 0.05). The results provide empirical support for incorporating the biopsychosocial model in evaluating and treating chronic pain in patients with HCV. C1 [Morasco, Benjamin J.; Lovejoy, Travis I.; Crain, Aysha; Dobscha, Steven K.] Portland VA Med Ctr, Mental Hlth & Clin Neurosci Div, R&D99, Portland, OR 97239 USA. [Morasco, Benjamin J.; Lovejoy, Travis I.; Dobscha, Steven K.] Portland VA Med Ctr, Ctr Study Chron Comorbid Med & Psychiat Disorders, Portland, OR 97239 USA. [Morasco, Benjamin J.; Lovejoy, Travis I.; Dobscha, Steven K.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Turk, Dennis C.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Turk, Dennis C.] Univ Washington, Ctr Pain Res Impact Measurement & Effectiveness, Seattle, WA 98195 USA. [Hauser, Peter] VISN 22 Network Off, Long Beach, CA USA. [Hauser, Peter] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. RP Morasco, BJ (reprint author), Portland VA Med Ctr, Mental Hlth & Clin Neurosci Div, R&D99, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM benjamin.morasco@va.gov FU NIDA NIH HHS [K23DA023467, R01 DA034083, K23 DA023467] NR 57 TC 3 Z9 3 U1 1 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0160-7715 EI 1573-3521 J9 J BEHAV MED JI J. Behav. Med. PD OCT PY 2014 VL 37 IS 5 BP 902 EP 911 DI 10.1007/s10865-013-9549-y PG 10 WC Psychology, Clinical SC Psychology GA AP1LB UT WOS:000341830300009 PM 24338521 ER PT J AU Zhao, YL Cudkowicz, ME Shefner, JM Krivickas, L David, WS Vriesendorp, F Pestronk, A Caress, JB Katz, J Simpson, E Rosenfeld, J Pascuzzi, R Glass, J Rezania, K Harmatz, JS Schoenfeld, D Greenblatt, DJ AF Zhao, Yanli Cudkowicz, Merit E. Shefner, Jeremy M. Krivickas, Lisa David, William S. Vriesendorp, Francine Pestronk, Alan Caress, James B. Katz, Jonathan Simpson, Ericka Rosenfeld, Jeffrey Pascuzzi, Robert Glass, Jonathan Rezania, Kourosh Harmatz, Jerold S. Schoenfeld, David Greenblatt, David J. TI Systemic Pharmacokinetics and Cerebrospinal Fluid Uptake of Intravenous Ceftriaxone in Patients With Amyotrophic Lateral Sclerosis SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE amyotrophic lateral sclerosis; ceftriaxone; plasma pharmacokinetics; cerebrospinal fluid uptake; HPLC micromethod ID BETA-LACTAM ANTIBIOTICS; PLASMA-PROTEIN BINDING; CEPHALOSPORINS; DIFFUSION; KINETICS; CHILDREN; ALS; PHARMACODYNAMICS; MENINGITIS; STROKE AB The cephalosporin antibiotic ceftriaxone was evaluated as a potential therapeutic agent for the treatment of amyotrophic lateral sclerosis (ALS). The pharmacokinetics (PK) of ceftriaxone in plasma and cerebrospinal fluid (CSF) were investigated in 66 participants in a previously reported clinical trial. Their mean age was 51 years, and 65% were male. Participants were randomly assigned to 1 of 3 treatment groups receiving intravenous infusions (mean duration: 25minutes) every 12hours of either: placebo and placebo; 2g ceftriaxone and placebo; or 2g ceftriaxone twice. Mean steady-state plasma PK variables were: volume of distribution, 14L (0.17L/kg); elimination half-life, 8-9h; total clearance, 17-21mL/min (0.22-0.25mL/min/kg). Values were not different between dosage groups. CSF PK analysis, determined through sparse CSF sampling, indicated apparent entry and elimination half-life values of 1.0 and 34hours, respectively. With both dosage regimens, CSF concentrations were maintained above the target threshold of 1.0 mu M (0.55 mu g/mL) as determined from in vitro models. The plasma and CSF PK profiles of ceftriaxone were used as a basis for planning the Phase 3 clinical trial of ceftriaxone in ALS. C1 [Zhao, Yanli; Harmatz, Jerold S.; Greenblatt, David J.] Tufts Univ, Sch Med, Program Pharmacol & Expt Therapeut, Boston, MA 02111 USA. [Cudkowicz, Merit E.; Krivickas, Lisa; David, William S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurol Clin Res Inst, Boston, MA USA. [Shefner, Jeremy M.; Vriesendorp, Francine] SUNY Upstate Med Univ, Dept Neurol, Syracuse, NY 13210 USA. [Pestronk, Alan] Washington Univ, Dept Neurol, St Louis, MO USA. [Caress, James B.] Wake Forest Univ, Dept Neurol, Winston Salem, NC 27109 USA. [Katz, Jonathan] Calif Pacific Med Ctr, Dept Neurol, San Francisco, CA USA. [Simpson, Ericka] Methodist Neurol Inst, Dept Neurol, Houston, TX USA. [Rosenfeld, Jeffrey] Univ Calif San Francisco Fresno, Dept Neurol, Neurosci Inst, Fresno, CA USA. [Pascuzzi, Robert] Indiana Univ, Dept Neurol, Indianapolis, IN 46204 USA. [Glass, Jonathan] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Rezania, Kourosh] Univ Chicago, Dept Neurol, Chicago, IL 60637 USA. [Schoenfeld, David] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. RP Greenblatt, DJ (reprint author), Tufts Univ, Sch Med, 136 Harrison Ave, Boston, MA 02111 USA. EM dj.greenblatt@tufts.edu OI Caress, James/0000-0002-5814-6083 FU National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health [U01 NS049640-05]; Institute of Clinical and Translational Sciences [UL1 TR000448] FX This research was supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (U01 NS049640-05), and from the Institute of Clinical and Translational Sciences (UL1 TR000448). NR 33 TC 2 Z9 2 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD OCT PY 2014 VL 54 IS 10 BP 1180 EP 1187 DI 10.1002/jcph.317 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AP1EG UT WOS:000341808800012 PM 24771634 ER PT J AU Freeman, MP Cohen, LS McInerney, K AF Freeman, Marlene P. Cohen, Lee S. McInerney, Kathryn TI Omega-3 Fatty Acids and Gestational Length in a High-Risk Psychiatric Population Due to Psychiatric Morbidity and Medication Exposure During Pregnancy SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE pregnancy; depression; omega-3; antidepressant; antipsychotic; gestational length ID POLYUNSATURATED FATTY-ACIDS; RANDOMIZED-CONTROLLED-TRIAL; FISH-OIL SUPPLEMENTATION; SEROTONIN REUPTAKE INHIBITORS; PRETERM BIRTH; PROSPECTIVE COHORT; ERYTHROCYTE OMEGA-3; GROWTH MEASURES; FETAL-GROWTH; WOMEN AB Objective: Premature birth is associated with infant morbidity and mortality. Women with psychiatric disorders represent an at-risk population for premature delivery and other obstetrical complications. The primary aim of this study was to assess the association between omega-3 fatty acid use and length of gestation. Methods: Data from the National Pregnancy Registry for Atypical Antipsychotics were used. This prospective study included pregnant women exposed and unexposed to atypical antipsychotics during pregnancy. The outcomes of gestational length, birth weight, and preeclampsia were examined in relation to omega-3 use during pregnancy. Omega-3 use was operationalized from a first-trimester interview as a dichotomous variable. Results: Of 361 women who were examined for eligibility, 233 women had a singleton birth as well as a valid response on the omega-3 item and information on at least one of the outcome measures. Ninety-seven (41.6%) women used omega-3 during pregnancy. Omega-3 users were older, more educated, and more likely to be married than nonusers. The users were less likely to have smoked during their first trimester and were marginally less likely to use antidepressant medications anytime during pregnancy. There were no significant differences in primary diagnoses or atypical antipsychotic, alcohol, or prenatal vitamin use. In an un-adjusted model, there was a significant increase of between 4 and 5 days (0.65 weeks; 0.00-1.25) in gestational length among the omega-3 users. This result was no longer significant after adjusting for confounding variables, with an increase of approximately 4 days (0.53 weeks; -0.11 to 1.16). Omega-3 use was not significantly associated with a difference in birth weight or preeclampsia. Conclusions: We found a trend for a modestly increased length of gestation among the omega-3 fatty acid users, although these were not significant after controlling for the exposures of smoking and antidepressant use. We did not find a decreased risk for preeclampsia among the users of omega-3 fatty acids or increased birth weight. In consideration of the risk factors for obstetrical and neonatal complications as well as implications for infant and child development, it would be clinically important to understand the variables that may additively decrease obstetrical risks in this population. C1 [Freeman, Marlene P.; Cohen, Lee S.] Harvard Univ, Sch Med, Boston, MA USA. [McInerney, Kathryn] Harvard Univ, Sch Publ Hlth, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Freeman, MP (reprint author), Massachusetts Gen Hosp, 185 Cambridge St,2nd Floor, Boston, MA 02114 USA. EM mfreeman@partners.org FU Lilly; GlaxoSmithKline; Bayer; Bristol-Myers Squibb; Cephalon; Forest; National Institute on Aging; National Institute of Mental Health; Ortho-McNeil-Janssen Pharmaceuticals; Pfizer; Sunovion; National Institutes of Health FX Marlene P. Freeman JDS therapeutics (consulting); received support from Lilly and GlaxoSmithKline (grant); Lundbeck, Takeda, Otsuka, Genentech, as well as Johnson & Johnson (advisory boards); and DSM Nutritionals (medical editing).; Lee S. Cohen received support from GlaxoSmithKline (research); Lilly, Noven, and PamLab (consultant); and Bayer, Bristol-Myers Squibb, Cephalon, Forest, National Institute on Aging, National Institute of Mental Health, Ortho-McNeil-Janssen Pharmaceuticals, Pfizer, Sunovion, as well as National Institutes of Health (grants). NR 58 TC 0 Z9 0 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0271-0749 EI 1533-712X J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD OCT PY 2014 VL 34 IS 5 BP 627 EP 632 DI 10.1097/JCP.0000000000000168 PG 6 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA AP1EO UT WOS:000341809700017 PM 25006815 ER PT J AU Chou, SH Mantzoros, C AF Chou, Sharon H. Mantzoros, Christos TI Role of leptin in human reproductive disorders SO JOURNAL OF ENDOCRINOLOGY LA English DT Review DE leptin; metabolism; reproduction; neuroendocrinology ID POLYCYSTIC-OVARY-SYNDROME; FUNCTIONAL HYPOTHALAMIC AMENORRHEA; INDUCED LUTEINIZING-HORMONE; BODY-MASS INDEX; ENDOCRINE-METABOLIC ABERRATIONS; ACTIVE ANTIRETROVIRAL THERAPY; PRIMED OVARIECTOMIZED RATS; LEAN HYPOLEPTINEMIC WOMEN; RECOMBINANT HUMAN LEPTIN; NEUROPEPTIDE-Y AB Leptin, as a key hormone in energy homeostasis, regulates neuroendocrine function, including reproduction. It has a permissive role in the initiation of puberty and maintenance of the hypothalamic-pituitary-gonadal axis. This is notable in patients with either congenital or acquired leptin deficiency from a state of chronic energy insufficiency. Hypothalamic amenorrhea is the best-studied, with clinical trials confirming a causative role of leptin in hypogonadotropic hypogonadism. Implications of leptin deficiency have also emerged in the pathophysiology of hypogonadism in type 1 diabetes. At the other end of the spectrum, hyperleptinemia may play a role in hypogonadism associated with obesity, polycystic ovarian syndrome, and type 2 diabetes. In these conditions of energy excess, mechanisms of reproductive dysfunction include central leptin resistance as well as direct effects at the gonadal level. Thus, reproductive dysfunction due to energy imbalance at both ends can be linked to leptin. C1 [Chou, Sharon H.] Univ Chicago, Sect Adult & Pediat Endocrinol Diabet & Metab, Chicago, IL 60637 USA. [Mantzoros, Christos] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Mantzoros, Christos] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA 02215 USA. RP Mantzoros, C (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, 330 Brookline Ave,FD-876, Boston, MA 02215 USA. EM cmantzor@bidmc.harvard.edu NR 152 TC 19 Z9 19 U1 1 U2 19 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 EI 1479-6805 J9 J ENDOCRINOL JI J. Endocrinol. PD OCT PY 2014 VL 223 IS 1 BP T49 EP T62 DI 10.1530/JOE-14-0245 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP2CY UT WOS:000341881300006 PM 25056118 ER PT J AU Goodman, M Carpenter, D Tang, CY Goldstein, KE Avedon, J Fernandez, N Mascitelli, KA Blair, NJ New, AS Triebwasser, J Siever, LJ Hazlett, EA AF Goodman, Marianne Carpenter, David Tang, Cheuk Y. Goldstein, Kim E. Avedon, Jennifer Fernandez, Nicolas Mascitelli, Kathryn A. Blair, Nicholas J. New, Antonia S. Triebwasser, Joseph Siever, Larry J. Hazlett, Erin A. TI Dialectical behavior therapy alters emotion regulation and amygdala activity in patients with borderline personality disorder SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Borderline personality disorder; Emotion regulation; Amygdala; Habituation; fMRI ID POSTTRAUMATIC-STRESS-DISORDER; AFFECTIVE INSTABILITY; FEMALE-PATIENTS; FUNCTIONAL MRI; FMRI; DEPRESSION; WOMEN; DYSREGULATION; METAANALYSIS; VALIDATION AB Objective: Siever and Davis' (1991) psychobiological framework of borderline personality disorder (BPD) identifies affective instability (Al) as a core dimension characterized by prolonged and intense emotional reactivity. Recently, deficient amygdala habituation, defined as a change in response to repeated relative to novel unpleasant pictures within a session, has emerged as a biological correlate of Al in BPD. Dialectical behavior therapy (DBT), an evidence-based treatment, targets Al by teaching emotion-regulation skills. This study tested the hypothesis that BPD patients would exhibit decreased amygdala activation and improved habituation, as well as improved emotion regulation with standard 12-month DBT. Methods: Event-related fMRI was obtained pre- and post-12-months of standard-DBT in unmedicated BPD patients. Healthy controls (HCs) were studied as a benchmark for normal amygdala activity and change over time (n = 11 per diagnostic-group). During each scan, participants viewed an intermixed series of unpleasant, neutral and pleasant pictures presented twice (novel, repeat). Change in emotion regulation was measufed with the Difficulty in Emotion Regulation (DERS) scale. Results: fMRI results showed the predicted Group x Time interaction: compared with HCs, BPD patients exhibited decreased amygdala activation with treatment. This post-treatment amygdala reduction in BPD was observed for all three pictures types, but particularly marked in the left hemisphere and during repeated-emotional pictures. Emotion regulation measured with the DERS significantly improved with DBT in BPD patients. Improved amygdala habituation to repeated-unpleasant pictures in patients was associated with improved overall emotional regulation measured by the DERS (total score and emotion regulation strategy use subscale). Conclusion: These findings have promising treatment implications and support the notion that DBT targets amygdala hyperactivity part of the disturbed neural circuitry underlying emotional dysregulation in BPD. Future work includes examining how DBT-induced amygdala changes interact with frontal-lobe regions implicated in emotion regulation. Published by Elsevier Ltd. C1 [Goodman, Marianne; Goldstein, Kim E.; New, Antonia S.; Triebwasser, Joseph; Siever, Larry J.; Hazlett, Erin A.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Goodman, Marianne; Avedon, Jennifer; Fernandez, Nicolas; Mascitelli, Kathryn A.; Blair, Nicholas J.; New, Antonia S.; Siever, Larry J.; Hazlett, Erin A.] James J Peters VA Med Ctr, VISN Mental Illness Res Educ & Clin Ctr MIRECC 3, Bronx, NY USA. [Carpenter, David; Tang, Cheuk Y.] Icahn Sch Med Mt Sinai, Dept Radiol, New York, NY 10029 USA. [Goodman, Marianne; Triebwasser, Joseph; Siever, Larry J.] James J Peters VA Med Ctr, Bronx, NY 10468 USA. RP Goodman, M (reprint author), James J Peters VA Med Ctr, MIRECC, Room 6A-44, Bronx, NY 10468 USA. EM marianne.goodman@va.gov FU Veterans' Administration Advanced Career Development Award [3277-06-109]; NIMH [R01-MH073911]; National Center for Advancing Translational Sciences, a component of the National Institutes of Health [UL1TR000067] FX This research was supported by a Veterans' Administration Advanced Career Development Award (3277-06-109) to MG, NIMH Grant R01-MH073911 to EAH, Grant UL1TR000067 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health, and additional resources from the Mount Sinai GCRC, VISN 3 Mental Illness Research, Education and Clinical Center (MIRECC), James J. Peters Research Foundation. NR 71 TC 25 Z9 26 U1 6 U2 45 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD OCT PY 2014 VL 57 BP 108 EP 116 DI 10.1016/j.jpsychires.2014.06.020 PG 9 WC Psychiatry SC Psychiatry GA AO7RK UT WOS:000341550100014 PM 25038629 ER PT J AU Greenberg, JL Reuman, L Hartmann, AS Kasarskis, I Wilhelm, S AF Greenberg, Jennifer L. Reuman, Lillian Hartmann, Andrea S. Kasarskis, Irina Wilhelm, Sabine TI Visual hot spots: An eye tracking study of attention bias in body dysmorphic disorder SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Body dysmorphic disorder; BDD; Eye tracking; Attention bias; Obsessive-compulsive spectrum ID OBSESSIVE-COMPULSIVE DISORDER; POPULATION-BASED SURVEY; PREVALENCE; SCALE; PHENOMENOLOGY; RELIABILITY; VALIDITY; THERAPY; AGE AB Attentional biases have been implicated in the development and maintenance of BDD. In particular, a visual attention bias toward one's unattractive features and others' attractive features (negative bias), might underlie BDD symptoms. Healthy individuals typically pay more attention to others' unattractive and their own attractive features (positive bias). This study used eye tracking to examine visual attention in individuals with BDD relative to healthy controls (HC). We also explored the role of avoidance in attention bias. Participants with BDD and primary face/head concerns (n = 19) and HC (n = 20) completed computerized tasks and questionnaires. Eye movement data (i.e., fixations, dwell time) were recorded while participants viewed images of their own and a control face (selected for average attractiveness and neutral expression). Participants rated distress and perceived most and least attractive features of their own and another face. BDD participants demonstrated a negative mean total bias score compared to HC (fixation: p = 0.24; dwell: p = 0.08). Age (fixation: p = 0.006; dwell: p = 0.03) and gender (fixation: p = 0.03; dwell: p = 0.03) moderated the relationship. Avoidance was associated with a positive bias in BDD. Results suggest individuals with BOO overfocus on negative attributes, a potential factor in the disorder's etiology and maintenance. Conversely, HC had a more balanced focus on their traits. Elucidating the role of attention bias could help to identify risk and maintenance factors in BDD. (C) 2014 Elsevier Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Greenberg, JL (reprint author), Massachusetts Gen Hosp, Simches Res Bldg,185 Cambridge St,Suite 2000, Boston, MA 02114 USA. EM jlgreenberg@mgh.harvard.edu FU International Obsessive Compulsive Disorder Foundation FX This research was supported in part by a grant from the International Obsessive Compulsive Disorder Foundation awarded to Dr. Greenberg. NR 36 TC 6 Z9 6 U1 2 U2 26 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD OCT PY 2014 VL 57 BP 125 EP 132 DI 10.1016/j.jpsychires.2014.06.015 PG 8 WC Psychiatry SC Psychiatry GA AO7RK UT WOS:000341550100016 PM 25005739 ER PT J AU Heidenreich, PA Zhao, X Hernandez, AF Yancy, CW Schwamm, LH Albert, NM Fonarow, GC AF Heidenreich, Paul A. Zhao, Xin Hernandez, Adrian F. Yancy, Clyde W. Schwamm, Lee H. Albert, Nancy M. Fonarow, Gregg C. TI Impact of an Expanded Hospital Recognition Program for Heart Failure Quality of Care SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE awards; healthcare quality assessment; healthcare quality indicators; heart failure ID ACUTE MYOCARDIAL-INFARCTION; NEW-YORK-STATE; GUIDELINES PROGRAM; CARDIAC-SURGERY; MORTALITY; HAD AB Background-In 2009, the Get With The Guidelines-Heart Failure program enhanced the standard recognition of hospitals by offering additional recognition if hospitals performed well on certain quality measures. We sought to determine whether initiation of this enhanced recognition opportunity led to acceleration in quality of care for all hospitals participating in the program. Methods and Results-We examined hospital-level performance on 9 quality-of-care (process) measures that were added to an existing recognition program (based on existing published performance measures). The rate of increase in use over time 6 months to 2 years after the start of the program was compared with the rate of increase in use for the measures during the 18-month period prior to the start of the program. Use increased for all 9 new quality measures from 2008 to 2011. Among 4 measures with baseline use near or lower than 50%, a statistically significant greater increase in use during the program was seen for implantable cardioverter defibrillator use (program versus preprogram use: odds ratio 1.14, 95% CI 1.06 to 1.23). Among the 5 measures for which baseline use was 50% or higher, the increase in influenza vaccination rates actually slowed. There was no evidence of adverse impact on the 4 established quality measures, a composite of which actually increased faster during the expanded program (adjusted odds ratio 1.08, 95% CI 1.01 to 1.15). Conclusions-A program providing expanded hospital recognition for heart failure had mixed results in accelerating the use of 9 quality measures. C1 [Heidenreich, Paul A.] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Zhao, Xin; Hernandez, Adrian F.] Duke Clin Res Inst, Durham, NC USA. [Yancy, Clyde W.] Northwestern Univ, NW Mem Hosp, Bluhm Cardiovasc Inst, Chicago, IL 60611 USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Albert, Nancy M.] Cleveland Clin, Cleveland, OH 44106 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Los Angeles, CA USA. RP Heidenreich, PA (reprint author), 111C Cardiol,3801 Miranda Ave, Palo Alto, CA 94306 USA. EM paul.heidenreich@va.gov FU Medtronic; GlaxoSmithKline; Ortho-McNeil; American Heart Association Pharmaceutical Roundtable; Veteran Administration's Quality Enhancement and Research Initiative [04-326] FX The Get With The Guidelines-Heart Failure (GWTG-HF) program is provided by the American Heart Association. GWTG-HF has been funded in the past through support from Medtronic, GlaxoSmithKline, Ortho-McNeil, and the American Heart Association Pharmaceutical Roundtable. Dr Heidenreich is supported by a grant from the Veteran Administration's Quality Enhancement and Research Initiative 04-326. NR 12 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD OCT PY 2014 VL 3 IS 5 AR e000950 DI 10.1161/JAHA.114.000950 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AP1VX UT WOS:000341861200005 PM 25208954 ER PT J AU Ho, JE Arora, P Walford, GA Ghorbani, A Guanaga, DP Dhakal, BP Nathan, DI Buys, ES Florez, JC Newton-Cheh, C Lewis, GD Wang, TJ AF Ho, Jennifer E. Arora, Pankaj Walford, Geoffrey A. Ghorbani, Anahita Guanaga, Derek P. Dhakal, Bishnu P. Nathan, Daniel I. Buys, Emmanuel S. Florez, Jose C. Newton-Cheh, Christopher Lewis, Gregory D. Wang, Thomas J. TI Effect of Phosphodiesterase Inhibition on Insulin Resistance in Obese Individuals SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE cGMP; insulin resistance; obesity; phosphodiesterase type 5 inhibition ID BETA-CELL FUNCTION; NITRIC-OXIDE SYNTHASE; SKELETAL-MUSCLE; AMBULATORY INDIVIDUALS; NATRIURETIC PEPTIDES; PLASMA-GLUCOSE; SENSITIVITY; RISK; HYPERTENSION; ASSOCIATION AB Background-Obesity is associated with cardiometabolic disease, including insulin resistance (IR) and diabetes. Cyclic guanosine monophosphate (cGMP) signaling affects energy balance, IR, and glucose metabolism in experimental models. We sought to examine effects of phosphodiesterase-5 inhibition with tadalafil on IR in a pilot study of obese nondiabetic individuals. Methods and Results-We conducted a randomized, double-blinded, placebo-controlled trial of adults age 18 to 50 years with obesity and elevated fasting insulin levels (>= 10 mu U/mL). Participants were randomized to tadalafil 20 mg daily or placebo for 3 months. Oral glucose tolerance tests were performed, and the effect of tadalafil on IR was examined. A total of 53 participants (mean age, 33 years; body mass index [BMI], 38 kg/m(2)) were analyzed, 25 randomized to tadalafil and 28 to placebo. In the overall sample, measures of IR did not differ between tadalafil and placebo groups at 3 months. However, in individuals with severe obesity (BMI >= 36.2 kg/m(2)), tadalafil use was associated with improved IR (homeostatic model assessment for IR), compared to placebo (P = 0.02, respectively). Furthermore, one measure of beta-cell compensation for IR (oral disposition index) improved with tadalafil in the overall sample (P = 0.009) and in the subgroup with severe obesity (P = 0.01). Conclusion-Results of this pilot study did not show improvements in IR with tadalafil, compared to placebo. However, tadalafil may have favorable effects on beta-cell compensation, particularly in individuals with severe obesity. Future studies evaluating the potential metabolic benefits of cGMP modulation in obesity are warranted. C1 [Ho, Jennifer E.] Boston Univ, Sch Med, Dept Med, Cardiovasc Med Sect, Boston, MA 02118 USA. [Arora, Pankaj] Univ Alabama Birmingham, Dept Med, Div Cardiol, Birmingham, AL 35294 USA. [Walford, Geoffrey A.; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Dhakal, Bishnu P.; Newton-Cheh, Christopher; Lewis, Gregory D.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Nathan, Daniel I.; Buys, Emmanuel S.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Ghorbani, Anahita] Mt Auburn Hosp, Dept Med, Cambridge, MA USA. [Guanaga, Derek P.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Newton-Cheh, Christopher] Broad Inst Harvard & MIT, Cambridge, MA USA. [Wang, Thomas J.] Vanderbilt Univ, Dept Med, Div Cardiovasc Med, Nashville, TN USA. RP Ho, JE (reprint author), Boston Univ, Med Ctr, 88 East Newton St,C-818, Boston, MA 02118 USA. EM Jennifer.Ho@bmc.org OI Ho, Jennifer/0000-0002-7987-4768; Arora, Pankaj/0000-0003-2420-3550 FU National Institutes of Health [K23-HL116780, R01-HL098283, R01-HL113933, R01-HL086875]; American Heart Association [10SDG2610313]; Boston University School of Medicine Department of Medicine Career Investment Award; Massachusetts General Hospital Research Scholars Award FX This study was supported, in part, by the National Institutes of Health (K23-HL116780 to Dr Ho; R01-HL098283 and R01-HL113933 to Dr Newton-Cheh; and R01-HL086875 to Dr Wang), the American Heart Association (10SDG2610313 to Dr Buys), a Boston University School of Medicine Department of Medicine Career Investment Award to Dr Ho, and a Massachusetts General Hospital Research Scholars Award to Dr Florez. NR 28 TC 4 Z9 4 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD OCT PY 2014 VL 3 IS 5 AR e001001 DI 10.1161/JAHA.114.001001 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AP1VX UT WOS:000341861200008 PM 25213566 ER PT J AU Sayadi, O Puppala, D Ishaque, N Doddamani, R Merchant, FM Barrett, C Singh, JP Heist, EK Mela, T Martinez, JP Laguna, P Armoundas, AA AF Sayadi, Omid Puppala, Dheeraj Ishaque, Nosheen Doddamani, Rajiv Merchant, Faisal M. Barrett, Conor Singh, Jagmeet P. Heist, E. Kevin Mela, Theofanie Pablo Martinez, Juan Laguna, Pablo Armoundas, Antonis A. TI A Novel Method to Capture the Onset of Dynamic Electrocardiographic Ischemic Changes and its Implications to Arrhythmia Susceptibility SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE ECG delineation; intracardiac signals; ischemic index; myocardial infarction; wavelet transform ID ACUTE MYOCARDIAL-ISCHEMIA; CORONARY-ARTERY OCCLUSION; FREQUENCY QRS COMPONENTS; SUB-ENDOCARDIAL ISCHEMIA; ST-SEGMENT DEVIATION; QT INTERVAL; INFARCTION; STANDARD; ECG; LEAD AB Background-This study investigates the hypothesis that morphologic analysis of intracardiac electrograms provides a sensitive approach to detect acute myocardial infarction or myocardial infarction-induced arrhythmia susceptibility. Large proportions of irreversible myocardial injury and fatal ventricular tachyarrhythmias occur in the first hour after coronary occlusion; therefore, early detection of acute myocardial infarction may improve clinical outcomes. Methods and Results-We developed a method that uses the wavelet transform to delineate electrocardiographic signals, and we have devised an index to quantify the ischemia-induced changes in these signals. We recorded body-surface and intracardiac electrograms at baseline and following myocardial infarction in 24 swine. Statistically significant ischemia-induced changes after the initiation of occlusion compared with baseline were detectable within 30 seconds in intracardiac left ventricle (P<0.0016) and right ventricle-coronary sinus (P<0.0011) leads, 60 seconds in coronary sinus leads (P<0.0002), 90 seconds in right ventricle leads (P<0.0020), and 360 seconds in body-surface electrocardiographic signals (P<0.0022). Intracardiac leads exhibited a higher probability of detecting ischemia-induced changes than body-surface leads (P<0.0381), and the right ventricle-coronary sinus configuration provided the highest sensitivity (96%). The 24-hour ECG recordings showed that the ischemic index is statistically significantly increased compared with baseline in lead I, aVR, and all precordial leads (P<0.0388). Finally, we showed that the ischemic index in intracardiac electrograms is significantly increased preceding ventricular tachyarrhythmic events (P<0.0360). Conclusions-We present a novel method that is capable of detecting ischemia-induced changes in intracardiac electrograms as early as 30 seconds following myocardial infarction or as early as 12 minutes preceding tachyarrhythmic events. C1 [Sayadi, Omid; Puppala, Dheeraj; Ishaque, Nosheen; Doddamani, Rajiv; Armoundas, Antonis A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Merchant, Faisal M.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. [Barrett, Conor; Singh, Jagmeet P.; Heist, E. Kevin; Mela, Theofanie] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Div Cardiol, Boston, MA 02114 USA. [Pablo Martinez, Juan; Laguna, Pablo] Univ Zaragoza, Biomed Signal Interpretat & Computat Simulat BSIC, Aragon Inst Engn Res, IIS Aragon, Zaragoza, Aragon, Spain. [Pablo Martinez, Juan; Laguna, Pablo] Ctr Invest Biomed Red Bioingn Biomat & Nanomed CI, Zaragoza, Aragon, Spain. RP Armoundas, AA (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. EM aarmoundas@partners.org RI Martinez, Juan Pablo/A-2759-2009; OI Martinez, Juan Pablo/0000-0002-7503-3339; laguna, Pablo/0000-0003-3434-9254 FU Scientist Development Grant [0635127N]; Founders Affiliate Postdoctoral Fellowship from the American Heart Association [12POST9310001]; Kenneth M. Rosen Fellowship in Cardiac Pacing and Electrophysiology from the Heart Rhythm Society [13-FA-32-HRS]; NIH [1R21AG035128]; Center for Integration of Medicine and Innovative Technology (CIMIT); Spanish government (MINECO); European Union (FEDER) [TEC2010-21703-C03-02, TEC2013-42140-R]; European Social Fund; Aragon government under Grupo Consolidado BSICoS; Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [8UL1TR000170-05]; Harvard University; Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Research Resources) FX This work was supported by a Scientist Development Grant (0635127N), a Founders Affiliate Postdoctoral Fellowship (12POST9310001) from the American Heart Association, the Kenneth M. Rosen Fellowship in Cardiac Pacing and Electrophysiology (13-FA-32-HRS) from the Heart Rhythm Society, and by NIH grant 1R21AG035128. This work was also supported by a Fellowship and a Science Award from the Center for Integration of Medicine and Innovative Technology (CIMIT), by the Spanish government (MINECO) and European Union (FEDER) under projects TEC2010-21703-C03-02 and TEC2013-42140-R and by the European Social Fund and the Aragon government under Grupo Consolidado BSICoS. This work was conducted with support from Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award 8UL1TR000170-05 and financial contributions from Harvard University and its affiliated academic health care centers). NR 33 TC 3 Z9 3 U1 1 U2 2 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 OCT PY 2014 VL 3 IS 5 AR e001055 DI 10.1161/JAHA.114.001055 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AP1VX UT WOS:000341861200013 PM 25187521 ER PT J AU Malkoski, SP Cleaver, TG Thompson, JJ Sutton, WP Haeger, SM Rodriguez, KJ Lu, SL Merrick, D Wang, XJ AF Malkoski, Stephen P. Cleaver, Timothy G. Thompson, Joshua J. Sutton, Whitney P. Haeger, Sarah M. Rodriguez, Karen J. Lu, Shi-Long Merrick, Daniel Wang, Xiao-Jing TI Role of PTEN in Basal Cell Derived Lung Carcinogenesis SO MOLECULAR CARCINOGENESIS LA English DT Article DE non-small cell lung cancer; adenocarcinoma; squamous cell carcinoma; Kras ID BRONCHIOALVEOLAR STEM-CELLS; TUMOR-SUPPRESSOR GENE; MOUSE MODEL; II RECEPTOR; CANCER; ADENOCARCINOMA; INACTIVATION; CARCINOMA; ORIGIN; MUTANT AB Lung adenocarcinoma (AdC) and lung squamous cell carcinoma (SCC) are the most common non-small cell lung cancer (NSCLC) subtypes, however, most genetic mouse models of lung cancer produce predominantly, if not exclusively, AdC. Whether this is secondary to targeting mutations to the distal airway cells or to the use of activating Kras mutations that drive AdC formation is unknown. We previously showed that targeting Kras(G12D) activation and transforming growth factor receptor type II (TGFRII) deletion to airway basal cells via a keratin promoter induced formation of both lung AdC and SCC. In this study we assessed if targeting phosphatase and tensin homologue (PTEN) deletion to airway basal cells could initiate lung tumor formation or increase lung SCC formation. We found that PTEN deletion is capable of initiating both lung AdC and SCC formation when targeted to basal cells and although PTEN deletion is a weaker tumor initiator than Kras(G12D) with low tumor multiplicity and long latency, tumors initiated by PTEN deletion were larger and displayed more malignant conversion than Kras(G12D) initiated tumors. That PTEN deletion did not increase lung SCC formation compared to Kras(G12D) activation, suggests that the initiating genetic event does not dictate tumor histology when genetic alterations are targeted to a specific cell. These studies also confirm that basal cells of the conducting airway are capable of giving rise to multiple NSCLC tumor types. (c) 2013 Wiley Periodicals, Inc. C1 [Malkoski, Stephen P.; Cleaver, Timothy G.; Thompson, Joshua J.; Sutton, Whitney P.; Haeger, Sarah M.; Rodriguez, Karen J.] Univ Colorado Denver, Div Pulm Sci & Crit Care Med, Aurora, CO USA. [Malkoski, Stephen P.; Wang, Xiao-Jing] Univ Colorado Denver, Dept Pathol, Aurora, CO USA. [Lu, Shi-Long; Wang, Xiao-Jing] Univ Colorado Denver, Dept Otolaryngol, Aurora, CO USA. [Merrick, Daniel] Denver VA Med Ctr, Dept Pathol, Denver, CO USA. RP Malkoski, SP (reprint author), Div Pulm Sci & Crit Care Med, 12700 E 19th Ave,RC2,Room 9112,Mail Stop C272, Aurora, CO 80045 USA. FU American Cancer Society Institutional Research Grant Pilot Project [57-001-50]; National Lung Cancer Partnership; NIH [K08 CA131483 DE015953 P30CA046934] FX Grant sponsor: American Cancer Society Institutional Research Grant Pilot Project; Grant number: IRG #57-001-50; Grant sponsor: National Lung Cancer Partnership and the NIH; Grant number: K08 CA131483 DE015953 P30CA046934 NR 37 TC 5 Z9 5 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD OCT PY 2014 VL 53 IS 10 BP 841 EP 846 DI 10.1002/mc.22030 PG 6 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA AP4QI UT WOS:000342062600008 PM 23625632 ER PT J AU Ren, X Ott, HC AF Ren, X. Ott, H. C. TI On the road to bioartificial organs SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Review DE Bioartificial organs; Decellularization; Bioprinting; Organoid; Tissue engineering; Organ engineering ID PLURIPOTENT STEM-CELLS; HUMAN LUNG; IN-VIVO; REGENERATIVE MEDICINE; ENDOTHELIAL-CELLS; SMALL-MOLECULE; BLOOD-VESSELS; ORTHOTOPIC TRANSPLANTATION; DIRECTED DIFFERENTIATION; PHENOTYPIC HETEROGENEITY AB Biological organs are highly orchestrated systems with well-coordinated positioning, grouping, and interaction of different cell types within their specialized extracellular environment. Bioartificial organs are intended to be functional replacements of native organs generated through bioengineering techniques and hold the potential to alleviate donor organ shortage for transplantation. The development, production, and evaluation of such bioartificial organs require synergistic efforts of biology, material science, engineering, and medicine. In this review, we highlight the emerging platforms enabling structured assembly of multiple cell types into functional grafts and discuss recent advances and challenges in the development of bioartificial organs, including cell sources, in vitro organ culture, in vivo evaluation, and clinical considerations. C1 [Ren, X.; Ott, H. C.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Ren, X.; Ott, H. C.] Harvard Univ, Sch Med, Boston, MA USA. [Ott, H. C.] Massachusetts Gen Hosp, Dept Surg, Div Thorac Surg, Boston, MA 02114 USA. [Ott, H. C.] Harvard Stem Cell Inst, Boston, MA USA. RP Ott, HC (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Thorac Surg, 185 Cambridge St,CPZN 4800, Boston, MA 02114 USA. EM hott@mgh.harvard.edu NR 95 TC 3 Z9 3 U1 5 U2 68 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0031-6768 EI 1432-2013 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD OCT PY 2014 VL 466 IS 10 BP 1847 EP 1857 DI 10.1007/s00424-014-1504-4 PG 11 WC Physiology SC Physiology GA AP2SH UT WOS:000341924500001 PM 24691559 ER PT J AU Zimmet, SE Min, RJ Comerota, AJ Meissner, MH Carman, TL Rathbun, SW Jaff, MR Wakefield, TW Feied, CF AF Zimmet, Steven E. Min, Robert J. Comerota, Anthony J. Meissner, Mark H. Carman, Teresa L. Rathbun, Suman W. Jaff, Michael R. Wakefield, Thomas W. Feied, Craig F. TI Core content for training in venous and lymphatic medicine SO PHLEBOLOGY LA English DT Article DE Curriculum; professional education; medical education; venous medicine; phlebology; lymphatic medicine; venous and lymphatic medicine training; fellowship training/standards; core content in venous and lymphatic medicine; specialization; clinical competence; certification AB The major venous societies in the United States share a common mission to improve the standards of medical practitioners, the educational goals for teaching and training programs in venous disease, and the quality of patient care related to the treatment of venous disorders. With these important goals in mind, a task force made up of experts from the specialties of dermatology, interventional radiology, phlebology, vascular medicine, and vascular surgery was formed to develop a consensus document describing the Core Content for venous and lymphatic medicine and to develop a core educational content outline for training. This outline describes the areas of knowledge considered essential for practice in the field, which encompasses the study, diagnosis, and treatment of patients with acute and chronic venous and lymphatic disorders. The American Venous Forum and the American College of Phlebology have endorsed the Core Content. C1 [Zimmet, Steven E.] Zimmet Vein & Dermatol, Austin, TX USA. [Min, Robert J.] Weill Cornell Med Coll, Dept Radiol, New York, NY USA. [Comerota, Anthony J.] Jobst Vasc Inst, Toledo, OH USA. [Meissner, Mark H.] Univ Washington, Sch Med, Dept Surg, Seattle, WA 98195 USA. [Carman, Teresa L.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Rathbun, Suman W.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Vasc Ctr, Boston, MA 02114 USA. [Wakefield, Thomas W.] Univ Michigan Hlth Syst, Vasc Surg Sect, Dept Surg, Ann Arbor, MI USA. [Feied, Craig F.] Georgetown Univ, Sch Med, Dept Emergency Med, Washington, DC USA. RP Zimmet, SE (reprint author), 1500 W 34 th St, Austin, TX 78703 USA. EM zimmet@drzimmet.com NR 0 TC 5 Z9 5 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0268-3555 EI 1758-1125 J9 PHLEBOLOGY JI Phlebology PD OCT PY 2014 VL 29 IS 9 BP 587 EP 593 DI 10.1177/0268355514545120 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA AP1HI UT WOS:000341818500003 PM 25059735 ER PT J AU Benson, G de Felipe, J Xiaodong Sano, M AF Benson, Gloria de Felipe, Jesus Xiaodong Sano, Mary TI Performance of Spanish-speaking community-dwelling elders in the United States on the Uniform Data Set SO ALZHEIMERS & DEMENTIA LA English DT Article DE Spanish speakers; Neuropsychological test; Normative performance; Elderly; Alzheimer's ID ALZHEIMERS-DISEASE CENTERS; NEUROPSYCHOLOGICAL ASSESSMENT; POPULATIONS; BATTERY; UDS AB Background: Spanish is the second-most common language spoken in the United States, and Spanish speakers represent one third of the aging population. The National Alzheimer's Coordinating Center's Uniform Data Set implemented a Spanish neuropsychological battery. Previous work described the neuropsychological performance for English speakers. Here we describe performance on the Spanish version. Methods: Data from 276 Spanish speakers with normal cognition were summarized, with descriptive tables of performance on individual cognitive tests. Regression techniques were used to evaluate the effect of demographics on cognitive performance. Results: Spanish speakers were younger (70.0 vs 74.0 years) and less educated (10.7 vs 15.7 years) with more females (76% vs 63% female) than the previously described English speakers. Higher education and lower age were associated with better performance. Conclusion: This national cohort of well-characterized Spanish-speaking elders provides descriptive data on cognitive performance, an important tool for clinical and research efforts. (C) 2014 The Alzheimer's Association. All rights reserved. C1 [Benson, Gloria; Xiaodong; Sano, Mary] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [de Felipe, Jesus] Fdn Jimenez Diaz Hosp, Dept Psychiat, Madrid, Spain. [de Felipe, Jesus] Univ Camilo Jose Cela, Villanueva De La Canada, Spain. [Xiaodong; Sano, Mary] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. RP Sano, M (reprint author), Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. EM mary.sano@mssm.edu FU National Institute on Aging; Fundacion de Conchita Rabago de Jimenez Diaz; [U01 AG016976]; [AG005138] FX This study is supported by the National Institute on Aging. The NACC database is funded by grant U01 AG016976 to The Mount Sinai School of Medicine Alzheimer's Disease Research Center, which is supported by grant AG005138. Jesus de Felipe was supported by the Fundacion de Conchita Rabago de Jimenez Diaz. NR 24 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 1552-5260 EI 1552-5279 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD OCT PY 2014 VL 10 IS 5 SU 1 BP S338 EP S343 DI 10.1016/j.jalz.2013.09.002 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA CZ0WW UT WOS:000366828100011 PM 24418057 ER PT J AU Fargo, KN Aisen, P Albert, M Au, R Corrada, MM DeKosky, S Drachman, D Fillit, H Gitlin, L Haas, M Herrup, K Kawas, C Khachaturian, AS Khachaturian, ZS Klunk, W Knopman, D Kukull, WA Lamb, B Logsdon, RG Maruff, P Mesulam, M Mobley, W Mohs, R Morgan, D Nixon, RA Paul, S Petersen, R Plassman, B Potter, W Reiman, E Reisberg, B Sano, M Schindler, R Schneider, LS Snyder, PJ Sperling, RA Yaffe, K Bain, LJ Thies, WH Carrillo, MC AF Fargo, Keith N. Aisen, Paul Albert, Marilyn Au, Rhoda Corrada, Maria M. DeKosky, Steven Drachman, David Fillit, Howard Gitlin, Laura Haas, Magali Herrup, Karl Kawas, Claudia Khachaturian, Ara S. Khachaturian, Zaven S. Klunk, William Knopman, David Kukull, Walter A. Lamb, Bruce Logsdon, Rebecca G. Maruff, Paul Mesulam, Marsel Mobley, William Mohs, Richard Morgan, David Nixon, Ralph A. Paul, Steven Petersen, Ronald Plassman, Brenda Potter, William Reiman, Eric Reisberg, Barry Sano, Mary Schindler, Rachel Schneider, Lon S. Snyder, Peter J. Sperling, Reisa A. Yaffe, Kristine Bain, Lisa J. Thies, William H. Carrillo, Maria C. CA Alzheimer's Assoc Natl Plan TI 2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease SO ALZHEIMERS & DEMENTIA LA English DT Editorial Material DE Policy; National Plan to Address Alzheimer's Disease; Milestones ID AFRICAN-AMERICANS; HYPOTHETICAL MODEL; DYNAMIC BIOMARKERS; DRUG-DEVELOPMENT; CLINICAL-TRIALS; DEMENTIA; RECRUITMENT; PREVALENCE; CHALLENGES; DIAGNOSIS AB With increasing numbers of people with Alzheimer's and other dementias across the globe, many countries have developed national plans to deal with the resulting challenges. In the United States, the National Alzheimer's Project Act, signed into law in 2011, required the creation of such a plan with annual updates thereafter. Pursuant to this, the US Department of Health and Human Services (HHS) released the National Plan to Address Alzheimer's Disease in 2012, including an ambitious research goal of preventing and effectively treating Alzheimer's disease by 2025. To guide investments, activities, and the measurement of progress toward achieving this 2025 goal, in its first annual plan update (2013) HHS also incorporated into the plan a set of short, medium and long-term milestones. HHS further committed to updating these milestones on an ongoing basis to account for progress and setbacks, and emerging opportunities and obstacles. To assist HHS as it updates these milestones, the Alzheimer's Association convened a National Plan Milestone Workgroup consisting of scientific experts representing all areas of Alzheimer's and dementia research. The workgroup evaluated each milestone and made recommendations to ensure that they collectively constitute an adequate work plan for reaching the goal of preventing and effectively treating Alzheimer's by 2025. This report presents these Workgroup recommendations. (C) 2014 The Alzheimer's Association. C1 [Fargo, Keith N.; Thies, William H.; Carrillo, Maria C.] Alzheimers Assoc, Div Med & Sci Relat, Chicago, IL 60631 USA. [Aisen, Paul; Mobley, William] Univ Calif San Diego, Sch Med, Dept Neurosci, San Diego, CA 92103 USA. [Albert, Marilyn] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Au, Rhoda] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Au, Rhoda] Boston Univ, Sch Med, Framingham Heart Study, Boston, MA 02118 USA. [Corrada, Maria M.] Univ Calif Irvine, Dept Neurol, Irvine, CA 92717 USA. [Corrada, Maria M.] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [DeKosky, Steven] Univ Virginia, Dept Neurol, Charlottesville, VA USA. [DeKosky, Steven] Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15260 USA. [DeKosky, Steven] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Drachman, David] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA. [Fillit, Howard] Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, Alzheimers Drug Discovery Fdn, New York, NY 10029 USA. [Fillit, Howard] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. Johns Hopkins Univ, Dept Community Publ Hlth, Baltimore, MD USA. [Gitlin, Laura] Johns Hopkins Univ, Dept Psychiat, Baltimore, MD USA. [Haas, Magali] Orion Bionetworks, Cambridge, MA USA. [Herrup, Karl] Hong Kong Univ Sci & Technol, Div Life Sci, Kowloon, Hong Kong, Peoples R China. [Herrup, Karl] Hong Kong Univ Sci & Technol, State Key Lab Mol Neurosci, Kowloon, Hong Kong, Peoples R China. [Kawas, Claudia] Univ Calif Irvine, Dept Neurobiol & Behav, Dept Neurol, Irvine, CA USA. [Kawas, Claudia] Univ Calif Irvine, Inst Memory Impairments & Neurol Disorders, Irvine, CA USA. [Khachaturian, Ara S.] Natl Biomed Res Eth Council, Rockville, MD USA. [Khachaturian, Zaven S.] PAD2020, Rockville, MD USA. [Klunk, William] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. [Knopman, David; Petersen, Ronald] Mayo Clin, Coll Med, Alzheimers Dis Res Ctr, Dept Neurol, Rochester, MN USA. [Kukull, Walter A.] Univ Washington, NACC, Seattle, WA 98195 USA. [Kukull, Walter A.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Lamb, Bruce] Cleveland Clin, Lerner Res Inst, Dept Neurosci, Cleveland, OH 44106 USA. [Logsdon, Rebecca G.] Univ Washington, Dept Psychosocial & Community Hlth, Seattle, WA 98195 USA. [Maruff, Paul] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Melbourne, Vic, Australia. [Maruff, Paul] CogState Ltd, Melbourne, Vic, Australia. [Mesulam, Marsel] Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA. [Mesulam, Marsel] Northwestern Univ, Feinberg Sch Med, Alzheimers Dis Ctr, Chicago, IL 60611 USA. [Mohs, Richard] Eli Lilly & Co, Neurosci Early Clin Dev, Indianapolis, IN 46285 USA. [Morgan, David] Univ S Florida, Byrd Alzheimers Inst, Tampa, FL USA. [Nixon, Ralph A.] NYU, Dept Psychiat, Langone Med Ctr, New York, NY 10016 USA. [Nixon, Ralph A.] NYU, Dept Cell Biol, Langone Med Ctr, New York, NY 10016 USA. [Nixon, Ralph A.] Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. [Paul, Steven] Fdn Natl Inst Hlth, Bethesda, MD USA. [Plassman, Brenda] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. [Potter, William] Fdn Natl Inst Hlth, Neuroscience Steering Comm Biomarkers Consortium, Phoenix, AZ USA. [Reiman, Eric] Univ Arizona, Coll Med, Banner Alzheimers Inst, Phoenix, AZ USA. [Reiman, Eric] Univ Arizona, Coll Med, Dept Psychiat, Phoenix, AZ USA. [Reisberg, Barry] NYU, Sch Med, Dept Psychiat, New York, NY USA. [Reisberg, Barry] NYU, Sch Med, Alzheimers Dis Res Ctr, New York, NY USA. [Schindler, Rachel] Pfizer Inc, New York, NY USA. [Schneider, Lon S.] Univ So Calif, Dept Psychiat & Behav Sci, Los Angeles, CA USA. [Schneider, Lon S.] Univ So Calif, Keck Sch Med, Dept Neurol, Los Angeles, CA 90033 USA. [Schneider, Lon S.] Univ So Calif, Leonard Davis Sch Gerontol, Los Angeles, CA USA. [Snyder, Peter J.] Brown Univ, Alpert Med Sch, Dept Neurol, Providence, RI 02912 USA. [Snyder, Peter J.] Rhode Isl Hosp, Dept Neurol, Providence, RI USA. [Sperling, Reisa A.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Sperling, Reisa A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. RP Carrillo, MC (reprint author), Alzheimers Assoc, Div Med & Sci Relat, Chicago, IL 60631 USA. EM mcarrillo@alz.org OI Reisberg, Barry/0000-0002-9104-7423; Kukull, Walter/0000-0001-8761-9014; corrada, maria/0000-0002-8168-8593; Maruff, Paul/0000-0002-6947-9537 NR 48 TC 14 Z9 14 U1 4 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 EI 1552-5279 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD OCT PY 2014 VL 10 IS 5 SU 1 BP S430 EP S452 DI 10.1016/j.jalz.2014.08.103 PG 23 WC Clinical Neurology SC Neurosciences & Neurology GA CZ0WW UT WOS:000366828100023 ER PT J AU Si, Y Cui, XQ Kim, S Wians, R Sorge, R Oh, SJ Kwan, T AlSharabati, M Lu, L Claussen, G Anderson, T Yu, SH Morgan, D Kazamel, M King, PH AF Si, Ying Cui, Xianqin Kim, Soojin Wians, Robert Sorge, Robert Oh, Shin J. Kwan, Thaddeus AlSharabati, Mohammad Lu, Liang Claussen, Gwen Anderson, Tina Yu, Shaohua Morgan, Dylan Kazamel, Mohamed King, Peter H. TI Smads as muscle biomarkers in amyotrophic lateral sclerosis SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article AB Objective: To identify molecular signatures in muscle from patients with amyotrophic lateral sclerosis (ALS) that could provide insight into the disease process and serve as biomarkers. Methods: RNA sequencing was performed on ALS and control muscle samples to identify Smad family members as potential markers of disease. Validation studies were performed in a cohort of 27 ALS patients and 33 controls. The markers were assessed in the G93A superoxide dismutase (SOD) 1 mouse at different stages of disease and in a model of sciatic nerve injury. Results: Smad8, and to a lesser extent Smad1 and 5, mRNAs were significantly elevated in human ALS muscle samples. The markers displayed a remarkably similar pattern in the G93A SOD1 mouse model of ALS with increases detected at preclinical stages. Expression at the RNA and protein levels as well as protein activation (phosphorylation) significantly increased with disease progression in the mouse. The markers were also elevated to a lesser degree in gastrocnemius muscle following sciatic nerve injury, but then reverted to baseline during the muscle reinnervation phase. Interpretation: These data indicate that Smad1, 5, 8 mRNA and protein levels, as well as Smad phosphorylation, are elevated in ALS muscle and could potentially serve as markers of disease progression or regression. C1 [Si, Ying; Kim, Soojin; Wians, Robert; Oh, Shin J.; Kwan, Thaddeus; AlSharabati, Mohammad; Lu, Liang; Claussen, Gwen; Anderson, Tina; Morgan, Dylan; Kazamel, Mohamed; King, Peter H.] Univ Alabama Birmingham, Dept Neurol, UAB Stn, Birmingham, AL 35294 USA. [Cui, Xianqin; Yu, Shaohua] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Sorge, Robert] Univ Alabama Birmingham, Dept Psychol, Birmingham, AL 35294 USA. [Oh, Shin J.; Lu, Liang; Kazamel, Mohamed] Birmingham VA Med Ctr, Birmingham, AL 35294 USA. [King, Peter H.] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA. [King, Peter H.] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL USA. RP King, PH (reprint author), Suite 260 Sparks Ctr,1720 2nd Ave S, Birmingham, AL 35294 USA. EM pking@uab.edu FU BLRD VA [I01 BX003035, I01 BX001148]; NINDS NIH HHS [K08 NS057664, R01 NS064133, P30 NS047466, R21 NS081743, R21 NS085497] NR 44 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD OCT PY 2014 VL 1 IS 10 BP 778 EP 787 DI 10.1002/acn3.117 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V45KN UT WOS:000209815600004 PM 25493269 ER PT J AU Horky, LL Gerbaudo, VH Zaitsev, A Plesniak, W Hainer, J Govindarajulu, U Kikinis, R Dietrich, J AF Horky, Laura L. Gerbaudo, Victor H. Zaitsev, Alexander Plesniak, Wen Hainer, Jon Govindarajulu, Usha Kikinis, Ron Dietrich, Jorg TI Systemic chemotherapy decreases brain glucose metabolism SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article AB Objective: Cancer patients may experience neurologic adverse effects, such as alterations in neurocognitive function, as a consequence of chemotherapy. The mechanisms underlying such neurotoxic syndromes remain poorly understood. We here describe the temporal and regional effects of systemically administered platinum-based chemotherapy on glucose metabolism in the brain of cancer patients. Methods: Using sequential FDG-PET/CT imaging prior to and after administration of chemotherapy, we retrospectively characterized the effects of intravenously administered chemotherapy on brain glucose metabolism in a total of 24 brain regions in a homogenous cohort of 10 patients with newly diagnosed non-small-cell lung cancer. Results: Significant alterations of glucose metabolism were found in response to chemotherapy in all gray matter structures, including cortical structures, deep nuclei, hippocampi, and cerebellum. Metabolic changes were also notable in frontotemporal white matter (WM) network systems, including the corpus callosum, subcortical, and periventricular WM tracts. Interpretation: Our data demonstrate a decrease in glucose metabolism in both gray and white matter structures associated with chemotherapy. Among the affected regions are those relevant to the maintenance of brain plasticity and global neurologic function. This study potentially offers novel insights into the spatial and temporal effects of systemic chemotherapy on brain metabolism in cancer patients. C1 [Horky, Laura L.; Gerbaudo, Victor H.; Zaitsev, Alexander; Plesniak, Wen; Hainer, Jon; Govindarajulu, Usha; Kikinis, Ron] Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, Div Nucl Med, 75 Francis St, Boston, MA 02115 USA. [Dietrich, Jorg] Massachusetts Gen Hosp, Ctr Canc, Dept Neurol, Div Neurooncol, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. [Dietrich, Jorg] Harvard Med Sch, Ctr Regenerat Med, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. RP Dietrich, J (reprint author), Harvard Med Sch, Dept Neurol, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. EM Dietrich.Jorg@mgh.harvard.edu FU NCI NIH HHS [K12 CA090354]; NCRR NIH HHS [P41 RR013218]; NIBIB NIH HHS [P41 EB015898, U54 EB005149, P41 EB015902] NR 45 TC 3 Z9 3 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD OCT PY 2014 VL 1 IS 10 BP 788 EP 798 DI 10.1002/acn3.121 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V45KN UT WOS:000209815600005 PM 25493270 ER PT J AU Zingone, A Wang, WX Corrigan-Cummins, M Wu, SP Plyler, R Korde, N Kwok, M Manasanch, EE Tageja, N Bhutani, M Mulquin, M Zuchlinski, D Yancey, MA Roschewski, M Zhang, Y Roccaro, AM Ghobrial, IM Calvo, KR Landgren, O AF Zingone, Adriana Wang, Weixin Corrigan-Cummins, Meghan Wu, S. Peter Plyler, Ryan Korde, Neha Kwok, Mary Manasanch, Elisabet E. Tageja, Nishant Bhutani, Manisha Mulquin, Marcia Zuchlinski, Diamond Yancey, Mary Ann Roschewski, Mark Zhang, Yong Roccaro, Aldo M. Ghobrial, Irene M. Calvo, Katherine R. Landgren, Ola TI Altered cytokine and chemokine profiles in multiple myeloma and its precursor disease SO CYTOKINE LA English DT Article DE Multiple myeloma; Chemokines; CXCL8 ID UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; PROGRESSION; CELLS; TRANSACTIVATION; MIGRATION; RECEPTOR; CANCER; RISK AB Currently, no reliable biomarkers are available to predict transformation from smoldering myeloma (SMM) to multiple myeloma (MM). Using an ultrasensitive enzyme-linked immunosorbent assay (ELISA) we assessed the levels of a broad range of cytokines and chemokines in the peripheral blood (PB) and bone marrow (BM) supernatant collected from 14 SMM and 38 MM patients and compared to healthy donors. We found significantly increased levels of key cytokines, in particular CXCL8 (IL-8), associated with progressive disease state (controls -> SMM -> MM). Cytokine profiles were found similar in PB and BM. Five of fourteen SMM patients (36%) progressed to MM. Our findings, although based on a limited number of patients, suggest that serum-based cytokines may have a future role as biomarkers for disease progression and could potentially be assessed as novel targets for treatment. Published by Elsevier Ltd. C1 [Zingone, Adriana; Wu, S. Peter; Korde, Neha; Kwok, Mary; Manasanch, Elisabet E.; Tageja, Nishant; Bhutani, Manisha; Mulquin, Marcia; Zuchlinski, Diamond; Yancey, Mary Ann; Roschewski, Mark; Landgren, Ola] NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. [Wang, Weixin; Corrigan-Cummins, Meghan; Plyler, Ryan; Calvo, Katherine R.] NIH, Hematol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Zhang, Yong; Roccaro, Aldo M.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Landgren, Ola] Mem Sloan Kettering Canc Ctr, Myeloma Serv, New York, NY 10065 USA. RP Landgren, O (reprint author), Mem Sloan Kettering Canc Ctr, Myeloma Serv, 1275 York Ave, New York, NY 10065 USA. EM landgrec@mskcc.org OI Roccaro, Aldo/0000-0002-1872-5128 FU Intramural NIH HHS [Z99 CA999999] NR 15 TC 3 Z9 3 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD OCT PY 2014 VL 69 IS 2 BP 294 EP 297 DI 10.1016/j.cyto.2014.05.017 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA AO6RB UT WOS:000341478100019 PM 25043675 ER PT J AU Ju, YS Futreal, CA Gerstung, M Martincorena, I Nik-Zainal, S Ramakrishna, M Davies, HR Papaemmanuil, E Gundem, G Shlien, A Bolli, N Behjati, S Tarpey, PS Nangalia, J Massie, CE Butler, AP Teague, JW Vassiliou, GS Green, AR Du, MQ Unnikrishnan, A Pimanda, JE Teh, BT Munshi, N Greaves, M Vyas, P El-Naggar, AK Santarius, T Collins, VP Grundy, R Taylor, JA Hayes, DN Malkin, D Foster, CS Warren, AY Whitaker, HC Brewer, D Eeles, R Cooper, C Neal, D Visakorpi, T Isaacs, WB Bova, GS Flanagan, AM Futreal, PA Lynch, AG Chinnery, PF McDermott, U Stratton, MR Campbell, PJ AF Ju, Young Seok Alexandrov, Ludmil B. Gerstung, Moritz Martincorena, Inigo Nik-Zainal, Serena Ramakrishna, Manasa Davies, Helen R. Papaemmanuil, Elli Gundem, Gunes Shlien, Adam Bolli, Niccolo Behjati, Sam Tarpey, Patrick S. Nangalia, Jyoti Massie, Charles E. Butler, Adam P. Teague, Jon W. Vassiliou, George S. Green, Anthony R. Du, Ming-Qing Unnikrishnan, Ashwin Pimanda, John E. Teh, Bin Tean Munshi, Nikhil Greaves, Mel Vyas, Paresh El-Naggar, Adel K. Santarius, Tom Collins, V. Peter Grundy, Richard Taylor, Jack A. Hayes, D. Neil Malkin, David Foster, Christopher S. Warren, Anne Y. Whitaker, Hayley C. Brewer, Daniel Eeles, Rosalind Cooper, Colin Neal, David Visakorpi, Tapio Isaacs, William B. Bova, G. Steven Flanagan, Adrienne M. Futreal, P. Andrew Lynch, Andy G. Chinnery, Patrick F. McDermott, Ultan Stratton, Michael R. Campbell, Peter J. CA ICGC Breast Canc Grp ICGC Chronic Myeloid Disorders Grp ICGC Prostate Canc Grp TI Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer SO ELIFE LA English DT Article ID 21 BREAST CANCERS; POPULATION-GENETICS; POLYMERASE-GAMMA; LAGGING-STRAND; HUMAN-DISEASE; STEM-CELLS; GENOME; HETEROPLASMY; REPLICATION; EVOLUTION AB Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mitochondrial DNA (mtDNA) are unclear. Here, we analysed somatic alterations in mtDNA from 1,675 tumors across 31 histologies. We identified 1,907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C>T and A>G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. Numbers of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria, and is fundamentally linked to mtDNA replication. C1 [Ju, Young Seok; Alexandrov, Ludmil B.; Gerstung, Moritz; Martincorena, Inigo; Nik-Zainal, Serena; Ramakrishna, Manasa; Davies, Helen R.; Papaemmanuil, Elli; Gundem, Gunes; Shlien, Adam; Bolli, Niccolo; Behjati, Sam; Tarpey, Patrick S.; Nangalia, Jyoti; Massie, Charles E.; Butler, Adam P.; Teague, Jon W.; Vassiliou, George S.; Futreal, P. Andrew; Stratton, Michael R.; ICGC Breast Canc Grp; ICGC Chronic Myeloid Disorders Grp] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England. [Nangalia, Jyoti; Massie, Charles E.; Vassiliou, George S.; Green, Anthony R.; Du, Ming-Qing; Santarius, Tom; Collins, V. Peter; Warren, Anne Y.; McDermott, Ultan; Campbell, Peter J.] Cambridge Univ Hosp NHS Trust, Cambridge, England. [Nangalia, Jyoti; Massie, Charles E.; Vassiliou, George S.; Green, Anthony R.; Campbell, Peter J.] Univ Cambridge, Dept Hematol, Cambridge, England. [Unnikrishnan, Ashwin; Pimanda, John E.] Univ New S Wales, Lowy Canc Res Ctr, Sydney, NSW, Australia. [Teh, Bin Tean] Natl Canc Ctr, Lab Canc Epigenome, Singapore, Singapore. [Teh, Bin Tean] Duke Nus Grad Med Sch, Singapore, Singapore. [Munshi, Nikhil] Dana Farber Canc Inst, Boston, MA 02115 USA. [Greaves, Mel; Brewer, Daniel; Eeles, Rosalind; Cooper, Colin] Inst Canc Res, Sutton, Surrey, England. [Vyas, Paresh] Univ Oxford, Weatherall Inst Mol Med, Oxford, England. [El-Naggar, Adel K.; Futreal, P. Andrew] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Grundy, Richard] Univ Nottingham, Childrens Brain Tumor Res Ctr, Nottingham NG7 2RD, England. [Taylor, Jack A.] NIH, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Hayes, D. Neil] Univ N Carolina, Chapel Hill, NC 27515 USA. [Malkin, David] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Whitaker, Hayley C.; Neal, David; ICGC Prostate Canc Grp] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge, England. [Foster, Christopher S.] Univ Liverpool, London, England. [Foster, Christopher S.] HCA Pathol Labs, London, England. [Brewer, Daniel; Cooper, Colin] Univ E Anglia, Norwich NR4 7TJ, Norfolk, England. [Visakorpi, Tapio; Bova, G. Steven] Univ Tampere, Inst Biomed Technol, FIN-33101 Tampere, Finland. [Visakorpi, Tapio; Bova, G. Steven] Univ Tampere, BioMediTech, FIN-33101 Tampere, Finland. [Isaacs, William B.] Johns Hopkins Univ, Baltimore, MD USA. [Flanagan, Adrienne M.] Royal Natl Orthopaed Hosp, Stanmore, Middx, England. [Flanagan, Adrienne M.] UCL, UCL Canc Inst, London, England. [Chinnery, Patrick F.] Univ Newcastle, Inst Med Genet, Wellcome Ctr Mitochondrial Res, Newcastle Upon Tyne, Tyne & Wear, England. RP Campbell, PJ (reprint author), Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England. EM pc8@sanger.ac.uk RI Ju, Young Seok/E-1324-2012; Bolli, Niccolo/D-4057-2011; OI taylor, jack/0000-0001-5303-6398; Ju, Young Seok/0000-0002-5514-4189; Bolli, Niccolo/0000-0002-1018-5139; Massie, Charlie/0000-0003-2314-4843; Ehinger, Anna/0000-0001-9225-7396; Gerstung, Moritz/0000-0001-6709-963X; Eeles, Rosalind/0000-0002-3698-6241; Vassiliou, George/0000-0003-4337-8022; Vyas, Paresh/0000-0003-3931-0914; McDermott, Ultan/0000-0001-9032-4700; Martin, Sancha/0000-0001-6213-5259; Unnikrishnan, Ashwin/0000-0001-5168-8755 FU Wellcome Trust; British Lung Foundation; Health Innovation Challenge Fund; Kay Kendall Leukaemia Fund; Chordoma Foundation; Adenoid Cystic Carcinoma Research Foundation; EMBO long-term fellowship [ALTF 1203-2012, ALTF 1287-2012]; National Institute for Health Research (NIHR) UCLH Biomedical Research Centre; Leukaemia Lymphoma Research; Cancer Research UK; Leukemia Lymphoma Society; European Union (BASIS); National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT) collaborative [G0500966/75466]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX Data used in this manuscript are described in the supplementary materials (Supplementary file 1). We thank Thomas Bleazard at Faculty of Medical and Human Sciences, University of Manchester for discussion and assistance with manuscript preparation. We would like to thank The Cancer Genome Atlas (TCGA) Project Team and their specimen donors for providing sequencing data. This work was supported by the Wellcome Trust, the British Lung Foundation, the Health Innovation Challenge Fund, the Kay Kendall Leukaemia Fund, the Chordoma Foundation and the Adenoid Cystic Carcinoma Research Foundation. Y.S.J and I.M. are supported by EMBO long-term fellowship (ALTF 1203-2012 and ALTF 1287-2012, respectively). P.J.C. is a Wellcome Trust Senior Clinical Fellow. Support was provided to A.M.F. by the National Institute for Health Research (NIHR) UCLH Biomedical Research Centre. A.R.G. receives support from Leukaemia Lymphoma Research, Cancer Research UK and the Leukemia Lymphoma Society. Samples from Addenbrooke's Hospital were collected with support from the NIHR Cambridge Biomedical Resource Centre. The ICGC Breast Cancer Consortium was supported by a grant from the European Union (BASIS) and the Wellcome Trust. The ICGC Prostate Cancer Consortium was funded by Cancer Research UK. We would also like to acknowledge the support of the National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT) collaborative (grant code G0500966/75466) which has funded tissue and urine collections in Cambridge. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (J.A.T.). We obtained informed consent and consent to publish from participants enrolled. NR 59 TC 45 Z9 45 U1 2 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD OCT 1 PY 2014 VL 3 AR e02935 DI 10.7554/eLife.02935 PG 53 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AR2JI UT WOS:000343409900003 ER PT J AU Khawaja, RDA Singh, S Madan, R Sharma, A Padole, A Pourjabbar, S Digumarthy, S Shepard, JA Kalra, MK AF Khawaja, Ranish Deedar Ali Singh, Sarabjeet Madan, Rachna Sharma, Amita Padole, Atul Pourjabbar, Sarvenaz Digumarthy, Subba Shepard, Jo-Anne Kalra, Mannudeep K. TI Ultra low-dose chest CT using filtered back projection: Comparison of 80-, 100- and 120 kVp protocols in a prospective randomized study SO EUROPEAN JOURNAL OF RADIOLOGY LA English DT Article DE Radiation dose reduction; Chest CT; Filtered back projection ID STATISTICAL ITERATIVE RECONSTRUCTION; COMPUTED-TOMOGRAPHY; IMAGE QUALITY; PULMONARY NODULES; REDUCTION; EXPERIENCE AB Purpose: To assess lesion detection and diagnostic image quality of filtered back projection (FBP) reconstruction technique in ultra low-dose chest CT examinations. Methods and materials: In this IRB-approved ongoing prospective clinical study, 116 CT-image-series at four different radiation-doses were performed for 29 patients (age, 57-87 years; F:M - 15:12; BMI 16-32 kg/m(2)). All patients provided written-informed-consent for the acquisitions of additional ultra low-dose (ULD) series on a 256-slice MDCT (iCT, Philips Healthcare). In-addition to their clinical standard-dose chest CT (SD, 120 kV mean CTDIvol, 6 +/- 1 mGy), ULD-CT was subsequently performed at three-dose-levels (0.9 mGy [120 kV]; 0.5 mGy [100 kV] and 0.2 mGy [80 kV[). Images were reconstructed with FBP (2.5 mm*1.25 mm) resulting into four-stacks: SD-FBP (reference-standard), FBP0.9, FBP0.5, and FBP0.2. Four thoracic-radiologists from two-teaching-hospitals independently-evaluated data for lesion-detection and visibility-of-small-structures. Friedman's-non-parametric-test with post hoc Dunn's-test was used for data-analysis. Results: Interobserver-agreement was substantial between radiologists (k = 0.6-0.8). With pooled analysis, 146-pulmonary (27-groundglass-opacities, 64-solid-lung-nodules, 7-consolidations, 27-emphysema) and 347-mediastinal/soft tissue lesions (87-mediastinal, 46-hilar, 62-axillary-lymphnodes, and 11-mediastinal-masses) were evaluated. Compared to the SD-FBP, 100% pulmonary-lesions were seen with FBP0.9, up to 81% with FBP0.5 (missed: 4), and up to 30% with FBP0.2 images (missed: 16). Compared to SD-FBP, all enlarged mediastinal-lymph-nodes were seen with FBP0.9 images. All mediastinal-masses (>2 cm, 11/11) were seen equivalent to SD-FBP images at 0.9 mGy. Across all sizes of patients, FBP0.9 images had optimal visualization for lung findings. They were optimal for mediastinal soft tissues for only non-obese patients. Conclusion: Filtered-back-projection technique allows optimal lesion detection and acceptable image quality for chest-CT examinations at CDTIvol of 0.9 mGy for lung and mediastinal findings in selected sizes of patients. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Khawaja, Ranish Deedar Ali; Singh, Sarabjeet; Sharma, Amita; Padole, Atul; Pourjabbar, Sarvenaz; Digumarthy, Subba; Shepard, Jo-Anne; Kalra, Mannudeep K.] Massachusetts Gen Hosp, Div Thorac Radiol, MGH Imaging, Boston, MA 02114 USA. [Khawaja, Ranish Deedar Ali; Singh, Sarabjeet; Madan, Rachna; Sharma, Amita; Padole, Atul; Pourjabbar, Sarvenaz; Digumarthy, Subba; Shepard, Jo-Anne; Kalra, Mannudeep K.] Harvard Univ, Sch Med, Boston, MA USA. [Madan, Rachna] Brigham & Womens Hosp, Div Thorac Radiol, Boston, MA 02115 USA. RP Khawaja, RDA (reprint author), 25 New Chardon St,4th Floor, Boston, MA 02114 USA. EM rkhawaja@mgh.harvard.edu OI Padole, Atul/0000-0002-3917-4871 FU Radiological Society of North America (RSNA); GE Healthcare; Philips Healthcare; Society of Thoracic Radiology; RSNA Educational Scholar Grant FX S.S. received research funding from the Radiological Society of North America (RSNA), GE Healthcare, Philips Healthcare, and the Society of Thoracic Radiology. M.K.K. has received RSNA Educational Scholar Grant. The remaining authors have no financial disclosures and had full control of study data during the study. NR 24 TC 8 Z9 8 U1 1 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0720-048X EI 1872-7727 J9 EUR J RADIOL JI Eur. J. Radiol. PD OCT PY 2014 VL 83 IS 10 BP 1934 EP 1944 DI 10.1016/j.ejrad.2014.06.024 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AO5WL UT WOS:000341417000034 PM 25063211 ER PT J AU Fava, M Gommoll, C Chen, C Greenberg, WM Ruth, A D'Souza, I Terner-Rosenthal, J AF Fava, M. Gommoll, C. Chen, C. Greenberg, W. M. Ruth, A. D'Souza, I. Terner-Rosenthal, J. TI The efficacy of levomilnacipran extended-release (ER) in the treatment of patients with depression-associated fatigue symptoms SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 27th Congress of the European-College-of-Neuropsychopharmacology (ECNP) CY OCT 18-21, 2014 CL Berlin, GERMANY SP European Coll Neuropsychopharmacol C1 [Fava, M.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Gommoll, C.; Chen, C.; Greenberg, W. M.; D'Souza, I.; Terner-Rosenthal, J.] Forest Res Inst, Jersey City, NJ USA. [Ruth, A.] Prescott Med Commun Grp, Chicago, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD OCT PY 2014 VL 24 SU 2 MA P.2.f.009 BP S456 EP S457 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CT5LL UT WOS:000362851700219 ER PT J AU Jeon, H Heo, JY Kim, JH Lim, BN Park, SJ Fava, M Mischoulon, D Kang, EH Roh, S Lee, D AF Jeon, H. Heo, J. Y. Kim, J. H. Lim, B. N. Park, S. J. Fava, M. Mischoulon, D. Kang, E. H. Roh, S. Lee, D. TI Sleep quality, posttraumatic stress, depression, and human errors in train drivers: a population-based nationwide study in South Korea SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 27th Congress of the European-College-of-Neuropsychopharmacology (ECNP) CY OCT 18-21, 2014 CL Berlin, GERMANY SP European Coll Neuropsychopharmacol C1 [Jeon, H.; Heo, J. Y.; Kim, J. H.; Lee, D.] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Psychiat, Seoul, South Korea. [Lim, B. N.; Park, S. J.] Seoul Natl Univ, Seoul, South Korea. [Fava, M.; Mischoulon, D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA USA. [Kang, E. H.] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea. [Roh, S.] Seoul Natl Hosp, Mental Hlth Res, Seoul, South Korea. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD OCT PY 2014 VL 24 SU 2 MA P.1.k.023 BP S354 EP S354 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CT5LL UT WOS:000362851700053 ER PT J AU Papakostas, G Dragheim, M Nielsen, RZ AF Papakostas, G. Dragheim, M. Nielsen, R. Z. TI Efficacy and tolerability of vortioxetine is independent of previous treatment in MDD patients switched after an inadequate response SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 27th Congress of the European-College-of-Neuropsychopharmacology (ECNP) CY OCT 18-21, 2014 CL Berlin, GERMANY SP European Coll Neuropsychopharmacol ID MAJOR DEPRESSIVE DISORDER; DOUBLE-BLIND; AGOMELATINE C1 [Papakostas, G.] Massachusetts Gen Hosp, Psychiat, Boston, MA 02114 USA. [Dragheim, M.] H Lundbeck & Co AS, Brintellix Sci Team, Copenhagen, Denmark. [Nielsen, R. Z.] H Lundbeck & Co AS, Brintellix Clin Sci, Copenhagen, Denmark. NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD OCT PY 2014 VL 24 SU 2 MA P.2.f.024 BP S466 EP S466 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CT5LL UT WOS:000362851700234 ER PT J AU Singh, J Fedgchin, M Daly, E De Boer, P Cooper, K Lim, P Pinter, C Murrough, J Sanacora, G Shelton, R Kurian, B Winokur, A Fava, M Manji, H Drevets, W Van Nueten, L AF Singh, J. Fedgchin, M. Daly, E. De Boer, P. Cooper, K. Lim, P. Pinter, C. Murrough, J. Sanacora, G. Shelton, R. Kurian, B. Winokur, A. Fava, M. Manji, H. Drevets, W. Van Nueten, L. TI Onset of efficacy of ketamine in treatment-resistant depression: a double-blind, randomised, placebo-controlled, dose frequency study SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 27th Congress of the European-College-of-Neuropsychopharmacology (ECNP) CY OCT 18-21, 2014 CL Berlin, GERMANY SP European Coll Neuropsychopharmacol C1 [Singh, J.; Fedgchin, M.; Daly, E.; Manji, H.; Drevets, W.] Janssen Res & Dev LLC, Neurosci, Titusville, NJ USA. [De Boer, P.; Van Nueten, L.] Janssen Res & Dev, Neurosci, Beerse, Belgium. [Cooper, K.] Janssen Res & Dev LLC, Clin Biostat, Spring House, PA USA. [Lim, P.] Janssen Res & Dev LLC, Clin Biostat, Titusville, NJ USA. [Pinter, C.] Janssen Res & Dev LLC, GTM, Titusville, NJ USA. [Murrough, J.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Sanacora, G.] Yale Univ, Sch Med, New Haven, CT USA. [Shelton, R.] Univ Alabama, Sch Med, Birmingham, W Midlands, England. [Kurian, B.] UT Southwestern Med Ctr, Dept Psychiat, Dallas, TX USA. [Winokur, A.] Inst Living, Psychiat, Hartford, CT USA. [Fava, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fava, M.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RI Murrough, James/J-7129-2013 OI Murrough, James/0000-0001-6286-1242 NR 1 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD OCT PY 2014 VL 24 SU 2 MA P.2.b.017 BP S387 EP S388 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CT5LL UT WOS:000362851700107 ER PT J AU Felker, GM Ahmad, T Anstrom, KJ Adams, KF Cooper, LS Ezekowitz, JA Fiuzat, M Houston-Miller, N Januzzi, JL Leifer, ES Mark, DB Desvigne-Nickens, P Paynter, G Pina, IL Whellan, DJ O'Connor, CM AF Felker, G. Michael Ahmad, Tariq Anstrom, Kevin J. Adams, Kirkwood F. Cooper, Lawton S. Ezekowitz, Justin A. Fiuzat, Mona Houston-Miller, Nancy Januzzi, James L. Leifer, Eric S. Mark, Daniel B. Desvigne-Nickens, Patrice Paynter, Gayle Pina, Ileana L. Whellan, David J. O'Connor, Christopher M. TI Rationale and Design of the GUIDE-IT Study Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure SO JACC-HEART FAILURE LA English DT Article DE biomarkers; clinical trial; heart failure ID BRAIN-NATRIURETIC PEPTIDE; RANDOMIZED CLINICAL-TRIALS; VAL-HEFT; SYSTOLIC DYSFUNCTION; DISEASE MANAGEMENT; PRIMARY-CARE; IMPROVE HF; BNP; CARDIOLOGY; MORTALITY AB OBJECTIVES The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) study is designed to determine the safety, efficacy, and cost-effectiveness of a strategy of adjusting therapy with the goal of achieving and maintaining a target N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of < 1,000 pg/ml compared with usual care in high-risk patients with systolic heart failure (HF). BACKGROUND Elevations in natriuretic peptide (NP) levels provide key prognostic information in patients with HF. Therapies proven to improve outcomes in patients with HF are generally associated with decreasing levels of NPs, and observational data show that decreases in NP levels over time are associated with favorable outcomes. Results from smaller prospective, randomized studies of this strategy thus far have been mixed, and current guidelines do not recommend serial measurement of NP levels to guide therapy in patients with HF. METHODS GUIDE-IT is a prospective, randomized, controlled, unblinded, multicenter clinical trial designed to randomize approximately 1,100 high-risk subjects with systolic HF (left ventricular ejection fraction <= 40%) to either usual care (optimized guideline-recommended therapy) or a strategy of adjusting therapy with the goal of achieving and maintaining a target NT-proBNP level of < 1,000 pg/ml. Patients in either arm of the study are followed up at regular intervals and after treatment adjustments for a minimum of 12 months. The primary endpoint of the study is time to cardiovascular death or first hospitalization for HF. Secondary endpoints include time to cardiovascular death and all-cause mortality, cumulative mortality, health-related quality of life, resource use, cost-effectiveness, and safety. CONCLUSIONS The GUIDE-IT study is designed to definitively assess the effects of an NP-guided strategy in high-risk patients with systolic HF on clinically relevant endpoints of mortality, hospitalization, quality of life, and medical resource use. (C) 2014 by the American College of Cardiology Foundation. C1 [Felker, G. Michael; Ahmad, Tariq; Fiuzat, Mona; Mark, Daniel B.; O'Connor, Christopher M.] Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. [Felker, G. Michael; Ahmad, Tariq; Anstrom, Kevin J.; Fiuzat, Mona; Mark, Daniel B.; Paynter, Gayle; O'Connor, Christopher M.] Duke Univ, Med Ctr, Div Cardiol, Duke Clin Res Inst, Durham, NC 27710 USA. [Adams, Kirkwood F.] Univ N Carolina, Div Cardiol, Chapel Hill, NC USA. [Cooper, Lawton S.; Leifer, Eric S.; Desvigne-Nickens, Patrice] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Ezekowitz, Justin A.] Univ Alberta, Div Cardiol, Edmonton, AB T6G 2M7, Canada. [Houston-Miller, Nancy] Stanford Univ, Div Cardiol, Palo Alto, CA 94304 USA. [Januzzi, James L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Pina, Ileana L.] Montefiore Einstein Med Ctr, Div Cardiol, Bronx, NY USA. [Whellan, David J.] Thomas Jefferson Univ, Div Cardiol, Philadelphia, PA 19107 USA. RP Felker, GM (reprint author), Duke Clin Res Inst, DUMC Box 3850, Durham, NC 27710 USA. EM michael.felker@duke.edu OI Mark, Daniel/0000-0001-6340-8087 FU National Heart Lung and Blood Institute [1R01HL105448-01A1, 1R01HL105451-01A1, 1R01HL105457-01A1]; Roche Diagnostics; BG Medicine; Critical Diagnostics; Daland Fellowship; National Institutes of Health; Alere Inc.; Siemens; Singulex; Thermo Fisher Scientific; Sphingotec; Amgen; Zensun; AstraZeneca; Gilead; Eli Lilly; Bristol-Myers Squibb; AGA Medical FX The GUIDE-IT study is funded by grants 1R01HL105448-01A1, 1R01HL105451-01A1, and 1R01HL105457-01A1 from the National Heart Lung and Blood Institute. Substudies for echocardiography as well as the GUIDE-IT biobank were funded by a grant from Roche Diagnostics. Dr. Felker has received research funding from Roche Diagnostics, BG Medicine, and Critical Diagnostics and has served as a consultant for Roche Diagnostics, Singulex, and HDL. Dr. Ahmad has received support from the Daland Fellowship in Clinical Investigation. Dr. Anstrom has served as a consultant for Abbott Vascular, AstraZeneca, Bristol-Myers Squibb, Gilead, Pfizer Inc., GlaxoSmithKline, Promedior, and Ikria; has served a member of data and safety monitoring boards for the National Institutes of Health, University of North Carolina, University of Miami, Forest Laboratories, Pfizer Inc., GlaxoSmithKline, and Vertex Pharmaceuticals; and is part owner of Biscardia, Inc. Dr. Adams has received research funding from Roche Diagnostics and Critical Diagnostics and has served as a consultant for Roche Diagnostics. Dr. Ezekowitz has received research funding from the National Institutes of Health and Alere Inc. Dr. Fiuzat has served as a consultant for Roche Diagnostics and has received research funding from Roche Diagnostics, BG Medicine, and Critical Diagnostics. Dr. Januzzi has served as a consultant for Critical Diagnostics and Novartis and has received research funding from Critical Diagnostics, Roche Diagnostics, Siemens, Singulex, Thermo Fisher Scientific, Sphingotec, Amgen, and Zensun. Dr. Mark has received grant funding from AstraZeneca, Gilead, Eli Lilly, Bristol-Myers Squibb, and AGA Medical; and has served as a consultant for Janssen, Medtronic, and Somahlution. Dr. O'Connor has served as a consultant for Roche Diagnostics and has received research funding from Roche Diagnostics, BG Medicine, and Critical Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. John R. Teerlink, MD, served as Guest Editor for this paper. NR 44 TC 26 Z9 26 U1 4 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD OCT PY 2014 VL 2 IS 5 BP 457 EP 465 DI 10.1016/j.jchf.2014.05.007 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CX4DK UT WOS:000365648500006 PM 25194287 ER PT J AU Ahmad, T Fiuzat, M Pencina, MJ Geller, NL Zannad, F Cleland, JGF Snider, JV Blankenberg, S Adams, KF Redberg, RF Kim, JB Mascette, A Mentz, RJ O'Connor, CM Felker, GM Januzzi, JL AF Ahmad, Tariq Fiuzat, Mona Pencina, Michael J. Geller, Nancy L. Zannad, Faiez Cleland, John G. F. Snider, James V. Blankenberg, Stephan Adams, Kirkwood F. Redberg, Rita F. Kim, Jae B. Mascette, Alice Mentz, Robert J. O'Connor, Christopher M. Felker, G. Michael Januzzi, James L. TI Charting a Roadmap for Heart Failure Biomarker Studies SO JACC-HEART FAILURE LA English DT Article DE biomarkers; heart failure; studies ID NATRIURETIC-PEPTIDE-MEASUREMENTS; BNP MEASUREMENTS USEFUL; DIAGNOSTIC-ACCURACY; PREDICTION MODELS; RANDOMIZED-TRIAL; RISK PREDICTION; THERAPY; RECLASSIFICATION; ROSUVASTATIN; MANAGEMENT AB Heart failure is a syndrome with a pathophysiological basis that can be traced to dysfunction in several interconnected molecular pathways. Identification of biomarkers of heart failure that allow measurement of the disease on a molecular level has resulted in enthusiasm for their use in prognostication and selection of appropriate therapies. However, despite considerable amounts of information available on numerous biomarkers, inconsistent research methodologies and lack of clinical correlations have made bench-to-bedside translations rare and left the literature with countless publications of varied quality. There is a need for a systematic and collaborative approach aimed at definitively studying the clinical benefits of novel biomarkers. In this review, on the basis of input from academia, industry, and governmental agencies, we propose a systematized approach based on adherence to specific quality measures for studies looking to augment current prediction model or use biomarkers to tailor therapeutics. We suggest that study quality, rather than results, should determine publication and propose a system for grading biomarker studies. We outline the need for collaboration between clinical investigators and statisticians to introduce more advanced statistical methodologies into the field of biomarkers that would allow for data from a large number of variables to be distilled into clinically actionable information. Lastly, we propose the creation of a heart failure biomarker consortium that would allow for a comprehensive list of biomarkers to be concomitantly analyzed in a pooled sample of randomized clinical trials and hypotheses to be generated for testing in biomarker-guided trials. Such a consortium could collaborate in sharing samples to identify biomarkers, undertake meta-analyses on completed trials, and spearhead clinical trials to test the clinical utility of new biomarkers. (C) 2014 by the American College of Cardiology Foundation. C1 [Ahmad, Tariq; Fiuzat, Mona; Pencina, Michael J.; Mentz, Robert J.; O'Connor, Christopher M.; Felker, G. Michael; Januzzi, James L.] Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. [Ahmad, Tariq; Fiuzat, Mona; O'Connor, Christopher M.; Felker, G. Michael] Duke Clin Res Inst, Durham, NC USA. [Geller, Nancy L.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Zannad, Faiez; Mascette, Alice] Nancy Univ, Nancy, France. [Cleland, John G. F.] Univ Hull, Kingston Upon Hull, Yorks, England. [Snider, James V.] Crit Diagnost, San Diego, CA USA. [Blankenberg, Stephan] Johannes Gutenberg Univ Mainz, D-55122 Mainz, Germany. [Adams, Kirkwood F.] Univ N Carolina, Div Cardiol, Chapel Hill, NC USA. [Redberg, Rita F.] UCSF, Div Cardiol, San Francisco, CA USA. [Kim, Jae B.] Amgen Inc, Thousand Oaks, CA USA. [Mascette, Alice] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Januzzi, James L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. EM jjanuzzi@partners.org OI Cleland, John/0000-0002-1471-7016 FU BG Medicine; Critical Diagnostics; Roche Diagnostics; Thermo Fisher; Singulex; Siemens AG FX Drs. Fiuzat and O'Connor have received research funding from BG Medicine, Critical Diagnostics, and Roche Diagnostics. Dr. Pencina served as a data safety and monitoring board member for DC Devices and the Cardiovascular Clinical Science Foundation; and served as a consultant for BioVentrix. Dr. Zannad has received research funding from BG Medicine and Roche Diagnostics; and served as a consultant for BG Medicine. Dr. Cleland has received research funding from Roche Diagnostics. Dr. Snider is an employee of Critical Diagnostics. Dr. Kim is an employee of Amgen. Dr. Mentz has received honoraria from Bristol-Myers Squibb and Novartis. Dr. Felker has received research funding from BG Medicine, Critical Diagnostics, and Roche Diagnostics; and has served as a consultant for BG Medicine and Roche Diagnostics. Dr. Januzzi has served as an advisor or consultant for Critical Diagnostics; and has received research funding from Critical Diagnostics, Roche Diagnostics, BG Medicine, Thermo Fisher, Singulex, and Siemens AG. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. John R. Teerlink, MD, served as Guest Editor for this article. NR 50 TC 29 Z9 29 U1 3 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD OCT PY 2014 VL 2 IS 5 BP 477 EP 488 DI 10.1016/j.jchf.2014.02.005 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CX4DK UT WOS:000365648500009 PM 24929535 ER PT J AU Zile, MR Gaasch, WH Patel, K Aban, IB Ahmed, A AF Zile, Michael R. Gaasch, William H. Patel, Kanan Aban, Inmaculada B. Ahmed, Ali TI Adverse Left Ventricular Remodeling in Community-Dwelling Older Adults Predicts Incident Heart Failure and Mortality SO JACC-HEART FAILURE LA English DT Article DE heart failure; left ventricle; structural remodeling ID ESSENTIAL-HYPERTENSION; MYOCARDIAL-INFARCTION; EJECTION FRACTION; PRESSURE-OVERLOAD; AORTIC-STENOSIS; WALL STRESS; HYPERTROPHY; GEOMETRY; MASS; PATTERNS AB OBJECTIVES This study sought to determine whether specific patterns of adverse left ventricular (LV) structural remodeling are associated with differential rates of cardiovascular (CV) outcomes. BACKGROUND It is not known whether a stepwise combinatorial assessment of LV volume, mass, and geometry done to define specific remodeling patterns provides incremental prognostic information. METHODS A total of 3,181 Cardiovascular Health Study participants (mean age, 73 years of age; 60% women, 5% African American) were categorized by LV remodeling patterns and related to a multivariate-adjusted (age, sex, race, ejection fraction, hypertension, myocardial infarction, diabetes mellitus, chronic kidney disease) analysis of CV outcomes (incident heart failure [HF], all-cause mortality, and a combined endpoint of HF and mortality) over a 13-year follow-up period. RESULTS Examined independently, either left ventricular enlargement (LVE) or left ventricular hypertrophy (LVH) was associated with a higher risk of HF (32%, 34%, respectively) than with normal geometry (17%; p < 0.001). When LV volume and mass were used in combination, important incremental prognostic information was achieved. In the absence of LVE, HF was more common in those with LVH than in those with normal mass (32% vs. 16%, respectively; p < 0.001). In the presence of LVE, HF was more common in those with LVH than in those with normal mass (37% vs. 29%, respectively; p = 0.021). The subgroup with normal volume and mass but relative wall thickness (RWT) >0.42 carried a higher risk of HF (21%) than those with normal geometry (15%; p = 0.011). Once LVH or LVE was present, the addition of RWT to this analysis did not affect HF rate. Similar results were obtained for the other CV outcomes. CONCLUSIONS Stepwise combinatorial assessment of LV volume, mass, and geometry provides incremental prognostic information regarding CV outcomes. (C) 2014 by the American College of Cardiology Foundation. C1 [Zile, Michael R.] Med Univ S Carolina, Charleston, SC 29425 USA. [Zile, Michael R.] Vet Affairs Med Ctr, Ralph H Johnson Dept, Charleston, SC 29403 USA. [Gaasch, William H.] Lahey Clin Med Ctr, Burlington, MA 01803 USA. [Patel, Kanan; Aban, Inmaculada B.; Ahmed, Ali] Univ Alabama Birmingham, Birmingham, AL USA. [Ahmed, Ali] Dept Vet Affairs Med Ctr, Birmingham, AL USA. RP Zile, MR (reprint author), Med Univ S Carolina, Dept Med, Div Cardiol, Ashley River Towers,Room 7067,25 Courtenay Dr, Charleston, SC 29425 USA. EM zilem@musc.edu FU Research Service of the Department of Veterans Affairs [5101CX000415-02, 5101BX000487-04]; National Institutes of Health from the National Heart, Lung, and Blood Institute [R01-HL097047] FX Dr. Zile is supported by the Research Service of the Department of Veterans Affairs (5101CX000415-02 and 5101BX000487-04). Dr. Ahmed is supported by National Institutes of Health R01-HL097047 from the National Heart, Lung, and Blood Institute and a generous gift from Ms. Jean B. Morris of Birmingham, Alabama. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 28 TC 21 Z9 22 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD OCT PY 2014 VL 2 IS 5 BP 512 EP 522 DI 10.1016/j.jchf.2014.03.016 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CX4DK UT WOS:000365648500013 PM 25194295 ER PT J AU Jha, MK Minhajuddin, A Thase, ME Jarrett, RB AF Jha, Manish Kumar Minhajuddin, Abu Thase, Michael E. Jarrett, Robin B. TI Improvement in self-reported quality of life with cognitive therapy for recurrent major depressive disorder SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Quality of life; Major depressive disorder; Cognitive therapy ID NATIONAL-EPIDEMIOLOGIC-SURVEY; LONG-TERM COURSE; REPORT QIDS-SR; PSYCHOMETRIC PROPERTIES; DOUBLE-BLIND; SATISFACTION QUESTIONNAIRE; PSYCHOSOCIAL DISABILITY; CLINICAL-SIGNIFICANCE; RANDOMIZED-TRIAL; QUICK INVENTORY AB Background: Major depressive disorder (MDD) is common, often recurrent and/or chronic. Theoretically, assessing quality of life (QoL) in addition to the current practice of assessing depressive symptoms has the potential to offer a more comprehensive evaluation of the effects of treatment interventions and course of illness. Methods: Before and after acute-phase cognitive therapy (CT), 492 patients from Continuation Phase Cognitive Therapy Relapse Prevention trial (Jarrett et al., 2013; Jarrett and Thase, 2010) completed the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), Inventory of Depressive Symptomatology Self-report (IDS-SR) and Beck Depression Inventory (BDI); clinicians completed Hamilton Rating Scale for Depression-17-items. Repeated measures analysis of variance evaluated the improvement in QoL before/after CT and measured the effect sizes. Change analyses to assess clinical significance (Hageman and Arrindell, 1999) were conducted. Results: At the end of acute-phase Cr, a repeated measure analysis of variance produced a statistically significant increase in Q-LES-Q scores with effect sizes of 0.48-13%; 76.9-91.4% patients reported clinically significant improvement. Yet, only 11-38.2% QoL scores normalized. An analysis of covariance showed that change in depression severity (covariates=IDS-SR, BDI) completely accounted for the improvement in Q-LES-Q scores. Limitations: There were only two time points of observation; clinically significant change analyses lacked matched normal controls; and generalizability is constrained by sampling characteristics. Conclusions: Quality of life improves significantly in patients with recurrent MDD after CT; however, this improvement is completely accounted for by change in depression severity. Normalization of QoL in all patients may require targeted, additional, and/or longer treatment. (C) 2014 Elsevier B.V. All rights reserved. C1 [Jha, Manish Kumar; Jarrett, Robin B.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Thase, Michael E.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Thase, Michael E.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Thase, Michael E.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15260 USA. [Minhajuddin, Abu] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. RP Jha, MK (reprint author), Univ Texas SW Med Ctr Dallas, Dept Psychiat, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM manishjha2201@yahoo.com; Robin.Jarrett@UTSouthwestern.edu FU National Institute of Mental Health [K24MH001571, R01MH058397, R01MH069619, R01MH058356, R01MH069618] FX This report was supported by Grants Nos. K24MH001571, R01MH058397, and R01MH069619 (to Robin B. Jarrett, Ph.D.) and R01MH058356 and R01MH069618 (to Michael E. Thase, M.D.) from the National Institute of Mental Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health (NIMH) or the National Institutes of Health (NIH). NR 61 TC 4 Z9 4 U1 1 U2 5 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 OCT 1 PY 2014 VL 167 BP 37 EP 43 DI 10.1016/j.jad.2014.05.038 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AO4UA UT WOS:000341335700007 PM 25082112 ER PT J AU Tondo, L Visioli, C Preti, A Baldessarini, RJ AF Tondo, Leonardo Visioli, Caterina Preti, Antonio Baldessarini, Ross J. TI Bipolar disorders following initial depression: Modeling predictive clinical factors SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder; Depressive onset; Diagnosis; Major depression; Prediction ID UNIPOLAR DEPRESSION; DIAGNOSIS; ILLNESS; EPISODE; ADOLESCENTS; COMORBIDITY; TRANSITION; ALCOHOL; DEFICIT; BRIDGE AB Objective: Most first lifetime episodes among persons eventually diagnosed with bipolar disorder are depressive, often with years of delay to a final differentiation from unipolar major depression. To support early differentiation, we tested several predictive factors for association with later diagnoses of bipolar disorder. Method: With data from mood-disorder patients with first-lifetime episodes of major depression, we used multivariate, logistic modeling and Bayesian methods including Receiver Operating Characteristic curves to evaluate ability of one or more selected factors to differentiate patients who later met DSM-IV-TR diagnostic criteria for bipolar disorder and not unipolar major depressive disorder. Results: We analyzed data from 2146 patients (642 bipolar, 1504 unipolar) at risk for 13 years following initial depressive episodes. In multivariate modeling for 812 subjects with information on all clinical factors considered, seven significantly and independently differentiated bipolar from unipolar disorders, ranking (by significance): (a) >= 4 previous depressive episodes, (b) suicidal acts, (c) cyclothymic temperament, (d) family history of bipolar disorder, (e) substance-abuse, (f) younger-at-onset, or onset-age <25, and (g) male sex; four of these (c, d, f, g) can be identified at illness-onset. Bayesian analysis indicated optimal sensitivity and specificity at 2-4 factors/person and correct classification of 64-67% of cases, and ROC analysis of factors/person yielded a significant area-under-the-curve of 0.72 [CI: 0.68-0.75]. Conclusions: In multivariate modeling, 7 factors were significantly and independently associated with bipolar disorder diagnosed up to 13 years after initial depression. (C) 2014 Elsevier B.V. All rights reserved. C1 [Tondo, Leonardo; Baldessarini, Ross J.] Massachusetts Gen Hosp, Int Consortium Bipolar Disorder Res, Mailman Res Ctr, McLean Div, Boston, MA 02114 USA. [Tondo, Leonardo; Visioli, Caterina; Preti, Antonio] Ctr Lucia Bini Mood Disorders Ctr, Cagliari, Italy. [Tondo, Leonardo; Visioli, Caterina; Preti, Antonio] Ctr Lucia Bini Mood Disorders Ctr, Rome, Italy. [Baldessarini, Ross J.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Tondo, L (reprint author), McLean Hosp, Mailman Res Ctr 212, 115 Mill St, Belmont, MA 02478 USA. EM ltondo@mclean.harvard.edu FU Aretaeus Research Fund; Stanley Medical Research Institute; Sardinia Regional Master-and-Back Fellowship; Bruce J. Anderson Foundation; McLean Private Donors Psychopharmacology Research Fund FX Supported in part by the Aretaeus Research Fund and Stanley Medical Research Institute (to LT), by a Sardinia Regional Master-and-Back Fellowship (to CV), a grant from the Bruce J. Anderson Foundation and by the McLean Private Donors Psychopharmacology Research Fund (to RJB). The funding sources had no role in the analysis of data or preparation of this report. NR 40 TC 13 Z9 14 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 OCT 1 PY 2014 VL 167 BP 44 EP 49 DI 10.1016/j.jad.2014.05.043 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AO4UA UT WOS:000341335700008 PM 25082113 ER PT J AU Bobo, WV Reilly-Harrington, NA Ketter, TA Brody, BD Kinrys, G Kemp, DE Shelton, RC McElroy, SL Sylvia, LG Kocsis, JH McInnis, MG Friedman, ES Singh, V Tohen, M Bowden, CL Deckersbach, T Calabrese, JR Thase, ME Nierenberg, AA Rabideau, DJ Schoenfeld, DA Faraone, SV Kamali, M AF Bobo, William V. Reilly-Harrington, Noreen A. Ketter, Terence A. Brody, Benjamin D. Kinrys, Gustavo Kemp, David E. Shelton, Richard C. McElroy, Susan L. Sylvia, Louisa G. Kocsis, James H. McInnis, Melvin G. Friedman, Edward S. Singh, Vivek Tohen, Mauricio Bowden, Charles L. Deckersbach, Thilo Calabrese, Joseph R. Thase, Michael E. Nierenberg, Andrew A. Rabideau, Dustin J. Schoenfeld, David A. Faraone, Stephen V. Kamali, Masoud TI Effect of adjunctive benzodiazepines on clinical outcomes in lithium- or quetiapine-treated outpatients with bipolar I or II disorder: Results from the bipolar CHOICE trial (vol 161, pg 30, 2014) SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Correction C1 [Bobo, William V.] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN 55905 USA. [Reilly-Harrington, Noreen A.; Kinrys, Gustavo; Sylvia, Louisa G.; Deckersbach, Thilo; Nierenberg, Andrew A.; Rabideau, Dustin J.; Schoenfeld, David A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ketter, Terence A.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Brody, Benjamin D.; Kocsis, James H.] Cornell Univ, Weill Cornell Med Coll, New York, NY 10021 USA. [Kemp, David E.; Calabrese, Joseph R.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Shelton, Richard C.] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [McElroy, Susan L.] Univ Cincinnati, Coll Med, Lindner Ctr HOPE, Cincinnati, OH USA. [McInnis, Melvin G.; Kamali, Masoud] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Friedman, Edward S.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Singh, Vivek; Bowden, Charles L.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Tohen, Mauricio] Univ New Mexico, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Thase, Michael E.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Syracuse, NY USA. RP Bobo, WV (reprint author), Mayo Clin, Dept Psychiat & Psychol, Rochester, MN 55905 USA. EM Bobo.William@mayo.edu NR 1 TC 0 Z9 0 U1 0 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 OCT 1 PY 2014 VL 167 BP 259 EP 260 DI 10.1016/j.jad.2014.06.025 PG 2 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AO4UA UT WOS:000341335700040 ER PT J AU Lu, Y Goti, V Chaturvedula, A Haberer, JE Fossler, MJ Sale, ME Bangsberg, D Baeten, J Celum, C Hendrix, CW AF Lu, Y. Goti, V. Chaturvedula, A. Haberer, J. E. Fossler, M. J. Sale, M. E. Bangsberg, D. Baeten, J. Celum, C. Hendrix, C. W. TI Population Pharmacokinetics of Tenofovir in HIV-1 Uninfected Members of Sero-discordant Couples and Effect of Dose Reporting Methods: An Analysis from the Partners PrEP Study SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Lu, Y.; Hendrix, C. W.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Goti, V.; Chaturvedula, A.] Mercer Univ, Macon, GA 31207 USA. [Haberer, J. E.; Bangsberg, D.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Fossler, M. J.] GlaxoSmithKline, King Of Prussia, PA USA. [Sale, M. E.] Next Level Solut Inc, Fresno, CA USA. [Baeten, J.; Celum, C.] Univ Washington, Seattle, WA 98195 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2014 VL 41 SU 1 MA W-003 BP S72 EP S72 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA V45QB UT WOS:000209830000150 ER PT J AU Madrasi, K Chaturvedula, A Haberer, J Sale, M Fossler, M Bangsberg, D Baeten, J Celum, C Hendrix, C AF Madrasi, Kumpal Chaturvedula, Ayyappa Haberer, Jessica Sale, Mark Fossler, Michael Bangsberg, David Baeten, Jared Celum, Connie Hendrix, Craig TI Markov Mixed Effects Modeling of Adherence using MEMS (R) Dosing Records from Partner's PrEP Ancillary Adherence Substudy SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Meeting Abstract C1 [Madrasi, Kumpal; Chaturvedula, Ayyappa] Mercer Univ, Macon, GA 31207 USA. [Haberer, Jessica; Bangsberg, David] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Hendrix, Craig] Johns Hopkins Univ, Baltimore, MD USA. [Sale, Mark] Next Level Solut LLC, Seattle, WA USA. [Fossler, Michael] GlaxoSmithKline, Seattle, WA USA. [Baeten, Jared; Celum, Connie] Univ Washington, Seattle, WA 98195 USA. NR 2 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X EI 1573-8744 J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2014 VL 41 SU 1 MA M-032 BP S21 EP S21 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA V45QB UT WOS:000209830000033 ER PT J AU Rasmussen, TA Tolstrup, M Brinkmann, CR Olesen, R Erikstrup, C Solomon, A Winckelmann, A Palmer, S Dinarello, C Buzon, M Lichterfeld, M Lewin, SR Ostergaard, L Sogaard, OS AF Rasmussen, Thomas A. Tolstrup, Martin Brinkmann, Christel R. Olesen, Rikke Erikstrup, Christian Solomon, Ajantha Winckelmann, Anni Palmer, Sarah Dinarello, Charles Buzon, Maria Lichterfeld, Mathias Lewin, Sharon R. Ostergaard, Lars Sogaard, Ole S. TI Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial SO LANCET HIV LA English DT Article ID T-CELLS; REPLICATION; RESERVOIR; VORINOSTAT; ACTIVATION; EXPRESSION; ACID; VIVO AB Background Activating the expression of latent virus is an approach that might form part of an HIV cure. We assessed the ability of the histone deacetylase inhibitor panobinostat to disrupt HIV-1 latency and the safety of this strategy. Methods In this phase 1/2 clinical trial, we included aviraemic adults with HIV treated at Aarhus University Hospital, Denmark. Participants received oral panobinostat (20 mg) three times per week every other week for 8 weeks while maintaining combination antiretroviral therapy. The primary outcome was change from baseline of cell-associated unspliced HIV RNA. Secondary endpoints were safety, plasma HIV RNA, total and integrated HIV DNA, infectious units per million CD4 T cells, and time to viral rebound during an optional analytical treatment interruption of antiretroviral therapy. This trial is registered with ClinicalTrial.gov, number NCT01680094. Findings We enrolled 15 patients. The level of cell-associated unspliced HIV RNA increased significantly at all timepoints when patients were taking panobinostat (p<0.0001). The median maximum increase in cell-associated unspliced HIV RNA during panobinostat treatment was 3.5-fold (range 2.1-14.4). Panobinostat induced plasma viraemia with an odds ratio of 10.5 (95% CI2.2-50.3; p=0.0002) compared with baseline. We recorded a transient decrease in total HIV DNA, but no cohort-wide reduction in total HIV DNA, integrated HIV DNA, or infectious units per million. Nine patients participated in the analytical treatment interruption, median time to viral rebound was 17 days (range 14-56). Panobinostat was well tolerated. 45 adverse events were reported, but only 16 (all grade 1) were presumed related to panobinostat. Interpretation Panobinostat effectively disrupts HIV latency in vivo and is a promising candidate for future combination clinical trials aimed at HIV eradication. However, panobinostat did not reduce the number of latently infected cells and this approach may need to be combined with others to significantly affect the latent HIV reservoir. C1 [Rasmussen, Thomas A.; Tolstrup, Martin; Brinkmann, Christel R.; Olesen, Rikke; Winckelmann, Anni; Ostergaard, Lars; Sogaard, Ole S.] Aarhus Univ Hosp, Dept Infect Dis, DK-8220 Aarhus N, Denmark. [Erikstrup, Christian] Aarhus Univ Hosp, Dept Clin Immunol, DK-8220 Aarhus N, Denmark. [Solomon, Ajantha; Lewin, Sharon R.] Alfred Hosp, Dept Infect Dis, Melbourne, Vic, Australia. [Solomon, Ajantha; Lewin, Sharon R.] Monash Univ, Melbourne, Vic 3004, Australia. [Palmer, Sarah] Univ Sydney, Westmead Millennium Inst Med Res, Westmead, NSW 2145, Australia. [Dinarello, Charles] Univ Colorado Denver, Dept Med, Div Infect Dis, Aurora, CO USA. [Buzon, Maria; Lichterfeld, Mathias] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Buzon, Maria; Lichterfeld, Mathias] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Lewin, Sharon R.] Burnet Inst, Ctr Biomed Res, Melbourne, Vic, Australia. RP Rasmussen, TA (reprint author), Aarhus Univ Hosp, Dept Infect Dis, Brendstrupgaardsvej 100, DK-8220 Aarhus N, Denmark. EM thomrasm@rm.dk RI Sogaard, Ole/P-6058-2016; OI Rasmussen, Thomas Aagaard/0000-0001-5354-2442; Olesen, Rikke/0000-0002-5157-080X; Lewin, Sharon Ruth/0000-0002-0330-8241 FU Australian National Health and Medical Research Council [1009533]; NHMRC Practitioner Fellowship; Division of AIDS, National Institute of Allergy and Infectious Disease, US National Institutes of Health (Delaney AIDS Research Enterprise) [U19AI096109] FX We thank Carsten Schade Larsen, Alex Laursen, and Merete Storgaard for clinical guidance during the study and Henrik Stovring for biostatistical support. Amy Shaw provided technical support and Paul W Denton provided input to the drafting of the report. The study was primarily funded by The Danish Council For Strategic Research, but also received contributions from The Danish AIDS Foundation, The Augustinus Foundation, Frode V Nyegaard Foundation, SSAC Foundation, Aarhus University, Aarhus University Hospital, and the American Fund for AIDS Research. Novartis supplied panobinostat for use in the study. SRL's contribution was supported by an Australian National Health and Medical Research Council project grant 1009533, an NHMRC Practitioner Fellowship and the Division of AIDS, National Institute of Allergy and Infectious Disease, US National Institutes of Health (Delaney AIDS Research Enterprise; U19AI096109). We wish to express our sincere gratitude to the study patients for their participation in the study. NR 33 TC 99 Z9 100 U1 0 U2 6 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 2352-3018 J9 LANCET HIV JI Lancet HIV PD OCT PY 2014 VL 1 IS 1 BP E13 EP E21 DI 10.1016/S2352-3018(14)70014-1 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CU8JC UT WOS:000363787300008 PM 26423811 ER PT J AU Pang, SC Wang, HP Li, KY Zhu, ZY Kang, JX Sun, YH AF Pang, Shao-Chen Wang, Hou-Peng Li, Kuo-Yu Zhu, Zuo-Yan Kang, Jing X. Sun, Yong-Hua TI Double Transgenesis of Humanized fat1 and fat2 Genes Promotes Omega-3 Polyunsaturated Fatty Acids Synthesis in a Zebrafish Model SO MARINE BIOTECHNOLOGY LA English DT Article DE Omega-3 fatty acids; Omega-6 fatty acids; Desaturase; Transgenic fish; Transcriptional regulation ID SALMON SALMO-SALAR; FISH-OIL; HETEROLOGOUS EXPRESSION; BIOSYNTHETIC-PATHWAY; MAMMALIAN-CELLS; DESATURASE GENE; VEGETABLE-OIL; N-3; MICE; GENERATION AB Omega-3 long-chain polyunsaturated fatty acid (n-3 LC-PUFA), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential nutrients for human health. However, vertebrates, including humans, have lost the abilities to synthesize EPA and DHA de novo, majorly due to the genetic absence of delta-12 desaturase and omega-3 desaturase genes. Fishes, especially those naturally growing marine fish, are major dietary source of EPA and DHA. Because of the severe decline of marine fishery and the decrease in n-3 LC-PUFA content of farmed fishes, it is highly necessary to develop alternative sources of n-3 LC-PUFA. In the present study, we utilized transgenic technology to generate n-3 LC-PUFA-rich fish by using zebrafish as an animal model. Firstly, fat1 was proved to function efficiently in fish culture cells, which showed an effective conversion of n-6 PUFA to n-3 PUFA with the n-6/n-3 ratio that decreased from 7.7 to 1.1. Secondly, expression of fat1 in transgenic zebrafish increased the 20:5n-3 and 22:6n-3 contents to 1.8- and 2.4-fold, respectively. Third, co-expression of fat2, a fish codon-optimized delta-12 desaturase gene, and fat1 in fish culture cell significantly promoted n-3 PUFA synthesis with the decreased n-6/n-3 ratio from 7.7 to 0.7. Finally, co-expression of fat1 and fat2 in double transgenic zebrafish increased the 20:5n-3 and 22:6n-3 contents to 1.7- and 2.8-fold, respectively. Overall, we generated two types of transgenic zebrafish rich in endogenous n-3 LC-PUFA, fat1 transgenic zebrafish and fat1/fat2 double transgenic zebrafish. Our results demonstrate that application of transgenic technology of humanized fat1 and fat2 in farmed fishes can largely improve the n-3 LC-PUFA production. C1 [Pang, Shao-Chen; Wang, Hou-Peng; Li, Kuo-Yu; Zhu, Zuo-Yan; Sun, Yong-Hua] Chinese Acad Sci, Inst Hydrobiol, State Key Lab Freshwater Ecol & Biotechnol, Wuhan 430072, Peoples R China. [Kang, Jing X.] Massachusetts Gen Hosp, Dept Med, Lab Lipid Med & Technol, Boston, MA 02114 USA. [Kang, Jing X.] Harvard Univ, Sch Med, Boston, MA USA. [Pang, Shao-Chen] Univ Chinese Acad Sci, Beijing 100049, Peoples R China. RP Sun, YH (reprint author), Chinese Acad Sci, Inst Hydrobiol, State Key Lab Freshwater Ecol & Biotechnol, Wuhan 430072, Peoples R China. EM yhsun@ihb.ac.cn RI Sun, Yong-Hua/B-5025-2012 OI Sun, Yong-Hua/0000-0001-9368-6969 FU China 863 High-Tech Program [2011AA100404]; China 973 Basic Research Program [2010CB126306, 2012CB944504]; National Science Fund for Excellent Young Scholars of NSFC [31222052]; FEBL [2011FBZ23] FX The authors thank Hanhua Hu, Xian-Tao Fang, Chun Cai, Junjie Zhang, and Guangzhao Chen for their technical support throughout the research project. This work was supported by the China 863 High-Tech Program Grant 2011AA100404, the China 973 Basic Research Program Grants 2010CB126306 and 2012CB944504, the National Science Fund for Excellent Young Scholars of NSFC Grant 31222052, and FEBL Grant 2011FBZ23 to Y. H. S. NR 54 TC 8 Z9 11 U1 0 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1436-2228 EI 1436-2236 J9 MAR BIOTECHNOL JI Mar. Biotechnol. PD OCT PY 2014 VL 16 IS 5 BP 580 EP 593 DI 10.1007/s10126-014-9577-9 PG 14 WC Biotechnology & Applied Microbiology; Marine & Freshwater Biology SC Biotechnology & Applied Microbiology; Marine & Freshwater Biology GA AO7AL UT WOS:000341504200009 PM 24832481 ER PT J AU Rodriguez, CLR Szu, JI Eberle, MM Wang, Y Hsu, MS Binder, DK Park, BH AF Rodriguez, Carissa L. R. Szu, Jenny I. Eberle, Melissa M. Wang, Yan Hsu, Mike S. Binder, Devin K. Park, B. Hyle TI Decreased light attenuation in cerebral cortex during cerebral edema detected using optical coherence tomography SO NEUROPHOTONICS LA English DT Article DE cerebral edema; optical coherence tomography; brain swelling AB Cerebral edema develops in response to a variety of conditions, including traumatic brain injury and stroke, and contributes to the poor prognosis associated with these injuries. This study examines the use of optical coherence tomography (OCT) for detecting cerebral edema in vivo. Three-dimensional imaging of an in vivo water intoxication model in mice was performed using a spectral-domain OCT system centered at 1300 nm. The change in attenuation coefficient was calculated and cerebral blood flow was analyzed using Doppler OCT techniques. We found that the average attenuation coefficient in the cerebral cortex decreased over time as edema progressed. The initial decrease began within minutes of inducing cerebral edema and a maximum decrease of 8% was observed by the end of the experiment. Additionally, cerebral blood flow slowed during late-stage edema. Analysis of local regions revealed the same trend at various locations in the brain, consistent with the global nature of the cerebral edema model used in this study. These results demonstrate that OCT is capable of detecting in vivo optical changes occurring due to cerebral edema and highlights the potential of OCT for precise spatiotemporal detection of cerebral edema. (C) The Authors. C1 [Rodriguez, Carissa L. R.; Eberle, Melissa M.; Park, B. Hyle] Univ Calif Riverside, Dept Bioengn, 900 Univ Ave, Riverside, CA 92521 USA. [Szu, Jenny I.; Hsu, Mike S.; Binder, Devin K.] Univ Calif Riverside, Div Biomed Sci, Sch Med, Riverside, CA 92521 USA. [Wang, Yan] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wang, Yan] Harvard Med Sch, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Hsu, Mike S.; Binder, Devin K.] Umbrella Neurotechnol, Irvine, CA 92620 USA. RP Park, BH (reprint author), Univ Calif Riverside, Dept Bioengn, 900 Univ Ave, Riverside, CA 92521 USA. EM hylepark@engr.ucr.edu FU NIBIB NIH HHS [R00 EB007241] NR 19 TC 6 Z9 6 U1 0 U2 0 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 2329-423X EI 2329-4248 J9 NEUROPHOTONICS JI Neurophotonics PD OCT-DEC PY 2014 VL 1 IS 2 AR 025004 DI 10.1117/1.NPh.1.2.025004 PG 7 WC Neurosciences; Optics SC Neurosciences & Neurology; Optics GA V45SP UT WOS:000209836600006 PM 25674578 ER PT J AU Tunkel, DE Bauer, CA Sun, GH Rosenfeld, RM Chandrasekhar, SS Cunningham, ER Archer, SM Blakley, BW Carter, JM Granieri, EC Henry, JA Hollingsworth, D Khan, FA Mitchell, S Monfared, A Newman, CW Omole, FS Phillips, CD Robinson, SK Taw, MB Tyler, RS Waguespack, R Whamond, EJ AF Tunkel, David E. Bauer, Carol A. Sun, Gordon H. Rosenfeld, Richard M. Chandrasekhar, Sujana S. Cunningham, Eugene R., Jr. Archer, Sanford M. Blakley, Brian W. Carter, John M. Granieri, Evelyn C. Henry, James A. Hollingsworth, Deena Khan, Fawad A. Mitchell, Scott Monfared, Ashkan Newman, Craig W. Omole, Folashade S. Phillips, C. Douglas Robinson, Shannon K. Taw, Malcolm B. Tyler, Richard S. Waguespack, Richard Whamond, Elizabeth J. TI Clinical Practice Guideline: Tinnitus SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE amplification; hearing aids; hearing loss; quality of life; sound therapy; tinnitus AB Objective. Tinnitus is the perception of sound without an external source. More than 50 million people in the United States have reported experiencing tinnitus, resulting in an estimated prevalence of 10% to 15% in adults. Despite the high prevalence of tinnitus and its potential significant effect on quality of life, there are no evidence-based, multidisciplinary clinical practice guidelines to assist clinicians with management. The focus of this guideline is on tinnitus that is both bothersome and persistent (lasting 6 months or longer), which often negatively affects the patient's quality of life. The target audience for the guideline is any clinician, including nonphysicians, involved in managing patients with tinnitus. The target patient population is limited to adults (18 years and older) with primary tinnitus that is persistent and bothersome. Purpose. The purpose of this guideline is to provide evidence-based recommendations for clinicians managing patients with tinnitus. This guideline provides clinicians with a logical framework to improve patient care and mitigate the personal and social effects of persistent, bothersome tinnitus. It will discuss the evaluation of patients with tinnitus, including selection and timing of diagnostic testing and specialty referral to identify potential underlying treatable pathology. It will then focus on the evaluation and treatment of patients with persistent primary tinnitus, with recommendations to guide the evaluation and measurement of the effect of tinnitus and to determine the most appropriate interventions to improve symptoms and quality of life for tinnitus sufferers. Action Statements. The development group made a strong recommendation that clinicians distinguish patients with bothersome tinnitus from patients with nonbothersome tinnitus. The development group made a strong recommendation against obtaining imaging studies of the head and neck in patients with tinnitus, specifically to evaluate tinnitus that does not localize to 1 ear, is nonpulsatile, and is not associated with focal neurologic abnormalities or an asymmetric hearing loss. The panel made the following recommendations: Clinicians should (a) perform a targeted history and physical examination at the initial evaluation of a patient with presumed primary tinnitus to identify conditions that if promptly identified and managed may relieve tinnitus; (b) obtain a prompt, comprehensive audiologic examination in patients with tinnitus that is unilateral, persistent (>= 6 months), or associated with hearing difficulties; (c) distinguish patients with bothersome tinnitus of recent onset from those with persistent symptoms (>= 6 months) to prioritize intervention and facilitate discussions about natural history and follow-up care; (d) educate patients with persistent, bothersome tinnitus about management strategies; (e) recommend a hearing aid evaluation for patients who have persistent, bothersome tinnitus associated with documented hearing loss; and (f) recommend cognitive behavioral therapy to patients with persistent, bothersome tinnitus. The panel recommended against (a) antidepressants, anticonvulsants, anxiolytics, or intratympanic medications for the routine treatment of patients with persistent, bothersome tinnitus; (b) Ginkgo biloba, melatonin, zinc, or other dietary supplements for treating patients with persistent, bothersome tinnitus; and (c) transcranial magnetic stimulation for the routine treatment of patients with persistent, bothersome tinnitus. The development group provided the following options: Clinicians may (a) obtain an initial comprehensive audiologic examination in patients who present with tinnitus (regardless of laterality, duration, or perceived hearing status); and (b) recommend sound therapy to patients with persistent, bothersome tinnitus. The development group provided no recommendation regarding the effect of acupuncture in patients with persistent, bothersome tinnitus. C1 [Tunkel, David E.] Johns Hopkins Outpatient Ctr, Otolaryngol Head & Neck Surg, 601 North Caroline St,Room 6231, Baltimore, MD 21287 USA. [Bauer, Carol A.] So Illinois Univ, Sch Med, Div Otolaryngol Head & Neck Surg, Springfield, IL USA. [Sun, Gordon H.] Partnership Hlth Analyt Res LLC, Los Angeles, CA USA. [Rosenfeld, Richard M.] Suny Downstate Med Ctr, Dept Otolaryngol, Brooklyn, NY 11203 USA. [Chandrasekhar, Sujana S.] New York Otol, New York, NY USA. [Cunningham, Eugene R., Jr.] Amer Acad Otolaryngol Head & Neck Surg Fdn, Dept Res & Qual Improvement, Alexandria, VA USA. [Archer, Sanford M.] Univ Kentucky, Div Rhinol & Sinus Surg, Lexington, KY USA. [Archer, Sanford M.] Univ Kentucky, Div Facial Plast & Reconstruct Surg, Lexington, KY USA. [Blakley, Brian W.] Univ Manitoba, Dept Otolaryngol, Winnipeg, MB, Canada. [Carter, John M.] Tulane Univ, Dept Otolaryngol, New Orleans, LA 70118 USA. [Granieri, Evelyn C.] Columbia Univ, Div Geriatr Med & Aging, New York, NY USA. [Henry, James A.] Portland VA Med Ctr, Natl Ctr Rehabil Auditory Res, Portland, OR USA. [Hollingsworth, Deena] ENT Specialists Northern Virginia, Falls Church, VA USA. [Khan, Fawad A.] Ochsner Hlth Syst, Kenner, LA USA. [Mitchell, Scott] Mitchell & Cavallo PC, Houston, TX USA. [Monfared, Ashkan] George Washington Univ, Dept Otol & Neurotol, Washington, DC USA. [Newman, Craig W.] Cleveland Clin, Lerner Coll Med, Dept Surg, Cleveland, OH 44106 USA. [Omole, Folashade S.] Morehouse Sch Med, East Point, GA USA. [Phillips, C. Douglas] New York Presbyterian Hosp, Weill Cornell Med Ctr, Dept Head & Neck Imaging, New York, NY USA. [Robinson, Shannon K.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Taw, Malcolm B.] Univ Calif Los Angeles, Dept Med, Ctr East West Med, Los Angeles, CA 90024 USA. [Tyler, Richard S.] Univ Iowa, Dept Otolaryngol Head & Neck Surg, Iowa City, IA USA. [Waguespack, Richard] Univ Alabama Birmingham, Sch Med, Dept Surg, Birmingham, AL 35294 USA. [Whamond, Elizabeth J.] Consumers United Evidence Based Healthcare, Fredericton, NB, Canada. RP Tunkel, DE (reprint author), Johns Hopkins Outpatient Ctr, Otolaryngol Head & Neck Surg, 601 North Caroline St,Room 6231, Baltimore, MD 21287 USA. EM dtunkel@jhmi.edu OI Phillips, C. Douglas/0000-0003-1773-8899 FU American Academy of Otolaryngology-Head and Neck Surgery Foundation FX American Academy of Otolaryngology-Head and Neck Surgery Foundation. NR 263 TC 51 Z9 58 U1 3 U2 27 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD OCT PY 2014 VL 151 SU 2 BP S1 EP S40 DI 10.1177/0194599814545325 PG 40 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA V43SX UT WOS:000209702200001 PM 25273878 ER PT J AU Joung, K AF Joung, Keith TI Targeted genome and epigenome editing using CRISPR-Cas and TALE technologies SO TRANSGENIC RESEARCH LA English DT Meeting Abstract C1 [Joung, Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. [Joung, Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02129 USA. NR 0 TC 0 Z9 0 U1 1 U2 14 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-8819 EI 1573-9368 J9 TRANSGENIC RES JI Transgenic Res. PD OCT PY 2014 VL 23 IS 5 MA 26 BP 840 EP 840 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA AO6BY UT WOS:000341434600038 ER PT J AU Chandra, A Lin, T Tribble, MB Zhu, J Altman, AR Tseng, WJ Zhang, YJ Akintoye, SO Cengel, K Liu, XS Qin, L AF Chandra, Abhishek Lin, Tiao Tribble, Mary Beth Zhu, Ji Altman, Allison R. Tseng, Wei-Ju Zhang, Yejia Akintoye, Sunday O. Cengel, Keith Liu, X. Sherry Qin, Ling TI PTH1-34 alleviates radiotherapy-induced local bone loss by improving osteoblast and osteocyte survival SO BONE LA English DT Article DE Parathyroid hormone; Radiotherapy; Image registration; Trabecular bone; Osteoblast; Apoptosis ID PARATHYROID-HORMONE 1-34; TRABECULAR BONE; MARROW MICROENVIRONMENT; IONIZING-RADIATION; BODY IRRADIATION; CANCELLOUS BONE; IN-VITRO; X-RAYS; MICE; CELLS AB Cancer radiotherapy is often complicated by a spectrum of changes in the neighboring bone from mild osteopenia to osteoradionecrosis. We previously reported that parathyroid hormone (PTH, 1-34), an anabolic agent for osteoporosis, reversed bone structural deterioration caused by multiple microcomputed tomography (microCT) scans in adolescent rats. To simulate clinical radiotherapy for cancer patients and to search for remedies, we focally irradiated the tibial metaphyseal region of adult rats with a newly available small animal radiation research platform (SARRP) and treated these rats with intermittent injections of PTH1-34. Using a unique 3D image registration method that we recently developed, we traced the local changes of the same trabecular bone before and after treatments, and observed that, while radiation caused a loss of small trabecular elements leading to significant decreases in bone mass and strength, PTH1-34 preserved all trabecular elements in irradiated bone with remarkable increases in bone mass and strength. Histomorphometry demonstrated that SARRP radiation severely reduced osteoblast number and activity, which were impressively reversed by PTH treatment. In contrast, suppressing bone resorption by alendronate failed to rescue radiation-induced bone loss and to block the rescue effect of PTH1-34. Furthermore, histological analyses revealed that PTH1-34 protected osteoblasts and osteocytes from radiation-induced apoptosis and attenuated radiation-induced bone marrow adiposity. Taken together, our data strongly support a robust radioprotective effect of PTH on trabecular bone integrity through preserving bone formation and shed light on further investigations of an anabolic therapy for radiation-induced bone damage. (C) 2014 Elsevier Inc. All rights reserved. C1 [Chandra, Abhishek; Lin, Tiao; Tribble, Mary Beth; Zhu, Ji; Altman, Allison R.; Tseng, Wei-Ju; Liu, X. Sherry; Qin, Ling] Univ Penn, Dept Orthopaed Surg, Perelman Sch Med, Philadelphia, PA 19104 USA. [Lin, Tiao] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Orthopaed Surg, Hangzhou 310009, Zhejiang, Peoples R China. [Zhang, Yejia] Univ Penn, Perelman Sch Med, Dept Phys Med & Rehabil, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Akintoye, Sunday O.] Univ Penn, Sch Dent Med, Dept Oral Med, Philadelphia, PA 19104 USA. [Cengel, Keith] Univ Penn, Perelman Sch Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA. RP Qin, L (reprint author), Univ Penn, Dept Orthopaed Surg, 424A Stemmler Hall,36th St & Hamilton Walk, Philadelphia, PA 19104 USA. EM qinling@mail.med.upenn.edu OI Zhang, Yejia/0000-0002-7484-8800; Liu, Xiaowei/0000-0001-7247-2232; Chandra, Abhishek/0000-0001-9423-9669 FU National Institute of Health [R01DK095803, K22CA169089]; Penn Center for Musculoskeletal Disorders [P30AR050950]; ASBMR Junior Faculty Osteoporosis Basic Research Award; McCabe Pilot Award FX This work was supported by the National Institute of Health (R01DK095803 to LQ and K22CA169089 to SOA), Penn Center for Musculoskeletal Disorders P30AR050950 (NIAMS/NIH), ASBMR Junior Faculty Osteoporosis Basic Research Award (to LQ) and McCabe Pilot Award (to XSL). NR 45 TC 15 Z9 18 U1 2 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD OCT PY 2014 VL 67 BP 33 EP 40 DI 10.1016/j.bone.2014.06.030 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AO3KJ UT WOS:000341227800005 PM 24998454 ER PT J AU Adeyemo, BO Biederman, J Zafonte, R Kagan, E Spencer, TJ Uchida, M Kenworthy, T Spencer, AE Faraone, SV AF Adeyemo, Bamidele O. Biederman, Joseph Zafonte, Ross Kagan, Elana Spencer, Thomas J. Uchida, Mai Kenworthy, Tara Spencer, Andrea E. Faraone, Stephen V. TI Mild Traumatic Brain Injury and ADHD: A Systematic Review of the Literature and Meta-Analysis SO JOURNAL OF ATTENTION DISORDERS LA English DT Review DE ADHD; traumatic brain injury; meta-analysis; review ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; PROFESSIONAL FOOTBALL PLAYERS; CLOSED-HEAD INJURY; RECURRENT CONCUSSION; PSYCHIATRIC-ILLNESS; LEAGUE PLAYER; YOUNG-ADULTS; CHILDREN; ADOLESCENTS AB Objective: This study investigated the association between mild traumatic brain injury (mTBI) and ADHD, which increases risk of injuries and accidents. Method: We conducted a systematic review and meta-analysis of studies that examined the relationship between mTBI and ADHD. Results: Five studies, comprising 3,023 mTBI patients and 9,716 controls, fit our a priori inclusion and exclusion criteria. A meta-analysis found a significant association between ADHD and mTBI, which was significant when limited to studies that reported on ADHD subsequent to mTBI and when the direction of the association was not specified, but not for studies that reported mTBI subsequent to ADHD. Heterogeneity of effect size and publication biases were not evident. Conclusion: The literature documents a significant association between mTBI and ADHD. Further clarification of the relationship and direction of effect between mTBI and ADHD and treatment implications could have large clinical, scientific, and public health implications. C1 [Adeyemo, Bamidele O.; Zafonte, Ross] Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Charlestown, MA USA. [Biederman, Joseph; Kenworthy, Tara; Spencer, Andrea E.] Massachusetts Gen Hosp, Res Program Autism Spectrum Disorders, Boston, MA 02114 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Syracuse, NY 13210 USA. [Spencer, Thomas J.; Uchida, Mai; Faraone, Stephen V.] Massachusetts Gen Hosp, Clin & Res Programs Pediat Psychopharmacol & Adul, Boston, MA 02114 USA. [Kagan, Elana; Kenworthy, Tara] Massachusetts Gen Hosp, Pediat Psychopharmacol Program, Boston, MA 02114 USA. RP Biederman, J (reprint author), Massachusetts Gen Hosp, Res Program Autism Spectrum Disorders, 55 Fruit St,Warren 705, Boston, MA 02114 USA. EM jbiederman@partners.org OI Faraone, Stephen/0000-0002-9217-3982 FU Pediatric Psychopharmacology Council Fund FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Pediatric Psychopharmacology Council Fund. NR 38 TC 9 Z9 9 U1 2 U2 27 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0547 EI 1557-1246 J9 J ATTEN DISORD JI J. Atten. Disord. PD OCT PY 2014 VL 18 IS 7 BP 576 EP 584 DI 10.1177/1087054714543371 PG 9 WC Psychology, Developmental; Psychiatry SC Psychology; Psychiatry GA AN8VJ UT WOS:000340883000002 PM 25047040 ER PT J AU Balboni, MJ Puchalski, CM Peteet, JR AF Balboni, Michael J. Puchalski, Christina M. Peteet, John R. TI The Relationship between Medicine, Spirituality and Religion: Three Models for Integration SO JOURNAL OF RELIGION & HEALTH LA English DT Article DE Spirituality; Medicine; Integration; Pluralism ID PALLIATIVE CARE; HEALTH; QUALITY AB The integration of medicine and religion is challenging for historical, ethical, practical and conceptual reasons. In order to make more explicit the bases and goals of relating spirituality and medicine, we distinguish here three complementary perspectives: a whole-person care model that emphasizes teamwork among generalists and spiritual professionals; an existential functioning view that identifies a role for the clinician in promoting full health, including spiritual well-being; and an open pluralism view, which highlights the importance of differing spiritual and cultural traditions in shaping the relationship. C1 [Balboni, Michael J.; Peteet, John R.] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Puchalski, Christina M.] George Washington Inst Spiritual & Hlth, Washington, DC 20036 USA. RP Peteet, JR (reprint author), Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave, Boston, MA 02115 USA. EM jpeteet@partners.org NR 40 TC 14 Z9 14 U1 1 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0022-4197 EI 1573-6571 J9 J RELIG HEALTH JI J. Relig. Health PD OCT PY 2014 VL 53 IS 5 BP 1586 EP 1598 DI 10.1007/s10943-014-9901-8 PG 13 WC Public, Environmental & Occupational Health; Religion SC Public, Environmental & Occupational Health; Religion GA AN4YE UT WOS:000340595100024 PM 24917445 ER PT J AU Takahashi, K Ohtani, K Larvie, M Moyo, P Chigweshe, L Van Cott, EM Wakamiya, N AF Takahashi, Kazue Ohtani, Katsuki Larvie, Mykol Moyo, Patience Chigweshe, Lorencia Van Cott, Elizabeth M. Wakamiya, Nobutaka TI Elevated plasma CL-K1 level is associated with a risk of developing disseminated intravascular coagulation (DIC) SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE Innate immunity; Collectin; Collectin kidney 1 (CL-K1); Disseminated intravascular coagulation; Respiratory diseases; Coagulation disorders; Vascular diseases ID MANNOSE-BINDING LECTIN; TRANSMITTANCE WAVE-FORM; C-REACTIVE PROTEIN; COLLECTIN 11 CL-11; EARLY IDENTIFICATION; COMPLEMENT; CLOT; LIPOPROTEIN; DEFICIENCY; ACTIVATION AB Collectin kidney 1 (CL-K1) is a recently identified collectin that is synthesized in most organs and circulates in blood. CL-K1 is an innate immune molecule that may play a significant role in host defense. As some collectins also play a role in coagulation, we hypothesized that an effect of CL-K1 may be apparent in disseminated intravascular coagulation (DIC), a gross derangement of the coagulation system that occurs in the setting of profound activation of the innate immune system. DIC is a grave medical condition with a high incidence of multiple organ failure and high mortality and yet there are no reliable biomarkers or risk factors. In our present study, we measured plasma CL-K1 concentration in a total of 659 specimens, including 549 DIC patients, 82 non-DIC patients and 27 healthy volunteers. The median plasma CL-K1 levels in these cohorts were 424, 238 and 245 ng/ml, respectively, with no significant difference in the latter two groups. The incidence of elevated plasma CL-K1 was significantly higher in the DIC patients compared to the non-DIC patients, resulting in an odds ratio of 1.929 (confidence interval 1.041-3.866). Infection, renal diseases, respiratory diseases, and cardiac diseases were more frequently observed in the DIC group than in the non-DIC group. In the DIC group, vascular diseases were associated with elevated plasma CL-K1 levels while age and acute illness had little effect on plasma CL-K1 levels. Independent of DIC, elevated plasma CL-K1 levels were associated with respiratory disease and coagulation disorders. These results suggest that specific diseases may affect CL-K1 synthesis in an organ dependent manner and that elevated plasma CL-K1 levels are associated with the presence of DIC. Further investigations in cohorts of patients are warranted. We propose that elevated plasma CL-K1 may be a new useful risk factor and possibly biomarker for the prediction of developing DIC. C1 [Takahashi, Kazue; Moyo, Patience; Chigweshe, Lorencia] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Ohtani, Katsuki; Wakamiya, Nobutaka] Asahikawa Med Univ, Dept Microbiol & Immunochem, Asahikawa, Hokkaido 0788510, Japan. [Larvie, Mykol] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Div Neuroradiol, Boston, MA 02114 USA. [Larvie, Mykol] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Van Cott, Elizabeth M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Takahashi, K (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pediat, 55 Fruit St, Boston, MA 02114 USA. EM ktakahashi1@gmail.com FU NIH [U01-074503]; Japan of Ministry of Education, Culture, Sports, Science, and Technology [19390227]; Fuso Pharmaceutical Industry, Co.; Smoking Research Foundation; Mizutani foundation for glycoscience FX The authors thank laboratory personnel in the Coagulation Laboratory at the Massachusetts General Hospital. The work was supported in part by NIH Grant U01-074503 (K. T.) and Grants-in-Aid for Scientific Research of the Japan of Ministry of Education, Culture, Sports, Science, and Technology, 19390227 (N.W). This work was also supported by grants from Fuso Pharmaceutical Industry, Co., the Smoking Research Foundation, and the Mizutani foundation for glycoscience (N.W). NR 34 TC 11 Z9 11 U1 0 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 EI 1573-742X J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD OCT PY 2014 VL 38 IS 3 BP 331 EP 338 DI 10.1007/s11239-013-1042-5 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AO1PK UT WOS:000341085300007 PM 24474086 ER PT J AU Bierer, LM Bader, HN Daskalakis, NP Lehrner, AL Makotkine, I Seckl, JR Yehuda, R AF Bierer, Linda M. Bader, Heather N. Daskalakis, Nikolaos P. Lehrner, Amy L. Makotkine, Iouri Seckl, Jonathan R. Yehuda, Rachel TI Elevation of 11 beta-hydroxysteroid dehydrogenase type 2 activity in Holocaust survivor offspring: Evidence for an intergenerational effect of maternal trauma exposure SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE 11 beta-Hydroxysterioddehydrogenase type 2; Cortisol; Gtucocorticoid metabolism; Developmental programming; Intergenerational; Holocaust; Offspring; Biomarkers; PTSD; HPA axis ID POSTTRAUMATIC-STRESS-DISORDER; BETA-HYDROXYSTEROID DEHYDROGENASE; MESSENGER-RIBONUCLEIC-ACID; GLUCOCORTICOID-RECEPTOR; PRENATAL STRESS; LOW CORTISOL; EPIGENETIC REGULATION; ADULT DISEASE; PARENTAL PTSD; EXPRESSION AB Background: Adult offspring of Holocaust survivors comprise an informative cohort in which to study intergenerational transmission of the effects of trauma exposure. Lower cortisol and enhanced glucocorticoid sensitivity have been previously demonstrated in Holocaust survivors with PTSD, and in offspring of Holocaust survivors in association with maternal PTSD. In other work, reduction in the activity of the enzyme 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD-2), which inactivates cortisol, was identified in Holocaust survivors in comparison to age-matched, unexposed Jewish controls. Therefore, we investigated glucocorticoid metabolism in offspring of Holocaust survivors to evaluate if similar enzymatic decrements would be observed that might help to explain glucocorticoid alterations previously shown for Holocaust offspring. Methods: Holocaust offspring (n = 85) and comparison subjects (n = 27) were evaluated with clinical diagnostic interview and self-rating scales, and asked to collect a 24-h urine sample from which concentrations of cortisol and glucocorticoid metabolites were assayed by GCMS. 11 beta-HSD-2 activity was determined as the ratio of urinary cortisone to cortisol. Results: Significantly reduced cortisol excretion was observed in Holocaust offspring compared to controls (p = .046), as had been shown for Holocaust survivors. However, 11 beta-HSD-2 activity was elevated for offspring compared to controls (p = .008), particularly among those whose mothers had been children, rather than adolescents or adults, during World War II (p = .032). The effect of paternal Holocaust exposure could not be reliably investigated in the current sample. Conclusions: The inverse association of offspring 11 beta-HSD-2 activity with maternal age at Holocaust exposure is consistent with the influence of glucocorticoid programming. Whereas a tong standing reduction in 11 beta-HSD-2 activity among survivors is readily interpreted, in the context of Holocaust related deprivation, understanding the directional effect on offspring will require replication and further exploration. Published by Elsevier Ltd. C1 [Bierer, Linda M.; Bader, Heather N.; Daskalakis, Nikolaos P.; Lehrner, Amy L.; Makotkine, Iouri; Yehuda, Rachel] James J Peters VA Med Ctr, Bronx, NY USA. [Bierer, Linda M.; Bader, Heather N.; Daskalakis, Nikolaos P.; Lehrner, Amy L.; Makotkine, Iouri; Yehuda, Rachel] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Seckl, Jonathan R.] Univ Edinburgh, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian, Scotland. RP Yehuda, R (reprint author), James J Peters Vet Affairs Med Ctr, Mental Hlth Care Ctr, Mt Sinai Sch Med, Traumat Stress Studies Div,Dept Psychiat, 526 OOMH PTSD 116-A,130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM Rachel.yehuda@va.gov RI Daskalakis, Nikolaos/B-7930-2014 OI Daskalakis, Nikolaos/0000-0003-1660-9112 FU Identification of an Epigenetic Risk Marker for PTSD [1RC1MH088101-01]; NIMH [R01 MH 64675-01]; National Institute of Health [5 M01 RR00071] FX This work was supported by 1RC1MH088101-01 "Identification of an Epigenetic Risk Marker for PTSD" and NIMH R01 MH 64675-01 "Biology of Risk and PTSD in Holocaust Survivor Offspring" and in part by a grant (5 M01 RR00071) for the Mount Sinai General Clinical Research Center from the National Institute of Health. The NIMH and NIH had no further role in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; or in the decision to submit the paper for publication. NR 48 TC 9 Z9 10 U1 3 U2 35 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD OCT PY 2014 VL 48 BP 1 EP 10 DI 10.1016/j.psyneuen.2014.06.001 PG 10 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA AN8JR UT WOS:000340851000001 PM 24971590 ER PT J AU Hodler, J Kransdorf, MJ Rosenthal, DI AF Hodler, Juerg Kransdorf, Mark J. Rosenthal, Daniel I. TI Polling the readers of Skeletal Radiology SO SKELETAL RADIOLOGY LA English DT Editorial Material C1 [Hodler, Juerg] Univ Zurich Hosp, AUFN C 18, CH-8091 Zurich, Switzerland. [Kransdorf, Mark J.] Mayo Clin, Phoenix, AZ USA. [Rosenthal, Daniel I.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Rosenthal, DI (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM juerg.hodler@usz.ch; kransdorf.mark@mayo.edu; DIRosenthal@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 EI 1432-2161 J9 SKELETAL RADIOL JI Skeletal Radiol. PD OCT PY 2014 VL 43 IS 10 BP 1351 EP 1351 DI 10.1007/s00256-014-1942-2 PG 1 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA AO1TR UT WOS:000341098200001 PM 25073608 ER PT J AU Kamath, RS Lukina, E Watman, N Dragosky, M Pastores, GM Arreguin, EA Rosenbaum, H Zimran, A Aguzzi, R Puga, AC Norfleet, AM Peterschmitt, MJ Rosenthal, DI AF Kamath, Ravi S. Lukina, Elena Watman, Nora Dragosky, Marta Pastores, Gregory M. Avila Arreguin, Elsa Rosenbaum, Hanna Zimran, Ari Aguzzi, Rasha Puga, Ana Cristina Norfleet, Andrea M. Peterschmitt, M. Judith Rosenthal, Daniel I. TI Skeletal improvement in patients with Gaucher disease type 1: a phase 2 trial of oral eliglustat SO SKELETAL RADIOLOGY LA English DT Article DE Gaucher disease type 1; Bone disease; Drug therapy; Targeted molecular therapy; Magnetic resonance imaging; Dual-energy X-ray absorptiometry ID ENZYME REPLACEMENT THERAPY; BONE-DISEASE; TARTRATE GENZ-112638; GLUCOCEREBROSIDASE; MARROW; IMIGLUCERASE; MACROPHAGE; REDUCTION; MIGLUSTAT AB Eliglustat is an investigational oral substrate reduction therapy for Gaucher disease type 1 (GD1). Its skeletal effects were evaluated by prospective monitoring of bone mineral density (BMD), fractures, marrow infiltration by Gaucher cells, focal bone lesions, and infarcts during an open-label, multi-site, single-arm phase 2 trial (NCT00358150). Institutional review board approval and patient informed consent were obtained. Eliglustat (50 or 100 mg) was self-administered by mouth twice daily; 19 patients completed 4 years of treatment. All were skeletally mature (age range, 18-55 years). DXA and MRI assessments were conducted at baseline and annually thereafter. X-rays were obtained annually until month 24, and then every other year. Lumbar spine BMD increased significantly (p = 0.02; n = 15) by a mean (SD) of 9.9 % (14.2 %) from baseline to year 4; corresponding T-scores increased significantly (p = 0.01) from a mean (SD) of -1.6 (1.1) to -0.9 (1.3). Mean femur T-score remained normal through 4 years. Femur MRI showed that 10/18 (56 %) patients had decreased Gaucher cell infiltration compared to baseline; one patient with early improvement had transient worsening at year 4. There were no lumbar spine or femoral fractures and no reported bone crises during the study. At baseline, 8/19 (42 %) patients had focal bone lesions, which remained stable, and 7/19 (37 %) patients had bone infarctions, which improved in one patient by year 2. At year 4, one new asymptomatic, indeterminate bone lesion was discovered that subsequently resolved. Eliglustat may be a therapeutic option for treating the skeletal manifestations of GD1. C1 [Kamath, Ravi S.; Rosenthal, Daniel I.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kamath, Ravi S.; Rosenthal, Daniel I.] Harvard Univ, Sch Med, Boston, MA USA. [Lukina, Elena] Russian Acad Med Sci, Moscow, Russia. [Watman, Nora] Hosp Ramos Mejia, Buenos Aires, DF, Argentina. [Dragosky, Marta] Inst Mexicano Seguro Social Hosp Especialidades, Col La Raza, Mexico. [Pastores, Gregory M.] NYU, New York, NY USA. [Avila Arreguin, Elsa] Inst Argentino Diagnost & Tratamiento, Buenos Aires, DF, Argentina. [Rosenbaum, Hanna] Rambam Med Ctr, Haifa, Israel. [Zimran, Ari] Shaare Zedek Hebrew Univ, Jerusalem, Israel. [Zimran, Ari] Hebrew Univ Jerusalem, Hadassah Med Sch, IL-91010 Jerusalem, Israel. [Aguzzi, Rasha; Puga, Ana Cristina; Norfleet, Andrea M.; Peterschmitt, M. Judith] Genzyme, Cambridge, MA USA. [Rosenthal, Daniel I.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Rosenthal, DI (reprint author), Massachusetts Gen Hosp, Dept Radiol, 175 Cambridge St, Boston, MA 02114 USA. EM dirosenthal@partners.org FU Genzyme, a Sanofi company FX The eliglustat phase 2 trial was sponsored by Genzyme, a Sanofi company. NR 32 TC 21 Z9 22 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 EI 1432-2161 J9 SKELETAL RADIOL JI Skeletal Radiol. PD OCT PY 2014 VL 43 IS 10 BP 1353 EP 1360 DI 10.1007/s00256-014-1891-9 PG 8 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA AO1TR UT WOS:000341098200002 PM 24816856 ER PT J AU Norris, RE Shusterman, S Gore, L Muscal, JA Macy, ME Fox, E Berkowitz, N Buchbinder, A Bagatell, R AF Norris, Robin E. Shusterman, Suzanne Gore, Lia Muscal, Jodi A. Macy, Margaret E. Fox, Elizabeth Berkowitz, Noah Buchbinder, Aby Bagatell, Rochelle TI Phase 1 Evaluation of EZN-2208, a Polyethylene Glycol Conjugate of SN38, in Children Adolescents and Young Adults With Relapsed or Refractory Solid Tumors SO PEDIATRIC BLOOD & CANCER LA English DT Article DE EZN-2208; pediatric cancer; pharmacokinetic; Phase 1 trial ID PROTRACTED IRINOTECAN SCHEDULE; ETIRINOTECAN PEGOL NKTR-102; TOPOISOMERASE-I INHIBITOR; PEDIATRIC-PATIENTS; ONCOLOGY-GROUP; RANDOMIZED PHASE-2; PEGYLATED SN-38; CANCER; TEMOZOLOMIDE; TRIALS AB Background. EZN-2208 is a water-soluble PEGylated conjugate of the topoisomerase inhibitor SN38, the active metabolite of irinotecan. Compared to irinotecan, EZN-2208 has a prolonged half-life permitting extended exposure to SN38. EZN-2208 has demonstrated clinical tolerability and antitumor activity in adults with advanced solid tumors. This Phase 1 study evaluated the safety, pharmacokinetics, and preliminary antitumor activity of EZN-2208 in children with relapsed or refractory solid tumors. Procedure. EZN-2208 was administered as a 1-hour intravenous infusion once every 21 days at five dose levels (12-30 mg/m(2)). Filgrastim or pegfilgrastim was administered 24-48 hours after treatment with EZN-2208. The rolling-six design was used for dose determination. Results. Thirty eligible patients (15 females; median [range] age 11.5 years [2-21 years]) were treated with EZN-2208. Dose-limiting diarrhea occurred in one patient receiving 16 mg/m(2) and dose-limiting dehydration was seen in one patient receiving 24 mg/m(2). At dose levels above 16 mg/m(2), Grade >= 3 myelosuppression was demonstrated in the majority of patients. Additional adverse events included nausea, vomiting, and fatigue. The maximum tolerated dose was identified as 24 mg/m(2) due to dose-limiting thrombocytopenia in two patients receiving 30 mg/m(2). Two of nine patients with neuroblastoma who were evaluable for response had partial responses. Five patients (four with neuroblastoma) remained on study for >= 8 cycles. Conclusions. EZN-2208 was generally well-tolerated and was associated with clinical benefit in patients with neuroblastoma. (C) 2014 Wiley Periodicals, Inc. C1 [Norris, Robin E.] Rainbow Babies & Childrens Hosp, Div Pediat Hematol Oncol, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Shusterman, Suzanne] Dana Farber Canc Inst, Dept Oncol, Boston, MA 02115 USA. [Shusterman, Suzanne] Childrens Hosp Boston, Div Oncol, Boston, MA USA. [Gore, Lia; Macy, Margaret E.] Univ Colorado, Aurora, CO USA. [Gore, Lia; Macy, Margaret E.] Childrens Hosp Colorado, Aurora, CO USA. [Muscal, Jodi A.] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. [Fox, Elizabeth; Bagatell, Rochelle] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Berkowitz, Noah; Buchbinder, Aby] Enzon Pharmaceut Inc, Bridgewater, NJ USA. RP Norris, RE (reprint author), Rainbow Babies & Childrens Hosp, Div Pediat Hematol Oncol, 11100 Euclid Ave,Mailstop RBC 6054, Cleveland, OH 44106 USA. EM robin.norris@uhhospitals.org FU Enzon Pharmaceuticals, Inc. FX Grant sponsor: Enzon Pharmaceuticals, Inc. NR 34 TC 3 Z9 4 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD OCT PY 2014 VL 61 IS 10 BP 1792 EP 1797 DI 10.1002/pbc.25105 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AN4ET UT WOS:000340541100016 PM 24962521 ER PT J AU Nichols-Vinueza, DX Gutierrez, A Veintemilla, G Perez-Atayde, AR AF Nichols-Vinueza, Diana X. Gutierrez, Alejandro Veintemilla, Galo Perez-Atayde, Antonio R. TI Letter to The Editor: Pseudopapillary Tumor of The Pancreas in a Child With Hemihypertrophy and a History of Wilms Tumor SO PEDIATRIC BLOOD & CANCER LA English DT Letter ID BETA-CATENIN; GENE; WTX C1 [Nichols-Vinueza, Diana X.; Gutierrez, Alejandro] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Hematol Oncol,Boston Childrens Hosp, Boston, MA 02115 USA. [Veintemilla, Galo] Inst Nacl Cancerol, Pediat Oncol Unit, Bogota, Colombia. [Perez-Atayde, Antonio R.] Harvard Univ, Sch Med, Dept Pathol, Boston Childrens Hosp, Boston, MA 02115 USA. RP Gutierrez, A (reprint author), Boston Childrens Hosp, Div Hematol Oncol, 300 Longwood Ave, Boston, MA 02115 USA. EM alejandro.gutierrez@childrens.harvard.edu; gveintemilla@cancer.gov.co NR 9 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD OCT PY 2014 VL 61 IS 10 BP 1901 EP 1902 DI 10.1002/pbc.25112 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AN4ET UT WOS:000340541100040 PM 24962628 ER PT J AU Pan, J Palmateer, J Schallert, T Hart, M Pandya, A Vandenbark, AA Offner, H Hurn, PD AF Pan, Jie Palmateer, Julie Schallert, Timothy Hart, Madison Pandya, Arushi Vandenbark, Arthur A. Offner, Halina Hurn, Patricia D. TI Novel Humanized Recombinant T Cell Receptor Ligands Protect the Female Brain After Experimental Stroke SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Cerebral ischemia; Gender; Sex; Immunotherapy; Partial MHC class II constructs; Stroke; Ultrasonic vocalization ID MIGRATION INHIBITORY FACTOR; TREATS EXPERIMENTAL STROKE; CLASS-II CONSTRUCTS; ULTRASONIC VOCALIZATION; CEREBRAL-ISCHEMIA; CD74 EXPRESSION; IMMUNE-SYSTEM; RATS; MICE; INJURY AB Transmigration of peripheral leukocytes to the brain is a major contributor to cerebral ischemic cell death mechanisms. Humanized partial major histocompatibility complex class II constructs (pMHC), covalently linked to myelin peptides, are effective for treating experimental stroke in males, but new evidence suggests that some inflammatory cell death mechanisms after brain injury are sex-specific. We here demonstrate that treatment with pMHC constructs also improves outcomes in female mice with middle cerebral artery occlusion (MCAO). HLA-DR2 transgenic female mice with MCAO were treated with RTL1000 (HLA-DR2 moiety linked to human MOG-35-55 peptide), HLA-DRa1-MOG-35-55, or vehicle (VEH) at 3, 24, 48, and 72 h after reperfusion and were recovered for 96 h or 2 weeks post-injury for measurement of histology (TTC staining) or behavioral testing. RTL1000- and DRa1-MOG-treated mice had profoundly reduced infarct volumes as compared to the VEH group, although higher doses of DRa1-MOG were needed for females vs. males evaluated previously. RTL1000-treated females also exhibited strongly improved functional recovery in a standard cylinder test. In novel studies of post-ischemic ultrasonic vocalization (USV), as measured by animal calls to their cage mates, we modeled in mice the post-stroke speech deficits common in human stroke survivors. The number of calls was reduced in injured animals relative to pre-MCAO baseline regardless of RTL1000 treatment status. However, call duration was significantly improved by RTL1000 treatment, suggesting benefit to the animal's recovery of vocalization capability. We conclude that both the parent RTL1000 molecule and the novel non-polymorphic DR alpha 1-MOG-35-55 construct were highly effective immunotherapies for treatment of transient cerebral ischemia in females. C1 [Pan, Jie] Nanjing Univ, Sch Med, Nanjing 210008, Jiangsu, Peoples R China. [Pan, Jie; Palmateer, Julie; Hurn, Patricia D.] Univ Texas Austin, Dept Neurosci, Austin, TX 78712 USA. [Schallert, Timothy; Hart, Madison; Pandya, Arushi] Univ Texas Austin, Dept Psychol, Austin, TX 78712 USA. [Vandenbark, Arthur A.; Offner, Halina] Oregon & Hlth Sci Univ, Dept Neurol, Portland, OR USA. [Vandenbark, Arthur A.; Offner, Halina] Neuroimmunol Res, Portland, OR USA. [Vandenbark, Arthur A.] Oregon & Hlth Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR USA. [Offner, Halina] Oregon & Hlth Sci Univ, Dept Anesthesiol & Perioperat Med, Portland Vet Affairs Med Ctr, Portland, OR USA. [Hurn, Patricia D.] Univ Texas Syst, Austin, TX USA. [Hurn, Patricia D.] Res & Innovat Univ Texas Syst, Austin, TX 78701 USA. RP Hurn, PD (reprint author), Res & Innovat Univ Texas Syst, 601 Colorado,Suite 211, Austin, TX 78701 USA. EM phurn@utsystem.edu FU NINDS NIH HHS [R42 NS065515] NR 40 TC 11 Z9 11 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD OCT PY 2014 VL 5 IS 5 BP 577 EP 585 DI 10.1007/s12975-014-0345-y PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AN1VV UT WOS:000340373000007 PM 24838614 ER PT J AU Zhu, WB Libal, NL Casper, A Bodhankar, S Offner, H Alkayed, NJ AF Zhu, Wenbin Libal, Nicole L. Casper, Amanda Bodhankar, Sheetal Offner, Halina Alkayed, Nabil J. TI Recombinant T Cell Receptor Ligand Treatment Improves Neurological Outcome in the Presence of Tissue Plasminogen Activator in Experimental Ischemic Stroke SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Ischemic stroke; Immunotherapy; Recombinant T cell receptor ligand; Tissue plasminogen activator; HLA-DR2 transgenic mice ID CEREBRAL-ARTERY; INFARCT SIZE; MICE; RECOMMENDATIONS; REPERFUSION; CLEARANCE; ANTIGEN; DESIGN AB RTL1000 is a partial human MHC molecule coupled to a human myelin peptide. We previously demonstrated that RTL1000 was protective against experimental ischemic stroke in HLA-DR2 transgenic (DR2-Tg) mice. Since thrombolysis with recombinant tissue plasminogen activator (t-PA) is a standard therapy for stroke, we determined if RTL1000 efficacy is altered when combined with t-PA in experimental stroke. Male DR2-Tg mice underwent 60 min of intraluminal middle cerebral artery occlusion (MCAO). t-PA or vehicle was infused intravenously followed by either a single or four daily subcutaneous injections of RTL1000 or vehicle. Infarct size was measured by 2, 3, 5-triphenyltetrazolium chloride staining at 24 or 96 h of reperfusion. Our data showed that t-PA alone reduced infarct size when measured at 24 h but not at 96 h after MCAO. RTL1000 alone reduced infarct size both at 24 and 96 h after MCAO. Combining RTL1000 with t-PA did not alter its ability to reduce infarct size at either 24 or 96 h after MCAO and provides additional protection in t-PA treated mice at 24 h after ischemic stroke. Taken together, RTL1000 treatment alone improves outcome and provides additional protection in t-PA-treated mice in experimental ischemic stroke. C1 [Zhu, Wenbin; Libal, Nicole L.; Casper, Amanda; Alkayed, Nabil J.] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97239 USA. [Alkayed, Nabil J.] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Portland, OR 97239 USA. [Bodhankar, Sheetal; Offner, Halina] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Bodhankar, Sheetal; Offner, Halina] Portland VA Med Ctr, Portland, OR 97239 USA. RP Alkayed, NJ (reprint author), Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97239 USA. EM alkayedn@ohsu.edu FU NIH [NS076013]; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development FX This work was supported by NIH Grants #NS076013 (STTR) and by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. NR 31 TC 11 Z9 11 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD OCT PY 2014 VL 5 IS 5 BP 612 EP 617 DI 10.1007/s12975-014-0348-8 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AN1VV UT WOS:000340373000011 PM 24953050 ER PT J AU Wilcox, T Hawkins, LB Hirshkowitz, A Boas, DA AF Wilcox, Teresa Hawkins, Laura B. Hirshkowitz, Amy Boas, David A. TI Cortical activation to object shape and speed of motion during the first year SO NEUROIMAGE LA English DT Article DE Object processing; Temporal cortex; Parietal cortex; Functional brain activation; Infants; Near-infrared spectroscopy ID NEAR-INFRARED SPECTROSCOPY; STRUCTURE-FROM-MOTION; MENTAL ROTATION; INFANT CORTEX; SPATIOTEMPORAL INFORMATION; NONHUMAN-PRIMATES; CEREBRAL-CORTEX; VISUAL-SYSTEM; BOLD ACTIVITY; PERCEPTION AB A great deal is known about the functional organization of cortical networks that mediate visual object processing in the adult. The current research is part of a growing effort to identify the functional maturation of these pathways in the developing brain. The current research used near-infrared spectroscopy to investigate functional activation of the infant cortex during the processing of featural information (shape) and spatiotemporal information (speed of motion) during the first year of life. Our investigation focused on two areas that were implicated in previous studies: anterior temporal cortex and posterior parietal cortex. Neuroimaging data were collected with 207 infants across three age groups: 3-6 months (Experiment 1), 7-8 months (Experiment 2), and 10-12 months (Experiments 3 and 4). The neuroimaging data revealed age-related changes in patterns of activation to shape and speed information, mostly involving posterior parietal areas, some of which were predicted and others that were not. We suggest that these changes reflect age-related differences in the perceptual and/or cognitive processes engaged during the task (C) 2014 Elsevier Inc. All rights reserved. C1 [Wilcox, Teresa; Hawkins, Laura B.; Hirshkowitz, Amy] Texas A&M Univ, Dept Psychol, College Stn, TX 77843 USA. [Boas, David A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Wilcox, T (reprint author), Texas A&M Univ, Dept Psychol, 4235 TAMU, College Stn, TX 77843 USA. EM twilcox@tamu.edu FU [BCS-0642996]; [R01-HD057999]; [P41-RR14075] FX We thank Marisa Biondi, Tracy Smith Brower, Jennifer Armstrong Haslup, Melissa Wallace Klapuch, Mariam Massoud, Jennifer Moore Norvell, Jessica Stubbs, Kayla Boone Upshaw, Lesley Wheeler, and the staff of the Infant Cognition Lab at Texas A&M University for help with data collection and management, and the infants and parents who so graciously participated in the research. This work was support by grants BCS-0642996 and R01-HD057999 to TW and grant P41-RR14075 to DAB. DAB is an inventor on a technology licensed to TechEn, a company whose medical pursuits focus on noninvasive, optical brain monitoring. DAB's interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. NR 77 TC 5 Z9 5 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2014 VL 99 BP 129 EP 141 DI 10.1016/j.neuroimage.2014.04.082 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AM4XR UT WOS:000339860000014 PM 24821531 ER PT J AU Cryan, JB Haidar, S Ramkissoon, LA Bi, WL Knoff, DS Schultz, N Abedalthagafi, M Brown, L Wen, PY Reardon, DA Dunn, IF Folkerth, RD Santagata, S Lindeman, NI Ligon, AH Beroukhim, R Hornick, JL Alexander, BM Ligon, KL Ramkissoon, SH AF Cryan, Jane B. Haidar, Sam Ramkissoon, Lori A. Bi, Wenya Linda Knoff, David S. Schultz, Nikolaus Abedalthagafi, Malak Brown, Loreal Wen, Patrick Y. Reardon, David A. Dunn, Ian F. Folkerth, Rebecca D. Santagata, Sandro Lindeman, Neal I. Ligon, Azra H. Beroukhim, Rameen Hornick, Jason L. Alexander, Brian M. Ligon, Keith L. Ramkissoon, Shakti H. TI Clinical multiplexed exome sequencing distinguishes adult oligodendroglial neoplasms from astrocytic and mixed lineage gliomas SO ONCOTARGET LA English DT Article DE oligodendroglioma; astrocytoma; oligoastrocytoma; sequencing; IDH ID CENTRAL-NERVOUS-SYSTEM; LOW-GRADE GLIOMAS; ADJUVANT TEMOZOLOMIDE; DIFFUSE GLIOMAS; IDH2 MUTATIONS; TUMOR SAMPLES; CLASSIFICATION; GLIOBLASTOMA; RADIOTHERAPY; CONCOMITANT AB Classifying adult gliomas remains largely a histologic diagnosis based on morphology; however astrocytic, oligodendroglial and mixed lineage tumors can display overlapping histologic features. We used multiplexed exome sequencing (OncoPanel) on 108 primary or recurrent adult gliomas, comprising 65 oligodendrogliomas, 28 astrocytomas and 15 mixed oligoastrocytomas to identify lesions that could enhance lineage classification. Mutations in TP53 (20/28, 71%) and ATRX (15/28, 54%) were enriched in astrocytic tumors compared to oligodendroglial tumors of which 4/65 (6%) had mutations in TP53 and 2/65 (3%) had ATRX mutations. We found that oligoastrocytomas harbored mutations in TP53 (80%, 12/15) and ATRX (60%, 9/15) at frequencies similar to pure astrocytic tumors, suggesting that oligoastrocytomas and astrocytomas may represent a single genetic or biological entity. p53 protein expression correlated with mutation status and showed significant increases in astrocytomas and oligoastrocytomas compared to oligodendrogliomas, a finding that also may facilitate accurate classification. Furthermore our OncoPanel analysis revealed that 15% of IDH1/2 mutant gliomas would not be detected by traditional IDH1 (p.R132H) antibody testing, supporting the use of genomic technologies in providing clinically relevant data. In all, our results demonstrate that multiplexed exome sequencing can support evaluation and classification of adult low-grade gliomas with a single clinical test. C1 [Cryan, Jane B.; Abedalthagafi, Malak; Folkerth, Rebecca D.; Santagata, Sandro; Lindeman, Neal I.; Ligon, Azra H.; Hornick, Jason L.; Ligon, Keith L.; Ramkissoon, Shakti H.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Haidar, Sam; Ramkissoon, Lori A.; Knoff, David S.; Brown, Loreal; Wen, Patrick Y.; Reardon, David A.; Beroukhim, Rameen; Ligon, Keith L.; Ramkissoon, Shakti H.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Santagata, Sandro; Ligon, Keith L.; Ramkissoon, Shakti H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Bi, Wenya Linda; Dunn, Ian F.] Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Alexander, Brian M.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Schultz, Nikolaus] Mem Sloan Kettering Canc Ctr, Kravis Ctr Mol Oncol, New York, NY 10021 USA. [Schultz, Nikolaus] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. RP Ramkissoon, SH (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM keith_ligon@dfci.harvard.edu; sramkissoon@partners.org OI Knoff, David/0000-0001-6233-2893 FU NCI NIH HHS [P01 CA142536, P50 CA165962, R01 CA170592]; NINDS NIH HHS [K08 NS087118] NR 26 TC 17 Z9 18 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 30 PY 2014 VL 5 IS 18 BP 8083 EP 8092 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ1YI UT WOS:000348030900010 PM 25257301 ER PT J AU Nishi, M Akutsu, H Kudoh, A Kimura, H Yamamoto, N Umezawa, A Lee, SW Ryo, A AF Nishi, Mayuko Akutsu, Hidenori Kudoh, Ayumi Kimura, Hirokazu Yamamoto, Naoki Umezawa, Akihiro Lee, Sam W. Ryo, Akihide TI Induced cancer stem-like cells as a model for biological screening and discovery of agents targeting phenotypic traits of cancer stem cell SO ONCOTARGET LA English DT Article DE Cancer stem cell; p21Cip1; drug screening; senescence; tumor sphere formation ID EPITHELIAL-MESENCHYMAL TRANSITION; PREMATURE SENESCENCE; WITHANIA-SOMNIFERA; PROSTATE-CANCER; WITHAFERIN; INDUCTION; GEROCONVERSION; IDENTIFICATION; EXPRESSION; GENERATION AB Cancer stem cells (CSCs) retain the capacity to propagate themselves through self-renewal and to produce heterogeneous lineages of cancer cells constituting the tumor. Novel drugs that target CSCs can potentially eliminate the tumor initiating cell population therefore resulting in complete cure of the cancer. We recently established a CSC-like model using induced pluripotent stem cell (iPSC) technology to reprogram and partially differentiate human mammary epithelial MCF-10A cells. Using the induced CSC-like (iCSCL) model, we developed a phenotypic drug assay system to identify agents that inhibit the stemness and self-renewal properties of CSCs. The selectivity of the agents was assessed using three distinct assays characterized by cell viability, cellular stemness and tumor sphere formation. Using this approach, we found that withaferin A (WA), an Ayurvedic medicine constituent, was a potent inhibitor of CSC stemness leading to cellular senescence primarily via the induction of p21(Cip1) expression. Moreover, WA exhibited strong anti-tumorigenic activity against the iCSCL. These results indicate that our iCSCL model provides an innovative high throughput platform for a simple, easy, and cost-effective method to search for novel CSC-targeting drugs. Furthermore, our current study identified WA as a putative drug candidate for abrogating the stemness and tumor initiating ability of CSCs. C1 [Nishi, Mayuko; Kudoh, Ayumi; Ryo, Akihide] Yokohama City Univ, Sch Med, Dept Microbiol, Yokohama, Kanagawa 232, Japan. [Akutsu, Hidenori; Umezawa, Akihiro] Natl Res Inst Child Hlth & Dev, Dept Reprod Biol, Tokyo, Japan. [Kimura, Hirokazu] Natl Inst Infect Dis, Infect Dis Surveillance Ctr, Tokyo, Japan. [Yamamoto, Naoki] Natl Univ Singapore, Dept Microbiol, Singapore 117548, Singapore. [Lee, Sam W.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. [Lee, Sam W.] Harvard Univ, Sch Med, Charlestown, MA USA. RP Ryo, A (reprint author), Yokohama City Univ, Sch Med, Dept Microbiol, Yokohama, Kanagawa 232, Japan. EM aryo@yokohama-cu.ac.jp FU Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program; Ministry of Education, Culture, Sports, Science and Technology of Japan FX We thank K Miyakawa, Y Watanabe, N Ikawa, H Nishikawa and N Kasuga for their excellent technical assistance. This work was supported in part by Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program and grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to A.R. and M.N.). NR 57 TC 20 Z9 20 U1 0 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 30 PY 2014 VL 5 IS 18 BP 8665 EP 8680 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ1YI UT WOS:000348030900054 PM 25228591 ER PT J AU Moore, NF Azarova, AM Bhatnagar, N Ross, KN Drake, LE Frumm, S Liu, QS Christie, AL Sanda, T Chesler, L Kung, AL Gray, NS Stegmaier, K George, RE AF Moore, Nathan F. Azarova, Anna M. Bhatnagar, Namrata Ross, Kenneth N. Drake, Lauren E. Frumm, Stacey Liu, Qinsong S. Christie, Amanda L. Sanda, Takaomi Chesler, Louis Kung, Andrew L. Gray, Nathanael S. Stegmaier, Kimberly George, Rani E. TI Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma SO ONCOTARGET LA English DT Article DE ALK; neuroblastoma; crizotinib; mTOR inhibitor; MYCN ID TRANSLATION INITIATION; THERAPEUTIC TARGET; AKT; MYC; PHOSPHORYLATION; AMPLIFICATION; ACTIVATION; MECHANISM; CANCERS; TUMORS AB Mutations in the ALK tyrosine kinase receptor gene represent important therapeutic targets in neuroblastoma, yet their clinical translation has been challenging. The ALK(F1174L) mutation is sensitive to the ALK inhibitor crizotinib only at high doses and mediates acquired resistance to crizotinib in ALK-translocated cancers. We have shown that the combination of crizotinib and an inhibitor of downstream signaling induces a favorable response in transgenic mice bearing ALK(F1174L)/MYCN-positive neuroblastoma. Here, we investigated the molecular basis of this effect and assessed whether a similar strategy would be effective in ALK-mutated tumors lacking MYCN overexpression. We show that in ALK-mutated, MYCN-amplified neuroblastoma cells, crizotinib alone does not affect mTORC1 activity as indicated by persistent RPS6 phosphorylation. Combined treatment with crizotinib and an ATP-competitive mTOR inhibitor abrogated RPS6 phosphorylation, leading to reduced tumor growth and prolonged survival in ALK(F1174L)/MYCN-positive models compared to single agent treatment. By contrast, this combination, while inducing mTORC1 downregulation, caused reciprocal upregulation of PI3K activity in ALK-mutated cells expressing wild-type MYCN. Here, an inhibitor with potency against both mTOR and PI3K was more effective in promoting cytotoxicity when combined with crizotinib. Our findings should enable a more precise selection of molecularly targeted agents for patients with ALK-mutated tumors. C1 [Moore, Nathan F.; Azarova, Anna M.; Bhatnagar, Namrata; Drake, Lauren E.; Frumm, Stacey; Sanda, Takaomi; Kung, Andrew L.; Stegmaier, Kimberly; George, Rani E.] Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. [Liu, Qinsong S.; Gray, Nathanael S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Christie, Amanda L.; Kung, Andrew L.] Dana Farber Canc Inst, Lurie Family Imaging Ctr, Boston, MA 02115 USA. [Ross, Kenneth N.; Stegmaier, Kimberly] Broad Inst MIT & Harvard, Cambridge, MA USA. [Liu, Qinsong S.; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem, Boston, MA 02115 USA. [Liu, Qinsong S.; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Mol Pharmacol, Boston, MA 02115 USA. [Sanda, Takaomi] Inst Canc Res, Sutton, Surrey, England. [Chesler, Louis] Canc Sci Inst Singapore, Singapore, Singapore. RP George, RE (reprint author), Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. EM rani_george@dfci.harvard.edu OI Kung, Andrew/0000-0002-9091-488X FU NIH [R01 CA148688]; Sidney Kimmel Translational Scholar Award [SKF-10-112]; Friends for Life Neuroblastoma Foundation FX This study was supported by NIH R01 CA148688 (R.E. George), a Sidney Kimmel Translational Scholar Award, SKF-10-112 (R.E. George) and the Friends for Life Neuroblastoma Foundation (R.E. George and K. Stegmaier). NR 32 TC 19 Z9 19 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 30 PY 2014 VL 5 IS 18 BP 8737 EP 8749 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ1YI UT WOS:000348030900060 PM 25228590 ER PT J AU Kilbourne, AM Almirall, D Eisenberg, D Waxmonsky, J Goodrich, DE Fortney, JC Kirchner, JE Solberg, LI Main, D Bauer, MS Kyle, J Murphy, SA Nord, KM Thomas, MR AF Kilbourne, Amy M. Almirall, Daniel Eisenberg, Daniel Waxmonsky, Jeanette Goodrich, David E. Fortney, John C. Kirchner, Joann E. Solberg, Leif I. Main, Deborah Bauer, Mark S. Kyle, Julia Murphy, Susan A. Nord, Kristina M. Thomas, Marshall R. TI Protocol: Adaptive Implementation of Effective Programs Trial (ADEPT): cluster randomized SMART trial comparing a standard versus enhanced implementation strategy to improve outcomes of a mood disorders program SO IMPLEMENTATION SCIENCE LA English DT Article DE Adaptive intervention; Depression; Health behavior change; Care management ID MENTAL-HEALTH-SERVICES; CARDIOVASCULAR-DISEASE RISK; PRIMARY-CARE PRACTICES; REPLICATING EFFECTIVE PROGRAMS; HIV PREVENTION INTERVENTIONS; PAY-FOR-PERFORMANCE; OF-VETERANS-AFFAIRS; BIPOLAR DISORDER; QUALITY-IMPROVEMENT; COLLABORATIVE CARE AB Background: Despite the availability of psychosocial evidence-based practices (EBPs), treatment and outcomes for persons with mental disorders remain suboptimal. Replicating Effective Programs (REP), an effective implementation strategy, still resulted in less than half of sites using an EBP. The primary aim of this cluster randomized trial is to determine, among sites not initially responding to REP, the effect of adaptive implementation strategies that begin with an External Facilitator (EF) or with an External Facilitator plus an Internal Facilitator (IF) on improved EBP use and patient outcomes in 12 months. Methods/Design: This study employs a sequential multiple assignment randomized trial (SMART) design to build an adaptive implementation strategy. The EBP to be implemented is life goals (LG) for patients with mood disorders across 80 community-based outpatient clinics (N = 1,600 patients) from different U. S. regions. Sites not initially responding to REP (defined as <50% patients receiving >= 3 EBP sessions) will be randomized to receive additional support from an EF or both EF/IF. Additionally, sites randomized to EF and still not responsive will be randomized to continue with EF alone or to receive EF/IF. The EF provides technical expertise in adapting LG in routine practice, whereas the on-site IF has direct reporting relationships to site leadership to support LG use in routine practice. The primary outcome is mental health-related quality of life; secondary outcomes include receipt of LG sessions, mood symptoms, implementation costs, and organizational change. Discussion: This study design will determine whether an off-site EF alone versus the addition of an on-site IF improves EBP uptake and patient outcomes among sites that do not respond initially to REP. It will also examine the value of delaying the provision of EF/IF for sites that continue to not respond despite EF. C1 [Kilbourne, Amy M.; Goodrich, David E.; Kyle, Julia; Nord, Kristina M.] VA Ann Arbor Healthcare Syst, VA Ctr Clin Management Res, Ann Arbor, MI 48105 USA. [Kilbourne, Amy M.; Goodrich, David E.; Kyle, Julia; Nord, Kristina M.] Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI 48109 USA. [Almirall, Daniel; Murphy, Susan A.] Univ Michigan, Inst Social Res, Ann Arbor, MI 48104 USA. [Eisenberg, Daniel] Univ Michigan, Sch Publ Hlth, Dept Hlth Management & Policy, Ann Arbor, MI 48109 USA. [Waxmonsky, Jeanette; Thomas, Marshall R.] Colorado Access, Denver, CO 80231 USA. [Waxmonsky, Jeanette; Thomas, Marshall R.] Univ Colorado, Sch Med, Dept Psychiat, Aurora, CO 80045 USA. [Fortney, John C.] VA Puget Sound Hlth Care Syst, Seattle HSR&D Ctr Innovat Vet Ctr & Value Driven, Seattle, WA 98108 USA. [Kirchner, Joann E.] VA Mental Hlth Qual Enhancement Res Initiat MH QU, North Little Rock, AR 72114 USA. [Kirchner, Joann E.] Univ Arkansas Med Sci, Coll Med, Dept Psychiat, Little Rock, AR 72205 USA. [Solberg, Leif I.] HealthPartners Inst Educ & Res, Bloomington, MN 55425 USA. [Main, Deborah] Univ Colorado, Dept Hlth & Behav Sci, Denver, CO 80217 USA. [Bauer, Mark S.] VA Boston Healthcare Syst, VA Ctr Healthcare Org & Implementat Res, Boston, MA 02130 USA. RP Kilbourne, AM (reprint author), VA Ann Arbor Healthcare Syst, VA Ctr Clin Management Res, 2215 Fuller Rd,Mailstop 152, Ann Arbor, MI 48105 USA. EM amykilbo@umich.edu OI Goodrich, David/0000-0003-3232-2189 FU National Institute of Mental Health [R01 099898] FX This research was supported by the National Institute of Mental Health (R01 099898). The views expressed in this article are those of the authors and do not necessarily represent the views of the VA. NR 122 TC 2 Z9 2 U1 6 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD SEP 30 PY 2014 VL 9 AR UNSP 132 DI 10.1186/s13012-014-0132-x PG 14 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AU2GY UT WOS:000345435700001 PM 25267385 ER PT J AU Meagher, DJ Morandi, A Inouye, SK Ely, W Adamis, D Maclullich, AJ Rudolph, JL Neufeld, K Leonard, M Bellelli, G Davis, D Teodorczuk, A Kreisel, S Thomas, C Hasemann, W Timmons, S O'Regan, N Grover, S Jabbar, F Cullen, W Dunne, C Kamholz, B Van Munster, BC De Rooij, SE De Jonghe, J Trzepacz, PT AF Meagher, David J. Morandi, Alessandro Inouye, Sharon K. Ely, Wes Adamis, Dimitrios Maclullich, Alasdair J. Rudolph, James L. Neufeld, Karin Leonard, Maeve Bellelli, Giuseppe Davis, Daniel Teodorczuk, Andrew Kreisel, Stefan Thomas, Christine Hasemann, Wolfgang Timmons, Suzanne O'Regan, Niamh Grover, Sandeep Jabbar, Faiza Cullen, Walter Dunne, Colum Kamholz, Barbara Van Munster, Barbara C. De Rooij, Sophia E. De Jonghe, Jos Trzepacz, Paula T. TI Concordance between DSM-IV and DSM-5 criteria for delirium diagnosis in a pooled database of 768 prospectively evaluated patients using the delirium rating scale-revised-98 SO BMC MEDICINE LA English DT Article DE Delirium; Classification; Diagnosis; Cognition; Neurocognitive disorders; Dementia ID CONFUSION ASSESSMENT METHOD; MEDICAL INPATIENTS; SCALE REVISED-98; DEMENTIA; PHENOMENOLOGY; VALIDATION; BEDSIDE; COHORT; RISK; CARE AB Background: The Diagnostic and Statistical Manual fifth edition (DSM-5) provides new criteria for delirium diagnosis. We examined delirium diagnosis using these new criteria compared with the Diagnostic and Statistical Manual fourth edition (DSM-IV) in a large dataset of patients assessed for delirium and related presentations. Methods: Patient data (n = 768) from six prospectively collected cohorts, clinically assessed using DSM-IV and the Delirium Rating Scale-Revised-98 (DRS-R98), were pooled. Post hoc application of DRS-R98 item scores were used to rate DSM-5 criteria. 'Strict' and 'relaxed' DSM-5 criteria to ascertain delirium were compared to rates determined by DSM-IV. Results: Using DSM-IV by clinical assessment, delirium was found in 510/768 patients (66%). Strict DSM-5 criteria categorized 158 as delirious including 155 (30%) with DSM-IV delirium, whereas relaxed DSM-5 criteria identified 466 as delirious, including 455 (89%) diagnosed by DSM-IV (P < 0.001). The concordance between the different diagnostic methods was: 53% (kappa = 0.22) between DSM-IV and the strict DSM-5, 91% (kappa = 0.82) between the DSM-IV and relaxed DSM-5 criteria and 60% (kappa = 0.29) between the strict versus relaxed DSM-5 criteria. Only 155 cases were identified as delirium by all three approaches. The 55 (11%) patients with DSM-IV delirium who were not rated as delirious by relaxed criteria had lower mean DRS-R98 total scores than those rated as delirious (13.7 +/- 3.9 versus 23.7 +/- 6.0; P < 0.001). Conversely, mean DRS-R98 score (21.1 +/- 6.4) for the 70% not rated as delirious by strict DSM-5 criteria was consistent with suggested cutoff scores for full syndromal delirium. Only 11 cases met DSM-5 criteria that were not deemed to have DSM-IV delirium. Conclusions: The concordance between DSM-IV and the new DSM-5 delirium criteria varies considerably depending on the interpretation of criteria. Overly-strict adherence for some new text details in DSM-5 criteria would reduce the number of delirium cases diagnosed; however, a more 'relaxed' approach renders DSM-5 criteria comparable to DSM-IV with minimal impact on their actual application and is thus recommended. C1 [Meagher, David J.; Leonard, Maeve; Cullen, Walter; Dunne, Colum] Univ Limerick, Grad Entry Med Sch, Limerick, Ireland. [Meagher, David J.; Adamis, Dimitrios; Leonard, Maeve; Cullen, Walter; Dunne, Colum] Univ Limerick, Grad Entry Med Sch, Ctr Intervent Infect Inflammat & Immun 4i, Cognit Impairment Res Grp, Limerick, Ireland. [Meagher, David J.; Leonard, Maeve] Univ Hosp Limerick, Dept Psychiat, Limerick, Ireland. [Morandi, Alessandro] Rehabil & Aged Care Unit Hosp Ancelle, Cremona, Italy. [Morandi, Alessandro; Bellelli, Giuseppe] Geriatr Res Grp, Brescia, Italy. [Inouye, Sharon K.] Hebrew SeniorLife, Inst Aging Res, Aging Brain Ctr, Boston, MA USA. [Inouye, Sharon K.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Gerontol,Dept Med, Boston, MA 02215 USA. [Ely, Wes] Vanderbilt Univ, Ctr Med, Nashville, TN 37232 USA. [Ely, Wes] Tennessee Valley VA Geriatr Res Educ Clin Ctr GRE, Nashville, TN USA. [Adamis, Dimitrios] Res & Acad Inst Athens, Athens 10677, Greece. [Adamis, Dimitrios] Sligo Mental Hlth Serv, Ballytivan, Sligo, Ireland. [Maclullich, Alasdair J.] Univ Edinburgh, Sch Clin Sci, Div Hlth Sci, Edinburgh Delirium Res Grp, Edinburgh, Midlothian, Scotland. [Maclullich, Alasdair J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Rudolph, James L.] VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, Boston, MA USA. [Rudolph, James L.] VA Boston Healthcare Syst, Div Geriatr & Palliat Care, Boston, MA USA. [Rudolph, James L.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Rudolph, James L.] Harvard Univ, Sch Med, Boston, MA USA. [Neufeld, Karin] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Bellelli, Giuseppe] Univ Milano Bicocca, Monza, Italy. [Bellelli, Giuseppe] San Gerardo Hosp, Monza, Italy. [Davis, Daniel] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Teodorczuk, Andrew] Newcastle Univ, Inst Ageing & Hlth, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Kreisel, Stefan] Bethel Evangel Krankenhaus, Dept Psychiat & Psychotherapy, Bielefeld, Germany. [Thomas, Christine] Klinikum Stuttgart, Ctr Mental Hlth, Dept Psychiat & Psychotherapy Aged, Stuttgart, Germany. [Hasemann, Wolfgang] Univ Basel Hosp, CH-4031 Basel, Switzerland. [Timmons, Suzanne; O'Regan, Niamh] Natl Univ Ireland Univ Coll Cork, Sch Med, Ctr Gerontol & Rehabil, Cork, Ireland. [Grover, Sandeep] Postgrad Inst Med Educ & Res, Dept Psychiat, Chandigarh 160012, India. [Jabbar, Faiza] Univ Coll Hosp, Psychiat Later Life Serv, Galway, Ireland. [Kamholz, Barbara] San Francisco VA Med Ctr, Mental Hlth Serv, San Francisco, CA USA. [Van Munster, Barbara C.; De Rooij, Sophia E.] Univ Amsterdam, Acad Med Ctr, Dept Internal Med, Geriatr Sect, NL-1105 AZ Amsterdam, Netherlands. [Van Munster, Barbara C.] Gelre Hosp, Dept Geriatr, Apeldoorn, Netherlands. [De Jonghe, Jos] Med Ctr Alkmaar, Dept Geriatr Med, Alkmaar, Netherlands. [Trzepacz, Paula T.] Lilly Res Labs, Indianapolis, IN USA. [Trzepacz, Paula T.] Univ Mississippi, Sch Med, Jackson, MS 39216 USA. [Trzepacz, Paula T.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Trzepacz, Paula T.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. RP Meagher, DJ (reprint author), Univ Limerick, Grad Entry Med Sch, Limerick, Ireland. EM david.meagher@ul.ie RI O'Regan, Niamh/I-6798-2016; Davis, Daniel/F-9995-2012; OI O'Regan, Niamh/0000-0003-2510-2495; Davis, Daniel/0000-0002-1560-1955; Cullen, Walter/0000-0003-1838-5052; Adamis, Dimitrios/0000-0003-1315-1695; Bellelli, Giuseppe/0000-0001-5430-0947; MacLullich, Alasdair/0000-0003-3159-9370; Teodorczuk, Andrew/0000-0003-0802-718X; Hasemann, Wolfgang/0000-0003-2417-3785 FU Johns Hopkins University from Ornim Medical LTD (PI Mandal); Wellcome Trust Research Training Fellowship [WT090661]; Health Research Board and All-Ireland Institute of Palliative Care; Swiss Alzheimer Association; Alzheimervereinigung beider Basel FX No specific funding was used to support this research. All of the authors are either members of the European Delirium Association or American Delirium Society, or both. PT is a salaried employee and shareholder of Eli Lilly and Company. Eli Lilly and Company do not presently have any product licensed for the treatment of delirium. Karin Neufeld receives Grant funding to Johns Hopkins University from Ornim Medical LTD (PI Mandal) for work exploring "The Relationship between NIRS and Delirium (Study of CerOx321F)" The purpose of this study is to understand the relationship between intraoperative cerebral autoregulation of blood pressure using the CerOx321F monitor and incidence of postoperative delirium in a group of older aged patients undergoing cardiac surgery who are free of delirium and major cognitive deficits in the preoperative setting. Daniel Davis was supported by a Wellcome Trust Research Training Fellowship (WT090661). David Meagher, Suzanne Timmons, Maeve Leonard and Niamh O'Regan are in receipt of project grants from the Health Research Board and All-Ireland Institute of Palliative Care. Wolfgang Hasemann has received funding from the Swiss Alzheimer Association and the Alzheimervereinigung beider Basel. The other authors declare that they have no competing interests. NR 39 TC 16 Z9 16 U1 5 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD SEP 30 PY 2014 VL 12 AR 164 DI 10.1186/s12916-014-0164-8 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AT4DF UT WOS:000344889100001 PM 25266390 ER PT J AU Bhattacharyya, S Kim, M AF Bhattacharyya, Shamik Kim, Minjee TI Cervical spine fracture associated with ankylosing spondylitis SO NEUROLOGY LA English DT Editorial Material C1 [Bhattacharyya, Shamik] Massachusetts Gen Hosp, Brigham & Womens Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Bhattacharyya, S (reprint author), Massachusetts Gen Hosp, Brigham & Womens Hosp, Boston, MA 02114 USA. EM sbhattacharyya3@partners.org NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 30 PY 2014 VL 83 IS 14 BP 1297 EP 1297 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AT3UN UT WOS:000344860700018 PM 25267984 ER PT J AU Alshareef, M Krishna, V Ferdous, J Alshareef, A Kindy, M Kolachalama, VB Shazly, T AF Alshareef, Mohammed Krishna, Vibhor Ferdous, Jahid Alshareef, Ahmed Kindy, Mark Kolachalama, Vijaya B. Shazly, Tarek TI Effect of Spinal Cord Compression on Local Vascular Blood Flow and Perfusion Capacity SO PLOS ONE LA English DT Article ID NO-REFLOW PHENOMENON; CEREBROSPINAL-FLUID; FINITE-ELEMENT; CERVICAL-SPINE; INJURY MODEL; TRAUMA; MECHANISMS; PATHOPHYSIOLOGY; NOREPINEPHRINE; PRESSURE AB Spinal cord injury (SCI) can induce prolonged spinal cord compression that may result in a reduction of local tissue perfusion, progressive ischemia, and potentially irreversible tissue necrosis. Due to the combination of risk factors and the varied presentation of symptoms, the appropriate method and time course for clinical intervention following SCI are not always evident. In this study, a three-dimensional finite element fluid-structure interaction model of the cervical spinal cord was developed to examine how traditionally sub-clinical compressive mechanical loads impact spinal arterial blood flow. The spinal cord and surrounding dura mater were modeled as linear elastic, isotropic, and incompressible solids, while blood was modeled as a single-phased, incompressible Newtonian fluid. Simulation results indicate that anterior, posterior, and anteroposterior compressions of the cervical spinal cord have significantly different ischemic potentials, with prediction that the posterior component of loading elevates patient risk due to the concomitant reduction of blood flow in the arterial branches. Conversely, anterior loading compromises flow through the anterior spinal artery but minimally impacts branch flow rates. The findings of this study provide novel insight into how sub-clinical spinal cord compression could give rise to certain disease states, and suggest a need to monitor spinal artery perfusion following even mild compressive loading. C1 [Alshareef, Mohammed] Med Univ S Carolina, Coll Med, Charleston, SC 29425 USA. [Krishna, Vibhor; Kindy, Mark] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Ferdous, Jahid; Shazly, Tarek] Univ S Carolina, Biomed Engn Program, Columbia, SC 29208 USA. [Alshareef, Ahmed] Duke Univ, Dept Biomed Engn, Durham, NC 27706 USA. [Kindy, Mark] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Kolachalama, Vijaya B.] Charles Stark Draper Lab, Cambridge, MA USA. [Shazly, Tarek] Univ S Carolina, Dept Mech Engn, Columbia, SC 29208 USA. RP Shazly, T (reprint author), Univ S Carolina, Biomed Engn Program, Columbia, SC 29208 USA. EM shazly@mailbox.sc.edu FU National Science Foundation [EPS-0903795, IIP-917987]; National Institutes of Health [R01 ES016774-01, 5 P20 RR016461, 8P20GM103444-04, P20RR021949-03]; VA Merit Award; Charles Stark Draper Laboratory [CSDL-29414-005] FX This work was supported by the National Science Foundation (EPS-0903795 and IIP-917987), the National Institutes of Health (R01 ES016774-01, 5 P20 RR016461, 8P20GM103444-04 and P20RR021949-03), a VA Merit Award, and a grant (CSDL-29414-005) from the Charles Stark Draper Laboratory. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 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 SEP 30 PY 2014 VL 9 IS 9 AR e108820 DI 10.1371/journal.pone.0108820 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR6CW UT WOS:000343671700170 PM 25268384 ER PT J AU Liao, J Jijon, HB Kim, IR Goel, G Sokol, H Bauer, H Herrmann, BG Lassen, KG Xavier, RJ AF Liao, Juan Jijon, Humberto B. Kim, Ira R. Goel, Gautam Sokol, Harry Bauer, Hermann Herrmann, Bernhard G. Lassen, Kara G. Xavier, Ramnik J. TI An Image-Based Genetic Assay Identifies Genes in T1D Susceptibility Loci Controlling Cellular Antiviral Immunity in Mouse SO PLOS ONE LA English DT Article ID HERPES-SIMPLEX-VIRUS; GENOME-WIDE ASSOCIATION; NF-KAPPA-B; TOLL-LIKE RECEPTORS; RHEUMATOID-ARTHRITIS RISK; I INTERFERON-PRODUCTION; GAMMA-INTERFERON; RIG-I; INTERLEUKIN-27 EXPRESSION; SIGNALING PROTEIN AB The pathogenesis of complex diseases, such as type 1 diabetes (T1D), derives from interactions between host genetics and environmental factors. Previous studies have suggested that viral infection plays a significant role in initiation of T1D in genetically predisposed individuals. T1D susceptibility loci may therefore be enriched in previously uncharacterized genes functioning in antiviral defense pathways. To identify genes involved in antiviral immunity, we performed an image-based high-throughput genetic screen using short hairpin RNAs (shRNAs) against 161 genes within T1D susceptibility loci. RAW 264.7 cells transduced with shRNAs were infected with GFP-expressing herpes simplex virus type 1 (HSV-1) and fluorescent microscopy was performed to assess the viral infectivity by fluorescence reporter activity. Of the 14 candidates identified with high confidence, two candidates were selected for further investigation, Il27 and Tagap. Administration of recombinant IL-27 during viral infection was found to act synergistically with interferon gamma (IFN-gamma) to activate expression of type I IFNs and proinflammatory cytokines, and to enhance the activities of interferon regulatory factor 3 (IRF3). Consistent with a role in antiviral immunity, Tagap-deficient macrophages demonstrated increased viral replication, reduced expression of proinflammatory chemokines and cytokines, and decreased production of IFN-beta. Taken together, our unbiased loss-of-function genetic screen identifies genes that play a role in host antiviral immunity and delineates roles for IL-27 and Tagap in the production of antiviral cytokines. C1 [Liao, Juan; Jijon, Humberto B.; Kim, Ira R.; Goel, Gautam; Lassen, Kara G.; Xavier, Ramnik J.] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA 02142 USA. [Liao, Juan; Jijon, Humberto B.; Kim, Ira R.; Goel, Gautam; Sokol, Harry; Lassen, Kara G.; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA. [Jijon, Humberto B.; Kim, Ira R.; Goel, Gautam; Bauer, Hermann; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Ctr Study Inflammatory Bowe, Boston, MA USA. [Jijon, Humberto B.] Univ Calgary, Dept Med, Div Gastroenterol, Calgary, AB, Canada. [Sokol, Harry] St Antoine Hosp, AP HP, Dept Gastroenterol, Paris, France. [Bauer, Hermann; Herrmann, Bernhard G.] Max Planck Inst Mol Genet, D-14195 Berlin, Germany. RP Xavier, RJ (reprint author), Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA 02142 USA. EM xavier@molbio.mgh.harvard.edu OI sokol, harry/0000-0002-2914-1822 FU Leona M. and Harry B. Helmsley Charitable Trust; Juvenile Diabetes Research Foundation FX This research was funded by the Leona M. and Harry B. Helmsley Charitable Trust (www.helmsleytrust.org) and Juvenile Diabetes Research Foundation (www.jdrf.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 2 Z9 2 U1 2 U2 5 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 SEP 30 PY 2014 VL 9 IS 9 AR e108777 DI 10.1371/journal.pone.0108777 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR6CW UT WOS:000343671700162 PM 25268627 ER PT J AU Podrid, PJ AF Podrid, Philip J. TI Response to Letter Regarding Article, "ECG Response: May 20, 2014" SO CIRCULATION LA English DT Letter C1 [Podrid, Philip J.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Podrid, Philip J.] Harvard Univ, Sch Med, Boston, MA USA. [Podrid, Philip J.] VA Boston Healthcare Syst, Boston, MA USA. RP Podrid, PJ (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD SEP 30 PY 2014 VL 130 IS 14 BP E128 EP E128 DI 10.1161/CIRCULATIONAHA.114.012965 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AQ8CA UT WOS:000343048800004 PM 25266866 ER PT J AU Gard, T Noggle, JJ Park, CL Vago, DR Wilson, A AF Gard, Tim Noggle, Jessica J. Park, Crystal L. Vago, David R. Wilson, Angela TI Potential self-regulatory mechanisms of yoga for psychological health SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE yoga; self-regulation; stress; executive control; viscerosomatic; top-down; bottom-up ID CARDIAC VAGAL TONE; POSTTRAUMATIC-STRESS-DISORDER; AUTONOMIC NERVOUS-SYSTEM; EMOTION-REGULATION; MEDITATION PRACTITIONERS; MINDFULNESS PRACTICE; COGNITIVE CONTROL; CHEMOREFLEX RESPONSE; PHYSICAL-ACTIVITY; BREATH AWARENESS AB Research suggesting the beneficial effects of yoga on myriad aspects of psychological health has proliferated in recent years, yet there is currently no overarching framework by which to understand yoga's potential beneficial effects. Here we provide a theoretical framework and systems-based network model of yoga that focuses on integration of top-down and bottom-up forms of self-regulation. We begin by contextualizing yoga in historical and contemporary settings, and then detail how specific components of yoga practice may affect cognitive, emotional, behavioral, and autonomic output under stress through an emphasis on interoception and bottom-up input, resulting in physical and psychological health. The model describes yoga practice as a comprehensive skillset of synergistic process tools that facilitate bidirectional feedback and integration between high- and low-level brain networks, and afferent and re-afferent input from interoceptive processes (somatosensory, viscerosensory, chemosensory). From a predictive coding perspective we propose a shift to perceptual inference for stress modulation and optimal self-regulation. We describe how the processes that sub-serve self-regulation become more automatized and efficient over time and practice, requiring less effort to initiate when necessary and terminate more rapidly when no longer needed. To support our proposed model, we present the available evidence for yoga affecting self-regulatory pathways, integrating existing constructs from behavior theory and cognitive neuroscience with emerging yoga and meditation research. This paper is intended to guide future basic and clinical research, specifically targeting areas of development in the treatment of stress-mediated psychological disorders. C1 [Gard, Tim] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Gard, Tim] Univ Giessen, Bender Inst Neuroimaging, D-35390 Giessen, Germany. [Gard, Tim] Maastricht Univ, Fac Psychol & Neurosci, Maastricht, Netherlands. [Noggle, Jessica J.; Vago, David R.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA USA. [Noggle, Jessica J.] Brigham & Womens Hosp, Div Sleep & Circadian Disorders, Boston, MA 02467 USA. [Park, Crystal L.] Univ Connecticut, Dept Psychol, Storrs, CT USA. [Vago, David R.] Brigham & Womens Hosp, Dept Psychiat, Funct Neuroimaging Lab, Boston, MA 02467 USA. [Wilson, Angela] Kripalu Ctr Yoga & Hlth, Inst Extraordinary Living, Stockbridge, MA USA. RP Vago, DR (reprint author), Brigham & Womens Hosp, Dept Psychiat, Funct Neuroimaging Lab, 824 Boylston St, Boston, MA 02467 USA. EM dvago@bics.bwh.harvard.edu OI Vago, David/0000-0002-6269-9027 NR 186 TC 30 Z9 31 U1 18 U2 73 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD SEP 30 PY 2014 VL 8 AR 770 DI 10.3389/fnhum.2014.00770 PG 20 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AP8PA UT WOS:000342339700001 PM 25368562 ER PT J AU Lepage, KQ Kramer, MA Chu, CJ AF Lepage, Kyle Q. Kramer, Mark A. Chu, Catherine J. TI A statistically robust EEG re-referencing procedure to mitigate reference effect SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article ID COMMON SPATIAL-PATTERNS; INFINITY REFERENCE; AVERAGE REFERENCE; ELECTROENCEPHALOGRAPHY; STANDARDIZE; POTENTIALS; COHERENCY; SIGNAL AB Background: The electroencephalogram (EEG) remains the primary tool for diagnosis of abnormal brain activity in clinical neurology and for in vivo recordings of human neurophysiology in neuroscience research. In EEG data acquisition, voltage is measured at positions on the scalp with respect to a reference electrode. When this reference electrode responds to electrical activity or artifact all electrodes are affected. Successful analysis of EEG data often involves re-referencing procedures that modify the recorded traces and seek to minimize the impact of reference electrode activity upon functions of the original EEG recordings. New method: We provide a novel, statistically robust procedure that adapts a robust maximum-likelihood type estimator to the problem of reference estimation, reduces the influence of neural activity from the re-referencing operation, and maintains good performance in a wide variety of empirical scenarios. Results: The performance of the proposed and existing re-referencing procedures are validated in simulation and with examples of EEG recordings. To facilitate this comparison, channel-to-channel correlations are investigated theoretically and in simulation. Comparison with existing methods: The proposed procedure avoids using data contaminated by neural signal and remains unbiased in recording scenarios where physical references, the common average reference (CAR) and the reference estimation standardization technique (REST) are not optimal. Conclusion: The proposed procedure is simple, fast, and avoids the potential for substantial bias when analyzing low-density EEG data. (C) 2014 Elsevier B.V. All rights reserved. C1 [Lepage, Kyle Q.; Kramer, Mark A.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Chu, Catherine J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Lepage, KQ (reprint author), Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. EM lepage@math.bu.edu; mak@bu.edu FU Burroughs Welcome Fund; NIH [5K12NS066225-03]; [DMS-1042134] FX KQL is supported by DMS-1042134. MAK holds a career award at the scientific interface from the Burroughs Welcome Fund. CJC is supported by NIH 5K12NS066225-03. NR 39 TC 6 Z9 7 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 SEP 30 PY 2014 VL 235 BP 101 EP 116 DI 10.1016/j.jneumeth.2014.05.008 PG 16 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AP7PO UT WOS:000342269400012 PM 24975291 ER PT J AU Schmeidler, J Lazzeroni, LC Swerdlow, NR Ferreira, RP Braff, DL Calkins, ME Cadenhead, KS Freedman, R Green, MF Greenwood, TA Gur, RE Gur, RC Light, GA Olincy, A Nuechterlein, KH Radant, AD Seidman, LJ Siever, LJ Stone, WS Sprock, J Sugar, CA Tsuang, DW Tsuang, MT Turetsky, BI Silverman, JM AF Schmeidler, James Lazzeroni, Laura C. Swerdlow, Neal R. Ferreira, Rui P. Braff, David L. Calkins, Monica E. Cadenhead, Kristin S. Freedman, Robert Green, Michael F. Greenwood, Tiffany A. Gur, Raquel E. Gur, Ruben C. Light, Gregory A. Olincy, Ann Nuechterlein, Keith H. Radant, Allen D. Seidman, Larry J. Siever, Larry J. Stone, William S. Sprock, Joyce Sugar, Catherine A. Tsuang, Debby W. Tsuang, Ming T. Turetsky, Bruce I. Silverman, Jeremy M. TI Paternal age of schizophrenia probands and endophenotypic differences from unaffected siblings SO PSYCHIATRY RESEARCH LA English DT Article DE De novo mutations; Copy number variants; Genetic risk; Familial schizophrenia; Sporadic schizophrenia ID DE-NOVO MUTATIONS; AUDITORY WORKING-MEMORY; RISK; GENETICS; PERFORMANCE; CONSORTIUM; STARTLE AB We evaluated the discrepancy of endophenotypic performance between probands with schizophrenia and unaffected siblings by paternal age at proband birth, a possible marker for de novo mutations. Pairs of schizophrenia probands and unaffected siblings (N=220 pairs) were evaluated on 11 neuropsychological or neurophysiological endophenotypes previously identified as heritable. For each endophenotype, the sibling-minus-proband differences were transformed to standardized scores. Then for each pair, the average discrepancy was calculated from its standardized scores. We tested the hypothesis that the discrepancy is associated with paternal age, controlling for the number of endophenotypes shared between proband and his or her sibling, and proband age, which were both associated with paternal age. The non-significant association between the discrepancy and paternal age was in the opposite direction from the hypothesis. Of the 11 endophenotypes only sensori-motor dexterity was significant, but in the opposite direction. Eight other endophenotypes were also in the opposite direction, but not significant. The results did not support the hypothesized association of increased differences between sibling/proband pairs with greater paternal age. A possible explanation is that the identification of heritable endophenotypes was based on samples for which schizophrenia was attributable to inherited rather than de novo/non-inherited causes. Published by Elsevier Ireland Ltd. C1 [Schmeidler, James; Ferreira, Rui P.; Siever, Larry J.; Silverman, Jeremy M.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Lazzeroni, Laura C.] Stanford Univ, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. [Swerdlow, Neal R.; Braff, David L.; Cadenhead, Kristin S.; Greenwood, Tiffany A.; Light, Gregory A.; Sprock, Joyce; Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Braff, David L.; Light, Gregory A.] VA San Diego Healthcare Syst, Educ & Clin Ctr, VISN Mental Illness Res 22, San Diego, CA USA. [Calkins, Monica E.; Gur, Raquel E.; Gur, Ruben C.; Turetsky, Bruce I.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Freedman, Robert; Olincy, Ann] Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Denver, CO 80262 USA. [Green, Michael F.; Nuechterlein, Keith H.; Sugar, Catherine A.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Geffen Sch Med, Los Angeles, CA 90024 USA. [Green, Michael F.; Sugar, Catherine A.] VA Greater Angeles Hlth Care Syst, Los Angeles, CA USA. [Radant, Allen D.; Tsuang, Debby W.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Seidman, Larry J.; Stone, William S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med,Dept Psychiat, Massachusetts Mental Hlth Ctr,Publ Psychiat Div, Boston, MA 02215 USA. [Siever, Larry J.] James J Peters VA Med Ctr, VISN Mental Illness Res Educ & Clin Ctr 3, New York, NY USA. [Tsuang, Debby W.] VA Puget Sound Hlth Care Syst, VISN Geriatr Res Educ & Clin Ctr 20, Seattle, WA USA. [Silverman, Jeremy M.] James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. RP Silverman, JM (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, One Gustave L Levy Pl,Box 1230, New York, NY 10029 USA. EM jeremy.silverman@mssm.edu RI Tsuang, Debby/L-7234-2016; OI Tsuang, Debby/0000-0002-4716-1894; Lazzeroni, Laura/0000-0002-1846-6920; Greenwood, Tiffany/0000-0002-6080-6503 FU NIMH [R01 MH65571, R01 MH042228, R01 MH65588, R01 MH65562, R01 MH65707, R01 MH65554, R01 MH65578, R01 MH086135, R01 MH65558] FX This material is based upon work supported by NIMH grants R01 MH65571, R01 MH042228, R01 MH65588, R01 MH65562, R01 MH65707, R01 MH65554, R01 MH65578, R01 MH086135, and R01 MH65558. We are grateful to all the subjects who participated in this study. NR 25 TC 1 Z9 1 U1 0 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD SEP 30 PY 2014 VL 219 IS 1 BP 67 EP 71 DI 10.1016/j.psychres.2014.05.035 PG 5 WC Psychiatry SC Psychiatry GA AL4ZQ UT WOS:000339143700006 PM 24913833 ER PT J AU Lynn, SK Hoge, EA Fischer, LE Barrett, LF Simon, NM AF Lynn, Spencer K. Hoge, Elizabeth A. Fischer, Laura E. Barrett, Lisa Feldman Simon, Naomi M. TI Gender differences in oxytocin-associated disruption of decision bias during emotion perception SO PSYCHIATRY RESEARCH LA English DT Article DE Signal detection theory; Face perception; Risk sensitivity; Behavioral economics ID INTRANASAL OXYTOCIN; FACIAL EXPRESSIONS; SOCIAL COGNITION; NEURAL CIRCUITRY; HUMANS; RECOGNITION; TRUST; METAANALYSIS; SENSITIVITY; DEPRESSION AB Oxytocin is associated with differences in the perception of and response to socially mediated information, such as facial expressions. Across studies, however, oxytocin's effect on emotion perception has been inconsistent. Outside the laboratory, emotion perception involves interpretation of perceptual uncertainty and assessment of behavioral risk. An account of these factors is largely missing from studies of oxytocin's effect on emotion perception and might explain inconsistent results across studies. Of relevance, studies of oxytocin's effect on learning and decision-making indicate that oxytocin attenuates risk aversion. We used the probability of encountering angry faces and the cost of misidentifying them as not angry to create a risky environment wherein bias to categorize faces as angry would maximize point earnings. Consistent with an underestimation of the factors creating risk (i.e., encounter rate and cost), men given oxytocin exhibited a worse (i.e., less liberal) response bias than men given placebo. Oxytocin did not influence women's performance. These results suggest that oxytocin may impair men's ability to adapt to changes in risk and uncertainty when introduced to novel or changing social environments. Because oxytocin also influences behavior in non-social realms, oxytocin pharmacotherapy could have unintended consequences (i.e., risk-prone decision-making) while nonetheless normalizing pathological social interaction. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Lynn, Spencer K.; Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Hoge, Elizabeth A.; Fischer, Laura E.; Simon, Naomi M.] Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Dept Psychiat, Boston, MA 02114 USA. [Barrett, Lisa Feldman] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Barrett, Lisa Feldman] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA USA. RP Lynn, SK (reprint author), Northeastern Univ, Dept Psychol, 360 Huntington Ave, Boston, MA 02115 USA. EM s.lynn@neu.edu RI Hoge, Elizabeth/H-5879-2012 OI Hoge, Elizabeth/0000-0002-5513-2292 FU Highland Street Foundation; National Institutes of Health [R01MH093394, DP1OD 003312] FX We thank the members of the Interdisciplinary Affective Science Laboratory, Dept. Psychology, Northeastern University, for helpful feedback during the development of the manuscript. Preparation of this manuscript was supported by the Highland Street Foundation (Hoge, Simon, Fischer) and the National Institutes of Health (R01MH093394 to Lynn & Simon and DP1OD 003312 to Barrett). NR 41 TC 8 Z9 8 U1 0 U2 16 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD SEP 30 PY 2014 VL 219 IS 1 BP 198 EP 203 DI 10.1016/j.psychres.2014.04.031 PG 6 WC Psychiatry SC Psychiatry GA AL4ZQ UT WOS:000339143700026 PM 24814142 ER PT J AU Tan-McGrory, A Betancourt, J AF Tan-McGrory, Aswita Betancourt, Joseph TI Addressing language barriers and improving quality of transitions and discharge SO ISRAEL JOURNAL OF HEALTH POLICY RESEARCH LA English DT Editorial Material ID LENGTH-OF-STAY; READMISSIONS; DISPARITIES; CONCORDANCE; CARE AB The article by Rayan et al., "Transitions from Hospital to Community Care: the Role of Patient-Provider Language Concordance", highlights the importance of language-concordant communication and care during the hospital discharge process. These findings are completely in line with previous research on the impact of language barriers on quality of care. We strongly agree with Rayan et al. and the findings of this important research, and support efforts that help meet the cultural and linguistic needs of patients. Undoubtedly, patient-provider language concordance during the hospitalization discharge process and post discharge follow-up have important implications for health care transitions, quality, and costs. How can hospitals improve their performance in this area? Based on extensive research, there are currently two major hospital guides that were developed in the United States that focus on this area-improving communication and care for patients of diverse backgrounds and with language barriers. One, Project RED-or Re-Engineered Discharge, and the second, Improving Patient Safety Systems for Patients With Limited English Proficiency: A Guide for Hospitals, both aim to address these challenges. If we are to truly delivery high-quality, safe, cost-effective care, meeting the needs of patients who experience language barriers during health care will be essential as global migration and diversity increases every day. C1 [Tan-McGrory, Aswita; Betancourt, Joseph] Massachusetts Gen Hosp, Dispar Solut Ctr, Boston, MA 02114 USA. RP Betancourt, J (reprint author), Massachusetts Gen Hosp, Dispar Solut Ctr, 50 Staniford St,9th Floor,Suite 901, Boston, MA 02114 USA. EM jbetancourt@partners.org NR 12 TC 0 Z9 0 U1 2 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-4015 J9 ISR J HEALTH POLICY JI Isr. J. Health Policy Res. PD SEP 29 PY 2014 VL 3 AR 31 DI 10.1186/2045-4015-3-31 PG 3 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AS1HG UT WOS:000344031000002 ER PT J AU Kai, X Chellappa, V Donado, C Reyon, D Sekigami, Y Ataca, D Louissaint, A Mattoo, H Joung, JK Pillai, S AF Kai, Xin Chellappa, Vasant Donado, Carlos Reyon, Deepak Sekigami, Yurie Ataca, Dalya Louissaint, Abner Mattoo, Hamid Joung, J. Keith Pillai, Shiv TI I kappa B Kinase beta(IKBKB) Mutations in Lymphomas That Constitutively Activate Canonical Nuclear Factor kappa B (NF kappa B) Signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MARGINAL ZONE LYMPHOMA; CELL LYMPHOMA; GENOME; LYMPHOCYTES; NOTCH2; PROLIFERATION; REGULATOR; MULTIPLE; PATHWAY; TALENS AB Somatic mutations altering lysine 171 of the IKBKB gene that encodes (IKK beta), the critical activating kinase in canonical (NF kappa B) signaling, have been described in splenic marginal zone lymphomas and multiple myeloma. Lysine 171 forms part of a cationic pocket that interacts with the activation loop phosphate in the activated wild type kinase. We show here that K171E IKK beta and K171T IKK beta represent kinases that are constitutively active even in the absence of activation loop phosphorylation. Predictive modeling and biochemical studies establish why mutations in a positively charged residue in the cationic pocket of an activation loop phosphorylation-dependent kinase result in constitutive activation. Transcription activator-like effector nuclease-based knock-in mutagenesis provides evidence from a B lymphoid context that K171E IKK beta contributes to lymphomagenesis. C1 [Kai, Xin; Chellappa, Vasant; Donado, Carlos; Sekigami, Yurie; Ataca, Dalya; Mattoo, Hamid; Pillai, Shiv] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res, Boston, MA 02129 USA. [Reyon, Deepak; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA 02129 USA. [Louissaint, Abner; Joung, J. Keith] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Louissaint, Abner; Joung, J. Keith] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Pillai, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res, Boston, MA 02129 USA. EM pillai@helix.mgh.harvard.edu OI Ataca, Dalya/0000-0003-3964-5618 FU National Institutes of Health [AI 064930, AI 076505]; National Institutes of Health Director's Pioneer Award [DP1 GM105378] FX This work was supported, in whole or in part, by Grants AI 064930 and AI 076505 from the National Institutes of Health (to S. P.) and National Institutes of Health Director's Pioneer Award DP1 GM105378 (to J. K. J.). J. K. J. has a financial interest in Editas Medicine and Transposagen Biopharmaceuticals. J. K. J.'s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. NR 35 TC 5 Z9 6 U1 0 U2 5 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 SEP 26 PY 2014 VL 289 IS 39 BP 26960 EP 26972 DI 10.1074/jbc.M114.598763 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AQ5MS UT WOS:000342853900026 PM 25107905 ER PT J AU Bourgeois, EB Johnson, BN McCoy, AJ Trippa, L Cohen, AS Marsh, ED AF Bourgeois, Elliot B. Johnson, Brian N. McCoy, Almedia J. Trippa, Lorenzo Cohen, Akiva S. Marsh, Eric D. TI A Toolbox for Spatiotemporal Analysis of Voltage-Sensitive Dye Imaging Data in Brain Slices SO PLOS ONE LA English DT Article ID TEMPORAL-LOBE EPILEPSY; IN-VITRO; HIPPOCAMPUS; MUTATIONS; MODEL AB Voltage-sensitive dye imaging (VSDI) can simultaneously monitor the spatiotemporal electrical dynamics of thousands of neurons and is often used to identify functional differences in models of neurological disease. While the chief advantage of VSDI is the ability to record spatiotemporal activity, there are no tools available to visualize and statistically compare activity across the full spatiotemporal range of the VSDI dataset. Investigators commonly analyze only a subset of the data, and a majority of the dataset is routinely excluded from analysis. We have developed a software toolbox that simplifies visual inspection of VSDI data, and permits unaided statistical comparison across spatial and temporal dimensions. First, the three-dimensional VSDI dataset (x, y, time) is geometrically transformed into a two-dimensional spatiotemporal map of activity. Second, statistical comparison between groups is performed using a non-parametric permutation test. The result is a 2D map of all significant differences in both space and time. Here, we used the toolbox to identify functional differences in activity in VSDI data from acute hippocampal slices obtained from epileptic Arx conditional knock-out and control mice. Maps of spatiotemporal activity were produced and analyzed to identify differences in the activity evoked by stimulation of each of two axonal inputs to the hippocampus: the perforant pathway and the temporoammonic pathway. In mutant hippocampal slices, the toolbox identified a widespread decrease in spatiotemporal activity evoked by the temporoammonic pathway. No significant differences were observed in the activity evoked by the perforant pathway. The VSDI toolbox permitted us to visualize and statistically compare activity across the spatiotemporal scope of the VSDI dataset. Sampling error was minimized because the representation of the data is standardized by the toolbox. Statistical comparisons were conducted quickly, across the spatiotemporal scope of the data, without a priori knowledge of the character of the responses or the likely differences between them. C1 [Bourgeois, Elliot B.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Bourgeois, Elliot B.] Harvard Univ, Sch Med, Boston, MA USA. [Johnson, Brian N.; McCoy, Almedia J.; Cohen, Akiva S.; Marsh, Eric D.] Childrens Hosp Philadelphia, Dept Pediat, Div Pediat Neurol, Philadelphia, PA 19104 USA. [Trippa, Lorenzo] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Cohen, Akiva S.; Marsh, Eric D.] Univ Penn, Dept Neurol, Div Pediat Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Bourgeois, EB (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM ebbourgeois@partners.org FU US National Institutes of Health [F32 NS080556, K02 NS065975, R01 NS082761, R01 HD059288, R01 NS069629, R01 NS046616] FX Funding for this work was provided by the US National Institutes of Health to EBB (F32 NS080556), EDM (K02 NS065975 and R01 NS082761), ASC (R01 HD059288 and R01 NS069629), and Jeffrey A. Golden (R01 NS046616). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 4 Z9 4 U1 1 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 SEP 26 PY 2014 VL 9 IS 9 AR e108686 DI 10.1371/journal.pone.0108686 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ3IP UT WOS:000342685600093 PM 25259520 ER PT J AU Pham-Kanter, G Zinner, DE Campbell, EG AF Pham-Kanter, Genevieve Zinner, Darren E. Campbell, Eric G. TI Codifying Collegiality: Recent Developments in Data Sharing Policy in the Life Sciences SO PLOS ONE LA English DT Article ID PATENTS AB Over the last decade, there have been significant changes in data sharing policies and in the data sharing environment faced by life science researchers. Using data from a 2013 survey of over 1600 life science researchers, we analyze the effects of sharing policies of funding agencies and journals. We also examine the effects of new sharing infrastructure and tools (i.e., third party repositories and online supplements). We find that recently enacted data sharing policies and new sharing infrastructure and tools have had a sizable effect on encouraging data sharing. In particular, third party repositories and online supplements as well as data sharing requirements of funding agencies, particularly the NIH and the National Human Genome Research Institute, were perceived by scientists to have had a large effect on facilitating data sharing. In addition, we found a high degree of compliance with these new policies, although noncompliance resulted in few formal or informal sanctions. Despite the overall effectiveness of data sharing policies, some significant gaps remain: about one third of grant reviewers placed no weight on data sharing plans in their reviews, and a similar percentage ignored the requirements of material transfer agreements. These patterns suggest that although most of these new policies have been effective, there is still room for policy improvement. C1 [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, Boston, MA 02115 USA. [Zinner, Darren E.] Brandeis Univ, Heller Sch Social Policy & Management, Waltham, MA USA. [Campbell, Eric G.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Campbell, Eric G.] Harvard Univ, Sch Med, Boston, MA USA. RP Pham-Kanter, G (reprint author), Drexel Univ, Sch Publ Hlth, Dept Hlth Management & Policy, Philadelphia, PA 19104 USA. EM gpkanter@drexel.edu OI Pham-Kanter, Genevieve/0000-0002-3044-7829 FU National Human Genome Research Institute [R01 HG006281]; Edmond J. Safra Center for Ethics at Harvard University; Brandeis University's Health Industry Forum FX This research was supported by the National Human Genome Research Institute (R01 HG006281). Genevieve Pham-Kanter is partially supported by the Edmond J. Safra Center for Ethics at Harvard University. Darren Zinner is partially supported by Brandeis University's Health Industry Forum, an independent policy consortium of major health care insurers, delivery systems, and biopharmaceutical and medical device firms. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 9 Z9 9 U1 1 U2 16 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 SEP 26 PY 2014 VL 9 IS 9 AR e108451 DI 10.1371/journal.pone.0108451 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ3IP UT WOS:000342685600074 PM 25259842 ER PT J AU Saeed, S Quintin, J Kerstens, HHD Rao, NA Aghajanirefah, A Matarese, F Cheng, SC Ratter, J Berentsen, K van der Ent, MA Sharifi, N Janssen-Megens, EM Ter Huurne, M Mandoli, A van Schaik, T Ng, A Burden, F Downes, K Frontini, M Kumar, V Giamarellos-Bourboulis, EJ Ouwehand, WH van der Meer, JWM Joosten, LAB Wijmenga, C Martens, JHA Xavier, RJ Logie, C Netea, MG Stunnenberg, HG AF Saeed, Sadia Quintin, Jessica Kerstens, Hindrik H. D. Rao, Nagesha A. Aghajanirefah, Ali Matarese, Filomena Cheng, Shih-Chin Ratter, Jacqueline Berentsen, Kim van der Ent, Martijn A. Sharifi, Nilofar Janssen-Megens, Eva M. Ter Huurne, Menno Mandoli, Amit van Schaik, Tom Ng, Aylwin Burden, Frances Downes, Kate Frontini, Mattia Kumar, Vinod Giamarellos-Bourboulis, Evangelos J. Ouwehand, Willem H. van der Meer, Jos W. M. Joosten, Leo A. B. Wijmenga, Cisca Martens, Joost H. A. Xavier, Ramnik J. Logie, Colin Netea, Mihai G. Stunnenberg, Hendrik G. TI Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity SO SCIENCE LA English DT Article ID LIVER X RECEPTOR; NF-KAPPA-B; GENE-EXPRESSION; DENDRITIC CELLS; HOST-DEFENSE; TRANSCRIPTION FACTORS; REGULATORY ELEMENTS; HUMAN GENOME; IRAK-M; INFLAMMATION AB Monocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. We characterized the transcriptomes and epigenomes in four primary cell types: monocytes and in vitro-differentiated naive, tolerized, and trained macrophages. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and we identified pathways functionally implicated in trained immunity. beta-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in deoxyribonuclease I hypersensitive sites at cell-type-specific epigenetic loci unveiled differentiation and treatment-specific repertoires. Altogether, we provide a resource to understand the epigenetic changes that underlie innate immunity in humans. C1 [Saeed, Sadia; Kerstens, Hindrik H. D.; Rao, Nagesha A.; Aghajanirefah, Ali; Matarese, Filomena; Berentsen, Kim; van der Ent, Martijn A.; Sharifi, Nilofar; Janssen-Megens, Eva M.; Ter Huurne, Menno; Mandoli, Amit; van Schaik, Tom; Martens, Joost H. A.; Logie, Colin; Stunnenberg, Hendrik G.] Radboud Univ Nijmegen, Dept Mol Biol, Fac Sci, Radboud Inst Mol Life Sci, NL-6500 HB Nijmegen, Netherlands. [Saeed, Sadia; Kerstens, Hindrik H. D.; Rao, Nagesha A.; Aghajanirefah, Ali; Matarese, Filomena; Berentsen, Kim; van der Ent, Martijn A.; Sharifi, Nilofar; Janssen-Megens, Eva M.; Ter Huurne, Menno; Mandoli, Amit; van Schaik, Tom; Martens, Joost H. A.; Logie, Colin; Stunnenberg, Hendrik G.] Radboud Univ Nijmegen, Dept Mol Biol, Fac Med, Radboud Inst Mol Life Sci, NL-6500 HB Nijmegen, Netherlands. [Quintin, Jessica; Cheng, Shih-Chin; Ratter, Jacqueline; van der Meer, Jos W. M.; Joosten, Leo A. B.; Netea, Mihai G.] Radboud Univ Nijmegen, Dept Internal Med, Med Ctr, NL-6525 GA Nijmegen, Netherlands. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Ng, Aylwin; Xavier, Ramnik J.] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA 02142 USA. [Burden, Frances; Downes, Kate; Frontini, Mattia; Ouwehand, Willem H.] Univ Cambridge, Dept Haematol, Cambridge, England. [Burden, Frances; Downes, Kate; Frontini, Mattia; Ouwehand, Willem H.] Blood & Transplant Cambridge Ctr, Natl Hlth Serv, Cambridge CB0 2PT, England. [Kumar, Vinod; Wijmenga, Cisca] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Giamarellos-Bourboulis, Evangelos J.] Univ Athens, Sch Med 1, Dept Internal Med 4, Athens 12462, Greece. RP Stunnenberg, HG (reprint author), Radboud Univ Nijmegen, Dept Mol Biol, Fac Sci, Radboud Inst Mol Life Sci, NL-6500 HB Nijmegen, Netherlands. EM c.logie@ncmls.ru.nl; mihai.netea@radboudumc.nl; h.stunnenberg@ncmls.ru.nl RI Stunnenberg, Hendrik/D-6875-2012; Netea, Mihai/N-5155-2014; Ratter, Jacqueline/G-6301-2016; van der Meer, Jos/C-8521-2013; Wijmenga, Cisca/D-2173-2009; CHENG, SHIH-CHIN/H-4567-2015; Logie, Colin/A-1528-2010; Joosten, Leo/H-3138-2015 OI Ratter, Jacqueline/0000-0002-3807-9442; van der Meer, Jos/0000-0001-5120-3690; Wijmenga, Cisca/0000-0002-5635-1614; CHENG, SHIH-CHIN/0000-0003-1251-8774; Giamarellos-Bourboulis, Evangelos/0000-0003-4713-3911; Ouwehand, Willem/0000-0002-7744-1790; Logie, Colin/0000-0002-8534-6582; FU European Union [282510-BLUEPRINT]; Netherlands Organization for Scientific Research; ERC [310372] FX The authors are grateful to J. Stamatoyannopoulos for help with DNaseI-seq. We thank S. van Heeringen for access to his databases and expertise. The research leading to the results described in this manuscript has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 282510-BLUEPRINT. M.G.N. was supported by a Vici grant of the Netherlands Organization for Scientific Research and an ERC Consolidator Grant (no. 310372) and J.H.A.M by a VIDI grant of the Netherlands Organization for Scientific Research. All the genome-wide data generated and analyzed in this study, as well as the sequencing details, can be accessed via GEO accession no. GSE58310. NR 68 TC 180 Z9 181 U1 16 U2 80 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 SEP 26 PY 2014 VL 345 IS 6204 BP 1578 EP + AR 1251086 DI 10.1126/science.1251086 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP6CG UT WOS:000342164500033 PM 25258085 ER PT J AU Cheng, SC Quintin, J Cramer, RA Shepardson, KM Saeed, S Kumar, V Giamarellos-Bourboulis, EJ Martens, JHA Rao, NA Aghajanirefah, A Manjeri, GR Li, Y Ifrim, DC Arts, RJW van der Meer, BMJW Deen, PMT Logie, C O'Neill, LA Willems, P van de Veerdonk, FL van der Meer, JWM Ng, A Joosten, LAB Wijmenga, C Stunnenberg, HG Xavier, RJ Netea, MG AF Cheng, Shih-Chin Quintin, Jessica Cramer, Robert A. Shepardson, Kelly M. Saeed, Sadia Kumar, Vinod Giamarellos-Bourboulis, Evangelos J. Martens, Joost H. A. Rao, Nagesha Appukudige Aghajanirefah, Ali Manjeri, Ganesh R. Li, Yang Ifrim, Daniela C. Arts, Rob J. W. van der Meer, Brian M. J. W. Deen, Peter M. T. Logie, Colin O'Neill, Luke A. Willems, Peter van de Veerdonk, Frank L. van der Meer, Jos W. M. Ng, Aylwin Joosten, Leo A. B. Wijmenga, Cisca Stunnenberg, Hendrik G. Xavier, Ramnik J. Netea, Mihai G. TI mTOR- and HIF-1 alpha-mediated aerobic glycolysis as metabolic basis for trained immunity SO SCIENCE LA English DT Article ID INNATE IMMUNITY; BETA-GLUCAN; CELLS; MACROPHAGES; ACTIVATION; INFECTION; INFLAMMATION; REINFECTION; EXPRESSION; PROTECTION AB Epigenetic reprogramming of myeloid cells, also known as trained immunity, confers nonspecific protection from secondary infections. Using histone modification profiles of human monocytes trained with the Candida albicans cell wall constituent beta-glucan, together with a genome-wide transcriptome, we identified the induced expression of genes involved in glucose metabolism. Trained monocytes display high glucose consumption, high lactate production, and a high ratio of nicotinamide adenine dinucleotide (NAD+) to its reduced form (NADH), reflecting a shift in metabolism with an increase in glycolysis dependent on the activation of mammalian target of rapamycin (mTOR) through a dectin-1-Akt-HIF-1 alpha (hypoxia-inducible factor-1 alpha) pathway. Inhibition of Akt, mTOR, or HIF-1 alpha blocked monocyte induction of trained immunity, whereas the adenosine monophosphate-activated protein kinase activator metformin inhibited the innate immune response to fungal infection. Mice with a myeloid cell-specific defect in HIF-1 alpha were unable to mount trained immunity against bacterial sepsis. Our results indicate that induction of aerobic glycolysis through an Akt-mTOR-HIF-1 alpha pathway represents the metabolic basis of trained immunity. C1 [Cheng, Shih-Chin; Quintin, Jessica; Ifrim, Daniela C.; Arts, Rob J. W.; van de Veerdonk, Frank L.; van der Meer, Jos W. M.; Joosten, Leo A. B.; Netea, Mihai G.] Radboud Univ Nijmegen, Dept Internal Med, Med Ctr, NL-6525 GA Nijmegen, Netherlands. [Cramer, Robert A.; Shepardson, Kelly M.] Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, Hanover, NH 03755 USA. [Saeed, Sadia; Martens, Joost H. A.; Rao, Nagesha Appukudige; Aghajanirefah, Ali; Logie, Colin] Radboud Univ Nijmegen, Fac Sci, Nijmegen Ctr Mol Life Sci, Dept Mol Biol, NL-6500 HB Nijmegen, Netherlands. [Saeed, Sadia; Martens, Joost H. A.; Rao, Nagesha Appukudige; Aghajanirefah, Ali; Logie, Colin] Radboud Univ Nijmegen, Fac Med, Nijmegen Ctr Mol Life Sci, Dept Mol Biol, NL-6500 HB Nijmegen, Netherlands. [Kumar, Vinod; Li, Yang; van der Meer, Brian M. J. W.; Wijmenga, Cisca; Stunnenberg, Hendrik G.] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Giamarellos-Bourboulis, Evangelos J.] Univ Athens, Sch Med, Dept Internal Med 4, Athens 12462, Greece. [Manjeri, Ganesh R.; Willems, Peter] Radboud Univ Nijmegen, Fac Sci, Nijmegen Ctr Mol Life Sci, Dept Biochem, NL-6500 HB Nijmegen, Netherlands. [Manjeri, Ganesh R.; Willems, Peter] Radboud Univ Nijmegen, Fac Med, Nijmegen Ctr Mol Life Sci, Dept Biochem, NL-6500 HB Nijmegen, Netherlands. [Deen, Peter M. T.] Radboud Univ Nijmegen, Dept Physiol, Med Ctr, NL-6525 GA Nijmegen, Netherlands. [O'Neill, Luke A.] Univ Dublin Trinity Coll, Trinity Biomed Sci Inst, Sch Biochem & Immunol, Dublin 2, Ireland. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Ng, Aylwin; Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Netea, MG (reprint author), Radboud Univ Nijmegen, Dept Internal Med, Med Ctr, NL-6525 GA Nijmegen, Netherlands. EM mihal.netea@radboudumc.nl RI Stunnenberg, Hendrik/D-6875-2012; Logie, Colin/A-1528-2010; Deen, P.M.T./H-8023-2014; Joosten, Leo/H-3138-2015; Netea, Mihai/N-5155-2014; Arts, Rob/P-8678-2015; van de Veerdonk, Frank/C-7256-2008; Willems, P.H.G.M./L-4759-2015; van der Meer, Jos/C-8521-2013; Wijmenga, Cisca/D-2173-2009; Cheng, Shih-Chin/H-4567-2015 OI Logie, Colin/0000-0002-8534-6582; Deen, P.M.T./0000-0002-7868-4655; Arts, Rob/0000-0002-6649-7190; van de Veerdonk, Frank/0000-0002-1121-4894; Willems, P.H.G.M./0000-0002-0915-1599; van der Meer, Jos/0000-0001-5120-3690; Cheng, Shih-Chin/0000-0003-1251-8774 FU Netherlands Organization of Scientific Research [863.13.011]; ERC [310372]; European Research Council under European Union [2012-322698]; National Institute of General Medical Sciences [5P30GM103415-03, 1P30GM106394-01]; National Institute of Allergy and Infectious Diseases [R01AI81838]; Helmsley Trust; JDRF; [DK43351]; [DK097485] FX S.-C. C., J.Q., and M.G.N. were supported by a Vici grant of the Netherlands Organization of Scientific Research and ERC Consolidator grant 310372 (both to M.G.N). C. W. is supported by funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC grant agreement 2012-322698). Y.L. is supported by Veni grant 863.13.011 of the Netherlands Organization for Scientific Research. R. A. C. and K. M. S. were supported by National Institute of General Medical Sciences grant 5P30GM103415-03 (William Green, PI) and 1P30GM106394-01 (Bruce Stanton, PI), and National Institute of Allergy and Infectious Diseases grant R01AI81838 (R. A. C., PI). R.A.C./K.M.S. thank B. Berwin for the S. aureus. R.J.X funded by DK43351, DK097485, Helmsley Trust, and JDRF. The detailed data have been deposited in the GEO database with accession number GSE57206. NR 46 TC 177 Z9 180 U1 21 U2 82 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 SEP 26 PY 2014 VL 345 IS 6204 BP 1579 EP + AR 1250684 DI 10.1126/science.1250684 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP6CG UT WOS:000342164500034 PM 25258083 ER PT J AU Chen, XY Spaeth, RB Retzepi, K Ott, D Kong, J AF Chen, Xiaoyan Spaeth, Rosa B. Retzepi, Kallirroi Ott, Daniel Kong, Jian TI Acupuncture modulates cortical thickness and functional connectivity in knee osteoarthritis patients SO SCIENTIFIC REPORTS LA English DT Article ID CHRONIC BACK-PAIN; SURFACE-BASED ANALYSIS; MEDIAL FRONTAL-CORTEX; CENTRAL SENSITIZATION; COGNITIVE CONTROL; BRAIN NETWORKS; ELECTROACUPUNCTURE STIMULATION; PERIAQUEDUCTAL GRAY; ADJUNCTIVE THERAPY; PLACEBO ANALGESIA AB In this study, we investigated cortical thickness and functional connectivity across longitudinal acupuncture treatments in patients with knee osteoarthritis (OA). Over a period of four weeks (six treatments), we collected resting state functional magnetic resonance imaging (fMRI) scans from 30 patients before their first, third and sixth treatments. Clinical outcome showed a significantly greater Knee Injury and Osteoarthritis Outcome Score (KOOS) pain score (improvement) with verum acupuncture compared to the sham acupuncture. Longitudinal cortical thickness analysis showed that the cortical thickness at left posterior medial prefrontal cortex (pMPFC) decreased significantly in the sham group across treatment sessions as compared with verum group. Resting state functional connectivity (rsFC) analysis using the left pMPFC as a seed showed that after longitudinal treatments, the rsFC between the left pMPFC and the rostral anterior cingulate cortex (rACC), medial frontal pole (mFP) and periaquiduct grey (PAG) are significantly greater in the verum acupuncture group as compared with the sham group. Our results suggest that acupuncture may achieve its therapeutic effect on knee OA pain by preventing cortical thinning and decreases in functional connectivity in major pain related areas, therefore modulating pain in the descending pain modulatory pathway. C1 [Chen, Xiaoyan; Spaeth, Rosa B.; Retzepi, Kallirroi; Ott, Daniel; Kong, Jian] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. RP Kong, J (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. EM kongj@nmr.mgh.harvard.edu FU NCCAM [R21AT004497, R01AT006364, R01AT005280, P01 AT006663]; NIDA [R03AT218317] FX This work was supported by R21AT004497 (NCCAM), R03AT218317 (NIDA), R01AT006364 (NCCAM) to Jian Kong, R01AT005280 (NCCAM) to Randy Gollub, and P01 AT006663 to Bruce Rosen. There is no conflict of interest for any of the authors. We thank Dr. Martin Reuter from Martino center at Massachusetts General Hospital for his technique support. NR 95 TC 9 Z9 11 U1 4 U2 22 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 SEP 26 PY 2014 VL 4 AR 6482 DI 10.1038/srep06482 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP8XB UT WOS:000342361600002 PM 25258037 ER PT J AU Lovett, DH Chu, C Wang, GY Ratcliffe, MB Baker, AJ AF Lovett, David H. Chu, Charles Wang, Guanying Ratcliffe, Mark B. Baker, Anthony J. TI A N-terminal truncated intracellular isoform of matrix metalloproteinase-2 impairs contractility of mouse myocardium SO FRONTIERS IN PHYSIOLOGY LA English DT Article DE contraction; heart failure; myofilament; Ca2+ transient; remodeling; MMP-2 ID ISCHEMIA-REPERFUSION INJURY; EXPRESSION; DYSFUNCTION; INFARCTION; MYOCYTES; DISEASE; TARGETS; RAT AB The full-length isoform of matrixmetalloproteinase-2 (FL-MMP-2) plays a role in turnover of the cardiac extracellular matrix. FL-MMP-2 is also present intracellularly in association with sarcomeres and, in the setting of oxidative stress, cleaves myofilament proteins with resultant impaired contractility. Recently, a novel N-terminal truncated MMP-2 isoform (NTT-MMP-2) generated during oxidative stress was identified and shown to induce severe systolic failure; however, the injury mechanisms remained unclear. In this study, cardiac-specific NTT-MMP-2 transgenic mice were used to determine the physiological effects of NTT-MMP-2 on: force development of intact myocardium; the function of cardiac myofilaments in demembranated myocardium; and on intracellular Ca2+ transients in isolated myocytes. We related the contractile defects arising from NTT-MMP-2 expression to the known intracellular locations of NTT-MMP-2 determined using immunohistochemistry. Comparison was made with the pathophysiology arising from cardiac-specific FL-MMP-2 transgenic mice. Consistent with previous studies, FL-MMP-2 was localized to myofilaments, while NTT-MMP-2 was concentrated within subsarcolemmal mitochondria and to sites in register with the Z-line. NTT-MMP-2 expression caused a 50% reduction of force development by intact myocardium. However, NTT-MMP-2 expression did not reduce myofilament force development, consistent with the lack of NTT-MMP-2 localization to myofilaments. NTT-MMP-2 expression caused a 50% reduction in the amplitude of Ca2+ transients, indicating impaired activation. Conclusions: Unlike FL-MMP-2, NTT-MMP-2 does not mediate myofilament damage. Instead, NTT-MMP-2 causes impaired myocyte activation, which may involve effects due to localization in mitochondria and/or to transverse tubules affecting Ca2+ transients. Thus, FL-MMP-2 and NTT-MMP-2 have discrete intracellular locations and mediate different intracellular damage to cardiac myocytes. C1 [Lovett, David H.; Chu, Charles; Wang, Guanying; Ratcliffe, Mark B.; Baker, Anthony J.] San Francisco VA Med Ctr, Div Cardiol, San Francisco, CA USA. [Lovett, David H.; Chu, Charles; Wang, Guanying; Baker, Anthony J.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA. [Ratcliffe, Mark B.] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94121 USA. [Ratcliffe, Mark B.] Joint UC Berkeley UCSF Bioengn Grp, San Francisco, CA USA. RP Baker, AJ (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Div Cardiol, 111C,4150 Clement St, San Francisco, CA 94121 USA. EM anthony.baker@ucsf.edu FU Department of Veterans Affairs Merit Review Awards [I01BX000593, I01BX000740]; National Heart, Lung and Blood Institute [R01-HL-84431, R01-HL-63348]; American Heart Association [10GRNT3720074] FX This work was supported by Department of Veterans Affairs Merit Review Awards I01BX000593 (David H. Lovett), and I01BX000740 (Anthony J. Baker), National Heart, Lung and Blood Institute Grants R01-HL-84431 and R01-HL-63348 (Mark B. Ratcliffe), and an American Heart Association Grant-in-Aid 10GRNT3720074 (Anthony J. Baker). We thank Paul Wang, and Kevin V. Thai for expert technical assistance. NR 24 TC 6 Z9 6 U1 0 U2 1 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD SEP 25 PY 2014 VL 5 AR 363 DI 10.3389/fphys.2014.00363 PG 7 WC Physiology SC Physiology GA AX7JQ UT WOS:000347092800001 PM 25309453 ER PT J AU Mazumder, R Murchison, C Bourdette, D Cameron, M AF Mazumder, Rajarshi Murchison, Charles Bourdette, Dennis Cameron, Michelle TI Falls in People with Multiple Sclerosis Compared with Falls in Healthy Controls SO PLOS ONE LA English DT Article ID OLDER-ADULTS; RISK-FACTORS; ACCIDENTAL FALLS; COHORT; CONSEQUENCES; COMMUNITY; BALANCE AB Objective: To compare the risk, circumstances, consequences and causes of prospectively recorded falls between people with multiple sclerosis (PwMS) and healthy controls of similar age and gender. Methods: 58 PwMS and 58 healthy controls, who are community-dwelling, were recruited in this 6-month prospective cohort study. 90% of PwMS and 84% of healthy controls completed the study. Participants counted falls prospectively using fall calendars and noted fall location, fall-related injuries, and the cause of the falls. Kaplan Meier survival analysis and log-rank tests were performed to compare the distributions of survival without falling between PwMS and healthy controls. Results: 40.8% of controls and 71.2% of PwMS fell at least once. 48.1% of PwMS and 18.4% of healthy controls fell at least twice. 42.3% of PwMS and 20.4% of health controls sustained a fall-related injury. After adjusting for age and gender, the time to first fall (HR: 1.87, p = 0.033) and the time to recurrent falls (HR: 2.87, p = 0.0082) were significantly different between PwMS and healthy controls. PwMS reported an almost equal number of falls inside and outside, 86% of the falls in healthy controls were outside. Healthy controls were more likely to fall due to slipping on a slippery surface (39.5% vs 10.4%). PwMS more often attributed falls to distraction (31% vs 7%) and uniquely attributed falls to fatigue or heat. Conclusions: Fall risk, circumstances, consequences, and causes are different for PwMS than for healthy people of the same age and gender. PwMS fall more, are more likely to be injured by a fall, and often fall indoors. PwMS, but not healthy controls, frequently fall because they are distracted, fatigued or hot. C1 [Mazumder, Rajarshi] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Murchison, Charles; Bourdette, Dennis; Cameron, Michelle] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Bourdette, Dennis; Cameron, Michelle] Portland VA Med Ctr, Portland, OR USA. RP Mazumder, R (reprint author), Oregon Hlth & Sci Univ, Portland, OR 97201 USA. EM mazumder.rajrishi@gmail.com FU Oregon Multidisciplinary Training Program in Health Services Research from the Agency for Healthcare Research and Quality (AHRQ) [T32 HS017582]; Foundation of the Consortium of Multiple Sclerosis Centers Workforce of the Future; Department of Veterans Affairs Rehabilitation Research & Development Service [CDA-2]; Oregon Clinical and Translational Research Institute [1 UL1 RR024140 01] FX Rajarshi Mazumder was supported by the Oregon Multidisciplinary Training Program in Health Services Research, grant number T32 HS017582 from the Agency for Healthcare Research and Quality (AHRQ), and by funding from the 2012 Foundation of the Consortium of Multiple Sclerosis Centers Workforce of the Future. To conduct this study, Michelle Cameron was supported by a CDA-2 from the Department of Veterans Affairs Rehabilitation Research & Development Service. Secure data storage was supported by the Oregon Clinical and Translational Research Institute grant support (1 UL1 RR024140 01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 8 Z9 8 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 25 PY 2014 VL 9 IS 9 AR e107620 DI 10.1371/journal.pone.0107620 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT3UZ UT WOS:000344862300026 PM 25254633 ER PT J AU Win, AZ Aparici, CM AF Win, Aung Zaw Aparici, Carina Mari TI Normal SUV Values Measured from NaF18-PET/CT Bone Scan Studies SO PLOS ONE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; STANDARDIZED UPTAKE VALUES; F-18-FLUORIDE PET; FDG PET/CT; METABOLISM; METASTASES; FLUORIDE; SCINTIGRAPHY; RADIONUCLIDE; TECHNOLOGY AB Objectives: Cancer and metabolic bone diseases can alter the SUV. SUV values have never been measured from healthy skeletons in NaF18-PET/CT bone scans. The primary aim of this study was to measure the SUV values from normal skeletons in NaF18-PET/CT bone scans. Methods: A retrospective study was carried out involving NaF18-PET/CT bone scans that were done at our institution between January 2010 to May 2012. Our excluding criteria was patients with abnormal real function and patients with past history of cancer and metabolic bone diseases including but not limited to osteoporosis, osteopenia and Paget's disease. Eleven studies met all the criteria. Results: The average normal SUVmax values from 11 patients were: cervical vertebrae 6.84 (range 4.38-8.64), thoracic vertebrae 7.36 (range 6.99-7.66), lumbar vertebrae 7.27 (range 7.04-7.72), femoral head 2.22 (range 1.1-4.3), humeral head 1.82 (range 1.2-2.9), mid sternum 5.51 (range 2.6-8.1), parietal bone 1.71 (range 1.3-2.4). Conclusion: According to our study, various skeletal sites have different normal SUV values. SUV values can be different between the normal bones and bones with tumor or metabolic bone disease. SUV can be used to quantify NaF-18 PET/CT studies. If the SUV values of the normal skeleton are known, they can be used in the characterization of bone lesions and in the assessment of treatment response to bone diseases. C1 [Win, Aung Zaw] San Francisco VA Med Ctr, Dept Radiol, San Francisco, CA 94121 USA. [Aparici, Carina Mari] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. RP Win, AZ (reprint author), San Francisco VA Med Ctr, Dept Radiol, San Francisco, CA 94121 USA. EM aungzwin@gmail.com FU NCI NIH HHS [R01 CA094121] NR 30 TC 1 Z9 1 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 25 PY 2014 VL 9 IS 9 AR e108429 DI 10.1371/journal.pone.0108429 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT3UZ UT WOS:000344862300081 PM 25254490 ER PT J AU Koppers-Lalic, D Hackenberg, M Bijnsdorp, IV van Eijndhoven, MAJ Sadek, P Sie, D Zini, N Middeldorp, JM Ylstra, B de Menezes, RX Wurdinger, T Meijer, GA Pegtel, DM AF Koppers-Lalic, Danijela Hackenberg, Michael Bijnsdorp, Irene V. van Eijndhoven, Monique A. J. Sadek, Payman Sie, Daud Zini, Nicoletta Middeldorp, Jaap M. Ylstra, Bauke de Menezes, Renee X. Wuerdinger, Thomas Meijer, Gerrit A. Pegtel, D. Michiel TI Nontemplated Nucleotide Additions Distinguish the Small RNA Composition in Cells from Exosomes SO CELL REPORTS LA English DT Article ID POTENTIAL REGULATORY FUNCTIONS; SMALL NONCODING RNA; 3' ADENYLATION; MIRNA ACTIVITY; VIRAL MIRNAS; MICRORNA; CANCER; STABILIZATION; TRANSFERASES; URIDYLATION AB Functional biomolecules, including small noncoding RNAs (ncRNAs), are released and transmitted between mammalian cells via extracellular vesicles (EVs), including endosome-derived exosomes. The small RNA composition in cells differs from exosomes, but underlying mechanisms have not been established. We generated small RNA profiles by RNA sequencing (RNA-seq) from a panel of human B cells and their secreted exosomes. A comprehensive bioinformatics and statistical analysis revealed nonrandomly distributed subsets of microRNA (miRNA) species between B cells and exosomes. Unexpectedly, 3' end adenylated miRNAs are relatively enriched in cells, whereas 3' end uridylated isoforms appear overrepresented in exosomes, as validated in naturally occurring EVs isolated from human urine samples. Collectively, our findings suggest that posttranscriptional modifications, notably 3' end adenylation and uridylation, exert opposing effects that may contribute, at least in part, to direct ncRNA sorting into EVs. C1 [Koppers-Lalic, Danijela; van Eijndhoven, Monique A. J.; Sadek, Payman; Sie, Daud; Middeldorp, Jaap M.; Ylstra, Bauke; Meijer, Gerrit A.; Pegtel, D. Michiel] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, NL-1007 MB Amsterdam, Netherlands. [Koppers-Lalic, Danijela; van Eijndhoven, Monique A. J.; Sadek, Payman; Pegtel, D. Michiel] Vrije Univ Amsterdam, Med Ctr, Exosomes Res Grp, NL-1007 MB Amsterdam, Netherlands. [Hackenberg, Michael] Univ Granada, Dept Genet, Computat Genom & Bioinformat Grp, E-18071 Granada, Spain. [Bijnsdorp, Irene V.] Vrije Univ Amsterdam, Med Ctr, Dept Urol, NL-1007 MB Amsterdam, Netherlands. [Zini, Nicoletta] CNR Natl Res Council Italy, IGM, I-40136 Bologna, Italy. [Zini, Nicoletta] IOR, SC Lab Musculoskeletal Cell Biol, I-40136 Bologna, Italy. [de Menezes, Renee X.] Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, NL-1007 MB Amsterdam, Netherlands. [Wuerdinger, Thomas] Vrije Univ Amsterdam, Med Ctr, Dept Neurosurg, Neurooncol Res Grp, NL-1007 MB Amsterdam, Netherlands. [Wuerdinger, Thomas] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Wuerdinger, Thomas] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Koppers-Lalic, D (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Pathol, NL-1007 MB Amsterdam, Netherlands. EM d.koppers@vumc.nl; d.pegtel@vumc.nl RI Hackenberg, Michael/A-2503-2009; Pegtel, Dirk/M-8393-2015; Ylstra, Bauke/D-2906-2012; OI Hackenberg, Michael/0000-0003-2248-3114; Pegtel, Dirk/0000-0002-7357-4406; Ylstra, Bauke/0000-0001-9479-3010; Sie, Daoud/0000-0001-6762-2582; ZINI, NICOLETTA/0000-0002-4442-7079; Middeldorp, Jaap/0000-0002-0765-4125 FU VIDI [91711366]; Dutch Cancer Society research award [KWF-5510]; AICR [11-0157]; NWO-VENI [91696087] FX We thank P.P. Eijk, F. Rustenburg, and Y. Sabogal Pineros for their technical assistance and J. Berenguer de Felipe for inspiring discussions. T.W. is supported by VIDI 91711366. D.M.P. is supported by personal Dutch Cancer Society research award (KWF-5510). This work was funded by AICR grant 11-0157 and NWO-VENI 91696087 awarded to D.M.P. NR 46 TC 98 Z9 100 U1 2 U2 19 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 SEP 25 PY 2014 VL 8 IS 6 BP 1649 EP 1658 DI 10.1016/j.celrep.2014.08.027 PG 10 WC Cell Biology SC Cell Biology GA AR9BZ UT WOS:000343867400006 PM 25242326 ER PT J AU Ting, DT Wittner, BS Ligorio, M Jordan, NV Shah, AM Miyamoto, DT Aceto, N Bersani, F Brannigan, BW Xega, K Ciciliano, JC Zhu, HL MacKenzie, OC Trautwein, J Arora, KS Shahid, M Ellis, HL Qu, N Bardeesy, N Rivera, MN Deshpande, V Ferrone, CR Kapur, R Ramaswamy, S Shioda, T Toner, M Maheswaran, S Haber, DA AF Ting, David T. Wittner, Ben S. Ligorio, Matteo Jordan, Nicole Vincent Shah, Ajay M. Miyamoto, David T. Aceto, Nicola Bersani, Francesca Brannigan, Brian W. Xega, Kristina Ciciliano, Jordan C. Zhu, Huili MacKenzie, Olivia C. Trautwein, Julie Arora, Kshitij S. Shahid, Mohammad Ellis, Haley L. Qu, Na Bardeesy, Nabeel Rivera, Miguel N. Deshpande, Vikram Ferrone, Cristina R. Kapur, Ravi Ramaswamy, Sridhar Shioda, Toshi Toner, Mehmet Maheswaran, Shyamala Haber, Daniel A. TI Single-Cell RNA Sequencing Identifies Extracellular Matrix Gene Expression by Pancreatic Circulating Tumor Cells SO CELL REPORTS LA English DT Article ID FACTOR BINDING PROTEIN-5; BREAST-CANCER; CLINICAL-RELEVANCE; COLON-CARCINOMA; STEM-CELLS; ADENOCARCINOMA; METASTASIS; STROMA; MOUSE; MICROARRAY AB Circulating tumor cells (CTCs) are shed from primary tumors into the bloodstream, mediating the hematogenous spread of cancer to distant organs. To define their composition, we compared genomewide expression profiles of CTCs with matched primary tumors in a mouse model of pancreatic cancer, isolating individual CTCs using epitope-independent microfluidic capture, followed by single-cell RNA sequencing. CTCs clustered separately from primary tumors and tumor-derived cell lines, showing low-proliferative signatures, enrichment for the stemcell-associated gene Aldh1a2, biphenotypic expression of epithelial and mesenchymal markers, and expression of Igfbp5, a gene transcript enriched at the epithelial-stromal interface. Mouse as well as human pancreatic CTCs exhibit a very high expression of stromal-derived extracellular matrix (ECM) proteins, including SPARC, whose knockdown in cancer cells suppresses cell migration and invasiveness. The aberrant expression by CTCs of stromal ECM genes points to their contribution of microenvironmental signals for the spread of cancer to distant organs. C1 [Ting, David T.; Wittner, Ben S.; Ligorio, Matteo; Jordan, Nicole Vincent; Miyamoto, David T.; Aceto, Nicola; Bersani, Francesca; Brannigan, Brian W.; Xega, Kristina; Ciciliano, Jordan C.; Zhu, Huili; MacKenzie, Olivia C.; Trautwein, Julie; Arora, Kshitij S.; Shahid, Mohammad; Ellis, Haley L.; Qu, Na; Bardeesy, Nabeel; Rivera, Miguel N.; Deshpande, Vikram; Ferrone, Cristina R.; Ramaswamy, Sridhar; Shioda, Toshi; Maheswaran, Shyamala; Haber, Daniel A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. [Shah, Ajay M.; Kapur, Ravi; Toner, Mehmet] Harvard Univ, Sch Med, Ctr Engn Med, Boston, MA 02114 USA. [Ting, David T.; Wittner, Ben S.; Jordan, Nicole Vincent; Aceto, Nicola; Bersani, Francesca; Brannigan, Brian W.; Xega, Kristina; Ciciliano, Jordan C.; Zhu, Huili; MacKenzie, Olivia C.; Trautwein, Julie; Ellis, Haley L.; Qu, Na; Bardeesy, Nabeel; Ramaswamy, Sridhar; Shioda, Toshi; Haber, Daniel A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Ligorio, Matteo; Shah, Ajay M.; Arora, Kshitij S.; Shahid, Mohammad; Ferrone, Cristina R.; Toner, Mehmet; Maheswaran, Shyamala] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02114 USA. [Miyamoto, David T.] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. [Arora, Kshitij S.; Shahid, Mohammad; Rivera, Miguel N.; Deshpande, Vikram] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Ligorio, Matteo] Univ Genoa, Dept Hlth Sci, I-16126 Genoa, Italy. [Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Maheswaran, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. EM maheswaran@helix.mgh.harvard.edu; haber@helix.mgh.harvard.edu RI Aceto, Nicola/O-2484-2014; OI Aceto, Nicola/0000-0001-9579-6918; Shahid, Mohammad/0000-0003-2615-9848; Ting, David/0000-0002-3261-2322 FU Stand Up to Cancer; Howard Hughes Medical Institute; NIBIB Quantum [5R01EB008047, NCI 2R01CA129933]; National Foundation for Cancer Research; Burroughs Wellcome Fund [K12CA087723-11A1]; Department of Defense; Affymetrix, Inc; Warshaw Institute for Pancreatic Cancer Research; Verville Family Pancreatic Cancer Research Fund FX We are grateful to Laura Libby for mouse colony care, Lev Silberstein for providing technical assistance in single-cell RNA sequencing, Linda Nieman for microscopy expertise, and engineering techs for their help in running samples on the CTC-iChip. This work was supported by Stand Up to Cancer (D.A.H., M.T., and S.M.), Howard Hughes Medical Institute (D.A.H. and M.N.R.), NIBIB Quantum grant 5R01EB008047 (M.T.), NCI 2R01CA129933 (D.A.H.), National Foundation for Cancer Research (D.A.H.), the Burroughs Wellcome Fund (D.T.T. and M.N.R.), K12CA087723-11A1 (D.T.T.), Department of Defense (D.T.M. and D.T.T.), Affymetrix, Inc. (D.T.T., M.N.R., and V.D.), the Warshaw Institute for Pancreatic Cancer Research (D.T.T.), and the Verville Family Pancreatic Cancer Research Fund (D.T.T.). NR 49 TC 58 Z9 59 U1 5 U2 40 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 SEP 25 PY 2014 VL 8 IS 6 BP 1905 EP 1918 DI 10.1016/j.celrep.2014.08.029 PG 14 WC Cell Biology SC Cell Biology GA AR9BZ UT WOS:000343867400029 PM 25242334 ER PT J AU Passingham, RE Chung, A Goparaju, B Cowey, A Vaina, LM AF Passingham, R. E. Chung, A. Goparaju, B. Cowey, A. Vaina, L. M. TI Using action understanding to understand the left inferior parietal cortex in the human brain SO BRAIN RESEARCH LA English DT Article DE Inferior parietal cortex; Human brain; Action understanding; Action observation; Pantomime; Apraxia; Cerebral dominance ID TRACTOGRAPHY-BASED PARCELLATION; SURFACE-BASED ANALYSIS; PREFRONTAL CORTEX; MACAQUE MONKEY; PREMOTOR CORTEX; TOOL USE; VENTRAL PREMOTOR; FRONTAL-CORTEX; NEURONS; FMRI AB Humans have a sophisticated knowledge of the actions that can be performed with objects. In an fMRI study we tried to establish whether this depends on areas that are homologous with the inferior parietal cortex (area PFG) in macaque monkeys. Cells have been described in area PFG that discharge differentially depending upon whether the observer sees an object being brought to the mouth or put in a container. In our study the observers saw videos in which the use of different objects was demonstrated in pantomime; and after viewing the videos, the subject had to pick the object that was appropriate to the pantomime. We found a cluster of activated voxels in parietal areas PFop and PFt and this cluster was greater in the left hemisphere than in the right. We suggest a mechanism that could account for this asymmetry, relate our results to handedness and suggest that they shed light on the human syndrome of apraxia. Finally, we suggest that during the evolution of the hominids, this same pantomime mechanism could have been used to 'name' or request objects. (C) 2014 Elsevier B.V. All rights reserved. C1 [Passingham, R. E.; Cowey, A.] Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. [Chung, A.; Goparaju, B.; Vaina, L. M.] Boston Univ, Brain & Vis Res Lab, Dept Biomed Engn, Boston, MA 02215 USA. [Vaina, L. M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol & Radiol, Boston, MA 02114 USA. RP Vaina, LM (reprint author), Boston Univ, Brain & Vis Res Lab, Dept Biomed Engn, 44 Cummington Mall, Boston, MA 02215 USA. EM vaina@bu.edu FU NIH [RO1NS064100] FX We thank Steve Wise for very detailed comments on a draft of this paper. We thank Rogier Mars for help with identifying the areas that were activated in parietal cortex and for comments on a draft of this paper. Finally, we thank Michael Nahhas for help with the imaging figures. This work was supported in part by the NIH grant RO1NS064100 to LMV. NR 65 TC 2 Z9 2 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD SEP 25 PY 2014 VL 1582 BP 64 EP 76 DI 10.1016/j.brainres.2014.07.035 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AR1PM UT WOS:000343357100007 PM 25086203 ER PT J AU Erkan, EP Strobel, T Lewandrowski, G Tannous, B Madlener, S Czech, T Saydam, N Saydam, O AF Erkan, E. P. Stroebel, T. Lewandrowski, G. Tannous, B. Madlener, S. Czech, T. Saydam, N. Saydam, O. TI Depletion of minichromosome maintenance protein 7 inhibits glioblastoma multiforme tumor growth in vivo SO ONCOGENE LA English DT Article DE glioblastoma multiforme; minichromosome maintenance; MCM7; the cancer genome atlas; prognostic marker ID CELL LUNG-CANCER; MCM PROTEINS; DNA-REPLICATION; PROGNOSTIC-SIGNIFICANCE; PHOSPHORYLATION; IDENTIFICATION; MARKER; FAMILY; PROLIFERATION; INITIATION AB Minichromosome maintenance (MCM) proteins are key elements that function as a part of the pre-replication complex to initiate DNA replication in eukaryotes. Consistent with their roles in initiating DNA replication, overexpression of MCM family members has been observed in several malignancies. Through bioinformatic analysis of The Cancer Genome Atlas's data on glioblastoma multiforme (GBM), we found that the genomic region containing MCM7 gene was amplified in more than 80% of the present cases. To validate this finding and to identify the possible contribution of the remaining members of the MCM family to GBM progression, we used quantitative real-time PCR to analyze the gene expression profiles of all MCM family members in Grade IV (GBM) tissue samples and observed a significant upregulation in GBM samples compared with normal white matter tissues. In addition, we compared the observed gene expression profiles with those of Grade II and Grade III astrocytoma samples and determined that the observed upregulation was restricted and specific to Grade IV. MCM7 was the most upregulated gene in the gene set we analyzed, and therefore we wanted to identify the role of MCM7 in GBM progression. We determined that siRNA-mediated knockdown of MCM7 expression reduced GBM cell proliferation and also inhibited tumor growth in both xenograft and orthotopic mouse models of GBM. Taken together, our data suggest that MCM7 can be a potential prognostic marker and a novel therapeutic target in GBM therapy. C1 [Erkan, E. P.; Madlener, S.; Saydam, N.; Saydam, O.] Med Univ Vienna, Dept Pediat, Mol Neurooncol Res Unit, A-1090 Vienna, Austria. [Stroebel, T.] Med Univ Vienna, Inst Neurol, A-1090 Vienna, Austria. [Lewandrowski, G.; Tannous, B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Expt Therapeut & Mol Imaging Lab, Boston, MA USA. [Czech, T.] Med Univ Vienna, Dept Neurosurg, A-1090 Vienna, Austria. RP Saydam, O (reprint author), Med Univ Vienna, Dept Pediat, Mol Neurooncol Res Unit, A-1090 Vienna, Austria. EM okay.saydam@meduniwien.ac.at OI Madlener, Sibylle/0000-0001-7099-9997 FU Forschungsgesellschaft for Brain Tumors; EU-FP7-PEOPLE-CIG; Association for Conduct of Scientific Research in the Field of Neonatology and Pediatric Intensive Care: 'Unser Kind' FX This work was supported, in part, by Forschungsgesellschaft for Brain Tumors (OS, NS), EU-FP7-PEOPLE-2011-CIG (OS) and Association for Conduct of Scientific Research in the Field of Neonatology and Pediatric Intensive Care: 'Unser Kind' (OS and NS). NR 39 TC 7 Z9 7 U1 1 U2 5 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 SEP 25 PY 2014 VL 33 IS 39 BP 4778 EP 4785 DI 10.1038/onc.2013.423 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AR0ED UT WOS:000343239500008 PM 24166506 ER PT J AU Mayeur, C Leyton, PA Kolodziej, SA Yu, BL Bloch, KD AF Mayeur, Claire Leyton, Patricio A. Kolodziej, Starsha A. Yu, Binglan Bloch, Kenneth D. TI BMP type II receptors have redundant roles in the regulation of hepatic hepcidin gene expression and iron metabolism SO BLOOD LA English DT Article ID PULMONARY ARTERIAL-HYPERTENSION; MORPHOGENETIC PROTEIN BMP; TARGETED DISRUPTION; DEFICIENCY; OVERLOAD; CELLS; MICE; GASTRULATION; INDUCTION; INSIGHTS AB Expression of hepcidin, the hepatic hormone controlling iron homeostasis, is regulated by bone morphogenetic protein (BMP) signaling. We sought to identify which BMP type II receptor expressed in hepatocytes, ActR2a or BMPR2, is responsible for regulating hepcidin gene expression. We studied Bmpr2 heterozygous mice (Bmpr2(+/-)), mice with hepatocyte-specific deficiency of BMPR2, mice with global deficiency of ActR2a, and mice in which hepatocytes lacked both BMPR2 and ActR2a. Hepatic hepcidin messenger RNA (mRNA) levels, serum hepcidin and iron levels, and tissue iron levels did not differ in wild-type mice, Bmpr2(+/-) mice, and mice in which either BMPR2 or ActR2a was deficient. Deficiency of both BMP type II receptors markedly reduced hepatic hepcidin gene expression and serum hepcidin levels leading to severe iron overload. Iron injection increased hepatic hepcidin mRNA levels in mice deficient in either BMPR2 or ActR2a, but not in mice deficient in both BMP type II receptors. In addition, in mouse and human primary hepatocytes, deficiency of both BMPR2 and ActR2a profoundly decreased basal and BMP6-induced hepcidin gene expression. These results suggest that BMP type II receptors, BMPR2 and ActR2a, have redundant roles in the regulation of hepatic hepcidin gene expression and iron metabolism. C1 [Mayeur, Claire; Leyton, Patricio A.; Kolodziej, Starsha A.; Yu, Binglan; Bloch, Kenneth D.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. [Bloch, Kenneth D.] Massachusetts Gen Hosp, Dept Med, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Bloch, Kenneth D.] Harvard Univ, Sch Med, Boston, MA USA. RP Mayeur, C (reprint author), Massachusetts Gen Hosp, Anesthesia Ctr Crit Care Res, 55 Fruit St,Thier 503, Boston, MA 02114 USA. EM cmayeur@mgh.harvard.edu FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [R01DK082971]; Fondation LeDucq FX This work was supported by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (R01DK082971) and by a grant from the Fondation LeDucq. NR 40 TC 9 Z9 11 U1 2 U2 6 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 SEP 25 PY 2014 VL 124 IS 13 BP 2116 EP 2123 DI 10.1182/blood-2014-04-572644 PG 8 WC Hematology SC Hematology GA AQ4JY UT WOS:000342763500018 PM 25075125 ER PT J AU Dotson, AL Zhu, WB Libal, N Alkayed, NJ Offner, H AF Dotson, Abby L. Zhu, Wenbin Libal, Nicole Alkayed, Nabil J. Offner, Halina TI Different immunological mechanisms govern protection from experimental stroke in young and older mice with recombinant TCR ligand therapy SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Article DE experimental stroke; aging; RTL1000; therapy; immune response; neuroinflammation ID REGULATORY T-CELLS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; TUMOR-NECROSIS-FACTOR; TREATS EXPERIMENTAL STROKE; ISCHEMIC BRAIN-INJURY; CEREBRAL-ISCHEMIA; RECEPTOR LIGANDS; INTERFERON-GAMMA; MULTIPLE-SCLEROSIS; CNS INFLAMMATION AB Stroke is a leading cause of death and disability in the United States. The lack of clinical success in stroke therapies can be attributed, in part, to inadequate basic research on aging rodents. The current study demonstrates that recombinant TCR ligand therapy uses different immunological mechanisms to protect young and older mice from experimental stroke. In young mice, RTL1000 therapy inhibited splenocyte efflux while reducing frequency of T cells and macrophages in the spleen. Older mice treated with RTL1000 exhibited a significant reduction in inflammatory cells in the brain and inhibition of splenic atrophy. Our data suggest age specific differences in immune response to stroke that allow unique targeting of stroke immunotherapies. C1 [Dotson, Abby L.; Offner, Halina] VA Med Ctr, Portland, OR USA. [Dotson, Abby L.; Alkayed, Nabil J.; Offner, Halina] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Zhu, Wenbin; Libal, Nicole; Alkayed, Nabil J.; Offner, Halina] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97201 USA. [Alkayed, Nabil J.] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Portland, OR 97201 USA. RP Offner, H (reprint author), Portland VA Med Ctr, R&D 31,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM offnerva@ohsu.edu FU NIH Grant [NS065515-02A1]; Department of Veterans Affairs; Veterans Health Administration; Office of Research and Development; Biomedical Laboratory Research and Development FX The authors wish to thank Gail Kent for assistance with manuscript submission. This work was supported by NIH Grants # NS065515-02A1 (STTR) and by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. Dr. Offner discloses US patent #8,491,913 B2 for the use of recombinant molecules in treatment of stroke. NR 68 TC 4 Z9 4 U1 0 U2 3 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD SEP 25 PY 2014 VL 8 AR 284 DI 10.3389/fncel.2014.00284 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AP5NE UT WOS:000342125100001 PM 25309326 ER PT J AU Hunt, DP Sahani, DV Corey, KE Masia, R AF Hunt, Daniel P. Sahani, Dushyant V. Corey, Kathleen E. Masia, Ricard TI Case 30-2014: A 29-Year-Old Man with Diarrhea, Nausea, and Weight Loss SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ELEVATED SERUM FERRITIN; AUTOIMMUNE HEPATITIS; WILSONS-DISEASE; FEATURES; EXPERIENCE; DIAGNOSIS; LIVER; MANAGEMENT; CIRRHOSIS C1 [Hunt, Daniel P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Sahani, Dushyant V.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Corey, Kathleen E.] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. [Masia, Ricard] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hunt, Daniel P.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Sahani, Dushyant V.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Corey, Kathleen E.] Harvard Univ, Sch Med, Boston, MA USA. [Masia, Ricard] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Hunt, DP (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 26 TC 1 Z9 1 U1 2 U2 7 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 SEP 25 PY 2014 VL 371 IS 13 BP 1238 EP 1247 DI 10.1056/NEJMcpc1405218 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AP4WH UT WOS:000342079700012 PM 25251619 ER PT J AU Peterson, JR De La Rosa, S Eboda, O Cilwa, KE Agarwal, S Buchman, SR Cederna, PS Xi, CW Morris, MD Herndon, DN Xiao, WZ Tompkins, RG Krebsbach, PH Wang, SC Levi, B AF Peterson, Jonathan R. De La Rosa, Sara Eboda, Oluwatobi Cilwa, Katherine E. Agarwal, Shailesh Buchman, Steven R. Cederna, Paul S. Xi, Chuanwu Morris, Michael D. Herndon, David N. Xiao, Wenzhong Tompkins, Ronald G. Krebsbach, Paul H. Wang, Stewart C. Levi, Benjamin TI Treatment of heterotopic ossification through remote ATP hydrolysis SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID OSTEOGENIC DIFFERENTIATION; STEM-CELLS; ADIPOCYTE DIFFERENTIATION; ENDOCHONDRAL OSSIFICATION; BONE-FORMATION; IN-VITRO; PROGRESSIVA; MODEL; TRAUMA; BURNS AB Heterotopic ossification (HO) is the pathologic development of ectopic bone in soft tissues because of a local or systemic inflammatory insult, such as burn injury or trauma. In HO, mesenchymal stem cells (MSCs) are inappropriately activated to undergo osteogenic differentiation. Through the correlation of in vitro assays and in vivo studies (dorsal scald burn with Achilles tenotomy), we have shown that burn injury enhances the osteogenic potential of MSCs and causes ectopic endochondral heterotopic bone formation and functional contractures through bone morphogenetic protein-mediated canonical SMAD signaling. We further demonstrated a prevention strategy for HO through adenosine triphosphate (ATP) hydrolysis at the burn site using apyrase. Burn site apyrase treatment decreased ATP, increased adenosine 3',5'-monophosphate, and decreased phosphorylation of SMAD1/5/8 in MSCs in vitro. This ATP hydrolysis also decreased HO formation and mitigated functional impairment in vivo. Similarly, selective inhibition of SMAD1/5/8 phosphorylation with LDN-193189 decreased HO formation and increased range of motion at the injury site in our burn model in vivo. Our results suggest that burn injury-exacerbated HO formation can be treated through therapeutics that target burn site ATP hydrolysis and modulation of SMAD1/5/8 phosphorylation. C1 [Peterson, Jonathan R.; De La Rosa, Sara; Eboda, Oluwatobi; Agarwal, Shailesh; Buchman, Steven R.; Cederna, Paul S.; Wang, Stewart C.; Levi, Benjamin] Univ Michigan, Sch Med, Dept Surg, Ann Arbor, MI 48109 USA. [Cilwa, Katherine E.] Naval Med Res Ctr, Dept Regenerat Med, Silver Spring, MD 20910 USA. [Cederna, Paul S.] Univ Michigan Hlth Syst, Dept Biomed Engn, Sect Plast Surg, Ann Arbor, MI 48109 USA. [Xi, Chuanwu] Univ Michigan, Sch Publ Hlth, Dept Environm & Hlth Sci, Ann Arbor, MI 48109 USA. [Morris, Michael D.] Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA. [Herndon, David N.] Univ Texas Med Branch, Dept Surg, Galveston, TX 77550 USA. [Herndon, David N.] Shriners Hosp Children, Galveston, TX 77550 USA. [Xiao, Wenzhong; Tompkins, Ronald G.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Krebsbach, Paul H.] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. RP Levi, B (reprint author), Univ Michigan, Sch Med, Dept Surg, Ann Arbor, MI 48109 USA. EM blevi@med.umich.edu RI Cilwa, Katherine/N-3840-2016 OI Cilwa, Katherine/0000-0003-3828-884X FU Plastic Surgery Foundation National Endowment Award; NIH [R01GM098350-02, R01 AR055222, P50-GM60338, R01-GM56687, T32-GM8256, U54-GM062119]; National Institute on Disability and Rehabilitation Research [H133A070026, H133A70019]; Shriners Hospitals for Children [85500, 71008]; [1K08GM109105-01]; [R24-GM102656] FX B.L. was funded by 1K08GM109105-01 and Plastic Surgery Foundation National Endowment Award. This research was partially supported by NIH grant R01GM098350-02 to C.X. and S.C.W.; NIH grant R01 AR055222 to M.D.M.; National Institute on Disability and Rehabilitation Research (grants H133A070026 and H133A70019), NIH (grants P50-GM60338, R01-GM56687, and T32-GM8256), and Shriners Hospitals for Children (grants 85500 and 71008) to D.N.H.; and NIH grant U54-GM062119 to R.G.T. and its legacy grant R24-GM102656 to W.X. for the Trauma-Related Database (TRDB). NR 33 TC 31 Z9 31 U1 1 U2 5 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 SEP 24 PY 2014 VL 6 IS 255 AR 255ra132 DI 10.1126/scitranslmed.3008810 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AR1BY UT WOS:000343316800008 PM 25253675 ER PT J AU Braverman, ER Han, D Oscar-Berman, M Karikh, T Truesdell, C Dushaj, K Kreuk, F Li, M Stratton, D Blum, K AF Braverman, Eric R. Han, David Oscar-Berman, Marlene Karikh, Tatiana Truesdell, Courtney Dushaj, Kristina Kreuk, Florian Li, Mona Stratton, Danielle Blum, Kenneth TI Menopause Analytical Hormonal Correlate Outcome Study (MAHCOS) and the Association to Brain Electrophysiology (P300) in a Clinical Setting SO PLOS ONE LA English DT Article ID MILD COGNITIVE IMPAIRMENT; PLASMA LEPTIN LEVELS; INCIDENT ALZHEIMER-DISEASE; BODY-MASS INDEX; POSTMENOPAUSAL WOMEN; LUTEINIZING-HORMONE; OLDER-ADULTS; RISK-FACTORS; MOUSE MODEL; WEIGHT-LOSS AB Various studies have demonstrated that increased leptin levels and obesity are inversely related to cognitive decline in menopausal women. It is hypothesized that adiposity is inversely correlated with cognitive decline, as women with increased weight are less vulnerable to diminishing cognition. However, it is increasingly observed that menopausal women, even with increased adiposity, experience significant cognitive decline. Positron emission tomography (PET) has been used to analyze cognitive function and processing in menopausal women. Evoked potentials (P300) and neurophysiologic tests have validated brain metabolism in cognitively impaired patients. Post-hoc analyses of 796 female patients entering PATH Medical Clinic, between January 4, 2009 and February 24, 2013, were performed as part of the "Menopause Analytical Hormonal Correlate Outcome Study" (MAHCOS). Patient age range was 39-76 years (46.7 +/- 0.2). P300 latency and amplitude correlated with a number of hormones: follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, estrone, estriol, DHEA, pregnenolone, progesterone, free and total testosterone, thyroid stimulating hormone (TSH), Vitamins D 1.25 and D 25OH, leptin, and insulin-like growth factor-binding protein 3 (IGF-BP3). Corrected statistics did not reveal significant associations with P300 latency or amplitude for these hormones except for leptin plasma levels. However, factor analysis showed that FSH and LH clustered together with Vitamin D1.25 and Vitamin D25OH, P300 latency (not amplitude), and log leptin were found to be associated in the same cluster. Utilizing regression analysis, once age adjusted, leptin was the only significant predictor for latency or speed (p = 0.03) with an effect size of 0.23. Higher plasma leptin levels were associated with abnormal P300 speed (OR = 0.98). Our findings show a significant relationship of higher plasma leptin levels, potentially due to leptin resistance, and prolonged P300 latency. This suggests leptin resistance may delay electrophysiological processing of memory and attention, which appears to be the first of such an association. C1 [Braverman, Eric R.; Karikh, Tatiana; Truesdell, Courtney; Dushaj, Kristina; Kreuk, Florian; Li, Mona; Stratton, Danielle; Blum, Kenneth] PATH Fdn NY, Dept Clin Neurol, New York, NY 10016 USA. [Braverman, Eric R.; Blum, Kenneth] Univ Florida, Coll Med, Dept Psychiat, Gainesville, FL USA. [Braverman, Eric R.; Blum, Kenneth] McKnight Brain Inst, Gainesville, FL USA. [Han, David] Univ Texas San Antonio, Dept Management Sci & Stat, San Antonio, TX USA. [Oscar-Berman, Marlene] Boston Univ, Sch Med, Dept Psychiat, Dept Neurol, Boston, MA 02118 USA. [Oscar-Berman, Marlene] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Oscar-Berman, Marlene] Boston VA Healthcare Syst, Boston, MA USA. [Blum, Kenneth] Univ Vermont, Ctr Clin & Translat Sci, Dept Psychiat, Human Integrated Serv Unit, Burlington, VT USA. [Blum, Kenneth] Inst Integrat Omics & Appl Biotechnol, Medinipur, W Bengal, India. [Blum, Kenneth] Domin Diagnost LLC, North Kingstown, RI USA. RP Blum, K (reprint author), PATH Fdn NY, Dept Clin Neurol, New York, NY 10016 USA. EM drd2gene@gmail.com FU Life Extension Foundation FX The authors are grateful to the Life Extension Foundation for their generous financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 84 TC 0 Z9 0 U1 1 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 SEP 24 PY 2014 VL 9 IS 9 AR e105048 DI 10.1371/journal.pone.0105048 PG 25 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ0SJ UT WOS:000342492700006 PM 25251414 ER PT J AU Dohi, K Kraemer, BC Erickson, MA McMillan, PJ Kovac, A Flachbartova, Z Hansen, KM Shah, GN Sheibani, N Salameh, T Banks, WA AF Dohi, Kenji Kraemer, Brian C. Erickson, Michelle A. McMillan, Pamela J. Kovac, Andrej Flachbartova, Zuzana Hansen, Kim M. Shah, Gul N. Sheibani, Nader Salameh, Therese Banks, William A. TI Molecular Hydrogen in Drinking Water Protects against Neurodegenerative Changes Induced by Traumatic Brain Injury SO PLOS ONE LA English DT Article ID INDUCED OXIDATIVE DAMAGE; TNF-ALPHA; BARRIER; TRANSPORT; PERICYTES; MATRIX-METALLOPROTEINASE-9; LIPOPOLYSACCHARIDE; PERMEABILITY; CYCLOPHILIN; EXPRESSION AB Traumatic brain injury (TBI) in its various forms has emerged as a major problem for modern society. Acute TBI can transform into a chronic condition and be a risk factor for neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, probably through induction of oxidative stress and neuroinflammation. Here, we examined the ability of the antioxidant molecular hydrogen given in drinking water (molecular hydrogen water; mHW) to alter the acute changes induced by controlled cortical impact (CCI), a commonly used experimental model of TBI. We found that mHW reversed CCI-induced edema by about half, completely blocked pathological tau expression, accentuated an early increase seen in several cytokines but attenuated that increase by day 7, reversed changes seen in the protein levels of aquaporin-4, HIF-1, MMP-2, and MMP-9, but not for amyloid beta peptide 1-40 or 1-42. Treatment with mHW also reversed the increase seen 4 h after CCI in gene expression related to oxidation/carbohydrate metabolism, cytokine release, leukocyte or cell migration, cytokine transport, ATP and nucleotide binding. Finally, we found that mHW preserved or increased ATP levels and propose a new mechanism for mHW, that of ATP production through the Jagendorf reaction. These results show that molecular hydrogen given in drinking water reverses many of the sequelae of CCI and suggests that it could be an easily administered, highly effective treatment for TBI. C1 [Dohi, Kenji; Kraemer, Brian C.; Erickson, Michelle A.; Kovac, Andrej; Hansen, Kim M.; Salameh, Therese; Banks, William A.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Dohi, Kenji] Jikei Univ, Sch Med, Dept Emergency Med, Tokyo, Japan. [Kraemer, Brian C.; Kovac, Andrej; Hansen, Kim M.; Salameh, Therese; Banks, William A.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA USA. [Kraemer, Brian C.; McMillan, Pamela J.] Vet Affairs Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA USA. [McMillan, Pamela J.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Flachbartova, Zuzana] Univ Vet Med & Pharm, Dept Microbiol & Immunol, Lab Biomed Microbiol & Immunol, Kosice, Slovakia. [Shah, Gul N.] St Louis Univ, Sch Med, Edward Doisy Res Ctr, Div Endocrinol,Dept Internal Med, St Louis, MO USA. [Sheibani, Nader] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. RP Banks, WA (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. EM wabanks1@uw.edu FU Kiban C grant [23592683]; VA Merit Review [RO-1 AG029839, R0-1 NS064131]; [RO-1 DK083485] FX KD was supported by Kiban C grant number 23592683. WAB was supported by VA Merit Review; RO-1 AG029839. WAB and GNS was supported by RO-1 DK083485. BCK was supported by VA Merit Review; R0-1 NS064131. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 3 Z9 4 U1 1 U2 14 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 SEP 24 PY 2014 VL 9 IS 9 AR e108034 DI 10.1371/journal.pone.0108034 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ0SJ UT WOS:000342492700070 PM 25251220 ER PT J AU Singhal, AB Lo, W AF Singhal, Aneesh B. Lo, Warren TI Life after stroke Beyond medications SO NEUROLOGY LA English DT Editorial Material ID YOUNG-ADULTS; ISCHEMIC-STROKE; EVENTS C1 [Singhal, Aneesh B.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Lo, Warren] Nationwide Childrens Hosp, Dept Neurol, Columbus, OH USA. RP Singhal, AB (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. EM asinghal@mgh.harvard.edu FU NINDS NIH HHS [U10NS0867290, R01NS051412, R21NS077442] NR 10 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 23 PY 2014 VL 83 IS 13 BP 1128 EP 1129 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AT3TE UT WOS:000344856400006 PM 25128181 ER PT J AU Falcone, GJ Radmanesh, F Brouwers, HB Battey, TWK Devan, WJ Valant, V Raffeld, MR Chitsike, LP Ayres, AM Schwab, K Goldstein, JN Viswanathan, A Greenberg, SM Selim, M Meschia, JF Brown, DL Worrall, BB Silliman, SL Tirschwell, DL Flaherty, ML Martini, SR Deka, R Biffi, A Kraft, P Woo, D Rosand, J Anderson, CD AF Falcone, Guido J. Radmanesh, Farid Brouwers, H. Bart Battey, Thomas W. K. Devan, William J. Valant, Valerie Raffeld, Miriam R. Chitsike, Lennox P. Ayres, Alison M. Schwab, Kristin Goldstein, Joshua N. Viswanathan, Anand Greenberg, Steven M. Selim, Magdy Meschia, James F. Brown, Devin L. Worrall, Bradford B. Silliman, Scott L. Tirschwell, David L. Flaherty, Matthew L. Martini, Sharyl R. Deka, Ranjan Biffi, Alessandro Kraft, Peter Woo, Daniel Rosand, Jonathan Anderson, Christopher D. CA Int Stroke Genetics Consortium TI APOE epsilon variants increase risk of warfarin-related intracerebral hemorrhage SO NEUROLOGY LA English DT Article ID CEREBRAL AMYLOID ANGIOPATHY; ATRIAL-FIBRILLATION; APOLIPOPROTEIN-E; ALZHEIMERS-DISEASE; CLINICAL-DIAGNOSIS; GENE-ENVIRONMENT; STROKE; ASSOCIATION; ANTICOAGULATION; METAANALYSIS AB Objective: We aimed to assess the effect of APOE epsilon variants on warfarin-related intracerebral hemorrhage (wICH), evaluated their predictive power, and tested for interaction with warfarin in causing wICH. Methods: This was a prospective, 2-stage (discovery and replication), case-control study. wICH was classified as lobar or nonlobar based on the location of the hematoma. Controls were sampled from ambulatory clinics (discovery) and random digit dialing (replication). APOE epsilon variants were directly genotyped. A case-control design and logistic regression analysis were utilized to test for association between APOE epsilon and wICH. A case-only design and logistic regression analysis were utilized to test for interaction between APOE epsilon and warfarin. Receiver operating characteristic curves were implemented to evaluate predictive power. Results: The discovery stage included 319 wICHs (44% lobar) and 355 controls. APOE epsilon 2 was associated with lobar (odds ratio [OR] 2.46; p < 0.001) and nonlobar wICH (OR 1.67; p = 0.04), whereas epsilon 4 was associated with lobar (OR 2.09; p < 0.001) but not nonlobar wICH (p = 0.35). The replication stage (63 wICHs and 1,030 controls) confirmed the association with epsilon 2 (p = 0.03) and e4 (p = 0.003) for lobar but not for nonlobar wICH (p > 0.20). Genotyping information on APOE epsilon variants significantly improved case/control discrimination of lobar wICH (C statistic 0.80). No statistical interaction between warfarin and APOE was found (p > 0.20). Conclusions: APOE epsilon variants constitute strong risk factors for lobar wICH. APOE exerts its effect independently of warfarin, although power limitations render this absence of interaction preliminary. Evaluation of the predictive ability of APOE in cohort studies is warranted. C1 [Falcone, Guido J.; Brouwers, H. Bart; Battey, Thomas W. K.; Devan, William J.; Valant, Valerie; Raffeld, Miriam R.; Chitsike, Lennox P.; Ayres, Alison M.; Schwab, Kristin; Viswanathan, Anand; Greenberg, Steven M.; Biffi, Alessandro; Rosand, Jonathan; Anderson, Christopher D.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Falcone, Guido J.; Radmanesh, Farid; Brouwers, H. Bart; Battey, Thomas W. K.; Devan, William J.; Valant, Valerie; Raffeld, Miriam R.; Biffi, Alessandro; Rosand, Jonathan; Anderson, Christopher D.] Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. [Falcone, Guido J.; Radmanesh, Farid; Brouwers, H. Bart; Battey, Thomas W. K.; Devan, William J.; Raffeld, Miriam R.; Biffi, Alessandro; Rosand, Jonathan; Anderson, Christopher D.] Massachusetts Gen Hosp, Dept Neurol, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA. [Goldstein, Joshua N.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Falcone, Guido J.; Radmanesh, Farid; Brouwers, H. Bart; Battey, Thomas W. K.; Devan, William J.; Raffeld, Miriam R.; Biffi, Alessandro; Rosand, Jonathan; Anderson, Christopher D.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Falcone, Guido J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Selim, Magdy] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Brown, Devin L.] Univ Michigan Hlth Syst, Dept Neurol, Stroke Program, Ann Arbor, MI USA. [Worrall, Bradford B.] Univ Virginia Hlth Syst, Dept Neurol, Charlottesville, VA USA. [Worrall, Bradford B.] Univ Virginia Hlth Syst, Dept Publ Hlth Sci, Charlottesville, VA USA. [Silliman, Scott L.] Univ Florida, Coll Med, Dept Neurol, Jacksonville, FL USA. [Tirschwell, David L.] Univ Washington, Harborview Med Ctr, Stroke Ctr, Seattle, WA 98104 USA. [Flaherty, Matthew L.; Martini, Sharyl R.; Deka, Ranjan; Woo, Daniel] Univ Cincinnati, Coll Med, Cincinnati, OH 45221 USA. RP Anderson, CD (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM cdanderson@partners.org RI Lee, Chaeyoung/C-7929-2012; Goldstein, Joshua/H-8953-2016; Falcone, Guido/L-2287-2016 OI Lee, Chaeyoung/0000-0002-2940-1778; Falcone, Guido/0000-0002-6407-0302 FU NIH; National Institute for Neurological Disorders and Stroke (NINDS) [R01NS059727, P50NS061343, NS36695, NS30678]; NIH-NINDS SPOTRIAS fellowship [P50NS061343]; American Brain Foundation; Massachusetts General Hospital Institute for Heart, Vascular, and Stroke Care FX Supported by the NIH and the National Institute for Neurological Disorders and Stroke (NINDS) through grants R01NS059727 and P50NS061343 (GOCHA Study), NS36695 (Genetic and Environmental Risk Factors for Hemorrhagic Stroke), and NS30678 (Hemorrhagic and Ischemic Stroke among Blacks and Whites). Drs. Falcone and Brouwers were supported by the NIH-NINDS SPOTRIAS fellowship grant P50NS061343. Dr. Anderson was supported by the American Brain Foundation, and received support from the Massachusetts General Hospital Institute for Heart, Vascular, and Stroke Care for his cerebrovascular disease research. NR 26 TC 10 Z9 11 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 23 PY 2014 VL 83 IS 13 BP 1139 EP 1146 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AT3TE UT WOS:000344856400009 PM 25150286 ER PT J AU Gkotzamanidou, M Sfikakis, PP Kyrtopoulos, SA Bamia, C Dimopoulos, MA Souliotis, VL AF Gkotzamanidou, M. Sfikakis, P. P. Kyrtopoulos, S. A. Bamia, C. Dimopoulos, M. A. Souliotis, V. L. TI Chromatin structure, transcriptional activity and DNA repair efficiency affect the outcome of chemotherapy in multiple myeloma SO BRITISH JOURNAL OF CANCER LA English DT Article DE multiple myeloma; melphalan; epigenetic changes; DNA damage response; transcription-coupled repair; clinical outcome; malignant bone marrow plasma cells; peripheral blood mononuclear cells ID INTERSTRAND CROSS-LINKS; HISTONE DEACETYLASE INHIBITORS; STEM-CELL TRANSPLANTATION; HIGH-DOSE MELPHALAN; GENOMIC INSTABILITY; NITROGEN MUSTARDS; DAMAGE RESPONSE; BONE-MARROW; IN-VITRO; CANCER AB Background: Melphalan is one of the most active chemotherapeutic agents in the treatment of multiple myeloma (MM). However, the mechanism underlying differential patient responses to melphalan therapy is unknown. Methods: Chromatin structure, transcriptional activity and DNA damage response signals were examined following ex vivo treatment with melphalan of both malignant bone marrow plasma cells (BMPCs) and peripheral blood mononuclear cells (PBMCs) of MM patients, responders (n = 57) or non-responders (n = 28) to melphalan therapy. PBMCs from healthy controls (n = 25) were also included in the study. Results: In both BMPCs and PBMCs, the local chromatin looseness, transcriptional activity and repair efficiency of the transcribed strand (TS) were significantly higher in non-responders than in responders and lowest in healthy controls (all P<0.05). Moreover, we found that melphalan-induced apoptosis inversely correlated with the repair efficiency of the TS, with the duration of the inhibition of mRNA synthesis, phosphorylation of p53 at serine 15 and apoptosis rates being higher in responders than in non-responders (all P<0.001). Conclusions: Our findings provide a mechanistic basis for the link between DNA repair efficiency and response to melphalan therapy. Interestingly, the observation of these phenomena in PBMCs provides a novel approach for the prediction of response to anti-myeloma therapy. C1 [Gkotzamanidou, M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Gkotzamanidou, M.; Dimopoulos, M. A.] Univ Athens, Sch Med, Dept Clin Therapeut, Athens 11528, Greece. [Sfikakis, P. P.] Univ Athens, Sch Med, Dept Propedeut Med 1, GR-11527 Athens, Greece. [Kyrtopoulos, S. A.; Souliotis, V. L.] Natl Hellen Res Fdn, Inst Biol Med Chem & Biotechnol, Athens 11635, Greece. [Bamia, C.] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. RP Souliotis, VL (reprint author), Natl Hellen Res Fdn, Inst Biol Med Chem & Biotechnol, 48 Vassileos Constantinou Ave, Athens 11635, Greece. EM vls@eie.gr FU ECNIS (Environmental Cancer, Nutrition and Individual Susceptibility) Network of Excellence of the European Union [513943] FX We would like to thank Professor Kenneth C Anderson (Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA) and Dr Evangelos Terpos (Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece) for their helpful comments and suggestions. This work was partly supported by the ECNIS (Environmental Cancer, Nutrition and Individual Susceptibility) Network of Excellence of the European Union (contract no. 513943). NR 51 TC 2 Z9 2 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD SEP 23 PY 2014 VL 111 IS 7 BP 1293 EP 1304 DI 10.1038/bjc.2014.410 PG 12 WC Oncology SC Oncology GA AR1DT UT WOS:000343323100007 PM 25051404 ER PT J AU Hara, T Truelove, J Tawakol, A Wojtkiewicz, GR Hucker, WJ MacNabb, MH Brownell, AL Jokivarsi, K Kessinger, CW Jaff, MR Henke, PK Weissleder, R Jaffer, FA AF Hara, Tetsuya Truelove, Jessica Tawakol, Ahmed Wojtkiewicz, Gregory R. Hucker, William J. MacNabb, Megan H. Brownell, Anna-Liisa Jokivarsi, Kimmo Kessinger, Chase W. Jaff, Michael R. Henke, Peter K. Weissleder, Ralph Jaffer, Farouc A. TI F-18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Enables the Detection of Recurrent Same-Site Deep Vein Thrombosis by Illuminating Recently Formed, Neutrophil-Rich Thrombus SO CIRCULATION LA English DT Article DE fluorodeoxyglucose F18; inflammation; neutrophils; positron-emission tomography; venous thrombosis ID CATHETER-DIRECTED THROMBOLYSIS; VENOUS THROMBOSIS; POSTTHROMBOTIC SYNDROME; ATHEROSCLEROTIC PLAQUES; VASCULAR INFLAMMATION; F-18-FDG PET; MOUSE MODEL; THROMBOEMBOLISM; RESOLUTION; FDG AB Background-Accurate detection of recurrent same-site deep vein thrombosis (DVT) is a challenging clinical problem. Because DVT formation and resolution are associated with a preponderance of inflammatory cells, we investigated whether noninvasive F-18-fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging could identify inflamed, recently formed thrombi and thereby improve the diagnosis of recurrent DVT. Methods and Results-We established a stasis-induced DVT model in murine jugular veins and also a novel model of recurrent stasis DVT in mice. C57BL/6 mice (n=35) underwent ligation of the jugular vein to induce stasis DVT. FDG-PET/computed tomography (CT) was performed at DVT time points of day 2, 4, 7, 14, or 2+ 16 (same-site recurrent DVT at day 2 overlying a primary DVT at day 16). Antibody-based neutrophil depletion was performed in a subset of mice before DVT formation and FDG-PET/CT. In a clinical study, 38 patients with lower extremity DVT or controls undergoing FDG-PET were analyzed. Stasis DVT demonstrated that the highest FDG signal occurred at day 2, followed by a time-dependent decrease (P<0.05). Histological analyses demonstrated that thrombus neutrophils (P<0.01), but not macrophages, correlated with thrombus PET signal intensity. Neutrophil depletion decreased FDG signals in day 2 DVT in comparison with controls (P=0.03). Recurrent DVT demonstrated significantly higher FDG uptake than organized day 14 DVT (P=0.03). The FDG DVT signal in patients also exhibited a time-dependent decrease (P<0.01). Conclusions-Noninvasive FDG-PET/CT identifies neutrophil-dependent thrombus inflammation in murine DVT, and demonstrates a time-dependent signal decrease in both murine and clinical DVT. FDG-PET/CT may offer a molecular imaging strategy to accurately diagnose recurrent DVT. C1 [Hara, Tetsuya; Kessinger, Chase W.; Jaffer, Farouc A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Truelove, Jessica; Wojtkiewicz, Gregory R.; Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. [Tawakol, Ahmed; Hucker, William J.; MacNabb, Megan H.; Jaff, Michael R.; Jaffer, Farouc A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Brownell, Anna-Liisa; Jokivarsi, Kimmo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Biomed Imaging Ctr, Boston, MA USA. [Henke, Peter K.] Univ Michigan, Dept Surg, Vasc Surg Sect, Ann Arbor, MI 48109 USA. RP Jaffer, FA (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Simches Res Bldg,Room 3206, Boston, MA 02114 USA. EM fjaffer@mgh.harvard.edu FU National Institutes of Health grant [HL108229]; Wagner-Torizuka Society of Nuclear Medicine Fellowship; American Heart Association Founders postdoctoral fellowship [13POST14640021]; [13GRNT17060040] FX This study was supported by National Institutes of Health grant HL108229 (to Dr Jaffer), Wagner-Torizuka Society of Nuclear Medicine Fellowship (to Dr Hara), American Heart Association Founders postdoctoral fellowship #13POST14640021 (to Dr Hara), and Grant-in-Aid #13GRNT17060040 (to Dr Jaffer). NR 47 TC 11 Z9 11 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD SEP 23 PY 2014 VL 130 IS 13 BP 1044 EP + DI 10.1161/CIRCULATIONAHA.114.008902 PG 17 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AQ3IK UT WOS:000342685100009 PM 25070665 ER PT J AU Quan, JH Adelmant, G Marto, JA Look, AT Yusufzai, T AF Quan, Jinhua Adelmant, Guillaume Marto, Jarrod A. Look, A. Thomas Yusufzai, Timur TI The Chromatin Remodeling Factor CHD5 Is a Transcriptional Repressor of WEE1 SO PLOS ONE LA English DT Article ID HISTONE DEACETYLASE; TUMOR-SUPPRESSOR; NEUROBLASTOMA-CELLS; PHD FINGERS; DNA-DAMAGE; COMPLEXES; GENE; EXPRESSION; CANCER; RECOGNITION AB Loss of the chromatin remodeling ATPase CHD5 has been linked to the progression of neuroblastoma tumors, yet the underlying mechanisms behind the tumor suppressor role of CHD5 are unknown. In this study, we purified the human CHD5 complex and found that CHD5 is a component of the full NuRD transcriptional repressor complex, which also contains methyl-CpG binding proteins and histone deacetylases. The CHD5/NuRD complex appears mutually exclusive with the related CHD4/NuRD complex as overexpression of CHD5 results in loss of the CHD4 protein in cells. Following a search for genes that are regulated by CHD5 in neuroblastoma cells, we found that CHD5 binds to and represses the G2/M checkpoint gene WEE1. Reintroduction of CHD5 into neuroblastoma cells represses WEE1 expression, demonstrating that CHD5 can function as a repressor in cells. A catalytically inactive mutant version of CHD5 is able to associate with a NuRD cofactor but fails to repress transcription. Our study shows that CHD5 is a NuRD-associated transcriptional repressor and identifies WEE1 as one of the CHD5-regulated genes that may link CHD5 to tumor suppression. C1 [Quan, Jinhua; Yusufzai, Timur] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Quan, Jinhua; Adelmant, Guillaume; Marto, Jarrod A.; Yusufzai, Timur] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Adelmant, Guillaume; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Dept Canc Biol, Boston, MA 02115 USA. [Look, A. Thomas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Yusufzai, T (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. EM timur_yusufzai@dfci.harvard.edu FU Dana-Farber Cancer Institute; William F. Milton Fund; Claudia Adams Barr Program FX This work was supported by the Dana-Farber Cancer Institute, the William F. Milton Fund, and the Claudia Adams Barr Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 6 Z9 6 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 23 PY 2014 VL 9 IS 9 AR e108066 DI 10.1371/journal.pone.0108066 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP8TL UT WOS:000342351800059 PM 25247294 ER PT J AU Ghosh, D Bagley, AF Na, YJ Birrer, MJ Bhatia, SN Belcher, AM AF Ghosh, Debadyuti Bagley, Alexander F. Na, Young Jeong Birrer, Michael J. Bhatia, Sangeeta N. Belcher, Angela M. TI Deep, noninvasive imaging and surgical guidance of submillimeter tumors using targeted M13-stabilized single-walled carbon nanotubes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer imaging; fluorescence-guided surgery; M13 bacteriophage ID NEAR-INFRARED WINDOW; IN-VIVO; QUANTUM DOTS; FLUORESCENCE; CANCER; NANOPARTICLES; PHAGE; MICE; LIBRARIES; LIGANDS AB Highly sensitive detection of small, deep tumors for early diagnosis and surgical interventions remains a challenge for conventional imaging modalities. Second-window near-infrared light (NIR2, 950-1,400 nm) is promising for in vivo fluorescence imaging due to deep tissue penetration and low tissue autofluorescence. With their intrinsic fluorescence in the NIR2 regime and lack of photobleaching, single-walled carbon nanotubes (SWNTs) are potentially attractive contrast agents to detect tumors. Here, targeted M13 virus-stabilized SWNTs are used to visualize deep, disseminated tumors in vivo. This targeted nanoprobe, which uses M13 to stably display both tumor-targeting peptides and an SWNT imaging probe, demonstrates excellent tumor-to-background uptake and exhibits higher signal-to-noise performance compared with visible and near-infrared (NIR1) dyes for delineating tumor nodules. Detection and excision of tumors by a gynecological surgeon improved with SWNT image guidance and led to the identification of submillimeter tumors. Collectively, these findings demonstrate the promise of targeted SWNT nanoprobes for noninvasive disease monitoring and guided surgery. C1 [Ghosh, Debadyuti; Bagley, Alexander F.; Bhatia, Sangeeta N.; Belcher, Angela M.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Ghosh, Debadyuti; Belcher, Angela M.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. [Bhatia, Sangeeta N.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Belcher, Angela M.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Bhatia, Sangeeta N.] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Bhatia, Sangeeta N.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Bhatia, Sangeeta N.] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. [Bagley, Alexander F.] Harvard Univ, Biophys Program, Boston, MA 02115 USA. [Bagley, Alexander F.] Harvard Univ, Sch Med, MD PhD Program, Boston, MA 02115 USA. [Na, Young Jeong; Birrer, Michael J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Bhatia, SN (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM sbhatia@mit.edu; belcher@mit.edu FU National Institutes of Health (NIH) Center for Cancer Nanotechnology Excellence [U54-CA119349-04, U54-CA151884]; Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund; Marie D. & Pierre Casimir-Lambert Fund; Professor Amar G. Bose Research Grant; NIH/Medical Scientist Training Program; [P30-ES002109] FX The authors thank Dr. Rod Bronson for tumor scoring, Mike Brown and the Koch Institute Tang Histology Facility for assistance with histology, and Heather Fleming for excellent assistance with editing of the manuscript. The authors acknowledge the Koch Institute Swanson Biotechnology Center for DNA sequencing. This work was supported by the National Institutes of Health (NIH) Center for Cancer Nanotechnology Excellence Grants U54-CA119349-04 and U54-CA151884 (to S.N.B. and A. M. B.). This work was supported in part by the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund. This work was funded in part by Grant P30-ES002109, the Marie D. & Pierre Casimir-Lambert Fund, and a Professor Amar G. Bose Research Grant. A. F. B. is supported by the NIH/Medical Scientist Training Program. S.N.B. is a Howard Hughes Medical Institute Investigator. NR 36 TC 43 Z9 43 U1 10 U2 64 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 SEP 23 PY 2014 VL 111 IS 38 BP 13948 EP 13953 DI 10.1073/pnas.1400821111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP3PC UT WOS:000341988200064 PM 25214538 ER PT J AU Lysaght, AC Yuan, Q Fan, Y Kalwani, N Caruso, P Cunnane, M Lanske, B Stankovic, KM AF Lysaght, Andrew C. Yuan, Quan Fan, Yi Kalwani, Neil Caruso, Paul Cunnane, MaryBeth Lanske, Beate Stankovic, Konstantina M. TI FGF23 Deficiency Leads to Mixed Hearing Loss and Middle Ear Malformation in Mice SO PLOS ONE LA English DT Article ID OTITIS-MEDIA; VITAMIN-D; INNER-EAR; HYPOPHOSPHATEMIC RICKETS; TUMORAL CALCINOSIS; KLOTHO PROTEIN; EXPRESSION; PHOSPHATE; HYPERPHOSPHATEMIA; OTOTOXICITY AB Fibroblast growth factor 23 (FGF23) is a circulating hormone important in phosphate homeostasis. Abnormal serum levels of FGF23 result in systemic pathologies in humans and mice, including renal phosphate wasting diseases and hyperphosphatemia. We sought to uncover the role FGF23 plays in the auditory system due to shared molecular mechanisms and genetic pathways between ear and kidney development, the critical roles multiple FGFs play in auditory development and the known hearing phenotype in mice deficient in klotho (KL), a critical co-factor for FGF23 signaling. Using functional assessments of hearing, we demonstrate that Fgf23(+/-) mice are profoundly deaf. Fgf23(+/-) mice have moderate hearing loss above 20 kHz, consistent with mixed conductive and sensorineural pathology of both middle and inner ear origin. Histology and high-voltage X-ray computed tomography of Fgf23(-/-) mice demonstrate dysplastic bulla and ossicles; Fgf23(+/-) mice have near-normal morphology. The cochleae of mutant mice appear nearly normal on gross and microscopic inspection. In wild type mice, FGF23 is ubiquitously expressed throughout the cochlea. Measurements from Fgf23(-/-) mice do not match the auditory phenotype of Kl(-/-) mice, suggesting that loss of FGF23 activity impacts the auditory system via mechanisms at least partially independent of KL. Given the extensive middle ear malformations and the overlap of initiation of FGF23 activity and Eustachian tube development, this work suggests a possible role for FGF23 in otitis media. C1 [Lysaght, Andrew C.] Harvard MIT Joint Div Hlth Sci & Technol, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA. [Lysaght, Andrew C.; Kalwani, Neil; Stankovic, Konstantina M.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Yuan, Quan; Fan, Yi; Lanske, Beate] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Caruso, Paul; Cunnane, MaryBeth] Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA 02114 USA. [Caruso, Paul; Cunnane, MaryBeth] Harvard Univ, Sch Med, Boston, MA USA. [Stankovic, Konstantina M.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Stankovic, Konstantina M.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. RP Lysaght, AC (reprint author), Harvard MIT Joint Div Hlth Sci & Technol, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA. EM andrew_lysaght@meei.harvard.edu FU National Institute on Deafness and Other Communication Disorders [K08 DC010419]; Bertarelli Foundation; National Institute of Diabetes and Digestive and Kidney Diseases grant [DK097105] FX The authors are grateful for support from National Institute on Deafness and Other Communication Disorders grant K08 DC010419 (KMS), the Bertarelli Foundation (KMS) and National Institute of Diabetes and Digestive and Kidney Diseases grant DK097105 (BL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 10 Z9 11 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 22 PY 2014 VL 9 IS 9 AR e107681 DI 10.1371/journal.pone.0107681 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR6FX UT WOS:000343679800043 PM 25243481 ER PT J AU Massimini, DF Warner, JJP Li, GA AF Massimini, Daniel F. Warner, Jon J. P. Li, Guoan TI Glenohumeral joint cartilage contact in the healthy adult during scapular plane elevation depression with external humeral rotation SO JOURNAL OF BIOMECHANICS LA English DT Article DE Shoulder; Kinematics; Fluoroscopy; Orthopaedics; Mechanics ID LATE PREPARATORY PHASE; SHOULDER ARTHROPLASTY; BICIPITAL GROOVE; IN-VIVO; SCAPULOHUMERAL RHYTHM; NATURAL-HISTORY; CUFF TEARS; KINEMATICS; ORIENTATION; MOTION AB The shoulder (glenohumeral) joint has the greatest range of motion of all human joints; as a result, it is particularly vulnerable to dislocation and injury. The ability to non-invasively quantify in-vivo articular cartilage contact patterns of joints has been and remains a difficult biomechanics problem. As a result, little is known about normal in-vivo glenohumeral joint contact patterns or the consequences that surgery has on altering them. In addition, the effect of quantifying glenohumeral joint contact patterns by means of proximity mapping, both with and without cartilage data, is unknown. Therefore, the objectives of this study are to (1) describe a technique for quantifying in-vivo glenohumeral joint contact patterns during dynamic shoulder motion, (2) quantify normal glenohumeral joint contact patterns in the young healthy adult during scapular plane elevation depression with external humeral rotation, and (3) compare glenohumeral joint contact patterns determined both with and without articular cartilage data. Our results show that the inclusion of articular cartilage data when quantifying in-vivo glenohumeral joint contact patterns has significant effects on the anterior-posterior contact centroid location, the superior-inferior contact centroid range of travel, and the total contact path length. As a result, our technique offers an advantage over glenohumeral joint contact pattern measurement techniques that neglect articular cartilage data. Likewise, this technique may be more sensitive than traditional 6-Degree-of-Freedom (6-DOF) joint kinematics for the assessment of overall glenohumeral joint health. Lastly, for the shoulder motion tested, we found that glenohumeral joint contact was located on the anterior-inferior glenoid surface. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Massimini, Daniel F.; Warner, Jon J. P.; Li, Guoan] Massachusetts Gen Hosp, Shoulder Biomot Lab, Boston, MA 02114 USA. [Warner, Jon J. P.; Li, Guoan] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Massimini, Daniel F.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Li, GA (reprint author), Massachusetts Gen Hosp, Shoulder Biomot Lab, 55 Fruit St,GRJ-1223, Boston, MA 02114 USA. EM gli1@partners.org FU Massachusetts General Hospital research funds in the Department of Orthopaedics FX Funding for this project was provided from unrestricted internal Massachusetts General Hospital research funds in the Department of Orthopaedics. No external funding sources were used for any part of this study. All study design elements, data analysis and manuscript preparation were performed exclusively by the authors without any input from hospital or external sources. NR 40 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 EI 1873-2380 J9 J BIOMECH JI J. Biomech. PD SEP 22 PY 2014 VL 47 IS 12 BP 3100 EP 3106 DI 10.1016/j.jbiomech.2014.06.034 PG 7 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA AR2CU UT WOS:000343392000038 PM 25047740 ER PT J AU Shingai, M Donau, OK Plishka, RJ Buckler-White, A Mascola, JR Nabel, GJ Nason, MC Montefiori, D Moldt, B Poignard, P Diskin, R Bjorkman, PJ Eckhaus, MA Klein, F Mouquet, H Lorenzi, JCC Gazumyan, A Burton, DR Nussenzweig, MC Martin, MA Nishimura, Y AF Shingai, Masashi Donau, Olivia K. Plishka, Ronald J. Buckler-White, Alicia Mascola, John R. Nabel, Gary J. Nason, Martha C. Montefiori, David Moldt, Brian Poignard, Pascal Diskin, Ron Bjorkman, Pamela J. Eckhaus, Michael A. Klein, Florian Mouquet, Hugo Lorenzi, Julio Cesar Cetrulo Gazumyan, Anna Burton, Dennis R. Nussenzweig, Michel C. Martin, Malcolm A. Nishimura, Yoshiaki TI Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RHESUS-MONKEYS; ENVELOPE GLYCOPROTEIN; RATIONAL DESIGN; ENV TRIMERS; IN-VITRO; CHALLENGE; MUCOSAL; PROTECTION; VACCINE AB It is widely appreciated that effective human vaccines directed against viral pathogens elicit neutralizing antibodies (NAbs). The passive transfer of anti-HIV-1 NAbs conferring sterilizing immunity to macaques has been used to determine the plasma neutralization titers, which must be present at the time of exposure, to prevent acquisition of SIV/HIV chimeric virus (SHIV) infections. We administered five recently isolated potent and broadly acting anti-HIV neutralizing monoclonal antibodies (mAbs) to rhesus macaques and challenged them intrarectally 24 h later with either of two different R5-tropic SHIVs. By combining the results obtained from 60 challenged animals, we determined that the protective neutralization titer in plasma preventing virus infection in 50% of the exposed monkeys was relatively modest (similar to 1:100) and potentially achievable by vaccination. C1 [Shingai, Masashi; Donau, Olivia K.; Plishka, Ronald J.; Buckler-White, Alicia; Martin, Malcolm A.; Nishimura, Yoshiaki] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Mascola, John R.; Nabel, Gary J.] NIAID, Virol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Nason, Martha C.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Montefiori, David] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Moldt, Brian; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Moldt, Brian; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Moldt, Brian; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Diskin, Ron] Weizmann Inst Sci, Dept Biol Struct, IL-7610001 Rehovot, Israel. [Bjorkman, Pamela J.] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Bjorkman, Pamela J.; Nussenzweig, Michel C.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Eckhaus, Michael A.] NIH, Diagnost & Res Serv Branch, Off Director, Bethesda, MD 20892 USA. [Klein, Florian; Lorenzi, Julio Cesar Cetrulo; Gazumyan, Anna; Nussenzweig, Michel C.] Rockefeller Univ,New, Lab Mol Immunol, New York, NY 10065 USA. [Mouquet, Hugo] Inst Pasteur, Dept Immunol, Lab Humoral Response Pathogens, F-75724 Paris, France. [Burton, Dennis R.] Massachusetts Inst Technol & Harvard, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. RP Martin, MA (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM malm@nih.gov; ynishimura@niaid.nih.gov RI Cetrulo Lorenzi, Julio Cesar/B-5264-2008; poignard, pascal/N-6678-2013 OI Cetrulo Lorenzi, Julio Cesar/0000-0003-2492-3961; FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 62 TC 83 Z9 84 U1 1 U2 10 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD SEP 22 PY 2014 VL 211 IS 10 BP 2061 EP 2074 DI 10.1084/jem.20132494 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AQ4EC UT WOS:000342744800013 PM 25155019 ER PT J AU Simon, RA Shirani, H Aslund, KOA Back, M Haroutunian, V Gandy, S Nilsson, KPR AF Simon, Rozalyn A. Shirani, Hamid Aslund, K. O. Andreas Back, Marcus Haroutunian, Vahram Gandy, Sam Nilsson, K. Peter R. TI Pentameric Thiophene-Based Ligands that Spectrally Discriminate Amyloid-beta and Tau Aggregates Display Distinct Solvatochromism and Viscosity-Induced Spectral Shifts SO CHEMISTRY-A EUROPEAN JOURNAL LA English DT Article DE fluorescence; imaging agents; luminescent conjugated oligothiophenes; protein aggregates; solvatochromism ID LUMINESCENT CONJUGATED OLIGOTHIOPHENES; THIOFLAVIN-T BINDING; CONFORMATIONAL STATES; MOLECULAR-MECHANISM; PROBES; POLYMERS; ASSIGNMENT; DERIVATIVES; DEPOSITS; FIBRILS AB A wide range of neurodegenerative diseases are characterized by the deposition of multiple protein aggregates. Ligands for molecular characterization and discrimination of these pathological hallmarks are thus important for understanding their potential role in pathogenesis as well as for clinical diagnosis of the disease. In this regard, luminescent conjugated oligothiophenes (LCOs) have proven useful for spectral discrimination of amyloid-beta (A beta) and tau neurofibrillary tangles (NFTs), two of the pathological hallmarks associated with Alzheimer's disease. Herein, the solvatochromism of a library of anionic pentameric thiophene-based ligands, as well as their ability to spectrally discriminate A beta and tau aggregates, were investigated. Overall, the results from this study identified distinct solvatochromic and viscosity-dependent behavior of thiophene-based ligands that can be applied as indices to direct the chemical design of improved LCOs for spectral separation of A beta and tau aggregates in brain tissue sections. The results also suggest that the observed spectral transitions of the ligands are due to their ability to conform by induced fit to specific microenvironments within the binding interface of each particular protein aggregate. We foresee that these findings might aid in the chemical design of thiophene-based ligands that are increasingly selective for distinct disease-associated protein aggregates. C1 [Simon, Rozalyn A.; Shirani, Hamid; Aslund, K. O. Andreas; Back, Marcus; Nilsson, K. Peter R.] Linkoping Univ, Dept Chem, S-58183 Linkoping, Sweden. [Haroutunian, Vahram; Gandy, Sam] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Haroutunian, Vahram; Gandy, Sam] Mt Sinai Sch Med, Alzheimers Dis Res Ctr, New York, NY 10029 USA. [Haroutunian, Vahram; Gandy, Sam] James J Peters VA Med Ctr, Bronx, NY 10468 USA. RP Nilsson, KPR (reprint author), Linkoping Univ, Dept Chem, S-58183 Linkoping, Sweden. EM petni@ifm.liu.se FU Swedish Foundation for Strategic Research; Alzheimer Disease Research Center (ADRC) (NIH) [NIH-AG05138]; ERC Starting Independent Researcher Grant (Project: MUMID) from the European Research Council FX Our work is supported by the Swedish Foundation for Strategic Research (K.P.R.N, R. S.) and the Alzheimer Disease Research Center (ADRC) (NIH grantNIH-AG05138; V. H., S. G.). K.P.R.N is financed by an ERC Starting Independent Researcher Grant (Project: MUMID) from the European Research Council. R. S. is enrolled in the doctoral program Forum Scientum. NR 36 TC 7 Z9 7 U1 0 U2 9 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 0947-6539 EI 1521-3765 J9 CHEM-EUR J JI Chem.-Eur. J. PD SEP 22 PY 2014 VL 20 IS 39 BP 12537 EP 12543 DI 10.1002/chem.201402890 PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA AQ2OL UT WOS:000342626200026 PM 25111601 ER PT J AU Buckholtz, JW Faigman, DL AF Buckholtz, Joshua W. Faigman, David L. TI Promises, promises for neuroscience and law SO CURRENT BIOLOGY LA English DT Editorial Material ID FUNCTIONAL MRI; LIE DETECTION; SCIENCE; DIRECTIONS; COURT; RISK C1 [Buckholtz, Joshua W.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Buckholtz, Joshua W.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Buckholtz, Joshua W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Buckholtz, Joshua W.] Massachusetts Gen Hosp, Ctr Law Brain & Behav, Boston, MA 02114 USA. [Faigman, David L.] Univ Calif San Francisco, Hastings Coll Law, San Francisco, CA 94102 USA. [Faigman, David L.] Univ Calif San Francisco, Dept Psychiat, Sch Med, San Francisco, CA 94102 USA. [Faigman, David L.] UCSF UC Hastings Consortium Law Sci & Hlth Policy, San Francisco, CA 94102 USA. RP Buckholtz, JW (reprint author), Harvard Univ, Dept Psychol, 52 Oxford St, Cambridge, MA 02138 USA. EM joshua_buckholtz@harvard.edu NR 25 TC 4 Z9 4 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD SEP 22 PY 2014 VL 24 IS 18 BP R861 EP R867 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AP9JU UT WOS:000342396900015 PM 25247363 ER PT J AU Gelfand, MV Hagan, N Tata, A Oh, WJ Lacoste, B Kang, KT Kopycinska, J Bischoff, J Wang, JH Gu, C AF Gelfand, Maria V. Hagan, Nellwyn Tata, Aleksandra Oh, Won-Jong Lacoste, Baptiste Kang, Kyu-Tae Kopycinska, Justyna Bischoff, Joyce Wang, Jia-Huai Gu, Chenghua TI Neuropilin-1 functions as a VEGFR2 co-receptor to guide developmental angiogenesis independent of ligand binding SO ELIFE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; PATHOLOGICAL ANGIOGENESIS; VASCULAR DEVELOPMENT; HEPARIN-BINDING; SEMAPHORIN-III; TUMOR-GROWTH; RECEPTOR; ISOFORMS; MICE; PHOSPHORYLATION AB During development, tissue repair, and tumor growth, most blood vessel networks are generated through angiogenesis. Vascular endothelial growth factor (VEGF) is a key regulator of this process and currently, both VEGF and its receptors, VEGFR1, VEGFR2, and Neuropilin1 (NRP1), are targeted in therapeutic strategies for vascular disease and cancer. NRP1 is essential for vascular morphogenesis, but how NRP1 functions to guide vascular development has not been completely elucidated. Here, we generated a mouse line harboring a point mutation in the endogenous Nrp1 locus that selectively abolishes VEGF-NRP1 binding (Nrp1(VEGF-)). Nrp1(VEGF-) mutants survive to adulthood with normal vasculature revealing that NRP1 functions independent of VEGF-NRP1 binding during developmental angiogenesis. Moreover, we found that Nrp1-deficient vessels have reduced VEGFR2 surface expression in vivo demonstrating that NRP1 regulates its co-receptor, VEGFR2. Given the resources invested in NRP1 targeted anti-angiogenesis therapies, our results will be integral for developing strategies to re-build vasculature in disease. C1 [Gelfand, Maria V.; Hagan, Nellwyn; Tata, Aleksandra; Oh, Won-Jong; Lacoste, Baptiste; Kopycinska, Justyna; Gu, Chenghua] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Oh, Won-Jong] Korea Brain Res Inst, Taegu, South Korea. [Kang, Kyu-Tae; Bischoff, Joyce] Harvard Univ, Boston Childrens Hosp, Sch Med, Vasc Biol Program, Boston, MA USA. [Kang, Kyu-Tae; Bischoff, Joyce] Harvard Univ, Boston Childrens Hosp, Sch Med, Dept Surg, Boston, MA USA. [Kang, Kyu-Tae] Duksung Womens Univ, Coll Pharm, Seoul, South Korea. [Wang, Jia-Huai] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Gu, C (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, 220 Longwood Ave, Boston, MA 02115 USA. EM chenghua_gu@hms.harvard.edu OI Bischoff, Joyce/0000-0002-6367-1974 FU Neural Imaging Center NINDS P30 Core Center grant [NS072030]; National Institutes of Health Fundamental Neurobiology Training grant [T32 NS007484-12]; Alice and Joseph Brooks Fund Postdoctoral Fellowship; Harvard Mahoney Neuroscience Institute Fund Postdoctoral Fellowship; National Institutes of Health [R01 HL096384, R01 NS064583]; Sloan research fellowship; Armenise junior faculty award; Genise Goldenson fund FX We thank members of the Gu laboratory for helpful comments on the manuscript, Lauren Byrnes for technical support, and both the Flow Cytometry Facility in the Systems Biology Department and the Neurobiology Imaging Facility in the Neurobiology Department of Harvard Medical School for consultation and instrument availability that facilitated this work. The Neurobiology Imaging Facility is supported in part by the Neural Imaging Center as part of an NINDS P30 Core Center grant #NS072030. This study was supported by the National Institutes of Health Fundamental Neurobiology Training grant T32 NS007484-12 (N. Hagan), the Alice and Joseph Brooks Fund Postdoctoral Fellowship (A. Tata), Harvard Mahoney Neuroscience Institute Fund Postdoctoral Fellowship (B. Lacoste), National Institutes of Health grant R01 HL096384 (K. Kang and J. Bischoff), and the following grants to C. Gu: Sloan research fellowship, Armenise junior faculty award, the Genise Goldenson fund, and National Institutes of Health grant R01 NS064583. NR 34 TC 25 Z9 25 U1 2 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD SEP 22 PY 2014 VL 3 AR e03720 DI 10.7554/eLife.03720 PG 40 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AP4ZN UT WOS:000342089600001 PM 25244320 ER PT J AU Lowalekar, SK Treanor, PR Thatte, HS AF Lowalekar, Samar K. Treanor, Patrick R. Thatte, Hemant S. TI Cardioplegia at subnormothermia facilitates rapid functional resuscitation of hearts preserved in SOMAH for transplants SO JOURNAL OF CARDIOTHORACIC SURGERY LA English DT Article DE Cardioplegia; Transplantation; Reperfusion injury; High energy phosphates ID MYOCARDIAL PROTECTION; CRYSTALLOID CARDIOPLEGIA; CARDIOCIRCULATORY DEATH; REPERFUSION INJURY; CARDIAC-SURGERY; DONOR HEARTS; BLOOD; METAANALYSIS; PERFUSION; STORAGE AB Objectives: Hearts preserved ex vivo at 4 degrees C undergo time-dependent irreversible injury due to extreme hypothermia. Studies using novel organ preservative solution SOMAH, suggest that hearts are optimally 'preserved' at subnormothermic temperature of 21 degrees C. Present study evaluates relative efficacy of SOMAH 'cardioplegia' at 4 and 21 degrees C in preservation of optimum heart function after in vitro storage at subnormothermia. Methods: Porcine hearts arrested with SOMAH cardioplegia at 4 or 21 degrees C were stored in SOMAH for 5-hour at 21 degrees C (n = 5). At the end of storage, the weight of hearts was recorded and biopsies taken for cardiac tissue high energy phosphate level measurements. The hearts were then attached to a reperfusion apparatus and biochemical parameters including cardiac enzyme release and myocardial oxygen consumption and lactate production were determined in perfusate samples at regular intervals during ex vivo perfusion experiment. Functional evaluation of the hearts intraoperatively and ex vivo was performed by 2D echocardiography using trans-esophageal echocardiography probe. Results: Post-storage heart weights were unaltered in both groups, while available high-energy phosphates (HEP) were greater in the 21 degrees C group. Upon ex vivo reperfusion, coronary flow was significantly greater (p < 0.05) in 21 degrees C group. 2D echo revealed a greater cardiac output, fractional area change and ejection fraction in 21 degrees C group that was not significantly different than the 4 degrees C group. However, unlike 4 degrees C hearts, 21 degrees C hearts did not require inotropic intervention. Upon reperfusion, rate of cardiac enzyme release temporally resolved in 21 degrees C group, but not in the 4 degrees C group. 21 degrees C working hearts maintained their energy state during the experimental duration but not the 4 degrees C group; albeit, both groups demonstrated robust metabolism and function during this period. Conclusions: Rapid metabolic switch, increased synthesis of HEP, decreased injury and optimal function provides evidence that hearts arrested at 21 degrees C remain viably and functionally superior to those arrested at 4 degrees C when stored in SOMAH at ambient temperature pre-transplant. C1 [Lowalekar, Samar K.; Thatte, Hemant S.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Div Cardiothorac Surg, Boston, MA 02132 USA. [Lowalekar, Samar K.; Thatte, Hemant S.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Dept Surg, Boston, MA 02115 USA. [Lowalekar, Samar K.; Treanor, Patrick R.; Thatte, Hemant S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, VA Boston Healthcare Syst, Boston, MA 02115 USA. RP Thatte, HS (reprint author), Brigham & Womens Hosp, VA Boston Healthcare Syst, Div Cardiothorac Surg, 1400 VFW Pkwy, Boston, MA 02132 USA. EM hemant_thatte@hms.harvard.edu FU VA Merit Review grant; Department of Veterans Affairs, Office of Research and Development, Washington DC FX This work was supported by VA Merit Review grant (Dr. Thatte), Department of Veterans Affairs, Office of Research and Development, Washington DC, and an unrestricted gift from Somahlution (Jupiter, Fl) to Boston VA Research Institute for research (Dr. Thatte). NR 27 TC 2 Z9 2 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1749-8090 J9 J CARDIOTHORAC SURG JI J. Cardiothorac. Surg. PD SEP 20 PY 2014 VL 9 AR 155 DI 10.1186/s13019-014-0155-z PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AS9LE UT WOS:000344563400001 PM 25238790 ER PT J AU Robert, C Ribas, A Wolchok, JD Hodi, FS Hamid, O Kefford, R Weber, JS Joshua, AM Hwu, WJ Gangadhar, TC Patnaik, A Dronca, R Zarour, H Joseph, RW Boasberg, P Chmielowski, B Mateus, C Postow, MA Gergich, K Elassaiss-Schaap, J Li, XN Iannone, R Ebbinghaus, SW Kang, SP Daud, A AF Robert, Caroline Ribas, Antoni Wolchok, Jedd D. Hodi, F. Stephen Hamid, Omid Kefford, Richard Weber, Jeffrey S. Joshua, Anthony M. Hwu, Wen-Jen Gangadhar, Tara C. Patnaik, Amita Dronca, Roxana Zarour, Hassane Joseph, Richard W. Boasberg, Peter Chmielowski, Bartosz Mateus, Christine Postow, Michael A. Gergich, Kevin Elassaiss-Schaap, Jeroen Li, Xiaoyun Nicole Iannone, Robert Ebbinghaus, Scot W. Kang, S. Peter Daud, Adil TI Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial SO LANCET LA English DT Article ID METASTATIC MELANOMA; RESPONSE CRITERIA; IMPROVED SURVIVAL; BRAF INHIBITORS; MEK INHIBITION; OPEN-LABEL; SAFETY; MUTATION; PD-1; IMMUNOTHERAPY AB Background The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma. We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma. Methods In an open-label, international, multicentre expansion cohort of a phase 1 trial, patients (aged >= 18 years) with advanced melanoma whose disease had progressed after at least two ipilimumab doses were randomly assigned with a computer-generated allocation schedule (1:1 final ratio) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. Primary endpoint was overall response rate (ORR) assessed with the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) by independent central review. Analysis was done on the full-analysis set (all treated patients with measurable disease at baseline). This study is registered with ClinicalTrials.gov, number NCT01295827. Findings 173 patients received pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84). Median follow-up duration was 8 months. ORR was 26% at both doses-21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0%, 95% CI -14 to 13; p=0.96). Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue (29 [33%] vs 31 [37%]), pruritus (23 [26%] vs 16 [19%]), and rash (16 [18%] vs 15 [18%]). Grade 3 fatigue, reported in five (3%) patients in the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse event reported in more than one patient. Interpretation The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options. C1 [Robert, Caroline; Mateus, Christine] Gustave Roussy, Paris, France. [Robert, Caroline; Mateus, Christine] INSERM, U981, Paris, France. [Ribas, Antoni; Chmielowski, Bartosz] Univ Calif Los Angeles, Los Angeles, CA USA. [Wolchok, Jedd D.; Postow, Michael A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Hodi, F. Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hamid, Omid; Boasberg, Peter] Angeles Clin & Res Inst, Los Angeles, CA USA. [Kefford, Richard] Westmead Hosp, Crown Princess Mary Canc Ctr, Westmead, NSW 2145, Australia. [Kefford, Richard] Melanoma Inst Australia, Westmead, NSW 2145, Australia. [Kefford, Richard] Univ Sydney, Sydney, NSW 2006, Australia. [Weber, Jeffrey S.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Joshua, Anthony M.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Hwu, Wen-Jen] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Gangadhar, Tara C.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Patnaik, Amita] South Texas Accelerated Res Therapeut, San Antonio, TX USA. [Dronca, Roxana] Mayo Clin, Rochester, MN USA. [Zarour, Hassane] Univ Pittsburgh, Pittsburgh, PA USA. [Joseph, Richard W.] Mayo Clin, Jacksonville, FL 32224 USA. [Gergich, Kevin; Elassaiss-Schaap, Jeroen; Li, Xiaoyun Nicole; Iannone, Robert; Ebbinghaus, Scot W.; Kang, S. Peter] Merck, Whitehouse Stn, NJ USA. [Daud, Adil] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Robert, C (reprint author), Inst Gustave Roussy, 114 Rue Edouard Vaillant, F-94805 Villejuif Paris Sud, France. EM caroline.robert@gustaveroussy.fr RI Li, Xiaoyun/P-8265-2014; Elassaiss-Schaap , Jeroen/Q-5451-2016; OI Chmielowski, Bartosz/0000-0002-2374-3320 FU Merck Sharp and Dohme FX Merck Sharp and Dohme. NR 32 TC 534 Z9 553 U1 16 U2 100 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 SEP 20 PY 2014 VL 384 IS 9948 BP 1109 EP 1117 DI 10.1016/S0140-6736(14)60958-2 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AQ2PU UT WOS:000342630600031 PM 25034862 ER PT J AU Nannini, M Astolfi, A Urbini, M Indio, V Santini, D Heinrich, MC Corless, CL Ceccarelli, C Saponara, M Mandrioli, A Lolli, C Ercolani, G Brandi, G Biasco, G Pantaleo, MA AF Nannini, Margherita Astolfi, Annalisa Urbini, Milena Indio, Valentina Santini, Donatella Heinrich, Michael C. Corless, Christopher L. Ceccarelli, Claudio Saponara, Maristella Mandrioli, Anna Lolli, Cristian Ercolani, Giorgio Brandi, Giovanni Biasco, Guido Pantaleo, Maria A. TI Integrated genomic study of quadruple-WT GIST (KIT/PDGFRA/SDH/RAS pathway wild-type GIST) SO BMC CANCER LA English DT Article DE Gastrointestinal stromal tumors (GIST); Wild-type; KIT; PDGFRA; Succinate dehydrogenase; SDHA; RAS; Quadruple(WT) ID GASTROINTESTINAL STROMAL TUMORS; DIFFERENTIAL EXPRESSION ANALYSIS; SUCCINATE-DEHYDROGENASE SUBUNIT; FAMILY TRANSCRIPTION FACTOR; TYROSINE-KINASE INHIBITOR; RECEPTOR-LIKE RECEPTOR; PHASE-I TRIAL; SDHA MUTATIONS; ANTITUMOR-ACTIVITY; DEFICIENT GISTS AB Background: About 10-15% of adult gastrointestinal stromal tumors (GIST) and the vast majority of pediatric GIST do not harbour KIT or platelet derived growth factor receptor alpha (PDGFRA) mutations Clin Oncol 223813-3825, 2004; Hematol Oncol Clin North Am 23:15-34,2009). The molecular biology of these GIST, originally defined as KIT/PDGFRA wild type (WT), is complex due to the existence of different subgroups with distinct molecular hallmarks, including defects in the succinate clehydrogenase (SDH) complex and mutations of neurofibromatosis type 1 (NF1), BRAF, or KRAS genes (HAS pathway or RAS-P). In this extremely heterogeneous landscape, the clinical profile and molecular abnormalities of the small subgroup of WT GIST suitably referred to as quadruple wild -type GIST (quadruple(WT) or KITWT /PDGFRA(WT)/SDHWT/RAS-P-WT) remains undefined. The aim of this study is to investigate the genomic profile of KITWT /PDGFRA(WT)/SDHWT/RAS-P-WT GIST, by using a massively parallel sequencing and ruicroarray approach, and compare it with the genoruic profile of other GIST subtypes. Methods: We performed El whole genome analysis using a massively parallel sequencing approuch on a total of 16 GIST cases (2 KITWT/PDGFRA(WT)/SDFWT and SDHBIHC+/SDHA(IHC+), 2 KITWT/PDGFRA(WT)/SDHA(mut) arid SDHBIHC-/SDHA(IHC-) and 12 cases of KITmut or PDGFRAM(mut) GIST). To confirm and extend the results, whole-genome gene expression analysis by microarray was performed on 9 out 16 patients analyzed by RNAseq and an additional 20 GIST patients (1 KITWT/PDGFHA(WT) SDHA(mut) GIST and 19 KITmut or PDGFRA(mut) GIST). The most impressive data were validated by quantitave PCR and Western Blot analysis. Results: We found that both cases of quadruple(WT) GIST had a genomic profile profoundly different from both either KIT/PDGFRA mutated or SDHA-mutated GIST. In particular, the quadruple(WT) GIST tumors are characterized by the overexpression of molecular markers (CALCRL and COL22A1) and of specific oncogenes including tyrosine and cyclin- dependent kinases (NTRK2 and CDK6) and one member of the ETS-transcription factor family (ERG). Conclusion: We report for the first e an integrated genomic picture of KITWT/PDGFRA(WT)/SDHWT/RAS-P-WT GIST, using massively parallel sequencing and gene expression analyses, and found that quadruple(WT) GIST have an expression signature that is distinct from SDH-mutant GIST as well as GIST harbouring mutations in KIT or PDGFRA. Our findings suggest that quadruple(WT) GIST represent another unique group within the family of gastrointestintal stromal tumors. C1 [Nannini, Margherita; Mandrioli, Anna; Lolli, Cristian; Brandi, Giovanni; Biasco, Guido; Pantaleo, Maria A.] Univ Bologna, St Orsola Malpighi Hosp, Dept Specialized Expt & Diagnost Med, I-40138 Bologna, Italy. [Astolfi, Annalisa; Urbini, Milena; Indio, Valentina; Saponara, Maristella; Biasco, Guido; Pantaleo, Maria A.] Univ Bologna, Giorgio Prodi Canc Res Ctr, I-40138 Bologna, Italy. [Santini, Donatella; Ceccarelli, Claudio] Univ Bologna, S Orsola Malpighi Hosp, Pathol Unit, I-40138 Bologna, Italy. [Heinrich, Michael C.] Oregon Hlth & Sci Univ, Portland VA Med Ctr, Portland, OR 97201 USA. [Heinrich, Michael C.; Corless, Christopher L.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Heinrich, Michael C.] Oregon Hlth & Sci Univ, Div Hematol & Oncol, Portland, OR 97201 USA. [Corless, Christopher L.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. [Ercolani, Giorgio] Univ Bologna, S Orsola Malpighi Hosp, Transplant Gen & Emergency Surg Dept, I-40138 Bologna, Italy. RP Pantaleo, MA (reprint author), Univ Bologna, St Orsola Malpighi Hosp, Dept Specialized Expt & Diagnost Med, Via Massarenti 9, I-40138 Bologna, Italy. EM maria.pantaleo@unibo.it RI Urbini, Milena/K-1351-2016; nannini, margherita/J-9866-2016; OI Urbini, Milena/0000-0002-3364-9098; PANTALEO, MARIA ABBONDANZA/0000-0002-0177-6957; Ceccarelli, Claudio/0000-0003-0743-2087; NANNINI, MARGHERITA/0000-0002-2103-1960; astolfi, annalisa/0000-0002-2732-0747; Indio, Valentina/0000-0002-8854-3821 FU Novartis Oncology, Italy; My First Grant, AIRC FX The present work was done with a financial contribution by Novartis Oncology, Italy, and with funds by My First Grant 2013, AIRC 2013. NR 64 TC 21 Z9 22 U1 2 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD SEP 20 PY 2014 VL 14 AR 685 DI 10.1186/1471-2407-14-685 PG 12 WC Oncology SC Oncology GA AQ0HW UT WOS:000342464900001 PM 25239601 ER PT J AU Adams, S Gray, RJ Demaria, S Goldstein, L Perez, EA Shulman, LN Martino, S Wang, M Jones, VE Saphner, TJ Wolff, AC Wood, WC Davidson, NE Sledge, GW Sparano, JA Badve, SS AF Adams, Sylvia Gray, Robert J. Demaria, Sandra Goldstein, Lori Perez, Edith A. Shulman, Lawrence N. Martino, Silvana Wang, Molin Jones, Vicky E. Saphner, Thomas J. Wolff, Antonio C. Wood, William C. Davidson, Nancy E. Sledge, George W. Sparano, Joseph A. Badve, Sunil S. TI Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ESTROGEN-RECEPTOR; CHEMOTHERAPY; CELLS AB Purpose Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Patients and Methods Full-face hematoxylin and eosin-stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence-free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. Results The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. Conclusion In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter. (C) 2014 by American Society of Clinical Oncology C1 [Adams, Sylvia; Demaria, Sandra] NYU, Sch Med, New York, NY 10016 USA. [Sparano, Joseph A.] Albert Einstein Med Ctr, Bronx, NY USA. [Shulman, Lawrence N.; Wang, Molin] Dana Farber Canc Inst, Boston, MA 02115 USA. [Goldstein, Lori] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Davidson, Nancy E.] Univ Pittsburgh, Pittsburgh, PA USA. [Perez, Edith A.] Mayo Clin, Jacksonville, FL 32224 USA. [Martino, Silvana] Angeles Clin & Res Inst, Santa Monica, CA USA. [Jones, Vicky E.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Saphner, Thomas J.] St Vincent Reg Canc, Green Bay, WI USA. [Wolff, Antonio C.] Johns Hopkins Univ, Baltimore, MD USA. [Wood, William C.] Emory Univ, Atlanta, GA 30322 USA. [Sledge, George W.; Badve, Sunil S.] Indiana Univ, Indianapolis, IN 46204 USA. RP Adams, S (reprint author), NYU, Inst Canc, Dept Med, 160 East 34th St, New York, NY 10016 USA. EM sylvia.adams@nyumc.org OI Wolff, Antonio/0000-0003-3734-1063; Demaria, Sandra/0000-0003-4426-0499 FU Public Health Service [CA23318, CA66636, CA21115, CA27525, CA21076, CA16116, CA39229, CA49883, CA14958, CA114737, CA32102, CA25224, CA31946, CA11789]; National Cancer Institute (NCI), National Institutes of Health; Department of Health and Human Services; sanofi-aventis; NCI [R01CA161891]; Komen Scholar Award [SAC110004]; Breast Cancer Research Foundation FX Coordinated by the Eastern Cooperative Oncology Group (ECOG) and supported in part by Public Health Service Grants No. CA23318, CA66636, CA21115, CA27525, CA21076, CA16116, CA39229, CA49883, CA14958, CA114737, CA32102, CA25224, CA31946, and CA11789; National Cancer Institute (NCI), National Institutes of Health; Department of Health and Human Services; grants from sanofi-aventis and Breast Cancer Research Foundation; NCI Grant No. R01CA161891 (S.A.); and Komen Scholar Award No. SAC110004 (S.S.B.). Biospecimens provided by ECOG Pathology Coordinating Office and Reference Laboratory. NR 25 TC 176 Z9 183 U1 9 U2 21 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 SEP 20 PY 2014 VL 32 IS 27 BP 2959 EP + DI 10.1200/JCO.2013.55.0491 PG 9 WC Oncology SC Oncology GA AP4QE UT WOS:000342062200008 PM 25071121 ER PT J AU Rosenberg, AR Orellana, L Kang, TI Geyer, JR Feudtner, C Dussel, V Wolfe, J AF Rosenberg, Abby R. Orellana, Liliana Kang, Tammy I. Geyer, J. Russell Feudtner, Chris Dussel, Veronica Wolfe, Joanne TI Differences in Parent-Provider Concordance Regarding Prognosis and Goals of Care Among Children With Advanced Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; PHYSICIAN-ASSISTED SUICIDE; PALLIATIVE CARE; ONCOLOGY-GROUP; LIFE; END; COMMUNICATION; ATTITUDES; IMPACT; TRANSPLANTATION AB Purpose Concordance between parents of children with advanced cancer and health care providers has not been described. We aimed to describe parent-provider concordance regarding prognosis and goals of care, including differences by cancer type. Patients and Methods A total of 104 pediatric patients with recurrent or refractory cancer were enrolled at three large children's hospitals. On enrollment, their parents and providers were invited to complete a survey assessing perceived prognosis and goals of care. Patients' survival status was retrospectively abstracted from medical records. Concordance was assessed via discrepancies in perceived prognosis, kappa statistics, and McNemar's test. Distribution of categorical variables and survival rates across cancer type were compared with Fisher's exact and log-rank tests, respectively. Results Data were available from 77 dyads (74% of enrolled). Parent-provider agreement regarding prognosis and goals of care was poor (kappa, 0.12 to 0.30). Parents were more likely to report cure was likely (P < .001). The frequency of perceived likelihood of cure and the goal of cure varied by cancer type for both parents and providers (P < .001 to .004). Relatively optimistic responses were more common among parents and providers of patients with hematologic malignancies, although there were no differences in survival. Conclusion Parent-provider concordance regarding prognosis and goals in advanced pediatric cancer is generally poor. Perceptions of prognosis and goals of care vary by cancer type. Understanding these differences may inform parent-provider communication and decision making. C1 [Rosenberg, Abby R.; Geyer, J. Russell] Seattle Childrens Hosp, Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Rosenberg, Abby R.; Geyer, J. Russell] Univ Washington, Seattle, WA 98195 USA. [Rosenberg, Abby R.] Treuman Katz Ctr Pediat Bioeth, Seattle, WA USA. [Orellana, Liliana; Dussel, Veronica] Natl Canc Inst, Buenos Aires, DF, Argentina. [Dussel, Veronica] Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. [Kang, Tammy I.; Feudtner, Chris] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Wolfe, Joanne] Dana Farber Canc Inst, Boston, MA 02215 USA. [Wolfe, Joanne] Boston Childrens Hosp, Boston, MA USA. RP Wolfe, J (reprint author), Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave, Boston, MA 02215 USA. EM joanne_wolfe@dfci.harvard.edu RI Orellana, Liliana/S-3302-2016 OI Orellana, Liliana/0000-0003-3736-4337 FU National Cancer Institute, National Institutes of Health [1K07 CA096746-01]; Charles H. Hood Foundation Child Health Research Award; American Cancer Society Pilot and Exploratory Project; St Baldrick's Foundation FX Supported by Grant No. 1K07 CA096746-01 from the National Cancer Institute, National Institutes of Health; a Charles H. Hood Foundation Child Health Research Award; an American Cancer Society Pilot and Exploratory Project Award in palliative care of cancer patients and their families; and a St Baldrick's Foundation Fellow Award (A.R.R.). NR 32 TC 6 Z9 6 U1 1 U2 13 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2014 VL 32 IS 27 BP 3005 EP + DI 10.1200/JCO.2014.55.4659 PG 8 WC Oncology SC Oncology GA AP4QE UT WOS:000342062200014 PM 25024073 ER PT J AU Siddiqui, MM Wilson, KM Epstein, MM Rider, JR Martin, NE Stampfer, MJ Giovannucci, EL Mucci, LA AF Siddiqui, Mohummad Minhaj Wilson, Kathryn M. Epstein, Mara M. Rider, Jennifer R. Martin, Neil E. Stampfer, Meir J. Giovannucci, Edward L. Mucci, Lorelei A. TI Vasectomy and Risk of Aggressive Prostate Cancer: A 24-Year Follow-Up Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID UNITED-STATES MEN; TRICHOMONAS-VAGINALIS; PLASMA ANTIBODIES; COHORT; HEALTH; ASSOCIATION AB Purpose Conflicting reports remain regarding the association between vasectomy, a common form of male contraception in the United States, and prostate cancer risk. We examined prospectively this association with extended follow-up and an emphasis on advanced and lethal disease. Patients and Methods Among 49,405 US men in the Health Professionals Follow-Up Study, age 40 to 75 years at baseline in 1986, 6,023 patients with prostate cancer were diagnosed during the follow-up to 2010, including 811 lethal cases. In total, 12,321 men (25%) had vasectomies. We used Cox proportional hazards models to estimate the relative risk (RR) and 95% CIs of total, advanced, high-grade, and lethal disease, with adjustment for a variety of possible confounders. Results Vasectomy was associated with a small increased risk of prostate cancer overall (RR, 1.10; 95% CI, 1.04 to 1.17). Risk was elevated for high-grade (Gleason score 8 to 10; RR, 1.22; 95% CI, 1.03 to 1.45) and lethal disease (death or distant metastasis; RR, 1.19; 95% CI, 1.00 to 1.43). Among a subcohort of men receiving regular prostate-specific antigen screening, the association with lethal cancer was stronger (RR, 1.56; 95% CI, 1.03 to 2.36). Vasectomy was not associated with the risk of low-grade or localized disease. Additional analyses suggested that the associations were not driven by differences in sex hormone levels, sexually transmitted infections, or cancer treatment. Conclusion Our data support the hypothesis that vasectomy is associated with a modest increased incidence of lethal prostate cancer. The results do not appear to be due to detection bias, and confounding by infections or cancer treatment is unlikely. (C) 2014 by American Society of Clinical Oncology C1 [Siddiqui, Mohummad Minhaj; Wilson, Kathryn M.; Epstein, Mara M.; Rider, Jennifer R.; Martin, Neil E.; Stampfer, Meir J.; Giovannucci, Edward L.; Mucci, Lorelei A.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wilson, Kathryn M.; Epstein, Mara M.; Rider, Jennifer R.; Stampfer, Meir J.; Giovannucci, Edward L.; Mucci, Lorelei A.] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. [Martin, Neil E.] Dana Farber Canc Inst, Boston, MA USA. [Epstein, Mara M.] Univ Massachusetts, Sch Med, Worcester, MA USA. RP Mucci, LA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM lmucci@hsph.harvard.edu RI Martin, Neil/E-2193-2014; OI Martin, Neil/0000-0002-8164-8516; Rider, Jennifer/0000-0002-2637-6036; Siddiqui, Mohummad/0000-0002-4484-6820 FU National Cancer Institute/National Institutes of Health [P01 CA055075, CA133891, CA141298, UM1CA167552-01, T32 CA09001] FX Supported by Grants No. P01 CA055075, CA133891, CA141298, and UM1CA167552-01 and by Training Grant No. T32 CA09001 (K.M.W., J.R.R., and M.M.E.) from the National Cancer Institute/National Institutes of Health. L.A.M., J.R.R., and N.E.M. are Young Investigators of the Prostate Cancer Foundation. NR 32 TC 15 Z9 17 U1 1 U2 9 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 SEP 20 PY 2014 VL 32 IS 27 BP 3033 EP + DI 10.1200/JCO.2013.54.8446 PG 7 WC Oncology SC Oncology GA AP4QE UT WOS:000342062200017 PM 25002716 ER PT J AU Campigotto, F Weller, E AF Campigotto, Federico Weller, Edie TI Impact of Informative Censoring on the Kaplan-Meier Estimate of Progression-Free Survival in Phase II Clinical Trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID STEM-CELL TRANSPLANTATION; DEPENDENT COMPETING RISKS; MULTIPLE-MYELOMA PATIENTS; SINGLE-CENTER EXPERIENCE; WALDENSTROMS MACROGLOBULINEMIA; AUTOLOGOUS TRANSPLANTATION; INTERNATIONAL WORKSHOP; INVERSE PROBABILITY; PROGNOSTIC-FACTORS; CHEMOTHERAPY AB Informative censoring in a progression-free survival (PFS) analysis arises when patients are censored for initiation of an effective anticancer treatment before the protocol-defined progression, and these patients are at a different risk for treatment failure than those who continue on therapy. This may cause bias in the estimated PFS when using the Kaplan-Meier method for analysis. Although there are several articles that discuss this issue from a theoretical perspective or in randomized phase III studies, there are little data to demonstrate the magnitude of the bias on the estimated quantities from a phase II trial. This article describes the issues by using two oncology phase II trials as examples, evaluates the impact of the bias using simulations, and provides recommendations. The two trials were selected because they demonstrate two different reasons for censoring. Simulations show that the magnitude of the bias depends primarily on the proportion of patients who are informatively censored and secondarily on the hazard ratio between the group of patients who remain on study and the group of patients who are informatively censored. Recommendations include using an alternative end point, which includes inadequate response and initial signs of clinical progression as treatment failure, and a competing risk analysis for studies in which competing events preclude or modify the probability of observing the primary event of interest. If informative censoring cannot be avoided, then all patients should be observed until progression, and sensitivity analyses should be used as appropriate. C1 [Campigotto, Federico; Weller, Edie] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Campigotto, F (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02115 USA. EM federico@jimmy.harvard.edu FU National Cancer Institute [5P50CA100707, 5P01CA078378] FX Supported by Grants No. 5P50CA100707 and 5P01CA078378 from the National Cancer Institute. NR 39 TC 6 Z9 6 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 SEP 20 PY 2014 VL 32 IS 27 BP 3068 EP 3074 DI 10.1200/JCO.2014.55.6340 PG 7 WC Oncology SC Oncology GA AP4QE UT WOS:000342062200021 PM 25113767 ER PT J AU Wang, JN Xu, LH Zeng, WG Hu, P Zeng, MS Rabkin, SD Liu, RB AF Wang, Jiani Xu, Lihua Zeng, Weigen Hu, Pan Zeng, Musheng Rabkin, Samuel D. Liu, Renbin TI Treatment of human hepatocellular carcinoma by the oncolytic herpes simplex virus G47delta SO CANCER CELL INTERNATIONAL LA English DT Article DE Hepatocellular carcinoma; Oncolytic herpes simplex virus; Cytotoxicity; Subcutaneous model ID REPLICATION-COMPETENT; MALIGNANT GLIOMA; VIRAL THERAPY; GENE-THERAPY; RISK-FACTORS; CANCER; MUTANT; MODEL; TUMORS; G207 AB Background: Oncolytic herpes simplex virus (HSV) can replicate in and kill cancer cells while sparing the adjacent normal tissue. Hepatocellular carcinoma (HCC) is amongst the most common and lethal cancers, especially in Third World countries. In this study, the cytotoxicity of a third-generation oncolytic HSV, G47 Delta, was investigated in different human HCC cell lines and in an immortalized human hepatic cell line. Additionally, subcutaneous models of HCC were established to evaluate the in vivo anti-tumor efficacy of G47 Delta. Methods: The HepG2, HepB, SMMC-7721, BEL-7404, and BEL-7405 human HCC cell lines and the HL-7702 human hepatic immortalized cell lines were infected with G47 Delta at different multiplicities of infection (MOIs). The viability of infected cells was determined, and the G47 Delta replication was identified by X-gal staining for LacZ expression. Two subcutaneous (s.c.) HCC tumor models of HCC were also established in Balb/c nude mice, which were intratumorally (i.t.) treated with either G47 Delta or mock virus. Tumor volume and mouse survival times were documented. Results: More than 95% of the HepG2, Hep3B, and SMMC-7721 HCC cells were killed on by day 5 after infection with a MOI's of 0.01. For the HL-7702 human hepatic immortalized cells, 100% of the cells were killed on by day 5 after infection with a MOI's of 0.01. The BEL-7404 HCC cell line was less susceptible with about 70% cells were killed by day 5 after infection with a MOI's of 0.01. Whereas the BEL-7405 HCC cells were the least susceptible, with only 30% of the cells were killed. Both the SMMC-7721 and BEL-7404 cells form aggressive sc tumor models. G47 Delta replicates in the tumors, such that most of the tumors regressed after the G47 Delta-treatment, and treated tumor-bearing mice survived much longer than the control animals. Conclusions: G47 Delta effectively kills human HCC cells and an immortalized hepatic cell line at low MOI. Intra-tumor injection of G47 Delta can induce a therapeutic effect and prolong the survival of treated mice bearing SMMC-7721 and BEL-7404 subcutaneously (s.c.) tumors. Thus, G47 Delta may be useful as a novel therapeutic agent for HCC. C1 [Wang, Jiani; Zeng, Weigen; Hu, Pan; Liu, Renbin] Sun Yat Sen Univ, Affiliated Hosp 3, Breast Canc Ctr, Guangzhou 510630, Guangdong, Peoples R China. [Xu, Lihua] Guangzhou Med Univ, Affiliated Hosp 1, Dept Hematol & Oncol, Guangzhou, Guangdong, Peoples R China. [Zeng, Weigen] Chinese Acad Med Sci, Peking Union Med Coll, Canc Hosp, Dept Colorectal Surg, Beijing 100021, Peoples R China. [Zeng, Musheng] Sun Yat Sen Univ, State Key Lab Oncol South China, Guangzhou 510630, Guangdong, Peoples R China. [Rabkin, Samuel D.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Rabkin, Samuel D.] Harvard Univ, Sch Med, Boston, MA USA. RP Liu, RB (reprint author), Sun Yat Sen Univ, Affiliated Hosp 3, Breast Canc Ctr, 600 Tianhe Rd, Guangzhou 510630, Guangdong, Peoples R China. EM liur@vip.163.com OI rabkin, samuel/0000-0003-2344-2795 FU National Natural Science Foundation of China [81372815, 81172523] FX Our work is supported by the National Natural Science Foundation of China (No. 81372815, 81172523). NR 43 TC 3 Z9 3 U1 2 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2867 J9 CANCER CELL INT JI Cancer Cell Int. PD SEP 19 PY 2014 VL 14 AR 83 DI 10.1186/s12935-014-0083-y PG 9 WC Oncology SC Oncology GA AW3PL UT WOS:000346198700001 PM 25360068 ER PT J AU Tierney, DB Franke, MF Becerra, MC Viru, FAA Bonilla, CA Sanchez, E Guerra, D Munoz, M Llaro, K Palacios, E Mestanza, L Hurtado, RM Furin, JJ Shin, S Mitnick, CD AF Tierney, Dylan B. Franke, Molly F. Becerra, Mercedes C. Alcantara Viru, Felix A. Bonilla, Cesar A. Sanchez, Epifanio Guerra, Dalia Munoz, Maribel Llaro, Karim Palacios, Eda Mestanza, Lorena Hurtado, Rocio M. Furin, Jennifer J. Shin, Sonya Mitnick, Carole D. TI Time to Culture Conversion and Regimen Composition in Multidrug-Resistant Tuberculosis Treatment SO PLOS ONE LA English DT Article ID PREDICTORS AB Sputum cultures are an important tool in monitoring the response to tuberculosis treatment, especially in multidrug-resistant tuberculosis. There has, however, been little study of the effect of treatment regimen composition on culture conversion. Well-designed clinical trials of new anti-tuberculosis drugs require this information to establish optimized background regimens for comparison. We conducted a retrospective cohort study to assess whether the use of an aggressive multidrug-resistant tuberculosis regimen was associated with more rapid sputum culture conversion. We conducted Cox proportional-hazards analyses to examine the relationship between receipt of an aggressive regimen for the 14 prior consecutive days and sputum culture conversion. Sputum culture conversion was achieved in 519 (87.7%) of the 592 patients studied. Among patients who had sputum culture conversion, the median time to conversion was 59 days (IQR: 31-92). In 480 patients (92.5% of those with conversion), conversion occurred within the first six months of treatment. Exposure to an aggressive regimen was independently associated with sputum culture conversion during the first six months of treatment (HR: 1.36; 95% CI: 1.10, 1.69). Infection with human immunodeficiency virus (HR 3.36; 95% CI: 1.47, 7.72) and receiving less exposure to tuberculosis treatment prior to the individualized multidrug-resistant tuberculosis regimen (HR: 1.58; 95% CI: 1.28, 1.95) were also independently positively associated with conversion. Tachycardia (HR: 0.77; 95% CI: 0.61, 0.98) and respiratory difficulty (HR: 0.78; 95% CI: 0.62, 0.97) were independently associated with a lower rate of conversion. This study is the first demonstrating that the composition of the multidrug-resistant tuberculosis treatment regimen influences the time to culture conversion. These results support the use of an aggressive regimen as the optimized background regimen in trials of new anti-TB drugs. C1 [Tierney, Dylan B.; Becerra, Mercedes C.; Shin, Sonya; Mitnick, Carole D.] Brigham & Womens Hosp, Div Global Hlth Equ, Boston, MA 02115 USA. [Tierney, Dylan B.; Franke, Molly F.; Becerra, Mercedes C.; Alcantara Viru, Felix A.; Guerra, Dalia; Munoz, Maribel; Llaro, Karim; Shin, Sonya; Mitnick, Carole D.] Partners Hlth, Boston, MA USA. [Tierney, Dylan B.; Franke, Molly F.; Becerra, Mercedes C.; Alcantara Viru, Felix A.; Guerra, Dalia; Munoz, Maribel; Llaro, Karim; Shin, Sonya; Mitnick, Carole D.] Socios Salud Sucursal Peru, Lima, Peru. [Franke, Molly F.; Becerra, Mercedes C.; Mitnick, Carole D.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA USA. [Bonilla, Cesar A.] Minist Hlth, Natl TB Strategy, Lima, Peru. [Sanchez, Epifanio] Hosp Nacl Sergio E Bernales, Lima, Peru. [Palacios, Eda; Mestanza, Lorena] Asociac Visionarios, Lima, Peru. [Hurtado, Rocio M.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Hurtado, Rocio M.] Global Hlth Comm, Boston, MA USA. [Furin, Jennifer J.] Case Western Reserve Univ, TB Res Unit, Cleveland, OH 44106 USA. RP Tierney, DB (reprint author), Brigham & Womens Hosp, Div Global Hlth Equ, 75 Francis St, Boston, MA 02115 USA. EM dtierney@partners.org FU Research Core of the Department of Global Health and Social Medicine at Harvard Medical School; Janssen Pharmaceuticals, Inc. FX This work was supported by the Research Core of the Department of Global Health and Social Medicine at Harvard Medical School. The fee for open access publication of this report was paid by a philanthropic contribution to Harvard Medical School from Janssen Pharmaceuticals, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 6 Z9 6 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 19 PY 2014 VL 9 IS 9 AR e108035 DI 10.1371/journal.pone.0108035 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AQ0RY UT WOS:000342491600080 PM 25238411 ER PT J AU Duan, ZF Zhang, JM Ye, SA Shen, J Choy, E Cote, G Harmon, D Mankin, H Hua, YQ Zhang, Y Gray, NS Hornicek, FJ AF Duan, Zhenfeng Zhang, Jianming Ye, Shunan Shen, Jacson Choy, Edwin Cote, Gregory Harmon, David Mankin, Henry Hua, Yingqi Zhang, Yu Gray, Nathanael S. Hornicek, Francis J. TI A-770041 reverses paclitaxel and doxorubicin resistance in osteosarcoma cells SO BMC CANCER LA English DT Article DE Osteosarcoma; MDR; Src kinase; Doxorubicin ID TYROSINE KINASE INHIBITOR; MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; CANCER-CELLS; CHEMOTHERAPEUTIC-AGENTS; ALLOGRAFT-REJECTION; INORGANIC-PHOSPHATE; DRUG-RESISTANCE; SARCOMA-CELLS; LUNG-CANCER AB Background: Reversing multidrug resistance (MDR) has been an important goal for clinical and investigational oncologists. In the last few decades, significant effort has been made to search for inhibitors to reverse MDR by targeting ATP-binding cassette (ABC) transporters (Pgp, MRP) directly, but these efforts have achieved little clinical success. Protein kinases play important roles in many aspects of tumor cell growth and survival. Combinations of kinase inhibitors and chemotherapeutics have been observed to overcome cancer drug resistance in certain circumstances. Methods: We screened a kinase specific inhibitor compound library in human osteosarcoma MDR cell lines to identify inhibitors that were capable of reversing chemoresistance to doxorubicin and paclitaxel. Results: We identified 18 small molecules that significantly increase chemotherapy drug-induced cell death in human osteosarcoma MDR cell lines U-2OS(MR) and KHOSR2. We identified A-770041 as one of the most effective MDR reversing agents when combined with doxorubicin or paclitaxel. A-770041 is a potent Src family kinase (Lck and Src) inhibitor. Western blot analysis revealed A-770041 inhibits both Src and Lck activation and expression. Inhibition of Src expression in U-2OS(MR) and KHOSR2 cell lines using lentiviral shRNA also resulted in increased doxorubicin and paclitaxel drug sensitivity. A-770041 increases the intracellular drug accumulation as demonstrated by calcein AM assay. Conclusions: These results indicate that small molecule inhibitor A-770041 may function to reverse ABCB1/Pgp-mediated chemotherapy drug resistance. Combination of Src family kinase inhibitor with regular chemotherapy drug could be clinically effective in MDR osteosarcoma. C1 [Duan, Zhenfeng; Ye, Shunan; Shen, Jacson; Choy, Edwin; Cote, Gregory; Harmon, David; Mankin, Henry; Hornicek, Francis J.] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. [Zhang, Jianming] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Boston, MA 02114 USA. [Hua, Yingqi] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 1, Shanghai 200080, Peoples R China. [Zhang, Yu] Liu Hua Qiao Hosp, Dept Orthoped Surg, Guangzhou 510010, Guangdong, Peoples R China. [Gray, Nathanael S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, 100 Blossom St,Jackson 1115, Boston, MA 02114 USA. EM zduan@mgh.harvard.edu OI Cote, Gregory/0000-0003-0181-886X FU Sarcoma Foundation of America (SFA); Gategno and Wechsler funds; NIH [U54 HG006097]; Jennifer Hunter Yates Foundation; Kenneth Stanton Fund FX This project was supported, in part, by a grant from Sarcoma Foundation of America (SFA), grants from the Gategno and Wechsler funds, and NIH U54 HG006097 (NSG and JZ). Support has also been provided by the Jennifer Hunter Yates Foundation and the Kenneth Stanton Fund. NR 45 TC 8 Z9 8 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD SEP 19 PY 2014 VL 14 AR 681 DI 10.1186/1471-2407-14-681 PG 11 WC Oncology SC Oncology GA AP5JN UT WOS:000342115600001 PM 25236161 ER PT J AU Kendall, RT Lee, MH Pleasant, DL Robinson, K Kuppuswamy, D McDermott, PJ Luttrell, LM AF Kendall, Ryan T. Lee, Mi-Hye Pleasant, Dorea L. Robinson, Katherine Kuppuswamy, Dhandapani McDermott, Paul J. Luttrell, Louis M. TI Arrestin-dependent Angiotensin AT(1) Receptor Signaling Regulates Akt and mTor-mediated Protein Synthesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR RECEPTOR; BETA-ARRESTIN; CARDIAC MYOCYTES; S6 KINASE; IN-VIVO; PHOSPHORYLATION; ACTIVATION; PATHWAY; ERK; COMPLEX AB Control of protein synthesis is critical to both cell growth and proliferation. The mammalian target of rapamycin (mTOR) integrates upstream growth, proliferation, and survival signals, including those transmitted via ERK1/2 and Akt, to regulate the rate of protein translation. The angiotensin AT(1) receptor has been shown to activate both ERK1/2 and Akt in arrestin-based signalsomes. Here, we examine the role of arrestin-dependent regulation of ERK1/2 and Akt in the stimulation of mTOR-dependent protein translation by the AT(1) receptor using HEK293 and primary vascular smooth muscle cell models. Nascent protein synthesis stimulated by both the canonical AT(1) receptor agonist angiotensin II (AngII), and the arrestin pathway-selective agonist [Sar(1)-Ile(4)-Ile(8)] AngII (SII), is blocked by shRNA silencing of beta arrestin1/2 or pharmacological inhibition of Akt, ERK1/2, or mTORC1. In HEK293 cells, SII activates a discrete arrestin-bound pool of Akt and promotes Akt-dependent phosphorylation of mTOR and its downstream effector p70/p85 ribosomal S6 kinase (p70/85S6K). In parallel, SII-activated ERK1/2 helps promote mTOR and p70/85S6K phosphorylation, and is required for phosphorylation of the known ERK1/2 substrate p90 ribosomal S6 kinase (p90RSK). Thus, arrestins coordinate AT(1) receptor regulation of ERK1/2 and Akt activity and stimulate protein translation via both Akt-mTOR-p70/85S6K and ERK1/2-p90RSK pathways. These results suggest that in vivo, arrestin pathway-selective AT(1) receptor agonists may promote cell growth or hypertrophy through arrestin-mediated mechanisms despite their antagonism of G protein signaling. C1 [Kendall, Ryan T.; Lee, Mi-Hye; Pleasant, Dorea L.; Robinson, Katherine; Kuppuswamy, Dhandapani; McDermott, Paul J.; Luttrell, Louis M.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Kuppuswamy, Dhandapani; McDermott, Paul J.; Luttrell, Louis M.] Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC 29401 USA. RP Luttrell, LM (reprint author), Med Univ S Carolina, Div Endocrinol Diabet & Med Genet, Dept Med, 96 Jonathan Lucas St, Charleston, SC 29425 USA. EM luttrell@musc.edu FU National Institutes of Health [5K12GM081265, 5R01DK055524]; Research Service of the Ralph H. Johnson Veterans Affairs Medical Center FX This work was supported by National Institutes of Health Grants 5K12GM081265 (to R. T. K.) and 5R01DK055524 (to L. M. L.), and the Research Service of the Ralph H. Johnson Veterans Affairs Medical Center. NR 44 TC 6 Z9 6 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 19 PY 2014 VL 289 IS 38 BP 26155 EP 26166 DI 10.1074/jbc.M114.595728 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AP5OP UT WOS:000342128800012 PM 25081544 ER PT J AU Zhao, YL Xiao, M Sun, BG Zhang, ZM Shen, T Duan, XY Yu, PB Feng, XH Lin, X AF Zhao, Yulan Xiao, Mu Sun, Baoguo Zhang, Zhengmao Shen, Tao Duan, Xueyan Yu, Paul Borchyung Feng, Xin-Hua Lin, Xia TI C-terminal Domain (CTD) Small Phosphatase-like 2 Modulates the Canonical Bone Morphogenetic Protein (BMP) Signaling and Mesenchymal Differentiation via Smad Dephosphorylation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL SELF-RENEWAL; BETA; PATHWAY; IDENTIFICATION; NUCLEUS AB The bone morphogenetic protein (BMP) signaling pathway regulates a wide range of cellular responses in metazoans. A key step in the canonical BMP signaling is the phosphorylation and activation of transcription factors Smad1, Smad5, and Smad8 (collectively Smad1/5/8) by the type I BMP receptors. We previously identified PPM1A as a phosphatase toward dephosphorylation of all receptor-regulated Smads (R-Smads), including Smad1/5/8. Here we report another nuclear phosphatase named SCP4/CTDSPL2, belonging to the FCP/SCP family, as a novel Smad phosphatase in the nucleus. SCP4 physically interacts with and specifically dephosphorylates Smad1/5/8, and as a result attenuates BMP-induced transcriptional responses. Knockdown of SCP4 in multipotent mesenchymal C2C12 cells leads to increased expression of BMP target genes and consequently promotes BMP-induced osteogenic differentiation. Collectively, our results demonstrate that SCP4, as a Smad phosphatase, plays a critical role in BMP-induced signaling and cellular functions. C1 [Zhao, Yulan; Xiao, Mu; Feng, Xin-Hua] Zhejiang Univ, Inst Life Sci, Hangzhou 310058, Zhejiang, Peoples R China. [Zhao, Yulan; Xiao, Mu; Feng, Xin-Hua] Zhejiang Univ, Innovat Ctr Cell Biol, Hangzhou 310058, Zhejiang, Peoples R China. [Sun, Baoguo; Zhang, Zhengmao; Shen, Tao; Feng, Xin-Hua; Lin, Xia] Baylor Coll Med, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. [Sun, Baoguo; Feng, Xin-Hua] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA. [Duan, Xueyan; Feng, Xin-Hua] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Shen, Tao] Texas A&M Hlth Sci Ctr, Inst Biosci & Technol, Houston, TX 77030 USA. [Yu, Paul Borchyung] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. RP Feng, XH (reprint author), Zhejiang Univ, Inst Life Sci, Hangzhou 310058, Zhejiang, Peoples R China. EM xhfeng@zju.edu.cn; xialin@bcm.edu RI Huang, Xiaoyan/N-2561-2014; OI Yu, Paul/0000-0003-2145-4944 FU Ministry of Science and Technology [2012CB966600]; National Natural Science Foundation of China [31090360]; National Institutes of Health [R01GM63773, R01AR053591, R01CA108454, R01DK073932]; Project 111 [B13026]; Project 985; Fundamental Research Funds for the Central Universities FX This research was partly supported by grants from the Ministry of Science and Technology (2012CB966600); the National Natural Science Foundation of China (31090360); the National Institutes of Health (R01GM63773, R01AR053591, and R01CA108454 to X.-H. F., and R01DK073932 to X. L.); Project 111 (B13026); Project 985; and the Fundamental Research Funds for the Central Universities. NR 32 TC 6 Z9 6 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 19 PY 2014 VL 289 IS 38 BP 26441 EP 26450 DI 10.1074/jbc.M114.568964 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AP5OP UT WOS:000342128800035 PM 25100727 ER PT J AU Kabrhel, C Rempell, JS Avery, LL Dudzinski, DM Weinberg, I AF Kabrhel, Christopher Rempell, Joshua S. Avery, Laura L. Dudzinski, David M. Weinberg, Ido TI Case 29-2014: A 60-Year-Old Woman with Syncope SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID IDIOPATHIC VENOUS THROMBOEMBOLISM; MASSIVE PULMONARY-EMBOLISM; EMERGENCY PHYSICIANS; SURGICAL-TREATMENT; METAANALYSIS; RISK; ECHOCARDIOGRAPHY; MANAGEMENT; THROMBOSIS; DIAGNOSIS C1 [Kabrhel, Christopher] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Avery, Laura L.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Dudzinski, David M.] Massachusetts Gen Hosp, Dept Echocardiog, Boston, MA 02114 USA. [Dudzinski, David M.; Weinberg, Ido] Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. [Rempell, Joshua S.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Kabrhel, Christopher] Harvard Univ, Sch Med, Dept Emergency Med, Boston, MA USA. [Avery, Laura L.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Dudzinski, David M.] Harvard Univ, Sch Med, Dept Echocardiog, Boston, MA USA. [Dudzinski, David M.; Weinberg, Ido] Harvard Univ, Sch Med, Dept Cardiol, Boston, MA USA. RP Kabrhel, C (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. FU Diagnostica Stago; Siemens Healthcare; Sanofi; Advantage Health Care; VIVA Physicians FX Dr. Kabrhel reports receiving consulting fees from Diagnostica Stago and grant support to his institution from Diagnostica Stago and Siemens Healthcare; Dr. Dudzinski, consulting fees from Sanofi and Advantage Health Care; and Dr. Weinberg, consulting fees from VIVA Physicians. No other potential conflict of interest relevant to this article was reported. NR 22 TC 4 Z9 4 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 18 PY 2014 VL 371 IS 12 BP 1143 EP 1150 DI 10.1056/NEJMcpc1403307 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AO9PI UT WOS:000341687300011 PM 25229919 ER PT J AU Azab, AK Sahin, I Azab, F Moschetta, M Mishima, Y Burwick, N Zimmermann, J Romagnoli, B Patel, K Chevalier, E Roccaro, AM Ghobrial, IM AF Azab, Abdel Kareem Sahin, Ilyas Azab, Feda Moschetta, Michele Mishima, Yuji Burwick, Nicholas Zimmermann, Johann Romagnoli, Barbara Patel, Kalpana Chevalier, Eric Roccaro, Aldo M. Ghobrial, Irene M. TI CXCR7-dependent angiogenic mononuclear cell trafficking regulates tumor progression in multiple myeloma SO BLOOD LA English DT Article ID ENDOTHELIAL PROGENITOR CELLS; BONE-MARROW MICROENVIRONMENT; MEDIATED DRUG-RESISTANCE; CHEMOKINE RECEPTOR; CXCR7; RDC1; ADHESION; CXCL12; PROLIFERATION; BEVACIZUMAB AB The CXCR4/stromal cell-derived factor-1 (SDF-1) axis is essential for cell trafficking and has been shown to regulate tumor progression and metastasis in many tumors including multiple myeloma (MM). A second chemokine receptor for SDF-1, CXCR7 was discovered recently and found on activated endothelial cells. We examined the role of CXCR7 in angiogenic mononuclear cells (AMCs) trafficking in MM. Our data demonstrate that AMCs are circulating in patients with MM and in vivo studies show that they specifically home to areas of MM tumor growth. CXCR7 expression is important for regulating trafficking and homing of AMCs into areas of MM tumor growth and neoangiogenesis. We demonstrate that the CXCR7 inhibitor, POL6926, abrogated trafficking of AMCs to areas of MM tumor progression leading to a significant inhibition of tumor progression. These effects were through regulation of endothelial cells and not through a direct tumor effect, indicating that targeting a bone marrow microenvironmental cell can lead to a delay in MM tumor progression. In conclusion, our studies demonstrate that CXCR7 may play an important role in the regulation of tumor progression in MM through an indirect effect on the recruitment of AMCs to areas of MM tumor growth in the bone marrow niche. C1 [Azab, Abdel Kareem; Sahin, Ilyas; Azab, Feda; Moschetta, Michele; Mishima, Yuji; Burwick, Nicholas; Roccaro, Aldo M.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Azab, Abdel Kareem; Azab, Feda] Washington Univ, Div Canc Biol, Dept Radiat Oncol, St Louis, MO USA. [Zimmermann, Johann; Romagnoli, Barbara; Patel, Kalpana; Chevalier, Eric] Polyphor Ltd, Allschwil, Switzerland. RP Ghobrial, IM (reprint author), Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM irene_ghobrial@dfci.harvard.edu OI Roccaro, Aldo/0000-0002-1872-5128 FU National Cancer Institute [R01CA154648, R01CA125690]; Leukemia and Lymphoma Society FX This study was supported in part by the National Cancer Institute (R01CA154648 and R01CA125690), and the Leukemia and Lymphoma Society. NR 42 TC 8 Z9 8 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD SEP 18 PY 2014 VL 124 IS 12 BP 1905 EP 1914 DI 10.1182/blood-2014-02-558742 PG 10 WC Hematology SC Hematology GA AQ4JT UT WOS:000342762800012 PM 25079359 ER PT J AU Ferrao, R Zhou, H Shan, YB Liu, Q Li, QB Shaw, DE Li, XX Wu, H AF Ferrao, Ryan Zhou, Hao Shan, Yibing Liu, Qun Li, Qiubai Shaw, David E. Li, Xiaoxia Wu, Hao TI IRAK4 Dimerization and trans-Autophosphorylation Are Induced by Myddosome Assembly SO MOLECULAR CELL LA English DT Article ID PYOGENIC BACTERIAL-INFECTIONS; RECEPTOR-ASSOCIATED KINASE-4; TOLL-LIKE RECEPTORS; KAPPA-B ACTIVATION; STRUCTURAL INSIGHTS; PROTEIN-KINASES; COMPLEX; MECHANISM; MYD88; CONFORMATION AB trans-autophosphorylation is among the most prevalent means of protein kinase activation, yet its molecular basis is poorly defined. In Toll-like receptor and interleukin-1 receptor signaling pathways, the kinase IRAK4 is recruited to the membrane-proximal adaptor MyD88 through death domain (DD) interactions, forming the oligomeric Myddosome and mediating NF-kappa B activation. Here we show that unphosphorylated IRAK4 dimerizes in solution with a K-D of 2.5 mu M and that Myddosome assembly greatly enhances IRAK4 kinase domain (KD) autophosphorylation at sub-K-D concentrations. The crystal structure of the unphosphorylated IRAK4(KD) dimer captures a conformation that appears to represent the actual trans-autophosphorylation reaction, with the activation loop phosphosite of one IRAK4 monomer precisely positioned for phosphotransfer by its partner. We show that dimerization is crucial for IRAK4 autophosphorylation in vitro and ligand-dependent signaling in cells. These studies identify a mechanism for oligomerization-driven allosteric autoactivation of IRAK4 that may be general to other kinases activated by autophosphorylation. C1 [Ferrao, Ryan; Li, Qiubai; Wu, Hao] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Ferrao, Ryan; Li, Qiubai; Wu, Hao] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Ferrao, Ryan; Wu, Hao] Weill Cornell Grad Sch Med Sci, New York, NY 10065 USA. [Zhou, Hao; Li, Xiaoxia] Cleveland Clin Fdn, Lerner Res Inst, Dept Immunol, Cleveland, OH 44195 USA. [Shan, Yibing; Shaw, David E.] DE Shaw Res, New York, NY 10036 USA. [Liu, Qun] Brookhaven Natl Lab, Natl Synchrotron Light Source X4, New York Struct Biol Ctr, Upton, NY 11961 USA. [Shaw, David E.] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. RP Wu, H (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM hao.wu@childrens.harvard.edu RI Liu, Qun/A-8757-2011 OI Liu, Qun/0000-0002-1179-290X FU National Institutes of Health [AI050872] FX We thank Dr. Wayne Hendrickson for suggesting the use of X4A beamline of NSLS for sulfur anomalous diffraction, Dr. Venkatesh Mysore for assistance in performing the MD simulation, Dr. Stewart Shuman and Dr. Heather Ordonez for their technical support and advice involving radiolabeled kinase assays, Dr. Stephen Harrison and Dr. Yoana Dimitrova for access to the SE-AUC equipment and assistance with the experiment, and the National Institutes of Health for funding support (AI050872 to H.W.). NR 39 TC 18 Z9 18 U1 2 U2 7 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 SEP 18 PY 2014 VL 55 IS 6 BP 891 EP 903 DI 10.1016/j.molcel.2014.08.006 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AQ2MA UT WOS:000342619200010 PM 25201411 ER PT J AU Smith-Bindman, R Aubin, C Bailitz, J Bengiamin, RN Camargo, CA Corbo, J Dean, AJ Goldstein, RB Griffey, RT Jay, GD Kang, TL Kriesel, DR Ma, OJ Mallin, M Manson, W Melnikow, J Miglioretti, DL Miller, SK Mills, LD Miner, JR Moghadassi, M Noble, VE Press, GM Stoller, ML Valencia, VE Wang, J Wang, RC Cummings, SR AF Smith-Bindman, R. Aubin, C. Bailitz, J. Bengiamin, R. N. Camargo, C. A., Jr. Corbo, J. Dean, A. J. Goldstein, R. B. Griffey, R. T. Jay, G. D. Kang, T. L. Kriesel, D. R. Ma, O. J. Mallin, M. Manson, W. Melnikow, J. Miglioretti, D. L. Miller, S. K. Mills, L. D. Miner, J. R. Moghadassi, M. Noble, V. E. Press, G. M. Stoller, M. L. Valencia, V. E. Wang, J. Wang, R. C. Cummings, S. R. TI Ultrasonography versus Computed Tomography for Suspected Nephrolithiasis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RADIATION-EXPOSURE; UROLITHIASIS; CHILDHOOD; DIAGNOSIS; SCANS; RISK; PAIN; CT AB BACKGROUND There is a lack of consensus about whether the initial imaging method for patients with suspected nephrolithiasis should be computed tomography (CT) or ultrasonography. METHODS In this multicenter, pragmatic, comparative effectiveness trial, we randomly assigned patients 18 to 76 years of age who presented to the emergency department with suspected nephrolithiasis to undergo initial diagnostic ultrasonography performed by an emergency physician (point-of-care ultrasonography), ultrasonography performed by a radiologist (radiology ultrasonography), or abdominal CT. Subsequent management, including additional imaging, was at the discretion of the physician. We compared the three groups with respect to the 30-day incidence of high-risk diagnoses with complications that could be related to missed or delayed diagnosis and the 6-month cumulative radiation exposure. Secondary outcomes were serious adverse events, related serious adverse events (deemed attributable to study participation), pain (assessed on an 11-point visual-analogue scale, with higher scores indicating more severe pain), return emergency department visits, hospitalizations, and diagnostic accuracy. RESULTS A total of 2759 patients underwent randomization: 908 to point-of-care ultrasonography, 893 to radiology ultrasonography, and 958 to CT. The incidence of high-risk diagnoses with complications in the first 30 days was low (0.4%) and did not vary according to imaging method. The mean 6-month cumulative radiation exposure was significantly lower in the ultrasonography groups than in the CT group (P<0.001). Serious adverse events occurred in 12.4% of the patients assigned to point-of-care ultrasonography, 10.8% of those assigned to radiology ultrasonography, and 11.2% of those assigned to CT (P = 0.50). Related adverse events were infrequent (incidence, 0.4%) and similar across groups. By 7 days, the average pain score was 2.0 in each group (P = 0.84). Return emergency department visits, hospitalizations, and diagnostic accuracy did not differ significantly among the groups. CONCLUSIONS Initial ultrasonography was associated with lower cumulative radiation exposure than initial CT, without significant differences in high-risk diagnoses with complications, serious adverse events, pain scores, return emergency department visits, or hospitalizations. C1 [Smith-Bindman, R.; Goldstein, R. B.; Moghadassi, M.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Smith-Bindman, R.; Stoller, M. L.; Valencia, V. E.; Wang, R. C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Smith-Bindman, R.; Stoller, M. L.; Valencia, V. E.; Wang, R. C.] Univ Calif San Francisco, Philip R Lee Inst Hlth Policy Studies, San Francisco, CA 94143 USA. [Kriesel, D. R.; Cummings, S. R.] Calif Pacific Med Ctr, Res Inst, San Francisco Coordinating Ctr, San Francisco, CA USA. [Bengiamin, R. N.] UCSF, Dept Emergency Med, Fresno, CA USA. [Kang, T. L.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Melnikow, J.] Univ Calif Davis, Ctr Healthcare Policy & Res, Davis, CA 95616 USA. [Miglioretti, D. L.] Univ Calif Davis, Div Biostat, Dept Publ Hlth Sci, Davis, CA 95616 USA. [Mills, L. D.] Univ Calif Davis, Dept Emergency Med, Davis, CA 95616 USA. [Aubin, C.; Griffey, R. T.] Washington Univ, Sch Med, Div Emergency Med, St Louis, MO 63130 USA. [Bailitz, J.] Rush Univ, Med Ctr, Dept Emergency Med, Jr Hosp Cook Cty, Chicago, IL 60612 USA. [Bailitz, J.] Rush Univ, Med Ctr, Dept Emergency Med, Chicago, IL 60612 USA. [Camargo, C. A., Jr.; Noble, V. E.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Camargo, C. A., Jr.; Noble, V. E.] Harvard Univ, Sch Med, Boston, MA USA. [Corbo, J.; Wang, J.] Jacobi Med Ctr, Dept Emergency Med, Bronx, NY USA. [Dean, A. J.] Univ Penn, Dept Emergency Med, Philadelphia, PA 19104 USA. [Jay, G. D.] Brown Univ, Rhode Isl Hosp, Providence, RI 02903 USA. [Jay, G. D.] Brown Univ, Dept Emergency Med, Providence, RI 02912 USA. [Ma, O. J.] Oregon Hlth & Sci Univ, Dept Emergency Med, Portland, OR 97201 USA. [Miglioretti, D. L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Mallin, M.] Univ Utah, Salt Lake City, UT USA. [Manson, W.] Emory Univ, Sch Med, Atlanta, GA USA. [Miller, S. K.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Press, G. M.] Univ Texas Houston, Houston Med Sch, Houston, TX USA. [Miner, J. R.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. RP Smith-Bindman, R (reprint author), Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. EM rebecca.smith-bindman@ucsf.edu RI Griffey, Richard/I-5256-2015 OI Jay, Gregory/0000-0003-1517-8488; Wang, Ralph/0000-0001-5382-9486; FU Agency for Healthcare Research and Quality through its Clinical and Health Outcomes Initiative in Comparative Effectiveness [R01HS019312] FX Supported by a grant (R01HS019312) from the Agency for Healthcare Research and Quality through its Clinical and Health Outcomes Initiative in Comparative Effectiveness. NR 18 TC 112 Z9 112 U1 1 U2 13 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 SEP 18 PY 2014 VL 371 IS 12 BP 1100 EP 1110 DI 10.1056/NEJMoa1404446 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AO9PI UT WOS:000341687300005 PM 25229916 ER PT J AU Boehmerle, W Huehnchen, P Peruzzaro, S Balkaya, M Endres, M AF Boehmerle, Wolfgang Huehnchen, Petra Peruzzaro, Sarah Balkaya, Mustafa Endres, Matthias TI Electrophysiological, behavioral and histological characterization of paclitaxel, cisplatin, vincristine and bortezomib-induced neuropathy in C57Bl/6 mice SO SCIENTIFIC REPORTS LA English DT Article ID INDUCED PERIPHERAL NEUROPATHY; MULTIPLE-MYELOMA; TAXOL NEUROPATHY; CHEMOTHERAPY; MODELS; CANCER; RESPONSES; SYSTEM; NERVES AB Polyneuropathy is a frequent and potentially severe side effect of clinical tumor chemotherapy. The goal of this study was to characterize paclitaxel-, cisplatin-, vincristine-and bortezomib-induced neuropathy in C57BL/6 mice with a comparative approach. The phenotype of the animals was evaluated at four time points with behavioral and electrophysiological tests, followed by histology. Treatment protocols used in this study were well tolerated and induced a sensory and predominantly axonal polyneuropathy. Behavioral testing revealed normal motor coordination, whereas all mice receiving verum treatment developed mechanical allodynia and distinct gait alterations. Electrophysiological evaluation showed a significant decrease of the caudal sensory nerve action potential amplitude for all cytostatic agents and a moderate reduction of nerve conduction velocity for cisplatin and paclitaxel. This finding was confirmed by histological analysis of the sciatic nerve which showed predominantly axonal damage: Paclitaxel and vincristine affected mostly large myelinated fibers, bortezomib small myelinated fibers and cisplatin damaged all types of myelinated fibers to a similar degree. Neuropathic symptoms developed faster in paclitaxel and vincristine treated animals compared to cisplatin and bortezomib treatment. The animal models in this study can be used to elucidate pathomechanisms underlying chemotherapy-induced polyneuropathy and for the development of novel therapeutic and preventative strategies. C1 [Boehmerle, Wolfgang; Huehnchen, Petra; Peruzzaro, Sarah; Balkaya, Mustafa; Endres, Matthias] Charite, Klin & Hochschulambulanz Neurol, D-13353 Berlin, Germany. [Boehmerle, Wolfgang; Huehnchen, Petra; Endres, Matthias] Charite, Cluster Excellence NeuroCure, D-13353 Berlin, Germany. [Balkaya, Mustafa; Endres, Matthias] Charite, Ctr Stroke Res, D-13353 Berlin, Germany. [Endres, Matthias] German Ctr Neurodegenerat Dis DZNE, Berlin, Germany. [Balkaya, Mustafa] Massachusetts Gen Hosp, Dept Radiol, Neurovasc Res Lab, Boston, MA 02114 USA. [Balkaya, Mustafa] Harvard Univ, Sch Med, Boston, MA USA. RP Boehmerle, W (reprint author), Charite, Klin & Hochschulambulanz Neurol, D-13353 Berlin, Germany. EM wolfgang.boehmerle@charite.de OI Boehmerle, Wolfgang/0000-0001-7195-3894; Huehnchen, Petra/0000-0002-6825-7270 FU federal ministry of education and research via center for stroke research Berlin [01 EO 0801]; Volkswagen foundation (Lichtenberg program); Deutsche Forschungsgemeinschaft DFG (NeuroCure); Charite Universitatsmedizin Berlin; Berlin Institute of Health FX We would like to thank Catherine Aubel for thoughtful text editing, Heather L. More for the Matlab routine used to perform semi-automatic nerve morphometry and Petra Loge for excellent technical assistance. The research leading to these results has received funding from the federal ministry of education and research via the grant center for stroke research Berlin (01 EO 0801), the Volkswagen foundation (Lichtenberg program to Matthias Endres), and Deutsche Forschungsgemeinschaft DFG (NeuroCure). W. Boehmerle is participant in the Charite Clinical Scientist Program funded by the Charite Universitatsmedizin Berlin and the Berlin Institute of Health. NR 39 TC 6 Z9 6 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD SEP 18 PY 2014 VL 4 AR 6370 DI 10.1038/srep06370 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP2YH UT WOS:000341941600001 PM 25231679 ER PT J AU Pugach, MK Gibson, CW AF Pugach, Megan K. Gibson, Carolyn W. TI Analysis of enamel development using murine model systems: approaches and limitations SO FRONTIERS IN PHYSIOLOGY LA English DT Review DE enamel development; transgenic; knockout; knockin; amelogenin; mineralization ID AMELOGENESIS IMPERFECTA PHENOTYPE; MICRO-COMPUTED TOMOGRAPHY; TRANSGENIC MICE; REPORTER GENE; DENTAL ENAMEL; PEPTIDE ALTERS; RAT INCISOR; TOOTH COLOR; IN-VIVO; EXPRESSION AB A primary goal of enamel research is to understand and potentially treat or prevent enamel defects related to amelogenesis imperfecta (AI). Rodents are ideal models to assist our understanding of how enamel is formed because they are easily genetically modified, and their continuously erupting incisors display all stages of enamel development and mineralization. While numerous methods have been developed to generate and analyze genetically modified rodent enamel, it is crucial to understand the limitations and challenges associated with these methods in order to draw appropriate conclusions that can be applied translationally, to AI patient care. We have highlighted methods involved in generating and analyzing rodent enamel and potential approaches to overcoming limitations of these methods: (1) generating transgenic, knockout, and knockin mouse models, and (2) analyzing rodent enamel mineral density and functional properties (structure and mechanics) of mature enamel. There is a need for a standardized workflow to analyze enamel phenotypes in rodent models so that investigators can compare data from different studies. These methods include analyses of gene and protein expression, developing enamel histology, enamel pigment, degree of mineralization, enamel structure, and mechanical properties. Standardization of these methods with regard to stage of enamel development and sample preparation is crucial, and ideally investigators can use correlative and complementary techniques with the understanding that developing mouse enamel is dynamic and complex. C1 [Pugach, Megan K.] Harvard Univ, Sch Dent Med, Dept Mineralized Tissue Biol, Forsyth Inst, Cambridge, MA 02142 USA. [Gibson, Carolyn W.] Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA 19104 USA. RP Pugach, MK (reprint author), Harvard Univ, Sch Dent Med, Dept Mineralized Tissue Biol, Forsyth Inst, 245 First St, Cambridge, MA 02142 USA. EM mpugach@forsyth.org FU National Institute of Dental and Craniofacial Research of the National Institutes of Health [R00DE022624, R01DE011089] FX Research reported in this publication was supported by the National Institute of Dental and Craniofacial Research of the National Institutes of Health, grants R00DE022624 (Megan K. Pugach) and R01DE011089 (Carolyn W. Gibson). NR 70 TC 6 Z9 6 U1 0 U2 8 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD SEP 17 PY 2014 VL 5 AR 313 DI 10.3389/fphys.2014.00313 PG 10 WC Physiology SC Physiology GA AX7IH UT WOS:000347089300001 PM 25278900 ER PT J AU Hansen, VJ Greene, ME Bragdon, MA Nebergall, AK Barr, CJ Huddleston, JI Bragdon, CR Malchau, H AF Hansen, Victor J. Greene, Meredith E. Bragdon, Marc A. Nebergall, Audrey K. Barr, Christopher J. Huddleston, J. I. Bragdon, Charles R. Malchau, Henrik TI Registries Collecting Level-I through IV Data: Institutional and Multicenter Use SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Editorial Material ID TOTAL HIP-ARTHROPLASTY; MOLECULAR-WEIGHT POLYETHYLENE; JOINT REPLACEMENT REGISTRY; CROSS-LINKED POLYETHYLENE; KNEE ARTHROPLASTY; UNITED-STATES; FOLLOW-UP; JOHN-CHARNLEY; WEAR; OSTEOLYSIS C1 [Hansen, Victor J.; Greene, Meredith E.; Bragdon, Marc A.; Nebergall, Audrey K.; Barr, Christopher J.; Huddleston, J. I.; Bragdon, Charles R.; Malchau, Henrik] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. RP Hansen, VJ (reprint author), Massachusetts Gen Hosp, Harris Orthopaed Lab, 55 Fruit St,GRJ 1121, Boston, MA 02114 USA. EM viktor.j.hansen@gmail.com NR 50 TC 3 Z9 3 U1 0 U2 0 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD SEP 17 PY 2014 VL 96A IS 18 AR e160 DI 10.2106/JBJS.M.01458 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AR8BF UT WOS:000343799800007 PM 25232090 ER PT J AU Gandy, S Ikonomovic, MD Mitsis, E Elder, G Ahlers, ST Barth, J Stone, JR DeKosky, ST AF Gandy, Sam Ikonomovic, Milos D. Mitsis, Effie Elder, Gregory Ahlers, Stephen T. Barth, Jeffrey Stone, James R. DeKosky, Steven T. TI Chronic traumatic encephalopathy: clinical-biomarker correlations and current concepts in pathogenesis SO MOLECULAR NEURODEGENERATION LA English DT Review ID AMYLOID-BETA-PROTEIN; AMYOTROPHIC-LATERAL-SCLEROSIS; POSTTRAUMATIC-STRESS-DISORDER; FOOTBALL-LEAGUE PLAYER; PITTSBURGH COMPOUND-B; MILD HEAD-INJURY; BRAIN-INJURY; DEMENTIA-PUGILISTICA; NEUROFIBRILLARY TANGLES; PROFESSIONAL BOXERS AB Background: Chronic traumatic encephalopathy (CTE) is a recently revived term used to describe a neurodegenerative process that occurs as a long term complication of repetitive mild traumatic brain injury (TBI). Corsellis provided one of the classic descriptions of CTE in boxers under the name "dementia pugilistica" (DP). Much recent attention has been drawn to the apparent association of CTE with contact sports (football, soccer, hockey) and with frequent battlefield exposure to blast waves generated by improvised explosive devices (IEDs). Recently, a promising serum biomarker has been identified by measurement of serum levels of the neuronal microtubule associated protein tau. New positron emission tomography (PET) ligands (e. g., [F-18] T807) that identify brain tauopathy have been successfully deployed for the in vitro and in vivo detection of presumptive tauopathy in the brains of subjects with clinically probable CTE. Methods: Major academic and lay publications on DP/CTE were reviewed beginning with the 1928 paper describing the initial use of the term CTE by Martland. Results: The major current concepts in the neurological, psychiatric, neuropsychological, neuroimaging, and body fluid biomarker science of DP/CTE have been summarized. Newer achievements, such as serum tau and [F-18] T807 tauopathy imaging, are also introduced and their significance has been explained. Conclusion: Recent advances in the science of DP/CTE hold promise for elucidating a long sought accurate determination of the true prevalence of CTE. This information holds potentially important public health implications for estimating the risk of contact sports in inflicting permanent and/or progressive brain damage on children, adolescents, and adults. C1 [Gandy, Sam; Elder, Gregory] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Gandy, Sam; Mitsis, Effie; Elder, Gregory] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Gandy, Sam; Mitsis, Effie; Elder, Gregory] Icahn Sch Med Mt Sinai, Mt Sinai Alzheimers Dis Res Ctr, New York, NY 10029 USA. [Gandy, Sam; Elder, Gregory] James J Peters VA Med Ctr, Bronx, NY 10468 USA. [Ikonomovic, Milos D.] Univ Pittsburgh, Dept Neurol, VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15213 USA. [Ikonomovic, Milos D.] Univ Pittsburgh, Dept Psychiat, VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15213 USA. [Ahlers, Stephen T.] Naval Med Res Ctr, Silver Spring, MD 20910 USA. [Barth, Jeffrey] Univ Virginia, Dept Psychiat, Charlottesville, VA 22908 USA. [Barth, Jeffrey] Univ Virginia, Dept Neurobehav Sci, Charlottesville, VA 22908 USA. [Stone, James R.] Univ Virginia, Dept Radiol, Charlottesville, VA 22908 USA. [DeKosky, Steven T.] Univ Virginia, Coll Med, Off Dean, Charlottesville, VA 22908 USA. [DeKosky, Steven T.] Univ Virginia, Dept Nerurol, Charlottesville, VA 22908 USA. RP Gandy, S (reprint author), Icahn Sch Med Mt Sinai, Dept Neurol, One Gustave L Levy Pl, New York, NY 10029 USA. EM samuel.gandy@mssm.edu RI Meijer, Anna/K-5118-2016 FU NIH [P01NS30318, P01AG14449, P50AG05133, P01AG25204]; VA MERIT [1I01BX000348, 1 I01 RX000684, 1 I01RX000511, 1I01RX000179, 1I01RX000996-01, I01 CX000190]; Mount Sinai School of Medicine CTSA [UL1-RR-029887]; Cure Alzheimer's Fund; US NIH [P50 AG05138]; Pittsburgh Foundation [M2010-0041]; Office of Naval Research [0601153 N.0000.00A0702]; Defense Health Program-US Army MRMC [W81XWH-09-2-0055, W81XWH-11-2-0109, W81XWH-09-2-0160]; USUHS [HU0001-08-1-0001] FX The authors gratefully acknowledge the support of NIH grants P01NS30318, P01AG14449 and P50AG05133 (S. T. DeKosky and M. D. Ikonomovic), P01AG25204 (M. Ikonomovic), and VA MERIT review grants 1I01BX000348 (S. Gandy), 1 I01 RX000684 (S. Gandy), 1 I01RX000511 (M. D. Ikonomovic), 1I01RX000179 (G. Elder), 1I01RX000996-01 (G. Elder), and I01 CX000190 (E. Mitsis). E. Mitsis was also supported by the Mount Sinai School of Medicine CTSA grant UL1-RR-029887. Gandy also acknowledges the support of the Cure Alzheimer's Fund and of US NIH P50 AG05138. Ikonomovic also acknowledges support from The Pittsburgh Foundation grant M2010-0041. Ahlers acknowledges support from the Office of Naval Research: 0601153 N.0000.00A0702. The authors also acknowledge Defense Health Program-US Army MRMC contracts W81XWH-09-2-0055 (J. Stone), W81XWH-11-2-0109 (J. Stone), W81XWH-09-2-0160 (S. Ahlers, J. Stone), and USUHS award HU0001-08-1-0001 (S. Ahlers, J. Stone). The authors thank P. Davies (North Shore-Hofstra) for helpful discussions. The authors also thank Corey Fernandez for outstanding administrative support. The opinions contained herein are those of the authors and are not to be construed as official or as reflecting the views of the Department of the Navy or of the Naval Service at large. NR 119 TC 18 Z9 18 U1 3 U2 31 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD SEP 17 PY 2014 VL 9 AR UNSP 37 DI 10.1186/1750-1326-9-37 PG 21 WC Neurosciences SC Neurosciences & Neurology GA AP3BZ UT WOS:000341951300001 PM 25231386 ER PT J AU Brilakis, E Banerjee, S Karmpaliotis, D Lombardi, W Tsai, TT Shunk, K Kennedy, KF Spertus, J Holmes, D Grantham, JA AF Brilakis, Emmanouil Banerjee, Subhash Karmpaliotis, Dimitri Lombardi, William Tsai, Thomas T. Shunk, Kendrick Kennedy, Kevin F. Spertus, John Holmes, David Grantham, J. Aaron TI Procedural Outcomes of Chronic Total Occlusion Percutaneous Coronary Intervention: A Report from NCDR SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 26th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY SEP 13-17, 2014 CL Washington, DC C1 [Brilakis, Emmanouil; Banerjee, Subhash] VA North Texas Hlth Care Syst, Dallas, TX USA. [Brilakis, Emmanouil; Banerjee, Subhash] UT Southwestern Med Ctr, Dallas, TX USA. [Karmpaliotis, Dimitri] Columbia Univ, Med Ctr, New York, NY USA. [Lombardi, William] Peacehlth St Joseph Med Ctr, Bellingham, WA USA. [Tsai, Thomas T.] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. [Tsai, Thomas T.] Univ Colorado, Denver, CO 80202 USA. [Shunk, Kendrick] San Francisco VA Med Ctr, San Francisco, CA USA. [Kennedy, Kevin F.; Spertus, John; Grantham, J. Aaron] St Lukes Hosp, Mid Amer Heart & Vasc Inst, Kansas City, MO USA. [Holmes, David] Mayo Clin, Coll Med, Rochester, MN 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 16 PY 2014 VL 64 IS 11 SU S MA TCT-192 BP B56 EP B57 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP1QG UT WOS:000359649700190 ER PT J AU Elmariah, S Passeri, JJ Inglessis, I Baker, JN Stewart, W Lindman, BR Xu, K Vlahakes, GJ Dal-Bianco, JP Melnitchouk, S Leon, M Svensson, L Weissman, N Pibarot, P Palacios, IF AF Elmariah, Sammy Passeri, Jonathan J. Inglessis, Ignacio Baker, Joshua N. Stewart, William Lindman, Brian R. Xu, Ke Vlahakes, Gus J. Dal-Bianco, Jacob P. Melnitchouk, Serguei Leon, Martin Svensson, Lars Weissman, Neil Pibarot, Philippe Palacios, Igor F. TI Impact of Left Ventricular Remodeling on Clinical Outcomes after TAVR: Insights from the PARTNER I Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 26th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY SEP 13-17, 2014 CL Washington, DC C1 [Elmariah, Sammy; Passeri, Jonathan J.; Baker, Joshua N.; Vlahakes, Gus J.; Dal-Bianco, Jacob P.; Melnitchouk, Serguei] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Inglessis, Ignacio; Palacios, Igor F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Stewart, William; Svensson, Lars] Cleveland Clin, Cleveland, OH 44106 USA. [Lindman, Brian R.] Washington Univ, Sch Med, St Louis, MO USA. [Xu, Ke] Cardiovasc Res Fdn, New York, NY USA. [Leon, Martin] Columbia Univ, Med Ctr, New York, NY USA. [Weissman, Neil] MedStar Washington Hosp Ctr, Washington, DC USA. [Pibarot, Philippe] Quebec Heart & Lung Inst, Quebec City, PQ, Canada. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 16 PY 2014 VL 64 IS 11 SU S MA TCT-686 BP B200 EP B201 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP1QG UT WOS:000359649700672 ER PT J AU Herrera, JE Herrera, JA Palacios, IF AF Herrera, Jose E. Herrera, Jose A. Palacios, Igor F. TI First Percutaneous Transluminal Caval flow Restriction in a Patient with Congestive Heart Failure SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 26th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY SEP 13-17, 2014 CL Washington, DC C1 [Herrera, Jose E.; Herrera, Jose A.] Ascardio, Barquisimeto, Venezuela. [Palacios, Igor F.] Massachusetts Gen Hosp, Boston, MA 02114 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 16 PY 2014 VL 64 IS 11 SU S MA TCT-428 BP B125 EP B126 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP1QG UT WOS:000359649700422 ER PT J AU Krishnan, K Ye, J Dvir, D Azadani, AN Guccione, J Ge, L Tseng, E AF Krishnan, Kapil Ye, Jian Dvir, Danny Azadani, Ali N. Guccione, Julius Ge, Liang Tseng, Elaine TI Finite Element Analyses Stent and Leaflet Stresses on 26mm Transcatheter Aortic Valve SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 26th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY SEP 13-17, 2014 CL Washington, DC C1 [Krishnan, Kapil; Guccione, Julius; Ge, Liang] Univ Calif San Francisco, Med Ctr, San Francisco, CA USA. [Ye, Jian; Dvir, Danny] St Pauls Hosp, Vancouver, BC V6Z 1Y6, Canada. [Azadani, Ali N.] Univ Denver, Denver, CO USA. [Tseng, Elaine] Univ Calif San Francisco, San Francisco Med Ctr, San Francisco, CA 94143 USA. [Tseng, Elaine] San Francisco VA Med Ctr, San Francisco, CA 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 16 PY 2014 VL 64 IS 11 SU S MA TCT-681 BP B198 EP B198 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP1QG UT WOS:000359649700667 ER PT J AU Ouweneel, DM Palacios, IF Popma, J Ohman, M O'Neill, WW Henriques, JP AF Ouweneel, Dagmar M. Palacios, Igor F. Popma, Jeffrey Ohman, Magnus O'Neill, William W. Henriques, Jose P. TI Evaluating The Learning Curve In A Clinical Trial Using A New Percutaneous Left Ventricular Support System. Observations From The PROTECT II Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 26th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY SEP 13-17, 2014 CL Washington, DC C1 [Ouweneel, Dagmar M.] AMC Amsterdam, Amsterdam, Netherlands. [Palacios, Igor F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Popma, Jeffrey] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Ohman, Magnus] Duke Univ, Med Ctr, Durham, NC USA. [O'Neill, William W.] Henry Ford Hosp, Detroit, MI 48202 USA. [Henriques, Jose P.] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 16 PY 2014 VL 64 IS 11 SU S MA TCT-69 BP B21 EP B21 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP1QG UT WOS:000359649700069 ER PT J AU Hsu, WC Lau, KHK Matsumoto, M Moghazy, D Keenan, H King, GL AF Hsu, William C. Lau, Ka Hei Karen Matsumoto, Motonobu Moghazy, Dalia Keenan, Hillary King, George L. TI Improvement of Insulin Sensitivity by Isoenergy High Carbohydrate Traditional Asian Diet: A Randomized Controlled Pilot Feasibility Study SO PLOS ONE LA English DT Article ID BODY-MASS INDEX; LOW-FAT DIETS; WEIGHT-LOSS; METABOLIZABLE ENERGY; PACIFIC ISLANDERS; NATIVE HAWAIIANS; RISK-FACTORS; LIFE-STYLE; INTERVENTION; INFLAMMATION AB The prevalence of diabetes is rising dramatically among Asians, with increased consumption of the typical Western diet as one possible cause. We explored the metabolic responses in East Asian Americans (AA) and Caucasian Americans (CA) when transitioning from a traditional Asian diet (TAD) to a typical Western diet (TWD), which has not been reported before. This 16-week randomized control pilot feasibility study, included 28AA and 22CA who were at risk of developing type 2 diabetes. Eight weeks of TAD were provided to all participants, followed by 8 weeks of isoenergy TWD (intervention) or TAD (control). Anthropometric measures, lipid profile, insulin resistance and inflammatory markers were assessed. While on TAD, both AA and CA improved in insulin AUC (-960.2 mu U/mLxh, P = 0.001) and reduced in weight (-1.6 kg; P<0.001), body fat (-1.7%, P<0.001) and trunk fat (-2.2%, P<0.001). Comparing changes from TAD to TWD, AA had a smaller weight gain (-1.8 to 0.3 kg, P<0.001) than CA (-1.4 to 0.9 kg, P = 0.001), but a greater increase in insulin AUC (AA: -1402.4 to 606.2 mu U/mLxh, P = 0.015 vs CA: -466.0 to 223.5 mu U/mLxh, P = 0.034) and homeostatic static model assessment-insulin resistance (HOMA-IR) (AA: -0.3 to 0.2, P = 0.042 vs CA: -0.1 to 0.0, P = 0.221). Despite efforts to maintain isoenergy state and consumption of similar energy, TAD induced weight loss and improved insulin sensitivity in both groups, while TWD worsened the metabolic profile. C1 [Hsu, William C.; Lau, Ka Hei Karen; Moghazy, Dalia; King, George L.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Asian Amer Diabet Initiat, Boston, MA 02115 USA. [Keenan, Hillary; King, George L.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dianne Nunnally Hoppes Lab Diabet Complicat, Boston, MA 02115 USA. [Matsumoto, Motonobu] Sunstar Inc, R&D Dept, Osaka, Japan. RP King, GL (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Asian Amer Diabet Initiat, Boston, MA 02115 USA. EM george.king@joslin.harvard.edu FU Asian American Diabetes Initiative; Joslin Diabetes Center; Sunstar, Inc. FX This study was funded by Asian American Diabetes Initiative, Joslin Diabetes Center and Sunstar, Inc. M. Matsumoto is a paid member of Sunstar, Inc. and was responsible in conducting the research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 3 Z9 3 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 16 PY 2014 VL 9 IS 9 AR e106851 DI 10.1371/journal.pone.0106851 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS5NP UT WOS:000344317700020 PM 25226279 ER PT J AU Shahian, DM Grover, FL AF Shahian, David M. Grover, Frederick L. TI Biomarkers and Risk Models in Cardiac Surgery SO CIRCULATION LA English DT Editorial Material DE Editorials; biomarkers; cardiac surgery; risk assessment ID BRAIN NATRIURETIC PEPTIDE; BYPASS-GRAFTING SURGERY; HEART-FAILURE; ELDERLY-PATIENTS; RECLASSIFICATION; TROPONIN; DYSFUNCTION; MORTALITY; THERAPY; SOCIETY C1 [Shahian, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Shahian, David M.] Harvard Univ, Sch Med, Boston, MA USA. [Grover, Frederick L.] Univ Colorado, Sch Med, Aurora, CO 80045 USA. [Grover, Frederick L.] Denver Dept Vet Affairs Med Ctr, Denver, CO USA. RP Grover, FL (reprint author), Univ Colorado, Sch Med, Div Cardiothorac Surg, 12631 E 17th Ave,C-310,Room 6602, Aurora, CO 80045 USA. EM frederick.grover@ucdenver.edu NR 23 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD SEP 16 PY 2014 VL 130 IS 12 BP 932 EP 935 DI 10.1161/CIRCULATIONAHA.114.011983 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AP6OU UT WOS:000342197900008 PM 25098241 ER PT J AU de la Riva, P Smith, K Xie, SX Weintraub, D AF de la Riva, Patricia Smith, Kara Xie, Sharon X. Weintraub, Daniel TI Course of psychiatric symptoms and global cognition in early Parkinson disease SO NEUROLOGY LA English DT Article ID DRUG-NAIVE PATIENTS; NONMOTOR SYMPTOMS; DEPRESSIVE SYMPTOMS; LONGITUDINAL DATA; MOTOR SUBTYPE; RATING-SCALE; IMPAIRMENT; DEMENTIA; INCIDENT; COMPLICATIONS AB Objective:To evaluate the course and predictors of neuropsychiatric symptoms (NPS) and cognition in patients with de novo Parkinson disease (PD).Methods:Cross-sectional study of the cohort of de novo, untreated (at enrollment) patients with PD and healthy controls (HCs) from the Parkinson's Progression Markers Initiative. Participants have serial assessments of global cognition and symptoms of depression, anxiety, psychosis, impulse control disorders (ICDs), sleep and wakefulness, apathy, and fatigue. Available data up to 24 months of follow-up were included.Results:The available sample size was as follows: baseline (PD = 423, HCs = 196), 12 months (PD = 261, HCs = 145), and 24 months (PD = 96, HCs = 83). Patients with PD experienced more depression, fatigue, apathy, and anxiety than HCs at all time points, and apathy (p = 0.001) and psychosis (p = 0.003) increased over time in patients with PD. Approximately two-thirds of patients with PD who screened positive for depression at any given visit were not taking an antidepressant. The Montreal Cognitive Assessment score decreased significantly over time in patients with PD (p < 0.001), but the change was comparable to that in HCs. At the 24-month visit, 44% of patients had been on dopamine replacement therapy (DRT) for at least 1 year, and this group reported more incident ICDs (p = 0.009) and excessive daytime sleepiness (p = 0.03).Conclusion:Multiple NPS are more common in de novo, untreated patients with PD compared with the general population, but they also remain relatively stable in early disease, while global cognition slightly deteriorates. In contrast, initiation of DRT is associated with increasing frequency of several other NPS. C1 [de la Riva, Patricia] Univ Hosp Donostia, Dept Neurol, San Sebastian, Spain. [Xie, Sharon X.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Smith, Kara] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Philadelphia VA Med Ctr, Dept Vet Affairs, Philadelphia, PA USA. RP de la Riva, P (reprint author), Univ Hosp Donostia, Dept Neurol, San Sebastian, Spain. EM patricia.delariva@gmail.com FU Michael J. Fox Foundation for Parkinson's Research; Abbott; Avid Radiopharmaceuticals; Biogen Idec; Covance; Bristol-Myers Squibb; Meso Scale Discovery; Piramal; Eli Lilly and Co; F. Hoffman-La Roche Ltd; GE Healthcare; Genentech; GlaxoSmithKline; Merck and Co; Pfizer Inc; UCB Pharma SA FX Supported by the Michael J. Fox Foundation for Parkinson's Research and funding partners: Abbott, Avid Radiopharmaceuticals, Biogen Idec, Covance, Bristol-Myers Squibb, Meso Scale Discovery, Piramal, Eli Lilly and Co, F. Hoffman-La Roche Ltd, GE Healthcare, Genentech, GlaxoSmithKline, Merck and Co, Pfizer Inc, and UCB Pharma SA. NR 38 TC 22 Z9 22 U1 4 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 16 PY 2014 VL 83 IS 12 BP 1096 EP 1103 DI 10.1212/WNL.0000000000000801 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AP7AU UT WOS:000342230700013 PM 25128183 ER PT J AU Damman, K Perez, AC Anand, IS Komajda, M McKelvie, RS Zile, MR Massie, B Carson, PE McMurray, JJV AF Damman, Kevin Perez, Ana C. Anand, Inder S. Komajda, Michel McKelvie, Robert S. Zile, Michael R. Massie, Barrie Carson, Peter E. McMurray, John J. V. TI Worsening Renal Function and Outcome in Heart Failure Patients With Preserved Ejection Fraction and the Impact of Angiotensin Receptor Blocker Treatment SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE angiotensin receptor blocker; HFpEF; prognosis; worsening renal function ID MYOCARDIAL-INFARCTION; BROAD-SPECTRUM; BLOOD-PRESSURE; BASE-LINE; SURVIVAL; EFFICACY; METAANALYSIS; DYSFUNCTION; INSIGHTS; THERAPY AB BACKGROUND Worsening renal function (WRF) associated with renin-angiotensin-aldosterone system (RAAS) inhibition does not confer excess risk in heart failure patients with reduced ejection fraction (HFrEF). OBJECTIVES The goal of this study was to investigate the relationship between WRF and outcomes in heart failure patients with preserved ejection fraction (HFpEF) and the interaction with RAAS blockade. METHODS In 3,595 patients included in the I-PRESERVE (Irbesartan in Heart Failure With Preserved Ejection Fraction) trial, change in estimated glomerular filtration rate (eGFR) and development of WRF after initiation of irbesartan or placebo were examined. We examined the association between WRF and the first occurrence of cardiovascular death or heart failure hospitalization (primary outcome in this analysis) and the interaction with randomized treatment. RESULTS Estimated GFR decreased early with irbesartan treatment and remained significantly lower than in the placebo group. WRF developed in 229 (6.4%) patients and occurred more frequently with irbesartan treatment (8% vs. 4%). Overall, WRF was associated with an increased risk of the primary outcome (adjusted hazard ratio [HR]: 1.43; 95% confidence interval [CI]: 1.10 to 1.85; p = 0.008). Although the risk related to WRF was greater in the irbesartan group (HR: 1.66; 95% CI: 1.21 to 2.28; p = 0.002) than with placebo (HR: 1.09; 95% CI: 0.66 to 1.79; p = 0.73), the interaction between treatment and WRF on outcome was not significant in an adjusted analysis. CONCLUSIONS The incidence of WRF in HFpEF was similar to that previously reported in HFrEF but more frequent with irbesartan than with placebo. WRF after initiation of irbesartan treatment in HFpEF was associated with excess risk, in contrast to WRF occurring with RAAS blockade in HFrEF. (c) 2014 by the American College of Cardiology Foundation. C1 [Damman, Kevin; Perez, Ana C.; McMurray, John J. V.] Univ Glasgow, British Heart Fdn, Inst Cardiovasc & Med Sci, Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Damman, Kevin] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Anand, Inder S.] Veterans Affairs Med Ctr, Minneapolis, MN USA. [Anand, Inder S.] Univ Minnesota, Minneapolis, MN USA. [Komajda, Michel] Univ Paris 06, Paris, France. [Komajda, Michel] Hop La Pitie Salpetriere, Paris, France. [McKelvie, Robert S.] McMaster Univ, Hamilton, ON, Canada. [Zile, Michael R.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Zile, Michael R.] Med Univ S Carolina, Charleston, SC 29425 USA. [Massie, Barrie] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Massie, Barrie] San Francisco VA Med Ctr, San Francisco, CA USA. [Carson, Peter E.] Georgetown Univ, Washington, DC USA. [Carson, Peter E.] Washington DC Vet Affairs Med Ctr, Washington, DC USA. RP Damman, K (reprint author), Univ Glasgow, British Heart Fdn, Inst Cardiovasc & Med Sci, Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. OI Perez Moreno, Ana Cristina/0000-0001-9265-6880; mcmurray, john/0000-0002-6317-3975 FU Netherlands Heart Institute (ICIN); European Society of Cardiology Heart Failure Association research grant; Bristol-Myers Squibb; Sanofi-Aventis; Merck Co.; Duke Clinical Research Institute; Momentum Research; Novartis; GlaxoSmithKline; Scias/Johnson Johnson; Corthera; Niles Therapeutics FX From the *British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom; dagger University of Groningen, Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands; double dagger Veterans Affairs Medical Center and University of Minnesota, Minneapolis, Minnesota; Universite Paris 6 and Pitie-Salpetriere Hospital, Paris, France; parallel to Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada; Ralph H. Johnson Veterans Affairs Medical Center and Medical University of South Carolina, Charleston, South Carolina; #University of California, San Francisco, and San Francisco Veterans Affairs Medical Center, San Francisco, California; and the **Georgetown University and Washington DC Veterans Affairs Medical Center, Washington, DC. Dr. Damman is supported by the Netherlands Heart Institute (ICIN) and a European Society of Cardiology Heart Failure Association research grant. Drs. Zile, Massie, Carson, Anand, McMurray, McKelvie, and Komajda have served as consultants and received honoraria from Bristol-Myers Squibb for their roles in conducting the I-PRESERVE trial, including serving on the coordinating committee, executive committee, and endpoint committee. Dr. Komajda has performed consulting/advisory activities for Servier, Menarini, Bristol-Myers Squibb, and AstraZeneca. Dr. Massie has received grant support from Bristol-Myers Squibb, Sanofi-Aventis, Merck & Co.; consulting fees from Bristol-Myers Squibb, Sanofi-Aventis, Merck & Co., Duke Clinical Research Institute, Momentum Research, Novartis, GlaxoSmithKline, Scias/Johnson & Johnson, Corthera, and Niles Therapeutics; and lecture fees from Merck & Co. Dr. Perez has reported that she has no relationships relevant to the contents of this paper to disclose. NR 22 TC 21 Z9 22 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 SEP 16 PY 2014 VL 64 IS 11 BP 1106 EP 1113 DI 10.1016/j.jacc.2014.01.087 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AO4GW UT WOS:000341295600006 PM 25212644 ER PT J AU Daskalakis, NP Cohen, H Cai, GQ Buxbaum, JD Yehuda, R AF Daskalakis, Nikolaos P. Cohen, Hagit Cai, Guiqing Buxbaum, Joseph D. Yehuda, Rachel TI Expression profiling associates blood and brain glucocorticoid receptor signaling with trauma-related individual differences in both sexes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE predator stress; transcription regulation; NR3C1; preventive treatment; psychiatry ID POSTTRAUMATIC-STRESS-DISORDER; HIGH-DOSE CORTICOSTERONE; GENE-EXPRESSION; SOCIAL DEFEAT; ANIMAL-MODELS; PTSD; MECHANISMS; SUSCEPTIBILITY; NEUROSCIENCE; BIOMARKERS AB Delineating the molecular basis of individual differences in the stress response is critical to understanding the pathophysiology and treatment of posttraumatic stress disorder (PTSD). In this study, 7 d after predator-scent-stress (PSS) exposure, male and female rats were classified into vulnerable (i.e., "PTSD-like") and resilient (i.e., minimally affected) phenotypes on the basis of their performance on a variety of behavioral measures. Genome-wide expression profiling in blood and two limbic brain regions (amygdala and hippocampus), followed by quantitative PCR validation, was performed in these two groups of animals, as well as in an unexposed control group. Differentially expressed genes were identified in blood and brain associated with PSS-exposure and with distinct behavioral profiles postexposure. There was a small but significant between-tissue overlap (4-21%) for the genes associated with exposure-related individual differences, indicating convergent gene expression in both sexes. To uncover convergent signaling pathways across tissue and sex, upstream activated/deactivated transcription factors were first predicted for each tissue and then the respective pathways were identified. Glucocorticoid receptor (GR) signaling was the only convergent pathway associated with individual differences when using the most stringent statistical threshold. Corticosterone treatment 1 h after PSS-exposure prevented anxiety and hyperarousal 7 d later in both sexes, confirming the GR involvement in the PSS behavioral response. In conclusion, genes and pathways associated with extreme differences in the traumatic stress behavioral response can be distinguished from those associated with trauma exposure. Blood-based biomarkers can predict aspects of brain signaling. GR signaling is a convergent signaling pathway, associated with trauma-related individual differences in both sexes. C1 [Daskalakis, Nikolaos P.; Cai, Guiqing; Buxbaum, Joseph D.; Yehuda, Rachel] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Cai, Guiqing; Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Buxbaum, Joseph D.; Yehuda, Rachel] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Daskalakis, Nikolaos P.; Yehuda, Rachel] James J Peters Vet Affairs Med Ctr, Mental Hlth Patient Care Ctr, Bronx, NY 10468 USA. [Cohen, Hagit] Ben Gurion Univ Negev, Anxiety & Stress Res Unit, Minist Hlth Mental Hlth Ctr, Fac Hlth Sci, IL-84170 Beer Sheva, Israel. RP Daskalakis, NP (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. EM nikolaos.daskalakis@mssm.edu RI Daskalakis, Nikolaos/B-7930-2014; OI Daskalakis, Nikolaos/0000-0003-1660-9112; Buxbaum, Joseph/0000-0001-8898-8313 FU Department of Defense [W81XWH-08-2-0021]; United States Army Medical Research and Materiel Command [W81XWH-13-1-0071] FX We thank Dr. Li Shen for advice on the bioinformatic analyses. This work was supported in part by Department of Defense Grant W81XWH-08-2-0021 (to R.Y.) and United States Army Medical Research and Materiel Command W81XWH-13-1-0071 (to R.Y.). NR 33 TC 20 Z9 20 U1 2 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 16 PY 2014 VL 111 IS 37 BP 13529 EP 13534 DI 10.1073/pnas.1401660111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO8UH UT WOS:000341630000067 PM 25114262 ER PT J AU Jirawatnotai, S Sharma, S Michowski, W Suktitipat, B Geng, Y Quackenbush, J Elias, JE Gygi, SP Wang, YYE Sicinski, P AF Jirawatnotai, Siwanon Sharma, Samanta Michowski, Wojciech Suktitipat, Bhoom Geng, Yan Quackenbush, John Elias, Joshua E. Gygi, Steven P. Wang, Yaoyu E. Sicinski, Piotr TI The cyclin D1-CDK4 oncogenic interactome enables identification of potential novel oncogenes and clinical prognosis SO CELL CYCLE LA English DT Article DE breast cancer; CDK4; cyclin D1; interactome; oncogenes; oncogenic signature ID NEGATIVE BREAST-CANCER; LARGE GENE LISTS; SIGNALING PATHWAY; TRANSGENIC MICE; D1; PROTEIN; CELLS; EXPRESSION; CDK4; PHOSPHORYLATION AB Overexpression of cyclin D1 and its catalytic partner, CDK4, is frequently seen in human cancers. We constructed cyclin D1 and CDK4 protein interaction network in a human breast cancer cell line MCF7, and identified novel CDK4 protein partners. Among CDK4 interactors we observed several proteins functioning in protein folding and in complex assembly. One of the novel partners of CDK4 is FKBP5, which we found to be required to maintain CDK4 levels in cancer cells. An integrative analysis of the extended cyclin D1 cancer interactome and somatic copy number alterations in human cancers identified BAIAPL21 as a potential novel human oncogene. We observed that in several human tumor types BAIAPL21 is expressed at higher levels as compared to normal tissue. Forced overexpression of BAIAPL21 augmented anchorage independent growth, increased colony formation by cancer cells and strongly enhanced the ability of cells to form tumors in vivo. Lastly, we derived an Aggregate Expression Score (AES), which quantifies the expression of all cyclin D1 interactors in a given tumor. We observed that AES has a prognostic value among patients with ER-positive breast cancers. These studies illustrate the utility of analyzing the interactomes of proteins involved in cancer to uncover potential oncogenes, or to allow better cancer prognosis. C1 [Jirawatnotai, Siwanon] Mahidol Univ, Siriraj Hosp, Fac Med, Dept Pharmacol, Bangkok 10700, Thailand. [Sharma, Samanta; Michowski, Wojciech; Geng, Yan; Sicinski, Piotr] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Sharma, Samanta; Michowski, Wojciech; Geng, Yan; Sicinski, Piotr] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Suktitipat, Bhoom] Mahidol Univ, Siriraj Hosp, Fac Med, Dept Biochem, Bangkok 10700, Thailand. [Quackenbush, John; Wang, Yaoyu E.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Ctr Canc Computat Biol, Boston, MA 02115 USA. [Elias, Joshua E.] Stanford Univ, Dept Chem & Syst Biol, Stanford, CA 94305 USA. [Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. RP Jirawatnotai, S (reprint author), Mahidol Univ, Siriraj Hosp, Fac Med, Dept Pharmacol, Bangkok 10700, Thailand. EM siwanon.jir@mahidol.ac.th; peter_sicinski@dfci.harvard.edu OI Suktitipat, Bhoom/0000-0001-8034-7757 FU Siriraj Research Development Fund; "Chalermphrakiat" Grant; Siriraj Foundation [D003421]; Faculty of Medicine Siriraj Hospital, Mahidol University; Thailand Research Fund [RSA5580018]; CCCB; Dana-Farber Strategic Plan Initiative; [R01 CA083688]; [P01 CA080111] FX This study was supported by Siriraj Research Development Fund and by R01 CA083688 and P01 CA080111 (to P.S.). S.J. is supported by "Chalermphrakiat" Grant and Siriraj Foundation D003421, Faculty of Medicine Siriraj Hospital, Mahidol University and the Thailand Research Fund RSA5580018. Y.E.W is supported through the CCCB and the Dana-Farber Strategic Plan Initiative. NR 49 TC 2 Z9 2 U1 1 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD SEP 15 PY 2014 VL 13 IS 18 BP 2889 EP 2900 DI 10.4161/15384101.2014.946850 PG 12 WC Cell Biology SC Cell Biology GA AZ6JI UT WOS:000348325800017 PM 25486477 ER PT J AU Lamming, DW AF Lamming, Dudley W. TI mTORC2 takes the longevity stAGE SO ONCOTARGET LA English DT Editorial Material ID INDUCED INSULIN-RESISTANCE; LIFE-SPAN; RAPAMYCIN; MICE C1 [Lamming, Dudley W.] Univ Wisconsin, Dept Med, Madison, WI 53718 USA. [Lamming, Dudley W.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Lamming, DW (reprint author), Univ Wisconsin, Dept Med, Madison, WI 53718 USA. EM dlamming@medicine.wisc.edu FU NIA NIH HHS [R00 AG041765] NR 9 TC 2 Z9 2 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 SEP 15 PY 2014 VL 5 IS 17 BP 7214 EP 7215 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ1XY UT WOS:000348029800002 PM 25294787 ER PT J AU Angin, M Sharma, S King, M Murooka, TT Ghebremichael, M Mempel, TR Walker, BD Bhasin, MK Addo, MM AF Angin, Mathieu Sharma, Siddhartha King, Melanie Murooka, Thomas T. Ghebremichael, Musie Mempel, Thorsten R. Walker, Bruce D. Bhasin, Manoj K. Addo, Marylyn M. TI HIV-1 Infection Impairs Regulatory T-Cell Suppressive Capacity on a Per-Cell Basis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE gene expression; HIV; immune activation; regulatory T cells; Tregs ID EXPRESSION; EXPANSION; BLOOD; FOXP3 AB The impact of CD4(+) regulatory T cells (Tregs) on human immunodeficiency virus type 1 (HIV-1) pathogenesis remains incompletely understood. Although it has been shown that Tregs can be infected with HIV-1, the consequences of infection on a per-cell basis are still unknown. In vitro HIV-GFP infected and noninfected Tregs were isolated by flow-based cell-sorting to investigate Treg suppressive capacity and gene expression profiles. Our data show that HIV-1-infected Tregs were significantly less suppressive than noninfected Tregs and demonstrated down-regulation of genes critical to Treg function. This impaired function may have detrimental consequences for the control of generalized immune activation and accelerate HIV disease progression. C1 [Angin, Mathieu; Sharma, Siddhartha; King, Melanie; Ghebremichael, Musie; Walker, Bruce D.; Addo, Marylyn M.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Bhasin, Manoj K.] Dana Farber Harvard Canc Ctr, BIDMC Genom & Prote Ctr, Boston, MA USA. [Murooka, Thomas T.; Mempel, Thorsten R.] Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Addo, Marylyn M.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Addo, Marylyn M.] Univ Klinikum Hamburg Eppendorf, Dept Med 1, D-20246 Hamburg, Germany. [Addo, Marylyn M.] Partner Site Hamburg Lubeck Borstel, German Ctr Infect Res DZIF, Hamburg, Germany. RP Addo, MM (reprint author), Univ Klinikum Hamburg Eppendorf, Med Klin & Poliklin 1, Martinistr 52, D-20246 Hamburg, Germany. EM m.addo@uke.de OI Angin, Mathieu/0000-0002-6867-4680 FU Elisabeth Glaser Pediatric AIDS Foundation (Pediatric HIV Vaccine Program Award) [MV-00-9-900-1429-0-00]; MGH/ECOR (Physician Scientist Development Award); NIH NIAID [KO8219 AI074405, AI074405-03S1]; Harvard University Center for AIDS Research (CFAR); NIH - NIH Co-Funding [P30 AI060354]; NIAID; NCI; NICHD; NHLBI; NIDA; NIH [R01 AI097052, R01 DA036298, P01 AI0178897]; Bill & Melinda Gates Foundation; Terry and Susan Ragon Foundation; Milton Fund; German Center for Infectious Diseases Research (DZIF) FX This work was supported in part by research funding from the Elisabeth Glaser Pediatric AIDS Foundation (Pediatric HIV Vaccine Program Award MV-00-9-900-1429-0-00 to M. M. A.), MGH/ECOR (Physician Scientist Development Award to M. M. A.), NIH NIAID (KO8219 AI074405 and AI074405-03S1 to M. M. A.), and the Harvard University Center for AIDS Research (CFAR), an NIH funded program (P30 AI060354) which is supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC, and OAR. T. R. M. and T. T. M. were supported by NIH grants R01 AI097052, R01 DA036298, and P01 AI0178897. These studies were furthermore supported by the Bill & Melinda Gates Foundation, the Terry and Susan Ragon Foundation, the Milton Fund, and the German Center for Infectious Diseases Research (DZIF). NR 15 TC 9 Z9 11 U1 2 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2014 VL 210 IS 6 BP 899 EP 903 DI 10.1093/infdis/jiu188 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0DW UT WOS:000344608300008 PM 24664171 ER PT J AU Kvaratskhelia, M Sharma, A Larue, RC Serrao, E Engelman, A AF Kvaratskhelia, Mamuka Sharma, Amit Larue, Ross C. Serrao, Erik Engelman, Alan TI Molecular mechanisms of retroviral integration site selection SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MURINE LEUKEMIA-VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; CELL GENE-THERAPY; TRANSCRIPTIONAL COACTIVATOR P75; CHRONIC GRANULOMATOUS-DISEASE; BET BROMODOMAIN INHIBITION; PAPILLOMAVIRUS E2 PROTEIN; WISKOTT-ALDRICH-SYNDROME; HIV-1 DNA INTEGRATION; VIRAL-DNA AB Retroviral replication proceeds through an obligate integrated DNA provirus, making retroviral vectors attractive vehicles for human gene-therapy. Though most of the host cell genome is available for integration, the process of integration site selection is not random. Retroviruses differ in their choice of chromatin-associated features and also prefer particular nucleotide sequences at the point of insertion. Lentiviruses including HIV-1 preferentially integrate within the bodies of active genes, whereas the prototypical gammaretrovirus Moloney murine leukemia virus (MoMLV) favors strong enhancers and active gene promoter regions. Integration is catalyzed by the viral integrase protein, and recent research has demonstrated that HIV-1 and MoMLV targeting preferences are in large part guided by integrase-interacting host factors (LEDGF/p75 for HIV-1 and BET proteins for MoMLV) that tether viral intasomes to chromatin. In each case, the selectivity of epigenetic marks on histones recognized by the protein tether helps to determine the integration distribution. In contrast, nucleotide preferences at integration sites seem to be governed by the ability for the integrase protein to locally bend the DNA duplex for pairwise insertion of the viral DNA ends. We discuss approaches to alter integration site selection that could potentially improve the safety of retroviral vectors in the clinic. C1 [Kvaratskhelia, Mamuka; Sharma, Amit; Larue, Ross C.] Ohio State Univ, Ctr Retrovirus Res, Columbus, OH 43210 USA. [Kvaratskhelia, Mamuka; Sharma, Amit; Larue, Ross C.] Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. [Serrao, Erik; Engelman, Alan] Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02215 USA. [Serrao, Erik; Engelman, Alan] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Engelman, A (reprint author), Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02215 USA. EM kvaratskhelia.1@osu.edu; alan_engelman@dfci.harvard.edu FU National Institutes of Health [AI062520, AI052014, GM103368]; Oxford University Press FX National Institutes of Health [AI062520 to M. K., AI052014 to A.E., GM103368 to M.K. and A.E.]. This article is a commissioned review and the open access publication charge has been waived by Oxford University Press. NR 185 TC 30 Z9 30 U1 1 U2 31 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP 15 PY 2014 VL 42 IS 16 BP 10209 EP U809 DI 10.1093/nar/gku769 PG 19 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT0TM UT WOS:000344647700008 PM 25147212 ER PT J AU Goel, G Conway, KL Jaeger, M Netea, MG Xavier, RJ AF Goel, Gautam Conway, Kara L. Jaeger, Martin Netea, Mihai G. Xavier, Ramnik J. TI Multivariate inference of pathway activity in host immunity and response to therapeutics SO NUCLEIC ACIDS RESEARCH LA English DT Article ID INTESTINAL EPITHELIAL-CELLS; INFLAMMATORY-BOWEL-DISEASE; GENE-EXPRESSION DATA; ULCERATIVE-COLITIS; COLONIC-MUCOSA; DIFFERENTIAL EXPRESSION; CANDIDA-ALBICANS; CROHNS-DISEASE; SET ANALYSIS; AUTOPHAGY AB Developing a quantitative view of how biological pathways are regulated in response to environmental factors is central for understanding of disease phenotypes. We present a computational framework, named Multivariate Inference of Pathway Activity (MIPA), which quantifies degree of activity induced in a biological pathway by computing five distinct measures from transcriptomic profiles of its member genes. Statistical significance of inferred activity is examined using multiple independent self-contained tests followed by a competitive analysis. The method incorporates a new algorithm to identify a subset of genes that may regulate the extent of activity induced in a pathway. We present an in-depth evaluation of specificity, robustness, and reproducibility of our method. We benchmarked MIPA's false positive rate at less than 1%. Using transcriptomic profiles representing distinct physiological and disease states, we illustrate applicability of our method in (i) identifying gene-gene interactions in autophagy-dependent response to Salmonella infection, (ii) uncovering gene-environment interactions in host response to bacterial and viral pathogens and (iii) identifying driver genes and processes that contribute to wound healing and response to anti-TNF alpha therapy. We provide relevant experimental validation that corroborates the accuracy and advantage of our method. C1 [Goel, Gautam; Conway, Kara L.; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Goel, Gautam; Conway, Kara L.; Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Goel, Gautam; Conway, Kara L.; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Goel, Gautam; Conway, Kara L.; Xavier, Ramnik J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Goel, Gautam; Conway, Kara L.; Xavier, Ramnik J.] Broad Inst Harvard Univ & Massachusetts Inst Tech, Cambridge, MA 02142 USA. [Jaeger, Martin; Netea, Mihai G.] Radboud Univ Nijmegen Med Ctr, Dept Internal Med, NL-6525 GA Nijmegen, Netherlands. [Jaeger, Martin; Netea, Mihai G.] Radboud Univ Nijmegen Med Ctr, Nijmegen Inst Infect Inflammat & Immun, NL-6525 GA Nijmegen, Netherlands. RP Xavier, RJ (reprint author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. EM ggoel@mgh.harvard.edu; xavier@molbio.mgh.harvard.edu RI Netea, Mihai/N-5155-2014; Jaeger, Martin/H-3359-2015 FU National Institutes of Health [DK043351, AI089992]; Leona M. and Harry B. Helmsley Charitable Trust; European Research Council [310372] FX National Institutes of Health [DK043351 and AI089992 to R.J.X.]; The Leona M. and Harry B. Helmsley Charitable Trust; European Research Council [310372 to M.G.N.]. Funding for open access charge: National Institutes of Health [AI089992 to R.J.X.]. NR 57 TC 3 Z9 3 U1 2 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP 15 PY 2014 VL 42 IS 16 BP 10288 EP U799 DI 10.1093/nar/gku722 PG 20 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT0TM UT WOS:000344647700014 PM 25147207 ER PT J AU Montemayor, EJ Katolik, A Clark, NE Taylor, AB Schuermann, JP Combs, DJ Johnsson, R Holloway, SP Stevens, SW Damha, MJ Hart, PJ AF Montemayor, Eric J. Katolik, Adam Clark, Nathaniel E. Taylor, Alexander B. Schuermann, Jonathan P. Combs, D. Joshua Johnsson, Richard Holloway, Stephen P. Stevens, Scott W. Damha, Masad J. Hart, P. John TI NAR Breakthrough Article Structural basis of lariat RNA recognition by the intron debranching enzyme Dbr1 SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SEDIMENTATION-VELOCITY EXPERIMENTS; STRAND-BREAK REPAIR; BRANCH POINT; NMR SYSTEM; TY1; RETROTRANSPOSITION; CRYSTALLOGRAPHY; RETROELEMENTS; MECHANISMS; INHIBITION AB The enzymatic processing of cellular RNA molecules requires selective recognition of unique chemical and topological features. The unusual 2',5'-phosphodiester linkages in RNA lariats produced by the spliceosome must be hydrolyzed by the intron debranching enzyme (Dbr1) before they can be metabolized or processed into essential cellular factors, such as snoRNA and miRNA. Dbr1 is also involved in the propagation of retrotransposons and retroviruses, although the precise role played by the enzyme in these processes is poorly understood. Here, we report the first structures of Dbr1 alone and in complex with several synthetic RNA compounds that mimic the branchpoint in lariat RNA. The structures, together with functional data on Dbr1 variants, reveal the molecular basis for 2',5'-phosphodiester recognition and explain why the enzyme lacks activity toward 3',5'-phosphodiester linkages. The findings illuminate structure/function relationships in a unique enzyme that is central to eukaryotic RNA metabolism and set the stage for the rational design of inhibitors that may represent novel therapeutic agents to treat retroviral infections and neurodegenerative disease. C1 [Montemayor, Eric J.; Clark, Nathaniel E.; Taylor, Alexander B.; Holloway, Stephen P.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Montemayor, Eric J.; Clark, Nathaniel E.; Taylor, Alexander B.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Xray Crystallog Core Lab, San Antonio, TX 78229 USA. [Katolik, Adam; Johnsson, Richard; Damha, Masad J.] McGill Univ, Dept Chem, Montreal, PQ H3A 0B8, Canada. [Schuermann, Jonathan P.] Cornell Univ, Dept Chem & Chem Biol, Northeastern Collaborat Access Team, Ithaca, NY 14853 USA. [Combs, D. Joshua] Univ Texas Austin, Program Cellular & Mol Biol, Austin, TX 78212 USA. [Stevens, Scott W.] Univ Texas Austin, Dept Mol Biosci, Austin, TX 78712 USA. [Stevens, Scott W.] Univ Texas Austin, Inst Cellular & Mol Biol, Austin, TX 78712 USA. [Hart, P. John] South Texas Vet Hlth Care Syst, Dept Vet Affairs, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. RP Hart, PJ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. EM scott.stevens@austin.utexas.edu; masad.damha@mcgill.ca; pjhart1@biochem.uthscsa.edu RI Johnsson, Richard/B-8954-2011 FU Robert A. Welch Foundation [AQ-1399]; Judith and Jean Pape Adams Charitable foundation; Barshop Institute for Longevity and Aging Studies [5 T32 AG021890]; National Science Foundation [DBI-0905865]; National Institutes of Health [NIH GM084246]; Swedish Research Council; National Science and Engineering Council of Canada Discovery Grant; National Cancer Institute P30 Cancer Center Support Grant [CA054174] FX Robert A. Welch Foundation [AQ-1399 to P.J.H.]; the Judith and Jean Pape Adams Charitable foundation [to P.J.H]; the Barshop Institute for Longevity and Aging Studies [5 T32 AG021890 to E.J.M. and N.E.C.]; National Science Foundation [DBI-0905865 to E.J.M.]; National Institutes of Health [NIH GM084246 to S.W.S.]; The Swedish Research Council [to R.J.]; National Science and Engineering Council of Canada Discovery Grant [to M.J.D.]. UTH-SCSA X-ray Crystallography Core Laboratory is provided by the Vice President for Research and the National Cancer Institute P30 Cancer Center Support Grant [CA054174] awarded to the Cancer Therapy Research Center at the University of Texas Health Science Center at San Antonio. NE-CAT beamline 24-ID-C is provided by the National Institute of Health [P41 GM103403] and Department of Energy [DE-AC02-06CH11357]. Source of open access funding: Robert A. Welch Foundation [AQ-1399 to P.J.H.]. NR 58 TC 10 Z9 10 U1 1 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP 15 PY 2014 VL 42 IS 16 BP 10845 EP 10855 DI 10.1093/nar/gku725 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT0TM UT WOS:000344647700057 PM 25123664 ER PT J AU Di Narzo, AF Kozlenkov, A Roussos, P Hao, K Hurd, Y Lewis, DA Sibille, E Siever, LJ Koonin, E Dracheva, S AF Di Narzo, Antonio Fabio Kozlenkov, Alexey Roussos, Panos Hao, Ke Hurd, Yasmin Lewis, David A. Sibille, Etienne Siever, Larry J. Koonin, Eugene Dracheva, Stella TI A unique gene expression signature associated with serotonin 2C receptor RNA editing in the prefrontal cortex and altered in suicide SO HUMAN MOLECULAR GENETICS LA English DT Article ID PRE-MESSENGER-RNA; MAJOR DEPRESSIVE DISORDER; DNA METHYLATION; 5-HT2C RECEPTORS; HUMAN BRAIN; CONSTITUTIVE ACTIVITY; NEURONAL CLASSES; TRANSCRIPTOME; MECHANISMS; ORGANIZATION AB Editing of the pre-mRNA for the serotonin receptor 2C (5-HT2CR) by site-specific adenosine deamination (A-to-I pre-mRNA editing) substantially increases the functional plasticity of this key neurotransmitter receptor and is thought to contribute to homeostatic mechanisms in neurons. 5-HT2CR mRNA editing generates up to 24 different receptor isoforms. The extent of editing correlates with 5-HT2CR functional activity: more highly edited isoforms exhibit the least function. Altered 5-HT2CR editing has been reported in postmortem brains of suicide victims. We report a comparative analysis of the connections among 5-HT2CR editing, genome-wide gene expression and DNA methylation in suicide victims, individuals with major depressive disorder and non-psychiatric controls. The results confirm previous findings of an overrepresentation of highly edited mRNA variants (which encode hypoactive 5-HT2CR receptors) in the brains of suicide victims. A large set of genes for which the expression level is associated with editing was detected. This signature set of editing-associated genes is significantly enriched for genes that are involved in synaptic transmission, genes that are preferentially expressed in neurons, and genes whose expression is correlated with the level of DNA methylation. Notably, we report that the link between 5-HT2CR editing and gene expression is disrupted in suicide victims. The results suggest that the postulated homeostatic function of 5-HT2CR editing is dysregulated in individuals who committed suicide. C1 [Di Narzo, Antonio Fabio; Roussos, Panos; Hao, Ke] Icahn Sch Med Mt Sinai, Friedman Brain Inst, Dept Genet & Genom Sci, New York, NY 10029 USA. [Kozlenkov, Alexey; Roussos, Panos; Hurd, Yasmin; Siever, Larry J.; Dracheva, Stella] Icahn Sch Med Mt Sinai, Friedman Brain Inst, Dept Psychiat, New York, NY 10029 USA. [Kozlenkov, Alexey; Roussos, Panos; Siever, Larry J.; Dracheva, Stella] James J Peters VA Med Ctr, Bronx, NY 10468 USA. [Lewis, David A.; Sibille, Etienne] Univ Pittsburgh, Dept Psychiat, Ctr Neurosci, Pittsburgh, PA USA. [Koonin, Eugene] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Dracheva, S (reprint author), James J Peters VA Med Ctr, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM stella.dracheva@mssm.edu RI Roussos, Panos/J-7090-2013 OI Roussos, Panos/0000-0002-4640-6239 FU VISN3 Mental Illness Research and Education Clinical Center (MIRECC), VA Merit Review Award [BX001829]; National Institute of Health [R21MH090352, R21DA031557, R01DA01 5446]; Hope for Depression Research Foundation grant; intramural funds of the US Department of Health and Human Services FX This work was funded by VISN3 Mental Illness Research and Education Clinical Center (MIRECC), VA Merit Review Award (BX001829 to S. D.); National Institute of Health (R21MH090352 and R21DA031557 to S. D.; and R01DA01 5446 to Y. H.); and Hope for Depression Research Foundation grant to S. D. E. V. K. is supported by intramural funds of the US Department of Health and Human Services to National Library of Medicine. NR 74 TC 7 Z9 7 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 SEP 15 PY 2014 VL 23 IS 18 BP 4801 EP 4813 DI 10.1093/hmg/ddu195 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AQ9OF UT WOS:000343184400005 PM 24781207 ER PT J AU Kopans, DB Webb, ML Cady, B AF Kopans, Daniel B. Webb, Matthew L. Cady, Blake TI The 20-Year Effort to Reduce Access to Mammography Screening Historical Facts Dispute a Commentary in Cancer SO CANCER LA English DT Editorial Material DE mammography; breast cancer; screening; mortality; cancer ID SWEDISH 2-COUNTY TRIAL; CARCINOMA IN-SITU; WOMEN 40-49 YEARS; BREAST-CANCER; MORTALITY REDUCTION; AGE; OVERDIAGNOSIS; SCIENCE; IMPACT; CONTROVERSY AB Mammography screening fulfills all requirements for an effective screening test. It detects many cancers earlier when they are at a smaller size and earlier stage, and it has been demonstrated that this reduces breast cancer deaths in randomized controlled trials. When screening is introduced into the population, the death rate from breast cancer declines. Nevertheless, scientifically unsupported arguments that appear in the medical literature are passed on to the public and continue to confuse women and physicians regarding the value of screening. Methodologically flawed challenges to mammography have been almost continuous since the 1990s. And, as each challenge has been invalidated, a new, specious challenge has been raised. The authors of this report address the long history of misinformation that has developed in the effort to reduce access to screening, and they address the issues raised by commentators concerning their recent publication in this journal. (C) 2014 American Cancer Society. C1 [Kopans, Daniel B.; Cady, Blake] Harvard Univ, Sch Med, Boston, MA USA. [Kopans, Daniel B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Webb, Matthew L.; Cady, Blake] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Webb, Matthew L.; Cady, Blake] Massachusetts Gen Hosp, Gillette Ctr Breast Canc, Boston, MA 02114 USA. [Cady, Blake] Cambridge Hosp, Cambridge Breast Ctr, Cambridge, MA 02139 USA. RP Cady, B (reprint author), 24 Walnut Pl, Brookline, MA 02445 USA. EM bcady123@comcast.net NR 73 TC 5 Z9 5 U1 0 U2 5 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 SEP 15 PY 2014 VL 120 IS 18 BP 2792 EP 2799 DI 10.1002/cncr.28791 PG 8 WC Oncology SC Oncology GA AQ2PM UT WOS:000342629700004 PM 24925233 ER PT J AU Fong, ZV Tanabe, KK AF Fong, Zhi Ven Tanabe, Kenneth K. TI The Clinical Management of Hepatocellular Carcinoma in the United States, Europe, and Asia A Comprehensive and Evidence-Based Comparison and Review SO CANCER LA English DT Review DE hepatocellular carcinoma; consensus guidelines; recommendations; review ID RANDOMIZED CONTROLLED-TRIAL; PORTAL-VEIN EMBOLIZATION; PERCUTANEOUS RADIOFREQUENCY ABLATION; PRESERVED LIVER-FUNCTION; SINGLE-AGENT SORAFENIB; LONG-TERM SURVIVAL; HEPATIC RESECTION; TRANSARTERIAL CHEMOEMBOLIZATION; ETHANOL INJECTION; SURGICAL RESECTION AB Hepatocellular carcinoma (HCC), the most common primary malignancy of the liver, represents 1 of the leading causes of cancer deaths in the world with an estimated 21,670 deaths in the United States in 2013. In contrast to other malignancies, there is an array of treatment options for HCC involving several specialties in the multidisciplinary care of the patient. Consequently, vast heterogeneity in management tendencies has been observed. The objective of this report was to review and compare guidelines on the management of HCC from the United States (National Comprehensive Cancer Network), Europe (European Association for the Study of the Liver-European Organization for Research and Treatment of Cancer), and Asia (consensus statement from the 2009 Asian Oncology Summit). By and large, all 3 guidelines are similar, with some variance in surveillance and treatment allocation recommendations because of regional differences in disease and other variables (diagnosis, staging systems) secondary to the lack of a concrete, high level of evidence. In contrast to other cancers, the geographic differences in tumor biology and resources make it impractical to have a globally universal guideline for all patients with HCC. Recommendations from the 3 groups are influenced by geographic differences in the prevalence and biology of the disease (ie, areas of increased hepatitis B prevalence) and available resources (organ availability for transplantation, finances, and accessibility to treatment). It is important for both physicians and policy makers to include these considerations when treating patients with HCC as well when structuring policies and guidelines. 2014 American Cancer Society. C1 [Fong, Zhi Ven; Tanabe, Kenneth K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Surg Oncol,Dept Surg, Boston, MA USA. RP Tanabe, KK (reprint author), 55 Fruit St, Boston, MA 02114 USA. EM ktanabe@partners.org FU UpToDate FX Dr. Tanabe reports personal fees from UpToDate. NR 135 TC 51 Z9 57 U1 5 U2 23 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 SEP 15 PY 2014 VL 120 IS 18 BP 2824 EP 2838 DI 10.1002/cncr.28730 PG 15 WC Oncology SC Oncology GA AQ2PM UT WOS:000342629700010 PM 24897995 ER PT J AU Webb, ML Cady, B Michaelson, JS Bush, DM Calvillo, KZ Kopans, DB Smith, BL AF Webb, Matthew L. Cady, Blake Michaelson, James S. Bush, Devon M. Calvillo, Katherina Zabicki Kopans, Daniel B. Smith, Barbara L. TI A Failure Analysis of Invasive Breast Cancer Most Deaths From Disease Occur in Women Not Regularly Screened SO CANCER LA English DT Article DE breast cancer; mortality; mammography; screening; cancer ID FOLLOW-UP; MORTALITY; MAMMOGRAPHY; CARCINOMA; IMPACT; US; REDUCTION; INSURANCE; INTERVAL; THERAPY AB BACKGROUND: Mortality reduction from mammographic screening is controversial. Individual randomized trials and meta-analyses demonstrate statistically significant mortality reductions in all age groups invited to screening. In women actually screened, mortality reductions are greater. Individual trials and meta-analyses show varying rates of mortality reduction, leading to questions about screening's value and whether treatment advances have diminished the importance of early detection. This study hypothesized that breast cancer deaths predominantly occurred in unscreened women. METHODS: Invasive breast cancers diagnosed between 1990 and 1999 were followed through 2007. Data included demographics, mammography use, surgical and pathology reports, and recurrence and death dates. Mammograms were categorized as screening or diagnostic based on absence or presence of breast signs or symptoms, and were substantiated by medical records. Breast cancer deaths were defined after documentation of prior distant metastases. Absence of recurrent cancer and lethal other diseases defined death from other causes. RESULTS: Invasive breast cancer failure analysis defined 7301 patients between 1990 and 1999, with 1705 documented deaths from breast cancer (n=609) or other causes (n=905). Among 609 confirmed breast cancer deaths, 29% were among women who had been screened (19% screen-detected and 10% interval cancers), whereas 71% were among unscreened women, including > 2 years since last mammogram (6%), or never screened (65%). Overall, 29% of cancer deaths were screened, whereas 71% were unscreened. Median age at diagnosis of fatal cancers was 49 years; in deaths not from breast cancer, median age at diagnosis was 72 years. CONCLUSIONS: Most deaths from breast cancer occur in unscreened women. To maximize mortality reduction and life-years gained, initiation of regular screening before age 50 years should be encouraged. (C) 2013 American Cancer Society. C1 [Webb, Matthew L.; Cady, Blake; Michaelson, James S.; Bush, Devon M.; Smith, Barbara L.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Webb, Matthew L.; Cady, Blake; Michaelson, James S.; Smith, Barbara L.] Massachusetts Gen Hosp, Gillette Ctr Breast Canc, Boston, MA 02114 USA. [Cady, Blake] Cambridge Hosp, Cambridge Breast Ctr, Cambridge, MA 02139 USA. [Cady, Blake; Calvillo, Katherina Zabicki; Kopans, Daniel B.; Smith, Barbara L.] Harvard Univ, Sch Med, Boston, MA USA. [Michaelson, James S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. [Calvillo, Katherina Zabicki] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Calvillo, Katherina Zabicki] Dana Farber Canc Inst, Breast Care Ctr, Boston, MA 02115 USA. [Kopans, Daniel B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. RP Cady, B (reprint author), 24 Walnut Pl, Brookline, MA 02445 USA. EM bcady123@comcast.net NR 44 TC 21 Z9 21 U1 2 U2 5 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 SEP 15 PY 2014 VL 120 IS 18 BP 2839 EP 2846 DI 10.1002/cncr.28199 PG 8 WC Oncology SC Oncology GA AQ2PM UT WOS:000342629700011 PM 24018987 ER PT J AU Webb, ML Kopans, DB Cady, B AF Webb, Matthew L. Kopans, Daniel B. Cady, Blake TI Reply to A Failure Analysis of Invasive Breast Cancer: Most Deaths From Disease Occur in Women Not Regularly Screened SO CANCER LA English DT Letter ID CARCINOMA MORTALITY; MAMMOGRAPHY; REDUCTION; OVERDIAGNOSIS C1 [Webb, Matthew L.] Massachusetts Gen Hosp, Dept Surg, Gillette Ctr Breast Canc, Breast Program, Boston, MA 02114 USA. [Kopans, Daniel B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Cady, Blake] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Breast Program,Dept Surg,Gillette Ctr Breast Canc, Boston, MA USA. [Cady, Blake] Cambridge Hosp, Breast Ctr, Cambridge Breast Ctr, Cambridge, MA 02139 USA. RP Webb, ML (reprint author), Massachusetts Gen Hosp, Dept Surg, Gillette Ctr Breast Canc, Breast Program, Boston, MA 02114 USA. NR 18 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD SEP 15 PY 2014 VL 120 IS 18 BP 2937 EP 2938 DI 10.1002/cncr.28525 PG 3 WC Oncology SC Oncology GA AQ2PM UT WOS:000342629700023 PM 24353038 ER PT J AU Coaxum, SD Blanton, MG Joyner, A Akter, T Bell, PD Luttrell, LM Raymond, JR Lee, MH Blichmann, PA Garnovskaya, MN Saigusa, T AF Coaxum, Sonya D. Blanton, Mary G. Joyner, Alisha Akter, Tanjina Bell, P. Darwin Luttrell, Louis M. Raymond, John R., Sr. Lee, Mi-Hye Blichmann, Paul A. Garnovskaya, Maria N. Saigusa, Takamitsu TI Epidermal growth factor-induced proliferation of collecting duct cells from Oak Ridge polycystic kidney mice involves activation of Na+/H+ exchanger SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE cytosensor microphysiometer; phosphorylation; polycystic kidney disease; AG1478 ID EPITHELIAL-CELLS; INTRACELLULAR PH; 5-HT1A RECEPTOR; EGF RECEPTOR; MUTANT MICE; DISEASE; KINASE; CILIA; PATHOGENESIS; EXPRESSION AB Epidermal growth factor (EGF) is linked to the pathogenesis of polycystic kidney disease (PKD). We explored signaling pathways activated by EGF in orpk cilia (-) collecting duct cell line derived from a mouse model of PKD (hypomorph of the Tg737/Ift88 gene) with severely stunted cilia, and in a control orpk cilia (+) cell line with normal cilia. RT-PCR demonstrated mRNAs for EGF receptor subunits ErbB1, ErbB2, ErbB3, ErbB4, and mRNAs for Na+/H+ exchangers (NHE), NHE-1, NHE-2, NHE-3, NHE-4, and NHE-5 in both cell lines. EGF stimulated proton efflux in both cell lines. This effect was significantly attenuated by MIA, 5-(n-methyl-N-isobutyl) amiloride, a selective inhibitor of NHE-1 and NHE-2, and orpk cilia (-) cells were more sensitive to MIA than control cells (P < 0.01). EGF significantly induced extracellular signal-regulated kinase (ERK) phosphorylation in both cilia (+) and cilia (-) cells (63.3 and 123.6%, respectively), but the effect was more pronounced in orpk cilia (-) cells (P < 0.01). MIA significantly attenuated EGF-induced ERK phosphorylation only in orpk cilia (-) cells (P < 0.01). EGF increased proliferation of orpk cilia (+) cells and orpk cilia (-) cells, respectively, and MIA at 1-5 mu M attenuated EGF-induced proliferation in orpk cilia (-) cells without affecting proliferation of orpk cilia (+) cells. EGF-induced proliferation of both cell lines was significantly decreased by the EGFR tyrosine kinase inhibitor AG1478 and MEK inhibitor PD98059. These results suggest that EGF exerts mitogenic effects in the orpk cilia (-) cells via activation of growth-associated amiloride-sensitive NHEs and ERK. C1 [Coaxum, Sonya D.; Blanton, Mary G.; Bell, P. Darwin; Blichmann, Paul A.; Garnovskaya, Maria N.; Saigusa, Takamitsu] Med Univ S Carolina, Dept Med, Div Nephrol, Charleston, SC 29425 USA. [Joyner, Alisha] Med Univ S Carolina, Coll Med, Charleston, SC 29425 USA. [Akter, Tanjina] Med Univ S Carolina, Dept Med, Div Rheumatol & Immunol, Charleston, SC 29425 USA. [Bell, P. Darwin] Ralph H Johnson VAMC, Med Serv, Charleston, SC USA. [Bell, P. Darwin] Ralph H Johnson VAMC, Res Serv, Charleston, SC USA. [Luttrell, Louis M.; Lee, Mi-Hye] Med Univ S Carolina, Dept Med, Div Endocrinol, Charleston, SC 29425 USA. [Raymond, John R., Sr.] Med Coll Wisconsin, Dept Med, Div Nephrol, Milwaukee, WI 53226 USA. [Raymond, John R., Sr.] Clement J Zablocki VA Med Ctr, Med Serv, Milwaukee, WI USA. RP Saigusa, T (reprint author), Med Univ S Carolina, Dept Med, Div Nephrol, Charleston, SC 29425 USA. EM saigusa@musc.edu FU National Institutes of Health [K01 HL-092606, R01 DK-52448]; Paul Teschan Research Fund of the Dialysis Clinic; Department of Veterans Affairs FX This work was supported by grants from the National Institutes of Health (K01 HL-092606 to S.D.C. and R01 DK-52448 to J.R.R.), the Paul Teschan Research Fund of the Dialysis Clinic (to S.D.C.), and the Department of Veterans Affairs (Merit Award to J.R.R., M.N.G., and P.D.B. and REAP Award to J.R.R. and M.N.G.). NR 41 TC 1 Z9 1 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 EI 1522-1563 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD SEP 15 PY 2014 VL 307 IS 6 BP C554 EP C560 DI 10.1152/ajpcell.00188.2014 PG 7 WC Cell Biology; Physiology SC Cell Biology; Physiology GA AP9AA UT WOS:000342369400007 PM 25055824 ER PT J AU Liu, Y Mallampalli, RK AF Liu, Yuan Mallampalli, Rama K. TI Decoding the Growth Advantage of Hypoxia-Sensitive Lung Cancer SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID UBIQUITIN LIGASE; DEGRADATION; PROTEIN C1 [Liu, Yuan; Mallampalli, Rama K.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Mallampalli, Rama K.] Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA USA. [Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA USA. RP Liu, Y (reprint author), Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. RI Liu, Yuan/B-4275-2015 FU BLRD VA [I01 BX002200]; NHLBI NIH HHS [UH2 HL123502, P01 HL114453, R01 HL081784, R01 HL096376, R01 HL097376, R01 HL098174] NR 15 TC 0 Z9 0 U1 0 U2 1 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 SEP 15 PY 2014 VL 190 IS 6 BP 603 EP 605 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AP7OM UT WOS:000342266600006 PM 25221878 ER PT J AU Haluska, P Menefee, M Plimack, ER Rosenberg, J Northfelt, D LaVallee, T Shi, L Yu, XQ Burke, P Huang, JQ Viner, J McDevitt, J LoRusso, P AF Haluska, Paul Menefee, Michael Plimack, Elizabeth R. Rosenberg, Jonathan Northfelt, Donald LaVallee, Theresa Shi, Li Yu, Xiang-Qing Burke, Patricia Huang, Jaiqi Viner, Jaye McDevitt, Jennifer LoRusso, Patricia TI Phase I Dose-Escalation Study of MEDI-573, a Bispecific, Antiligand Monoclonal Antibody against IGFI and IGFII, in Patients with Advanced Solid Tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; METASTATIC COLORECTAL-CANCER; BREAST-CANCER; BLADDER-CANCER; PROGNOSTIC-SIGNIFICANCE; PROGRESSION-FREE; PROSTATE-CANCER; CARCINOMA CELLS; ISOFORM-A; INSULIN AB Purpose: This phase I, multicenter, open-label, single-arm, dose-escalation, and dose-expansion study evaluated the safety, tolerability, and antitumor activity of MEDI-573 in adults with advanced solid tumors refractory to standard therapy or for which no standard therapy exists. Experimental Design: Patients received MEDI-573 in 1 of 5 cohorts (0.5, 1.5, 5, 10, or 15 mg/kg) dosed weekly or 1 of 2 cohorts (30 or 45 mg/kg) dosed every 3 weeks. Primary end points included the MEDI-573 safety profile, maximum tolerated dose (MTD), and optimal biologic dose (OBD). Secondary end points included MEDI-573 pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor activity. Results: In total, 43 patients (20 with urothelial cancer) received MEDI-573. No dose-limiting toxicities were identified, and only 1 patient experienced hyperglycemia related to treatment. Elevations in levels of insulin and/or growth hormone were not observed. Adverse events observed in >10% of patients included fatigue, anorexia, nausea, diarrhea, and anemia. PK evaluation demonstrated that levels of MEDI-573 increased with dose at all dose levels tested. At doses >5 mg/kg, circulating levels of insulin-like growth factor (IGF)-I and IGFII were fully suppressed. Of 39 patients evaluable for response, none experienced partial or complete response and 13 had stable disease as best response. Conclusions: The MTD of MEDI-573 was not reached. The OBD was 5 mg/kg weekly or 30 or 45 mg/kg every 3 weeks. MEDI-573 showed preliminary antitumor activity in a heavily pretreated population and had a favorable tolerability profile, with no notable perturbations in metabolic homeostasis. (C)2014 AACR. C1 [Haluska, Paul] Mayo Clin, Rochester, MN 55905 USA. [Menefee, Michael] Mayo Clin, Jacksonville, FL 32224 USA. [Plimack, Elizabeth R.] Temple Hlth, Fox Chase Canc Ctr, Philadelphia, PA USA. [Rosenberg, Jonathan] Dana Farber Canc Inst, Boston, MA 02115 USA. [Northfelt, Donald] Mayo Clin, Scottsdale, AZ USA. [LaVallee, Theresa; Shi, Li; Yu, Xiang-Qing; Burke, Patricia; Huang, Jaiqi; Viner, Jaye; McDevitt, Jennifer] MedImmune, Gaithersburg, MD USA. [LoRusso, Patricia] Barbara Ann Karmanos Canc Inst, Detroit, MO USA. RP Haluska, P (reprint author), Mayo Clin, 200 First St, Rochester, MN 55905 USA. EM haluska.paul@mayo.edu FU MedImmune FX This study was sponsored by MedImmune. Medical writing and editorial support were provided by Kristen W. Quinn, PhD, and Amy Zannikos, PharmD, of Peloton Advantage and were funded by MedImmune. No author received an honorarium or other form of financial support related to the development of this article. NR 55 TC 14 Z9 14 U1 0 U2 7 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 SEP 15 PY 2014 VL 20 IS 18 BP 4747 EP 4757 DI 10.1158/1078-0432.CCR-14-0114 PG 11 WC Oncology SC Oncology GA AP8VX UT WOS:000342358500004 PM 25024259 ER PT J AU Flavin, R Pettersson, A Hendrickson, WK Fiorentino, M Finn, S Kunz, L Judson, GL Lis, R Bailey, D Fiore, C Nuttall, E Martin, NE Stack, E Penney, KL Rider, JR Sinnott, J Sweeney, C Sesso, HD Fall, K Giovannucci, E Kantoff, P Stampfer, M Loda, M Mucci, LA AF Flavin, Richard Pettersson, Andreas Hendrickson, Whitney K. Fiorentino, Michelangelo Finn, Stephen Kunz, Lauren Judson, Gregory L. Lis, Rosina Bailey, Dyane Fiore, Christopher Nuttall, Elizabeth Martin, Neil E. Stack, Edward Penney, Kathryn L. Rider, Jennifer R. Sinnott, Jennifer Sweeney, Christopher Sesso, Howard D. Fall, Katja Giovannucci, Edward Kantoff, Philip Stampfer, Meir Loda, Massimo Mucci, Lorelei A. TI SPINK1 Protein Expression and Prostate Cancer Progression SO CLINICAL CANCER RESEARCH LA English DT Article ID ERG EXPRESSION; PSA RECURRENCE; PTEN; REARRANGEMENT; FUSION; IMMUNOHISTOCHEMISTRY; ASSOCIATION; TMPRSS2-ERG; PHYSICIANS; DELETION AB Purpose: SPINK1 overexpression has been described in prostate cancer and is linked with poor prognosis in many cancers. The objective of this study was to characterize the association between SPINK1 overexpression and prostate cancer-specific survival. Experimental Design: The study included 879 participants in the U. S. Physicians' Health Study and Health Professionals Follow-Up Study, diagnosed with prostate cancer (1983-2004) and treated by radical prostatectomy. Protein tumor expression of SPINK1 was evaluated by immunohistochemistry on tumor tissue microarrays. Results: Seventy-four of 879 (8%) prostate cancer tumors were SPINK1 positive. Immunohistochemical data were available for PTEN, p-Akt, pS6, stathmin, androgen receptor (AR), and ERG (as a measure of the TMPRSS2: ERG translocation). Compared with SPINK1-negative tumors, SPINK1-positive tumors showed higher PTEN and stathmin expression, and lower expression of AR (P < 0.01). SPINK1 overexpression was seen in 47 of 427 (11%) ERG-negative samples and in 19 of 427 (4%) ERG-positive cases (P = 0.0003). We found no significant associations between SPINK1 status and Gleason grade or tumor stage. There was no association between SPINK1 expression and biochemical recurrence (P = 0.56). Moreover, there was no association between SPINK1 expression and prostate cancer mortality (there were 75 lethal cases of prostate cancer during a mean of 13.5 years follow-up; HR = 0.71; 95% confidence interval, 0.29-1.76). Conclusions: Our results suggest that SPINK1 protein expression may not be a predictor of recurrence or lethal prostate cancer amongst men treated by radical prostatectomy. SPINK1 and ERG protein expression do not seem to be entirely mutually exclusive, as some previous studies have suggested. (C) 2014 AACR. C1 [Flavin, Richard; Fiorentino, Michelangelo; Finn, Stephen; Lis, Rosina; Bailey, Dyane; Fiore, Christopher; Stack, Edward; Loda, Massimo] Harvard Univ, Sch Publ Hlth, Ctr Mol Oncol Pathol, Cambridge, MA 02138 USA. [Sweeney, Christopher; Kantoff, Philip; Loda, Massimo] Harvard Univ, Sch Publ Hlth, Dept Med Oncol, Cambridge, MA 02138 USA. [Martin, Neil E.] Harvard Univ, Sch Publ Hlth, Dept Radiat Oncol, Dana Farber Canc Inst, Cambridge, MA 02138 USA. [Pettersson, Andreas; Hendrickson, Whitney K.; Kunz, Lauren; Judson, Gregory L.; Nuttall, Elizabeth; Penney, Kathryn L.; Rider, Jennifer R.; Sinnott, Jennifer; Fall, Katja; Giovannucci, Edward; Stampfer, Meir; Mucci, Lorelei A.] Harvard Univ, Sch Publ Hlth, Dept Med, Channing Div Network Med, Cambridge, MA 02138 USA. [Sesso, Howard D.] Harvard Univ, Sch Publ Hlth, Brigham & Womens Hosp, Div Prevent Med, Cambridge, MA 02138 USA. [Pettersson, Andreas; Hendrickson, Whitney K.; Kunz, Lauren; Judson, Gregory L.; Nuttall, Elizabeth; Penney, Kathryn L.; Rider, Jennifer R.; Sinnott, Jennifer; Fall, Katja; Giovannucci, Edward; Stampfer, Meir; Mucci, Lorelei A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Cambridge, MA 02138 USA. [Flavin, Richard; Finn, Stephen] St James Hosp, Dept Histopathol, Dublin 8, Ireland. [Flavin, Richard; Finn, Stephen] Univ Dublin Trinity Coll, Sch Med, Dublin 2, Ireland. RP Flavin, R (reprint author), St James Hosp, Dept Histopathol, Jamess St, Dublin 8, Ireland. EM rflavin@stjames.ie RI Martin, Neil/E-2193-2014; OI Martin, Neil/0000-0002-8164-8516; Rider, Jennifer/0000-0002-2637-6036; Finn, Stephen/0000-0002-8628-5814; Fall, Katja/0000-0002-3649-2639 FU Dana-Farber/Harvard Cancer Center Specialized Programs of Research Excellence [5P50CA090381-08]; National Cancer Institute [T32 CA009001, CA55075, CA141298, CA13389, CA34944, CA40360, CA097193, EDRN U01 CA113913, PO1 CA055075]; National Heart, Lung, and Blood Institute [HL26490, HL3595]; Prostate Cancer Foundation; Swedish Research Council [2009-7309]; Royal Physiographic Society in Lund FX This work was supported by the Dana-Farber/Harvard Cancer Center Specialized Programs of Research Excellence program in prostate cancer (5P50CA090381-08), the National Cancer Institute (T32 CA009001 to K. L. Penney, CA55075, CA141298, CA13389, CA34944, CA40360, CA097193, EDRN U01 CA113913, and PO1 CA055075), the National Heart, Lung, and Blood Institute (HL26490 and HL3595), the Prostate Cancer Foundation (to L. A. Mucci, N. E. Martin, and K. L. Penney), the Swedish Research Council (Reg. No. 2009-7309 to A. Pettersson), and the Royal Physiographic Society in Lund (to A. Pettersson). NR 24 TC 21 Z9 22 U1 0 U2 5 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 SEP 15 PY 2014 VL 20 IS 18 BP 4904 EP 4911 DI 10.1158/1078-0432.CCR-13-1341 PG 8 WC Oncology SC Oncology GA AP8VX UT WOS:000342358500019 PM 24687926 ER PT J AU Zhou, GL Na, SY Niedra, R Seed, B AF Zhou, Guo Ling Na, Soon-Young Niedra, Rasma Seed, Brian TI Deficits in receptor-mediated endocytosis and recycling in cells from mice with Gpr107 locus disruption SO JOURNAL OF CELL SCIENCE LA English DT Article DE GPR107; Embryonic lethality; Cubilin; Clathrin; Endocytosis ID EMBRYONIC STEM-CELLS; CUBILIN; MEGALIN; MOUSE; RETROMER; PROTEINS; LIPOPROTEIN; VITAMIN-D-3; METABOLISM; EXPRESSION AB GPR107 is a type III integral membrane protein that was initially predicted to be a member of the family of G-protein-coupled receptors. This report shows that deletion of Gpr107 leads to an embryonic lethal phenotype that is characterized by a reduction in cubilin transcript abundance and a decrease in the representation of multiple genes implicated in the cubilin-megalin endocytic receptor complex (megalin is also known as LRP2). Gpr107-null fibroblast cells exhibit reduced transferrin internalization, decreased uptake of low-density lipoprotein (LDL) receptor-related protein-1 (LRP1) cargo and resistance to toxins. Colocalization studies and proteomic analyses suggest that GPR107 associates with clathrin and the retromer protein VPS35 and that GPR107 might be responsible for the return of receptors to the plasma membrane from endocytic compartments. The highly selective deficits observed in Gpr107-null cells indicate that GPR107 interacts directly or indirectly with a limited subset of surface receptors. C1 [Zhou, Guo Ling; Na, Soon-Young; Niedra, Rasma; Seed, Brian] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Zhou, GL (reprint author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, 185 Cambridge St, Boston, MA 02114 USA. EM gzhou@ccib.mgh.harvard.edu; bseed@ccib.mgh.harvard.edu FU Massachusetts General Hospital FX This work was supported by Massachusetts General Hospital. NR 30 TC 2 Z9 2 U1 0 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD SEP 15 PY 2014 VL 127 IS 18 BP 3916 EP 3927 DI 10.1242/jcs.135269 PG 12 WC Cell Biology SC Cell Biology GA AP8VR UT WOS:000342357900006 PM 24849652 ER PT J AU Hagemann, AIH Kurz, J Kauffeld, S Chen, Q Reeves, PM Weber, S Schindler, S Davidson, G Kirchhausen, T Scholpp, S AF Hagemann, Anja I. H. Kurz, Jennifer Kauffeld, Silke Chen, Qing Reeves, Patrick M. Weber, Sabrina Schindler, Simone Davidson, Gary Kirchhausen, Tomas Scholpp, Steffen TI In vivo analysis of formation and endocytosis of the Wnt/beta-Catenin signaling complex in zebrafish embryos SO JOURNAL OF CELL SCIENCE LA English DT Article DE Wnt signaling; Development; Endocytosis; Signalosome; Zebrafish ID CLATHRIN AP-2 ADAPTER; PLANAR CELL POLARITY; BETA-CATENIN; LRP6 SIGNALOSOMES; PLASMA-MEMBRANE; INTERNALIZATION; WINGLESS; DISTINCT; XENOPUS; ACTIVATION AB After activation by Wnt/beta-Catenin ligands, a multi-protein complex assembles at the clustering membrane-bound receptors and intracellular signal transducers into the so-called Lrp6-signalosome. However, the mechanism of signalosome formation and dissolution is yet not clear. Our imaging studies of live zebrafish embryos show that the signalosome is a highly dynamic structure. It is continuously assembled by Dvl2-mediated recruitment of the transducer complex to the activated receptors and partially disassembled by endocytosis. We find that, after internalization, the ligand-receptor complex and the transducer complex take separate routes. The Wnt-Fz-Lrp6 complex follows a Rab-positive endocytic path. However, when still bound to the transducer complex, Dvl2 forms intracellular aggregates. We show that this endocytic process is not only essential for ligand-receptor internalization but also for signaling. The mu 2-subunit of the endocytic Clathrin adaptor Ap2 interacts with Dvl2 to maintain its stability during endocytosis. Blockage of Ap2 mu 2 function leads to Dvl2 degradation, inhibiton of signalosome formation at the plasma membrane and, consequently, reduction of signaling. We conclude that Ap2 mu 2-mediated endocytosis is important to maintain Wnt/beta-catenin signaling in vertebrates. C1 [Hagemann, Anja I. H.; Kurz, Jennifer; Kauffeld, Silke; Chen, Qing; Weber, Sabrina; Schindler, Simone; Davidson, Gary; Scholpp, Steffen] Karlsruhe Inst Technol, Inst Toxicol & Genet, D-76021 Karlsruhe, Germany. [Reeves, Patrick M.; Kirchhausen, Tomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Reeves, Patrick M.; Kirchhausen, Tomas] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Reeves, Patrick M.; Kirchhausen, Tomas] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. RP Scholpp, S (reprint author), Karlsruhe Inst Technol, Inst Toxicol & Genet, D-76021 Karlsruhe, Germany. EM steffen.scholpp@kit.edu RI Scholpp, Steffen/H-2060-2013; Davidson, Gary/J-6059-2013; OI Scholpp, Steffen/0000-0002-4903-9657; Schindler, Simone/0000-0003-1028-3115 FU DFG Emmy Noether fellowship [847/2]; DFG Wnt research group [DFG FOR 1036]; National Institutes of Health [GM-075252] FX A.I.H.H., J.K., S.K., S.W. and S.S. were supported by the DFG Emmy Noether fellowship 847/2 and the and the DFG Wnt research group DFG FOR 1036. P.R. and T.K. are supported by the National Institutes of Health [grant numbers GM-075252]. Deposited in PMC for immediate release. NR 57 TC 13 Z9 14 U1 0 U2 10 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD SEP 15 PY 2014 VL 127 IS 18 BP 3970 EP 3982 DI 10.1242/jcs.148767 PG 13 WC Cell Biology SC Cell Biology GA AP8VR UT WOS:000342357900010 PM 25074807 ER PT J AU Liu, N Guo, XH Chen, ZQ Qi, Q Shi, W Guo, ZQ Zeng, Y Sun, CG Liu, ZJ AF Liu, Ning Guo, Xinhu Chen, Zhongqiang Qi, Qiang Shi, Wei Guo, Zhaoqing Zeng, Yan Sun, Chuiguo Liu, Zhongjun TI Radiological Signs of Scheuermann Disease and Low Back Pain Retrospective Categorization of 188 Hospital Staff Members With 6-Year Follow-up SO SPINE LA English DT Article DE Scheuermann disease; atypical Scheuermann disease; lumbar Scheuermann disease; low back pain; lumbar spine; magnetic resonance imaging; Schmorl node; irregular endplate; wedged vertebra; hospital ID FOLLOW-UP; LUMBAR SCHEUERMANN; DISC-DEGENERATION; RISK-FACTORS; KYPHOSIS; SPINE; PREVALENCE; INJURIES; HISTORY; TWINS AB Study Design. Retrospective cohort study. Objective. To investigate the relationship between radiological signs of Scheuermann disease (SD) and low back pain (LBP) in a local population using lumbar magnetic resonance (MR) images. Summary of Background Data. SD is a spinal disorder, and both its classic and atypical (lumbar) forms are associated with LBP. However, radiological signs of SD are present in 18% to 40% of the general population, in whom the clinical significance of "SD-like" spine remains largely unknown. Methods. This retrospective cohort study included 188 staff members from a single hospital. Participants' lumbar MR images and self-administered questionnaires concerning demographic information, LBP status, consequences, and functional limitations were collected. Participants were classified into 2 groups according to whether lumbar MR images met SD diagnostic criteria, and LBP status, consequences, and functional limitation were compared. Follow-up interviews were conducted after 6 years to compare LBP progression. Results. Thirty-four participants (18.1%) had SD-like spine. Rates of lifetime, previous 1-year, and point LBP did not significantly differ between groups. However, among participants who had ever had LBP, SD-like spine was associated with higher rates of work absence (42.1% vs. 9.5%, chi(2) = 9.620, P = 0.002) and seeking medical care (68.4% vs. 39.2%, chi(2) = 5.216, P = 0.022) due to LBP, as well as significantly greater intensity of the most severe LBP episode in the past 2 years (6.4 +/- 2.5 vs. 4.1 +/- 2.5, t = 3.564, P = 0.001). Among the 159 participants who completed the 6-year follow-up, a significantly higher proportion of people with SD-like spine reported aggravated LBP during the follow-up. Conclusion. Our results suggest that in the general population, lumbar MR images of many people meet SD diagnostic criteria, and having SD-like spine seemed to be associated with the severity and progressive nature of LBP. Our findings should inspire further research in this field. C1 [Liu, Ning; Guo, Xinhu; Chen, Zhongqiang; Qi, Qiang; Shi, Wei; Guo, Zhaoqing; Zeng, Yan; Sun, Chuiguo; Liu, Zhongjun] Peking Univ, Dept Orthopaed, Hosp 3, Beijing 100191, Peoples R China. [Liu, Ning] Massachusetts Gen Hosp, Dept Orthopaed Surg, Spine Serv, Boston, MA 02114 USA. RP Chen, ZQ (reprint author), Peking Univ, Dept Orthopaed, Hosp 3, 49 North Garden Rd, Beijing 100191, Peoples R China. EM zhongqiang_chen@yahoo.com FU AOSpine China Research Grant FX 2013 AOSpine China Research Grant was received to support this work. NR 42 TC 1 Z9 1 U1 4 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD SEP 15 PY 2014 VL 39 IS 20 BP 1666 EP 1675 DI 10.1097/BRS.0000000000000479 PG 10 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA AP4EU UT WOS:000342030800012 PM 24979145 ER PT J AU Yeo, S Choe, IH Van den Noort, M Bosch, P Jahng, GH Rosen, B Kim, SH Lim, S AF Yeo, Sujung Choe, Il-Hwan Van den Noort, Maurits Bosch, Peggy Jahng, Geon-Ho Rosen, Bruce Kim, Sung-Hoon Lim, Sabina TI Acupuncture on GB34 activates the precentral gyrus and prefrontal cortex in Parkinson's disease SO BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE LA English DT Article DE Functional magnetic resonance imaging; Parkinson's; Healthy; Patient ID MOTOR CORTEX; MOUSE MODEL; ELECTROACUPUNCTURE STIMULATION; ALTERNATIVE THERAPIES; NEURONAL SPECIFICITY; FUNCTIONAL MRI; FMRI; BRAIN; MOVEMENT; TASK AB Background: Acupuncture is increasingly used as an additional treatment for patients with Parkinson's disease (PD). Methods: In this functional magnetic resonance imaging study, brain activation in response to acupuncture in a group of 12 patients with PD was compared with a group of 12 healthy participants. Acupuncture was conducted on a specific acupoint, the right GB 34 (Yanglingquan), which is a frequently used acupoint for motor function treatment in the oriental medical field. Results: Acupuncture stimulation on this acupoint activates the prefrontal cortex, precentral gyrus, and putamen in patients with PD; areas that are known to be impaired in patients with PD. Compared with healthy participants, patients with PD showed significantly higher brain activity in the prefrontal cortex and precentral gyrus, especially visible in the left hemisphere. Conclusions: The neuroimaging results of our study suggest that in future acupuncture research; the prefrontal cortex as well as the precentral gyrus should be treated for symptoms of Parkinson's disease and that GB 34 seems to be a suitable acupoint. Moreover, acupuncture evoked different brain activations in patients with Parkinson's disease than in healthy participants in our study, stressing the importance of conducting acupuncture studies on both healthy participants as well as patients within the same study, in order to detect acupuncture efficacy. C1 [Yeo, Sujung; Choe, Il-Hwan; Lim, Sabina] Kyung Hee Univ, WHO Collaborating Ctr, Neurosci WHO Collaborating Ctr East, Res Grp Pain & Neurosci, Seoul, South Korea. [Yeo, Sujung; Choe, Il-Hwan; Kim, Sung-Hoon; Lim, Sabina] Kyung Hee Univ, Coll Oriental Med, Seoul, South Korea. [Van den Noort, Maurits] Univ Libre Brussels, Brussels, Belgium. [Bosch, Peggy] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behaviour, NL-6525 ED Nijmegen, Netherlands. [Jahng, Geon-Ho] Kyung Hee Univ, Coll Med, Seoul, South Korea. [Rosen, Bruce] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula Martinos Ctr Biomed Imaging,Dept Radiol, Boston, MA USA. RP Lim, S (reprint author), Kyung Hee Univ, WHO Collaborating Ctr, Neurosci WHO Collaborating Ctr East, Res Grp Pain & Neurosci, Seoul, South Korea. EM lims@khu.ac.kr FU Ministry of Health and Welfare, Republic of Korea [B080049]; National Research Foundation of Korea (NRF) - Korea government [2007-0054931, NRF-2014R1A1A1004100] FX This study was supported by the Ministry of Health and Welfare, Republic of Korea (Oriental Medicine R&D Project, B080049) and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (No. 2007-0054931, NRF-2014R1A1A1004100). NR 70 TC 9 Z9 10 U1 2 U2 20 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6882 J9 BMC COMPLEM ALTERN M JI BMC Complement. Altern. Med. PD SEP 15 PY 2014 VL 14 AR 336 DI 10.1186/1472-6882-14-336 PG 9 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA AP5FK UT WOS:000342104900001 PM 25220656 ER PT J AU Vriz, O Aboyans, V D'Andrea, A Ferrara, F Acri, E Limongelli, G Della Corte, A Driussi, C Bettio, M Pluchinotta, FR Citro, R Russo, MG Isselbacher, E Bossone, E AF Vriz, Olga Aboyans, Victor D'Andrea, Antonello Ferrara, Francesco Acri, Edvige Limongelli, Giuseppe Della Corte, Alessandro Driussi, Caterina Bettio, Manola Pluchinotta, Francesca R. Citro, Rodolfo Russo, Maria Giovanna Isselbacher, Eric Bossone, Eduardo TI Normal Values of Aortic Root Dimensions in Healthy Adults SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID EUROPEAN-SOCIETY; BODY-SIZE; RECOMMENDATIONS; AGE; ECHOCARDIOGRAPHY; CARDIOLOGY; ANATOMY; WEIGHT; VALVE AB The reported ranges of aortic root (AR) diameters are limited by small sample size, different measurement sites, and heterogeneous cohorts. The aim of this study was to explore the full spectrum of AR diameters by 2-dimensional transthoracic color Doppler echocardiography (TTE) in a large cohort of healthy adults. From June 2007 to December 2013, a total of 1,043 Caucasian healthy volunteers (mean age 44.7 +/- 15.9 years, range 16 to 92 years, 503 men [48%]) underwent comprehensive TTE. TTE measurements of the AR were made at end-diastole in parasternal long-axis views at 4 levels: (1) annulus, (2) sinuses of Valsalva, (3) sinotubular junction, and (4) proximal ascending aorta. The absolute aortic diameters were significantly greater in men than in women at all levels, whereas body surface area indexed aortic diameters were greater in women (p = 0.0001). No significant gender differences were registered for sinuses of Valsalva and sinotubular junction to annulus diameter ratios (p = 0.9), whereas ascending aorta to annulus diameter ratio was higher in women (p = 0.0001). There was a straight correlation between aortic diameters (absolute and indexed values), their ratios, and age in both genders (p = 0.0001). In conclusion, we provide the full range of AR diameters by TTE. Knowledge of upper physiological limits of aortic dimensions is mandatory to detect aorta dilatation, follow up the disease over time, and plan appropriate therapeutic interventions. (C) 2014 Elsevier Inc. All rights reserved. C1 [Vriz, Olga; Bettio, Manola] San Antonio Hosp, Cardiol & Emergency Dept, Udine, Italy. [Aboyans, Victor] Dupuytren Univ Hosp, Dept Cardiol, Limoges, France. [D'Andrea, Antonello; Limongelli, Giuseppe; Russo, Maria Giovanna] Univ Naples 2, Dept Cardiol, Naples, Italy. [Della Corte, Alessandro] Univ Naples 2, Dept Cardiovasc Surg & Transplant, Naples, Italy. [Ferrara, Francesco; Citro, Rodolfo; Bossone, Eduardo] Univ Hosp, Heart Dept, Salerno, Italy. [Acri, Edvige] Univ Messina, Clin Expt Dept Med & Pharmacol, Messina, Italy. [Driussi, Caterina] Univ Udine, Sch Sports Med, I-33100 Udine, Italy. [Pluchinotta, Francesca R.] IRCCS Policlin San Donato, Dept Cardiac Surg, Milan, Italy. [Isselbacher, Eric] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Bossone, E (reprint author), Univ Hosp, Heart Dept, Salerno, Italy. EM ebossone@hotmail.com RI Della Corte, Alessandro/K-9383-2016; OI Della Corte, Alessandro/0000-0002-4636-3339; Pluchinotta, Francesca Romana/0000-0001-7185-7157; LImongelli, Giuseppe/0000-0002-8291-9517; RUSSO, Maria Giovanna/0000-0003-3860-6158; Aboyans, Victor/0000-0002-0322-9818 NR 17 TC 10 Z9 11 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 15 PY 2014 VL 114 IS 6 BP 921 EP 927 DI 10.1016/j.amjcard.2014.06.028 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AP0JF UT WOS:000341746900018 PM 25108304 ER PT J AU Hooijman, PE Paul, MA Stienen, GJM Beishuizen, A Van Hees, HWH Singhal, S Bashir, M Budak, MT Morgen, J Barsotti, RJ Levine, S Ottenheijm, CAC AF Hooijman, Pleuni E. Paul, Marinus A. Stienen, Ger J. M. Beishuizen, Albertus Van Hees, Hieronymus W. H. Singhal, Sunil Bashir, Muhammad Budak, Murat T. Morgen, Jacqueline Barsotti, Robert J. Levine, Sanford Ottenheijm, Coen A. C. TI Unaffected contractility of diaphragm muscle fibers in humans on mechanical ventilation SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE diaphragm; single muscle fiber; contractility; mechanical ventilation ID OBSTRUCTIVE PULMONARY-DISEASE; RAT DIAPHRAGM; FORCE GENERATION; DYSFUNCTION; WEAKNESS; ATROPHY; INACTIVITY; DISUSE; TITIN; MYOPATHY AB Several studies have indicated that diaphragm dysfunction develops in patients on mechanical ventilation (MV). Here, we tested the hypothesis that the contractility of sarcomeres, i.e., the smallest contractile unit in muscle, is affected in humans on MV. To this end, we compared diaphragm muscle fibers of nine brain-dead organ donors (cases) that had been on MV for 26 +/- 5 h with diaphragm muscle fibers from nine patients (controls) undergoing surgery for lung cancer that had been on MV for less than 2 h. In each diaphragm specimen we determined 1) muscle fiber cross-sectional area in cryosections by immunohistochemical methods and 2) the contractile performance of permeabilized single muscle fibers by means of maximum specific force, kinetics of cross-bridge cycling by rate of tension redevelopment, myosin heavy chain content and concentration, and calcium sensitivity of force of slow-twitch and fast-twitch muscle fibers. In case subjects, we noted no statistically significant decrease in outcomes compared with controls in slow-twitch or fast-twitch muscle fibers. These observations indicate that 26 h of MV of humans is not invariably associated with changes in the contractile performance of sarcomeres in the diaphragm. C1 [Hooijman, Pleuni E.; Stienen, Ger J. M.; Ottenheijm, Coen A. C.] Vrije Univ Amsterdam, Med Ctr, Dept Physiol, Amsterdam, Netherlands. [Paul, Marinus A.] Vrije Univ Amsterdam, Med Ctr, Dept Cardiothorac Surg, Amsterdam, Netherlands. [Beishuizen, Albertus] Vrije Univ Amsterdam, Med Ctr, Dept Intens Care, Amsterdam, Netherlands. [Stienen, Ger J. M.] Vrije Univ Amsterdam, Fac Sci, Dept Phys & Astron, Amsterdam, Netherlands. [Van Hees, Hieronymus W. H.] Radboud Univ Nijmegen, Med Ctr, Dept Pulm Dis, NL-6525 ED Nijmegen, Netherlands. [Singhal, Sunil; Bashir, Muhammad; Budak, Murat T.; Morgen, Jacqueline; Levine, Sanford] Univ Penn, Dept Surg, Philadelphia, PA 19104 USA. [Singhal, Sunil; Bashir, Muhammad; Budak, Murat T.; Morgen, Jacqueline; Levine, Sanford] Vet Affairs Med Ctr, Philadelphia, PA USA. [Barsotti, Robert J.] Philadelphia Coll Osteopath Med, Dept Physiol, Philadelphia, PA USA. [Levine, Sanford] Gift Life Donor Program, Philadelphia, PA USA. [Ottenheijm, Coen A. C.] Univ Arizona, Dept Cellular & Mol Med, Tucson, AZ 85721 USA. RP Ottenheijm, CAC (reprint author), Univ Arizona, Dept Cellular & Mol Med, Tucson, AZ 85721 USA. EM coeno@email.arizona.edu RI van Hees, Jeroen HWH/A-1276-2011 FU VIDI grant from the Netherlands Foundation for Scientific Research; National Heart, Lung, and Blood Institute (NHLBI) [HL-121500, HL-078834] FX C. A. C. Ottenheijm was supported by a VIDI grant from the Netherlands Foundation for Scientific Research and National Heart, Lung, and Blood Institute (NHLBI) Grant HL-121500. S. Levine was supported by NHLBI Grant HL-078834. NR 39 TC 6 Z9 6 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 EI 1522-1504 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD SEP 15 PY 2014 VL 307 IS 6 BP L460 EP L470 DI 10.1152/ajplung.00076.2014 PG 11 WC Physiology; Respiratory System SC Physiology; Respiratory System GA AO9VO UT WOS:000341707400004 PM 25038190 ER PT J AU John, J Kodama, T Siegel, JM AF John, Joshi Kodama, Tohru Siegel, Jerome M. TI Caffeine promotes glutamate and histamine release in the posterior hypothalamus SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE microdialysis; sleep; histamine; glutamate; caffeine ID ADENOSINE A(2A) RECEPTORS; TUBEROMAMMILLARY NUCLEUS; PSYCHOMOTOR PERFORMANCE; GABA RELEASE; SLEEP; RAT; NEURONS; BRAIN; WAKEFULNESS; ACTIVATION AB Histamine neurons are active during waking and largely inactive during sleep, with minimal activity during rapid-eye movement (REM) sleep. Caffeine, the most widely used stimulant, causes a significant increase of sleep onset latency in rats and humans. We hypothesized that caffeine increases glutamate release in the posterior hypothalamus (PH) and produces increased activity of wake-active histamine neurons. Using in vivo microdialysis, we collected samples from the PH after caffeine administration in freely behaving rats. HPLC analysis and biosensor measurements showed a significant increase in glutamate levels beginning 30 min after caffeine administration. Glutamate levels remained elevated for at least 140 min. GABA levels did not significantly change over the same time period. Histamine level significantly increased beginning 30 min after caffeine administration and remained elevated for at least 140 min. Immunostaining showed a significantly elevated number of c-Fos-labeled histamine neurons in caffeine-treated rats compared with saline-treated animals. We conclude that increased glutamate levels in the PH activate histamine neurons and contribute to caffeine-induced waking and alertness. C1 [John, Joshi; Siegel, Jerome M.] Univ Calif Los Angeles, Inst Neuropsychiat, VA Greater Los Angeles Hlthcare Syst, North Hills, CA 91343 USA. [John, Joshi; Siegel, Jerome M.] Univ Calif Los Angeles, Brain Res Inst, North Hills, CA 91343 USA. [Kodama, Tohru] Tokyo Metropolitan Inst Med Sci, Dept Physiol & Psychol, Tokyo 113, Japan. RP John, J (reprint author), Univ Calif Los Angeles, Inst Neuropsychiat, VA Greater Los Angeles Hlthcare Syst, North Hills, CA 91343 USA. EM jjohn@ucla.edu FU Medical Research Service of the Dept. of Veterans Affairs; National Institutes of Health [NS-14610, MH-064109] FX This study was supported by the Medical Research Service of the Dept. of Veterans Affairs, and National Institutes of Health Grants NS-14610 and MH-064109. NR 47 TC 3 Z9 4 U1 1 U2 22 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 EI 1522-1490 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD SEP 15 PY 2014 VL 307 IS 6 BP R704 EP R710 DI 10.1152/ajpregu.00114.2014 PG 7 WC Physiology SC Physiology GA AO9TN UT WOS:000341700300013 PM 25031227 ER PT J AU Jabaji, Z Brinkley, GJ Khalil, HA Sears, CM Lei, NY Lewis, M Stelzner, M Martin, MG Dunn, JCY AF Jabaji, Ziyad Brinkley, Garrett J. Khalil, Hassan A. Sears, Connie M. Lei, Nan Ye Lewis, Michael Stelzner, Matthias Martin, Martin G. Dunn, James C. Y. TI Type I Collagen as an Extracellular Matrix for the In Vitro Growth of Human Small Intestinal Epithelium SO PLOS ONE LA English DT Article ID BASEMENT-MEMBRANE MATRIX; STEM-CELLS; ALKALINE-PHOSPHATASE; BIOLOGICAL-ACTIVITY; CULTURE; EXPANSION; NICHE; MODEL AB Background: We previously reported in vitro maintenance and proliferation of human small intestinal epithelium using Matrigel, a proprietary basement membrane product. There are concerns over the applicability of Matrigel-based methods for future human therapies. We investigated type I collagen as an alternative for the culture of human intestinal epithelial cells. Methods: Human small intestine was procured from fresh surgical pathology specimens. Small intestinal crypts were isolated using EDTA chelation. Intestinal subepithelial myofibroblasts were isolated from a pediatric sample and expanded in vitro. After suspension in Matrigel or type I collagen gel, crypts were co-cultured above a confluent layer of myofibroblasts. Crypts were also grown in monoculture with exposure to myofibroblast conditioned media; these were subsequently sub-cultured in vitro and expanded with a 1:2 split ratio. Cultures were assessed with light microscopy, RTPCR, histology, and immunohistochemistry. Results: Collagen supported viable human epithelium in vitro for at least one month in primary culture. Sub-cultured epithelium expanded through 12 passages over 60 days. Histologic sections revealed polarized columnar cells, with apical brush borders and basolaterally located nuclei. Collagen-based cultures gave rise to monolayer epithelial sheets at the gel-liquid interface, which were not observed with Matrigel. Immunohistochemical staining identified markers of differentiated intestinal epithelium and myofibroblasts. RT-PCR demonstrated expression of alpha-smooth muscle actin and vimentin in myofibroblasts and E-Cadherin, CDX2, villin 1, intestinal alkaline phosphatase, chromogranin A, lysozyme, and Lgr5 in epithelial cells. These markers were maintained through several passages. Conclusion: Type I collagen gel supports long-term in vitro maintenance and expansion of fully elaborated human intestinal epithelium. Collagen-based methods yield familiar enteroid structures as well as a new pattern of sheet-like growth, and they eliminate the need for Matrigel for in vitro human intestinal epithelial growth. Future research is required to further develop this cell culture system for tissue engineering applications. C1 [Jabaji, Ziyad; Brinkley, Garrett J.; Khalil, Hassan A.; Sears, Connie M.; Lei, Nan Ye; Stelzner, Matthias; Dunn, James C. Y.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Div Pediat Surg, Los Angeles, CA 90095 USA. [Lei, Nan Ye; Dunn, James C. Y.] Univ Calif Los Angeles, Henry Samueli Sch Engn, Dept Bioengn, Los Angeles, CA USA. [Lewis, Michael] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Pathol, Los Angeles, CA USA. [Martin, Martin G.] Univ Calif Los Angeles, Dept Pediat, Div Gastroenterol & Nutr, Mattel Childrens Hosp, Los Angeles, CA 90024 USA. [Martin, Martin G.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Stelzner, Matthias] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA USA. [Martin, Martin G.] Univ Calif Los Angeles, Eli & Edythe Broad, Ctr Regenerat Med & Stem Cell Res, Los Angeles, CA USA. RP Dunn, JCY (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Div Pediat Surg, Los Angeles, CA 90095 USA. EM JDunn@mednet.ucla.edu OI Khalil, Hassan/0000-0002-3835-1290 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases [DK085535-01, DK085535-02S2, DK083762, DK083319]; California Institute for Regenerative Medicine [RT2-01985] FX This work was performed as a project of the Intestinal Stem Cell Consortium (https://iscc.coh.org), a collaborative research project funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Allergy and Infectious Diseases (DK085535-01 and DK085535-02S2, DK083762, and DK083319), and the California Institute for Regenerative Medicine (RT2-01985). The funding agencies have an internet presence at http://www.niddk.nih.gov, http://www.niaid.nih.gov, http://www.nih.gov, and http://www.cirm.ca.gov. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 12 Z9 12 U1 2 U2 17 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 SEP 15 PY 2014 VL 9 IS 9 AR e107814 DI 10.1371/journal.pone.0107814 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP0SR UT WOS:000341774800097 PM 25222024 ER PT J AU Makiyama, AM Gibson, LJ Harris, RS Venegas, JG AF Makiyama, A. M. Gibson, L. J. Harris, R. S. Venegas, J. G. TI Stress concentration around an atelectatic region: A finite element model SO RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY LA English DT Article DE Atelectasis; Lung parenchyma; Lung heterogeneity; Finite element analysis; Cellular materials ID ALVEOLAR DUCT MODEL; 2-DIMENSIONAL CELLULAR SOLIDS; END-EXPIRATORY PRESSURE; LUNG PARENCHYMA; DOG LUNGS; NONPERIODIC MICROSTRUCTURE; PULMONARY ELASTICITY; INTERDEPENDENCE; BEHAVIOR; MECHANICS AB Lung parenchyma surrounding an atelectatic region is thought to be subjected to increased stress compared with the rest of the lung. Using 37 hexagonal cells made of linear springs, Mead et al. (1970) measured a stress concentration greater than 30% in the springs surrounding a stiffer central cell. We re-examine the problem using a 2D finite element model of 500 cells made of thin filaments with a non-linear stress-strain relationship. We study the consequences of increasing the central stiff region from one to nine contiguous cells in regular hexagonal honeycombs and random Voronoi honeycombs. The honeycomb structures were uniformly expanded with strains of 15%, 30%, 45% and 55% above their resting, non-deformed geometry. The curve of biaxial stress vs. fractional area change has a similar shape to that of the pressure-volume curve of the lung, showing an initial regime with relatively flat slope and a final regime with decreasing slope, tending toward an asymptote. Regular honeycombs had little variability in the maximum stress in radially oriented filaments adjacent to the central stiff region. In contrast, some filaments in random Voronoi honeycombs were subjected to stress concentration approximately 16 times the average stress concentration in the radially oriented filaments adjacent to the stiff region. These results may have implications in selecting the appropriate strategy for mechanical ventilation in ARDS and defining a "safe" level of alveolar pressure for ventilating atelectatic lungs. (C) 2014 Elsevier B.V. All rights reserved. C1 [Makiyama, A. M.; Gibson, L. J.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. [Harris, R. S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Pulm & Crit Care Unit, Boston, MA 02114 USA. [Venegas, J. G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia, Boston, MA 02114 USA. RP Makiyama, AM (reprint author), Av Paulista 352 Cj 32, Sao Paulo, Brazil. EM makiyama@alum.mit.edu; jvenegas@partners.org NR 41 TC 3 Z9 3 U1 1 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-9048 EI 1878-1519 J9 RESP PHYSIOL NEUROBI JI Respir. Physiol. Neuro. PD SEP 15 PY 2014 VL 201 BP 101 EP 110 DI 10.1016/j.resp.2014.06.017 PG 10 WC Physiology; Respiratory System SC Physiology; Respiratory System GA AO6PZ UT WOS:000341475300015 PM 25048678 ER PT J AU Scalea, JR Villani, V Gillon, BC Weiner, J Gianello, P Turcotte, N Arn, JS Yamada, K Sachs, DH AF Scalea, Joseph R. Villani, Vincenzo Gillon, Bradford C. Weiner, Joshua Gianello, Pierre Turcotte, Nicole Arn, John Scott Yamada, Kazuhiko Sachs, David H. TI Development of Antidonor Antibody Directed Toward Non-Major Histocompatibility Complex Antigens in Tolerant Animals SO TRANSPLANTATION LA English DT Article DE Antibody; MHC; Antigen specificity; Tolerance; MGH swine ID MISMATCHED RENAL-ALLOGRAFTS; MINIATURE SWINE; CLASS-I; TRANSPLANTATION; REJECTION; INDUCTION; IMMUNOSUPPRESSION; REQUIREMENT; MAINTENANCE; PREDICTOR AB Background The clinical significance of antibodies directed against antigens other than major histocompatibility complex (MHC) antigens is poorly understood, and there are few large animal models in which such antibodies can be examined. We studied, both retrospectively and prospectively, the development of antibodies to non-MHC antigens in tolerant miniature swine. Methods Our database was assessed for cases of antidonor antibody formation in tolerant animals over the last 20 years. Flow cytometry, absorption assays, and familial analyses for inheritance pattern of the gene(s) potentially responsible for the antibody reactivities were carried out, and an animal determined to be negative for this reactivity was immunized by a skin graft and subcutaneous injections of peripheral blood monocyte cells from an antigen-positive donor. Results Sixteen of 469 tolerant animals tested were found to have developed antidonor antibodies. These antibodies were found to be specific for the same, presumably single, non-MHC antigen. Familial analyses indicated that the gene encoding this antigen was expressed in an autosomal-dominant manner in approximately 95% of the herd. In a prospective study, antidonor antibodies with the same specificity as those observed retrospectively were successfully induced in an antigen-negative animal after immunization with peripheral blood monocyte cells. Conclusion To our knowledge, this is the first report of the development of antibodies to a highly prevalent, non-MHC antigen present on peripheral blood mononuclear cells and developing in tolerant animals without signs of graft dysfunction. Considering the concern often raised by the appearance of antidonor antibodies in transplant recipients, these data could have important implications for clinical transplantation. C1 [Scalea, Joseph R.; Villani, Vincenzo; Gillon, Bradford C.; Weiner, Joshua; Turcotte, Nicole; Arn, John Scott; Yamada, Kazuhiko; Sachs, David H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA USA. [Gianello, Pierre] Catholic Univ Louvain, Louvain, Belgium. RP Sachs, DH (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, MGH East, Bldg 149-9019,13th St, Boston, MA 02129 USA. EM david.sachs@tbrc.mgh.harvard.edu OI Villani, Vincenzo/0000-0002-6078-9766 FU American Society of Transplantation; NIAID [5U19AI102405, RO1AI084903, 5P01AI45897]; [CO6RR020135-01] FX This work was sponsored by a grant from the American Society of Transplantation (awarded to J.R.S.), and NIAID 5U19AI102405, RO1AI084903, and 5P01AI45897.; The authors also thank the support from CO6RR020135-01 for construction of the facility used for production and maintenance of miniature swine. NR 26 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD SEP 15 PY 2014 VL 98 IS 5 BP 514 EP 519 DI 10.1097/TP.0000000000000249 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AP1TQ UT WOS:000341854800019 PM 24933456 ER PT J AU Spencer, KM AF Spencer, Kevin M. TI Time to Be Spontaneous: A Renaissance of Intrinsic Brain Activity in Psychosis Research? SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID SCHIZOPHRENIA; RHYTHMS C1 [Spencer, Kevin M.] Harvard Univ, Sch Med, Res Serv, VA Boston Healthcare Syst, Boston, MA USA. [Spencer, Kevin M.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Spencer, KM (reprint author), VA Boston Healthcare Syst, 151C,150 S Huntington Ave, Boston, MA 02130 USA. EM kevin_spencer@hms.harvard.edu FU CSRD VA [I01 CX000154]; NIMH NIH HHS [R01 MH080187, R01 MH093450] NR 10 TC 1 Z9 1 U1 1 U2 2 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 SEP 15 PY 2014 VL 76 IS 6 BP 434 EP 435 DI 10.1016/j.biopsych.2014.07.009 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AN8WT UT WOS:000340887100005 PM 25149349 ER PT J AU Swirski, FK Nahrendorf, M AF Swirski, Filip K. Nahrendorf, Matthias TI Do Vascular Smooth Muscle Cells Differentiate to Macrophages in Atherosclerotic Lesions? SO CIRCULATION RESEARCH LA English DT Editorial Material ID ACCUMULATION; ORIGIN C1 [Swirski, Filip K.; Nahrendorf, Matthias] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. RP Nahrendorf, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. EM fswirski@mgh.harvard.edu; mnahrendorf@mgh.harvard.edu FU NHLBI NIH HHS [R01HL095612, R01HL117829, R01 HL095612, R01 HL117829, R01HL114477, R01 HL114477]; NIAID NIH HHS [R56 AI104695, R56AI104695]; NINDS NIH HHS [R01 NS084863] NR 11 TC 7 Z9 7 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD SEP 12 PY 2014 VL 115 IS 7 BP 605 EP 606 DI 10.1161/CIRCRESAHA.114.304925 PG 2 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AP4VI UT WOS:000342076700005 PM 25214571 ER PT J AU Block, M Stern, DB Raman, K Lee, S Carey, J Humphreys, AA Mulhern, F Calder, B Schultz, D Rudick, CN Blood, AJ Breiter, HC AF Block, Martin Stern, Daniel B. Raman, Kalyan Lee, Sang Carey, Jim Humphreys, Ashlee A. Mulhern, Frank Calder, Bobby Schultz, Don Rudick, Charles N. Blood, Anne J. Breiter, Hans C. TI The relationship between self-report of depression and media usage SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE depression; big data; marketing communications; media use ID COMORBIDITY SURVEY REPLICATION; DSM-IV DISORDERS; SOCIAL NETWORKING; LONELINESS; PREVALENCE; AGE; ASSOCIATION; ADOLESCENTS; ANXIETY; LIFE AB Depression is a debilitating condition that adversely affects many aspects of a person's life and general health. Earlier work has supported the idea that there may be a relationship between the use of certain media and depression. In this study, we tested if self-report of depression (SRD), which is not a clinically based diagnosis, was associated with increased internet, television, and social media usage by using data collected in the Media Behavior and Influence Study (MBIS) database (N = 19,776 subjects). We further assessed the relationship of demographic variables to this association. These analyses found that SRD rates were in the range of published rates of clinically diagnosed major depression. It found that those who tended to use more media also tended to be more depressed, and that segmentation of SRD subjects was weighted toward internet and television usage, which was not the case with non-SRD subjects, who were segmented along social media use. This study found that those who have suffered either economic or physical life setbacks are orders of magnitude more likely to be depressed, even without disproportionately high levels of media use. However, among those that have suffered major life setbacks, high media users particularly television watchers were even more likely to report experiencing depression, which suggests that these effects were not just due to individuals having more time for media consumption. These findings provide an example of how Big Data can be used for medical and mental health research, helping to elucidate issues not traditionally tested in the fields of psychiatry or experimental psychology. C1 [Block, Martin; Raman, Kalyan; Carey, Jim; Humphreys, Ashlee A.; Mulhern, Frank; Schultz, Don] Northwestern Univ, Medill Integrated Mkt Commun, Evanston, IL 60208 USA. [Block, Martin; Stern, Daniel B.; Raman, Kalyan; Lee, Sang; Carey, Jim; Humphreys, Ashlee A.; Mulhern, Frank; Calder, Bobby; Schultz, Don; Rudick, Charles N.; Blood, Anne J.; Breiter, Hans C.] Northwestern Univ, Medill Kellogg & Feinberg Sch, Appl Neuromarketing Consortium, Evanston, IL 60208 USA. [Stern, Daniel B.; Breiter, Hans C.] Northwestern Univ, Warren Wright Adolescent Ctr, Feinberg Sch Med, Dept Psychiat & Behav Sci, Chicago, IL USA. [Lee, Sang; Blood, Anne J.; Breiter, Hans C.] Massachusetts Gen Hosp, Dept Psychiat, Lab Neuroimaging & Genet, Boston, MA 02114 USA. [Calder, Bobby] Northwestern Univ, Kellogg Sch Management, Dept Mkt, Evanston, IL 60208 USA. [Rudick, Charles N.] Northwestern Univ, Feinberg Sch Med, Dept Urol, Chicago, IL USA. [Blood, Anne J.; Breiter, Hans C.] Massachusetts Gen Hosp, Dept Psychiat, Mood & Motor Control Lab, Boston, MA 02114 USA. RP Block, M (reprint author), Northwestern Univ, Medill Integrated Mkt Commun, MTC 3-123,1845 Sheridan Rd, Evanston, IL 60208 USA. EM mp-block@northwestern.edu NR 35 TC 4 Z9 4 U1 9 U2 99 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD SEP 12 PY 2014 VL 8 AR 712 DI 10.3389/fnhum.2014.00712 PG 10 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AO7WB UT WOS:000341562200001 PM 25309388 ER PT J AU Salat, DH AF Salat, D. H. TI IMAGING SMALL VESSEL-ASSOCIATED WHITE MATTER CHANGES IN AGING SO NEUROSCIENCE LA English DT Review DE aging; white matter; cerebrovascular; microvascular; cerebral blood flow; hyperintensities ID CEREBRAL AMYLOID ANGIOPATHY; VASCULAR RISK-FACTORS; MIDLIFE BLOOD-PRESSURE; DIFFUSION TENSOR MRI; AGE-RELATED-CHANGES; GLOBAL FUNCTIONAL DECLINE; LATE-LIFE DEPRESSION; NORMAL ADULT BRAIN; TOTAL GRAY-MATTER; ALZHEIMERS-DISEASE AB Alterations in cerebrovascular structure and function may underlie the most common age-associated cognitive, psychiatric, and neurological conditions presented by older adults. Although much remains to understand, existing research suggests several age-associated detrimental conditions may be mediated through sometimes subtle small vessel-induced damage to the cerebral white matter. Here we review a selected portion of the vast work that demonstrates links between changes in vascular and neural health as a function of advancing age, and how even changes in low-to-moderate risk individuals, potentially beginning early in the adult age-span, may have an important impact on functional status in late life. This article is part of a Special Issue entitled: The CNS White Matter. Published by Elsevier Ltd. on behalf of IBRO. C1 [Salat, D. H.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Salat, D. H.] Boston VA Healthcare Syst, Neuroimaging Res Vet Ctr, Boston, MA USA. RP Salat, DH (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. EM salat@nmr.mgh.harvard.edu FU National Institutes of Health/National Institute of Nursing Research [R01NR010827] FX This work was supported by National Institutes of Health/National Institute of Nursing Research R01NR010827. We thank Dr. Jean Augustinack for providing helpful comments on this manuscript and Jean-Philippe Coutu for assistance with figure preparation. NR 186 TC 4 Z9 6 U1 3 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD SEP 12 PY 2014 VL 276 BP 174 EP 186 DI 10.1016/j.neuroscience.2013.11.041 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AO4UT UT WOS:000341337600015 PM 24316059 ER PT J AU Pukkila-Worley, R Nardi, V Branda, JA AF Pukkila-Worley, Read Nardi, Valentina Branda, John A. TI Case 28-2014: A 39-Year-Old Man with a Rash, Headache, Fever, Nausea, and Photophobia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID STRONGYLOIDES HYPERINFECTION SYNDROME; STREPTOCOCCUS-BOVIS MENINGITIS; ENTEROCOCCAL MENINGITIS; BACTERIAL-MENINGITIS; DIFFERENTIAL-DIAGNOSIS; INFECTIVE DERMATITIS; RHEUMATOID-ARTHRITIS; UNITED-STATES; STERCORALIS; ADULTS C1 [Pukkila-Worley, Read] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Nardi, Valentina; Branda, John A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Pukkila-Worley, Read] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Nardi, Valentina; Branda, John A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Pukkila-Worley, R (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 40 TC 2 Z9 2 U1 1 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 11 PY 2014 VL 371 IS 11 BP 1051 EP 1060 DI 10.1056/NEJMcpc1405886 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AO5KD UT WOS:000341382800012 PM 25207769 ER PT J AU Pinna, G Rasmusson, AM AF Pinna, Graziano Rasmusson, Ann M. TI Ganaxolone improves behavioral deficits in a mouse model of post-traumatic stress disorder SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Article DE ganaxolone; allopregnanolone; selective brain steroidogenic stimulants; 5 alpha-reductase type I; PTSD; PTSD therapy; anxiety disorders; GABA(A) receptor ID PROGESTERONE WITHDRAWAL INCREASES; PROLIFERATOR-ACTIVATED RECEPTORS; FEAR MEMORY RECONSOLIDATION; PROTRACTED SOCIAL-ISOLATION; RANDOMIZED CONTROLLED-TRIAL; GABA-A RECEPTORS; PROTEIN 18 KDA; TRANSLOCATOR PROTEIN; NEUROSTEROID BIOSYNTHESIS; PREFRONTAL CORTEX AB Allopregnanolone and its equipotent stereoisomer, pregnanolone (together termed ALLO), are neuroactive steroids that positively and allosterically modulate the action of gamma-amino-butyric acid (GABA) at GABA(A) receptors. Levels of ALLO are reduced in the cerebrospinal fluid of female premenopausal patients with post-traumatic stress disorder (PTSD), a severe, neuropsychiatric condition that affects millions, yet is without a consistently effective therapy. This suggests that restoring downregulated brain ALLO levels in PTSD may be beneficial. ALLO biosynthesis is also decreased in association with the emergence of PTSD-like behaviors in socially isolated (SI) mice. Similar to PTSD patients, SI mice also exhibit changes in the frontocortical and hippocampal expression of GABA(A) receptor subunits, resulting in resistance to benzodiazepine-mediated sedation and anxiolysis. ALLO acts at a larger spectrum of GABA(A) receptor subunits than benzodiazepines, and increasing corticolimbic ALLO levels in SI mice by injecting ALLO or stimulating ALLO biosynthesis with a selective brain steroidogenic stimulant, such as S-norfluoxetine, at doses far below those that block serotonin reuptake, reduces PTSD-like behavior in these mice. This suggests that synthetic analogs of ALLO, such as ganaxolone, may also improve anxiety, aggression, and other PTSD-like behaviors in the SI mouse model. Consistent with this hypothesis, ganaxolone (3.75-30 mg/kg, s.c.) injected 60 min before testing of SI mice, induced a dose-dependent reduction in aggression toward a same-sex intruder and anxiety-like behavior in an elevated plus maze. The EC50 dose of ganaxolone used in these tests also normalized exaggerated contextual fear conditioning and, remarkably, enhanced fear extinction retention in SI mice. At these doses, ganaxolone failed to change locomotion in an open field test. Therefore, unlike benzodiazepines, ganaxolone at non-sedating concentrations appears to improve dysfunctional emotional behavior associated with deficits in ALLO in mice and may provide an alternative treatment for PTSD patients with deficits in the synthesis of ALLO. Selective serotonin reuptake inhibitors (SSRIs) are the only medications currently approved by the FDA for treatment of PTSD, although they are ineffective in a substantial proportion of PTSD patients. Hence, an ALLO analog such as ganaxolone may offer a therapeutic GABAergic alternative to SSRIs for the treatment of PTSD or other disorders in which ALLO biosynthesis may be impaired. C1 [Pinna, Graziano] Univ Illinois, Coll Med, Inst Psychiat, Chicago, IL 60640 USA. [Rasmusson, Ann M.] VA Boston Healthcare Syst, VA Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA USA. [Rasmusson, Ann M.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Pinna, G (reprint author), Univ Illinois, Coll Med, Inst Psychiat, 1601 W Taylor St, Chicago, IL 60640 USA. EM gpinna@psych.uic.edu FU National Institute of Mental Health [MH 085999]; Marinus Pharmaceuticals, Inc. FX The work was supported by National Institute of Mental Health Grant MH 085999 and Marinus Pharmaceuticals, Inc., funding to Graziano Pinna. NR 108 TC 16 Z9 16 U1 2 U2 15 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD SEP 11 PY 2014 VL 8 AR 256 DI 10.3389/fncel.2014.00256 PG 11 WC Neurosciences SC Neurosciences & Neurology GA AS7UW UT WOS:000344461000001 PM 25309317 ER PT J AU Gingold, H Tehler, D Christoffersen, NR Nielsen, MM Asmar, F Kooistra, SM Christophersen, NS Christensen, LL Borre, M Sorensen, KD Andersen, LD Andersen, CL Hulleman, E Wurdinger, T Ralfkiaer, E Helin, K Gronbaek, K Omtoft, T Waszak, SM Dahan, O Pedersen, JS Lund, AH Pilpel, Y AF Gingold, Hila Tehler, Disa Christoffersen, Nanna R. Nielsen, Morten M. Asmar, Fazila Kooistra, Susanne M. Christophersen, Nicolaj S. Christensen, Lise Lotte Borre, Michael Sorensen, Karina D. Andersen, Lars D. Andersen, Claus L. Hulleman, Esther Wurdinger, Tom Ralfkiaer, Elisabeth Helin, Kristian Gronbaek, Kirsten Omtoft, Torben Waszak, Sebastian M. Dahan, Orna Pedersen, Jakob Skou Lund, Anders H. Pilpel, Yitzhak TI A Dual Program for Translation Regulation in Cellular Proliferation and Differentiation SO CELL LA English DT Article ID TRANSFER-RNA GENES; NONOPTIMAL CODON USAGE; EMBRYONIC STEM-CELLS; POLYMERASE-II; HUMAN GENOME; POL II; EXPRESSION; CANCER; EFFICIENCY; SEQUENCE AB A dichotomous choice for metazoan cells is between proliferation and differentiation. Measuring tRNA pools in various cell types, we found two distinct subsets, one that is induced in proliferating cells, and repressed otherwise, and another with the opposite signature. Correspondingly, we found that genes serving cell-autonomous functions and genes involved in multicellularity obey distinct codon usage. Proliferation-induced and differentiation-induced tRNAs often carry anticodons that correspond to the codons enriched among the cell-autonomous and the multicellularity genes, respectively. Because mRNAs of cell-autonomous genes are induced in proliferation and cancer in particular, the concomitant induction of their codon-enriched tRNAs suggests coordination between transcription and translation. Histone modifications indeed change similarly in the vicinity of cell-autonomous genes and their corresponding tRNAs, and in multicellularity genes and their tRNAs, suggesting the existence of transcriptional programs coordinating tRNA supply and demand. Hence, we describe the existence of two distinct translation programs that operate during proliferation and differentiation. C1 [Gingold, Hila; Dahan, Orna; Pilpel, Yitzhak] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel. [Tehler, Disa; Christoffersen, Nanna R.; Kooistra, Susanne M.; Christophersen, Nicolaj S.; Helin, Kristian; Lund, Anders H.] Univ Copenhagen, Biotech Res & Innovat Ctr, DK-2200 Copenhagen, Denmark. [Helin, Kristian] Univ Copenhagen, Ctr Epigenet, DK-2200 Copenhagen, Denmark. [Helin, Kristian] Univ Copenhagen, Danish Stem Cell Ctr Danstem, DK-2200 Copenhagen, Denmark. [Nielsen, Morten M.; Sorensen, Karina D.; Andersen, Lars D.; Andersen, Claus L.; Omtoft, Torben; Pedersen, Jakob Skou] Aarhus Univ Hosp, Dept Mol Med, DK-8000 Aarhus, Denmark. [Borre, Michael] Aarhus Univ Hosp, Dept Urol, DK-8000 Aarhus, Denmark. [Andersen, Claus L.] Aarhus Univ Hosp, Dept Surg, DK-8000 Aarhus, Denmark. [Pedersen, Jakob Skou] Aarhus Univ Hosp, Bioinformat Res Ctr, DK-8000 Aarhus, Denmark. [Asmar, Fazila; Gronbaek, Kirsten] Univ Copenhagen, Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark. [Ralfkiaer, Elisabeth] Univ Copenhagen, Rigshosp, Dept Pathol, DK-2100 Copenhagen, Denmark. [Hulleman, Esther] Vrije Univ Amsterdam, Med Ctr, Canc Ctr Amsterdam, Dept Pediat Oncol, NL-1007 MB Amsterdam, Netherlands. [Wurdinger, Tom] Vrije Univ Amsterdam, Med Ctr, Canc Ctr Amsterdam, Dept Neurosurg,Neurooncol Res Grp, NL-1007 MB Amsterdam, Netherlands. [Wurdinger, Tom] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Wurdinger, Tom] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Waszak, Sebastian M.] Ecole Polytech Fed Lausanne, Sch Life Sci, Inst Bioengn, CH-1015 Lausanne, Switzerland. RP Lund, AH (reprint author), Univ Copenhagen, Biotech Res & Innovat Ctr, DK-2200 Copenhagen, Denmark. EM anders.lund@bric.ku.dk; pilpel@weizmann.ac.il RI Waszak, Sebastian/D-7828-2015; Andersen, Claus Lindbjerg/A-9217-2012; Andersen, Claus/C-1477-2017; Pedersen, Jakob/G-3382-2012; OI Waszak, Sebastian/0000-0003-3042-9521; Andersen, Claus Lindbjerg/0000-0002-7406-2103; Andersen, Claus/0000-0002-7406-2103; Pedersen, Jakob/0000-0002-7236-4001; Gronbaek, Kirsten/0000-0002-1535-9601; Lund, Anders/0000-0002-7407-3398; Sorensen, Karina Dalsgaard/0000-0002-4902-5490; Helin, Kristian/0000-0003-1975-6097 FU European Research Council (ERC) grant; Danish National Advanced Technology Foundation; Danish Council for Strategic Research; Danish Council for Independent Research; Novo Nordisk Foundation; Lundbeck Foundation; Danish Cancer Society; Netherlands Organisation for scientific research (NWO); Danish National Research Foundation [DNRF82] FX Work in the authors' laboratory is supported by a European Research Council (ERC) grant (Y.P.) and by the Danish National Advanced Technology Foundation, the Danish Council for Strategic Research, the Danish Council for Independent Research, the Novo Nordisk Foundation, the Lundbeck Foundation, and the Danish Cancer Society (A.H.L.). Y.P. is an incumbent of the Ben-May Professorial Chair. S.M.K. was supported by a postdoctoral fellowship from the Netherlands Organisation for scientific research (NWO). The Centre for Epigenetics is supported by the Danish National Research Foundation (DNRF82). We thank Simon Kasif and Erez Dekel for stimulating discussions. NR 48 TC 71 Z9 72 U1 5 U2 30 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD SEP 11 PY 2014 VL 158 IS 6 BP 1281 EP 1292 DI 10.1016/j.cell.2014.08.011 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AQ8QK UT WOS:000343094200011 PM 25215487 ER PT J AU Wang, YH Israelsen, WJ Lee, DJ Yu, VWC Jeanson, NT Clish, CB Cantley, LC Heiden, MGV Scadden, DT AF Wang, Ying-Hua Israelsen, William J. Lee, Dongjun Yu, Vionnie W. C. Jeanson, Nathaniel T. Clish, Clary B. Cantley, Lewis C. Heiden, Matthew G. Vander Scadden, David T. TI Cell-State-Specific Metabolic Dependency in Hematopoiesis and Leukemogenesis SO CELL LA English DT Article ID PYRUVATE-KINASE M2; STEM-CELLS; TUMOR-GROWTH; BONE-MARROW; LACTATE-DEHYDROGENASE; OXIDATIVE STRESS; MYELOID-LEUKEMIA; HYPOXIC NICHE; ISOFORM; PKM2 AB The balance between oxidative and nonoxidative glucose metabolism is essential for a number of pathophysiological processes. By deleting enzymes that affect aerobic glycolysis with different potencies, we examine how modulating glucose metabolism specifically affects hematopoietic and leukemic cell populations. We find that a deficiency in the M2 pyruvate kinase isoform (PKM2) reduces the levels of metabolic intermediates important for biosynthesis and impairs progenitor function without perturbing hematopoietic stem cells (HSCs), whereas lactate dehydrogenase A (LDHA) deletion significantly inhibits the function of both HSCs and progenitors during hematopoiesis. In contrast, leukemia initiation by transforming alleles putatively affecting either HSCs or progenitors is inhibited in the absence of either PKM2 or LDHA, indicating that the cell-state-specific responses to metabolic manipulation in hematopoiesis do not apply to the setting of leukemia. This finding suggests that fine-tuning the level of glycolysis may be explored therapeutically for treating leukemia while preserving HSC function. C1 [Wang, Ying-Hua; Lee, Dongjun; Yu, Vionnie W. C.; Jeanson, Nathaniel T.; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Wang, Ying-Hua; Lee, Dongjun; Yu, Vionnie W. C.; Jeanson, Nathaniel T.; Scadden, David T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Wang, Ying-Hua; Lee, Dongjun; Yu, Vionnie W. C.; Jeanson, Nathaniel T.; Scadden, David T.] Harvard Stem Cell Inst, Cambridge, MA 02114 USA. [Wang, Ying-Hua; Lee, Dongjun; Yu, Vionnie W. C.; Jeanson, Nathaniel T.; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Israelsen, William J.; Heiden, Matthew G. Vander] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Heiden, Matthew G. Vander] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Clish, Clary B.] Broad Inst & Harvard, Metabolite Profiling Platform, Cambridge, MA 02142 USA. [Cantley, Lewis C.] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA. RP Scadden, DT (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. EM david_scadden@harvard.edu RI Cantley, Lewis/D-1800-2014; OI Cantley, Lewis/0000-0002-1298-7653; Yu, Vionnie W. C./0000-0002-6658-0285; lee, dongjun/0000-0001-6828-401X FU NIH-HSCI Training Grant [5T32HL87735-4]; American Cancer Society; MGH Fund; MGH Federal Share of the Program Income [C06 CA059267]; Proton Therapy Research and Treatment Center; BD Biosciences stem cell grant; Bullock-Wellman Fellowship; NIH [P30CA147882, R01CA168653, DK050234, HL044851, CA148180]; Burroughs Wellcome Fund; Ludwig Foundation; Damon Runyon Cancer Research Foundation; Tosteson Fund FX We thank Drs. Borja Saez, Rushdia Yusuf, Dongsu Park, Stephen Sykes, Demetrios Kalaitzidis, and Ninib Baryawno for technical help and valuable suggestions; the MGH CRM Flow Core for help with flow cytometry; and Min Wu and the laboratory of Marcia Haigis at HMS for help with the Seahorse Analyzer. Y.H.W. was supported by NIH-HSCI Training Grant 5T32HL87735-4 and by the American Cancer Society. D.L. was supported by the MGH Fund for Medical Discovery. V.W.C.Y. was supported by an MGH Federal Share of the Program Income under C06 CA059267, by the Proton Therapy Research and Treatment Center, by a BD Biosciences stem cell grant, by a Bullock-Wellman Fellowship, and by a Tosteson Fund for Medical Discovery fellowship. M.V.H. was supported by NIH grants P30CA147882 and R01CA168653 as well as by the Smith family, the Stern family, the Burroughs Wellcome Fund, the Ludwig Foundation, and the Damon Runyon Cancer Research Foundation. M.V.H. is a consultant and scientific advisory board member for Agios Pharmaceuticals. D.T.S. is supported by NIH grants DK050234, HL044851, and CA148180. NR 38 TC 45 Z9 47 U1 3 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD SEP 11 PY 2014 VL 158 IS 6 BP 1309 EP 1323 DI 10.1016/j.cell.2014.07.048 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AQ8QK UT WOS:000343094200013 PM 25215489 ER PT J AU Glavey, SV Manier, S Natoni, A Sacco, A Moschetta, M Reagan, MR Murillo, LS Sahin, I Wu, P Mishima, Y Zhang, Y Zhang, WJ Zhang, Y Morgan, G Joshi, L Roccaro, AM Ghobrial, IM O'Dwyer, ME AF Glavey, Siobhan V. Manier, Salomon Natoni, Alessandro Sacco, Antonio Moschetta, Michele Reagan, Michaela R. Murillo, Laura S. Sahin, Ilyas Wu, Ping Mishima, Yuji Zhang, Yu Zhang, Wenjing Zhang, Yong Morgan, Gareth Joshi, Lokesh Roccaro, Aldo M. Ghobrial, Irene M. O'Dwyer, Michael E. TI The sialyltransferase ST3GAL6 influences homing and survival in multiple myeloma SO BLOOD LA English DT Article ID SELECTIN GLYCOPROTEIN LIGAND-1; BONE-MARROW MICROENVIRONMENT; P-SELECTIN; CELL-ADHESION; CANCER-CELLS; EXPRESSION; METASTASIS; MIGRATION; PROLIFERATION; GLYCOSYLATION AB Glycosylation is a stepwise procedure of covalent attachment of oligosaccharide chains to proteins or lipids, and alterations in this process, especially increased sialylation, have been associated with malignant transformation and metastasis. The role of altered sialylation in multiple myeloma (MM) cell trafficking has not been previously investigated. In the present study we identified high expression of beta-galactoside alpha-2,3-sialyltransferase, ST3GAL6, in MM cell lines and patients. This gene plays a key role in selectin ligand synthesis in humans through the generation of functional sialyl Lewis X. In MRC IX patients, high expression of this gene is associated with inferior overall survival. In this study we demonstrate that knockdown of ST3GAL6 results in a significant reduction in levels of alpha-2,3-linked sialic acid on the surface of MM cells with an associated significant reduction in adhesion to MM bone marrow stromal cells and fibronectin along with reduced transendothelial migration in vitro. In support of our in vitro findings, we demonstrate significantly reduced homing and engraftment of ST3GAL6 knockdown MM cells to the bone marrow niche in vivo, along with decreased tumor burden and prolonged survival. This study points to the importance of altered glycosylation, particularly sialylation, in MM cell adhesion and migration. C1 [Glavey, Siobhan V.; Manier, Salomon; Sacco, Antonio; Moschetta, Michele; Reagan, Michaela R.; Sahin, Ilyas; Mishima, Yuji; Zhang, Yu; Zhang, Wenjing; Zhang, Yong; Roccaro, Aldo M.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Glavey, Siobhan V.; Natoni, Alessandro; Murillo, Laura S.; O'Dwyer, Michael E.] Natl Univ Ireland, Dept Hematol, Galway, Ireland. [Glavey, Siobhan V.; Natoni, Alessandro; Murillo, Laura S.; O'Dwyer, Michael E.] Galway Univ Hosp, Galway, Ireland. [Morgan, Gareth] Inst Canc Res, Ctr Myeloma Res, Div Mol Pathol, London SW3 6JB, England. [Joshi, Lokesh; O'Dwyer, Michael E.] Natl Univ Ireland, Glycosci Res Grp, Galway, Ireland. RP O'Dwyer, ME (reprint author), Natl Univ Ireland, Room G011,Biosci Res Bldg, Galway, Ireland. EM michael.odwyer@nuigalway.ie RI Sacco, Antonio/K-4681-2016; Reagan, Michaela/E-3549-2017; OI Sacco, Antonio/0000-0003-2945-9416; Roccaro, Aldo/0000-0002-1872-5128; o'dwyer, michael/0000-0002-6173-7140; Reagan, Michaela/0000-0003-2884-6481 FU Health Research Board (HRB) NSAFP; HRB CSA, Ireland; National Institutes of Health, National Cancer Institute [RO1 CA154648] FX This work was supported in part by the Health Research Board (HRB) NSAFP, and HRB CSA 2012, Ireland; and in part by the National Institutes of Health, National Cancer Institute grant (RO1 CA154648). NR 40 TC 18 Z9 18 U1 1 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD SEP 11 PY 2014 VL 124 IS 11 BP 1765 EP 1776 DI 10.1182/blood-2014-03-560862 PG 12 WC Hematology SC Hematology GA AQ4JR UT WOS:000342762600012 PM 25061176 ER PT J AU Sowell, ER Charness, ME Riley, EP AF Sowell, Elizabeth R. Charness, Michael E. Riley, Edward P. TI Pregnancy: no safe level of alcohol SO NATURE LA English DT Letter C1 [Sowell, Elizabeth R.] Univ So Calif, Los Angeles, CA 90089 USA. [Sowell, Elizabeth R.] Childrens Hosp Los Angeles, Los Angeles, CA USA. [Charness, Michael E.] VA Boston Healthcare Syst, Jamaica Plain, MA USA. [Charness, Michael E.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Charness, Michael E.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Riley, Edward P.] San Diego State Univ, San Diego, CA 92182 USA. RP Sowell, ER (reprint author), Univ So Calif, Los Angeles, CA 90089 USA. EM esowell@chla.usc.edu NR 4 TC 3 Z9 3 U1 1 U2 15 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 SEP 11 PY 2014 VL 513 IS 7517 BP 172 EP 172 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO5DP UT WOS:000341362800031 PM 25209788 ER PT J AU Bass, AJ Thorsson, V Shmulevich, I Reynolds, SM Miller, M Bernard, B Hinoue, T Laird, PW Curtis, C Shen, H Weisenberger, DJ Schultz, N Shen, RL Weinhold, N Keiser, DP Bowlby, R Sipahimalani, P Cherniack, AD Getz, G Liu, YC Noble, MS Pedamallu, C Sougnez, C Taylor-Weiner, A Akbani, R Lee, JS Liu, WB Mills, GB Yang, D Zhang, W Pantazi, A Parfenov, M Gulley, M Piazuelo, MB Schneider, BG Kim, J Boussioutas, A Sheth, M Demchok, JA Rabkin, CS Willis, JE Ng, S Garman, K Beer, DG Pennathur, A Raphael, BJ Wu, HT Odze, R Kim, HK Bowen, J Leraas, KM Lichtenberg, TM Weaver, L McLellan, M Wiznerowicz, M Sakai, R Getz, G Sougnez, C Lawrence, MS Cibulskis, K Lichtenstein, L Fisher, S Gabriel, SB Lander, ES Ding, L Niu, BF Ally, A Balasundaram, M Birol, I Bowlby, R Brooks, D Butterfield, YSN Carlsen, R Chu, A Chu, J Chuah, E Chun, HJE Clarke, A Dhalla, N Guin, R Holt, RA Jones, SJM Kasaian, K Lee, D Li, HYA Lim, E Ma, Y Marra, MA Mayo, M Moore, RA Mungall, AJ Mungall, KL Nip, KM Robertson, AG Schein, JE Sipahimalani, P Tam, A Thiessen, N Beroukhim, R Carter, SL Cherniack, AD Cho, J Cibulskis, K DiCara, D Frazer, S Fisher, S Gabriel, SB Gehlenborg, N Heiman, DI Jung, J Kim, J Lander, ES Lawrence, MS Lichtenstein, L Lin, P Meyerson, M Ojesina, AI Pedamallu, CS Saksena, G Schumacher, SE Sougnez, C Stojanov, P Tabak, B Taylor-Weiner, A Voet, D Rosenberg, M Zack, TI Zhang, HL Zou, LH Protopopov, A Santoso, N Parfenov, M Lee, S Zhang, J Mahadeshwar, HS Tang, JB Ren, XJ Seth, S Yang, LX Xu, AW Song, XZ Pantazi, A Xi, RB Bristow, CA Hadjipanayis, A Seidman, J Chin, L Park, PJ Kucherlapati, R Akbani, R Ling, SY Liu, WB Rao, A Weinstein, JN Kim, SB Lee, JS Lu, YL Mills, G Hinoue, T Weisenberger, DJ Bootwalla, MS Lai, PH Shen, H Triche, T Van Den Berg, DJ Baylin, SB Herman, JG Getz, G Chin, L Liu, YC Murray, BA Noble, MS Askoy, BA Ciriello, G Dresdner, G Gao, JJ Gross, B Jacobsen, A Lee, W Ramirez, R Sander, C Schultz, N Senbabaoglu, Y Sinha, R Sumer, SO Sun, YC Weinhold, N Thorsson, V Bernard, B Iype, L Kramer, RW Kreisberg, R Miller, M Reynolds, SM Rovira, H Tasman, N Shmulevich, I Ng, S Haussler, D Stuart, JM Akbani, R Ling, SY Liu, WB Rao, A Weinstein, JN Verhaak, RGW Mills, GB Leiserson, MDM Raphael, BJ Wu, HT Taylor, BS Black, AD Bowen, J Carney, JA Gastier-Foster, JM Helsel, C Leraas, KM Lichtenberg, TM McAllister, C Ramirez, NC Tabler, TR Wise, L Zmuda, E Penny, R Crain, D Gardner, J Lau, K Curely, E Mallery, D Morris, S Paulauskis, J Shelton, T Shelton, C Sherman, M Benz, C Lee, JH Fedosenko, K Manikhas, G Voronina, O Belyaev, D Dolzhansky, O Rathmell, WK Brzezinski, J Ibbs, M Korski, K Kycler, W Lazniak, R Leporowska, E Mackiewicz, A Murawa, D Murawa, P Spychala, A Suchorska, WM Tatka, H Teresiak, M Wiznerowicz, M Abdel-Misih, R Bennett, J Brown, J Iacocca, M Rabeno, B Kwon, SY Penny, R Gardner, J Kemkes, A Mallery, D Morris, S Shelton, T Shelton, C Curley, E Alexopoulou, I Engel, J Bartlett, J Albert, M Park, DY Dhir, R Luketich, J Landreneau, R Janjigian, YY Kelsen, DP Cho, E Ladanyi, M Tang, L McCall, SJ Park, YS Cheong, JH Ajani, J Camargo, MC Alonso, S Ayala, B Jensen, MA Pihl, T Raman, R Walton, J Wan, YH Demchok, JA Eley, G Shaw, KRM Sheth, M Tarnuzzer, R Wang, ZN Yang, LM Zenklusen, JC Davidsen, T Hutter, CM Sofia, HJ Burton, R Chudamani, S Liu, J AF Bass, Adam J. Thorsson, Vesteinn Shmulevich, Ilya Reynolds, Sheila M. Miller, Michael Bernard, Brady Hinoue, Toshinori Laird, Peter W. Curtis, Christina Shen, Hui Weisenberger, Daniel J. Schultz, Nikolaus Shen, Ronglai Weinhold, Nils Keiser, David P. Bowlby, Reanne Sipahimalani, Payal Cherniack, Andrew D. Getz, Gad Liu, Yingchun Noble, Michael S. Pedamallu, Chandra Sougnez, Carrie Taylor-Weiner, Amaro Akbani, Rehan Lee, Ju-Seog Liu, Wenbin Mills, Gordon B. Yang, Da Zhang, Wei Pantazi, Angeliki Parfenov, Michael Gulley, Margaret Piazuelo, M. Blanca Schneider, Barbara G. Kim, Jihun Boussioutas, Alex Sheth, Margi Demchok, John A. Rabkin, Charles S. Willis, Joseph E. Ng, Sam Garman, Katherine Beer, David G. Pennathur, Arjun Raphael, Benjamin J. Wu, Hsin-Ta Odze, Robert Kim, Hark K. Bowen, Jay Leraas, Kristen M. Lichtenberg, Tara M. Weaver, Lichtenberg McLellan, Michael Wiznerowicz, Maciej Sakai, Ryo Getz, Gad Sougnez, Carrie Lawrence, Michael S. Cibulskis, Kristian Lichtenstein, Lee Fisher, Sheila Gabriel, Stacey B. Lander, Eric S. Ding, Li Niu, Beifang Ally, Adrian Balasundaram, Miruna Birol, Inanc Bowlby, Reanne Brooks, Denise Butterfield, Yaron S. N. Carlsen, Rebecca Chu, Andy Chu, Justin Chuah, Eric Chun, Hye-Jung E. Clarke, Amanda Dhalla, Noreen Guin, Ranabir Holt, Robert A. Jones, Steven J. M. Kasaian, Katayoon Lee, Darlene Li, Haiyan A. Lim, Emilia Ma, Yussanne Marra, Marco A. Mayo, Michael Moore, Richard A. Mungall, Andrew J. Mungall, Karen L. Nip, Ka Ming Robertson, A. Gordon Schein, Jacqueline E. Sipahimalani, Payal Tam, Angela Thiessen, Nina Beroukhim, Rameen Carter, Scott L. Cherniack, Andrew D. Cho, Juok Cibulskis, Kristian DiCara, Daniel Frazer, Scott Fisher, Sheila Gabriel, Stacey B. Gehlenborg, Nils Heiman, David I. Jung, Joonil Kim, Jaegil Lander, Eric S. Lawrence, Michael S. Lichtenstein, Lee Lin, Pei Meyerson, Matthew Ojesina, Akinyemi I. Pedamallu, Chandra Sekhar Saksena, Gordon Schumacher, Steven E. Sougnez, Carrie Stojanov, Petar Tabak, Barbara Taylor-Weiner, Amaro Voet, Doug Rosenberg, Mara Zack, Travis I. Zhang, Hailei Zou, Lihua Protopopov, Alexei Santoso, Netty Parfenov, Michael Lee, Semin Zhang, Jianhua Mahadeshwar, Harshad S. Tang, Jiabin Ren, Xiaojia Seth, Sahil Yang, Lixing Xu, Andrew W. Song, Xingzhi Pantazi, Angeliki Xi, Ruibin Bristow, Christopher A. Hadjipanayis, Angela Seidman, Jonathan Chin, Lynda Park, Peter J. Kucherlapati, Raju Akbani, Rehan Ling, Shiyun Liu, Wenbin Rao, Arvind Weinstein, John N. Kim, Sang-Bae Lee, Ju-Seog Lu, Yiling Mills, Gordon Hinoue, Toshinori Weisenberger, Daniel J. Bootwalla, Moiz S. Lai, Phillip H. Shen, Hui Triche, Timothy, Jr. Van Den Berg, David J. Baylin, Stephen B. Herman, James G. Getz, Gad Chin, Lynda Liu, Yingchun Murray, Bradley A. Noble, Michael S. Askoy, B. Arman Ciriello, Giovanni Dresdner, Gideon Gao, Jianjiong Gross, Benjamin Jacobsen, Anders Lee, William Ramirez, Ricardo Sander, Chris Schultz, Nikolaus Senbabaoglu, Yasin Sinha, Rileen Sumer, S. Onur Sun, Yichao Weinhold, Nils Thorsson, Vesteinn Bernard, Brady Iype, Lisa Kramer, Roger W. Kreisberg, Richard Miller, Michael Reynolds, Sheila M. Rovira, Hector Tasman, Natalie Shmulevich, Ilya Ng, Sam Haussler, David Stuart, Josh M. Akbani, Rehan Ling, Shiyun Liu, Wenbin Rao, Arvind Weinstein, John N. Verhaak, Roeland G. W. Mills, Gordon B. Leiserson, Mark D. M. Raphael, Benjamin J. Wu, Hsin-Ta Taylor, Barry S. Black, Aaron D. Bowen, Jay Carney, Julie Ann Gastier-Foster, Julie M. Helsel, Carmen Leraas, Kristen M. Lichtenberg, Tara M. McAllister, Cynthia Ramirez, Nilsa C. Tabler, Teresa R. Wise, Lisa Zmuda, Erik Penny, Robert Crain, Daniel Gardner, Johanna Lau, Kevin Curely, Erin Mallery, David Morris, Scott Paulauskis, Joseph Shelton, Troy Shelton, Candace Sherman, Mark Benz, Christopher Lee, Jae-Hyuk Fedosenko, Konstantin Manikhas, Georgy Voronina, Olga Belyaev, Dmitry Dolzhansky, Oleg Rathmell, W. Kimryn Brzezinski, Jakub Ibbs, Matthew Korski, Konstanty Kycler, Witold Lazniak, Radoslaw Leporowska, Ewa Mackiewicz, Andrzej Murawa, Dawid Murawa, Pawel Spychala, Arkadiusz Suchorska, Wiktoria M. Tatka, Honorata Teresiak, Marek Wiznerowicz, Maciej Abdel-Misih, Raafat Bennett, Joseph Brown, Jennifer Iacocca, Mary Rabeno, Brenda Kwon, Sun-Young Penny, Robert Gardner, Johanna Kemkes, Ariane Mallery, David Morris, Scott Shelton, Troy Shelton, Candace Curley, Erin Alexopoulou, Iakovina Engel, Jay Bartlett, John Albert, Monique Park, Do-Youn Dhir, Rajiv Luketich, James Landreneau, Rodney Janjigian, Yelena Y. Kelsen, David P. Cho, Eunjung Ladanyi, Marc Tang, Laura McCall, Shannon J. Park, Young S. Cheong, Jae-Ho Ajani, Jaffer Camargo, M. Constanza Alonso, Shelley Ayala, Brenda Jensen, Mark A. Pihl, Todd Raman, Rohini Walton, Jessica Wan, Yunhu Demchok, John A. Eley, Greg Shaw, Kenna R. Mills Sheth, Margi Tarnuzzer, Roy Wang, Zhining Yang, Liming Zenklusen, Jean Claude Davidsen, Tanja Hutter, Carolyn M. Sofia, Heidi J. Burton, Robert Chudamani, Sudha Liu, Jia CA Canc Genome Atlas Res Network TI Comprehensive molecular characterization of gastric adenocarcinoma SO NATURE LA English DT Article ID SOMATIC MUTATIONS; GENE-EXPRESSION; CELL LYMPHOMAS; EBV-INFECTION; CANCER; EXOME; METHYLATION; SUBTYPES; KINASE; CLASSIFICATION AB Gastric cancer is a leading cause of cancer deaths, but analysis of molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roalmap for patient stratification and trials of targeted therapies. C1 [Bass, Adam J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Bass, Adam J.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA. [Thorsson, Vesteinn; Shmulevich, Ilya; Reynolds, Sheila M.; Miller, Michael; Bernard, Brady; Iype, Lisa; Kramer, Roger W.; Kreisberg, Richard; Rovira, Hector; Tasman, Natalie] Inst Syst Biol, Seattle, WA 98109 USA. [Hinoue, Toshinori; Laird, Peter W.; Shen, Hui; Weisenberger, Daniel J.; Bootwalla, Moiz S.; Lai, Phillip H.; Triche, Timothy, Jr.; Van Den Berg, David J.] Univ So Calif, USC Epigenome Ctr, Los Angeles, CA 90033 USA. [Curtis, Christina] Univ So Calif, Dept Prevent Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Schultz, Nikolaus; Weinhold, Nils; Askoy, B. Arman; Ciriello, Giovanni; Dresdner, Gideon; Gao, Jianjiong; Gross, Benjamin; Jacobsen, Anders; Lee, William; Ramirez, Ricardo; Sander, Chris; Senbabaoglu, Yasin; Sinha, Rileen; Sumer, S. Onur; Sun, Yichao] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA. [Shen, Ronglai] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Keiser, David P.; Janjigian, Yelena Y.; Kelsen, David P.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Bowlby, Reanne; Sipahimalani, Payal; Ally, Adrian; Balasundaram, Miruna; Birol, Inanc; Brooks, Denise; Butterfield, Yaron S. N.; Carlsen, Rebecca; Chu, Andy; Chu, Justin; Chuah, Eric; Chun, Hye-Jung E.; Clarke, Amanda; Dhalla, Noreen; Guin, Ranabir; Holt, Robert A.; Jones, Steven J. M.; Kasaian, Katayoon; Lee, Darlene; Li, Haiyan A.; Lim, Emilia; Ma, Yussanne; Marra, Marco A.; Mayo, Michael; Moore, Richard A.; Mungall, Andrew J.; Mungall, Karen L.; Nip, Ka Ming; Robertson, A. Gordon; Schein, Jacqueline E.; Tam, Angela; Thiessen, Nina] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Cherniack, Andrew D.; Getz, Gad; Liu, Yingchun; Noble, Michael S.; Pedamallu, Chandra; Sougnez, Carrie; Taylor-Weiner, Amaro; Lawrence, Michael S.; Cibulskis, Kristian; Lichtenstein, Lee; Fisher, Sheila; Gabriel, Stacey B.; Lander, Eric S.; Beroukhim, Rameen; Carter, Scott L.; Cho, Juok; DiCara, Daniel; Frazer, Scott; Gehlenborg, Nils; Heiman, David I.; Jung, Joonil; Kim, Jaegil; Lin, Pei; Meyerson, Matthew; Ojesina, Akinyemi I.; Pedamallu, Chandra Sekhar; Saksena, Gordon; Schumacher, Steven E.; Stojanov, Petar; Tabak, Barbara; Voet, Doug; Rosenberg, Mara; Zack, Travis I.; Zhang, Hailei; Zou, Lihua; Murray, Bradley A.] Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. [Akbani, Rehan; Lee, Ju-Seog; Liu, Wenbin; Ling, Shiyun; Rao, Arvind; Weinstein, John N.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Mills, Gordon B.; Kim, Sang-Bae; Lee, Ju-Seog; Lu, Yiling; Mills, Gordon] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Yang, Da; Zhang, Wei] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Pantazi, Angeliki; Parfenov, Michael; Santoso, Netty; Ren, Xiaojia; Hadjipanayis, Angela; Seidman, Jonathan; Kucherlapati, Raju] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Gulley, Margaret] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Piazuelo, M. Blanca; Schneider, Barbara G.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA. [Kim, Jihun; Park, Young S.] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul 138736, South Korea. [Boussioutas, Alex] Univ Melbourne, Sir Peter MacCallum Canc Dept Oncol, East Melbourne 3002, Australia. [Sheth, Margi; Demchok, John A.; Eley, Greg; Shaw, Kenna R. Mills; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zenklusen, Jean Claude] NCI, Bethesda, MD 20892 USA. [Rabkin, Charles S.; Camargo, M. Constanza] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Willis, Joseph E.] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. [Ng, Sam; Haussler, David; Stuart, Josh M.] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. [Haussler, David; Stuart, Josh M.] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Garman, Katherine] Duke Univ, Dept Med, Div Gastroenterol, Durham, NC 27710 USA. [Beer, David G.] Univ Michigan, Ctr Canc, Dept Thorac Surg, Ann Arbor, MI 48109 USA. [Pennathur, Arjun; Dhir, Rajiv; Luketich, James; Landreneau, Rodney] Univ Pittsburgh, Pittsburgh, PA 15213 USA. [Raphael, Benjamin J.; Wu, Hsin-Ta; Leiserson, Mark D. M.] Brown Univ, Dept Comp Sci, Providence, RI 02912 USA. [Wu, Hsin-Ta; Leiserson, Mark D. M.] Brown Univ, Ctr Computat Mol Biol, Providence, RI 02912 USA. [Odze, Robert] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Kim, Hark K.] Natl Canc Ctr, Goyang 410769, South Korea. [Bowen, Jay; Leraas, Kristen M.; Lichtenberg, Tara M.; Weaver, Lichtenberg; Black, Aaron D.; Carney, Julie Ann; Gastier-Foster, Julie M.; Helsel, Carmen; McAllister, Cynthia; Ramirez, Nilsa C.; Tabler, Teresa R.; Wise, Lisa; Zmuda, Erik] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA. [McLellan, Michael; Ding, Li; Niu, Beifang] Washington Univ, Genome Inst, St Louis, MO 63108 USA. [Wiznerowicz, Maciej; Brzezinski, Jakub; Ibbs, Matthew; Korski, Konstanty; Kycler, Witold; Lazniak, Radoslaw; Leporowska, Ewa; Mackiewicz, Andrzej; Murawa, Dawid; Murawa, Pawel; Spychala, Arkadiusz; Suchorska, Wiktoria M.; Tatka, Honorata; Teresiak, Marek] Greater Poland Canc Ctr, PL-61866 Poznan, Poland. [Sakai, Ryo] Katholieke Univ Leuven, Dept Elect Engn ESAT STADIUS, Leuven, Belgium. [Protopopov, Alexei; Zhang, Jianhua; Mahadeshwar, Harshad S.; Tang, Jiabin; Seth, Sahil; Song, Xingzhi; Bristow, Christopher A.; Chin, Lynda; Verhaak, Roeland G. W.] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Dept Genom Med, Houston, TX 77054 USA. [Lee, Semin; Yang, Lixing; Xu, Andrew W.; Xi, Ruibin; Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Baylin, Stephen B.; Herman, James G.] Johns Hopkins Univ, Canc Biol Div, Baltimore, MD 21231 USA. [Taylor, Barry S.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Penny, Robert; Crain, Daniel; Gardner, Johanna; Lau, Kevin; Curely, Erin; Mallery, David; Morris, Scott; Paulauskis, Joseph; Shelton, Troy; Shelton, Candace; Sherman, Mark; Kemkes, Ariane] Int Genom Consortium, Phoenix, AZ 85004 USA. [Benz, Christopher] Buck Inst Res Aging, Novato, CA 94945 USA. [Lee, Jae-Hyuk] Chonnam Natl Univ, Sch Med, Kwangju 501746, South Korea. [Fedosenko, Konstantin; Manikhas, Georgy] City Clin Oncol Dispensary, St Petersburg 198255, Russia. [Voronina, Olga; Belyaev, Dmitry; Dolzhansky, Oleg] Cureline Inc, San Francisco, CA 94080 USA. [Rathmell, W. Kimryn] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Rathmell, W. Kimryn] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Abdel-Misih, Raafat; Bennett, Joseph; Brown, Jennifer; Iacocca, Mary; Rabeno, Brenda] Christiana Care Hlth Syst, Helen Graham Canc Ctr & Res Inst, Newark, DE 19713 USA. [Kwon, Sun-Young] Keimyung Univ, Sch Med, Taegu 700712, South Korea. [Alexopoulou, Iakovina] St Josephs Healthcare Hamilton, Ontario Tumour Bank, Hamilton, ON L8N 3Z5, Canada. [Engel, Jay] Kingston Gen Hosp, Ontario Tumour Bank, Kingston, ON K7L 5H6, Canada. [Bartlett, John; Albert, Monique] Ontario Inst Canc Res, Ontario Tumour Bank, Toronto, ON M5G 0A3, Canada. [Park, Do-Youn] Pusan Natl Univ Hosp, Pusan 602739, South Korea. [Cho, Eunjung; Ladanyi, Marc; Tang, Laura] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [McCall, Shannon J.] Duke Univ, Dept Pathol, Durham, NC 27710 USA. [Cheong, Jae-Ho] Yonsei Univ, Coll Med, Dept Surg, Seoul 120752, South Korea. [Ajani, Jaffer] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Alonso, Shelley; Ayala, Brenda; Jensen, Mark A.; Pihl, Todd; Raman, Rohini; Walton, Jessica; Wan, Yunhu] SRA Int, Fairfax, VA 22033 USA. [Davidsen, Tanja] NCI, Ctr Biomed Informat & Informat Technol, Rockville, MD 20850 USA. [Hutter, Carolyn M.; Sofia, Heidi J.] NHGRI, Bethesda, MD 20892 USA. [Burton, Robert; Chudamani, Sudha; Liu, Jia] SAIC Frederick Inc, Frederick, MD 21702 USA. RP Bass, AJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM adam_bass@dfci.harvard.edu RI Laird, Peter/G-8683-2012; Jacobsen, Anders/K-1081-2013; Ling, Shiyun/P-2242-2014; Schein, Jacquie/G-3674-2015; Holt, Robert/C-3303-2009; Jones, Steven/C-3621-2009; Camargo, M. Constanza/R-9891-2016; Lee, Semin/S-2629-2016; Marra, Marco/B-5987-2008; Birol, Inanc/G-5440-2011; Senbabaoglu, Yasin/I-4922-2013; OI Schultz, Nikolaus/0000-0002-0131-4904; Ojesina, Akinyemi/0000-0003-0755-3639; Ibbs, Matthew/0000-0003-2510-3447; Schneider, Barbara/0000-0003-4421-1355; Jacobsen, Anders/0000-0001-6847-4980; Lee, Semin/0000-0002-9015-6046; Birol, Inanc/0000-0003-0950-7839; Senbabaoglu, Yasin/0000-0003-0958-958X; McCall, Shannon/0000-0003-3957-061X; Seth, Sahil/0000-0003-4579-3959; Sinha, Rileen/0000-0001-5497-5055; Yang, Da/0000-0002-8336-9457; Boussioutas, Alex/0000-0002-8109-6897; Gehlenborg, Nils/0000-0003-0327-8297 FU Intramural Research Program; United States National Institutes of Health [5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, U54HG003273, P30CA16672] FX We are grateful to all the patients and families who contributed to this study and to C. Gunter and J. Weinstein for scientific editing, to M. Sheth for administrative support and to L. Omberg for support with the Sage Bionetworks Synapse platform. This work was supported by the Intramural Research Program and the following grants from the United States National Institutes of Health: 5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, U54HG003273 and P30CA16672. NR 40 TC 373 Z9 393 U1 31 U2 146 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 SEP 11 PY 2014 VL 513 IS 7517 BP 202 EP 209 DI 10.1038/nature13480 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO5DP UT WOS:000341362800044 ER PT J AU Hsieh, C Kong, J Kirsch, I Edwards, RR Jensen, KB Kaptchuk, TJ Gollub, RL AF Hsieh, Christine Kong, Jian Kirsch, Irving Edwards, Robert R. Jensen, Karin B. Kaptchuk, Ted J. Gollub, Randy L. TI Well-Loved Music Robustly Relieves Pain: A Randomized, Controlled Trial SO PLOS ONE LA English DT Article ID PLACEBO-INDUCED EXPECTATIONS; DOPAMINE RELEASE; NUCLEUS-ACCUMBENS; OPIOID SYSTEMS; ANALGESIA; EMOTION; EXPECTANCY; RESPONSES; REWARD; BRAIN AB Music has pain-relieving effects, but its mechanisms remain unclear. We sought to verify previously studied analgesic components and further elucidate the underpinnings of music analgesia. Using a well-characterized conditioning-enhanced placebo model, we examined whether boosting expectations would enhance or interfere with analgesia from strongly preferred music. A two-session experiment was performed with 48 healthy, pain experiment-naive participants. In a first cohort, 36 were randomized into 3 treatment groups, including music enhanced with positive expectancy, non-musical sound enhanced with positive expectancy, and no expectancy enhancement. A separate replication cohort of 12 participants received only expectancy-enhanced music following the main experiment to verify the results of expectancy-manipulation on music. Primary outcome measures included the change in subjective pain ratings to calibrated experimental noxious heat stimuli, as well as changes in treatment expectations. Without conditioning, expectations were strongly in favor of music compared to non-musical sound. While measured expectations were enhanced by conditioning, this failed to affect either music or sound analgesia significantly. Strongly preferred music on its own was as pain relieving as conditioning-enhanced strongly preferred music, and more analgesic than enhanced sound. Our results demonstrate the pain-relieving power of personal music even over enhanced expectations. C1 [Hsieh, Christine; Kong, Jian; Jensen, Karin B.; Gollub, Randy L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Hsieh, Christine; Kong, Jian; Jensen, Karin B.; Gollub, Randy L.] Harvard Univ, Sch Med, Boston, MA USA. [Kirsch, Irving; Kaptchuk, Ted J.] Harvard Univ, Sch Med, Program Placebo Studies & Therapeut Encounter PiP, Boston, MA USA. [Kirsch, Irving; Kaptchuk, Ted J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Kirsch, Irving] Univ Plymouth, Dept Psychol, Plymouth PL4 8AA, Devon, England. [Edwards, Robert R.] Brigham & Womens Hosp, Dept Anesthesiol, Boston, MA 02115 USA. [Jensen, Karin B.; Gollub, Randy L.] Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA USA. [Jensen, Karin B.; Gollub, Randy L.] Massachusetts Gen Hosp, Charlestown, MA USA. RP Hsieh, C (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM xtine.hsieh@gmail.com OI Jensen, Karin/0000-0003-2521-3160 FU Harvard-MIT Health Sciences and Technology IDEA2 award; NIH [R01 AT 005280] FX Funding was provided by the Harvard-MIT Health Sciences and Technology IDEA2 award (Hsieh) and NIH grant R01 AT 005280 (Gollub/Kaptchuk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 2 Z9 2 U1 3 U2 25 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 SEP 11 PY 2014 VL 9 IS 9 AR e107390 DI 10.1371/journal.pone.0107390 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP1UA UT WOS:000341855900070 PM 25211164 ER PT J AU McMurray, JJV Packer, M Desai, AS Gong, JJ Lefkowitz, MP Rizkala, AR Rouleau, JL Shi, VC Solomon, SD Swedberg, K Zile, MR AF McMurray, John J. V. Packer, Milton Desai, Akshay S. Gong, Jianjian Lefkowitz, Martin P. Rizkala, Adel R. Rouleau, Jean L. Shi, Victor C. Solomon, Scott D. Swedberg, Karl Zile, Michael R. CA PARADIGM-HF Investigators Comm TI Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID NEUTRAL ENDOPEPTIDASE INHIBITION; CONVERTING ENZYME-INHIBITION; NATRIURETIC-PEPTIDE; RANDOMIZED-TRIAL; EJECTION FRACTION; DOUBLE-BLIND; MORTALITY; SURVIVAL; RECEPTOR; MORBIDITY AB BACKGROUND We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. METHODS In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. RESULTS The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P = 0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. CONCLUSIONS LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. C1 [McMurray, John J. V.] Univ Glasgow, British Heart Fdn BHF Cardiovasc Res Ctr, Glasgow G12 8QQ, Lanark, Scotland. [Packer, Milton] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. [Desai, Akshay S.; Solomon, Scott D.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Gong, Jianjian; Lefkowitz, Martin P.; Rizkala, Adel R.; Shi, Victor C.] Novartis Pharmaceut, E Hanover, NJ USA. [Rouleau, Jean L.] Univ Montreal, Inst Cardiol Montreal, Montreal, PQ, Canada. [Swedberg, Karl] Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden. [Swedberg, Karl] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW7 2AZ, England. [Zile, Michael R.] Med Univ S Carolina, Charleston, SC USA. [Zile, Michael R.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Packer, M (reprint author), Univ Texas SW Med Ctr Dallas, Dept Clin Sci, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM john.mcmurray@glasgow.ac.uk; milton.packer@utsouthwestern.edu RI Ramires, Felix/D-5996-2012; FMUP, CINTESIS/C-6631-2014; Silva-Cardoso, Jose/L-8033-2013; Libis, Roman/O-9193-2015; Rafalskiy, Vladimir/G-3172-2013; Zhilyaev, Evgeny/E-3774-2016; Torres, Filipa/G-9742-2016; Urina, Miguel/H-2605-2016; Drapkina, Oxana/G-8443-2016 OI Nightingale, Angus/0000-0001-9435-726X; Mohindra, Raj/0000-0002-8437-5066; Martinez-Selles, Manuel/0000-0003-0289-6229; Danzi, Gian Battista/0000-0003-0897-8006; mcmurray, john/0000-0002-6317-3975; Ramires, Felix/0000-0003-2437-2485; FMUP, CINTESIS/0000-0001-7248-2086; Silva-Cardoso, Jose/0000-0002-9774-9864; Libis, Roman/0000-0003-0130-990X; Bello, Natalie/0000-0003-3257-3623; Rafalskiy, Vladimir/0000-0002-2503-9580; Zhilyaev, Evgeny/0000-0002-9443-1164; Torres, Filipa/0000-0002-3138-9309; Urina, Miguel/0000-0001-6003-4622; Drapkina, Oxana/0000-0002-4453-8430 FU Novartis FX Supported by Novartis. NR 28 TC 579 Z9 599 U1 13 U2 95 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 SEP 11 PY 2014 VL 371 IS 11 BP 993 EP 1004 DI 10.1056/NEJMoa1409077 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA AO5KD UT WOS:000341382800005 PM 25176015 ER PT J AU Ryan, DP Hong, TS Bardeesy, N AF Ryan, David P. Hong, Theodore S. Bardeesy, Nabeel TI Pancreatic Adenocarcinoma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID PHASE-III TRIAL; RANDOMIZED CONTROLLED-TRIAL; CONTROL CONSORTIUM PANC4; LONG-TERM OUTCOMES; DUCTAL ADENOCARCINOMA; INTRAEPITHELIAL NEOPLASIA; ADJUVANT CHEMOTHERAPY; CANCER STATISTICS; PLUS GEMCITABINE; POOLED ANALYSIS C1 [Ryan, David P.; Bardeesy, Nabeel] Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. [Hong, Theodore S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Ryan, DP (reprint author), Massachusetts Gen Hosp, Dept Med, 15 Fruit St, Boston, MA 02114 USA. EM dpryan@mgh.harvard.edu FU MedImmune; Boehringer Ingelheim; Illumina FX Dr. Ryan reports receiving fees for serving on an advisory board from MedImmune, consulting fees from Boehringer Ingelheim and Illumina, and travel support from EMD Serono. No other potential conflict of interest relevant to this article was reported. NR 76 TC 267 Z9 277 U1 11 U2 61 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 SEP 11 PY 2014 VL 371 IS 11 BP 1039 EP 1049 DI 10.1056/NEJMra1404198 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AO5KD UT WOS:000341382800009 PM 25207767 ER PT J AU Graubert, TA AF Graubert, Timothy A. TI A Call to Action for Acute Lymphoblastic Leukemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID KINASE C1 Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Graubert, TA (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. OI Graubert, Timothy/0000-0002-7710-1171 NR 6 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 11 PY 2014 VL 371 IS 11 BP 1064 EP 1066 DI 10.1056/NEJMe1407477 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AO5KD UT WOS:000341382800014 PM 25207770 ER PT J AU Bartley, K Wildiers, H Kim, SB Krop, IE Kang, J Yu, R Leung, ACF Trudeau, C Gonzalez-Martin, A AF Bartley, Karen Wildiers, Hans Kim, Sung-Bae Krop, Ian E. Kang, Jennifer Yu, Ron Leung, Abraham C. F. Trudeau, Caroline Gonzalez-Martin, Antonio TI Patient-reported outcomes (PkOs) from TH3RESA, a phase 3 study of trastuzumab emtansine, (T-DM1) versus treatment of physician's choice (TPC) in patients With pretreated HER2-positive advanced breast cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Breast Cancer Symposium CY SEP 04-06, 2014 CL San Francisco, CA SP Amer Soc Clin Oncol C1 Genentech Inc, San Francisco, CA 94080 USA. Univ Hosp Leuven, Leuven, Belgium. Univ Ulsan, Coll Med, Asan Med Ctr, Dept Oncol, Seoul, South Korea. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. MD Anderson Canc Ctr, Madrid, Spain. 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 SEP 10 PY 2014 VL 32 IS 26 SU S MA 153 PG 1 WC Oncology SC Oncology GA CN2JK UT WOS:000358246700151 ER PT J AU Kroenke, CH Michael, Y Shu, XO Poole, E Kwan, ML Caan, BJ Nechuta, S Pierce, JP Chen, WY AF Kroenke, Candyce H. Michael, Yvonne Shu, Xiao-Ou Poole, Elizabeth Kwan, Marilyn L. Caan, Bette J. Nechuta, Sarah Pierce, John P. Chen, Wendy Y. TI Poodiagnosis social networks and liteslyle and treatment mechanisms in the Ater Hreast Cancer Pooling Project (ABCPP) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Breast Cancer Symposium CY SEP 04-06, 2014 CL San Francisco, CA SP Amer Soc Clin Oncol C1 Kaiser Pemianente Div Res, Oakland, CA USA. Drexel Univ, Philadelphia, PA 19104 USA. Vanderbilt Univ, Med Ctr, Nashville, TN USA. Harvard Univ, Sch Med, Channing Lab, Boston, MA 02115 USA. Kaiser Permanente No Calif, Oakland, CA USA. UCSD Moores Canc Ctr, La Jolla, CA 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 SEP 10 PY 2014 VL 32 IS 26 SU S MA 116 PG 1 WC Oncology SC Oncology GA CN2JK UT WOS:000358246700114 ER PT J AU Munster, PN Hamilton, EP Estevez, LG De Boer, RH Mayer, IA Campone, M Asano, S Bhansali, S Zhang, V Hewes, B Juric, D AF Munster, Pamela N. Hamilton, Erika Paige Estevez, Laura G. De Boer, Richard H. Mayer, Ingrid A. Campone, Mario Asano, Shizuka Bhansali, Suraj Zhang, Vickie Hewes, Becker Juric, Dejan TI Ph IB study of LEE011 and BYL719 in combination with letrozole in ER+, Her2-breast cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Breast Cancer Symposium CY SEP 04-06, 2014 CL San Francisco, CA SP Amer Soc Clin Oncol C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Sarch Cannon Res Inst, Nashville, TN USA. Hosp San Chinarro, Madrid, Spain. Royal Melbourne Hosp, Melbourne, Vic, Australia. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Inst Cancerol Ouest, Nantes, France. Novartis Inst BioMed Res, Cambridge, MA USA. Novartis Pharmaceut, E Hanover, NJ USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 10 PY 2014 VL 32 IS 26 SU S MA 143 PG 1 WC Oncology SC Oncology GA CN2JK UT WOS:000358246700141 ER PT J AU Sparano, JA Gray, RJ Zujewski, JA Whelan, TJ Albain, KS Hayes, D Geyer, CE Dees, EC Perez, EA Keane, MM Sologuren, CV Goggins, TF Mayer, IA Brufsky, A Toppmeyer, DL Kaklamani, VG Atkins, JN Berenberg, JL Sledge, GW AF Sparano, Joseph A. Gray, Robert J. Zujewski, Jo Anne Whelan, Timothy Joseph Albain, Kathy S. Hayes, Daniel Geyer, Charles E. Dees, Elizabeth Claire Perez, Edith A. Keane, Maccon M. Sologuren, Carlos Vallejos Goggins, Timothy F. Mayer, Ingrid A. Brufsky, Adam Toppmeyer, Deborah L. Kaklamani, Virginia G. Atkins, James N. Berenberg, Jeffrey L. Sledge, George W. TI Recurrence score and clinicopathologic characteristics of TAILORx participants by race and ethnicity SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Breast Cancer Symposium CY SEP 04-06, 2014 CL San Francisco, CA SP Amer Soc Clin Oncol C1 Montefiore Med Ctr, Bronx, NY 10467 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, NIH, Bethesda, MD 20892 USA. Juravinski Canc Ctr, Hamilton, ON, Canada. Loyola Univ, Med Ctr, Maywood, IL 60153 USA. Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. Allegheny Canc Ctr, Pittsburgh, PA USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Mayo Clin, Jacksonville, FL 32224 USA. Univ Coll Hosp Galway, Dept Med Oncol, Galway, Ireland. Inst Nacl Enfermedades Neoplas, Lima, Peru. Fox Valley Hematol & Oncol, Appleton, WI USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. Northwestern Univ, Chicago, IL 60611 USA. SE Canc Control Consortium, Goldsboro, NC USA. Univ Hawaii, MBCOPP, Honolulu, HI 96822 USA. Stanford Univ, Palo Alto, CA 94304 USA. RI Whelan, Timothy/D-3185-2017 NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 10 PY 2014 VL 32 IS 26 SU S MA 36 PG 1 WC Oncology SC Oncology GA CN2JK UT WOS:000358246700037 ER PT J AU Margolis, HC Kwak, SY Yamazaki, H AF Margolis, Henry C. Kwak, Seo-Young Yamazaki, Hajime TI Role of mineralization inhibitors in the regulation of hard tissue biomineralization: relevance to initial enamel formation and maturation SO FRONTIERS IN PHYSIOLOGY LA English DT Review DE amorphous calcium phosphate; biomineralization; dental enamel; inhibitors; mineral phase transformation ID AMORPHOUS CALCIUM-PHOSPHATE; AMELOGENESIS IMPERFECTA PHENOTYPE; HUMAN SALIVARY PROTEINS; FORMATION IN-VITRO; OCTACALCIUM PHOSPHATE; CRYSTAL-GROWTH; RAT INCISOR; MATRIX PROTEINS; DENTAL ENAMEL; MICE DISPLAY AB Vertebrate mineralized tissues, i.e., enamel, dentin, cementum, and bone, have unique hierarchical structures and chemical compositions. Although these tissues are similarly comprised of a crystalline calcium apatite mineral phase and a protein component, they differ with respect to crystal size and shape, level and distribution of trace mineral ions, the nature of the proteins present, and their relative proportions of mineral and protein components. Despite apparent differences, mineralized tissues are similarly derived by highly concerted extracellular processes involving matrix proteins, proteases, and mineral ion fluxes that collectively regulate the nucleation, growth and organization of forming mineral crystals. Nature, however, provides multiple ways to control the onset, rate, location, and organization of mineral deposits in developing mineralized tissues. Although our knowledge is quite limited in some of these areas, recent evidence suggests that hard tissue formation is, in part, controlled through the regulation of specific molecules that inhibit the mineralization process. This paper addresses the role of mineralization inhibitors in the regulation of biological mineralization with emphasis on the relevance of current findings to the process of amelogenesis. Mineralization inhibitors can also serve to maintain driving forces for calcium phosphate precipitation and prevent unwanted mineralization. Recent evidence shows that native phosphorylated amelogenins have the capacity to prevent mineralization through the stabilization of an amorphous calcium phosphate precursor phase, as observed in vitro and in developing teeth. Based on present findings, the authors propose that the transformation of initially formed amorphous mineral deposits to enamel crystals is an active process associated with the enzymatic processing of amelogenins. Such processing may serve to control both initial enamel crystal formation and subsequent maturation. C1 [Margolis, Henry C.; Kwak, Seo-Young; Yamazaki, Hajime] Forsyth Inst, Ctr Biomineralizat, Dept Appl Oral Sci, Cambridge, MA 02142 USA. [Margolis, Henry C.; Kwak, Seo-Young; Yamazaki, Hajime] Harvard Univ, Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. RP Margolis, HC (reprint author), Forsyth Inst, Ctr Biomineralizat, Dept Appl Oral Sci, 245 First St, Cambridge, MA 02142 USA. EM hmargolis@forsyth.org FU NIDCR [R01-DE023091] FX This work is supported by NIDCR grant R01-DE023091 (Henry C. Margolis). NR 99 TC 7 Z9 7 U1 5 U2 36 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD SEP 10 PY 2014 VL 5 AR 339 DI 10.3389/fphys.2014.00339 PG 10 WC Physiology SC Physiology GA AX7HP UT WOS:000347087600001 PM 25309443 ER PT J AU Wessling, R Epple, P Altmann, S He, YJ Yang, L Henz, SR McDonald, N Wiley, K Bader, KC Glasser, C Mukhtar, MS Haigis, S Ghamsari, L Stephens, AE Ecker, JR Vidal, M Jones, JDG Mayer, KFX van Themaat, EV Weigel, D Schulze-Lefert, P Dangl, JL Panstruga, R Braun, P AF Wessling, Ralf Epple, Petra Altmann, Stefan He, Yijian Yang, Li Henz, Stefan R. McDonald, Nathan Wiley, Kristin Bader, Kai Christian Glaesser, Christine Mukhtar, M. Shahid Haigis, Sabine Ghamsari, Lila Stephens, Amber E. Ecker, Joseph R. Vidal, Marc Jones, Jonathan D. G. Mayer, Klaus F. X. van Themaat, Emiel Ver Loren Weigel, Detlef Schulze-Lefert, Paul Dangl, Jeffery L. Panstruga, Ralph Braun, Pascal TI Convergent Targeting of a Common Host Protein-Network by Pathogen Effectors from Three Kingdoms of Life SO CELL HOST & MICROBE LA English DT Article ID PLANT IMMUNE-SYSTEM; ARABIDOPSIS-THALIANA; TRIGGERED IMMUNITY; OBLIGATE BIOTROPH; GENOME; EVOLUTION; RESISTANCE; CELL; LOCALIZATION; PARASITISM AB While conceptual principles governing plant immunity are becoming clear, its systems-level organization and the evolutionary dynamic of the host-pathogen interface are still obscure. We generated a systematic protein-protein interaction network of virulence effectors from the ascomycete pathogen Golovinomyces orontii and Arabidopsis thaliana host proteins. We combined this data set with corresponding data for the eubacterial pathogen Pseudomonas syringae and the oomycete pathogen Hyaloperonospora arabidopsidis. The resulting network identifies host proteins onto which intraspecies and interspecies pathogen effectors converge. Phenotyping of 124 Arabidopsis effector-interactor mutants revealed a correlation between intraspecies and interspecies convergence and several altered immune response phenotypes. Several effectors and the most heavily targeted host protein colocalized in subnuclear foci. Products of adaptively selected Arabidopsis genes are enriched for interactions with effector targets. Our data suggest the existence of a molecular host-pathogen interface that is conserved across Arabidopsis accessions, while evolutionary adaptation occurs in the immediate network neighborhood of effector targets. C1 [Wessling, Ralf; Haigis, Sabine; Stephens, Amber E.; van Themaat, Emiel Ver Loren; Schulze-Lefert, Paul; Panstruga, Ralph] Max Planck Inst Plant Breeding Res, Dept Plant Microbe Interact, D-50829 Cologne, Germany. [Epple, Petra; He, Yijian; Yang, Li; McDonald, Nathan; Wiley, Kristin; Mukhtar, M. Shahid; Dangl, Jeffery L.] Univ N Carolina, Howard Hughes Med Inst, Chapel Hill, NC 27599 USA. [Epple, Petra; He, Yijian; Yang, Li; McDonald, Nathan; Wiley, Kristin; Mukhtar, M. Shahid; Dangl, Jeffery L.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Altmann, Stefan; Braun, Pascal] TUM, Ctr Life & Food Sci Weihenstephan, Dept Plant Syst Biol, D-85354 Freising Weihenstephan, Germany. [Henz, Stefan R.; Weigel, Detlef] Max Planck Inst Dev Biol, Dept Mol Biol, D-72076 Tubingen, Germany. [Bader, Kai Christian; Glaesser, Christine; Mayer, Klaus F. X.] Helmholtz Zentrum Munchen, Plant Genome & Syst Biol, D-85764 Neuherberg, Germany. [Mukhtar, M. Shahid] Univ Alabama Birmingham, Dept Biol, Birmingham, AL 35294 USA. [Ghamsari, Lila; Vidal, Marc] Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA. [Ghamsari, Lila; Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Ghamsari, Lila; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02215 USA. [Ecker, Joseph R.] Howard Hughes Med Inst, La Jolla, CA 92037 USA. [Ecker, Joseph R.] Salk Inst Biol Studies, Plant Biol Lab, La Jolla, CA 92037 USA. [Jones, Jonathan D. G.] John Innes Ctr, Sainsbury Lab, Norwich NR4 7UH, Norfolk, England. [Dangl, Jeffery L.] Univ N Carolina, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA. [Dangl, Jeffery L.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Dangl, Jeffery L.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Panstruga, Ralph] Univ Aachen, Rhein Westfal TH Aachen, Inst Biol 1, Unit Plant Mol Cell Biol, D-52074 Aachen, Germany. RP Dangl, JL (reprint author), Univ N Carolina, Howard Hughes Med Inst, Chapel Hill, NC 27599 USA. EM dangl@email.unc.edu; panstruga@bio1.rwth-aachen.de; pbraun@wzw.tum.de RI Weigel, Detlef/C-1418-2008; Panstruga, Ralph/F-3340-2011; Ecker, Joseph/B-9144-2008; Braun, Pascal/B-9669-2013; Mayer, Klaus/M-7941-2015; Schulze-Lefert, Paul/B-6707-2011; Jones, Jonathan/J-5129-2012 OI Weigel, Detlef/0000-0002-2114-7963; Panstruga, Ralph/0000-0002-3756-8957; Ecker, Joseph/0000-0001-5799-5895; Braun, Pascal/0000-0003-2012-6746; Mayer, Klaus/0000-0001-6484-1077; Jones, Jonathan/0000-0002-4953-261X FU National Science Foundation [IOS-1257373]; National Institutes of Health [1RO1 GM107444]; Gordon and Betty Moore Foundation [GBMF3030, GBMF 2550.02]; HHMIDistinguished Guest Professorship, Eberhard-Karls-Universitat, Tubingen, Germany; International Max-Planck Research School (IMPRS); Deutsche Forschungsgemeinschaft (DFG) [SFB924]; Max-Planck society FX We thank Axel Kunstner for helpful discussions about the population genetic analysis. This work was funded by grants to J.L.D. from the National Science Foundation (IOS-1257373), the National Institutes of Health (1RO1 GM107444), the Gordon and Betty Moore Foundation (GBMF3030), and the HHMI. R.W. was supported by a PhD fellowship from the International Max-Planck Research School (IMPRS). J.L.D. is an Investigator of the Howard Hughes Medical Institute. L.Y. was funded in part by the Gordon and Betty Moore Foundation through Grant GBMF 2550.02 to the Life Sciences Research Foundation. Y.H. was supported by a Distinguished Guest Professorship, Eberhard-Karls-Universitat, Tubingen, Germany to J.L.D.S.A. and P.B. are supported by the Deutsche Forschungsgemeinschaft (DFG) grant SFB924. R.P. and P.S.- L. were supported by grants from the Max-Planck society. We thank Dr. Meng Chen, Duke University, for 35S: phyB-CFP and useful discussions regarding subnuclear foci. NR 47 TC 49 Z9 50 U1 8 U2 69 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 SEP 10 PY 2014 VL 16 IS 3 BP 364 EP 375 DI 10.1016/j.chom.2014.08.004 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AP4OL UT WOS:000342057000013 PM 25211078 ER PT J AU Sheehan, JP Yen, CP Lee, CC Loeffler, JS AF Sheehan, Jason P. Yen, Chun-Po Lee, Cheng-Chia Loeffler, Jay S. TI Cranial Stereotactic Radiosurgery: Current Status of the Initial Paradigm Shifter SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID GAMMA-KNIFE RADIOSURGERY; NONFUNCTIONING PITUITARY-ADENOMAS; BRAIN RADIATION-THERAPY; CEREBRAL ARTERIOVENOUS-MALFORMATIONS; MULTISESSION CYBERKNIFE RADIOSURGERY; LINEAR-ACCELERATOR RADIOSURGERY; FAILED TRANSSPHENOIDAL SURGERY; RANDOMIZED PHASE-III; LONG-TERM OUTCOMES; FOLLOW-UP AB The concept of stereotactic radiosurgery (SRS) was first described by Lars Leksell in 1951. It was proposed as a noninvasive alternative to open neurosurgical approaches to manage a variety of conditions. In the following decades, SRS emerged as a unique discipline involving a collegial partnership among neurosurgeons, radiation oncologists, and medical physicists. SRS relies on the precisely guided delivery of high-dose ionizing radiation to an intracranial target. The focused convergence of multiple beams yields a potent therapeutic effect on the target and a steep dose fall-off to surrounding structures, thereby minimizing the risk of collateral damage. SRS is typically administered in a single session but can be given in as many as five sessions or fractions. By providing an ablative effect noninvasively, SRS has altered the treatment paradigms for benign and malignant intracranial tumors, functional disorders, and vascular malformations. Literature on extensive intracranial radiosurgery has unequivocally demonstrated the favorable benefit-to-risk profile that SRS affords for appropriately selected patients. In a departure from conventional radiotherapeutic strategies, radiosurgical principles have recently been extended to extracranial indications such as lung, spine, and liver tumors. The paradigm shift resulting from radiosurgery continues to alter the landscape of related fields. (C) 2014 by American Society of Clinical Oncology C1 [Sheehan, Jason P.; Yen, Chun-Po; Lee, Cheng-Chia] Univ Virginia, Charlottesville, VA 22908 USA. [Loeffler, Jay S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Sheehan, JP (reprint author), Univ Virginia, Dept Neurol Surg, Charlottesville, VA 22908 USA. EM jsheehan@virginia.edu NR 134 TC 7 Z9 7 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 10 PY 2014 VL 32 IS 26 BP 2836 EP 2846 DI 10.1200/JCO.2013.53.7365 PG 11 WC Oncology SC Oncology GA AP4PQ UT WOS:000342060700004 PM 25113762 ER PT J AU Mitin, T Zietman, AL AF Mitin, Timur Zietman, Anthony L. TI Promise and Pitfalls of Heavy-Particle Therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID PARTIAL-BREAST IRRADIATION; PROTON RADIATION-THERAPY; LOCALIZED PROSTATE-CANCER; PHASE-II TRIAL; LUNG-CANCER; PHOTON RADIOTHERAPY; CHILDHOOD-CANCER; RANGE UNCERTAINTIES; PROGNOSTIC-FACTORS; BENIGN MENINGIOMA AB Proton beam therapy, the most common form of heavy-particle radiation therapy, is not a new invention, but it has gained considerable public attention because of the high cost of installing and operating the rapidly increasing number of treatment centers. This article reviews the physical properties of proton beam therapy and focuses on the up-to-date clinical evidence comparing proton beam therapy with the more standard and widely available radiation therapy treatment alternatives. In a cost-conscious era of health care, the hypothetical benefits of proton beam therapy will have to be supported by demonstrable clinical gains. Proton beam therapy represents, through its scale and its cost, a battleground for the policy debate around managing expensive technology in modern medicine. (C) 2014 by American Society of Clinical Oncology C1 [Mitin, Timur] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Mitin, T (reprint author), Oregon Hlth & Sci Univ, Dept Radiat Med, 3181 SW Sam Jackson Pk Rd,M-C KPV4, Portland, OR 97239 USA. EM mitin@ohsu.edu NR 87 TC 19 Z9 21 U1 2 U2 15 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 SEP 10 PY 2014 VL 32 IS 26 BP 2855 EP + DI 10.1200/JCO.2014.55.1945 PG 10 WC Oncology SC Oncology GA AP4PQ UT WOS:000342060700006 PM 25113772 ER PT J AU Wang, DH Buckner, RL Liu, HS AF Wang, Danhong Buckner, Randy L. Liu, Hesheng TI Functional Specialization in the Human Brain Estimated By Intrinsic Hemispheric Interaction SO JOURNAL OF NEUROSCIENCE LA English DT Article DE asymmetry; cognitive control; default mode; fMRI; functional connectivity; lateralization ID RESTING-STATE; PREFRONTAL CORTEX; DEFAULT NETWORK; CEREBRAL-CORTEX; REGIONAL-VARIATION; CONNECTIVITY MRI; CORPUS-CALLOSUM; MOTOR CORTEX; HEAD MOTION; LATERALIZATION AB The human brain demonstrates functional specialization, including strong hemispheric asymmetries. Here specialization was explored using fMRI by examining the degree to which brain networks preferentially interact with ipsilateral as opposed to contralateral networks. Preferential within-hemisphere interaction was prominent in the heteromodal association cortices and minimal in the sensorimotor cortices. The frontoparietal control network exhibited strong within-hemisphere interactions but with distinct patterns in each hemisphere. The frontoparietal control network preferentially coupled to the default network and language-related regions in the left hemisphere but to attention networks in the right hemisphere. This arrangement may facilitate control of processing functions that are lateralized. Moreover, the regions most linked to asymmetric specialization also display the highest degree of evolutionary cortical expansion. Functional specialization that emphasizes processing within a hemisphere may allow the expanded hominin brain to minimize between-hemisphere connectivity and distribute domain-specific processing functions. C1 [Wang, Danhong; Buckner, Randy L.; Liu, Hesheng] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Wang, Danhong; Buckner, Randy L.; Liu, Hesheng] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Wang, Danhong; Buckner, Randy L.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Buckner, Randy L.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Buckner, Randy L.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. RP Liu, HS (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM Hesheng@nmr.mgh.harvard.edu FU National Institute of Neurological Disorders and Stroke [K25NS069805]; National Alliance for Research on Schizophrenia and Depression Young Investigator Grant; National Institute on Aging [AG021910]; National Center for Research Resources [P41RR14074]; Massachusetts General Hospital-University of California; Los Angeles Human Connectome Project [U54MH091665]; Simons Foundation FX This work was supported by National Institute of Neurological Disorders and Stroke Grant K25NS069805, National Alliance for Research on Schizophrenia and Depression Young Investigator Grant, National Institute on Aging Grant AG021910, National Center for Research Resources Grant P41RR14074, the Massachusetts General Hospital-University of California, Los Angeles Human Connectome Project (U54MH091665), and the Simons Foundation. The authors thank B. T. Thomas Yeo, Mert Sabuncu, Avram Holmes, and Sophia Mueller for discussion and technical assistance. NR 76 TC 27 Z9 28 U1 3 U2 28 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 10 PY 2014 VL 34 IS 37 BP 12341 EP 12352 DI 10.1523/JNEUROSCI.0787-14.2014 PG 12 WC Neurosciences SC Neurosciences & Neurology GA AP0QH UT WOS:000341766900010 PM 25209275 ER PT J AU Price, JD Park, KY Chen, JD Salinas, RD Cho, MJ Kriegstein, AR Lim, DA AF Price, James D. Park, Ki-Youb Chen, Jiadong Salinas, Ryan D. Cho, Mathew J. Kriegstein, Arnold R. Lim, Daniel A. TI The Ink4a/Arf Locus Is a Barrier to Direct Neuronal Transdifferentiation SO JOURNAL OF NEUROSCIENCE LA English DT Article DE astroglia; induced neuron; Ink4a/Arf; transcription factor; transdifferentiation ID NEURAL STEM-CELLS; GROWTH-FACTOR RECEPTOR; POSTNATAL ASTROGLIA; SELF-RENEWAL; GENERATION; INK4/ARF; CANCER; CORTEX; GLIA AB Non-neurogenic cell types, such as cortical astroglia and fibroblasts, can be directly converted into neurons by the overexpression of defined transcription factors. Normally, the cellular phenotype of such differentiated cells is remarkably stable and resists direct cell transdifferentiation. Here we show that the Ink4a/Arf (also known as Cdkn2a) locus is a developmental barrier to direct neuronal transdifferentiation induced by transcription factor overexpression. With serial passage in vitro, wild-type postnatal cortical astroglia become progressively resistant to Dlx2-induced neuronal transdifferentiation. In contrast, the neurogenic competence of Ink4a/Arf-deficient astroglia is both greatly increased and does not diminish through serial cell culture passage. Electrophysiological analysis further demonstrates the neuronal identity of cells induced from Ink4a/Arf-null astroglia, and short hairpin RNA-mediated acute knockdown of p16Ink4a and p19Arf p16(Ink4a) and p19(Arf) indicates that these gene products function postnatally as a barrier to cellular transdifferentiation. Finally, we found that mouse fibroblasts deficient for Ink4a/Arf also exhibit greatly enhanced transcription factor-induced neuronal induction. These data indicate that Ink4a/Arf is a potent barrier to direct neuronal transdifferentiation and further suggest that this locus functions normally in the progressive developmental restriction of postnatal astrocytes. C1 [Price, James D.; Park, Ki-Youb; Chen, Jiadong; Salinas, Ryan D.; Cho, Mathew J.; Kriegstein, Arnold R.; Lim, Daniel A.] Univ Calif San Francisco, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA. [Price, James D.; Lim, Daniel A.] Univ Calif San Francisco, Dev & Stem Cell Biol Grad Program, San Francisco, CA 94143 USA. [Price, James D.; Park, Ki-Youb; Salinas, Ryan D.; Cho, Mathew J.; Lim, Daniel A.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Chen, Jiadong; Kriegstein, Arnold R.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Lim, Daniel A.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. RP Lim, DA (reprint author), Univ Calif San Francisco, 35 Med Ctr Way, San Francisco, CA 94143 USA. EM Limd@neurosurg.ucsf.edu FU National Institutes of Health [DP2-OD006505-01]; Sontag Foundation; Northern California Institute for Research and Education/Department of Defense; Shurl and Kay Curci Foundation; San Francisco Veterans Affairs Medical Center FX This work was supported by National Institutes of Health DP2-OD006505-01, the Sontag Foundation, a Northern California Institute for Research and Education/Department of Defense subaward to D.A.L., the Shurl and Kay Curci Foundation, and the San Francisco Veterans Affairs Medical Center for resources. NR 31 TC 5 Z9 5 U1 2 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 10 PY 2014 VL 34 IS 37 BP 12560 EP 12567 DI 10.1523/JNEUROSCI.3159-13.2014 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AP0QH UT WOS:000341766900028 PM 25209293 ER PT J AU Sheets, L Hagen, MW Nicolson, T AF Sheets, Lavinia Hagen, Matthew W. Nicolson, Teresa TI Characterization of Ribeye Subunits in Zebrafish Hair Cells Reveals That Exogenous Ribeye B-Domain and CtBP1 Localize to the Basal Ends of Synaptic Ribbons SO PLOS ONE LA English DT Article ID CA2+ CHANNELS; SYNAPSES; PROTEINS; EXOCYTOSIS; RELEASE; BASSOON; GENES AB Synaptic ribbons are presynaptic structures formed by the self-association of RIBEYE-the main structural component of ribbon synapses. RIBEYE consists of two domains: a unique N-terminal A-domain and a C-terminal B-domain that is identical to the transcription co-repressor C-terminal binding protein 2 (CtBP2). Previous studies in cell lines have shown that RIBEYE A-domain alone is sufficient to form ribbon-like aggregates and that both A- and B-domains form homo-and heterotypic interactions. As these interactions are likely the basis for synaptic-ribbon assembly and structural plasticity, we wanted to examine how zebrafish Ribeye A- and B-domains interact with synaptic ribbons in vivo. To that end, we characterized the localization of exogenously expressed Ribeye A-and B-domains and the closely related protein, CtBP1, in the hair cells of transgenic zebrafish larvae. Unexpectedly, exogenously expressed Ribeye A-domain showed variable patterns of localization in hair cells; one zebrafish paralog of A-domain failed to self-associate or localize to synaptic ribbons, while the other self-assembled but sometimes failed to localize to synaptic ribbons. By contrast, Ribeye B-domain/CtBP2 was robustly localized to synaptic ribbons. Moreover, both exogenously expressed B-domain/CtBP2 and CtBP1 were preferentially localized to the basal end of ribbons adjacent to the postsynaptic density. Overexpression of B-domain/CtBP2 also appeared to affect synaptic-ribbon composition; endogenous levels of ribbon-localized Ribeye were significantly reduced as hair cells matured in B-domain/CtBP2 transgenic larvae compared to wild-type. These results reveal how exogenously expressed Ribeye domains interact with synaptic ribbons, and suggest a potential organization of elements within the ribbon body. C1 [Sheets, Lavinia] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Sheets, Lavinia] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Hagen, Matthew W.; Nicolson, Teresa] Oregon Hlth & Sci Univ, Oregon Hearing Res Ctr, Portland, OR 97201 USA. [Hagen, Matthew W.; Nicolson, Teresa] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97201 USA. RP Sheets, L (reprint author), Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. EM Lavinia_Sheets@meei.harvard.edu OI Hagen, Matthew/0000-0002-9812-2262; Sheets, Lavinia/0000-0001-5231-2450 FU National Institutes of Health [R01 DC006880]; Howard Hughes Medical Institute; National Institute on Deafness and Other Communicative Disorders (Eaton-Peabody Lab) [P30 DC05029]; Jean Vollum Fund; Amelia Peabody Charitable Fund FX Funding was provided by National Institutes of Health R01 DC006880 (TN), Howard Hughes Medical Institute (TN), National Institute on Deafness and Other Communicative Disorders P30 DC05029 (M. Charles Liberman Core Grant, Eaton-Peabody Lab), Jean Vollum Fund (MWH), and Amelia Peabody Charitable Fund (LS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 5 Z9 5 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 SEP 10 PY 2014 VL 9 IS 9 AR e107256 DI 10.1371/journal.pone.0107256 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AP4EP UT WOS:000342030300068 PM 25208216 ER PT J AU Linos, E Schroeder, SA Chren, MM AF Linos, Eleni Schroeder, Steven A. Chren, Mary-Margaret TI Potential Overdiagnosis of Basal Cell Carcinoma in Older Patients With Limited Life Expectancy SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID NONMELANOMA-SKIN-CANCER C1 [Linos, Eleni; Chren, Mary-Margaret] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Schroeder, Steven A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Chren, Mary-Margaret] San Francisco VA Med Ctr, Dermatol Serv, San Francisco, CA USA. RP Linos, E (reprint author), Univ Calif San Francisco, Dept Dermatol, 2340 Sutter St,Room N421, San Francisco, CA 94143 USA. EM linose@derm.ucsf.edu OI Linos, Eleni/0000-0002-5856-6301; , Eleni/0000-0003-2538-0700 FU NCATS NIH HHS [KL2 TR000143]; NIAMS NIH HHS [K24 AR052667] NR 8 TC 10 Z9 10 U1 1 U2 4 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 SEP 10 PY 2014 VL 312 IS 10 BP 997 EP 998 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AO5LF UT WOS:000341385600013 PM 25203077 ER PT J AU O'Donoghue, ML Braunwald, E White, HD Steen, DP Lukas, MA Tarka, E Steg, PG Hochman, JS Bode, C Maggioni, AP Im, K Shannon, JB Davies, RY Murphy, SA Crugnale, SE Wiviott, SD Bonaca, MP Watson, DF Weaver, WD Serruys, PW Cannon, CP AF O'Donoghue, Michelle L. Braunwald, Eugene White, Harvey D. Steen, Dylan P. Lukas, Mary Ann Tarka, Elizabeth Steg, P. Gabriel Hochman, Judith S. Bode, Christoph Maggioni, Aldo P. Im, KyungAh Shannon, Jennifer B. Davies, Richard Y. Murphy, Sabina A. Crugnale, Sharon E. Wiviott, Stephen D. Bonaca, Marc P. Watson, David F. Weaver, W. Douglas Serruys, Patrick W. Cannon, Christopher P. CA SOLID-TIMI 52 Investigators TI Effect of Darapladib on Major Coronary Events After an Acute Coronary Syndrome The SOLID-TIMI 52 Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ACTIVATING-FACTOR ACETYLHYDROLASE; PHOSPHOLIPASE A(2); HEART-DISEASE; CARDIOVASCULAR OUTCOMES; ATHEROSCLEROTIC PLAQUE; MYOCARDIAL-INFARCTION; ISCHEMIC EVENTS; LIPOPROTEIN; RISK; MACROPHAGES AB IMPORTANCE Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has been hypothesized to be involved in atherogenesis through pathways related to inflammation. Darapladib is an oral, selective inhibitor of the Lp-PLA2 enzyme. OBJECTIVE To evaluate the efficacy and safety of darapladib in patients after an acute coronary syndrome (ACS) event. DESIGN, SETTING, AND PARTICIPANTS SOLID-TIMI 52 was a multinational, double-blind, placebo-controlled trial that randomized 13 026 participants within 30 days of hospitalization with an ACS (non-ST-elevation or ST-elevation myocardial infarction [MI]) at 868 sites in 36 countries. INTERVENTIONS Patients were randomized to either once-daily darapladib (160 mg) or placebo on a background of guideline-recommended therapy. Patients were followed up for a median of 2.5 years between December 7, 2009, and December 6, 2013. MAIN OUTCOMES AND MEASURES The primary end point (major coronary events) was the composite of coronary heart disease (CHD) death, MI, or urgent coronary revascularization for myocardial ischemia. Kaplan-Meier event rates are reported at 3 years. RESULTS During a median duration of 2.5 years, the primary end point occurred in 903 patients in the darapladib group and 910 in the placebo group (16.3% vs 15.6% at 3 years; hazard ratio [HR], 1.00 [95% CI, 0.91-1.09]; P = .93). The composite of cardiovascular death, MI, or stroke occurred in 824 in the darapladib group and 838 in the placebo group (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90-1.09]; P = .78). There were no differences between the treatment groups for additional secondary end points, for individual components of the primary end point, or in all-cause mortality (371 events in the darapladib group and 395 in the placebo group [7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82-1.08]; P = .40). Patients were more likely to report an odor-related concern in the darapladib group vs the placebo group (11.5% vs 2.5%) and also more likely to report diarrhea (10.6% vs 5.6%). CONCLUSIONS AND RELEVANCE In patients who experienced an ACS event, direct inhibition of Lp-PLA2 with darapladib added to optimal medical therapy and initiated within 30 days of hospitalization did not reduce the risk of major coronary events. C1 [O'Donoghue, Michelle L.; Braunwald, Eugene; Steen, Dylan P.; Im, KyungAh; Murphy, Sabina A.; Crugnale, Sharon E.; Wiviott, Stephen D.; Bonaca, Marc P.; Cannon, Christopher P.] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Boston, MA 02115 USA. [White, Harvey D.] Univ Auckland, Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland 1, New Zealand. [Lukas, Mary Ann] GlaxoSmithKline, Metab Pathways & Cardiovasc Therapeut Area, Philadelphia, PA USA. [Tarka, Elizabeth; Davies, Richard Y.] GlaxoSmithKline, Metab Pathways & Cardiovasc Therapeut Area, King Of Prussia, PA USA. [Steg, P. Gabriel] Hop Bichat Claude Bernard, AP HP, Dept Hosp Univ FIRE, F-75877 Paris, France. [Steg, P. Gabriel] Univ Paris Diderot, Paris, France. [Steg, P. Gabriel] NHLI Imperial Coll, ICMS Royal Brompton Hosp, London, England. [Hochman, Judith S.] NYU Langone Med Ctr, Dept Med, New York, NY USA. [Bode, Christoph] Univ Freiburg, Ctr Heart, Dept Cardiol & Angiol 1, D-79106 Freiburg, Germany. [Maggioni, Aldo P.] ANMCO Res Ctr, Florence, Italy. [Shannon, Jennifer B.; Watson, David F.] GlaxoSmithKline, Metab Pathways & Cardiovasc Therapeut Area, Res Triangle Pk, NC USA. [Weaver, W. Douglas] Henry Ford Hosp, Henry Ford Heart & Vasc Inst, Detroit, MI 48202 USA. [Serruys, Patrick W.] Erasmus Univ, Thoraxctr, NL-3000 DR Rotterdam, Netherlands. [Serruys, Patrick W.] Univ London Imperial Coll Sci Technol & Med, Int Ctr Circulatory Hlth, London, England. RP O'Donoghue, ML (reprint author), Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, 350 Longwood Ave,First Floor, Boston, MA 02115 USA. EM modonoghue@partners.org RI Lotufo, Paulo/A-9843-2008; Frey, Norbert/A-9695-2010; Benedek, Imre/E-7052-2017; Benedek, Theodora/F-6353-2016; Kobayashi, Junjiro/J-8547-2015; Libis, Roman/O-9193-2015; Arkhipov, Mikhail/Q-2316-2015; Colquhoun, David/F-9078-2013; Urina, Miguel/H-2605-2016; Zadionchenko, Vladimir/A-7445-2016; Katus, Hugo/P-1712-2016; Nicolau, Jose/E-1487-2012; ESPOSITO, Giovanni/F-2880-2010; OI Lotufo, Paulo/0000-0002-4856-8450; Benedek, Imre/0000-0003-0051-4047; Benedek, Theodora/0000-0001-8326-1537; Libis, Roman/0000-0003-0130-990X; Urina, Miguel/0000-0001-6003-4622; Zadionchenko, Vladimir/0000-0003-2377-5266; Goessling, Wolfram/0000-0001-9972-1569; ESPOSITO, Giovanni/0000-0003-0565-7127; Hochman, Judith/0000-0002-5889-5981; Maggioni, Aldo Pietro/0000-0003-2764-6779 FU GlaxoSmithKline FX The SOLID-TIMI 52 trial was funded by GlaxoSmithKline. NR 20 TC 99 Z9 106 U1 4 U2 44 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 SEP 10 PY 2014 VL 312 IS 10 BP 1006 EP 1015 DI 10.1001/jama.2014.11061 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AO5LF UT WOS:000341385600018 PM 25173516 ER PT J AU Tolenaar, JL Froehlich, W Jonker, FHW Upchurch, GR Rampoldi, V Tsai, TT Bossone, E Evangelista, A O'Gara, P Pape, L Montgomery, D Isselbacher, EM Nienaber, CA Eagle, KA Trimarchi, S AF Tolenaar, Jip L. Froehlich, Whit Jonker, Frederik H. W. Upchurch, Gilbert R., Jr. Rampoldi, Vincenzo Tsai, Thomas T. Bossone, Eduardo Evangelista, Arturo O'Gara, Patrick Pape, Linda Montgomery, Dan Isselbacher, Eric M. Nienaber, Christoph A. Eagle, Kim A. Trimarchi, Santi TI Predicting In-Hospital Mortality in Acute Type B Aortic Dissection Evidence From International Registry of Acute Aortic Dissection SO CIRCULATION LA English DT Article DE aorta; aortic dissection; risk model; type B dissection ID ENDOVASCULAR REPAIR; IRAD; INSIGHTS; OUTCOMES; SURGERY; THERAPY AB Background-The outcome of patients with acute type B aortic dissection (ABAD) is strongly related to their clinical presentation. The purpose of this study was to investigate predictors for mortality among patients presenting with ABAD and to create a predictive model to estimate individual risk of in-hospital mortality using the International Registry of Acute Aortic Dissection (IRAD). Methods and Results-All patients with ABAD enrolled in IRAD between 1996 and 2013 were included for analysis. Multivariable logistic regression analysis was used to investigate predictors of in-hospital mortality. Significant risk factors for in-hospital death were used to develop a prediction model. A total of 1034 patients with ABAD were included for analysis (673 men; mean age, 63.5 +/- 14.0 years), with an overall in-hospital mortality of 10.6%. In multivariable analysis, the following variables at admission were independently associated with increased in-hospital mortality: increasing age (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.00-1.06; P= 0.044), hypotension/shock (OR, 6.43; 95% CI, 2.88-18.98; P=0.001), periaortic hematoma (OR, 3.06; 95% CI, 1.38-6.78; P=0.006), descending diameter >= 5.5 cm (OR, 6.04; 95% CI, 2.87-12.73; P<0.001), mesenteric ischemia (OR, 9.03; 95% CI, 3.49-23.38; P<0.001), acute renal failure (OR, 3.61; 95% CI, 1.68-7.75; P=0.001), and limb ischemia (OR, 3.02; 95% CI, 1.05-8.68; P=0.040). Based on these multivariable results, a reliable and simple bedside risk prediction tool was developed. Conclusions-We present a simple prediction model using variables that are independently associated with in-hospital mortality in patients with ABAD. Although it needs to be validated in an independent population, this model could be used to assist physicians in their choice of management and for informing patients and their families. C1 [Tolenaar, Jip L.; Rampoldi, Vincenzo; Trimarchi, Santi] Policlin San Donato IRCCS, Thorac Aorta Res Ctr, Milan, Italy. [Tolenaar, Jip L.; Jonker, Frederik H. W.] Univ Med Ctr Utrecht, Dept Vasc Surg, Utrecht, Netherlands. [Froehlich, Whit; Montgomery, Dan; Eagle, Kim A.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Upchurch, Gilbert R., Jr.] Univ Virginia, Hlth Syst, Div Vasc & Endovasc Surg, Charlottesville, VA USA. [Tsai, Thomas T.] Univ Colorado, Dept Cardiol, Aurora, CO USA. [Bossone, Eduardo] Univ Salerno, Div Cardiol, I-84100 Salerno, Italy. [Evangelista, Arturo] Hosp Gen Univ Vall Hebron, Serv Cardiol, Barcelona, Spain. [O'Gara, Patrick] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. [Pape, Linda] Univ Massachusetts Hosp, Worcester, MA USA. [Isselbacher, Eric M.] Massachusetts Gen Hosp, Thorac Aort Ctr, Boston, MA 02114 USA. [Nienaber, Christoph A.] Univ Rostock, Dept Internal Med, D-18055 Rostock, Germany. RP Trimarchi, S (reprint author), Univ Milan, Policlin San Donato IRCCS, Thorac Aorta Res Ctr, Dept Cardiovasc Surg, Via Morandi 30, I-20097 San Donato Milanese, Italy. EM santi.trimarchi@unimi.it RI Trimarchi, Santi/J-7361-2016 OI Trimarchi, Santi/0000-0001-5996-3264 FU W. L. Gore & Associates, Inc; Medtronic; Varbedian Aortic Research Fund; Hewlett Foundation; Mardigian Foundation; UM Faculty Group Practice; Terumo; Ann and Bob Aikens FX The International Registry of Acute Aortic Dissection is generously supported by W. L. Gore & Associates, Inc, Medtronic, Varbedian Aortic Research Fund, Hewlett Foundation, Mardigian Foundation, UM Faculty Group Practice, Terumo, and Ann and Bob Aikens. NR 15 TC 15 Z9 15 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD SEP 9 PY 2014 VL 130 IS 11 SU 1 BP S45 EP S50 DI 10.1161/CIRCULATIONAHA.113.007117 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AT9ZW UT WOS:000345283800007 PM 25200055 ER PT J AU Shipitsin, M Small, C Choudhury, S Giladi, E Friedlander, S Nardone, J Hussain, S Hurley, AD Ernst, C Huang, YE Chang, H Nifong, TP Rimm, DL Dunyak, J Loda, M Berman, DM Blume-Jensen, P AF Shipitsin, M. Small, C. Choudhury, S. Giladi, E. Friedlander, S. Nardone, J. Hussain, S. Hurley, A. D. Ernst, C. Huang, Y. E. Chang, H. Nifong, T. P. Rimm, D. L. Dunyak, J. Loda, M. Berman, D. M. Blume-Jensen, P. TI Identification of proteomic biomarkers predicting prostate cancer aggressiveness and lethality despite biopsy-sampling error SO BRITISH JOURNAL OF CANCER LA English DT Article DE prostate cancer; biopsy; biomarkers; prognosis; sampling error; tumour heterogeneity ID GLEASON GRADING SYSTEM; RADICAL PROSTATECTOMY; ACTIVE SURVEILLANCE; RISK-ASSESSMENT; GENE PANEL; PROGRESSION; SCORE; VALIDATION; EXPRESSION; MEN AB Background: Key challenges of biopsy-based determination of prostate cancer aggressiveness include tumour heterogeneity, biopsy-sampling error, and variations in biopsy interpretation. The resulting uncertainty in risk assessment leads to significant overtreatment, with associated costs and morbidity. We developed a performance-based strategy to identify protein biomarkers predictive of prostate cancer aggressiveness and lethality regardless of biopsy-sampling variation. Methods: Prostatectomy samples from a large patient cohort with long follow-up were blindly assessed by expert pathologists who identified the tissue regions with the highest and lowest Gleason grade from each patient. To simulate biopsy-sampling error, a core from a high-and a low-Gleason area from each patient sample was used to generate a 'high' and a 'low' tumour microarray, respectively. Results: Using a quantitative proteomics approach, we identified from 160 candidates 12 biomarkers that predicted prostate cancer aggressiveness (surgical Gleason and TNM stage) and lethal outcome robustly in both high-and low-Gleason areas. Conversely, a previously reported lethal outcome-predictive marker signature for prostatectomy tissue was unable to perform under circumstances of maximal sampling error. Conclusions: Our results have important implications for cancer biomarker discovery in general and development of a sampling error-resistant clinical biopsy test for prediction of prostate cancer aggressiveness. C1 [Shipitsin, M.; Small, C.; Choudhury, S.; Giladi, E.; Friedlander, S.; Nardone, J.; Hussain, S.; Hurley, A. D.; Ernst, C.; Huang, Y. E.; Chang, H.; Nifong, T. P.; Dunyak, J.; Blume-Jensen, P.] Metamark Genet Inc, Cambridge, MA 02142 USA. [Rimm, D. L.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. [Loda, M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pathol, Boston, MA 02215 USA. [Berman, D. M.] Queens Univ, Dept Pathol & Mol Med, Kingston, ON K7L 3N6, Canada. [Berman, D. M.] Queens Univ, Queens Canc Res Inst, Kingston, ON K7L 3N6, Canada. RP Blume-Jensen, P (reprint author), Metamark Genet Inc, Cambridge, MA 02142 USA. EM Bermand@queensu.ca; pblumejensen@metamarkgenetics.com FU Metamark Genetics Inc FX We would like to thank Drs Raju Kucherlapati, Ronald DePinho, Lynda Chin, Philip Kantoff, and collaborators at Metamark for insightful comments and suggestions. We thank Rowena Hughes and Winnie McFadzean from Oxford PharmaGenesis Ltd for editorial support in collating comments from authors and finalisation of the manuscript for submission. Research support: this project was funded by Metamark Genetics Inc. NR 71 TC 25 Z9 26 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD SEP 9 PY 2014 VL 111 IS 6 BP 1201 EP 1212 DI 10.1038/bjc.2014.396 PG 12 WC Oncology SC Oncology GA AP2OA UT WOS:000341910900020 PM 25032733 ER PT J AU Schneider, BP Li, L Shen, F Miller, KD Radovich, M O'Neill, A Gray, RJ Lane, D Flockhart, DA Jiang, G Wang, Z Lai, D Koller, D Pratt, JH Dang, CT Northfelt, D Perez, EA Shenkier, T Cobleigh, M Smith, ML Railey, E Partridge, A Gralow, J Sparano, J Davidson, NE Foroud, T Sledge, GW AF Schneider, B. P. Li, L. Shen, F. Miller, K. D. Radovich, M. O'Neill, A. Gray, R. J. Lane, D. Flockhart, D. A. Jiang, G. Wang, Z. Lai, D. Koller, D. Pratt, J. H. Dang, C. T. Northfelt, D. Perez, E. A. Shenkier, T. Cobleigh, M. Smith, M. L. Railey, E. Partridge, A. Gralow, J. Sparano, J. Davidson, N. E. Foroud, T. Sledge, G. W. TI Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100 SO BRITISH JOURNAL OF CANCER LA English DT Article DE breast cancer; bevacizumab; hypertension; SNP; SV2C ID ENDOTHELIAL GROWTH-FACTOR; METASTATIC BREAST-CANCER; GENOME-WIDE ASSOCIATION; PACLITAXEL PLUS BEVACIZUMAB; PHASE-III; TRIAL; POLYMORPHISMS; SUNITINIB; EFFICACY; THERAPY AB Background: Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension. Methods: A genome-wide association study (GWAS) was performed in the phase III bevacizumab-based adjuvant breast cancer trial, ECOG-5103, to evaluate for an association between genotypes and hypertension. GWAS was conducted in those who had experienced systolic blood pressure (SBP) > 160mm Hg during therapy using binary analysis and a cumulative dose model for the total exposure of bevacizumab. Common toxicity criteria (CTC) grade 3-5 hypertension was also assessed. Candidate SNP validation was performed in the randomised phase III trial, ECOG-2100. Results: When using the phenotype of SBP>160mm Hg, the most significant association in SV2C (rs6453204) approached and met genome-wide significance in the binary model (P = 6.0 x 10(-8); OR = 3.3) and in the cumulative dose model (P =4.7 x 10(-8); HR = 2.2), respectively. Similar associations with rs6453204 were seen for CTC grade 3-5 hypertension but did not meet genome-wide significance. Validation study from ECOG-2100 demonstrated a statistically significant association between this SNP and grade 3/4 hypertension using the binary model (P-value = 0.037; OR = 2.4). Conclusions: A genetic variant in SV2C predicted clinically relevant bevacizumab-induced hypertension in two independent, randomised phase III trials. C1 [Schneider, B. P.; Shen, F.; Miller, K. D.; Lane, D.; Pratt, J. H.] Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Li, L.; Jiang, G.; Wang, Z.; Lai, D.; Koller, D.; Foroud, T.] Indiana Univ, Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Radovich, M.] Indiana Univ, Sch Med, Dept Gen Surg, Indianapolis, IN 46202 USA. [O'Neill, A.; Gray, R. J.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Flockhart, D. A.] Indiana Univ, Sch Med, Indiana Inst Personalized Med, Indianapolis, IN 46202 USA. [Dang, C. T.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Northfelt, D.] Mayo Clin, Dept Med, Scottsdale, AZ 85054 USA. [Perez, E. A.] Mayo Clin, Jacksonville, FL 32224 USA. [Shenkier, T.] British Columbia Canc Agcy, Vancouver Canc Ctr, Vancouver, BC V5Z 4E6, Canada. [Cobleigh, M.] Rush Presbyterian St Lukes Med Ctr, Dept Internal Med, Chicago, IL 60612 USA. [Smith, M. L.; Railey, E.] Res Advocacy Network, Plano, TX 75093 USA. [Partridge, A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Gralow, J.] Univ Washington, Seattle, WA 98195 USA. [Sparano, J.] Montefiore Hosp & Med Ctr, Dept Oncol, Bronx, NY 10467 USA. [Davidson, N. E.] Inst Canc Res, Pittsburgh, PA 15232 USA. [Davidson, N. E.] Univ Pittsburgh, Ctr Canc, Pittsburgh, PA 15232 USA. [Sledge, G. W.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. RP Schneider, BP (reprint author), Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46202 USA. EM bpschnei@iupui.edu FU Public Health Service Grants [CA23318, CA66636, CA21115, CA49883, CA14958, CA16116, CA39229, CA25224, CA12027, CA32102, CA20319, CA77202]; National Cancer Institute, National Institutes of Health and the Department of Health and Human Services; Susan G Komen for the Cure Promise Award; [CA155311-01A1] FX This study was coordinated by the Eastern Cooperative Oncology Group (Robert L Comis) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA49883, CA14958, CA16116, CA39229, CA25224, CA12027, CA32102, CA20319, CA77202, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Biospecimens were provided by the ECOG Pathology Coordinating Office and Reference Laboratory, and the procurement and preparation of samples was supported by the Breast Cancer Research Foundation (Daniel Hayes; PI). The science was also supported by a Susan G Komen for the Cure Promise Award (BPS; PI) and CA155311-01A1 (BPS; PI). NR 31 TC 9 Z9 10 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD SEP 9 PY 2014 VL 111 IS 6 BP 1241 EP 1248 DI 10.1038/bjc.2014.430 PG 8 WC Oncology SC Oncology GA AP2OA UT WOS:000341910900025 PM 25117820 ER PT J AU Berkowitz, AL Westover, MB Bianchi, MT Chou, SHY AF Berkowitz, Aaron L. Westover, M. Brandon Bianchi, Matt T. Chou, Sherry H-Y. TI Aspirin for secondary prevention after stroke of unknown etiology in resource-limited settings SO NEUROLOGY LA English DT Article ID ACUTE ISCHEMIC-STROKE; INTRACEREBRAL HEMORRHAGE; DEVELOPING-COUNTRIES; DECISION-ANALYSIS; ATRIAL-FIBRILLATION; REGIONAL BURDEN; GLOBAL BURDEN; RISK-FACTORS; DISEASE; TRIALS AB Objective: To analyze the potential impact of aspirin therapy for long-term secondary prevention after stroke of undetermined etiology in resource-limited settings without access to neuroimaging to distinguish ischemic stroke from intracerebral hemorrhage (ICH). Methods: We conducted a decision analysis using a Markov state transition model. Sensitivity analyses were performed across the worldwide reported range of the proportion of strokes due to ICH and the 95% confidence intervals (CIs) of aspirin-associated relative risks in patients with ICH. Results: For patients with stroke of undetermined etiology, long-term aspirin was the preferred treatment strategy across the worldwide reported range of the proportion of strokes due to ICH. At 34% of strokes due to ICH (the highest proportion reported in a large epidemiologic study), the benefit of aspirin remained beyond the upper bounds of the 95% CIs of aspirin-associated post-ICH relative risks most concerning to clinicians (ICH recurrence risk and mortality risk if ICH recurs on aspirin). Based on the estimated 11,590,204 strokes in low- and middle-income countries in 2010, our model predicts that aspirin therapy for secondary stroke prevention in all patients with stroke in these countries could lead to an estimated yearly decrease of 84,492 recurrent strokes and 4,056 stroke-related mortalities. Conclusions: The concern that the risks of aspirin in patients with stroke of unknown etiology could outweigh the benefits is not supported by our model, which predicts that aspirin for secondary prevention in patients with stroke of undetermined etiology in resource-limited settings could lead to decreased stroke-related mortality and stroke recurrence. C1 [Berkowitz, Aaron L.; Chou, Sherry H-Y.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Westover, M. Brandon; Bianchi, Matt T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. RP Berkowitz, AL (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. EM aberkowitz3@partners.org RI Chou, Sherry/G-5779-2015 FU American Heart Association; NIH; National Institute of Neurological Disorders and Stroke; Novartis FX A. Berkowitz receives royalties from Clinical Pathophysiology Made Ridiculously Simple (Medmaster, Inc.) and The Improvising Mind (Oxford University Press). M. Brandon Westover and M. Bianchi report no disclosures relevant to the manuscript. S. Chou has been funded by the American Heart Association and the NIH; is currently funded by the National Institute of Neurological Disorders and Stroke; and serves on the endpoint committee of a clinical trial funded by Novartis. Go to Neurology.org for full disclosures. NR 33 TC 2 Z9 3 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 9 PY 2014 VL 83 IS 11 BP 1004 EP 1011 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AP2DV UT WOS:000341883600011 PM 25122202 ER PT J AU Narendra, DP Wang, N Erkkinen, MG Jagadeesan, J Lee, TC Zimmerman, EE Klein, JP AF Narendra, Derek P. Wang, Nancy Erkkinen, Michael G. Jagadeesan, Jayender Lee, Thomas C. Zimmerman, Eli E. Klein, Joshua P. TI An anomalous developmental venous anomaly SO NEUROLOGY LA English DT Editorial Material C1 [Narendra, Derek P.; Wang, Nancy; Erkkinen, Michael G.; Jagadeesan, Jayender; Lee, Thomas C.; Zimmerman, Eli E.; Klein, Joshua P.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Narendra, Derek P.; Wang, Nancy; Erkkinen, Michael G.; Zimmerman, Eli E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Narendra, Derek P.; Wang, Nancy; Erkkinen, Michael G.; Jagadeesan, Jayender; Lee, Thomas C.; Zimmerman, Eli E.; Klein, Joshua P.] Harvard Univ, Sch Med, Boston, MA USA. RP Klein, JP (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM jpklein@partners.org NR 2 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 9 PY 2014 VL 83 IS 11 BP 1033 EP 1034 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AP2DV UT WOS:000341883600017 PM 25200715 ER PT J AU Chavarri-Guerra, Y St Louis, J Liedke, PER Symecko, H Villarreal-Garza, C Mohar, A Finkelstein, DM Goss, PE AF Chavarri-Guerra, Yanin St Louis, Jessica Liedke, Pedro E. R. Symecko, Heather Villarreal-Garza, Cynthia Mohar, Alejandro Finkelstein, Dianne M. Goss, Paul E. TI Access to care issues adversely affect breast cancer patients in Mexico: oncologists' perspective SO BMC CANCER LA English DT Article DE Breast cancer; Socioeconomic disparities; Mexico; Access to care; Patterns of care; Survey ID SYSTEM FACTORS; HEALTH SYSTEM; UNITED-STATES; PHYSICIAN; TRIAL AB Background: Despite recently implemented access to care programs, Mexican breast cancer (BC) mortality rates remain substantially above those in the US. We conducted a survey among Mexican Oncologists to determine whether practice patterns may be responsible for these differences. Methods: A web-based survey was sent to 851 oncologists across Mexico using the Vanderbilt University REDCap database. Analyses of outcomes are reported using exact and binomial confidence bounds and tests. Results: 138 participants (18.6% of those surveyed) from the National capital and 26 Mexican states, responded. Respondents reported that 58% of newly diagnosed BC patients present with stage III IV disease; 63% undergo mastectomy, 52% axillary lymph node dissection (ALND) and 48% sentinel lymph node biopsy (SLNB). Chemotherapy is recommended for tumors > 1 cm (89%), positive nodes (86.5%), triple-negative (TN) (80%) and HER2 positive tumors (58%). Trastuzumab is prescribed in 54.3% and 77.5% for HER2 < 1 cm and > 1 cm tumors, respectively. Tamoxifen is indicated for premenopausal hormone receptor (HR) positive tumors in 86.5% of cases and aromatase inhibitors (AI's) for postmenopausal in 86%. 24% of physicians reported treatment limitations, due to delayed or incomplete pathology reports and delayed or limited access to medications. Conclusions: Even though access to care programs have been recently applied nationwide, women commonly present with advanced BC, leading to increased rates of mastectomy and ALND. Mexican physicians are dissatisfied with access to appropriate medical care. Our survey detects specific barriers that may impact BC outcomes in Mexico and warrant further investigation. C1 [Chavarri-Guerra, Yanin; St Louis, Jessica; Liedke, Pedro E. R.; Finkelstein, Dianne M.; Goss, Paul E.] Massachusetts Gen Hosp, MGH Avon Int Breast Canc Program, Boston, MA 02114 USA. [Chavarri-Guerra, Yanin] Natl Inst Med Sci & Nutr Salvador Zubiran, Hemato Oncol Dept, Mexico City, DF, Mexico. [Symecko, Heather; Finkelstein, Dianne M.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Villarreal-Garza, Cynthia] Natl Canc Inst, Med Oncol & Breast Canc Dept, Mexico City, DF, Mexico. [Mohar, Alejandro] Univ Nacl Autonoma Mexico, Biomed Res Unit Canc, Mexico City 04510, DF, Mexico. [Mohar, Alejandro] Natl Canc Inst, Mexico City, DF, Mexico. [Goss, Paul E.] Harvard Univ, Sch Med, Boston, MA USA. [Goss, Paul E.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Goss, PE (reprint author), Massachusetts Gen Hosp, MGH Avon Int Breast Canc Program, Boston, MA 02114 USA. EM pgoss@partners.org FU Mexican Oncology Board; Avon Foundation New York FX We would like to thank and acknowledge all the Mexican physicians who participated in the survey. We would also like to thank the Mexican Oncology Board for their support and provision of the email address list. This work was supported by the Avon Foundation New York. This funding source had no role in the planning or writing of this manuscript. NR 22 TC 3 Z9 3 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD SEP 9 PY 2014 VL 14 AR 658 DI 10.1186/1471-2407-14-658 PG 8 WC Oncology SC Oncology GA AO9EH UT WOS:000341658100001 PM 25199766 ER PT J AU Yaffe, K Scola, M Boustani, M AF Yaffe, Kristine Scola, Marie Boustani, Malaz TI Benzodiazepines and risk of Alzheimer's disease SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID POTENTIALLY INAPPROPRIATE MEDICATIONS; COGNITIVE IMPAIRMENT; WOMEN C1 [Yaffe, Kristine] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. [Boustani, Malaz] Indiana Univ, Ctr Aging Res, Indianapolis, IN 46204 USA. [Boustani, Malaz] Regenstrief Inst Hlth Care, Indianapolis, IN USA. RP Yaffe, K (reprint author), 4150 Clement St,Box 181G, San Francisco, CA 94121 USA. EM kristine.yaffe@ucsf.edu NR 9 TC 2 Z9 2 U1 3 U2 10 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 SEP 9 PY 2014 VL 349 AR g5312 DI 10.1136/bmj.g5312 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AO9QM UT WOS:000341691000006 PM 25205606 ER PT J AU Majithia, AR Flannick, J Shahinian, P Guo, M Bray, MA Fontanillas, P Gabriel, SB Rosen, ED Altshuler, D AF Majithia, Amit R. Flannick, Jason Shahinian, Peter Guo, Michael Bray, Mark-Anthony Fontanillas, Pierre Gabriel, Stacey B. Rosen, Evan D. Altshuler, David CA GoT2D Consortium NHGRI JHS-FHS Allelic Spectrum Pr SIGMA T2D Consortium T2D-GENES Consortium TI Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DOMINANT-NEGATIVE MUTATIONS; ACTIVATED-RECEPTOR-GAMMA; INSULIN-RESISTANCE; PRO12ALA POLYMORPHISM; LIPODYSTROPHY; HYPERTENSION; POPULATION; CONTRIBUTE; GENES; SCORE AB Peroxisome proliferator-activated receptor gamma (PPARG) is a master transcriptional regulator of adipocyte differentiation and a canonical target of antidiabetic thiazolidinedione medications. In rare families, loss-of-function (LOF) mutations in PPARG are known to cosegregate with lipodystrophy and insulin resistance; in the general population, the common P12A variant is associated with a decreased risk of type 2 diabetes (T2D). Whether and how rare variants in PPARG and defects in adipocyte differentiation influence risk of T2D in the general population remains undetermined. By sequencing PPARG in 19,752 T2D cases and controls drawn from multiple studies and ethnic groups, we identified 49 previously unidentified, nonsynonymous PPARG variants (MAF < 0.5%). Considered in aggregate (with or without computational prediction of functional consequence), these rare variants showed no association with T2D (OR = 1.35; P = 0.17). The function of the 49 variants was experimentally tested in a novel high-throughput human adipocyte differentiation assay, and nine were found to have reduced activity in the assay. Carrying any of these nine LOF variants was associated with a substantial increase in risk of T2D (OR = 7.22; P = 0.005). The combination of large-scale DNA sequencing and functional testing in the laboratory reveals that approximately 1 in 1,000 individuals carries a variant in PPARG that reduces function in a human adipocyte differentiation assay and is associated with a substantial risk of T2D. C1 [Majithia, Amit R.; Flannick, Jason; Shahinian, Peter; Bray, Mark-Anthony; Fontanillas, Pierre; Gabriel, Stacey B.; Altshuler, David] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Majithia, Amit R.; Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Majithia, Amit R.; Altshuler, David] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Majithia, Amit R.; Rosen, Evan D.; Altshuler, David] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Guo, Michael; Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Rosen, Evan D.] Beth Israel Deaconess Med Ctr, Div Endocrinol & Metab, Boston, MA 02115 USA. [Altshuler, David] MIT, Dept Biol, Cambridge, MA 02139 USA. RP Altshuler, D (reprint author), Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA. EM altshuler@molbio.mgh.harvard.edu RI Meisinger, Christine/B-5358-2014; Bray, Mark/C-5973-2008; Fernandez, Juan Carlos/C-4976-2013; Meitinger, Thomas/O-1318-2015; Hrabe de Angelis, Martin/F-5531-2012; OI Zeggini, Eleftheria/0000-0003-4238-659X; Meisinger, Christa/0000-0002-9026-6544; Small, Kerrin/0000-0003-4566-0005; Ikram, Mohammad Kamran/0000-0003-0173-9571; Tai, E Shyong/0000-0003-2929-8966; Hattersley, Andrew/0000-0001-5620-473X; Mercader, Josep M/0000-0001-8494-3660; Lunter, Gerton/0000-0002-3798-2058; Grossman, Robert/0000-0003-3741-5739; Locke, Adam/0000-0001-6227-198X; van de Bunt, Martijn/0000-0002-6744-6125; Gieger, Christian/0000-0001-6986-9554; Bray, Mark/0000-0002-9748-3592; Fernandez, Juan Carlos/0000-0003-3680-4193; Hrabe de Angelis, Martin/0000-0002-7898-2353; Maller, Julian/0000-0002-1565-9559; Fuchsberger, Christian/0000-0002-5918-8947 FU National Institutes of Health (NIH) [GM089652]; NIH U01 [DK085501, DK085524, DK085545, DK085584]; National Heart, Lung, and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities; National Human Genome Research Institute of the US NIH [U54 HG003067]; Carlos Slim Health Institute; [5U01DK085526]; [DK088389]; [U54HG003067] FX We thank John Doench, Joseph Avruch, Suzanne Jacobs, Noel Burtt, and Victor Rusu for helpful discussions, laboratory assistance, and manuscript review. We also thank Anne Carpenter, who is supported by National Institutes of Health (NIH) Grant GM089652, for assistance with image analysis. Funding for the GoT2D and T2D-GENES studies was provided by Grants 5U01DK085526 (Multiethnic Study of Type 2 Diabetes Genes), DK088389 (Low-Pass Sequencing and High-Density SNP Genotyping for Type 2 Diabetes), and U54HG003067 (Large-Scale Sequencing and Analysis of Genomes), as well as NIH U01 Grants DK085501, DK085524, DK085545, and DK085584. The Jackson Heart Study (JHS) is supported by Contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268201300050C from the National Heart, Lung, and Blood Institute and National Institute on Minority Health and Health Disparities. The NHGRI JHS/FHS Allelic Spectrum Project was supported by grants from the National Human Genome Research Institute of the US NIH [Medical Sequencing Program Grant U54 HG003067 (to E. Lander, Broad Institute Principal Investigator)]. The SIGMA T2D Consortium, a joint US-Mexico project, was funded by the Carlos Slim Health Institute. NR 19 TC 39 Z9 39 U1 1 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 9 PY 2014 VL 111 IS 36 BP 13127 EP 13132 DI 10.1073/pnas.1410428111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO8SV UT WOS:000341625600043 PM 25157153 ER PT J AU Murciano-Goroff, YR Wolfsberger, LD Parekh, A Fennessy, FM Tuncali, K Orio, PF Niedermayr, TR Suh, WW Devlin, PM Tempany, CMC Sugar, EHN O'Farrell, DA Steele, G O'Leary, M Buzurovic, I Damato, AL Cormack, RA Fedorov, AY Nguyen, PL AF Murciano-Goroff, Yonina R. Wolfsberger, Luciant D. Parekh, Arti Fennessy, Fiona M. Tuncali, Kemal Orio, Peter F., III Niedermayr, Thomas R. Suh, W. Warren Devlin, Phillip M. Tempany, Clare Mary C. Sugar, Emily H. Neubauer O'Farrell, Desmond A. Steele, Graeme O'Leary, Michael Buzurovic, Ivan Damato, Antonio L. Cormack, Robert A. Fedorov, Andriy Y. Nguyen, Paul L. TI Variability in MRI vs. ultrasound measures of prostate volume and its impact on treatment recommendations for favorable-risk prostate cancer patients: a case series SO RADIATION ONCOLOGY LA English DT Article DE Prostate volume; Favorable-risk prostate cancer; Brachytherapy; Active surveillance; MRI; Ultrasound ID ACUTE URINARY RETENTION; MAGNETIC-RESONANCE; BRACHYTHERAPY; GLANDS; DOSIMETRY; QUALITY; CM(3) AB Background: Prostate volume can affect whether patients qualify for brachytherapy (desired size = 20 mL and = 60 mL) and/or active surveillance (desired PSA density = 0.15 for very low risk disease). This study examines variability in prostate volume measurements depending on imaging modality used (ultrasound versus MRI) and volume calculation technique (contouring versus ellipsoid) and quantifies the impact of this variability on treatment recommendations for men with favorable-risk prostate cancer. Methods: We examined 70 patients who presented consecutively for consideration of brachytherapy for favorable-risk prostate cancer who had volume estimates by three methods: contoured axial ultrasound slices, ultrasound ellipsoid (height x width x length x 0.523) calculation, and endorectal coil MRI (erMRI) ellipsoid calculation. Results: Average gland size by the contoured ultrasound, ellipsoid ultrasound, and erMRI methods were 33.99, 37.16, and 39.62 mLs, respectively. All pairwise comparisons between methods were statistically significant (all p < 0.015). Of the 66 patients who volumetrically qualified for brachytherapy on ellipsoid ultrasound measures, 22 (33.33%) did not qualify on ellipsoid erMRI or contoured ultrasound measures. 38 patients (54.28%) had PSA density = 0.15 ng/dl as calculated using ellipsoid ultrasound volumes, compared to 34 (48.57%) and 38 patients (54.28%) using contoured ultrasound and ellipsoid erMRI volumes, respectively. Conclusions: The ultrasound ellipsoid and erMRI ellipsoid methods appeared to overestimate ultrasound contoured volume by an average of 9.34% and 16.57% respectively. 33.33% of those who qualified for brachytherapy based on ellipsoid ultrasound volume would be disqualified based on ultrasound contoured and/or erMRI ellipsoid volume. As treatment recommendations increasingly rely on estimates of prostate size, clinicians must consider method of volume estimation. C1 [Murciano-Goroff, Yonina R.; Wolfsberger, Luciant D.; Parekh, Arti; Fennessy, Fiona M.; Tuncali, Kemal; Orio, Peter F., III; Niedermayr, Thomas R.; Devlin, Phillip M.; Tempany, Clare Mary C.; Sugar, Emily H. Neubauer; O'Farrell, Desmond A.; Steele, Graeme; O'Leary, Michael; Buzurovic, Ivan; Damato, Antonio L.; Cormack, Robert A.; Fedorov, Andriy Y.; Nguyen, Paul L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Murciano-Goroff, Yonina R.; Wolfsberger, Luciant D.; Parekh, Arti; Fennessy, Fiona M.; Tuncali, Kemal; Orio, Peter F., III; Niedermayr, Thomas R.; Devlin, Phillip M.; Tempany, Clare Mary C.; Sugar, Emily H. Neubauer; O'Farrell, Desmond A.; Steele, Graeme; O'Leary, Michael; Buzurovic, Ivan; Damato, Antonio L.; Cormack, Robert A.; Nguyen, Paul L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Murciano-Goroff, Yonina R.; Fennessy, Fiona M.; Tuncali, Kemal; Orio, Peter F., III; Niedermayr, Thomas R.; Devlin, Phillip M.; Tempany, Clare Mary C.; Steele, Graeme; O'Leary, Michael; Fedorov, Andriy Y.; Nguyen, Paul L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Suh, W. Warren] Ctr Canc, Santa Barbara, CA 93105 USA. RP Nguyen, PL (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM Pnguyen@lroc.harvard.edu RI Buzurovic, Ivan/C-8036-2011; OI Buzurovic, Ivan/0000-0001-9632-3434; Fedorov, Andrey/0000-0003-4806-9413 FU An Anonymous Family Foundation; David and Cynthia Chapin; Harvard Medical School Research Grant; Prostate Cancer Foundation FX This project was made possible by funding from: An Anonymous Family Foundation; David and Cynthia Chapin; a Harvard Medical School Research Grant; and the Prostate Cancer Foundation. NR 27 TC 1 Z9 1 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-717X J9 RADIAT ONCOL JI Radiat. Oncol. PD SEP 9 PY 2014 VL 9 DI 10.1186/1748-717X-9-200 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AO7JT UT WOS:000341530000001 PM 25205146 ER PT J AU Taqueti, VR Nahrendorf, M Di Carli, MF AF Taqueti, Viviany R. Nahrendorf, Matthias Di Carli, Marcelo F. TI Translational Molecular Imaging Repurposing an Old Technique to Track Cell Migration Into Human Atheroma SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE atherosclerosis; inflammation; molecular imaging ID ACUTE CORONARY SYNDROMES; ATHEROSCLEROSIS; INFLAMMATION C1 [Taqueti, Viviany R.; Di Carli, Marcelo F.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Noninvas Cardiovasc Imaging Program,Dept Med, Boston, MA 02115 USA. [Taqueti, Viviany R.; Di Carli, Marcelo F.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Noninvas Cardiovasc Imaging Program,Dept Radiol, Boston, MA 02115 USA. [Taqueti, Viviany R.; Di Carli, Marcelo F.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Nucl Med & Mol Imaging,Dept Radiol, Boston, MA 02115 USA. [Taqueti, Viviany R.; Di Carli, Marcelo F.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Cardiovasc Div,Dept Med, Boston, MA 02115 USA. [Nahrendorf, Matthias] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. RP Di Carli, MF (reprint author), Brigham & Womens Hosp, ASB L1,Room 037 C,75 Francis St, Boston, MA 02115 USA. EM mdicarli@partners.org NR 11 TC 1 Z9 1 U1 1 U2 4 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 SEP 9 PY 2014 VL 64 IS 10 BP 1030 EP 1032 DI 10.1016/j.jacc.2014.07.004 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AO1PQ UT WOS:000341085900012 PM 25190239 ER PT J AU Goldstein, JM Holsen, L Handa, R Tobet, S AF Goldstein, Jill M. Holsen, Laura Handa, Robert Tobet, Stuart TI Fetal hormonal programming of sex differences in depression: linking women's mental health with sex differences in the brain across the lifespan SO FRONTIERS IN NEUROSCIENCE LA English DT Editorial Material DE major depression; sex differences; women's health; stress; mood; fetal programming ID PITUITARY-ADRENAL AXIS; CORTICOTROPIN-RELEASING-FACTOR; DEXAMETHASONE SUPPRESSION TEST; INCREASES AMYGDALA REACTIVITY; POSITRON-EMISSION-TOMOGRAPHY; FACTOR-LIKE IMMUNOREACTIVITY; RECURRENT MAJOR DEPRESSION; ESTROGEN-RECEPTOR-ALPHA; MENSTRUAL-CYCLE PHASE; ADULT HUMAN BRAIN C1 [Goldstein, Jill M.; Holsen, Laura] Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, Dept Psychiat, Div Womens Hlth, Boston, MA 02115 USA. [Goldstein, Jill M.; Holsen, Laura] Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, Dept Med, Boston, MA 02115 USA. [Goldstein, Jill M.; Holsen, Laura] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Goldstein, Jill M.; Holsen, Laura] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Goldstein, Jill M.] Massachusetts Gen Hosp, Dept Psychiat, Div Psychiat Neurosci, Boston, MA 02114 USA. [Handa, Robert] Univ Arizona, Coll Med, Dept Basic Med Sci, Phoenix, AZ USA. [Tobet, Stuart] Colorado State Univ, Coll Vet Med & Biomed Sci, Dept Biomed Sci, Ft Collins, CO 80523 USA. [Tobet, Stuart] Colorado State Univ, Coll Vet Med & Biomed Sci, Sch Biomed Engn, Ft Collins, CO 80523 USA. RP Goldstein, JM (reprint author), Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, Dept Psychiat, Div Womens Hlth, 75 Francis St, Boston, MA 02115 USA. EM jill_goldstein@hms.harvard.edu FU NIMH NIH HHS [P50 MH082679] NR 156 TC 12 Z9 12 U1 2 U2 10 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD SEP 8 PY 2014 VL 8 AR 247 DI 10.3389/fnins.2014.00247 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AW8MU UT WOS:000346517400001 PM 25249929 ER PT J AU Helming, KC Wang, XF Roberts, CWM AF Helming, Katherine C. Wang, Xiaofeng Roberts, Charles W. M. TI Vulnerabilities of Mutant SWI/SNF Complexes in Cancer SO CANCER CELL LA English DT Review ID CHROMATIN-REMODELING COMPLEX; SMALL-CELL CARCINOMA; IDENTIFIES FREQUENT MUTATION; MALIGNANT RHABDOID TUMORS; SWI-SNF COMPLEX; BAF COMPLEXES; LUNG-CANCER; SOMATIC MUTATIONS; CYCLE ARREST; ONCOGENIC TRANSFORMATION AB Cancer genome sequencing efforts have revealed the novel theme that chromatin modifiers are frequently mutated across a wide spectrum of cancers. Mutations in genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are particularly prevalent, occurring in 20% of all human cancers. As these are typically loss-of-function mutations and not directly therapeutically targetable, central goals have been to elucidate mechanism and identify vulnerabilities created by these mutations. Here, we discuss emerging data that these mutations lead to the formation of aberrant residual SWI/SNF complexes that constitute a specific vulnerability and discuss the potential for exploiting these dependencies in SWI/SNF mutant cancers. C1 [Helming, Katherine C.; Wang, Xiaofeng; Roberts, Charles W. M.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Helming, Katherine C.; Wang, Xiaofeng; Roberts, Charles W. M.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02215 USA. [Helming, Katherine C.; Wang, Xiaofeng; Roberts, Charles W. M.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Helming, Katherine C.; Wang, Xiaofeng] Harvard Univ, Sch Med, Biol & Biomed Sci Program, Boston, MA 02115 USA. RP Roberts, CWM (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. EM charles_roberts@dfci.harvard.edu FU NIH [R01CA172152, R01CA113794]; U01NCI Mouse Models of Cancer Consortium Award; Alex's Lemonade Stand Foundation; Hyundai Hope on Wheels; Cure AT/RT Now fund; Avalanna Fund; Garrett B. Smith Foundation; Miles for Mary; Ellison Foundation; Cookies for Kids Cancer; P.A.L.S.-St. Baldrick's research grant; Rally Foundation; David Abraham Foundation FX The work in C.W.M.R.'s laboratory is partly supported by NIH grants R01CA172152 (to C.W.M.R.) and R01CA113794 (to C.W.M.R.) and a U01NCI Mouse Models of Cancer Consortium Award (to C.W.M.R.). Alex's Lemonade Stand Foundation, Hyundai Hope on Wheels, the Cure AT/RT Now fund, the Avalanna Fund, the Garrett B. Smith Foundation, Miles for Mary, the Ellison Foundation, and Cookies for Kids Cancer provided additional support. X.W. is a recipient of a P.A.L.S.-St. Baldrick's research grant and is supported by postdoctoral fellowships from the Rally Foundation and the David Abraham Foundation. NR 105 TC 58 Z9 59 U1 4 U2 20 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 SEP 8 PY 2014 VL 26 IS 3 BP 309 EP 317 DI 10.1016/j.ccr.2014.07.018 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AP2AD UT WOS:000341873800005 PM 25203320 ER PT J AU Davis, CF Ricketts, CJ Wang, M Yang, LX Cherniack, AD Shen, H Buhay, C Kang, H Kim, SC Fahey, CC Hacker, KE Bhanot, G Gordenin, DA Chu, A Gunaratne, PH Biehl, M Seth, S Kaipparettu, BA Bristow, CA Donehower, LA Wallen, EM Smith, AB Tickoo, SK Tamboli, P Reuter, V Schmidt, LS Hsieh, JJ Choueiri, TK Hakimi, AA Chin, L Meyerson, M Kucherlapati, R Park, WY Robertson, AG Laird, PW Henske, EP Kwiatkowski, DJ Park, PJ Morgan, M Shuch, B Muzny, D Wheeler, DA Linehan, WM Gibbs, RA Rathmell, WK Creighton, CJ Signoretti, S Seiler, M Chao, H Dahdouli, M Xi, L Kakkar, N Reid, JG Downs, B Drummond, J Morton, D Doddapaneni, H Lewis, L English, A Meng, QC Kovar, C Wang, QY Hale, W Hawes, A Kalra, D Walker, K Murray, BA Sougnez, C Saksena, G Carter, SL Schumacher, SE Tabak, B Zack, TI Getz, G Beroukhim, R Gabriel, SB Ally, A Balasundaram, M Birol, I Brooks, D Butterfield, YS Chuah, E Clarke, A Dhalla, N Guin, R Holt, RA Kasaian, K Lee, D Li, HI Lim, E Ma, Y Mayo, M Moore, RA Mungall, AJ Schein, JE Sipahimalani, P Tam, A Thiessen, N Wong, T Jones, SJ Marra, MA Auman, JT Tan, DH Meng, SW Jones, CD Hoadley, KA Mieczkowski, PA Mose, LE Jefferys, SR Roach, J Veluvolu, U Wilkerson, MD Waring, S Buda, E Wu, JY Bodenheimer, T Hoyle, AP Simons, JV Soloway, MG Balu, S Parker, JS Hayes, DN Perou, CM Weisenberger, DJ Bootwalla, MS Triche, T Lai, PH Van Den Berg, DJ Baylin, SB Chen, FJ Coarfa, C Noble, MS DiCara, D Zhang, HL Cho, J Heiman, DI Gehlenborg, N Voet, D Lin, P Frazer, S Stojanov, P Liu, YC Zou, LH Kim, J Lawrence, MS Protopopov, A Song, XZ Zhang, JH Pantazi, A Hadjipanayis, A Lee, E Luquette, LJ Lee, S Parfenov, M Santoso, N Seidman, J Xu, AW Lee, J Roberts, SA Klimczak, LJ Fargo, D Lang, M Choi, YL Lee, JK Wang, WY Fan, Y Ahn, J Akbani, R Weinstein, JN Haussler, D Stuart, JM Benz, CC Ma, S Radenbaugh, A Zhul, JC Lichtenberg, TM Zmuda, E Black, AD Hanf, B Ramirez, NC Wise, L Bowen, J Leraas, KM Hall, TM Gastier-Foster, JM Kaelin, WG Thorne, L Boice, L Huang, M Vocke, C Peterson, J Worrell, R Merino, M Czerniak, BA Aldape, KD Wood, CG Spellman, PT Atkins, MB Cheville, J Thompson, RH Jensen, MA Pihl, T Wan, YH Ayala, B Baboud, J Velaga, S Walton, J Liu, J Chudamani, S Wu, Y Sheth, M Shaw, KRM Demchok, JA Davidsen, T Yang, LM Wang, ZN Tarnuzzer, RW Zhang, JS Eley, G Felau, I Zenklusen, JC Hutter, CM Guyer, MS Ozenberger, BA Sofia, HJ AF Davis, Caleb F. Ricketts, Christopher J. Wang, Min Yang, Lixing Cherniack, Andrew D. Shen, Hui Buhay, Christian Kang, Hyojin Kim, Sang Cheol Fahey, Catherine C. Hacker, Kathryn E. Bhanot, Gyan Gordenin, Dmitry A. Chu, Andy Gunaratne, Preethi H. Biehl, Michael Seth, Sahil Kaipparettu, Benny A. Bristow, Christopher A. Donehower, Lawrence A. Wallen, Eric M. Smith, Angela B. Tickoo, Satish K. Tamboli, Pheroze Reuter, Victor Schmidt, Laura S. Hsieh, James J. Choueiri, Toni K. Hakimi, A. Ari Chin, Lynda Meyerson, Matthew Kucherlapati, Raju Park, Woong-Yang Robertson, A. Gordon Laird, Peter W. Henske, Elizabeth P. Kwiatkowski, David J. Park, Peter J. Morgan, Margaret Shuch, Brian Muzny, Donna Wheeler, David A. Linehan, W. Marston Gibbs, Richard A. Rathmell, W. Kimryn Creighton, Chad J. Signoretti, Sabina Seiler, Michael Chao, Hsu Dahdouli, Mike Xi, Liu Kakkar, Nipun Reid, Jeffrey G. Downs, Brittany Drummond, Jennifer Morton, Donna Doddapaneni, Harsha Lewis, Lora English, Adam Meng, Qingchang Kovar, Christie Wang, Qiaoyan Hale, Walker Hawes, Alicia Kalra, Divya Walker, Kimberly Murray, Bradley A. Sougnez, Carrie Saksena, Gordon Carter, Scott L. Schumacher, Steven E. Tabak, Barbara Zack, Travis I. Getz, Gad Beroukhim, Rameen Gabriel, Stacey B. Ally, Adrian Balasundaram, Miruna Birol, Inanc Brooks, Denise Butterfield, Yaron S. N. Chuah, Eric Clarke, Amanda Dhalla, Noreen Guin, Ranabir Holt, Robert A. Kasaian, Katayoon Lee, Darlene Li, Haiyan I. Lim, Emilia Ma, Yussanne Mayo, Michael Moore, Richard A. Mungall, Andrew J. Schein, Jacqueline E. Sipahimalani, Payal Tam, Angela Thiessen, Nina Wong, Tina Jones, Steven J. M. Marra, Marco A. Auman, J. Todd Tan, Donghui Meng, Shaowu Jones, Corbin D. Hoadley, Katherine A. Mieczkowski, Piotr A. Mose, Lisle E. Jefferys, Stuart R. Roach, Jeffrey Veluvolu, Umadevi Wilkerson, Matthew D. Waring, Scot Buda, Elizabeth Wu, Junyuan Bodenheimer, Tom Hoyle, Alan P. Simons, Janae V. Soloway, Mathew G. Balu, Saianand Parker, Joel S. Hayes, D. Neil Perou, Charles M. Weisenberger, Daniel J. Bootwalla, Moiz S. Triche, Timothy, Jr. Lai, Phillip H. Van Den Berg, David J. Baylin, Stephen B. Chen, Fengju Coarfa, Cristian Noble, Michael S. DiCara, Daniel Zhang, Hailei Cho, Juok Heiman, David I. Gehlenborg, Nils Voet, Doug Lin, Pei Frazer, Scott Stojanov, Petar Liu, Yingchun Zou, Lihua Kim, Jaegil Lawrence, Michael S. Protopopov, Alexei Song, Xingzhi Zhang, Jianhua Pantazi, Angeliki Hadjipanayis, Angela Lee, Eunjung Luquette, Lovelace J. Lee, Semin Parfenov, Michael Santoso, Netty Seidman, Jonathan Xu, Andrew W. Lee, Junehawk Roberts, Steven A. Klimczak, Leszek J. Fargo, David Lang, Martin Choi, Yoon-La Lee, June-Koo Wang, Wenyi Fan, Yu Ahn, Jaeil Akbani, Rehan Weinstein, John N. Haussler, David Stuart, Josh M. Benz, Christopher C. Ma, Singer Radenbaugh, Amie Zhul, Jingchun Lichtenberg, Tara M. Zmuda, Erik Black, Aaron D. Hanf, Benjamin Ramirez, Nilsa C. Wise, Lisa Bowen, Jay Leraas, Kristen M. Hall, Tracy M. Gastier-Foster, Julie M. Kaelin, William G. Thorne, Leigh Boice, Lori Huang, Mei Vocke, Cathy Peterson, James Worrell, Robert Merino, Maria Czerniak, Bogdan A. Aldape, Kenneth D. Wood, Christopher G. Spellman, Paul T. Atkins, Michael B. Cheville, John Thompson, R. Houston Jensen, Mark A. Pihl, Todd Wan, Yunhu Ayala, Brenda Baboud, Julien Velaga, Sudhakar Walton, Jessica Liu, Jia Chudamani, Sudha Wu, Ye Sheth, Margi Shaw, Kenna R. Mills Demchok, John A. Davidsen, Tanja Yang, Liming Wang, Zhining Tarnuzzer, Roy W. Zhang, Jiashan Eley, Greg Felau, Ina Zenklusen, Jean Claude Hutter, Carolyn M. Guyer, Mark S. Ozenberger, Bradley A. Sofia, Heidi J. CA Canc Genome Atlas Res Network TI The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma SO CANCER CELL LA English DT Article ID HOGG-DUBE-SYNDROME; MITOCHONDRIAL-DNA MUTATIONS; TERT PROMOTER MUTATIONS; HUMAN BREAST-TUMORS; COMPLEX-I; CANCER GENOME; MOLECULAR PORTRAITS; KIDNEY CANCER; ONCOCYTOMA; CHROMOSOME-10 AB We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations. C1 [Davis, Caleb F.; Wang, Min; Buhay, Christian; Gunaratne, Preethi H.; Donehower, Lawrence A.; Morgan, Margaret; Muzny, Donna; Wheeler, David A.; Gibbs, Richard A.; Creighton, Chad J.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Ricketts, Christopher J.; Schmidt, Laura S.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Yang, Lixing; Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Cherniack, Andrew D.; Chin, Lynda; Meyerson, Matthew; Henske, Elizabeth P.; Kwiatkowski, David J.] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA. [Shen, Hui; Laird, Peter W.] Univ So Calif, USC Epigenome Ctr, Los Angeles, CA 90033 USA. [Kim, Sang Cheol; Park, Woong-Yang] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Samsung Genome Inst, Seoul, South Korea. [Fahey, Catherine C.; Hacker, Kathryn E.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA. [Bhanot, Gyan] Rutgers State Univ, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA. [Bhanot, Gyan] Canc Inst New Jersey, New Brunswick, NJ 08903 USA. [Gordenin, Dmitry A.] NIEHS, Res Triangle Pk, NC 27709 USA. [Chu, Andy; Robertson, A. Gordon] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Gunaratne, Preethi H.] Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA. [Biehl, Michael] Univ Groningen, Intelligent Syst Grp, Johann Bernoulli Inst Math & Comp Sci, NL-9700 AK Groningen, Netherlands. [Seth, Sahil; Bristow, Christopher A.; Chin, Lynda] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Dept Genom Med, Houston, TX 77030 USA. [Kaipparettu, Benny A.; Creighton, Chad J.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Kaipparettu, Benny A.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Wallen, Eric M.; Smith, Angela B.; Rathmell, W. Kimryn] Univ N Carolina, Dept Urol, Chapel Hill, NC 27599 USA. [Tickoo, Satish K.; Reuter, Victor] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Tamboli, Pheroze] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Schmidt, Laura S.] Frederick Natl Lab Canc Res, Basic Sci Program, Leidos Biomed Res, Frederick, MD 21702 USA. [Hsieh, James J.] Weill Cornell Med Coll, Dept Med, New York, NY 10021 USA. [Hsieh, James J.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Choueiri, Toni K.; Meyerson, Matthew; Henske, Elizabeth P.; Kwiatkowski, David J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Choueiri, Toni K.; Hakimi, A. Ari; Henske, Elizabeth P.; Kwiatkowski, David J.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Hakimi, A. Ari] Mem Sloan Kettering Canc Ctr, Urol Serv, Dept Surg, New York, NY 10065 USA. [Kucherlapati, Raju; Park, Peter J.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Kucherlapati, Raju] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Park, Woong-Yang] Sungkyunkwan Univ, Sch Med, Seoul, South Korea. [Rathmell, W. Kimryn] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Rathmell, W. Kimryn] Univ N Carolina, Dept Med, Div Hematol & Oncol, Chapel Hill, NC 27599 USA. [Creighton, Chad J.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Kang, Hyojin] Korea Inst Sci & Technol Informat, Natl Inst Supercomp & Networking, Taejon, South Korea. [Shuch, Brian] Yale Univ, Sch Med, Dept Urol, New Haven, CT 06520 USA. RP Rathmell, WK (reprint author), Univ N Carolina, Dept Urol, Chapel Hill, NC 27599 USA. EM rathmell@med.unc.edu; creighto@bcm.edu RI Kalra, Divya/N-5453-2014; Laird, Peter/G-8683-2012; Holt, Robert/C-3303-2009; Biehl, Michael/B-5105-2009; Jones, Steven/C-3621-2009; Lee, Semin/S-2629-2016; Marra, Marco/B-5987-2008; Birol, Inanc/G-5440-2011; OI Biehl, Michael/0000-0001-5148-4568; Lee, Semin/0000-0002-9015-6046; Triche, Tim/0000-0001-5665-946X; Lang, Martin/0000-0002-0242-6713; Gordenin, Dmitry/0000-0002-8399-1836; Seth, Sahil/0000-0003-4579-3959; Birol, Inanc/0000-0003-0950-7839; Perou, Charles/0000-0001-9827-2247 FU NIH [5U24CA143843, U54HG003273, 5U24CA143866, KL2TR001109, UL1TR001111, 5P50CA101942, U54 HG003067, K24CA172355]; NIH, National Cancer Institute, Center for Cancer Research; Frederick National Lab, NIH [HHSN261200800001E]; NIH, National Institute of Environmental Health Sciences; Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia [T15 LM007093]; J. Randall AMP; Kathleen L. MacDonald Kidney Cancer Research Fund; Tuttle Family Kidney Cancer Research Fund; Ministry of Health AMP; Welfare, Republic of Korea [HI13C2096]; Korea Institute of Science and Technology Information [K-14-L01-C02-S04, KSC-2013-C3-037] FX We wish to thank all patients and families who contributed to this study. This work was supported by the following grants from the NIH: 5U24CA143843 (D.A.W.), U54HG003273 (R.A.G.), 5U24CA143866 (M.A. Marra), KL2TR001109 and UL1TR001111 (A.B.S.), 5P50CA101942 (S. Signoretti), 5P50CA101942 (T.K.C.), U54 HG003067 (E. Lander); K24CA172355 (W.K.R.), Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (W.M.L., L.S.S., C.J.R., M.J. Merino), with federal funds from the Frederick National Lab, NIH, under contract HHSN261200800001E (L.S.S.), Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (D.A.G., S.A. Roberts, L.J. Klimczak, D. Fargo), and a training fellowship from the Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia (Grant No. T15 LM007093 to C.F.D.). Other grant support includes the J. Randall & Kathleen L. MacDonald Kidney Cancer Research Fund, the Tuttle Family Kidney Cancer Research Fund (J.J.H.), the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI13C2096 to W.-Y.P.), and the Korea Institute of Science and Technology Information (K-14-L01-C02-S04 and KSC-2013-C3-037) (for supercomputing resources including technical support). NR 44 TC 112 Z9 113 U1 8 U2 30 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 SEP 8 PY 2014 VL 26 IS 3 BP 319 EP 330 DI 10.1016/j.ccr.2014.07.014 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AP2AD UT WOS:000341873800006 PM 25155756 ER PT J AU Gustafson, WC Meyerowitz, JG Nekritz, EA Chen, J Benes, C Charron, E Simonds, EF Seeger, R Matthay, KK Hertz, NT Eilers, M Shokat, KM Weiss, WA AF Gustafson, William Clay Meyerowitz, Justin Gabriel Nekritz, Erin A. Chen, Justin Benes, Cyril Charron, Elise Simonds, Erin F. Seeger, Robert Matthay, Katherine K. Hertz, Nicholas T. Eilers, Martin Shokat, Kevan M. Weiss, William A. TI Drugging MYCN through an Allosteric Transition in Aurora Kinase A SO CANCER CELL LA English DT Article ID SMALL-MOLECULE INHIBITOR; BET BROMODOMAIN INHIBITION; THERAPEUTIC TARGETS; N-MYC; C-MYC; HUMAN NEUROBLASTOMA; HISTONE H3; DFG FLIP; A KINASE; IN-VIVO AB MYC proteins are major drivers of cancer yet are considered undruggable because their DNA binding domains are composed of two extended alpha helices with no apparent surfaces for small-molecule binding. Proteolytic degradation of MYCN protein is regulated in part by a kinase-independent function of Aurora A. We describe a class of inhibitors that disrupts the native conformation of Aurora A and drives the degradation of MYCN protein across MYCN-driven cancers. Comparison of cocrystal structures with structure-activity relationships across multiple inhibitors and chemotypes, coupled with mechanistic studies and biochemical assays, delineates an Aurora A conformation-specific effect on proteolytic degradation of MYCN, rather than simple nanomolar-level inhibition of Aurora A kinase activity. C1 [Gustafson, William Clay; Nekritz, Erin A.; Charron, Elise; Matthay, Katherine K.; Weiss, William A.] Univ Calif San Francisco, UCSF Benioff Childrens Hosp, Dept Pediat, San Francisco, CA 94158 USA. [Meyerowitz, Justin Gabriel; Chen, Justin; Charron, Elise; Simonds, Erin F.; Weiss, William A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA. [Meyerowitz, Justin Gabriel; Chen, Justin; Charron, Elise; Simonds, Erin F.; Weiss, William A.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94158 USA. [Meyerowitz, Justin Gabriel; Hertz, Nicholas T.; Shokat, Kevan M.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA. [Gustafson, William Clay; Meyerowitz, Justin Gabriel; Nekritz, Erin A.; Charron, Elise; Simonds, Erin F.; Matthay, Katherine K.; Weiss, William A.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA. [Shokat, Kevan M.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA. [Eilers, Martin] Univ Wurzburg, Theodor Boveri Inst, Bioctr, D-97074 Wurzburg, Germany. [Benes, Cyril] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Charlestown, MA 02114 USA. [Seeger, Robert] Childrens Hosp Los Angeles, Div Hematol Oncol, Los Angeles, CA 90027 USA. RP Weiss, WA (reprint author), Univ Calif San Francisco, UCSF Benioff Childrens Hosp, Dept Pediat, San Francisco, CA 94158 USA. EM waweiss@gmail.com OI Hertz, Nicholas/0000-0002-6527-6898; Eilers, Martin/0000-0002-0376-6533; Simonds, Erin/0000-0002-3497-4861; Weiss, William/0000-0003-2230-9132 FU NIH [K08NS079485]; Alex's Lemonade Stand; Frank A. Campini Foundation; CureSearch Grand Challenge Award; NIH LINCS [1U54HG006097-01]; Katie Dougherty Foundation; Howard Hughes Medical Institute; Samuel Waxman Cancer Research Foundation; [P01CA081403]; [F30CA174154]; [R01CA102321]; [R01CA159859]; [R01CA148699]; [P30CA82103] FX We thank Ulf Peters, Arvin Dar, and Chris Waddling for technical assistance; Yoon-Jae Cho for the medulloblastoma cells; and Alex Warkentin, Mike Lopez, Greg Hamilton, Qi Wen Fan, Miller Huang, Shirin Ilkhanizadeh, and other members of the Shokat and Weiss labs for helpful discussion and critical review. This research was supported by NIH K08NS079485 (W.C.G.); Alex's Lemonade Stand (W.C.G., K.K.M., and W.A.W.); Frank A. Campini Foundation (W.C.G. and K.K.M.); P01CA081403 (W.A.W., K.M.S., K.K.M., and R.S.); F30CA174154 (J.G.M.); CureSearch Grand Challenge Award (W.A.W.); NIH LINCS grant 1U54HG006097-01 (C.B.); R01CA102321 (W.A.W.); R01CA159859 (W.A.W.); R01CA148699 (W.A.W.); P30CA82103 (W.A.W.); Katie Dougherty Foundation (W.A.W. and K.K.M.); Howard Hughes Medical Institute (K.M.S.); and The Samuel Waxman Cancer Research Foundation (K.M.S. and W.A.W.). NR 44 TC 47 Z9 47 U1 2 U2 23 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 SEP 8 PY 2014 VL 26 IS 3 BP 414 EP 427 DI 10.1016/j.ccr.2014.07.015 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AP2AD UT WOS:000341873800013 PM 25175806 ER PT J AU Gordon, RR Wu, MC Huang, CY Harris, WP Sim, HG Lucas, JM Coleman, I Higano, CS Gulati, R True, LD Vessella, R Lange, PH Garzotto, M Beer, TM Nelson, PS AF Gordon, Ryan R. Wu, Mengchu Huang, Chung-Ying Harris, William P. Sim, Hong Gee Lucas, Jared M. Coleman, Ilsa Higano, Celestia S. Gulati, Roman True, Lawrence D. Vessella, Robert Lange, Paul H. Garzotto, Mark Beer, Tomasz M. Nelson, Peter S. TI Chemotherapy-Induced Monoamine Oxidase Expression in Prostate Carcinoma Functions as a Cytoprotective Resistance Enzyme and Associates with Clinical Outcomes SO PLOS ONE LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; NEOADJUVANT DOCETAXEL; RADICAL PROSTATECTOMY; IN-VIVO; CANCER-CELLS; IONIZING-RADIATION; L-DEPRENYL; PHASE-II; MITOXANTRONE; CLORGYLINE AB To identify molecular alterations in prostate cancers associating with relapse following neoadjuvant chemotherapy and radical prostatectomy patients with high-risk localized prostate cancer were enrolled into a phase I-II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pre-treatment prostate tissue was acquired by needle biopsy and post-treatment tissue was acquired by prostatectomy. Prostate cancer gene expression measurements were determined in 31 patients who completed 4 cycles of neoadjuvant chemotherapy. We identified 141 genes with significant transcript level alterations following chemotherapy that associated with subsequent biochemical relapse. This group included the transcript encoding monoamine oxidase A (MAOA). In vitro, cytotoxic chemotherapy induced the expression of MAOA and elevated MAOA levels enhanced cell survival following docetaxel exposure. MAOA activity increased the levels of reactive oxygen species and increased the expression and nuclear translocation of HIF1 alpha. The suppression of MAOA activity using the irreversible inhibitor clorgyline augmented the apoptotic responses induced by docetaxel. In summary, we determined that the expression of MAOA is induced by exposure to cytotoxic chemotherapy, increases HIF1 alpha, and contributes to docetaxel resistance. As MAOA inhibitors have been approved for human use, regimens combining MAOA inhibitors with docetaxel may improve clinical outcomes. C1 [Gordon, Ryan R.; Wu, Mengchu; Huang, Chung-Ying; Harris, William P.; Sim, Hong Gee; Lucas, Jared M.; Coleman, Ilsa; Gulati, Roman; Nelson, Peter S.] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98104 USA. [Gordon, Ryan R.; Wu, Mengchu; Huang, Chung-Ying; Harris, William P.; Sim, Hong Gee; Lucas, Jared M.; Coleman, Ilsa; Gulati, Roman; Nelson, Peter S.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Beer, Tomasz M.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Higano, Celestia S.; Nelson, Peter S.] Univ Washington, Dept Med, Seattle, WA USA. [True, Lawrence D.; Nelson, Peter S.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Higano, Celestia S.; True, Lawrence D.; Vessella, Robert; Lange, Paul H.; Nelson, Peter S.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Garzotto, Mark] Oregon Hlth & Sci Univ, Dept Urol, Portland, OR 97201 USA. [Garzotto, Mark] Oregon Hlth & Sci Univ, Inst Canc, Portland, OR 97201 USA. [Garzotto, Mark] Portland VA Med Ctr, Urol Sect, Portland, OR USA. RP Nelson, PS (reprint author), Fred Hutchinson Canc Res Ctr, Div Human Biol, 1124 Columbia St, Seattle, WA 98104 USA. EM pnelson@fhcrc.org FU AUA Foundation; DOD CDMRP in Prostate Cancer [PC050489, PC110257]; PNW Prostate Cancer SPORE [CA097186]; [R01CA119125]; [PC093509]; [P01CA085859] FX MW was supported by a fellowship from the AUA Foundation. CYH was supported by a fellowship from the DOD CDMRP in Prostate Cancer (PC050489). RG was supported by a fellowship from the DOD CDMRP in Prostate Cancer (PC110257). This work was supported by grants R01CA119125, PC093509, P01CA085859, and the PNW Prostate Cancer SPORE (CA097186). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 4 Z9 4 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 8 PY 2014 VL 9 IS 9 AR e104271 DI 10.1371/journal.pone.0104271 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO4JX UT WOS:000341304700008 PM 25198178 ER PT J AU Scirica, BM AF Scirica, Benjamin M. TI Evaluating the efficacy of mineralocorticoid receptor antagonism in patients with STEMI without heart failure SO EUROPEAN HEART JOURNAL LA English DT Editorial Material ID LEFT-VENTRICULAR DYSFUNCTION; ACUTE MYOCARDIAL-INFARCTION; ACUTE CORONARY SYNDROMES; TIMI 43 TRIAL; NATRIURETIC PEPTIDE; PROGNOSTIC VALUE; ALDOSTERONE; MORBIDITY; MORTALITY; CAPTOPRIL AB This editorial refers to 'Early eplerenone treatment in patients with acute ST-elevation myocardial infarction without heart failure: the randomized double-blind REMINDER study', byG. Montalescot et al., on page 2295 C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, TIMI Study Grp,Cardiovasc Div, Boston, MA 02138 USA. RP Scirica, BM (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, TIMI Study Grp,Cardiovasc Div, Boston, MA 02138 USA. EM bscirica@partners.org NR 18 TC 0 Z9 0 U1 0 U2 1 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 SEP 7 PY 2014 VL 35 IS 34 BP 2276 EP 2278 DI 10.1093/eurheartj/ehu191 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AP7BX UT WOS:000342233800009 PM 24780613 ER PT J AU Huston, RK Christensen, JM Karnpracha, C Rosa, JE Clark, SM Migaki, EA Wu, YX AF Huston, Robert K. Christensen, J. Mark Karnpracha, Chanida Rosa, Jill E. Clark, Sara M. Migaki, Evelyn A. Wu, YingXing TI Calcium Chloride in Neonatal Parenteral Nutrition: Compatibility Studies Using Laser Methodology SO PLOS ONE LA English DT Article ID INORGANIC-PHOSPHATE SALTS; ORGANIC CALCIUM; ALUMINUM CONTAMINATION; PHYSICAL COMPATIBILITY; NUTRIENT ADMIXTURES; SODIUM-PHOSPHATE; PRECIPITATION; TROPHAMINE; STABILITY; GLUCONATE AB Introduction: We have previously reported results of precipitation studies for neonatal parenteral nutrition solutions containing calcium chloride and sodium phosphate using visual methods to determine compatibility. The purpose of this study was to do further testing of compatibility for solutions containing calcium chloride using more sensitive methods. Methods: Solutions of Trophamine (Braun Medical Inc, Irvine, CA) and Premasol (Baxter Pharmaceuticals, Deerfield, IL) were compounded with calcium chloride and potassium phosphate. Controls contained no calcium or phosphate. After incubation at 37 degrees for 24 hours solutions without visual precipitation were analyzed to determine mean particle size using dynamic light scattering from a laser light source. Results: Particle sizes were similar for control solutions and those without visual precipitation and a mean particle size <1000 nm. Compatible solutions were defined as those with added calcium and phosphate with no visual evidence of precipitation and mean particle size <1000 nm. In solutions containing 2.5-3% amino acids and 10 mmol/L of calcium chloride the maximum amount of potassium phosphate that was compatible was 7.5 mmol/L. Conclusion: Maximum amounts of phosphate that could be added to parenteral nutrition solutions containing Trophamine and calcium chloride were about 7.5-10 mmol/L less for a given concentration of calcium based upon laser methodology compared to visual techniques to determine compatibility. There were minor differences in compatibility when adding calcium chloride and potassium phosphate to Premasol versus Trophamine. C1 [Huston, Robert K.] Northwest Newborn Specialists, PC & Pediatrix Med Grp, Portland, OR 97227 USA. [Christensen, J. Mark; Karnpracha, Chanida] Oregon State Univ, Coll Pharm, Dept Pharmaceut Sci, Corvallis, OR 97331 USA. [Rosa, Jill E.] Denver Vet Affairs Med Ctr, Dept Pharm, Denver, CO USA. [Clark, Sara M.; Migaki, Evelyn A.] Neonatal Pharm Providence St Vincent Med Ctr, Portland, OR USA. [Wu, YingXing] Med Data Res Ctr, Portland, OR USA. RP Huston, RK (reprint author), Northwest Newborn Specialists, PC & Pediatrix Med Grp, Portland, OR 97227 USA. EM Robert_Huston@pediatrix.com FU Northwest Newborn Specialists PC; RKH at Providence Health Services, Portland OR FX Funding was provided by Northwest Newborn Specialists PC. Funding was sent directly to the research account of RKH at Providence Health Services, Portland OR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 2 Z9 2 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 5 PY 2014 VL 9 IS 9 AR e106825 DI 10.1371/journal.pone.0106825 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AZ1IR UT WOS:000347993600069 PM 25192060 ER PT J AU Stoeck, CT Kalinowska, A von Deuster, C Harmer, J Chan, RW Niemann, M Manka, R Atkinson, D Sosnovik, DE Mekkaoui, C Kozerke, S AF Stoeck, Christian T. Kalinowska, Aleksandra von Deuster, Constantin Harmer, Jack Chan, Rachel W. Niemann, Markus Manka, Robert Atkinson, David Sosnovik, David E. Mekkaoui, Choukri Kozerke, Sebastian TI Dual-Phase Cardiac Diffusion Tensor Imaging with Strain Correction SO PLOS ONE LA English DT Article ID MAGNETIC-RESONANCE; IN-VIVO; FIBER ARCHITECTURE; HISTOLOGICAL VALIDATION; LAMINAR STRUCTURE; HUMAN HEART; MRI; MYOCARDIUM; MOTION; QUANTIFICATION AB Purpose: In this work we present a dual-phase diffusion tensor imaging (DTI) technique that incorporates a correction scheme for the cardiac material strain, based on 3D myocardial tagging. Methods: In vivo dual-phase cardiac DTI with a stimulated echo approach and 3D tagging was performed in 10 healthy volunteers. The time course of material strain was estimated from the tagging data and used to correct for strain effects in the diffusion weighted acquisition. Mean diffusivity, fractional anisotropy, helix, transverse and sheet angles were calculated and compared between systole and diastole, with and without strain correction. Data acquired at the systolic sweet spot, where the effects of strain are eliminated, served as a reference. Results: The impact of strain correction on helix angle was small. However, large differences were observed in the transverse and sheet angle values, with and without strain correction. The standard deviation of systolic transverse angles was significantly reduced from 35.9 +/- 3.9 degrees to 27.8 degrees +/- 3.5 degrees (p<0.001) upon strain-correction indicating more coherent fiber tracks after correction. Myocyte aggregate structure was aligned more longitudinally in systole compared to diastole as reflected by an increased transmural range of helix angles (71.8 degrees +/- 3.9 degrees systole vs. 55.6 degrees +/- 5.6 degrees, p<0.001 diastole). While diastolic sheet angle histograms had dominant counts at high sheet angle values, systolic histograms showed lower sheet angle values indicating a reorientation of myocyte sheets during contraction. Conclusion: An approach for dual-phase cardiac DTI with correction for material strain has been successfully implemented. This technique allows assessing dynamic changes in myofiber architecture between systole and diastole, and emphasizes the need for strain correction when sheet architecture in the heart is imaged with a stimulated echo approach. C1 [Stoeck, Christian T.; von Deuster, Constantin; Niemann, Markus; Manka, Robert; Kozerke, Sebastian] Univ Zurich, Inst Biomed Engn, Zurich, Switzerland. [Stoeck, Christian T.; von Deuster, Constantin; Niemann, Markus; Manka, Robert; Kozerke, Sebastian] ETH, Zurich, Switzerland. [Kalinowska, Aleksandra] MIT, Dept Mech & Biomed Engn, Cambridge, MA 02139 USA. [von Deuster, Constantin; Harmer, Jack; Kozerke, Sebastian] Kings Coll London, London WC2R 2LS, England. [Chan, Rachel W.; Atkinson, David] UCL, Ctr Med Imaging, London, England. [Niemann, Markus; Manka, Robert] Univ Zurich Hosp, Dept Cardiol, CH-8091 Zurich, Switzerland. [Manka, Robert] Univ Zurich Hosp, Dept Radiol, CH-8091 Zurich, Switzerland. [Sosnovik, David E.; Mekkaoui, Choukri] Harvard Univ, Sch Med, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging,Massachus, Boston, MA 02115 USA. [Sosnovik, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr,Cardiol Div, Boston, MA USA. [Mekkaoui, Choukri] Univ Hosp Ctr Nimes, Dept Radiol, EA 2415, Nimes, France. [Mekkaoui, Choukri] Univ Montpellier I, Fac Med, Montpellier, France. RP Kozerke, S (reprint author), Univ Zurich, Inst Biomed Engn, Zurich, Switzerland. EM kozerke@biomed.ee.ethz.ch RI Kozerke, Sebastian/J-3209-2015; Atkinson, David/C-2270-2008; Stoeck, Christian/S-6280-2016 OI Kozerke, Sebastian/0000-0003-3725-8884; Atkinson, David/0000-0003-1124-6666; FU Swiss National Science Foundation [CR3213_132671/1]; UK EPSRC [EP/I018808/1]; Adult Congenital Heart Disease Service GSTT; National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust; King's College London; National Institutes of Health [5R01HL112831] FX This work was supported by the Swiss National Science Foundation, grant #CR3213_132671/1; UK EPSRC (EP/I018808/1), Adult Congenital Heart Disease Service GSTT and the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London; and the National Institutes of Health (5R01HL112831). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 19 Z9 19 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 5 PY 2014 VL 9 IS 9 AR e107159 DI 10.1371/journal.pone.0107159 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AZ1IR UT WOS:000347993600103 PM 25191900 ER PT J AU Albertsson, AM Bi, D Duan, LQ Zhang, XL Leavenworth, JW Qiao, LL Zhu, CL Cardell, S Cantor, H Hagberg, H Mallard, C Wang, XY AF Albertsson, Anna-Maj Bi, Dan Duan, Luqi Zhang, Xiaoli Leavenworth, Jianmei W. Qiao, Lili Zhu, Changlian Cardell, Susanna Cantor, Harvey Hagberg, Henrik Mallard, Carina Wang, Xiaoyang TI The immune response after hypoxia-ischemia in a mouse model of preterm brain injury SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Brain injury; Preterm; Hypoxia-ischemia; Immune response ID PERINATAL WHITE-MATTER; NASU-HAKOLA DISEASE; PERIVENTRICULAR LEUKOMALACIA; PREMATURE-INFANT; INTERFERON-GAMMA; DAMAGE; INFLAMMATION; EXPRESSION; INFECTION; STROKE AB Background: Preterm brain injury consists primarily of periventricular leukomalacia accompanied by elements of gray-matter injury, and these injuries are associated with cerebral palsy and cognitive impairments. Inflammation is believed to be an important contributing factor to these injuries. The aim of this study was to examine the immune response in a postnatal day (PND) 5 mouse model of preterm brain injury induced by hypoxia-ischemia (HI) that is characterized by focal white and gray-matterinjury. Methods: C57Bl/6 mice at PND 5 were subjected to unilateral HI induced by left carotid artery ligation and subsequent exposure to 10% O-2 for 50 minutes, 70 minutes, or 80 minutes. At seven days post-HI, the white/ gray-matter injury was examined. The immune responses in the brain after HI were examined at different time points after HI using RT-PCR and immunohistochemical staining. Results: HI for 70 minutes in PND 5 mice induced local white-matter injury with focal cortical injury and hippocampal atrophy, features that are similar to those seen in preterm brain injury in human infants. HI for 50 minutes resulted in a small percentage of animals being injured, and HI for 80 minutes produced extensive infarction in multiple brain areas. Various immune responses, including changes in transcription factors and cytokines that are associated with a T-helper (Th)1/Th17-typeresponse,an increased numberof CD4+ T-cells, and elevated levels of triggering receptor expressed on myeloid cells 2 (TREM-2) and its adaptor protein DNAX activation protein of 12 kDa (DAP12) were observed using the HI 70 minute preterm brain injury model. Conclusions: We have established a reproducible model of HI in PND 5 mice that produces consistent local white/ gray-matter brain damage that is relevant to preterm brain injury in human infants. This model provides a useful tool for studying preterm brain injury. Both innate and adaptive immune responses are observed after HI, and these show a strong pro-inflammatory Th1/Th17-type bias. Such findings provide a critical foundation for future studies on the mechanism of preterm brain injury and suggest that blocking the Th1/Th17-type immune response might provide neuroprotection after preterm brain injury. C1 [Albertsson, Anna-Maj; Bi, Dan; Duan, Luqi; Zhang, Xiaoli; Qiao, Lili; Hagberg, Henrik; Mallard, Carina; Wang, Xiaoyang] Univ Gothenburg, Sahlgrenska Acad, Dept Neurosci & Physiol, Perinatal Ctr, SE-40530 Gothenburg, Sweden. [Bi, Dan; Duan, Luqi; Zhang, Xiaoli; Zhu, Changlian; Wang, Xiaoyang] Zhengzhou Univ, Affiliated Hosp 3, Dept Pediat, Zhengzhou, Peoples R China. [Leavenworth, Jianmei W.; Cantor, Harvey] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Leavenworth, Jianmei W.; Cantor, Harvey] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA USA. [Qiao, Lili] Song Jiang Cent Hosp, Dept Pediat, Shanghai, Peoples R China. [Zhu, Changlian] Univ Gothenburg, Sahlgrenska Acad, Dept Neurosci & Physiol, Ctr Brain Repair & Rehabil, SE-40530 Gothenburg, Sweden. [Cardell, Susanna] Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Microbiol & Immunol, SE-40530 Gothenburg, Sweden. [Hagberg, Henrik] East Hosp, Dept Clin Sci, S-41685 Gothenburg, Sweden. [Hagberg, Henrik] Kings Coll London, St Thomas Hosp, Dept Perinatal Imaging & Hlth, Ctr Developing Brain, London SE1 7EH, England. RP Wang, XY (reprint author), Univ Gothenburg, Sahlgrenska Acad, Dept Neurosci & Physiol, Perinatal Ctr, Box 432, SE-40530 Gothenburg, Sweden. EM xiaoyang.wang@fysiologi.gu.se RI Albertsson, Ann-Christine /Q-6107-2016; OI Albertsson, Ann-Christine /0000-0001-8696-9143; Hagberg, Henrik/0000-0003-3962-1448 FU Swedish Medical Research Council [VR 2008-2286, VR 2013-2475, VR 2012-3500, VR 2012-2992]; Bill & Melinda Gates Foundation [OPP1036135]; VINNMER-Marie Curie international qualification (VINNOVA) [2011-03458]; Wilhelm and Martina Lundgren [37/2013, 35/2012]; Ahlen Foundation; Wellcome Trust [WT094823]; Frimurare Barnhus Foundation; Byggmastare Olle Engqvist Foundation; Leducq Foundation [DSRR-P34404]; Swedish Brain Foundation [FO2013-0095, 2013-0035]; Wilhelm and Martina Lundgren Foundation; [ALFGBG-367051]; [ALFGBG-2863]; [ALFGBG-142881] FX This work was supported by the Swedish Medical Research Council (VR 2008-2286 and VR 2013-2475 to XW, VR 2012-3500 to HH, and VR 2012-2992 to CM), the Bill & Melinda Gates Foundation Grand Challenge Explorations and Global Health (OPP1036135 to XW), Swedish governmental grants to researchers in the public health service (ALFGBG-367051 to XW, ALFGBG-2863 to HH, and ALFGBG-142881 to CM), VINNMER-Marie Curie international qualification (VINNOVA, 2011-03458 to XW), Wilhelm and Martina Lundgren (37/2013 to XW and 35/2012 to AM), Wilhelm and Martina Lundgren Foundation (HH), the Ahlen Foundation (HH, CM), Wellcome Trust (WT094823 HH), the Frimurare Barnhus Foundation (HH), the Byggmastare Olle Engqvist Foundation (HH, CM), the Leducq Foundation (DSRR-P34404 to CM and HH), and the Swedish Brain Foundation (FO2013-0095 to CM, 2013-0035 HH). NR 68 TC 9 Z9 11 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD SEP 5 PY 2014 VL 11 AR 153 DI 10.1186/s12974-014-0153-z PG 14 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA AW1BL UT WOS:000346025600001 PM 25187205 ER PT J AU Molcanyi, M Mehrjardi, NZ Schafer, U Haj-Yasein, NN Brockmann, M Penner, M Riess, P Reinshagen, C Rieger, B Hannes, T Hescheler, J Bosche, B AF Molcanyi, Marek Mehrjardi, Narges Zare Schaefer, Ute Haj-Yasein, Nadia Nabil Brockmann, Michael Penner, Marina Riess, Peter Reinshagen, Clemens Rieger, Bernhard Hannes, Tobias Hescheler, Juergen Bosche, Bert TI Impurity of stem cell graft by murine embryonic fibroblasts - implications for cell-based therapy of the central nervous system SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Article DE stem cell transplantation; feeder-based cell line; murine embryonic fibroblasts; stroke; brain injury; cell graft contamination ID TRAUMATIC BRAIN-INJURY; PARKINSONS-DISEASE; DOPAMINE NEURONS; NEURAL DIFFERENTIATION; RAPID DIFFERENTIATION; EXPERIMENTAL STROKE; ISCHEMIC BRAIN; FEEDER CELLS; RAT-BRAIN; IPS CELLS AB Stem cells have been demonstrated to possess a therapeutic potential in experimental models of various central nervous system disorders, including stroke. The types of implanted cells appear to play a crucial role. Previously, groups of the stem cell network NRW implemented a feeder-based cell line within the scope of their projects, examining the implantation of stem cells after ischemic stroke and traumatic brain injury. Retrospective evaluation indicated the presence of spindle-shaped cells in several grafts implanted in injured animals, which indicated potential contamination by co-cultured feeder cells (murine embryonic fibroblasts - MEFs). Because feeder-based cell lines have been previously exposed to a justified criticism with regard to contamination by animal glycans, we aimed to evaluate the effects of stem cell/MEF co-transplantation. MEFs accounted for 5.3 +/- 2.8% of all cells in the primary FACS-evaluated co-culture. Depending on the culture conditions and subsequent purification procedure, the MEF-fraction ranged from 0.9 to 9.9% of the cell suspensions in vitro. MEF survival and related formation of extracellular substances in vivo were observed after implantation into the uninjured rat brain. Impurity of the stem cell graft by MEFs interferes with translational strategies, which represents a threat to the potential recipient and may affect the graft microenvironment. The implications of these findings are critically discussed. C1 [Molcanyi, Marek; Mehrjardi, Narges Zare; Hannes, Tobias; Hescheler, Juergen] Univ Cologne, Fac Med, Inst Neurophysiol, D-50931 Cologne, Germany. [Molcanyi, Marek; Penner, Marina; Rieger, Bernhard] Univ Cologne, Fac Med, Clin Neurosurg, D-50931 Cologne, Germany. [Schaefer, Ute] Med Univ Graz, Res Unit Expt Neurotraumatol, Graz, Austria. [Haj-Yasein, Nadia Nabil] Univ Oslo, Inst Basic Med Sci, Fac Med, Dept Nutr, Oslo, Norway. [Brockmann, Michael] Univ Witten Herdecke, Cologne Merheim Hosp, Kliniken Stadt Koln, Dept Pathol, Cologne, Germany. [Riess, Peter] HELIOS Klin Bad Berleburg, Dept Traumatol & Orthoped, Bad Berleburg, Germany. [Reinshagen, Clemens] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurotherapy & Imaging Lab, Boston, MA USA. [Reinshagen, Clemens] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Hannes, Tobias] Univ Hosp Cologne, Fac Med, Heart Ctr Cologne, Dept Pediat Cardiol, Cologne, Germany. [Bosche, Bert] St Michaels Hosp, Keenan Res Ctr Biomed Sci, Div Neurosurg, Toronto, ON M5C 1N8, Canada. [Bosche, Bert] Univ Toronto, St Michaels Hosp, Li Ka Shing Knowledge Inst, Dept Surg, Toronto, ON, Canada. [Bosche, Bert] Univ Duisburg Essen, Univ Hosp Essen, Dept Neurol, Essen, Germany. RP Bosche, B (reprint author), St Michaels Hosp, Keenan Res Ctr Biomed Sci, Div Neurosurg, 209 Victoria St, Toronto, ON M5C 1N8, Canada. EM bert.bosche@gmail.com OI Bosche, Bert/0000-0002-5313-3195; Reinshagen, Clemens/0000-0002-8524-4578; Hannes, Tobias/0000-0002-8550-2282 FU Deutsche Forschungsgemeinschaft [BO 4229/1-1] FX This study was supported by a grant of the Deutsche Forschungsgemeinschaft (BO 4229/1-1; novel strategies to protect the neurovascular unit in cerebrovascular diseases) to Dr. Bert Bosche. We are thankful to Prof. Jurgen Hampl for efficient structural cooperation and providing additional laboratory background; Prof. Edmund Neugebauer for his enthusiastic initiative and support of Dr. Marek Molcanyi during all primary experiments, Fulya Firuze Hatay for helping with the literature search and evaluation; Heba Abdel Razik and Gunter Rapel for support during FACS analysis; Bernhard Schaftke for supporting the initial confocal analysis, Tomo Saric for his constructive critical appraisal and staff support; Birte Baudes for accepting the delays of the concomitant study, Sebastian Zachar for the support with Figure preparation and formatting and Pascal Schulte for Riopan supply. NR 45 TC 1 Z9 1 U1 0 U2 6 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD SEP 5 PY 2014 VL 8 AR 257 DI 10.3389/fncel.2014.00257 PG 10 WC Neurosciences SC Neurosciences & Neurology GA AS7UX UT WOS:000344461100001 PM 25249934 ER PT J AU Shin, J Carr, A Corner, GA Togel, L Davaos-Salas, M Tran, H Chueh, AC Al-Obaidi, S Chionh, F Ahmed, N Buchanan, DD Young, JP Malo, MS Hodin, RA Arango, D Sieber, OM Augenlicht, LH Dhillon, AS Weber, TK Mariadason, JM AF Shin, Joongho Carr, Azadeh Corner, Georgia A. Toegel, Lars Davaos-Salas, Mercedes Hoanh Tran Chueh, Anderly C. Al-Obaidi, Sheren Chionh, Fiona Ahmed, Naseem Buchanan, Daniel D. y Young, Joanne P. Malo, Madhu S. Hodin, Richard A. Arango, Diego Sieber, Oliver M. Augenlicht, Leonard H. Dhillon, Amardeep S. Weber, Thomas K. Mariadason, John M. TI The Intestinal Epithelial Cell Differentiation Marker Intestinal Alkaline Phosphatase (ALPi) Is Selectively Induced by Histone Deacetylase Inhibitors (HDACi) in Colon Cancer Cells in a Kruppel-like Factor 5 (KLF5)-dependent Manner SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; CHAIN FATTY-ACIDS; TRANSCRIPTION FACTOR; GENE-EXPRESSION; CPG ISLAND; COLORECTAL-CANCER; MYELOID-LEUKEMIA; DNA METHYLATION; CARCINOMA-CELLS; BUTYRATE AB The histone deacetylase inhibitor (HDACi) sodium butyrate promotes differentiation of colon cancer cells as evidenced by induced expression and enzyme activity of the differentiation marker intestinal alkaline phosphatase (ALPi). Screening of a panel of 33 colon cancer cell lines identified cell lines sensitive (42%) and resistant (58%) to butyrate induction of ALP activity. This differential sensitivity was similarly evident following treatment with the structurally distinct HDACi, MS-275. Resistant cell lines were significantly enriched for those harboring the CpG island methylator phenotype (p = 0.036, Chi square test), and resistant cell lines harbored methylation of the ALPi promoter, particularly of a CpG site within a critical KLF/Sp regulatory element required for butyrate induction of ALPi promoter activity. However, butyrate induction of an exogenous ALPi promoter-reporter paralleled up-regulation of endogenous ALPi expression across the cell lines, suggesting the presence or absence of a key transcriptional regulator is the major determinant of ALPi induction. Through microarray profiling of sensitive and resistant cell lines, we identified KLF5 to be both basally more highly expressed as well as preferentially induced by butyrate in sensitive cell lines. KLF5 overexpression induced ALPi promoter-reporter activity in resistant cell lines, KLF5 knockdown attenuated butyrate induction of ALPi expression in sensitive lines, and butyrate selectively enhanced KLF5 binding to the ALPi promoter in sensitive cells. These findings demonstrate that butyrate induction of the cell differentiation marker ALPi is mediated through KLF5 and identifies subsets of colon cancer cell lines responsive and refractory to this effect. C1 [Shin, Joongho; Carr, Azadeh; Ahmed, Naseem; Augenlicht, Leonard H.; Mariadason, John M.] Albert Einstein Coll Med, Dept Oncol, Montefiore Med Ctr, Bronx, NY 10461 USA. [Corner, Georgia A.; Toegel, Lars; Davaos-Salas, Mercedes; Hoanh Tran; Chueh, Anderly C.; Al-Obaidi, Sheren; Chionh, Fiona; Mariadason, John M.] Austin Hlth, Ludwig Inst Canc Res, Melbourne, Vic 3084, Australia. [Buchanan, Daniel D. y; Young, Joanne P.] Queensland Inst Med Res, Herston, Qld 4006, Australia. [Malo, Madhu S.; Hodin, Richard A.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Arango, Diego] Univ Autonoma Barcelona, Ctr Invest Bioquim & Biol Mol Nanomed, Vall dHebron Univ Hosp, Grp Mol Oncol,Res Inst, Barcelona 08035, Spain. [Arango, Diego] Ctr Invest Biomed Red Bioingn Biomat & Nanomed, Barcelona, Spain. [Sieber, Oliver M.] Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3052, Australia. [Dhillon, Amardeep S.] Peter MacCallum Canc Ctr, Melbourne, Vic 3002, Australia. [Weber, Thomas K.] Vet Affairs New York Harbor Hlth Care Syst, Brooklyn, NY 11209 USA. RP Mariadason, JM (reprint author), Austin Hlth, Ludwig Inst Canc Res, Level Olivia Newton John Canc & Wellness Ctr 5, 145-163 Studley Rd, Heidelberg, Vic 3084, Australia. EM john.mariadason@ludwig.edu.au RI Sieber, Oliver/M-9473-2015; Arango, Diego/M-5667-2016 OI Sieber, Oliver/0000-0001-9480-0786; Arango, Diego/0000-0003-2953-3284 FU Operational Infrastructure Support Program (Victorian government, Australia); Spanish Ministry for Economy and Competitiveness [CP05/00256, TRA2009-0093, SAF2008-00789, PI12/03112, PI12/01095]; Association for International Cancer Research Grant [AICR13-0245]; Agencia de Gestio d'Ajuts Universitaris i de Recerca [SGR 157]; Australian Research Council [FT0992234]; National Health and Medical Research Council [1046092]; CONACyT Mexico [186310] FX This work was supported in part by the Operational Infrastructure Support Program (Victorian government, Australia), Spanish Ministry for Economy and Competitiveness Grants CP05/00256, TRA2009-0093, SAF2008-00789, PI12/03112, and PI12/01095, the Association for International Cancer Research Grant AICR13-0245, Agencia de Gestio d'Ajuts Universitaris i de Recerca SGR 157 (to D. A.), and Australian Research Council Future Fellowship FT0992234 and National Health and Medical Research Council Senior Research Fellowship 1046092 (to J. M. M.).; Supported by a fellowship from CONACyT Mexico (186310). NR 41 TC 9 Z9 9 U1 0 U2 5 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 SEP 5 PY 2014 VL 289 IS 36 BP 25306 EP 25316 DI 10.1074/jbc.M114.557546 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AP3OH UT WOS:000341985300049 PM 25037223 ER PT J AU Derbyshire, ER Zuzarte-Luis, V Magalhaes, AD Kato, N Sanschagrin, PC Wang, JH Zhou, WJ Miduturu, CV Mazitschek, R Sliz, P Mota, MM Gray, NS Clardy, J AF Derbyshire, Emily R. Zuzarte-Luis, Vanessa Magalhaes, Andreia D. Kato, Nobutaka Sanschagrin, Paul C. Wang, Jinhua Zhou, Wenjun Miduturu, Chandrasekhar V. Mazitschek, Ralph Sliz, Piotr Mota, Maria M. Gray, Nathanael S. Clardy, Jon TI Chemical Interrogation of the Malaria Kinome SO CHEMBIOCHEM LA English DT Article DE bioinformatics; chemical probes; high-throughput screening; kinases; malaria; Plasmodium ID FALCIPARUM DIHYDROOROTATE DEHYDROGENASE; PARASITE PLASMODIUM-FALCIPARUM; ANTIMALARIAL-DRUG DISCOVERY; GLYCOGEN-SYNTHASE KINASE-3; LIVER-STAGE; SELECTIVE INHIBITORS; PROTEIN-KINASES; ACCURATE DOCKING; CRUCIAL ROLE; LIFE-CYCLE AB Malaria, an infectious disease caused by eukaryotic parasites of the genus Plasmodium, afflicts hundreds of millions of people every year. Both the parasite and its host utilize protein kinases to regulate essential cellular processes. Bioinformatic analyses of parasite genomes predict at least 65 protein kinases, but their biological functions and therapeutic potential are largely unknown. We profiled 1358 small-molecule kinase inhibitors to evaluate the role of both the human and the malaria kinomes in Plasmodium infection of liver cells, the parasites' obligatory but transient developmental stage that precedes the symptomatic blood stage. The screen identified several small molecules that inhibit parasite load in liver cells, some with nanomolar efficacy, and each compound was subsequently assessed for activity against blood-stage malaria. Most of the screening hits inhibited both liver-and blood-stage malaria parasites, which have dissimilar gene expression profiles and infect different host cells. Evaluation of existing kinase activity profiling data for the library members suggests that several kinases are essential to malaria parasites, including cyclin-dependent kinases (CDKs), glycogen synthase kinases, and phosphoinositide-3-kinases. CDK inhibitors were found to bind to Plasmodium protein kinase 5, but it is likely that these compounds target multiple parasite kinases. The dual-stage inhibition of the identified kinase inhibitors makes them useful chemical probes and promising starting points for antimalarial development. C1 [Derbyshire, Emily R.; Magalhaes, Andreia D.; Sanschagrin, Paul C.; Wang, Jinhua; Zhou, Wenjun; Miduturu, Chandrasekhar V.; Sliz, Piotr; Gray, Nathanael S.; Clardy, Jon] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Zuzarte-Luis, Vanessa; Mota, Maria M.] Univ Lisbon, Inst Med Mol, P-1649028 Lisbon, Portugal. [Mazitschek, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Kato, Nobutaka; Mazitschek, Ralph] Broad Inst, Cambridge, MA 02142 USA. RP Derbyshire, ER (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM emily.derbyshire@duke.edu; jon_clardy@hms.harvard.edu RI Sanschagrin, Paul/G-2179-2011; OI Sanschagrin, Paul/0000-0003-4074-4066; Zuzarte-Luis, Vanessa/0000-0003-0023-5953; Mota, Maria Manuel/0000-0002-2858-1041; Sliz, Piotr/0000-0002-6522-0835 FU Harvard Medical School-Portugal Program in Translational Research; NIH [GM099796] FX We thank David Drewry and William Zuercher (GSK, Raleigh-Durham) for helpful input concerning the GSK PKIS set and Paul Gillespie (Roche, Nutley) for kindly supplying RO1153853 and input with the Roche kinase inhibitor set. We thank Dr. Oliver Billker for sharing his phylogenetic analysis of malaria kinases and the ICCB-Longwood screening center where the screen was performed. We also thank Ines Albuquerque for preliminary mouse experiments with CDK 1/2. This work was supported by the Harvard Medical School-Portugal Program in Translational Research (M.M.M. and J.C.) and the NIH K99 Pathway to Independence Award (GM099796, to E.R.D.). NR 59 TC 3 Z9 3 U1 3 U2 26 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1439-4227 EI 1439-7633 J9 CHEMBIOCHEM JI ChemBioChem PD SEP 5 PY 2014 VL 15 IS 13 BP 1920 EP 1930 DI 10.1002/cbic.201400025 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA AO8EL UT WOS:000341586100012 PM 25111632 ER PT J AU Holt, DJ Boeke, EA Wolthusen, RPF Nasr, S Milad, MR Tootell, RBH AF Holt, Daphne J. Boeke, Emily A. Wolthusen, Rick P. F. Nasr, Shahin Milad, Mohammed R. Tootell, Roger B. H. TI A parametric study of fear generalization to faces and non-face objects: relationship to discrimination thresholds SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE fear; faces; emotion; learning; generalization; perception ID GENERALIZATION GRADIENTS; ANXIETY DISORDER; CONDITIONED FEAR; FACIAL EXPRESSIONS; DENTATE GYRUS; HUMANS; CORTEX; SCHIZOPHRENIA; EXTINCTION; MEMORY AB Fear generalization is the production of fear responses to a stimulus that is similar-but not identical-to a threatening stimulus. Although prior studies have found that fear generalization magnitudes are qualitatively related to the degree of perceptual similarity to the threatening stimulus, the precise relationship between these two functions has not been measured systematically. Also, it remains unknown whether fear generalization mechanisms differ for social and non-social information. To examine these questions, we measured perceptual discrimination and fear generalization in the same subjects, using images of human faces and non-face control stimuli ("blobs") that were perceptually matched to the faces. First, each subject's ability to discriminate between pairs of faces or blobs was measured. Each subject then underwent a Pavlovian fear conditioning procedure, in which each of the paired conditioned stimuli (CS) were either followed (CS+) or not followed (CS-) by a shock. Skin conductance responses (SCRs) were also measured. Subjects were then presented with the CS+, CS- and five levels of a CS+-to-CS- morph continuum between the paired stimuli, which were identified based on individual discrimination thresholds. Finally, subjects rated the likelihood that each stimulus had been followed by a shock. Subjects showed both autonomic (SCR based) and conscious (ratings-based) fear responses to morphs that they could not discriminate from the CS+ (generalization). For both faces and non-face objects, fear generalization was not found above discrimination thresholds. However, subjects exhibited greater fear generalization in the shock likelihood ratings compared to the SCRs, particularly for faces. These findings reveal that autonomic threat detection mechanisms in humans are highly sensitive to small perceptual differences between stimuli. Also, the conscious evaluation of threat shows broader generalization than autonomic responses, biased towards labeling a stimulus as threatening. C1 [Holt, Daphne J.; Boeke, Emily A.; Wolthusen, Rick P. F.; Milad, Mohammed R.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02129 USA. [Holt, Daphne J.; Milad, Mohammed R.; Tootell, Roger B. H.] Harvard Univ, Sch Med, Boston, MA USA. [Holt, Daphne J.; Nasr, Shahin; Tootell, Roger B. H.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Wolthusen, Rick P. F.] Tech Univ Dresden, Fac Med Carl Gustav Carus, Dept Child & Adolescent Psychiat, D-01062 Dresden, Germany. [Nasr, Shahin; Tootell, Roger B. H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02129 USA. RP Holt, DJ (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 149 13th St,Room 2608, Boston, MA 02129 USA. EM dholt@partners.org FU National Institute of Mental Health [RO1MH095904]; National Eye Institute [R01EY017081] FX This work was supported by the National Institute of Mental Health (Daphne J. Holt: RO1MH095904) and the National Eye Institute (Roger B. H. Tootell R01EY017081). NR 56 TC 4 Z9 4 U1 4 U2 19 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD SEP 5 PY 2014 VL 8 AR 624 DI 10.3389/fnhum.2014.00624 PG 12 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AO5DI UT WOS:000341362000001 PM 25249955 ER PT J AU Glykys, J Dzhala, V Egawa, K Balena, T Saponjian, Y Kuchibhotla, KV Bacskai, BJ Kahle, KT Zeuthen, T Staley, KJ AF Glykys, J. Dzhala, V. Egawa, K. Balena, T. Saponjian, Y. Kuchibhotla, K. V. Bacskai, B. J. Kahle, K. T. Zeuthen, T. Staley, K. J. TI Response to Comments on "Local impermeant anions establish the neuronal chloride concentration" SO SCIENCE LA English DT Editorial Material ID CULTURED HIPPOCAMPAL-NEURONS; NEONATAL SEIZURES; BIPOLAR CELLS; MEMBRANE; DEPOLARIZATION; CLOMELEON; INDICATOR; BRAIN C1 [Glykys, J.; Dzhala, V.; Egawa, K.; Balena, T.; Saponjian, Y.; Bacskai, B. J.; Staley, K. J.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Kuchibhotla, K. V.] NYU, Sch Med, Skirball Inst Biomol Med, New York, NY USA. [Kahle, K. T.] Harvard Univ, Sch Med, Dept Neurosurg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Zeuthen, T.] Univ Copenhagen, Dept Cellular & Mol Med, DK-1168 Copenhagen, Denmark. RP Staley, KJ (reprint author), Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM staley.kevin@mgh.harvard.edu FU NIMH NIH HHS [U01 MH106013]; NINDS NIH HHS [R01 NS040109, R25 NS065743] NR 24 TC 6 Z9 6 U1 1 U2 25 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 SEP 5 PY 2014 VL 345 IS 6201 DI 10.1126/science.1253146 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO2TV UT WOS:000341179800034 PM 25190789 ER PT J AU Godinho, SA Pellman, D AF Godinho, S. A. Pellman, D. TI Causes and consequences of centrosome abnormalities in cancer SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE centrosome amplification; centriole; clustering; cancer; aneuploidy; microtubules ID POLO-LIKE KINASE; INTEGRIN-LINKED KINASE; CHROMOSOMAL INSTABILITY; HUMAN-CELLS; C-ELEGANS; PERICENTRIOLAR MATERIAL; CENTRIOLE DUPLICATION; EXTRA-CENTROSOMES; PRIMARY CILIUM; SPINDLE ORGANIZATION AB Centrosome amplification is a hallmark of cancer. However, despite significant progress in recent years, we are still far from understanding how centrosome amplification affects tumorigenesis. Boveri's hypothesis formulated more than 100 years ago was that aneuploidy induced by centrosome amplification promoted tumorigenesis. Although the hypothesis remains appealing 100 years later, it is also clear that the role of centrosome amplification in cancer is more complex than initially thought. Here, we review how centrosome abnormalities are generated in cancer and the mechanisms cells employ to adapt to centrosome amplification, in particular centrosome clustering. We discuss the different mechanisms by which centrosome amplification could contribute to tumour progression and the new advances in the development of therapies that target cells with extra centrosomes. C1 [Godinho, S. A.] Queen Mary Univ London, Barts Canc Inst, London EC1M 6BQ, England. [Pellman, D.] Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. [Pellman, D.] Childrens Hosp, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Pellman, D.] Childrens Hosp, Boston, MA 02115 USA. [Pellman, D.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Godinho, SA (reprint author), Queen Mary Univ London, Barts Canc Inst, Charterhouse Sq, London EC1M 6BQ, England. EM s.godinho@qmul.ac.uk FU Howard Hughes Medical Institute; National Institutes of Health FX D.P. is supported by Howard Hughes Medical Institute and awards from the National Institutes of Health. NR 151 TC 37 Z9 37 U1 1 U2 18 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD SEP 5 PY 2014 VL 369 IS 1650 AR 20130467 DI 10.1098/rstb.2013.0467 PG 13 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AM1YZ UT WOS:000339646500017 ER PT J AU Reinherz, EL Keskin, DB Reinhold, B AF Reinherz, Ellis L. Keskin, Derin B. Reinhold, Bruce TI Forward vaccinology: CTL targeting based upon pnysical cetection of HLA-bound peptides SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE T cell epitopes; mass spectrometry; vaccines; proteomics; CTL; resident-memory T cells; TCR ID T-CELL DIFFERENTIATION; STRUCTURAL BASIS; HIGH-AVIDITY; MEMORY; RECOGNITION; LYMPHOCYTES; VACCINATION; INFECTION; FREQUENCY; EFFECTOR AB Vaccine-elicited cytotoxic T lymphocytes (CTL) recognizing conserved fragments of a pathogen's proteome could greatly impact infectious diseases and cancers. Enabling this potential are recent advances in mass spectrometry that identify specific target peptides among the myriad HLA-bound peptides on altered cells. Ultrasensitivity of these physical detection methods allows for the direct assessment of peptide presentation on small numbers of tissue-derived cells. In addition, concurrent advances in immunobiology suggest ways to induce CTLs with requisite functional avidity and tissue deployment. Elicitation of high-avidity resident-memory T cells through vaccination may shift the vaccinology paradigm both for preventive and therapeutic approaches to human disease control. C1 [Reinherz, Ellis L.; Keskin, Derin B.; Reinhold, Bruce] Dana Farber Canc Inst, Dept Med Oncol, Immunobiol Lab, Boston, MA 02115 USA. [Reinherz, Ellis L.; Keskin, Derin B.; Reinhold, Bruce] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Reinherz, EL (reprint author), Dana Farber Canc Inst, 77 Ave Louis Pasteur,HIM 418, Boston, MA 02115 USA. EM ellis_reinherz@dfci.harvard.edu FU NIAID [AI090043] FX This work was supported by funding from NIAID AI090043. NR 29 TC 3 Z9 4 U1 0 U2 2 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD SEP 4 PY 2014 VL 5 AR 418 DI 10.3389/fimmu.2014.00418 PG 4 WC Immunology SC Immunology GA CI0QG UT WOS:000354442000001 PM 25237310 ER PT J AU West, JA Davis, CP Sunwoo, H Simon, MD Sadreyev, RI Wang, PI Tolstorukov, MY Kingston, RE AF West, Jason A. Davis, Christopher P. Sunwoo, Hongjae Simon, Matthew D. Sadreyev, Ruslan I. Wang, Peggy I. Tolstorukov, Michael Y. Kingston, Robert E. TI The Long Noncoding RNAs NEAT1 and MALAT1 Bind Active Chromatin Sites SO MOLECULAR CELL LA English DT Article ID NUCLEAR PARASPECKLES; ESTROGEN-RECEPTOR; SPLICING FACTORS; BREAST-CANCER; X-CHROMOSOME; P-TEFB; TRANSCRIPTION; CELLS; RELOCATION; PROTEINS AB Mechanistic roles for many lncRNAs are poorly understood, in part because their direct interactions with genomic loci and proteins are difficult to assess. Using a method to purify endogenous RNAs and their associated factors, we mapped the genomic binding sites for two highly expressed human lncRNAs, NEAT1 and MALAT1. We show that NEAT1 and MALAT1 localize to hundreds of genomic sites in human cells, primarily over active genes. NEAT1 and MALAT1 exhibit colocalization to many of these loci, but display distinct gene body binding patterns at these sites, suggesting independent but complementary functions for these RNAs. We also identified numerous proteins enriched by both lncRNAs, supporting complementary binding and function, in addition to unique associated proteins. Transcriptional inhibition or stimulation alters localization of NEAT1 on active chromatin sites, implying that underlying DNA sequence does not target NEAT1 to chromatin, and that localization responds to cues involved in the transcription process. C1 [West, Jason A.; Davis, Christopher P.; Sunwoo, Hongjae; Simon, Matthew D.; Sadreyev, Ruslan I.; Wang, Peggy I.; Tolstorukov, Michael Y.; Kingston, Robert E.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [West, Jason A.; Davis, Christopher P.; Sunwoo, Hongjae; Simon, Matthew D.; Kingston, Robert E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Sadreyev, Ruslan I.; Wang, Peggy I.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sadreyev, Ruslan I.; Wang, Peggy I.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Kingston, RE (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM kingston@molbio.mgh.harvard.edu RI West, Jason/I-4445-2014 OI West, Jason/0000-0002-7252-8651 FU National Institute of General Medical Sciences of the NIH [F32GM093491, R01GM043901, R37GM048405]; National Science Foundation graduate fellowship; Helen Hay Whitney Foundation FX We thank J. Engreitz, M. Guttman, and the R. E. K. lab for helpful discussions; A. Plys for critical reading of the manuscript; S. Bowman for library construction optimization; D. Levens, S. Diederichs, T. Gutschner, F. Rigo, and ISIS Pharmaceuticals for reagents not directly used in this study; R. Tomaino for advice on proteomic analysis; and U. Kim and the MGH Sequencing Core. J. A. W. and R. E. K. were supported by the National Institute of General Medical Sciences of the NIH (F32GM093491 to J.A.W.; R01GM043901 and R37GM048405 to R. E. K.). C. P. D. was supported by a National Science Foundation graduate fellowship. M. D. S. was supported by the Helen Hay Whitney Foundation. NR 57 TC 77 Z9 80 U1 5 U2 48 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 SEP 4 PY 2014 VL 55 IS 5 BP 791 EP 802 DI 10.1016/j.molcel.2014.07.012 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AQ2LW UT WOS:000342618700014 PM 25155612 ER PT J AU Wu, T Liu, YF Wen, DC Tseng, ZT Tahmasian, M Zhong, M Rafii, S Stadtfeld, M Hochedlinger, K Xiao, A AF Wu, Tao Liu, Yifei Wen, Duancheng Tseng, Zito Tahmasian, Martik Zhong, Mei Rafii, Shahin Stadtfeld, Matthias Hochedlinger, Konrad Xiao, Andrew TI Histone Variant H2A.X Deposition Pattern Serves as a Functional Epigenetic Mark for Distinguishing the Developmental Potentials of iPSCs SO CELL STEM CELL LA English DT Article ID EMBRYONIC STEM-CELLS; SELF-RENEWAL; TRANSCRIPTION FACTORS; GENOMIC INSTABILITY; REGULATORY NETWORKS; GENES; DIFFERENTIATION; CHROMATIN; FATE; CDX2 AB For future application of induced pluripotent stem cell (iPSC) technology, the ability to assess the overall quality of iPSC clones will be an important issue. Here we show that the histone variant H2A.X is a functional marker that can distinguish the developmental potentials of mouse iPSC lines. We found that H2A.X is specifically targeted to and negatively regulates extraembryonic lineage gene expression in embryonic stem cells (ESCs) and prevents trophectoderm lineage differentiation. ESC-specific H2A.X deposition patterns are faithfully recapitulated in iPSCs that support the development of "all-iPS'' animals via tetraploid complementation, the most stringent test available of iPSC quality. In contrast, iPSCs that fail to support all-iPS embryonic development show aberrant H2A.X deposition, upregulation of extraembryonic lineage genes, and a predisposition to extraembryonic differentiation. Thus, our work has highlighted an epigenetic mechanism for maintaining cell lineage commitment in ESCs and iPSCs that can be used to distinguish the quality of iPSC lines. C1 [Wu, Tao; Liu, Yifei; Tseng, Zito; Tahmasian, Martik; Zhong, Mei; Xiao, Andrew] Yale Univ, Sch Med, Yale Stem Cell Ctr, New Haven, CT 06520 USA. [Wu, Tao; Liu, Yifei; Tseng, Zito; Tahmasian, Martik; Xiao, Andrew] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. [Wen, Duancheng; Rafii, Shahin] Weill Cornell Med Coll, Ronald O Perelman & Claudia Cohen Ctr Reprod Med, New York, NY 10065 USA. [Zhong, Mei] Yale Univ, Sch Med, Dept Cell Biol, New Haven, CT 06520 USA. [Stadtfeld, Matthias; Hochedlinger, Konrad] Harvard Univ, Howard Hughes Med Inst, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Stadtfeld, Matthias; Hochedlinger, Konrad] Harvard Univ, Dept Stem Cell & Regenerat Med, Boston, MA 02114 USA. RP Xiao, A (reprint author), Yale Univ, Sch Med, Yale Stem Cell Ctr, 333 Cedar St, New Haven, CT 06520 USA. EM andrew.xiao@yale.edu RI Liu, Yifei/H-1730-2014; Wu, Tao/A-1063-2013; OI Wu, Tao/0000-0002-9859-4534; Rafii, Shahin/0000-0001-5605-1067; Stadtfeld, Matthias/0000-0002-5852-9906 FU Howard Teming Award from NCI [K99/R00 CA1311560]; Yale startup funding; CT Stem Cell Foundation [11SCA34] FX We thank Dr. Fredrick Alt (Harvard Medical School) for providing H2A.X KO ESC, Drs. David Gilbert and Tyrone Ryba for sharing the data, Dr. Anna-Katerina Hadjantonakis and Dr. Nestor Saiz Arenales for TSC line (TS3.5-GFP). A. X. is supported by a Howard Teming Award from NCI (K99/R00 CA1311560) and Yale startup funding. T. W. is partially supported by CT Stem Cell Foundation (11SCA34). NR 38 TC 21 Z9 23 U1 2 U2 23 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 SEP 4 PY 2014 VL 15 IS 3 BP 281 EP 294 DI 10.1016/j.stem.2014.06.004 PG 14 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AO6EF UT WOS:000341441600009 PM 25192463 ER PT J AU Benboubker, L Dimopoulos, MA Dispenzieri, A Catalano, J Belch, AR Cavo, M Pinto, A Weisel, K Ludwig, H Bahlis, N Banos, A Tiab, M Delforge, M Cavenagh, J Geraldes, C Lee, JJ Chen, C Oriol, A de la Rubia, J Qiu, LG White, DJ Binder, D Anderson, K Fermand, JP Moreau, P Attal, M Knight, R Chen, G Van Oostendorp, J Jacques, C Ervin-Haynes, A Avet-Loiseau, H Hulin, C Facon, T AF Benboubker, Lotfi Dimopoulos, Meletios A. Dispenzieri, Angela Catalano, John Belch, Andrew R. Cavo, Michele Pinto, Antonello Weisel, Katja Ludwig, Heinz Bahlis, Nizar Banos, Anne Tiab, Mourad Delforge, Michel Cavenagh, Jamie Geraldes, Catarina Lee, Je-Jung Chen, Christine Oriol, Albert de la Rubia, Javier Qiu, Lugui White, Darrell J. Binder, Daniel Anderson, Kenneth Fermand, Jean-Paul Moreau, Philippe Attal, Michel Knight, Robert Chen, Guang Van Oostendorp, Jason Jacques, Christian Ervin-Haynes, Annette Avet-Loiseau, Herve Hulin, Cyrille Facon, Thierry CA FIRST Trial Team TI Lenalidomide and Dexamethasone in Transplant-Ineligible Patients with Myeloma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID REFRACTORY MULTIPLE-MYELOMA; PREDNISONE PLUS THALIDOMIDE; STEM-CELL TRANSPLANTATION; BORTEZOMIB-MELPHALAN-PREDNISONE; RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; ELDERLY-PATIENTS; CLINICAL-TRIALS; RESPONSE CRITERIA; INITIAL TREATMENT AB BACKGROUND The combination melphalan-prednisone-thalidomide (MPT) is considered a standard therapy for patients with myeloma who are ineligible for stem-cell transplantation. However, emerging data on the use of lenalidomide and low-dose dexamethasone warrant a prospective comparison of the two approaches. METHODS We randomly assigned 1623 patients to lenalidomide and dexamethasone in 28-day cycles until disease progression (535 patients), to the same combination for 72 weeks (18 cycles; 541 patients), or to MPT for 72 weeks (547 patients). The primary end point was progression-free survival with continuous lenalidomide-dexamethasone versus MPT. RESULTS The median progression-free survival was 25.5 months with continuous lenalidomide-dexamethasone, 20.7 months with 18 cycles of lenalidomide-dexamethasone, and 21.2 months with MPT (hazard ratio for the risk of progression or death, 0.72 for continuous lenalidomide-dexamethasone vs. MPT and 0.70 for continuous lenalidomide-dexamethasone vs. 18 cycles of lenalidomide-dexamethasone; P<0.001 for both comparisons). Continuous lenalidomide-dexamethasone was superior to MPT for all secondary efficacy end points, including overall survival (at the interim analysis). Overall survival at 4 years was 59% with continuous lenalidomide-dexamethasone, 56% with 18 cycles of lenalidomide-dexamethasone, and 51% with MPT. Grade 3 or 4 adverse events were somewhat less frequent with continuous lenalidomide-dexamethasone than with MPT (70% vs. 78%). As compared with MPT, continuous lenalidomide-dexamethasone was associated with fewer hematologic and neurologic toxic events, a moderate increase in infections, and fewer second primary hematologic cancers. CONCLUSIONS As compared with MPT, continuous lenalidomide-dexamethasone given until disease progression was associated with a significant improvement in progression-free survival, with an overall survival benefit at the interim analysis, among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. C1 [Benboubker, Lotfi] CHRU, Serv Hematol & Therapie Cellulaire, Hop Bretonneau, Tours, France. [Banos, Anne] Ctr Hosp Cote Basque, Bayonne, France. [Tiab, Mourad] Ctr Hosp Dept Oudairies, La Roche Sur Yon, France. [Fermand, Jean-Paul] Hop St Louis, Paris, France. [Moreau, Philippe] CHU Nantes, Serv Hematol, F-44035 Nantes 01, France. [Attal, Michel; Avet-Loiseau, Herve] CHRU Hop Purpan, Toulouse, France. [Hulin, Cyrille] CHU Nancy Brabois, Vandoeuvre Les Nancy, France. [Facon, Thierry] Ctr Hosp Reg Univ, Serv Malad Sang, Hop Claude Huriez, F-59037 Lille, France. [Dimopoulos, Meletios A.] Univ Athens, Sch Med, Athens, Greece. [Dispenzieri, Angela] Mayo Clin, Ctr Canc, Rochester, MN USA. [Catalano, John] Monash Univ, Frankston Hosp, Frankston, Vic, Australia. [Belch, Andrew R.] Univ Alberta, Edmonton, AB, Canada. [Belch, Andrew R.] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Bahlis, Nizar] Univ Calgary, Calgary, AB, Canada. [Chen, Christine] Princess Margaret Canc Ctr, Dept Med Oncol & Hematol, Toronto, ON, Canada. [White, Darrell J.] Dalhousie Univ, Halifax, NS, Canada. [White, Darrell J.] Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. [Cavo, Michele] Univ Bologna, Sch Med, Seragnoli Inst Hematol, Bologna, Italy. [Pinto, Antonello] Ist Ricovero & Cura Carattere Sci, Unita Operat Complessa Ematol Oncol, Ist Nazl Tumori Fdn G Pascale, Naples, Italy. [Weisel, Katja] Univ Tubingen, Tubingen, Germany. [Ludwig, Heinz] Wilhelminenspital Stadt Wien, Dept Internal Med 1, Ctr Oncol & Hematol, Vienna, Austria. [Delforge, Michel] Univ Hosp Leuven, Leuven, Belgium. [Cavenagh, Jamie] Barts Hlth NHS Trust, Dept Haematol, St Bartholomews Hosp, London, England. [Geraldes, Catarina] Coimbra Univ Hosp, Dept Clin Hematol, Coimbra, Portugal. [Lee, Je-Jung] Chonnam Natl Univ, Hwasun Hosp, Dept Hematol & Oncol, Hwasun, Jeollanamdo, South Korea. [Oriol, Albert] Inst Josep Carreras, Dept Clin Hematol, Inst Catal Oncol Hosp Germans Trias & Pujol, Barcelona, Spain. [de la Rubia, Javier] Hosp Univ La Fe, Valencia, Spain. [de la Rubia, Javier] Univ Catolica Valencia San Vicente Martir, Valencia, Spain. [Qiu, Lugui] Chinese Acad Med Sci, Inst Hematol, State Key Lab Expt Hematol, Tianjin, Peoples R China. [Qiu, Lugui] Chinese Acad Med Sci, Blood Dis Hosp, Tianjin, Peoples R China. [Qiu, Lugui] Peking Union Med Coll, Tianjin, Peoples R China. [Binder, Daniel] Kantonsspital Winterthur, Winterthur, Switzerland. [Anderson, Kenneth] Dana Farber Canc Inst, Boston, MA 02115 USA. [Knight, Robert; Chen, Guang; Van Oostendorp, Jason; Jacques, Christian; Ervin-Haynes, Annette] Celgene, Summit, NJ USA. RP Facon, T (reprint author), Ctr Hosp Reg Univ, Serv Malad Sang, Hop Claude Huriez, F-59037 Lille, France. EM thierry.facon@chru-lille.fr RI FACON, THIERRY/M-9736-2014; richard, chrystelle/K-8595-2015; Greil, Richard/C-7673-2017; Ottmann, Oliver/D-5007-2016; OI FACON, THIERRY/0000-0001-7705-8460; Greil, Richard/0000-0002-4462-3694; Geraldes, Catarina/0000-0001-8627-6187; Ottmann, Oliver/0000-0001-9559-1330; pierre, philippe/0000-0003-0863-8255; CAVO, MICHELE/0000-0003-4514-3227; Salles, Gilles/0000-0002-9541-8666; nahi, hareth/0000-0003-4711-5094; Dispenzieri, Angela/0000-0001-8780-9512 FU Intergroupe Francophone du Myelome; Celgene FX Supported by Intergroupe Francophone du Myelome and Celgene. NR 38 TC 166 Z9 168 U1 4 U2 27 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 SEP 4 PY 2014 VL 371 IS 10 BP 906 EP 917 DI 10.1056/NEJMoa1402551 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA AO5NB UT WOS:000341390600008 PM 25184863 ER PT J AU Liu, KD Dong, N Truwit, JD AF Liu, Kathleen D. Dong, Ning Truwit, Jonathon D. TI Rosuvastatin for Sepsis-Associated ARDS Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Liu, Kathleen D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Dong, Ning] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Truwit, Jonathon D.] Froedtert, Milwaukee, WI USA. [Truwit, Jonathon D.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. RP Liu, KD (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 4 PY 2014 VL 371 IS 10 BP 968 EP 969 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AO5NB UT WOS:000341390600022 PM 25184876 ER PT J AU Hasegawa, E Sweigard, H Husain, D Olivares, AM Chang, B Smith, KE Birsner, AE D'Amato, RJ Michaud, NA Han, YN Vavvas, DG Miller, JW Haider, NB Connor, KM AF Hasegawa, Eiichi Sweigard, Harry Husain, Deeba Olivares, Ana M. Chang, Bo Smith, Kaylee E. Birsner, Amy E. D'Amato, Robert J. Michaud, Norman A. Han, Yinan Vavvas, Demetrios G. Miller, Joan W. Haider, Neena B. Connor, Kip M. TI Characterization of a Spontaneous Retinal Neovascular Mouse Model SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; MACULAR DEGENERATION; ANGIOMATOUS PROLIFERATION; SUBRETINAL NEOVASCULARIZATION; CHOROIDAL NEOVASCULARIZATION; CHORIORETINAL ANASTOMOSIS; PIGMENT EPITHELIUM; TRANSGENIC MICE; MULLER CELLS; EXPRESSION AB Background: Vision loss due to vascular disease of the retina is a leading cause of blindness in the world. Retinal angiomatous proliferation (RAP) is a subgroup of neovascular age-related macular degeneration (AMD), whereby abnormal blood vessels develop in the retina leading to debilitating vision loss and eventual blindness. The novel mouse strain, neoretinal vascularization 2 (NRV2), shows spontaneous fundus changes associated with abnormal neovascularization. The purpose of this study is to characterize the induction of pathologic angiogenesis in this mouse model. Methods: The NRV2 mice were examined from postnatal day 12 (p12) to 3 months. The phenotypic changes within the retina were evaluated by fundus photography, fluorescein angiography, optical coherence tomography, and immunohistochemical and electron microscopic analysis. The pathological neovascularization was imaged by confocal microscopy and reconstructed using three-dimensional image analysis software. Results: We found that NRV2 mice develop multifocal retinal depigmentation in the posterior fundus. Depigmented lesions developed vascular leakage observed by fluorescein angiography. The spontaneous angiogenesis arose from the retinal vascular plexus at postnatal day (p) 15 and extended toward retinal pigment epithelium (RPE). By three months of age, histological analysis revealed encapsulation of the neovascular lesion by the RPE in the photoreceptor cell layer and subretinal space. Conclusions: The NRV2 mouse strain develops early neovascular lesions within the retina, which grow downward towards the RPE beginning at p15. This retinal neovascularization model mimics early stages of human retinal angiomatous proliferation (RAP) and will likely be a useful in elucidating targeted therapeutics for patients with ocular neovascular disease. C1 [Hasegawa, Eiichi; Sweigard, Harry; Husain, Deeba; Smith, Kaylee E.; Michaud, Norman A.; Vavvas, Demetrios G.; Miller, Joan W.; Connor, Kip M.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Angiogenesis Lab, Boston, MA 02114 USA. [Hasegawa, Eiichi; Sweigard, Harry; Husain, Deeba; D'Amato, Robert J.; Vavvas, Demetrios G.; Miller, Joan W.; Haider, Neena B.; Connor, Kip M.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Olivares, Ana M.; Han, Yinan; Haider, Neena B.] Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA 02114 USA. [Chang, Bo] Jackson Lab, Bar Harbor, ME 04609 USA. [Birsner, Amy E.; D'Amato, Robert J.] Harvard Univ, Sch Med, Boston Childrens Hosp, Vasc Biol Program,Dept Surg, Boston, MA USA. RP Connor, KM (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Angiogenesis Lab, Boston, MA 02114 USA. EM kip_connor@meei.harvard.edu OI Connor, Kip/0000-0002-2048-9080; Vavvas, Demetrios/0000-0002-8622-6478 FU Research to Prevent Blindness; Bright Focus Foundation; National Eye Institute of the National Institutes of Health [R01EY022084/S1, P30EY014104] FX Research reported in this publication was supported by a Special Scholar Award (to KMC) and unrestricted grant (to JM) from Research to Prevent Blindness, as well as a Bright Focus Foundation grant (to KMC and NH). Additionally, research reported in this publication was supported by National Eye Institute of the National Institutes of Health under award numbers R01EY022084/S1 (to KMC) and P30EY014104. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 4 Z9 4 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 SEP 4 PY 2014 VL 9 IS 9 AR e106507 DI 10.1371/journal.pone.0106507 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3XV UT WOS:000341271500047 PM 25188381 ER PT J AU Kir, S White, JP Kleiner, S Kazak, L Cohen, P Baracos, VE Spiegelman, BM AF Kir, Serkan White, James P. Kleiner, Sandra Kazak, Lawrence Cohen, Paul Baracos, Vickie E. Spiegelman, Bruce M. TI Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia SO NATURE LA English DT Article ID HORMONE-RELATED PROTEIN; SKELETAL-MUSCLE; MONOCLONAL-ANTIBODY; NUDE-MICE; MECHANISMS; CELL; THERMOGENESIS; ACTIVATION; SURVIVAL AB Cachexia is a wasting disorder of adipose and skeletal muscle tissues that leads to profound weight loss and frailty. About half of all cancer patients suffer from cachexia, which impairs quality of life, limits cancer therapy and decreases survival. One key characteristic of cachexia is higher resting energy expenditure levels than in healthy individuals, which has been linked to greater thermogenesis by brown fat(1-6). How tumours induce brown fat activity is unknown. Here, using a Lewis lung carcinoma model of cancer cachexia, we show that tumour-derived parathyroid-hormone-related protein (PTHrP) has an important role in wasting, through driving the expression of genes involved in thermogenesis in adipose tissues. Neutralization of PTHrP in tumour-bearing mice blocked adipose tissue browning and the loss of muscle mass and strength. Our results demonstrate that PTHrP mediates energy wasting in fat tissues and contributes to the broader aspects of cancer cachexia. Thus, neutralization of PTHrP might hold promise for ameliorating cancer cachexia and improving patient survival. C1 [Kir, Serkan; White, James P.; Kleiner, Sandra; Kazak, Lawrence; Cohen, Paul; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Baracos, Vickie E.] Univ Alberta, Div Palliat Care Med, Dept Oncol, Edmonton, AB T6G 1Z2, Canada. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM bruce_spiegelman@dfci.harvard.edu OI Baracos, Vickie/0000-0002-9609-1001 FU American Cancer Society [PF-13-385-01-TBE]; National Institutes of Health [DK31405] FX We thank M. Mourtzakis and C. Prado for their help with the human study. S. Kir is a Robert Black Fellow of the Damon Runyon Cancer Research Foundation (DRG-2153-13), and J.P.W. is supported by a postdoctoral fellowship from the American Cancer Society (PF-13-385-01-TBE). This work was supported by National Institutes of Health grant DK31405 to B.M.S. NR 24 TC 83 Z9 84 U1 6 U2 46 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 SEP 4 PY 2014 VL 513 IS 7516 BP 100 EP + DI 10.1038/nature13528 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO2SD UT WOS:000341174800038 PM 25043053 ER PT J AU Saha, SK Parachoniak, CA Ghanta, KS Fitamant, J Ross, KN Najem, MS Gurumurthy, S Akbay, EA Sia, D Cornella, H Miltiadous, O Walesky, C Deshpande, V Zhu, AX Hezel, AF Yen, KE Straley, KS Travins, J Popovici-Muller, J Gliser, C Ferrone, CR Apte, U Llovet, JM Wong, KK Ramaswamy, S Bardeesy, N AF Saha, Supriya K. Parachoniak, Christine A. Ghanta, Krishna S. Fitamant, Julien Ross, Kenneth N. Najem, Mortada S. Gurumurthy, Sushma Akbay, Esra A. Sia, Daniela Cornella, Helena Miltiadous, Oriana Walesky, Chad Deshpande, Vikram Zhu, Andrew X. Hezel, Aram F. Yen, Katharine E. Straley, Kimberly S. Travins, Jeremy Popovici-Muller, Janeta Gliser, Camelia Ferrone, Cristina R. Apte, Udayan Llovet, Josep M. Wong, Kwok-Kin Ramaswamy, Sridhar Bardeesy, Nabeel TI Mutant IDH inhibits HNF-4 alpha to block hepatocyte differentiation and promote biliary cancer SO NATURE LA English DT Article ID INTRAHEPATIC CHOLANGIOCARCINOMA; LIVER-REGENERATION; MUTATION; GROWTH; MICE; PROLIFERATION; PROGENITORS; HOMEOSTASIS; EXPRESSION AB Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer(1-5). Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing themto convert alpha-ketoglutarate (alpha KG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple alpha KG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation(6-10). However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4 alpha, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury, characterized by HNF-4 alpha silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation. Moreover, IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs4,5, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy. C1 [Saha, Supriya K.; Parachoniak, Christine A.; Ghanta, Krishna S.; Fitamant, Julien; Ross, Kenneth N.; Najem, Mortada S.; Gurumurthy, Sushma; Deshpande, Vikram; Zhu, Andrew X.; Ferrone, Cristina R.; Ramaswamy, Sridhar; Bardeesy, Nabeel] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. [Akbay, Esra A.; Wong, Kwok-Kin] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Dept Med, Boston, MA 02115 USA. [Sia, Daniela; Cornella, Helena; Llovet, Josep M.] Univ Barcelona, Hosp Clin, Barcelona Clin Liver Canc Grp, HCC Translat Res Lab,IDIBAPS,Liver Unit, Catalonia 08036, Spain. [Sia, Daniela; Miltiadous, Oriana; Llovet, Josep M.] Icahn Sch Med Mt Sinai, Dept Med, Div Liver Dis, Mt Sinai Liver Canc Program, New York, NY 10029 USA. [Sia, Daniela] Natl Canc Inst, Gastrointestinal Surg & Liver Transplantat Unit, I-20133 Milan, Italy. [Sia, Daniela] Dept Expt Oncol, I-20133 Milan, Italy. [Walesky, Chad; Apte, Udayan] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. [Hezel, Aram F.] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Yen, Katharine E.; Straley, Kimberly S.; Travins, Jeremy; Popovici-Muller, Janeta; Gliser, Camelia] Agios Pharmaceut, Cambridge, MA 02139 USA. [Llovet, Josep M.] Inst Catalana Recerca & Estudis Avancats, Barcelona 08010, Catalonia, Spain. [Llovet, Josep M.] Univ Barcelona, Catalonia 08036, Spain. [Ramaswamy, Sridhar] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. RP Bardeesy, N (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. EM Bardeesy.Nabeel@mgh.harvard.edu RI Llovet, Josep M /D-4340-2014 OI Llovet, Josep M /0000-0003-0547-2667 FU TargetCancer Foundation; National Institutes of Health [R01CA136567-02, P50CA1270003]; Cholangiocarcinoma Foundation/Conquer Cancer Foundation of ASCO Young Investigator Award; American Cancer Society Postdoctoral Fellowship [PF-13-294-01-TBG]; Canadian Institutes of Health Research postdoctoral fellowship; Asociacion Espanola para el Estudio del Cancer FX We thank R. Mostoslavsky, L. Ellisen, A. Kimmelman, and members of the Bardeesy laboratory for valuable input. We also thank S. Thorgeirsson and J. Andersen for sharing unpublished data sets. This work was supported by grants from TargetCancer Foundation and the National Institutes of Health (R01CA136567-02 and P50CA1270003) to N.B. N.B. holds the Gallagher Endowed Chair in Gastrointestinal Cancer Research at Massachusetts General Hospital. S. K. S. is the recipient of a Cholangiocarcinoma Foundation/Conquer Cancer Foundation of ASCO Young Investigator Award, and an American Cancer Society Postdoctoral Fellowship (PF-13-294-01-TBG). C. A. P. is the recipient of a Canadian Institutes of Health Research postdoctoral fellowship. N.B., J. M. L. and D. S are members of the Samuel Waxman Cancer Research Foundation Institute Without Walls. J. M. L. and D. S. are supported by the Asociacion Espanola para el Estudio del Cancer. NR 38 TC 70 Z9 74 U1 2 U2 27 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 SEP 4 PY 2014 VL 513 IS 7516 BP 110 EP + DI 10.1038/nature13441 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO2SD UT WOS:000341174800040 PM 25043045 ER PT J AU Halko, MA Farzan, F Eldaief, MC Schmahmann, JD Pascual-Leone, A AF Halko, Mark A. Farzan, Faranak Eldaief, Mark C. Schmahmann, Jeremy D. Pascual-Leone, Alvaro TI Intermittent Theta-Burst Stimulation of the Lateral Cerebellum Increases Functional Connectivity of the Default Network SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cerebellar hemispheres; cerebellum vermis; default mode network; functional connectivity; noninvasive brain stimulation; resting state ID TRANSCRANIAL MAGNETIC STIMULATION; COGNITIVE-AFFECTIVE SYNDROME; HUMAN MOTOR CORTEX; EYE-MOVEMENTS; DISTINCT; DISEASE; BRAIN; ORGANIZATION; DEPRESSION; CIRCUITS AB Cerebral cortical intrinsic connectivity networks share topographically arranged functional connectivity with the cerebellum. However, the contribution of cerebellar nodes to distributed network organization and function remains poorly understood. In humans, we applied theta-burst transcranial magnetic stimulation, guided by subject-specific connectivity, to regions of the cerebellum to evaluate the functional relevance of connections between cerebellar and cerebral cortical nodes in different networks. We demonstrate that changing activity in the human lateral cerebellar Crus I/II modulates the cerebral default mode network, whereas vermal lobule VII stimulation influences the cerebral dorsal attention system. These results provide novel insights into the distributed, but anatomically specific, modulatory impact of cerebellar effects on large-scale neural network function. C1 [Halko, Mark A.; Farzan, Faranak; Eldaief, Mark C.; Pascual-Leone, Alvaro] Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA 02215 USA. [Farzan, Faranak] Univ Toronto, Ctr Addict & Mental Hlth, Temerty Ctr Therapeut Brain Intervent, Toronto, ON M6J 1H4, Canada. [Eldaief, Mark C.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Schmahmann, Jeremy D.] Massachusetts Gen Hosp, Dept Neurol, Lab Neuroanat & Cerebellar Neurobiol, Ataxia Unit,Cognit & Behav Neurol Unit, Boston, MA 02114 USA. RP Halko, MA (reprint author), Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, 330 Brookline Ave,E-KS 158, Boston, MA 02215 USA. EM mhalko@bidmc.harvard.edu RI Halko, Mark/G-8633-2016; OI Halko, Mark/0000-0002-7427-0789; Farzan, Faranak/0000-0001-9249-2994 FU Sidney R. Baer Jr. Foundation; National Institutes of Health (NIH)/National Institutes for Neurological Disorders and Stroke Grant [R21 NS085491]; Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources and National Center for Advanced Translational Sciences/NIH) [8KL2TR000168-05]; Birmingham Foundation; NIH [R21 NS085491, R01HD069776, R01NS073601, R21 MH099196, R21 NS082870, R21 HD07616, UL1 RR025758]; Michael J. Fox Foundation; Sidney R. Baer Foundation; MINDlink Foundation FX Work on this project is supported grants from the Sidney R. Baer Jr. Foundation and National Institutes of Health (NIH)/National Institutes for Neurological Disorders and Stroke Grant R21 NS085491. M.A.H. is supported by a KL2 Medical Research Investigator Training award (an appointed KL2 award) from the Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources and National Center for Advanced Translational Sciences/NIH Grant 8KL2TR000168-05). J.D.S. is supported in part by the Sidney R. Baer Jr. Foundation and the MINDlink and Birmingham Foundations. A.P.L. is supported by NIH Grants R01HD069776, R01NS073601, R21 MH099196, R21 NS082870, R21 NS085491, R21 HD07616, and UL1 RR025758, the Michael J. Fox Foundation, and the Sidney R. Baer Foundation. We are grateful for the assistance of Ned Gold, Rain Thomas, Carrie Hinchman, and Sam Rendall for collecting this data, Mike Fox for helpful discussions, and Stephanie McMains and the staff of the Harvard Center for Brain Science for assistance in collecting and analyzing the data. NR 51 TC 20 Z9 20 U1 0 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 3 PY 2014 VL 34 IS 36 BP 12049 EP 12056 DI 10.1523/JNEUROSCI.1776-14.2014 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AP0PU UT WOS:000341765400017 PM 25186750 ER PT J AU Vaina, LM Buonanno, F Rushton, SK AF Vaina, Lucia M. Buonanno, Ferdinando Rushton, Simon K. TI Spared Ability to Perceive Direction of Locomotor Heading and Scene-Relative Object Movement Despite Inability to Perceive Relative Motion SO MEDICAL SCIENCE MONITOR LA English DT Article DE Motion Perception; Stroke; Vision Disorders ID MOVING OBSERVERS; BRAIN-DAMAGE; SELECTIVE IMPAIRMENT; CEREBRAL-LESIONS; SELF-MOTION; OPTIC FLOW; PERCEPTION; INTEGRATION; MECHANISMS; DEFICITS AB Background: All contemporary models of perception of locomotor heading from optic flow (the characteristic patterns of retinal motion that result from self-movement) begin with relative motion. Therefore it would be expected that an impairment on perception of relative motion should impact on the ability to judge heading and other 3D motion tasks. Material/Methods: We report two patients with occipital lobe lesions whom we tested on a battery of motion tasks. Patients were impaired on all tests that involved relative motion in plane (motion discontinuity, form from differences in motion direction or speed). Despite this they retained the ability to judge their direction of heading relative to a target. A potential confound is that observers can derive information about heading from scale changes bypassing the need to use optic flow. Therefore we ran further experiments in which we isolated optic flow and scale change. Results: Patients' performance was in normal ranges on both tests. The finding that ability to perceive heading can be retained despite an impairment on ability to judge relative motion questions the assumption that heading perception proceeds from initial processing of relative motion. Furthermore, on a collision detection task, SS and SR's performance was significantly better for simulated forward movement of the observer in the 3D scene, than for the static observer. This suggests that in spite of severe deficits on relative motion in the frontoparlel (xy) plane, information from self-motion helped identification objects moving along an intercept 3D relative motion trajectory. Conclusions: This result suggests a potential use of a flow parsing strategy to detect in a 3D world the trajectory of moving objects when the observer is moving forward. These results have implications for developing rehabilitation strategies for deficits in visually guided navigation. C1 [Vaina, Lucia M.] Boston Univ, Brain & Vis Res Lab, Boston, MA 02215 USA. [Vaina, Lucia M.; Buonanno, Ferdinando] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Neurol Vis Lab, Boston, MA USA. [Rushton, Simon K.] Cardiff Univ, Sch Psychol, Cardiff CF10 3AX, S Glam, Wales. RP Vaina, LM (reprint author), Boston Univ, Brain & Vis Res Lab, Boston, MA 02215 USA. EM vaina@bu.edu FU National Institutes of Health [RO1 NS064100]; Wellcome Trust [089934] FX This research was supported in part by a grant from the National Institutes of Health - RO1 NS064100 to LMV. SKR was supported by a grant from the Wellcome Trust (089934) NR 50 TC 2 Z9 2 U1 1 U2 3 PU INT SCIENTIFIC LITERATURE, INC PI SMITHTOWN PA 361 FOREST LANE, SMITHTOWN, NY 11787 USA SN 1643-3750 J9 MED SCI MONITOR JI Med. Sci. Monitor PD SEP 3 PY 2014 VL 20 BP 1563 EP 1571 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AP0JX UT WOS:000341748700001 PM 25183375 ER PT J AU Garza, JLB Eijckelhof, BHW Huysmans, MA Johnson, PW van Dieen, JH Catalano, PJ Katz, JN van der Beek, AJ Dennerlein, JT AF Garza, Jennifer L. Bruno Eijckelhof, Belinda H. W. Huysmans, Maaike A. Johnson, Peter W. van Dieen, Jaap H. Catalano, Paul J. Katz, Jeffrey N. van der Beek, Allard J. Dennerlein, Jack T. TI Prediction of trapezius muscle activity and shoulder, head, neck, and torso postures during computer use: results of a field study SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article ID ARM-WRIST-HAND; MUSCULOSKELETAL DISORDERS; EXPOSURE ASSESSMENT; OFFICE WORKERS; KEYBOARD USE; ERGONOMIC EPIDEMIOLOGY; MOUSE USE; SYMPTOMS; REWARD; PATHOPHYSIOLOGY AB Background: Due to difficulties in performing direct measurements as an exposure assessment technique, evidence supporting an association between physical exposures such as neck and shoulder muscle activities and postures and musculoskeletal disorders during computer use is limited. Alternative exposure assessment techniques are needed. Methods: We predicted the median and range of amplitude (90th-10th percentiles) of trapezius muscle activity and the median and range of motion (90th-10th percentiles) of shoulder, head, neck, and torso postures based on two sets of parameters: the distribution of keyboard/mouse/idle activities only ("task-based" predictions), and a comprehensive set of task, questionnaire, workstation, and anthropometric parameters ("expanded model" predictions). We compared the task-based and expanded model predictions based on R-2 values, root mean squared (RMS) errors, and relative RMS errors calculated compared to direct measurements. Results: The expanded model predictions of the median and range of amplitude of trapezius muscle activity had consistently better R-2 values (range 0.40-0.55 compared to 0.00-0.06), RMS errors (range 2-3% MVC compared to 3-4% MVC), and relative RMS errors (range 10-14% MVC compared to 16-19% MVC) than the task-based predictions. The expanded model predictions of the median and range of amplitude of postures also had consistently better R-2 values (range 0.22-0.58 compared to 0.00-0.35), RMS errors (range 2-14 degrees compared to 3-22 degrees), and relative RMS errors (range 9-21 degrees compared to 13-42 degrees) than the task-based predictions. Conclusions: The variation in physical exposures across users performing the same task is large, especially in comparison to the variation across tasks. Thus, expanded model predictions of physical exposures during computer use should be used rather than task-based predictions to improve exposure assessment for future epidemiological studies. Clinically, this finding also indicates that computer users will have differences in their physical exposures even when performing the same tasks. C1 [Garza, Jennifer L. Bruno; Katz, Jeffrey N.; Dennerlein, Jack T.] Harvard Univ, Dept Environm Hlth, Boston, MA 02115 USA. [Garza, Jennifer L. Bruno] UConn Hlth, Div Occupat & Environm Med, Farmington, CT USA. [Eijckelhof, Belinda H. W.; Huysmans, Maaike A.; van der Beek, Allard J.] Vrije Univ Amsterdam, Med Ctr, Dept Publ & Occupat Hlth, Amsterdam, Netherlands. [Eijckelhof, Belinda H. W.; Huysmans, Maaike A.; van der Beek, Allard J.; Dennerlein, Jack T.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Eijckelhof, Belinda H. W.; Huysmans, Maaike A.; van der Beek, Allard J.] TNO VU VUmc, Body Work Res Ctr Phys Act Work & Hlth, Amsterdam, Netherlands. [Johnson, Peter W.] Univ Washington, Dept Environm Hlth, Seattle, WA 98195 USA. [van Dieen, Jaap H.] Vrije Univ Amsterdam, Fac Human Movement Sci, Amsterdam, Netherlands. [Catalano, Paul J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Catalano, Paul J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Katz, Jeffrey N.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Katz, Jeffrey N.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Katz, Jeffrey N.] Brigham & Womens Hosp, Dept Orthopaed Surg, Boston, MA 02115 USA. [Dennerlein, Jack T.] Northeastern Univ, Bouve Coll Hlth Sci, Dept Phys Therapy, Boston, MA 02115 USA. RP Dennerlein, JT (reprint author), Harvard Univ, Dept Environm Hlth, Boston, MA 02115 USA. EM j.dennerlein@neu.edu OI Dennerlein, Jack/0000-0001-7703-643X; van Dieen, Jaap/0000-0002-7719-5585 FU CDC/NIOSH [RO1-0H-08781] FX This study was funded in part by CDC/NIOSH grant RO1-0H-08781 (PI: Dennerlein). The authors would like to thank Sachin Raina and Patrik Rynell for their contributions to the design, data collection, and analysis for this study. NR 49 TC 1 Z9 1 U1 0 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD SEP 3 PY 2014 VL 15 AR 292 DI 10.1186/1471-2474-15-292 PG 14 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA AO6KO UT WOS:000341460400001 ER PT J AU Su, ZM Zhang, YJ Gendron, TF Bauer, PO Chew, J Yang, WY Fostvedt, E Jansen-West, K Belzil, VV Desaro, P Johnston, A Overstreet, K Oh, SY Todd, PK Berry, JD Cudkowicz, ME Boeve, BF Dickson, D Floeter, MK Traynor, BJ Morelli, C Ratti, A Silani, V Rademakers, R Brown, RH Rothstein, JD Boylan, KB Petrucelli, L Disney, MD AF Su, Zhaoming Zhang, Yongjie Gendron, Tania F. Bauer, Peter O. Chew, Jeannie Yang, Wang-Yong Fostvedt, Erik Jansen-West, Karen Belzil, Veronique V. Desaro, Pamela Johnston, Amelia Overstreet, Karen Oh, Seok-Yoon Todd, Peter K. Berry, James D. Cudkowicz, Merit E. Boeve, Bradley F. Dickson, Dennis Floeter, Mary Kay Traynor, Bryan J. Morelli, Claudia Ratti, Antonia Silani, Vincenzo Rademakers, Rosa Brown, Robert H. Rothstein, Jeffrey D. Boylan, Kevin B. Petrucelli, Leonard Disney, Matthew D. TI Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS SO NEURON LA English DT Article ID C9ORF72 HEXANUCLEOTIDE REPEAT; G-QUADRUPLEX STRUCTURES; FRONTOTEMPORAL DEMENTIA; ANTISENSE TRANSCRIPTS; RNA FOCI; PROTEINS; EXPANSION; DISEASE; FORMS; ALS AB A repeat expansion in C9ORF72 causes frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ ALS). RNA of the expanded repeat (r(GGGGCC)(exp)) forms nuclear foci or undergoes repeat-associated non-ATG (RAN) translation, producing "c9RAN proteins.'' Since neutralizing r(GGGGCC) exp could inhibit these potentially toxic events, we sought to identify small-molecule binders of r(GGGGCC) exp. Chemical and enzymatic probing of r(GGGGCC) 8 indicate that it adopts a hairpin structure in equilibrium with a quadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC) exp were designed and found to significantly inhibit RAN translation and foci formation in cultured cells expressing r(GGGGCC) 66 and neurons transdifferentiated from fibroblasts of repeat expansion carriers. Finally, we show that poly(GP) c9RANproteins are specifically detected in c9ALS patient cerebrospinal fluid. Our findings highlight r(GGGGCC)(exp)-binding small molecules as a possible c9FTD/ALS therapeutic and suggest that c9RAN proteins could potentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)(exp). C1 [Su, Zhaoming; Yang, Wang-Yong; Fostvedt, Erik; Disney, Matthew D.] Scripps Florida, Scripps Res Inst, Dept Chem, Jupiter, FL 33458 USA. [Zhang, Yongjie; Gendron, Tania F.; Bauer, Peter O.; Chew, Jeannie; Jansen-West, Karen; Belzil, Veronique V.; Dickson, Dennis; Rademakers, Rosa; Petrucelli, Leonard] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Desaro, Pamela; Johnston, Amelia; Overstreet, Karen; Boylan, Kevin B.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Oh, Seok-Yoon; Todd, Peter K.] Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA. [Berry, James D.; Cudkowicz, Merit E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Boeve, Bradley F.] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA. [Floeter, Mary Kay] NINDS, Spast & Spinal Physiol Unit, NIH, Bethesda, MD 20892 USA. [Traynor, Bryan J.] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. [Morelli, Claudia; Ratti, Antonia] IRCCS Ist Auxol Italiano, Dept Neurol & Lab Neurosci, I-20095 Milan, Italy. [Ratti, Antonia; Silani, Vincenzo] Univ Milan, Dino Ferrari Ctr, Dept Pathophysiol & Transplantat, I-20122 Milan, Italy. [Silani, Vincenzo; Brown, Robert H.] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA. [Rothstein, Jeffrey D.] Johns Hopkins Univ, Brain Sci Inst, Dept Neurol, Baltimore, MD 21205 USA. RP Petrucelli, L (reprint author), Mayo Clin, Dept Neurosci, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM petrucelli.leonard@mayo.edu; disney@scripps.edu RI Su, Zhaoming/E-6146-2015; OI Dickson, Dennis W/0000-0001-7189-7917; Silani, Vincenzo/0000-0002-7698-3854 FU National Institutes of Health (NIH)/National Institute on Aging [R01GM097455, R01AG026251]; NIH/National Institute of Neurological Disorders and Stroke [R21NS074121, R21NS079807, R21NS084528, R01NS088689, R01NS063964, R01NS077402, R01NS050557]; ARRA Award [RC2-NS070-342, P01NS084974]; National Institute of Environmental Health Services [R01 ES20395]; Department of Defense [ALSRP AL130125]; Intramural Program of the NIH, the National Institute on Aging [Z01-AG000949- 02]; National Institute of Neurological Disorders and Stroke [Z01 NS002976-16]; Mayo Clinic Foundation; Mayo Clinic Center for Regenerative Medicine; Mayo Clinic Center for Individualized Medicine; ALS Association; Alzheimer's Association; Robert Packard Center for ALS Research at Johns Hopkins; Target ALS; Canadian Institutes of Health Research; Siragusa Foundation; Robert and Clarice Smith & Abigail Van Buren Alzheimer's Disease Research Foundation; Digiovanni Sundry Fund; ATA; Project ALS; Angel Fund; Italian Ministry of Health [RF-2009-1473856]; European Commission; FRAXA Research Foundation FX We are grateful to patients who donated CSF, skin samples, and postmortem tissue. We acknowledge Lillian Daughrity, Luc Pregent, and Mary Davis for technical support, Dr. Xiangming Kong for help with 1D 1H NMR experiments. This work was supported by the National Institutes of Health (NIH)/National Institute on Aging (R01GM097455 [M. D. D.]; R01AG026251 [L. P.]); NIH/National Institute of Neurological Disorders and Stroke (R21NS074121 [K. B. B., T. F. G.], R21NS079807 [Y. Z.], R21NS084528 [L. P.], R01NS088689 [R. H. B., L. P.], R01NS063964 [L. P.]; R01NS077402 [L. P.]; R01NS050557 [R. H. B.]; ARRA Award RC2-NS070-342 [R. H. B.], P01NS084974 [L. P., D. D., R. R., K. B. B.]); National Institute of Environmental Health Services (R01 ES20395 [L. P.]); Department of Defense (ALSRP AL130125 [L. P., M. D. D.]); the Intramural Program of the NIH, the National Institute on Aging (Z01-AG000949- 02 [B. J. T.]), and the National Institute of Neurological Disorders and Stroke (Z01 NS002976-16 to M. F. K. and B. J. T.); Mayo Clinic Foundation (L. P.); Mayo Clinic Center for Regenerative Medicine (P. O. B.), Mayo Clinic Center for Individualized Medicine (T. F. G., L. P., K. B. B.), ALS Association (K. B. B., P. O. B., L. P., T. F. G., Y. Z., and M. E. D.), Alzheimer's Association (Y. Z.), Robert Packard Center for ALS Research at Johns Hopkins (L. P., J. D. R.), Target ALS (L. P., M. D. D.), Canadian Institutes of Health Research (V. V. B.), Siragusa Foundation (V. V. B.), Robert and Clarice Smith & Abigail Van Buren Alzheimer's Disease Research Foundation (V. V. B.), Digiovanni Sundry Fund (M. E. D.), ATA (M. E. D.), Project ALS (R. H. B.), Angel Fund (R. H. B.), AriSLA cofinanced with support of '5x1000'-Healthcare research of the Italian Ministry of Health (grants EXOMEFALS 2009 [V. S.] and NOVALS 2012 [V. S.]), the Italian Ministry of Health (RF-2009-1473856 [C. M., A. R., V. S.]), and the European Commission (JNPD SOPHIA and STRENGTH [C. M., A. R., V. S.]). Z. S. and V. B. are Milton Safenowitz Postdoctoral Fellows funded by the ALS Association. W-Y. Y is a FRAXA Postdoctoral Fellow funded by FRAXA Research Foundation. Antibodies to c9RAN proteins have been licensed to a commercial entity. R. R. holds a patent on methods to screen for the hexanucleotide repeat expansion in the C9ORF72 gene. NR 22 TC 71 Z9 71 U1 3 U2 33 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD SEP 3 PY 2014 VL 83 IS 5 BP 1043 EP 1050 DI 10.1016/j.neuron.2014.07.041 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AO5XB UT WOS:000341419000008 PM 25132468 ER PT J AU Bera, A VenkataSubbaRao, K Manoharan, MS Hill, P Freeman, JW AF Bera, Alakesh VenkataSubbaRao, Kolaparthi Manoharan, Muthu Saravanan Hill, Ping Freeman, James W. TI A miRNA Signature of Chemoresistant Mesenchymal Phenotype Identifies Novel Molecular Targets Associated with Advanced Pancreatic Cancer SO PLOS ONE LA English DT Article ID MICRORNA EXPRESSION; PROSTATE-CANCER; STEM-CELLS; CHEMOTHERAPEUTIC-AGENTS; REPRESSORS ZEB1; BREAST-CANCER; UP-REGULATION; GEMCITABINE; RESISTANT; MIR-200 AB In this study a microRNA (miRNA) signature was identified in a gemcitabine resistant pancreatic ductal adenocarcinoma (PDAC) cell line model (BxPC3-GZR) and this signature was further examined in advanced PDAC tumor specimens from The Cancer Genome Atlas (TCGA) database. BxPC3-GZR showed a mesenchymal phenotype, expressed high levels of CD44 and showed a highly significant deregulation of 17 miRNAs. Based on relevance to cancer, a seven-miRNA signature (miR-100, miR-125b, miR-155, miR-21, miR-205, miR-27b and miR-455-3p) was selected for further studies. A strong correlation was observed for six of the seven miRNAs in 43 advanced tumor specimens compared to normal pancreas tissue. To assess the functional relevance we initially focused on miRNA-125b, which is over-expressed in both the BxPC3-GZR model and advanced PDAC tumor specimens. Knockdown of miRNA-125b in BxPC3-GZR and Panc-1 cells caused a partial reversal of the mesenchymal phenotype and enhanced response to gemcitabine. Moreover, RNA-seq data from each of 40 advanced PDAC tumor specimens from the TCGA data base indicate a negative correlation between expression of miRNA-125b and five of six potential target genes (BAP1, BBC3, NEU1, BCL2, STARD13). Thus far, two of these target genes, BBC3 and NEU1, that are tumor suppressor genes but not yet studied in PDAC, appear to be functional targets of miR-125b since knockdown of miR125b caused their up regulation. These miRNAs and their molecular targets may serve as targets to enhance sensitivity to chemotherapy and reduce metastatic spread. C1 [Bera, Alakesh; VenkataSubbaRao, Kolaparthi; Hill, Ping; Freeman, James W.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Hematol & Oncol, San Antonio, TX 78229 USA. [Freeman, James W.] Canc Therapy & Res Ctr S Texas, Expt & Dev Therapeut Program, San Antonio, TX 78229 USA. [Manoharan, Muthu Saravanan; Freeman, James W.] Audie L Murphy Mem Vet Adm Med Ctr, San Antonio, TX USA. RP Freeman, JW (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Hematol & Oncol, San Antonio, TX 78229 USA. EM freemanjw@uthscsa.edu FU National Institutes of Health [RO1CA069122]; Veterans Affairs Merit Award [1I01BX000927]; William and Eula Owens Medical Research Foundation FX Funding provided by National Institutes of Health-RO1CA069122 to JWF, Veterans Affairs Merit Award 1I01BX000927 to JWF and William and Eula Owens Medical Research Foundation to JWF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 19 Z9 20 U1 1 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 SEP 3 PY 2014 VL 9 IS 9 AR e106343 DI 10.1371/journal.pone.0106343 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3TB UT WOS:000341257700057 PM 25184537 ER PT J AU Olausson, KH Maire, CL Haidar, S Ling, J Learner, E Nister, M Ligon, KL AF Olausson, Karl Holmberg Maire, Cecile L. Haidar, Sam Ling, Jason Learner, Emily Nister, Monica Ligon, Keith L. TI Prominin-1 (CD133) Defines Both Stem and Non-Stem Cell Populations in CNS Development and Gliomas SO PLOS ONE LA English DT Article ID NEURAL PROGENITOR CELLS; HUMAN BRAIN; PROSPECTIVE IDENTIFICATION; SPLICE VARIANTS; CANCER GENOMICS; GLIOBLASTOMA; EXPRESSION; PROTEIN; TUMORS; MARKER AB Prominin-1 (CD133) is a commonly used cancer stem cell marker in central nervous system (CNS) tumors including glioblastoma (GBM). Expression of Prom1 in cancer is thought to parallel expression and function in normal stem cells. Using RNA in situ hybridization and antibody tools capable of detecting multiple isoforms of Prom1, we find evidence for two distinct Prom1 cell populations in mouse brain. Prom1 RNA is first expressed in stem/progenitor cells of the ventricular zone in embryonic brain. Conversely, in adult mouse brain Prom1 RNA is low in SVZ/SGZ stem cell zones but high in a rare but widely distributed cell population (Prom1(hi)). Lineage marker analysis reveals Prom1(hi) cells are Olig2+Sox2+glia but Olig1/2 knockout mice lacking oligodendroglia retain Prom1(hi) cells. Bromodeoxyuridine labeling identifies Prom1 hi as slow-dividing distributed progenitors distinct from NG2+Olig2+oligodendrocyte progenitors. In adult human brain, PROM1 cells are rarely positive for OLIG2, but express astroglial markers GFAP and SOX2. Variability of PROM1 expression levels in human GBM and patient-derived xenografts (PDX) - from no expression to strong, uniform expression - highlights that PROM1 may not always be associated with or restricted to cancer stem cells. TCGA and PDX data show that high expression of PROM1 correlates with poor overall survival. Within proneural subclass tumors, high PROM1 expression correlates inversely with IDH1 (R132H) mutation. These findings support PROM1 as a tumor cell-intrinsic marker related to GBM survival, independent of its stem cell properties, and highlight potentially divergent roles for this protein in normal mouse and human glia. C1 [Olausson, Karl Holmberg; Maire, Cecile L.; Haidar, Sam; Ling, Jason; Learner, Emily; Ligon, Keith L.] Dana Farber Canc Inst, Dept Med Oncol, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Olausson, Karl Holmberg; Nister, Monica] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Ligon, Keith L.] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Ligon, Keith L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ligon, Keith L.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Ligon, KL (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. EM keith_ligon@dfci.harvard.edu FU NIH [R01 RO1CA170592]; Sontag Foundation; Karolinska Institutet; Swedish Childhood Cancer Foundation; Swedish Cancer Society; Swedish Research Council FX Financial support for this study was provided by NIH R01 RO1CA170592 (KLL, CLM) the Sontag Foundation (KLL) and PhD-funding from the Karolinska Institutet (KHO) as well as additional financial support from the Swedish Childhood Cancer Foundation, The Swedish Cancer Society and The Swedish Research Council (MN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 7 Z9 7 U1 0 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 SEP 3 PY 2014 VL 9 IS 9 AR e106694 DI 10.1371/journal.pone.0106694 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3TB UT WOS:000341257700107 ER PT J AU Kurz, FT Aon, MA O'Rourke, B Armoundas, AA AF Kurz, Felix T. Aon, Miguel A. O'Rourke, Brian Armoundas, Antonis A. TI Cardiac mitochondria exhibit dynamic functional clustering SO FRONTIERS IN PHYSIOLOGY LA English DT Article DE mitochondrial clustering; mitochondrial oscillator; functional connectivity; wavelets; cardiac myocyte ID WHOLE-CELL OSCILLATIONS; INDIVIDUAL MITOCHONDRIA; OXIDATIVE-PHOSPHORYLATION; COUPLED OSCILLATORS; ROS RELEASE; HEART-CELLS; NETWORK; MYOCYTES; BRAIN; ORGANIZATION AB Multi-oscillatory behavior of mitochondrial inner membrane potential Delta Psi(m) in self-organized cardiac mitochondrial networks can be triggered by metabolic or oxidative stress. Spatio-temporal analyses of cardiac mitochondrial networks have shown that mitochondria are heterogeneously organized in synchronously oscillating clusters in which the mean cluster frequency and size are inversely correlated, thus suggesting a modulation of cluster frequency through local inter-mitochondrial coupling. In this study, we propose a method to examine the mitochondrial network's topology through quantification of its dynamic local clustering coefficients. Individual mitochondrial Delta Psi(m) oscillation signals were identified for each cardiac myocyte and cross-correlated with all network mitochondria using previously described methods (Kurz et al., 2010a). Time-varying inter-mitochondrial connectivity, defined for mitochondria in the whole network whose signals are at least 90% correlated at any given time point, allowed considering functional local clustering coefficients. It is shown that mitochondrial clustering in isolated cardiac myocytes changes dynamically and is significantly higher than for random mitochondrial networks that are constructed using the Erdos-Renyi model based on the same sets of vertices. The network's time-averaged clustering coefficient for cardiac myocytes was found to be 0.500 +/- 0.051 (N = 9) vs. 0.061 +/- 0.020 for random networks, respectively. Our results demonstrate that cardiac mitochondria constitute a network with dynamically connected constituents whose topological organization is prone to clustering. Cluster partitioning in networks of coupled oscillators has been observed in scale-free and chaotic systems and is therefore in good agreement with previous models of cardiac mitochondrial networks. C1 [Kurz, Felix T.] Univ Heidelberg Hosp, Dept Neuroradiol, Heidelberg, Germany. [Kurz, Felix T.; Armoundas, Antonis A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Aon, Miguel A.; O'Rourke, Brian] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. RP Armoundas, AA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th Street, Charlestown, MA 02129 USA. EM aarmoundas@partners.org RI Aon, Miguel/A-6564-2008 OI Aon, Miguel/0000-0002-4355-5431 FU NHLBI NIH HHS [R37 HL054598] NR 43 TC 6 Z9 6 U1 0 U2 6 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD SEP 2 PY 2014 VL 5 AR 329 DI 10.3389/fphys.2014.00329 PG 8 WC Physiology SC Physiology GA AX7GY UT WOS:000347085900001 PM 25228884 ER PT J AU Cypess, AM Haft, CR Laughlin, MR Hu, HCH AF Cypess, Aaron M. Haft, Carol R. Laughlin, Maren R. Hu, Houchun H. TI Brown Fat in Humans: Consensus Points and Experimental Guidelines SO CELL METABOLISM LA English DT Review ID ADIPOSE-TISSUE THERMOGENESIS; ADULT HUMANS; SUPRACLAVICULAR REGION; ENERGY-EXPENDITURE; BLOOD-FLOW; COLD; ACTIVATION; TEMPERATURE; METABOLISM; ADIPOGENESIS AB As part of a current worldwide effort to understand the physiology of human BAT (hBAT) and whether its thermogenic activity can be manipulated to treat obesity, the workshop "Exploring the Roles of Brown Fat in Humans'' was convened at the National Institutes of Health on February 25-26, 2014. Presentations and discussion indicated that hBAT and its physiological roles are highly complex, and research is needed to understand the health impact of hBAT beyond thermogenesis and body weight regulation, and to define its interactions with core physiological processes like glucose homeostasis, cachexia, physical activity, bone structure, sleep, and circadian rhythms. C1 [Cypess, Aaron M.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Haft, Carol R.; Laughlin, Maren R.] NIDDK, NIH, Bethesda, MD 20892 USA. [Hu, Houchun H.] Childrens Hosp Los Angeles, Dept Radiol, Los Angeles, CA 90027 USA. RP Haft, CR (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM haftc@extra.niddk.nih.gov; maren.laughlin@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; Chugai Pharmaceutical Co., Ltd. through Joslin Diabetes Center; Molecular Metabolism, LLC through Joslin Diabetes Center FX We would like to thank the presenters and attendees of the workshop for their outstanding research and insightful discussion, and the National Institute of Diabetes and Digestive and Kidney Diseases for sponsorship. Special thanks go to Drs. Barbara Cannon, Kong Chen, Rebecca Brown, and Bruce Spiegelman for their insight and helpful comments. A. M. C. is a recipient of sponsored research grants from Chugai Pharmaceutical Co., Ltd., and Molecular Metabolism, LLC, both through Joslin Diabetes Center. NR 55 TC 39 Z9 41 U1 1 U2 30 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 SEP 2 PY 2014 VL 20 IS 3 BP 408 EP 415 DI 10.1016/j.cmet.2014.07.025 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA AO5RL UT WOS:000341402800007 PM 25185947 ER PT J AU Hucker, WJ Chatzizisis, YS Steigner, ML Winters, GL Kirshenbaum, JM AF Hucker, William J. Chatzizisis, Yiannis S. Steigner, Michael L. Winters, Gayle L. Kirshenbaum, James M. TI Myocardial Catastrophe A Case of Sudden, Severe Myocardial Dysfunction SO CIRCULATION LA English DT Article DE anticoagulants; antiphospholipid syndrome; heart-assist devices; shock; cardiogenic ID CARDIOVASCULAR MAGNETIC-RESONANCE; PRIMARY ANTIPHOSPHOLIPID SYNDROME; VENTRICULAR ASSIST DEVICE; NONVALVULAR ATRIAL-FIBRILLATION; ENDOMYOCARDIAL BIOPSY; LUPUS ANTICOAGULANT; PROGNOSTIC-FACTORS; RISK-FACTORS; ANTIBODIES; MORTALITY C1 [Hucker, William J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Div,Dept Med, Boston, MA 02115 USA. [Steigner, Michael L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Winters, Gayle L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Kirshenbaum, JM (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Cardiovasc Div,Dept Med, 75 Francis St, Boston, MA 02115 USA. EM jkirshenbaum@partners.org NR 40 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD SEP 2 PY 2014 VL 130 IS 10 BP 854 EP 862 DI 10.1161/CIRCULATIONAHA.113.007417 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AO9PW UT WOS:000341689100013 PM 25210096 ER PT J AU Brouwers, HB Raffeld, MR van Nieuwenhuizen, KM Falcone, GJ Ayres, AM McNamara, KA Schwab, K Romero, JM Velthuis, BK Viswanathan, A Greenberg, SM Ogilvy, CS van der Zwan, A Rinkel, GJE Goldstein, JN Klijn, CJM Rosand, J AF Brouwers, H. Bart Raffeld, Miriam R. van Nieuwenhuizen, Koen M. Falcone, Guido J. Ayres, Alison M. McNamara, Kristen A. Schwab, Kristin Romero, Javier M. Velthuis, Birgitta K. Viswanathan, Anand Greenberg, Steven M. Ogilvy, Christopher S. van der Zwan, Albert Rinkel, Gabriel J. E. Goldstein, Joshua N. Klijn, Catharina J. M. Rosand, Jonathan TI CT angiography spot sign in intracerebral hemorrhage predicts active bleeding during surgery SO NEUROLOGY LA English DT Article ID INITIAL CONSERVATIVE TREATMENT; HEMATOMA EXPANSION; IDENTIFIES PATIENTS; RANDOMIZED-TRIAL; HIGHEST RISK; MORTALITY; EXTRAVASATION; CONTRAST; DEATH; SCORE AB Objective:To determine whether the CT angiography (CTA) spot sign marks bleeding complications during and after surgery for spontaneous intracerebral hemorrhage (ICH).Methods:In a 2-center study of consecutive spontaneous ICH patients who underwent CTA followed by surgical hematoma evacuation, 2 experienced readers (blinded to clinical and surgical data) reviewed CTAs for spot sign presence. Blinded raters assessed active intraoperative and postoperative bleeding. The association between spot sign and active intraoperative bleeding, postoperative rebleeding, and residual ICH volumes was evaluated using univariable and multivariable logistic regression.Results:A total of 95 patients met inclusion criteria: 44 lobar, 17 deep, 33 cerebellar, and 1 brainstem ICH; 1 spot sign was identified in 32 patients (34%). The spot sign was the only independent marker of active bleeding during surgery (odds ratio [OR] 3.4; 95% confidence interval [CI] 1.3-9.0). Spot sign (OR 4.1; 95% CI 1.1-17), female sex (OR 6.9; 95% CI 1.7-37), and antiplatelet use (OR 4.6; 95% CI 1.2-21) were predictive of postoperative rebleeding. Larger residual hematomas and postoperative rebleeding were associated with higher discharge case fatality (OR 3.4; 95% CI 1.1-11) and a trend toward increased case fatality at 3 months (OR 2.9; 95% CI 0.9-8.8).Conclusions:The CTA spot sign is associated with more intraoperative bleeding, more postoperative rebleeding, and larger residual ICH volumes in patients undergoing hematoma evacuation for spontaneous ICH. The spot sign may therefore be useful to select patients for future surgical trials. C1 [Brouwers, H. Bart; Raffeld, Miriam R.; Falcone, Guido J.; Rosand, Jonathan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02163 USA. [Brouwers, H. Bart; Raffeld, Miriam R.; Falcone, Guido J.; Ayres, Alison M.; McNamara, Kristen A.; Schwab, Kristin; Romero, Javier M.; Viswanathan, Anand; Greenberg, Steven M.; Ogilvy, Christopher S.; Goldstein, Joshua N.; Rosand, Jonathan] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Brouwers, H. Bart; Raffeld, Miriam R.; Falcone, Guido J.; Ayres, Alison M.; McNamara, Kristen A.; Schwab, Kristin; Romero, Javier M.; Viswanathan, Anand; Greenberg, Steven M.; Ogilvy, Christopher S.; Goldstein, Joshua N.; Rosand, Jonathan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA USA. [Brouwers, H. Bart; van Nieuwenhuizen, Koen M.; Velthuis, Birgitta K.; van der Zwan, Albert; Rinkel, Gabriel J. E.; Klijn, Catharina J. M.] Univ Utrecht, Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol & Neurosurg, NL-3508 TC Utrecht, Netherlands. [Brouwers, H. Bart; van Nieuwenhuizen, Koen M.; Velthuis, Birgitta K.; van der Zwan, Albert; Rinkel, Gabriel J. E.; Klijn, Catharina J. M.] Univ Utrecht, Univ Med Ctr Utrecht, Dept Radiol, NL-3508 TC Utrecht, Netherlands. RP Brouwers, HB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02163 USA. EM H.B.Brouwers-4@umcutrecht.nl RI Klijn, C.J.M. (Karin)/E-1700-2016; Goldstein, Joshua/H-8953-2016; Falcone, Guido/L-2287-2016 OI Falcone, Guido/0000-0002-6407-0302 FU NIH-National Institute of Neurological Disorders and Stroke (NIH-NINDS) [R01NS073344, R01NS059727, 5K23NS059774]; NIH-NINDS SPOTRIAS [P50NS051343]; Netherlands Heart Foundation [2012 T077] FX No funding entities had involvement in study design, data collection, analysis, and interpretation, writing of the manuscript, or in the decision to submit for publication. The project described was supported by grants R01NS073344, R01NS059727, and 5K23NS059774 from the NIH-National Institute of Neurological Disorders and Stroke (NIH-NINDS). Drs. Brouwers and Falcone were supported by the NIH-NINDS SPOTRIAS fellowship grant P50NS051343. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or NINDS. Dr. Klijn is supported by a clinical established investigator grant of the Netherlands Heart Foundation (grant 2012 T077). NR 23 TC 14 Z9 15 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 2 PY 2014 VL 83 IS 10 BP 883 EP 889 DI 10.1212/WNL.0000000000000747 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA AO9RA UT WOS:000341692500006 PM 25098540 ER PT J AU Henrich, TJ Hanhauser, E Marty, FM Sirignano, MN Keating, S Lee, TH Robles, YP Davis, BT Li, JZ Heisey, A Hill, AL Busch, MP Armand, P Soiffer, RJ Altfeld, M Kuritzkes, DR AF Henrich, Timothy J. Hanhauser, Emily Marty, Francisco M. Sirignano, Michael N. Keating, Sheila Lee, Tzong-Hae Robles, Yvonne P. Davis, Benjamin T. Li, Jonathan Z. Heisey, Andrea Hill, Alison L. Busch, Michael P. Armand, Philippe Soiffer, Robert J. Altfeld, Marcus Kuritzkes, Daniel R. TI Antiretroviral-Free HIV-1 Remission and Viral Rebound After Allogeneic Stem Cell Transplantation Report of 2 Cases SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID BONE-MARROW-TRANSPLANTATION; STRUCTURED TREATMENT INTERRUPTIONS; VIRUS TYPE-1 INFECTION; POSITIVE PATIENTS; PCR ASSAY; THERAPY; VIREMIA; RNA; PLASMA; BLOOD AB Background: It is unknown whether the reduction in HIV-1 reservoirs seen after allogeneic hematopoietic stem cell transplantation (HSCT) with susceptible donor cells is sufficient to achieve sustained HIV-1 remission. Objective: To characterize HIV-1 reservoirs in blood and tissues and perform analytic antiretroviral treatment interruptions to determine the potential for allogeneic HSCT to lead to sustained, antiretroviral-free HIV-1 remission. Design: Case report with characterization of HIV-1 reservoirs and immunity before and after antiretroviral interruption. Setting: Tertiary care center. Patients: Two men with HIV with undetectable HIV-1 after allogeneic HSCT for hematologic tumors. Measurements: Quantification of HIV-1 in various tissues after HSCT and the duration of antiretroviral-free HIV-1 remission after treatment interruption. Results: No HIV-1 was detected from peripheral blood or rectal mucosa before analytic treatment interruption. Plasma HIV-1 RNA and cell-associated HIV-1 DNA remained undetectable until 12 and 32 weeks after antiretroviral cessation. Both patients experienced rebound viremia within 2 weeks of the most recent negative viral load measurement and developed symptoms consistent with the acute retroviral syndrome. One patient developed new efavirenz resistance after reinitiation of antiretroviral therapy. Reinitiation of active therapy led to viral decay and resolution of symptoms in both patients. Limitation: The study involved only 2 patients. Conclusion: Allogeneic HSCT may lead to loss of detectable HIV-1 from blood and gut tissue and variable periods of antiretroviral-free HIV-1 remission, but viral rebound can occur despite a minimum 3-log10 reduction in reservoir size. Long-lived tissue reservoirs may have contributed to viral persistence. The definition of the nature and half-life of such reservoirs is essential to achieve durable antiretroviral-free HIV-1 remission. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Leibniz Inst Expt Virol, Heinrich Pette Inst, Hamburg, Germany. Blood Syst Res Inst, San Francisco, CA 94118 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. MIT, Ragon Inst Massachusetts Gen Hosp, Cambridge, MA 02139 USA. Harvard Univ, Cambridge, MA 02139 USA. RP Henrich, TJ (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Infect Dis, 65 Landsdowne St, Cambridge, MA 02139 USA. EM thenrich@partners.org FU Foundation for AIDS Research; National Institute of Allergy and Infectious Diseases; Foundation for AIDS Research (amfAR Research Consortium on HIV Eradication grant); National Institute of Allergy and Infectious Disease, National Institutes of Health [1K23AI098480-01A1]; AIDS Clinical Trials Group Virology Support Laboratory [UM1 AI068636]; Harvard University Center for AIDS Research Therapeutics Program [P30 AI060354]; Delaney AIDS Research Enterprise Collaboratory [U19 AI096109]; Ragon Institute of Massachusetts General Hospital; Massachusetts Institute of Technology; Harvard University; Bill & Melinda Gates Foundation (Global Health grant) [OPP1017716] FX Foundation for AIDS Research and National Institute of Allergy and Infectious Diseases.; By the Foundation for AIDS Research (amfAR Research Consortium on HIV Eradication grant); National Institute of Allergy and Infectious Disease, National Institutes of Health (1K23AI098480-01A1); AIDS Clinical Trials Group Virology Support Laboratory (UM1 AI068636); Harvard University Center for AIDS Research Therapeutics Program (P30 AI060354); Delaney AIDS Research Enterprise Collaboratory (U19 AI096109); and Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University. This article is also based on research funded in part by the Bill & Melinda Gates Foundation (Global Health grant OPP1017716). NR 39 TC 115 Z9 116 U1 2 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 SEP 2 PY 2014 VL 161 IS 5 BP 319 EP + DI 10.7326/M14-1027 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AO7VT UT WOS:000341561400002 PM 25047577 ER PT J AU Samur, MK AF Samur, Mehmet Kemal TI RTCGAToolbox: A New Tool for Exporting TCGA Firehose Data SO PLOS ONE LA English DT Article ID CANCER GENOME ATLAS; SIGNATURES; LANDSCAPE; PROFILES; CIRCOS AB Background & Objective: Managing data from large-scale projects (such as The Cancer Genome Atlas (TCGA)) for further analysis is an important and time consuming step for research projects. Several efforts, such as the Firehose project, make TCGA pre-processed data publicly available via web services and data portals, but this information must be managed, downloaded and prepared for subsequent steps. We have developed an open source and extensible R based data client for pre-processed data from the Firehouse, and demonstrate its use with sample case studies. Results show that our RTCGAToolbox can facilitate data management for researchers interested in working with TCGA data. The RTCGAToolbox can also be integrated with other analysis pipelines for further data processing. C1 [Samur, Mehmet Kemal] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Samur, Mehmet Kemal] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Samur, Mehmet Kemal] Dana Farber Canc Inst, Inst Myeloma Therapeut, Boston, MA 02115 USA. [Samur, Mehmet Kemal] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Samur, Mehmet Kemal] Harvard Univ, Sch Med, Boston, MA USA. RP Samur, MK (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. EM samur@jimmy.harvard.edu FU National Institutes of Health [PO1CA155258, P50CA100707, PO1CA78378, RO1-124929] FX This work is supported by grants from the National Institutes of Health, Grants: PO1CA155258, P50CA100707, PO1CA78378, and RO1-124929. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 13 Z9 14 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 2 PY 2014 VL 9 IS 9 AR e106397 DI 10.1371/journal.pone.0106397 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3LR UT WOS:000341231500087 PM 25181531 ER PT J AU Lee, WC Wolfson, JM Catalano, PJ Rudnick, SN Koutrakis, P AF Lee, Wan-Chen Wolfson, Jack M. Catalano, Paul J. Rudnick, Stephen N. Koutrakis, Petros TI Size-Resolved Deposition Rates for Ultrafine and Submicrometer Particles in a Residential Housing Unit SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Article ID PARTICULATE AIR-POLLUTION; FINE PARTICLES; INDOOR ENVIRONMENT; OCCUPIED TOWNHOUSE; DECAY-RATES; OUTDOOR; PENETRATION; INFILTRATION; VENTILATION; MORTALITY AB We estimated the size-resolved particle deposition rates for the ultrafine and submicrometer particles using a nonlinear regression method with unknown particle background concentrations during nonsourced period following a controlled sourced period in a well-mixed residential environment. A dynamic adjustment method in conjunction with the constant injection of tracer gas was used to maintain the air exchange rate at three target levels across the range of 0.61-1.24 air change per hour (ACH). Particle deposition was found to be highly size dependent with rates ranging from 0.68 +/- 0.10 to 5.03 +/- 0.20 h(-1) (mean +/- s.e.). Our findings also suggest that the effect of air exchange on the particle deposition under enhanced air mixing was relatively small when compared to both the strong influence of size-dependent deposition mechanisms and the effects of mechanical air mixing by fans. Nonetheless, the significant association between air exchange and particle deposition rates for a few size categories indicated potential influence of air exchange on particle deposition. In the future, the proposed approach can be used to explore the separate or composite effects between air exchange and air mixing on particle deposition rates, which will contribute to improved assessment of human exposure to ultrafine and submicrometer particles. C1 [Lee, Wan-Chen; Wolfson, Jack M.; Koutrakis, Petros] Harvard Univ, Dept Environm Hlth, Sch Publ Hlth, Boston, MA 02215 USA. [Catalano, Paul J.] Harvard Univ, Dana Farber Canc Inst, Sch Publ Hlth, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Catalano, Paul J.] Harvard Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02115 USA. [Rudnick, Stephen N.] Harvard Univ, Dept Environm Hlth, Sch Publ Hlth, Boston, MA 02115 USA. RP Lee, WC (reprint author), Harvard Univ, Dept Environm Hlth, Sch Publ Hlth, 401 Pk Dr,Landmark Ctr West,Room 412E, Boston, MA 02215 USA. EM wal954@mail.harvard.edu OI Lee, Wanchen/0000-0003-0853-8561 FU Coway Co., Ltd.; USEPA [RD 83479801]; Taiwan Ministry of Education FX We thank Stephen T. Ferguson for his assistance in setting up the particle generation system, as well as Joy Lawrence and Vasileios Papapostolou for their helpful feedback in the preliminary experiments in the laboratory. This study was funded by Coway Co., Ltd. This publication is also made possible by the support of the USEPA grant RD 83479801. Wan-Chen Lee was supported by the Graduate Fellowship from the Taiwan Ministry of Education. NR 27 TC 5 Z9 5 U1 1 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X EI 1520-5851 J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD SEP 2 PY 2014 VL 48 IS 17 BP 10282 EP 10290 DI 10.1021/es502278k PG 9 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA AO3KY UT WOS:000341229300042 PM 25126897 ER PT J AU Dec, GW AF Dec, G. William TI Leaning Toward a Better Understanding of CRT in Women SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE cardiac resynchronization therapy; heart failure; women ID CARDIAC-RESYNCHRONIZATION THERAPY; BRANCH BLOCK MORPHOLOGY; HEART-FAILURE; QRS MORPHOLOGY; PREDICTORS; DURATION; OUTCOMES C1 [Dec, G. William] Massachusetts Gen Hosp, Heart Failure Transplant Ctr, Boston, MA 02114 USA. RP Dec, GW (reprint author), Massachusetts Gen Hosp, Bigelow 817,55 Fruit St, Boston, MA 02114 USA. EM gdec@partners.org NR 12 TC 1 Z9 1 U1 0 U2 2 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 SEP 2 PY 2014 VL 64 IS 9 BP 895 EP 897 DI 10.1016/j.jacc.2014.06.1161 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN8XH UT WOS:000340888600008 PM 25169174 ER PT J AU Nathan, DP Tang, GL AF Nathan, Derek P. Tang, Gale L. TI The impact of chronic renal insufficiency on vascular surgery patient outcomes SO SEMINARS IN VASCULAR SURGERY LA English DT Article ID CHRONIC-KIDNEY-DISEASE; AORTIC-ANEURYSM REPAIR; GLOMERULAR-FILTRATION-RATE; CAROTID-ARTERY STENOSIS; STATIN THERAPY; SERUM CREATININE; ENDARTERECTOMY; SURVIVAL; PREDICTION; MORTALITY AB Renal insufficiency is associated with an increased incidence of poor outcomes, including cardiovascular events and death, in the general population. Renal dysfunction appears to have a particularly negative impact in patients undergoing vascular surgery and endovascular therapy. Although the exact mechanism is unknown, increased levels of inflammatory and biochemical modulators associated with adverse cardiovascular outcomes, as well as endothelial dysfunction, appear to play a role in the association between renal insufficiency and adverse outcomes. Outcomes after the surgical and endovascular treatment of abdominal aortic aneurysms, carotid disease, and peripheral arterial disease are all negatively affected by renal insufficiency. Patients with renal dysfunction may warrant intervention for the treatment of critical limb ischemia and symptomatic carotid stenosis, given the comparatively worse outcomes associated with medical management. Open repair of aortic aneurysms and carotid intervention for asymptomatic disease in patients with severe renal dysfunction should be performed with significant caution, as the risks of repair may outweigh the benefits in this population. Further study is needed to better delineate the risks of medical management for these conditions in patients with coexisting severe renal dysfunction. Lastly, current guidelines for the management of vascular diseases, including objective performance goals for critical limb ischemia, are likely not applicable in patients with severe renal insufficiency. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). C1 [Nathan, Derek P.; Tang, Gale L.] Univ Washington, Dept Surg, Div Vasc Surg, Seattle, WA 98195 USA. [Tang, Gale L.] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. RP Tang, GL (reprint author), Univ Washington, Dept Surg, Div Vasc Surg, Seattle, WA 98195 USA. EM gtang@uw.edu NR 48 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0895-7967 EI 1558-4518 J9 SEMIN VASC SURG JI Semin. Vasc. Surg. PD SEP-DEC PY 2014 VL 27 IS 3-4 BP 162 EP 169 DI 10.1053/j.semvascsurg.2015.01.006 PG 8 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CM5XH UT WOS:000357761800007 PM 26073826 ER PT J AU Watson, JDB Gifford, SM Clouse, WD AF Watson, J. Devin B. Gifford, Shaun M. Clouse, W. Darrin TI Biochemical markers of acute limb ischemia, rhabdomyolysis, and impact on limb salvage SO SEMINARS IN VASCULAR SURGERY LA English DT Article ID PERCUTANEOUS CORONARY INTERVENTION; NEUTROPHIL-LYMPHOCYTE RATIO; EXTREMITY VASCULAR INJURY; ACUTE-RENAL-FAILURE; SKELETAL-MUSCLE; CREATINE-KINASE; NEUTROPHIL/LYMPHOCYTE RATIO; POSTCONDITIONING PROTECTS; NEUROMUSCULAR RECOVERY; CONTROLLED REPERFUSION AB Biochemical markers of ischemia reperfusion injury have been of interest to vascular surgeons and researchers for many years. Acute limb ischemia is the quintessential clinical scenario where these markers would seem relevant. The use of biomarkers to preoperatively or perioperatively predict which patients will not tolerate limb-salvage efforts or who will have poor functional outcomes after salvage is of immense interest. Creatinine phosphokinase, myoglobin, lactate, lactate dehydrogenase, potassium, bicarbonate, and neutrophil/leukocyte ratios are a few of the studied biomarkers available. Currently, the most well-studied aspect of ischemia reperfusion injury is rhabdomyolysis leading to acute kidney injury. The last 10 years have seen significant progression and improvement in the treatment of rhabdomyolysis, from minor supportive care to use of continuous renal replacement therapy. Identification of specific biomarkers with predictive outcome characteristics in the setting of ischemia reperfusion injury will help guide therapeutic development and potentially mitigate pathophysiologic changes in acute limb ischemia, including rhabdomyolysis. These may further lead to improvements in short- and long-term surgical outcomes and limb salvage, as well as a better understanding of the timing and selection of intervention. (C) 2015 Elsevier Inc. All rights reserved. C1 [Watson, J. Devin B.; Gifford, Shaun M.] San Antonio Mil Med Ctr, Div Vasc Surg, Ft Sam Houston, TX USA. [Clouse, W. Darrin] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. RP Clouse, WD (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Vasc & Endovasc Surg, 15 Parkman St,WACC 440, Boston, MA 02114 USA. EM wclouse@partners.org NR 38 TC 2 Z9 2 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0895-7967 EI 1558-4518 J9 SEMIN VASC SURG JI Semin. Vasc. Surg. PD SEP-DEC PY 2014 VL 27 IS 3-4 BP 176 EP 181 DI 10.1053/j.semvascsurg.2015.01.007 PG 6 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CM5XH UT WOS:000357761800009 PM 26073828 ER PT J AU Luckianow, GM Kaplan, LJ AF Luckianow, Gina M. Kaplan, Lewis J. TI Ladder advancement for hospital-based physician assistants: A timely idea SO JAAPA-JOURNAL OF THE AMERICAN ACADEMY OF PHYSICIAN ASSISTANTS LA English DT Editorial Material C1 [Luckianow, Gina M.] Yale New Haven Med Ctr, Dept Surg, New Haven, CT 06504 USA. [Kaplan, Lewis J.] Philadelphia VA Med Ctr, Surg, Philadelphia, PA USA. [Kaplan, Lewis J.] Univ Penn, Perelman Sch Med, Surg, Philadelphia, PA 19104 USA. RP Luckianow, GM (reprint author), Yale New Haven Med Ctr, Dept Surg, 20 York St, New Haven, CT 06504 USA. 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 1547-1896 EI 0893-7400 J9 JAAPA-J AM ACAD PHYS JI JAAPA-J. Am. Acad. Physician Assist. PD SEP PY 2014 VL 27 IS 9 BP 9 EP 9 DI 10.1097/01.JAA.0000453250.61086.0d PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CM3IJ UT WOS:000357575100006 ER PT J AU Liu, YY AF Liu, Yang-Yu TI Theoretical progress and practical challenges in controlling complex networks SO NATIONAL SCIENCE REVIEW LA English DT Editorial Material ID CONTROLLABILITY C1 [Liu, Yang-Yu] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Channing Div Network Med, Cambridge, MA 02138 USA. [Liu, Yang-Yu] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA USA. RP Liu, YY (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Channing Div Network Med, Cambridge, MA 02138 USA. EM yyl@channing.harvard.edu NR 12 TC 0 Z9 0 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2095-5138 EI 2053-714X J9 NATL SCI REV JI Natl. Sci. Rev. PD SEP PY 2014 VL 1 IS 3 BP 341 EP 343 DI 10.1093/nsr/nwu025 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL3NK UT WOS:000356856400011 ER PT J AU Mifflin, J AF Mifflin, Jeffrey TI THE RED MAN'S BONES: George Catlin, Artist and Showman 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 FAL PY 2014 VL 53 IS 4 BP 86 EP 86 PG 1 WC History SC History GA CI8YY UT WOS:000355058800014 ER PT J AU Kirkham, JC Lee, JH Austen, WG AF Kirkham, John C. Lee, Jeffrey H. Austen, William Gerald TI Fat Graft Survival Physics Matters: Invited Commentary to "The Impact of Liposuction Cannula Size on Adipocyte Viability" SO ANNALS OF PLASTIC SURGERY LA English DT Letter ID STORAGE C1 [Kirkham, John C.; Lee, Jeffrey H.; Austen, William Gerald] Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. RP Kirkham, JC (reprint author), Massachusetts Gen Hosp, WAC 435,15 Parkman St, Boston, MA 02114 USA. EM jkirkham@partners.org NR 6 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0148-7043 EI 1536-3708 J9 ANN PLAS SURG JI Ann. Plast. Surg. PD SEP PY 2014 VL 73 IS 3 BP 359 EP 359 DI 10.1097/SAP.0b013e318295dee0 PG 1 WC Surgery SC Surgery GA CI6QN UT WOS:000354885800014 PM 25121420 ER PT J AU Chitnis, T AF Chitnis, T. TI Emerging therapies and clinical trials in pediatric MS SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Chitnis, T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partners Pediat MS Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA TC8.2 BP 8 EP 8 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300020 ER PT J AU Gianni, C Govindarajan, ST Fan, AP Louapre, C Loggia, M Catana, C Tinelli, E Hooker, J Sloane, J Kinkel, RP Mainero, C AF Gianni, C. Govindarajan, S. T. Fan, A. P. Louapre, C. Loggia, M. Catana, C. Tinelli, E. Hooker, J. Sloane, J. Kinkel, R. P. Mainero, C. TI [C-11]-PBR28 MR-PET imaging detects in vivo inflammation in normal appearing white matter and cortical sulci in multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Gianni, C.; Govindarajan, S. T.; Fan, A. P.; Louapre, C.; Loggia, M.; Catana, C.; Hooker, J.; Mainero, C.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Fan, A. P.] MIT, Cambridge, MA 02139 USA. [Tinelli, E.] Univ Rome, Rome, Italy. [Sloane, J.; Kinkel, R. P.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA PS8.5 BP 51 EP 52 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300129 ER PT J AU Rintell, D Cross, T Shanks, A Fico, C Duffy, L Camposano, S Chitnis, T AF Rintell, D. Cross, T. Shanks, A. Fico, C. Duffy, L. Camposano, S. Chitnis, T. TI Parents' experience of pediatric multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Rintell, D.; Shanks, A.; Fico, C.; Chitnis, T.] Massachusetts Gen Hosp, Partners Pediat Multiple Sclerosis Ctr, Boston, MA 02114 USA. [Cross, T.] Univ Illinois, Children & Family Res Ctr, Urbana, IL 61801 USA. [Duffy, L.; Camposano, S.] Boston Childrens Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA HT6.3 BP 66 EP 66 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300163 ER PT J AU Yadav, V Maracci, G Kim, E Spain, R Cameron, M Overs, S Lewis, A McDougall, J Lovera, J Murchison, C Bourdette, DN AF Yadav, V. Maracci, G. Kim, E. Spain, R. Cameron, M. Overs, S. Lewis, A. McDougall, J. Lovera, J. Murchison, C. Bourdette, D. N. TI Effects of a very low fat, plant-food-based diet on fatigue in multiple sclerosis: report of a pilot trial SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Yadav, V.; Maracci, G.; Kim, E.; Spain, R.; Cameron, M.; Lewis, A.; Murchison, C.; Bourdette, D. N.] Oregon Hlth & Sci Univ, Neurol, Portland, OR 97201 USA. [Yadav, V.; Maracci, G.; Kim, E.; Spain, R.; Cameron, M.; Bourdette, D. N.] Portland VA Med Ctr, Neurol, Portland, OR USA. [Overs, S.] Novant Med Grp, Charlotte, OR USA. [McDougall, J.] McDougall Res & Educ Fdn, Santa Rosa, CA USA. [Lovera, J.] Louisiana State Univ, Neurol, New Orleans, LA USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P055 BP 91 EP 91 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300219 ER PT J AU Vandenbark, AA Meza-Romero, R Benedek, G Offner, H AF Vandenbark, A. A. Meza-Romero, R. Benedek, G. Offner, H. TI A novel MIF inhibitor as therapy for multiple sclerosis and stroke SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Vandenbark, A. A.; Meza-Romero, R.; Benedek, G.; Offner, H.] Portland VA Med Ctr, Neuroimmunol Res, R&D 31, Portland, OR USA. [Vandenbark, A. A.; Benedek, G.; Offner, H.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P310 BP 205 EP 206 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300473 ER PT J AU Chitnis, T Karlsson, G Haring, DA Ghezzi, A Pohl, D Putzki, N AF Chitnis, T. Karlsson, G. Haering, D. A. Ghezzi, A. Pohl, D. Putzki, N. TI Fingolimod effect on clinical and MRI disease activity in young adult patients with relapsing multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Chitnis, T.] Massachusetts Gen Hosp, Partners Pediat Multiple Sclerosis Ctr, Boston, MA 02114 USA. [Karlsson, G.; Haering, D. A.; Putzki, N.] Novartis Pharma AG, Basel, Switzerland. [Ghezzi, A.] Ctr Studi Sclerosi Multipla, Gallarate, Italy. [Pohl, D.] Childrens Hosp Eastern Ontario, Ottawa, ON K1H 8L1, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P317 BP 208 EP 209 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300480 ER PT J AU McDonald, J Graves, J Lulu, S Waldman, A Belman, A Greenberg, B Weinstock-Guttman, B Aaen, G Mendelt-Tillema, J Hart, J Ness, J Rubin, J Krupp, L Gorman, M Benson, L Rodriguez, M Chitnis, T Simmons, T Casper, TC Rose, J Waubant, E AF McDonald, J. Graves, J. Lulu, S. Waldman, A. Belman, A. Greenberg, B. Weinstock-Guttman, B. Aaen, G. Mendelt-Tillema, J. Hart, J. Ness, J. Rubin, J. Krupp, L. Gorman, M. Benson, L. Rodriguez, M. Chitnis, T. Simmons, T. Casper, T. C. Rose, J. Waubant, E. TI A prospective case-control study of dietary salt intake and risk of pediatric MS SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [McDonald, J.; Graves, J.; Lulu, S.; Hart, J.; Waubant, E.] UCSF Reg Pediat MS Ctr, San Francisco, CA USA. [Waldman, A.] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Belman, A.; Krupp, L.] SUNY Stony Brook, Dept Neurol, Stony Brook, NY 11794 USA. [Greenberg, B.] UT Southwestern, Dept Neurol, Dallas, TX USA. [Weinstock-Guttman, B.] SUNY Buffalo, Pediat MS Ctr, Jacobs Neurol Inst, Buffalo, NY 14260 USA. [Aaen, G.] Loma Linda Univ, Dept Child Neurol, Loma Linda, CA 92350 USA. [Mendelt-Tillema, J.; Rodriguez, M.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Ness, J.] Alabama Pediat MS Ctr, Birmingham, AL USA. [Rubin, J.] Northwestern Feinberg Sch Med, Dept Neurol, Chicago, IL USA. [Gorman, M.; Benson, L.; Chitnis, T.] Massachusetts Gen Hosp, Partners Pediat MS Ctr, Boston, MA 02114 USA. [Simmons, T.; Casper, T. C.] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Rose, J.] Univ Utah, Dept Neurol, Salt Lake City, UT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P348 BP 222 EP 222 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300509 ER PT J AU Graham, D Huang, S Choi, JK Rudin, S Yu, D Jenkins, B Mandeville, J Dai, G Chang, R Tomkinson, B Dellovade, T AF Graham, D. Huang, S. Choi, J-K Rudin, S. Yu, D. Jenkins, B. Mandeville, J. Dai, G. Chang, R. Tomkinson, B. Dellovade, T. TI ATX-MS-1467 reduces MRI lesions and prevents disease progression in a humanized mouse model of multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Graham, D.; Huang, S.; Rudin, S.; Yu, D.; Chang, R.; Tomkinson, B.; Dellovade, T.] EMD Serono Res & Dev Inst Inc, Neurol ETIP, Translat & Biomarker Res Grp, Billerica, MA USA. [Choi, J-K; Jenkins, B.; Mandeville, J.; Dai, G.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P378 BP 235 EP 235 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300539 ER PT J AU Huang, SY Tobyne, SM Nummenmaa, A Witzel, T Wald, LL Mcnab, JA Klawiter, EC AF Huang, S. Y. Tobyne, S. M. Nummenmaa, A. Witzel, T. Wald, L. L. Mcnab, J. A. Klawiter, E. C. TI In vivo characterization of axonal damage in multiple sclerosis using high-gradient diffusion magnetic resonance imaging SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Huang, S. Y.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Huang, S. Y.; Nummenmaa, A.; Witzel, T.; Wald, L. L.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Tobyne, S. M.; Klawiter, E. C.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Mcnab, J. A.] Stanford Univ, Richard M Lucas Ctr Imaging, Dept Radiol, Stanford, CA 94305 USA. RI Wald, Lawrence/D-4151-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P446 BP 265 EP 265 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300607 ER PT J AU Tobyne, SM Boratyn, D Sherman, J Rosen, B Mainero, C Klawiter, EC AF Tobyne, S. M. Boratyn, D. Sherman, J. Rosen, B. Mainero, C. Klawiter, E. C. TI Disrupted distant functional connectivity within the temporoparietal junction is linked to impaired attention in multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Tobyne, S. M.; Boratyn, D.; Sherman, J.; Klawiter, E. C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurol, Boston, MA USA. [Sherman, J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Psychiat, Boston, MA USA. [Rosen, B.; Mainero, C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Radiol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P452 BP 267 EP 268 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300613 ER PT J AU Boratyn, DA Tobyne, SA Klawiter, EC AF Boratyn, D. A. Tobyne, S. A. Klawiter, E. C. TI Altered resting state homologous inter-hemispheric functional connectivity is related to clinical measures of disabilityin multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Boratyn, D. A.; Tobyne, S. A.] Massachusetts Gen Hosp, Neurol, Charlestown, MA USA. [Klawiter, E. C.] Massachusetts Gen Hosp, Neurol, Boston, MA 02114 USA. [Klawiter, E. C.] Harvard Univ, Sch Med, Neurol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P541 BP 307 EP 308 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300702 ER PT J AU Tobyne, S Boratyn, D Klawiter, EC AF Tobyne, S. Boratyn, D. Klawiter, E. C. TI Impaired homologous interhemispheric functional connectivity is related to atrophy of the corpus callosum in multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT Joint ACTRIMS-ECTRIMS Meeting CY SEP 10-13, 2014 CL Boston, MA SP ACTRIMS, ECTRIMS C1 [Tobyne, S.; Boratyn, D.; Klawiter, E. C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2014 VL 20 SU 1 MA P554 BP 313 EP 313 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI0QA UT WOS:000354441300715 ER PT J AU Wu, AC Li, LL Fung, V Kharbanda, EO Larkin, EK Vollmer, WM Butler, MG Miroshnik, I Rusinak, D Davis, RL Hartert, T Weiss, ST Lieu, TA AF Wu, Ann Chen Li, Lingling Fung, Vicki Kharbanda, Elyse O. Larkin, Emma K. Vollmer, William M. Butler, Melissa G. Miroshnik, Irina Rusinak, Donna Davis, Robert L. Hartert, Tina Weiss, Scott T. Lieu, Tracy A. TI Use of Leukotriene Receptor Antagonists Are Associated with a Similar Risk of Asthma Exacerbations as Inhaled Corticosteroids SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Article DE Asthma; Controller medications; Effectiveness; Inhaled corticosteroids; Leukotriene antagonist; Long-acting beta-agonist ID MILD PERSISTENT ASTHMA; RANDOMIZED CONTROLLED-TRIAL; TERM CLINICAL-TRIAL; CHILDHOOD ASTHMA; ORAL MONTELUKAST; FLUTICASONE PROPIONATE; RESOURCE USE; CHILDREN; ADHERENCE; BUDESONIDE AB BACKGROUND: Based on results of clinical trials, inhaled corticosteroids (ICS) are the most-effective controller medications for preventing asthma-related exacerbations, yet few studies in real-life populations have evaluated the comparative effectiveness of ICS. OBJECTIVE: To determine the likelihood of asthma exacerbations among children with asthma after initiation of controller medications: ICS, leukotriene antagonists (LTRA), and ICSelong-acting beta-agonist (LABA) combination therapy. METHODS: This was a retrospective cohort study of subjects who were part of the Population-Based Effectiveness in Asthma and Lung Diseases Network. We conducted Cox regression analyses by adjusting for baseline covariates, adherence by using proportion of days covered, and high-dimensional propensity scores. The main outcome measurements were emergency department visits, hospitalizations, or oral corticosteroid use. RESULTS: Our population included 15,567 health plan subjects and 10,624 TennCare Medicaid subjects with uncontrolled asthma. Overall adherence to controller medications was low, with no more than 50% of the subjects refilling the medication after the initial fill. For subjects with allergic rhinitis, the subjects in TennCare Medicaid treated with LTRAs were less likely to experience ED visits (hazard ratio 0.44 [95% CI, 0.21-0.93]) compared with the subjects treated with ICS. For all other groups, the subjects treated with LTRA or ICS-LABA were just as likely to experience ED visits or hospitalizations, or need oral corticosteroids as the subjects treated with ICS. CONCLUSION: Risks of asthma-related exacerbations did not differ between children who initiated LTRA and ICS. These findings may be explainable by LTRA, which has similar effectiveness as ICS in real-life usage by residual confounding by indication or other unmeasured factors. (C) 2014 American Academy of Allergy, Asthma & Immunology C1 [Wu, Ann Chen; Li, Lingling; Miroshnik, Irina; Rusinak, Donna; Lieu, Tracy A.] Harvard Pilgrim Hlth Care Inst, Ctr Child Hlth Care Studies, Dept Populat Med, Boston, MA USA. [Wu, Ann Chen; Li, Lingling; Fung, Vicki; Miroshnik, Irina; Rusinak, Donna; Lieu, Tracy A.] Harvard Univ, Sch Med, Boston, MA USA. [Wu, Ann Chen; Lieu, Tracy A.] Childrens Hosp, Dept Pediat, Div Gen Pediat, Boston, MA 02115 USA. [Fung, Vicki] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Kharbanda, Elyse O.] HealthPartners Inst Educ & Res, Dept Res, Minneapolis, MN USA. [Larkin, Emma K.; Hartert, Tina] Vanderbilt Univ, Sch Med, Dept Med, Div Allergy Pulm & Crit Care, Nashville, TN 37212 USA. [Vollmer, William M.] Kaiser Permanente, Ctr Hlth Res Northwest, Portland, OR USA. [Butler, Melissa G.; Davis, Robert L.] Kaiser Permanente Georgia, Ctr Hlth Res Southeast, Atlanta, GA USA. [Weiss, Scott T.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Weiss, Scott T.] Partners Hlth Care, Partners Ctr Personalized Genet Med, Boston, MA USA. [Lieu, Tracy A.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. RP Wu, AC (reprint author), Dept Populat Med, 133 Brookline Ave,6th Fl, Boston, MA 02215 USA. EM ann.wu@childrens.harvard.edu FU Agency for Healthcare Research and Quality (AHRQ) [1R01HS019669] FX The Population-Based Effectiveness in Asthma and Lung Diseases Network is supported by Agency for Healthcare Research and Quality (AHRQ) 1R01HS019669 (PI, Steve Soumerai). NR 41 TC 5 Z9 5 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD SEP-OCT PY 2014 VL 2 IS 5 BP 607 EP 613 DI 10.1016/j.jaip.2014.05.009 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA CH7GZ UT WOS:000354205300016 PM 25213056 ER PT J AU Keet, C Radano, MC Shreffler, W AF Keet, Corinne Radano, Marcella C. Shreffler, Wayne TI RE: Cesarean section implicated in more long-term medical problems REPLY SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Letter C1 [Keet, Corinne] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Allergy & Immunol, Baltimore, MD 21205 USA. [Radano, Marcella C.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Radano, Marcella C.; Shreffler, Wayne] Harvard Univ, Sch Med, Boston, MA USA. [Shreffler, Wayne] Massachusetts Gen Hosp, Dept Pediat, Div Allergy & Immunol, Food Allergy Ctr MGH, Boston, MA 02114 USA. RP Keet, C (reprint author), Johns Hopkins Univ Hosp, CMSC 1102,600 N Wolfe St, Baltimore, MD 21287 USA. EM ckeet1@jhmi.edu FU NIAID NIH HHS [1K23AI103187-01] NR 4 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD SEP-OCT PY 2014 VL 2 IS 5 BP 643 EP 644 DI 10.1016/j.jaip.2014.06.014 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA CH7GZ UT WOS:000354205300031 PM 25213070 ER PT J AU Guanci, MM AF Guanci, Mary McKenna TI Clinical Q & A: Translating Therapeutic Temperature Management from Theory to Practice SO THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT LA English DT Letter ID SPINAL-CORD-INJURY; SHIVERING THRESHOLD; CARDIAC-ARREST; ADDITIVELY REDUCE; HYPOTHERMIA; MEPERIDINE; GUIDELINE C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Guanci, MM (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 23 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2153-7658 EI 2153-7933 J9 THER HYPOTHERMIA TEM JI Ther. Hypothermia Temp. Manag. PD SEP 1 PY 2014 VL 4 IS 3 BP 145 EP 145 DI 10.1089/ther.2014.1510 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA CF3VT UT WOS:000352477600009 ER PT J AU Whitebird, RR Solberg, LI Jaeckels, NA Pietruszewski, PB Hadzic, S Unutzer, J Ohnsorg, KA Rossom, RC Beck, A Joslyn, KE Rubenstein, LV AF Whitebird, Robin R. Solberg, Leif I. Jaeckels, Nancy A. Pietruszewski, Pamela B. Hadzic, Senka Unuetzer, Juergen Ohnsorg, Kris A. Rossom, Rebecca C. Beck, Arne Joslyn, Kenneth E. Rubenstein, Lisa V. TI Effective Implementation of Collaborative Care for Depression: What Is Needed? SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID LATE-LIFE DEPRESSION; MENTAL-HEALTH CONDITIONS; IMPROVING PRIMARY-CARE; QUALITY IMPROVEMENT; COST-EFFECTIVENESS; TERM OUTCOMES; MANAGEMENT; MODELS; METAANALYSIS; TRIAL AB Objectives To identify the care model factors that were key for successful implementation of collaborative depression care in a statewide Minnesota primary care initiative. Study Design We used a mixed-methods design incorporating both qualitative data from clinic site visits and quantitative measures of patient activation and 6-month remission rates. Methods Care model factors identified from the site visits were tested for association with rates of activation into the program and remission rates. Results Nine factors were identified as important for successful implementation of collaborative care by the consultants who had trained and interviewed participating clinic teams, and rated according to a Likert Scale. Factors correlated with higher patient activation rates were: strong leadership support (0.63), well-defined and -implemented care manager roles (0.62), a strong primary care physician champion (0.60), and an on-site and accessible care manager (0.59). However, remission rates at 6 months were correlated with: an engaged psychiatrist (0.62), not seeing operating costs as a barrier to participation (0.56), and face-to-face communication (warm handoffs) between the care manager and primary care physician for new patients (0.54). Conclusions Care model factors most important for successful program implementation differ for patient activation into the program versus remission at 6 months. Knowing which implementation factors are most important for successful activation will be useful for those interested in adopting this evidence-based approach to improving primary care for patients with depression. C1 [Whitebird, Robin R.; Solberg, Leif I.; Ohnsorg, Kris A.; Rossom, Rebecca C.] HealthPartners Inst Educ & Res, Minneapolis, MN 55425 USA. [Jaeckels, Nancy A.] Hlth Management Associates, Chicago, IL USA. [Pietruszewski, Pamela B.; Hadzic, Senka] Inst Clin Syst Improvement, Minneapolis, MN USA. [Unuetzer, Juergen] Univ Washington, AIMS Ctr, Div Integrated Care & Publ Hlth, Seattle, WA 98195 USA. [Beck, Arne] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. [Joslyn, Kenneth E.] Univ Minnesota, Sch Med, Dept Family Med, Minneapolis, MN USA. [Rubenstein, Lisa V.] VA Greater Los Angeles Healthcare Syst, VA Qual Enhancement Res Initiat, Ctr Implementat Practice & Res Support, Los Angeles, CA USA. RP Whitebird, RR (reprint author), HealthPartners Inst Educ & Res, 8170 33rd Ave So,Mail Stop 23301A, Minneapolis, MN 55425 USA. EM robin.r.whitebird@healthpartners.com FU National Institute of Mental Health [5R01MH080692] FX This research was funded by grant #5R01MH080692 from the National Institute of Mental Health. NR 31 TC 8 Z9 8 U1 2 U2 5 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD SEP PY 2014 VL 20 IS 9 BP 699 EP 707 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CD3QC UT WOS:000350993300009 PM 25365745 ER PT J AU Zant, JC Kim, T Kalinchuk, A Yang, C Brown, RE McNally, JM Thankachan, S McKenna, JT Strecker, RE McCarley, RW Basheer, R AF Zant, J. C. Kim, T. Kalinchuk, A. Yang, C. Brown, R. E. McNally, J. M. Thankachan, S. McKenna, J. T. Strecker, R. E. McCarley, R. W. Basheer, R. TI Defining the role of specific neuronal populations of the basal forebrain in sleep-wake behaviour using opto-dialysis: a novel method combining optogenetics and in vivo microdialysis SO JOURNAL OF SLEEP RESEARCH LA English DT Meeting Abstract CT 22nd Congress of the European-Sleep-Research-Society CY SEP 16-20, 2014 CL Tallinn, ESTONIA SP European Sleep Res Soc C1 [Zant, J. C.; Kim, T.; Kalinchuk, A.; Basheer, R.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA USA. [Yang, C.; Brown, R. E.; McNally, J. M.; Thankachan, S.; McKenna, J. T.; Strecker, R. E.; McCarley, R. W.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Brockton, MA 02401 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1105 EI 1365-2869 J9 J SLEEP RES JI J. Sleep Res. PD SEP PY 2014 VL 23 SU 1 SI SI MA P812 BP 255 EP 256 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CB9OG UT WOS:000349960600698 ER PT J AU Muenster, S Beloiartsev, A Du, SE Dao, M Zapol, WM AF Muenster, S. Beloiartsev, A. Du, S. E. Dao, M. Zapol, W. M. TI Transient ex vivo Exposure of Stored Red Blood Cells (RBCs) to Nitric Oxide Gas Prevents Pulmonary Hypertension in Awake Lambs SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Muenster, S.; Beloiartsev, A.; Zapol, W. M.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. [Muenster, S.; Beloiartsev, A.; Zapol, W. M.] Harvard Univ, Sch Med, Boston, MA USA. [Du, S. E.; Dao, M.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. RI Dao, Ming/B-1602-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA S80-040A BP 50A EP 50A PG 1 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300087 ER PT J AU Chapuy, CI Nicholson, RT Aguad, MD Laubach, JP Chapuy, B Doshi, P Kaufman, RM AF Chapuy, C. I. Nicholson, R. T. Aguad, M. D. Laubach, J. P. Chapuy, B. Doshi, P. Kaufman, R. M. TI Development of a Robust Method to Negate the Daratumumab Interference with Routine Blood Bank Testing SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Chapuy, C. I.; Nicholson, R. T.; Aguad, M. D.; Kaufman, R. M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Laubach, J. P.; Chapuy, B.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Doshi, P.] Janssen Inc, Spring House, PA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA SP254 BP 157A EP 157A PG 1 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300346 ER PT J AU Milbradt-Pohan, S Williams, C Szklarski, P LaFary, K Garis, M Hawker, YC Eichbaum, Q Young, P AF Milbradt-Pohan, S. Williams, C. Szklarski, P. LaFary, K. Garis, M. Hawker, Y. C. Eichbaum, Q. Young, P. TI Assessment of the Bio-Rad IH System for Blood Grouping SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting CY OCT 25-28, 2014 CL Philadelphia, PA SP AABB C1 [Milbradt-Pohan, S.; Williams, C.] BioRad, Benicia, CA USA. [Szklarski, P.; LaFary, K.; Garis, M.; Hawker, Y. C.; Eichbaum, Q.; Young, P.] Vanderbilt, Pathol, Nashville, TN USA. [Young, P.] US Dept Vet Affairs, Nashville, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2014 VL 54 SU 2 SI SI MA SP271 BP 164A EP 164A PG 1 WC Hematology SC Hematology GA CB9PX UT WOS:000349965300363 ER PT J AU Garvey, WT Garber, AJ Mechanick, JI Bray, GA Dagogo-Jack, S Einhorn, D Grunberger, G Handelsman, Y Hennekens, CH Hurley, DL McGill, J Palumbo, P Umpierrez, G AF Garvey, W. Timothy Garber, Alan J. Mechanick, Jeffrey I. Bray, George A. Dagogo-Jack, Samuel Einhorn, Daniel Grunberger, George Handelsman, Yehuda Hennekens, Charles H. Hurley, Daniel L. McGill, Janet Palumbo, Pasquale Umpierrez, Guillermo CA AACE Obesity Sci Comm TI AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY CONSENSUS CONFERENCE ON OBESITY: BUILDING AN EVIDENCE BASE FOR COMPREHENSIVE ACTION SO ENDOCRINE PRACTICE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; LIFE-STYLE INTERVENTION; DIABETES PREVENTION PROGRAM; CARDIOVASCULAR RISK-FACTORS; BODY-MASS INDEX; IMPAIRED GLUCOSE-TOLERANCE; WEIGHT-LOSS MAINTENANCE; GLYCEMIC INDEX; COST-EFFECTIVENESS; METABOLIC SYNDROME AB Objective/Methods: The American Association of Clinical Endocrinologists/American College of Endocrinology "Consensus conference on obesity: building an evidence base for comprehensive action" convened March 23-25, 2014, in Washington, D.C. The premise of the conference was that by bringing together stakeholders in U.S. obesity care, representing the biomedical and public health models, new information would emerge to formulate actionable recommendations. Results: Key conference findings include 5 affirmed and 8 emergent concepts. These concepts include the need for a medically meaningful and actionable diagnosis of obesity, research that evaluates and refines a complications-centric clinical approach to obesity, the need for a better understanding of reimbursement mechanisms and the value associated with obesity prevention and management, increased nutrition and obesity education, and enhanced public awareness and health literacy. Conclusion: Next steps include deriving a more robust medical definition of obesity, translation of the affirmed and emergent concepts into actionable recommendations in the interests of patients with obesity, and developing logistics for effective implementation. C1 [Garvey, W. Timothy] Univ Alabama, Dept Nutr Sci, Tuscaloosa, AL 35487 USA. [Garvey, W. Timothy] UAB Diabet Res Ctr, Birmingham, AL USA. [Garvey, W. Timothy] Birmingham VA Med Ctr, Birmingham, AL USA. [Garber, Alan J.] Baylor Coll Med, Houston, TX 77030 USA. [Mechanick, Jeffrey I.] Icahn Sch Med Mt Sinai, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. [Bray, George A.] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Dagogo-Jack, Samuel] Univ Tennessee, Memphis, TN USA. [Einhorn, Daniel] Univ Calif San Diego, Scripps Whittier Diabet Inst, Diab & Endocrine Associates, La Jolla, CA 92093 USA. [Grunberger, George] Wayne State Univ, Sch Med, Grunberger Diabet Inst, Bloomfield Hills, MI USA. [Handelsman, Yehuda] Metab Inst Amer, Tarzana, CA USA. [Hennekens, Charles H.] Florida Atlantic Univ, Boca Raton, FL 33431 USA. [Hurley, Daniel L.] Mayo Clin, Sch Med, Rochester, MN USA. [McGill, Janet] Washington Univ, Div Endocrinol Metab & Lipid Res, St Louis, MO USA. [Palumbo, Pasquale] Mayo Clin, Scottsdale, AZ USA. [Umpierrez, Guillermo] Emory Univ, Dept Med Endocrinol, Atlanta, GA 30322 USA. RP Garvey, WT (reprint author), Amer Assoc Clin Endocrinologists, 245 Riverside Ave,Suite 200, Jacksonville, FL 32202 USA. EM publications@aace.com FU Astra Zeneca; Merck Co., Inc.; Weight Watchers International, Inc.; Sanofi US; Eisai Inc.; Novo Nordisk; AstraZeneca; Boehringer Ingelheim GmbH; MannKind Corporation; Takeda Pharmaceutical Company Limited; Eli Lilly and Company; Janssen Pharmaceuticals, Inc.; Bristol - Myers Squibb Company; GlaxoSmithKline; Amgen Inc.; Gilead; Intarcia Therapeutics, Inc.; Lexicon Pharmaceuticals, Inc.; Charles E. Schmidt College of Medicine at Florida Atlantic University (FAU); Bayer AG; British Heart Foundation; Cadila Pharmaceuticals Limited; Canadian Institutes of Health; Wellcome Trust; U.S. Food and Drug Administration; National Institutes of Health; UpToDate, Inc.; Stryker Corporation; Novartis AG FX Dr. W. Timothy Garvey reports that he has received research support from Astra Zeneca, Merck & Co., Inc., Weight Watchers International, Inc., Sanofi US, and Eisai Inc.; he has received Advisory Board honoraria from Eisai Inc., Alkermes, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company/AstraZeneca, Daiichi-Sankyo, Janssen Pharmaceuticals, Inc., LipoScience, Inc., Novo Nordisk, Takeda Pharmaceutical Company Limited, and Vivus, Inc.; Dr. Samuel Dagogo-Jack reports that he has received consultant honoraria from Merck & Co., Inc., Santarus, Inc., and Janssen Pharmaceuticals, Inc.; he has also received consultant honoraria and research grant support for his role as Principal Investigator for Novo Nordisk; and he has received research grant support for his role as Principal Investigator from AstraZeneca and Boehringer Ingelheim GmbH.; Dr. Daniel Einhorn reports that he has received consultant honoraria from Halozyme Therapeutics, Novo Nordisk, Bristol-Myers Squibb Company/AstraZeneca, GlySens Incorporated, and Freedom Meditech, Inc.; he has also received research grant support from AstraZeneca, MannKind Corporation, Sanofi US, and Takeda Pharmaceutical Company Limited; he has received consultant honoraria and research grant support from Eli Lilly and Company; and has received speaker/consultant honoraria and research grant support from Janssen Pharmaceuticals, Inc.; Dr. George Grunberger reported that he has received speaker honoraria and research support as an investigator from Eli Lilly and Company, Novo Nordisk and Bristol - Myers Squibb Company; he has received speaker honoraria from Sanofi-Aventis US LLC, Amarin Corporation, Valeritas, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals USA, Inc., Santarus, Inc. and Merck & Co., Inc.; Dr. Yehuda Handelsman reports that he has received research grant support and consultant and speaker honoraria from Boehringer Ingelheim GmbH, GlaxoSmithKline, and Novo Nordisk; he has received consultant and speaker honoraria from Amarin Corp., Amylin Pharmaceuticals, Janssen Pharmaceuticals, Inc., and Vivus, Inc.; he has received research grant support and consultant honoraria from Amgen Inc., Gilead, Merck & Co., Inc., and Sanofi US; he has received consultant honoraria from Halozyme; and he has received research grant support from Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., and Takeda Pharmaceutical Company Limited.; Dr. Charles H. Hennekens reports that he has received research support from the Charles E. Schmidt College of Medicine at Florida Atlantic University (FAU); he has also received support for his role as an independent scientist and advisor from Amgen Inc., Bayer AG, the British Heart Foundation, Cadila Pharmaceuticals Limited., the Canadian Institutes of Health, Eli Lilly and Company, the Wellcome Trust, the U.S. Food and Drug Administration, the National Institutes of Health, and UpToDate, Inc.; and received support for his role as an independent scientist and advisor to legal counsel from GlaxoSmithKline and Stryker Corporation. Dr. Hennekens reports receiving royalties for authorship or editorship of three textbooks, royalties as co-inventor on patents concerning inflammatory markers and cardiovascular disease which are held by Brigham and Women's Hospital, and has an investment management relationship with The West-Bacon Group within SunTrust Investment Services which has discretionary investment authority.; Dr. Janet B. McGill reports that she has received research grant support for her role as Principal Investigator (paid to the University of Washington) from Novartis AG and Takeda Pharmaceutical Company Limited.; Dr. Guillermo E. Umpierrez reports that he has received research grant support and consultant and Advisory Board honoraria from Sanofi US, Merck & Co., Inc., Novo Nordisk, and Boehringer Ingelheim GmbH. NR 121 TC 12 Z9 14 U1 0 U2 3 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD SEP PY 2014 VL 20 IS 9 BP 956 EP 976 DI 10.4158/EP14279.CS PG 21 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CC0LN UT WOS:000350027300019 PM 25253226 ER PT J AU Garvey, WT Garber, AJ Mechanick, JI Bray, GA Dagogo-Jack, S Einhorn, D Grunberger, G Handelsman, Y Hennekens, CH Hurley, DL McGill, J Palumbo, P Umpierrez, G AF Garvey, W. Timothy Garber, Alan J. Mechanick, Jeffrey I. Bray, George A. Dagogo-Jack, Samuel Einhorn, Daniel Grunberger, George Handelsman, Yehuda Hennekens, Charles H. Hurley, Daniel L. McGill, Janet Palumbo, Pasquale Umpierrez, Guillermo CA AACE Obesity Sci Comm TI AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON THE 2014 ADVANCED FRAMEWORK FOR A NEW DIAGNOSIS OF OBESITY AS A CHRONIC DISEASE SO ENDOCRINE PRACTICE LA English DT Article ID WEIGHT C1 [Garvey, W. Timothy] Univ Alabama, Dept Nutr Sci, Tuscaloosa, AL 35487 USA. [Garvey, W. Timothy] UAB Diabet Res Ctr, Birmingham, AL USA. [Garvey, W. Timothy] Birmingham VA Med Ctr, Birmingham, AL USA. [Garber, Alan J.] Baylor Coll Med, Houston, TX 77030 USA. [Mechanick, Jeffrey I.] Icahn Sch Med Mt Sinai, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. [Bray, George A.] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Dagogo-Jack, Samuel] Univ Tennessee, Memphis, TN USA. [Einhorn, Daniel] Univ Calif San Diego, Scripps Whittier Diabet Inst, Diabet & Endocrine Associates, La Jolla, CA 92093 USA. [Grunberger, George] Wayne State Univ, Sch Med, Grunberger Diabet Inst, Bloomfield Hills, MI USA. [Handelsman, Yehuda] Metab Inst Amer, Tarzana, CA USA. [Hennekens, Charles H.] Florida Atlantic Univ, Boca Raton, FL 33431 USA. [Hurley, Daniel L.] Mayo Clin, Sch Med, Rochester, MN USA. [McGill, Janet] Washington Univ, Div Endocrinol Metab & Lipid Res, St Louis, MO USA. [Palumbo, Pasquale] Mayo Clin, Scottsdale, AZ USA. [Umpierrez, Guillermo] Emory Univ, Dept Med Endocrinol, Atlanta, GA 30322 USA. RP Garvey, WT (reprint author), Amer Assoc Clin Endocrinologists, 245 Riverside Ave,Suite 200, Jacksonville, FL 32202 USA. EM publications@aace.com FU Astra Zeneca; Merck Co., Inc.; Weight Watchers International, Inc.; Sanofi US; Eisai Inc.; Novo Nordisk; AstraZeneca; Boehringer Ingelheim GmbH; MannKind Corporation; Takeda Pharmaceutical Company Limited; Eli Lilly and Company; Janssen Pharmaceuticals, Inc.; Bristol - Myers Squibb Company; GlaxoSmithKline; Amgen Inc.; Gilead; Intarcia Therapeutics, Inc.; Lexicon Pharmaceuticals, Inc.; Charles E. Schmidt College of Medicine at Florida Atlantic University (FAU); Bayer AG; British Heart Foundation; Cadila Pharmaceuticals Limited.; Canadian Institutes of Health; Wellcome Trust; U.S. Food and Drug Administration; National Institutes of Health; UpToDate, Inc.; Stryker Corporation; Novartis AG FX Dr. W. Timothy Garvey reports that he has received research support from Astra Zeneca, Merck & Co., Inc., Weight Watchers International, Inc., Sanofi US, and Eisai Inc.; he has received Advisory Board honoraria from Eisai Inc., Alkermes, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company/AstraZeneca, Daiichi-Sankyo, Janssen Pharmaceuticals, Inc., LipoScience, Inc., Novo Nordisk, Takeda Pharmaceutical Company Limited, and Vivus, Inc.; Dr. Samuel Dagogo-Jack reports that he has received consultant honoraria from Merck & Co., Inc., Santarus, Inc., and Janssen Pharmaceuticals, Inc.; he has also received consultant honoraria and research grant support for his role as Principal Investigator for Novo Nordisk; and he has received research grant support for his role as Principal Investigator from AstraZeneca and Boehringer Ingelheim GmbH.; Dr. Daniel Einhorn reports that he has received consultant honoraria from Halozyme Therapeutics, Novo Nordisk, Bristol-Myers Squibb Company/AstraZeneca, GlySens Incorporated, and Freedom Meditech, Inc.; he has also received research grant support from AstraZeneca, MannKind Corporation, Sanofi US, and Takeda Pharmaceutical Company Limited; he has received consultant honoraria and research grant support from Eli Lilly and Company; and has received speaker/consultant honoraria and research grant support from Janssen Pharmaceuticals, Inc.; Dr. George Grunberger reported that he has received speaker honoraria and research support as an investigator from Eli Lilly and Company, Novo Nordisk and Bristol - Myers Squibb Company; he has received speaker honoraria from Sanofi-Aventis US LLC, Amarin Corporation, Valeritas, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals USA, Inc., Santarus, Inc. and Merck & Co., Inc.; Dr. Yehuda Handelsman reports that he has received research grant support and consultant and speaker honoraria from Boehringer Ingelheim GmbH, GlaxoSmithKline, and Novo Nordisk; he has received consultant and speaker honoraria from Amarin Corp., Amylin Pharmaceuticals, Janssen Pharmaceuticals, Inc., and Vivus, Inc.; he has received research grant support and consultant honoraria from Amgen Inc., Gilead, Merck & Co., Inc., and Sanofi US; he has received consultant honoraria from Halozyme; and he has received research grant support from Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., and Takeda Pharmaceutical Company Limited.; Dr. Charles H. Hennekens reports that he has received research support from the Charles E. Schmidt College of Medicine at Florida Atlantic University (FAU); he has also received support for his role as an independent scientist and advisor from Amgen Inc., Bayer AG, the British Heart Foundation, Cadila Pharmaceuticals Limited., the Canadian Institutes of Health, Eli Lilly and Company, the Wellcome Trust, the U.S. Food and Drug Administration, the National Institutes of Health, and UpToDate, Inc.; and received support for his role as an independent scientist and advisor to legal counsel from GlaxoSmithKline and Stryker Corporation. Dr. Hennekens reports receiving royalties for authorship or editorship of three textbooks, royalties as co-inventor on patents concerning inflammatory markers and cardiovascular disease which are held by Brigham and Women's Hospital, and has an investment management relationship with The West-Bacon Group within SunTrust Investment Services which has discretionary investment authority.; Dr. Janet B. McGill reports that she has received research grant support for her role as Principal Investigator (paid to the University of Washington) from Novartis AG and Takeda Pharmaceutical Company Limited.; Dr. Guillermo E. Umpierrez reports that he has received research grant support and consultant and Advisory Board honoraria from Sanofi US, Merck & Co., Inc., Novo Nordisk, and Boehringer Ingelheim GmbH. NR 10 TC 34 Z9 46 U1 0 U2 3 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD SEP PY 2014 VL 20 IS 9 BP 977 EP 989 DI 10.4158/EP14280.PS PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CC0LN UT WOS:000350027300020 PM 25253227 ER PT J AU Le, K Milanesi, A Weinreb, JE AF Le, Karen Milanesi, Anna Weinreb, Jane E. TI HOW LONG SHOULD WE CONTINUE PREDNISONE AFTER ABIRATERONE DISCONTINUATION? SO ENDOCRINE PRACTICE LA English DT Letter ID RESISTANT PROSTATE-CANCER; ACETATE C1 [Le, Karen; Milanesi, Anna; Weinreb, Jane E.] VA Greater Los Angeles Healthcare Syst, Div Endocrinol Diabet & Metab, Los Angeles, CA 90073 USA. [Le, Karen] Cedars Sinai Med Ctr, Los Angeles, CA USA. [Milanesi, Anna; Weinreb, Jane E.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Le, K (reprint author), VA Greater Los Angeles Healthcare Syst, Div Endocrinol Diabet & Metab, Los Angeles, CA 90073 USA. EM Jane.Weinreb@va.gov FU NIDDK NIH HHS [K08 DK097295] NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD SEP PY 2014 VL 20 IS 9 BP 992 EP 993 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CC0LN UT WOS:000350027300022 PM 25253228 ER PT J AU Fisher, DF Chenelle, CT Marchese, AD Kratohvil, JP Kacmarek, RM AF Fisher, Daniel F. Chenelle, Christopher T. Marchese, Andrew D. Kratohvil, Joseph P. Kacmarek, Robert M. TI Comparison of Commercial and Noncommercial Endotracheal Tube-Securing Devices SO RESPIRATORY CARE LA English DT Article DE airway holder; endotracheal tube; secure airway; tracheal intubation; mechanical ventilation ID INTENSIVE-CARE-UNIT; UNPLANNED EXTUBATION; TAPE AB BACKGROUND: Tracheal intubation is used to establish a secure airway in patients who require mechanical ventilation. Unexpected extubation can have serious complications, including airway trauma and death. Various methods and devices have been developed to maintain endotracheal tube (ETT) security. Associated complications include pressure ulcers due to decreased tissue perfusion. Device consideration includes ease of use, rapid application, and low exerted pressure around the airway. METHODS: Sixteen ETT holders were evaluated under a series of simulated clinical conditions. ETT security was tested by measuring distance displaced after a tug. Nine of the 16 methods could be evaluated for speed of moving the ETT to the opposite side of the mouth. Sensors located on a mannequin measured applied forces when the head was rotated vertically or horizontally. Data were analyzed using multivariate analysis of variance, with P < .05. RESULTS: Median displacement of the ETT by the tug test was 0 cm (interquartile range of 0.0-0.10 cm, P < .001). The mean time to move the ETT from one side of the mouth to the other ranged from 1.25 +/- 0.2 s to 34.4 +/- 3.4 s (P <.001). Forces applied to the face with a vertical head lift ranged from < 0.2 newtons (N) to a maximum of 3.52 N (P < .001). Forces applied to the face with a horizontal rotation ranged from < 0.2 N to 3.52 N (P < .001). Commercial devices produced greater force than noncommercial devices. CONCLUSIONS: Noncommercial airway holders exert less force on a patient's face than commercial devices. Airway stability is affected by the type of securing method. Many commercial holders allow for rapid but secure movement of the artificial airway from one side of the mouth to the other. C1 [Fisher, Daniel F.; Chenelle, Christopher T.; Marchese, Andrew D.; Kratohvil, Joseph P.] Massachusetts Gen Hosp, Resp Care Serv, Boston, MA 02114 USA. [Marchese, Andrew D.] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Anesthesiol Crit Care & Pain Med, Boston, MA 02114 USA. [Kacmarek, Robert M.] Harvard Univ, Sch Med, Boston, MA USA. RP Fisher, DF (reprint author), Massachusetts Gen Hosp, Blake 652,55 Fruit St, Boston, MA 02114 USA. EM dfisher2@partners.org OI Chenelle, Christopher/0000-0002-1499-9973 FU Hollister; Covidien; Hamilton Medical; GE Healthcare; Newport; Drager FX This work was funded by a gift from Hollister. Dr Kacmarek received research grants from Covidien, Hamilton Medical, GE Healthcare, Newport, and Drager and an honorarium for lecturing from Covidien and Maquet and is a consultant for Newport. The other authors have disclosed no conflicts of interest. NR 15 TC 7 Z9 7 U1 0 U2 2 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD SEP PY 2014 VL 59 IS 9 BP 1315 EP 1323 DI 10.4187/respcare.02951 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CA8VX UT WOS:000349200100002 PM 24368866 ER PT J AU Mietto, C Foley, K Salerno, L Oleksak, J Pinciroli, R Goverman, J Berra, L AF Mietto, Cristina Foley, Kevin Salerno, Lindsay Oleksak, Jenna Pinciroli, Riccardo Goverman, Jeremy Berra, Lorenzo TI Removal of Endotracheal Tube Obstruction With a Secretion Clearance Device SO RESPIRATORY CARE LA English DT Article DE respiration; artificial; positive-pressure ventilation; respiratory failure; airway obstruction; airway resistance; pneumonia; ventilator-associated; biofilms ID MECHANICAL VENTILATION; MUCUS SHAVER; DIAMETER; BIOFILM AB Accumulation of secretions may suddenly occlude an endotracheal tube (ETT), requiring immediate medical attention. The endOclear catheter (Endoclear LLC, Petoskey, Michigan) is a novel device designed to clear mucus and debris from an ETT and restore luminal patency. We present 3 subsequent cases of life-threatening partial ETT occlusions recorded over a period of 6 months at Massachusetts General Hospital. After conventional methods (standard tracheal suctioning and bronchoscopy) failed, the endOclear was used, with successful restoration of the airways in all 3 cases. The respiratory conditions rapidly improved, and all 3 patients tolerated the ETT-cleaning maneuver. These results show that such a device is safe and easy to use during an emergency airway situation for efficient and rapid removal of secretions from obstructed ETTs by respiratory therapists. C1 [Mietto, Cristina; Pinciroli, Riccardo; Berra, Lorenzo] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Foley, Kevin; Salerno, Lindsay; Oleksak, Jenna] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Goverman, Jeremy] Massachusetts Gen Hosp, Dept Surg, Burn Serv, Boston, MA 02114 USA. RP Berra, L (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, White 434-B,55 Fruit St, Boston, MA 02114 USA. EM lberra@partners.org FU Department of Anesthesia, Critical Care and Pain Medicine; Department of Respiratory Care, Massachusetts General Hospital, Boston, Massachusetts FX This work was supported by the Department of Anesthesia, Critical Care and Pain Medicine and the Department of Respiratory Care, Massachusetts General Hospital, Boston, Massachusetts. Endoclear LLC provided equipment to Massachusetts General Hospital for 6 months for clinical trial (free of cost) from April to September 2013. The authors have disclosed no conflicts of interest. NR 16 TC 7 Z9 7 U1 0 U2 3 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD SEP PY 2014 VL 59 IS 9 BP E122 EP E126 DI 10.4187/respcare.02995 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CA8VX UT WOS:000349200100023 PM 24368863 ER PT J AU McEllistrem, MC McGraw, M Sahud, AG Chan-Tompkins, NH Goswami, R Bhanot, N AF McEllistrem, M. Catherine McGraw, Molly Sahud, Andrew G. Chan-Tompkins, Noreen H. Goswami, Raktima Bhanot, Nitin TI High Frequency of Nonadherence to Clostridium difficile Treatment Guidelines SO SOUTHERN MEDICAL JOURNAL LA English DT Article DE Clostridium difficile infections; computerized clinical decision support; Infectious Diseases Society of America; Society for Healthcare Epidemiology of America ID DIARRHEA; DISEASE; METRONIDAZOLE; VANCOMYCIN; INFECTION; EMERGENCE; EPIDEMIC; AMERICA; STRAIN AB Objectives The 2010 Infectious Diseases Society of America/Society for Healthcare Epidemiology of America treatment guidelines for Clostridium difficile infections (CDI) recommend oral metronidazole for mild-to-moderate disease and oral vancomycin for severe disease. Given that disease severity is easily determined by the peripheral white blood cell count and serum creatinine level, a computerized decision support (CDS) pathway to guide treatment is inherently appealing. Because providers often override or ignore the computer-based alerts, the proposed CDS pathway should be justified before implementation. Methods We undertook this study to ascertain the frequency of nonadherence to CDI guidelines. Between October 1, 2007 and September 30, 2008, a total of 229 cases were screened and 78 cases were included in the study, which took place at a 661-bed acute tertiary care teaching hospital. Results During the year-long study of CDI cases at our tertiary care hospital, 61.5% (48/78) of the patients received an antibiotic regimen that was not recommended by the 2010 guidelines. Among the 35 patients with mild-to-moderate CDI, 85.7% (30/35) received the recommended treatment of oral metronidazole monotherapy; in contrast, among the 43 patients with severe disease, none (0/43) received the recommended treatment of oral vancomycin monotherapy (P < 0.01). Moreover, 17.9% (14/78) of patients received concurrent oral metronidazole and vancomycin, a regimen that is not recommended anywhere in the Infectious Diseases Society of America/Society for Healthcare Epidemiology of America guidelines and which may be associated with a poor outcome. Patients who received combination oral metronidazole and vancomycin were not more likely to have comorbidities or severe CDI compared with those who received a single antibiotic agent. Conclusions As a result of this study, we plan to educate our providers on the treatment of CDI through a CDS pathway in an effort to increase guideline adherence, decrease inappropriate antibiotic use, and potentially improve patient outcomes. C1 [McEllistrem, M. Catherine] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. RP McEllistrem, MC (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Univ Dr C,Mail Stop 130-U, Pittsburgh, PA 15240 USA. EM mary.mcellistrem@va.gov NR 11 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0038-4348 EI 1541-8243 J9 SOUTH MED J JI South.Med.J. PD SEP PY 2014 VL 107 IS 9 BP 597 EP 599 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CA6VK UT WOS:000349053700013 PM 25188627 ER PT J AU Solomon, JL Bokhour, BG Butler, J Golden, JF Hare, K Kertz, B Kan, V Rodriguez-Barradas, M Knapp, H Anaya, HD AF Solomon, Jeffrey L. Bokhour, Barbara G. Butler, Jaimi Golden, Joya F. Hare, Katherine Kertz, Barbara Kan, Virginia Rodriguez-Barradas, Maria Knapp, Herschel Anaya, Henry D. TI Sustaining Nurse-Rapid HIV Testing in the US Department of Veterans Affairs: Lessons Learned from a Comparative Evaluation SO JOURNAL FOR HEALTHCARE QUALITY LA English DT Article DE HIV testing; nurses; primary care; qualitative methods; US Department of Veterans Affairs AB Routine HIV testing in primary care is now recommended in the United States. The U.S. Department of Veterans Affairs (VA) has increased the number of patients tested for HIV, but overall HIV testing rates remain low. A promising intervention for increasing HIV testing is nurse-initiated rapid testing (NRT). The purpose of this study was to build upon our previous research by implementing NRT in primary care clinics at two geographically distinct VA medical centers, and then conduct an evaluation to identify the barriers and facilitators to implementing and sustaining it. Semistructured telephone interviews were conducted with providers and stakeholders at two VA medical centers, one each on the East Coast and in the Southwest. Fieldnotes were developed following each interview and qualitatively coded for emerging themes. Findings indicate NRT was well integrated in both settings. NRT took little time to conduct, was well received by patients, and did not disrupt clinical scheduling. However, there were some sustainability challenges, including difficulties using the electronic medical record, and the challenges of new care practice structures. Implementing NRT is feasible in VA primary care settings. However, organizational challenges should be taken into account for subsequent efforts to implement NRT in VA primary care settings. C1 [Bokhour, Barbara G.] Boston Univ, Sch Publ Health, Ctr Healthcare Organizat & Implementat Res, Boston, MA 02215 USA. [Butler, Jaimi] US Dept Affairs, Washington, DC USA. [Golden, Joya F.] Greater Angeles VA Healthcare Syst, MIRECC, Los Angeles, CA USA. [Hare, Katherine; Kertz, Barbara] VA Med Ctr, Washington, DC USA. [Kan, Virginia] George Washington Univ, Sch Med, Washington, DC 20052 USA. [Knapp, Herschel] US Dept Vet Affairs, Washington, DC USA. [Anaya, Henry D.] UCLA, US Dept Vet Affairs, David Geffen Sch Med, Los Angeles, CA USA. RP Solomon, JL (reprint author), Boston Univ, Sch Publ Health, Ctr Healthcare Organizat & Implementat Res, Boston, MA 02215 USA. EM Jeffrey.Solomon@va.gov NR 11 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1062-2551 EI 1945-1474 J9 J HEALTHC QUAL JI J. Healthc. Qual. PD SEP-OCT PY 2014 VL 36 IS 5 BP 26 EP 31 DI 10.1111/jhq.12015 PG 6 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AZ8CZ UT WOS:000348443700003 PM 23731235 ER PT J AU Cervone, D Pillai, NS Pati, D Berbeco, R Lewis, JH AF Cervone, Daniel Pillai, Natesh S. Pati, Debdeep Berbeco, Ross Lewis, John Henry TI A LOCATION-MIXTURE AUTOREGRESSIVE MODEL FOR ONLINE FORECASTING OF LUNG TUMOR MOTION SO ANNALS OF APPLIED STATISTICS LA English DT Article DE Lung tumor tracking; external beam radiotherapy; nonlinear time series; mixture autoregressive process; time series motifs; likelihood approximation; multiple-step prediction ID TIME-SERIES; RESPIRATORY MOTION; COMPARATIVE PERFORMANCE; PREDICTION; TRACKING; RADIOTHERAPY; LIKELIHOOD; REGRESSION; NETWORKS; STATE AB Lung tumor tracking for radiotherapy requires real-time, multiple-step ahead forecasting of a quasi-periodic time series recording instantaneous tumor locations. We introduce a location-mixture autoregressive (LMAR) process that admits multimodal conditional distributions, fast approximate inference using the EM algorithm and accurate multiple-step ahead predictive distributions. LMAR outperforms several commonly used methods in terms of out-of-sample prediction accuracy using clinical data from lung tumor patients. With its superior predictive performance and real-time computation, the LMAR model could be effectively implemented for use in current tumor tracking systems. C1 [Cervone, Daniel; Pillai, Natesh S.] Harvard Univ, Dept Stat, Cambridge, MA 02138 USA. [Pati, Debdeep] Florida State Univ, Dept Stat, Tallahassee, FL 32306 USA. [Berbeco, Ross; Lewis, John Henry] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Berbeco, Ross; Lewis, John Henry] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Cervone, D (reprint author), Harvard Univ, Dept Stat, 1 Oxford St, Cambridge, MA 02138 USA. EM dcervone@fas.harvard.edu; pillai@stat.harvard.edu; debdeep@stat.fsu.edu; rberbeco@lroc.harvard.edu; jhlewis@lroc.harvard.edu FU NSF [DMS-11-07070]; National Cancer Institute [R21CA156068]; Radiological Society of North America [RSCH1206] FX Supported in part by the NSF Grant DMS-11-07070. Supported in part by R21CA156068 from the National Cancer Institute. Supported in part by Award Numbers RSCH1206 from the Radiological Society of North America. NR 46 TC 0 Z9 0 U1 0 U2 1 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 SEP PY 2014 VL 8 IS 3 BP 1341 EP 1371 DI 10.1214/14-AOAS744 PG 31 WC Statistics & Probability SC Mathematics GA AY4DW UT WOS:000347529300003 ER PT J AU Calles, A Thorner, AR Sholl, LM Butaney, M Capelletti, M Mentzer, SJ van Hummelen, P Janne, PA AF Calles, A. Thorner, A. R. Sholl, L. M. Butaney, M. Capelletti, M. Mentzer, S. J. van Hummelen, P. Janne, P. A. TI GENOMIC CHANGES IN LUNG CANCER PATIENTS WITH MULTIPLE LUNG RELAPSES SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Calles, A.; Butaney, M.; Capelletti, M.; Janne, P. A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Thorner, A. R.; van Hummelen, P.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Sholl, L. M.; Mentzer, S. J.] Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA 1180PD PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000344 ER PT J AU De Nicolo, A Giobbie-Hurder, A Pathania, S Parisini, E Gelman, RS Ladias, JAA Joukov, V AF De Nicolo, A. Giobbie-Hurder, A. Pathania, S. Parisini, E. Gelman, R. S. Ladias, J. A. A. Joukov, V. TI FUNCTIONAL ANALYSIS OF THE BRCA1 H1686Q SEQUENCE VARIANT: FROM BIOLOGY TO CLINIC SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [De Nicolo, A.; Pathania, S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Giobbie-Hurder, A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Parisini, E.] Italian Inst Technol, Ctr Nano Sci & Technol, Milan, Italy. [Gelman, R. S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Ladias, J. A. A.] Harvard Univ, Sch Med, Mol Med Lab, Boston, MA USA. [Ladias, J. A. A.] Harvard Univ, Sch Med, Macromol Crystallog Unit, Boston, MA USA. [Joukov, V.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA 492PD PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000213 ER PT J AU Drake, CG Kibel, AS Adams, GW Karsh, LI Elfiky, A Shore, ND Vogelzang, NJ Corman, JM Tyler, RC Mccoy, C Devries, T Sheikh, N Antonarakis, ES AF Drake, C. G. Kibel, A. S. Adams, G. W. Karsh, L. I. Elfiky, A. Shore, N. D. Vogelzang, N. J. Corman, J. M. Tyler, R. C. Mccoy, C. Devries, T. Sheikh, N. Antonarakis, E. S. TI A RANDOMIZED PHASE 2 STUDY EVALUATING OPTIMAL SEQUENCING OF SIPULEUCEL-T (SIP-T) AND ANDROGEN DEPRIVATION THERAPY (ADT) IN BIOCHEMICALLY-RECURRENT PROSTATE CANCER (BRPC): VARIABLES THAT CORRELATE WITH IMMUNE RESPONSE SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Drake, C. G.] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Drake, C. G.] Brady Urol Inst, Baltimore, MD USA. [Kibel, A. S.] Harvard Univ, Brigham & Womens Hosp, Boston, MA 02115 USA. [Adams, G. W.] Urol Ctr Alabama, Homewood, AL USA. [Karsh, L. I.] Urol Ctr Colorado, Denver, CO USA. [Elfiky, A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Shore, N. D.] Carolina Urol Res Ctr, Myrtle Beach, SC USA. [Vogelzang, N. J.] Comprehens Canc Ctr Nevada, US Oncol Res, Las Vegas, NV USA. [Corman, J. M.] Virginia Mason Med Ctr, Seattle, WA 98101 USA. [Tyler, R. C.; Mccoy, C.; Devries, T.] Dendreon Corp, Med Affairs, Seattle, WA USA. [Sheikh, N.] Dendreon Corp, Res & Dev, Seattle, WA USA. [Antonarakis, E. S.] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA 775P DI 10.1093/annonc/mdu336.23 PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000247 PM 28170521 ER PT J AU Gettinger, S Bazhenova, L Salgia, R Langer, C Gold, K Rosell, R Shaw, A Weiss, GJ Narasimhan, NI Dorer, DJ Rivera, VM Clackson, T Haluska, FG Camidge, R AF Gettinger, S. Bazhenova, L. Salgia, R. Langer, C. Gold, K. Rosell, R. Shaw, A. Weiss, G. J. Narasimhan, N. I. Dorer, D. J. Rivera, V. M. Clackson, T. Haluska, F. G. Camidge, R. TI ALK INHIBITOR AP26113 IN PATIENTS WITH ADVANCED MALIGNANCIES, INCLUDING ALK plus NON-SMALL CELL LUNG CANCER (NSCLC): UPDATED EFFICACY AND SAFETY DATA SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Gettinger, S.] Yale Univ, Sch Med, Thorac Oncol Program, New Haven, CT USA. [Bazhenova, L.] UCSD Moores Canc Ctr, La Jolla, CA USA. [Salgia, R.] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. [Langer, C.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Gold, K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Rosell, R.] USP Dexeus Univ Inst, Inst Oncol Dr Rosell, Med Oncol Serv, Barcelona, Spain. [Shaw, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Weiss, G. J.] Scottsdale Healthcare, Virginia G Piper Canc Ctr Clin Trials, Scottsdale, AZ USA. [Narasimhan, N. I.] ARIAD Pharmaceut Inc, DMPK, Cambridge, MA USA. [Dorer, D. J.] ARIAD Pharmaceut Inc, Biostat, Cambridge, MA USA. [Rivera, V. M.] ARIAD Pharmaceut, Preclin & Translat Res, Cambridge, MA USA. [Clackson, T.] ARIAD Pharmaceut Inc, Res & Dev, Cambridge, MA USA. [Haluska, F. G.] ARIAD Pharmaceut Inc, Clin Res & Dev, Cambridge, MA USA. [Camidge, R.] Univ Colorado, Div Med Oncol, Denver, CO 80202 USA. NR 0 TC 2 Z9 2 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA 1292P DI 10.1093/annonc/mdu349.71 PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000368 PM 28172024 ER PT J AU Hammers, H Plimack, ER Infante, JR Ernstoff, M Rini, BI McDermott, DF Razak, A Pal, SK Voss, M Sharma, P Kollmannsberger, CK Heng, D Shen, Y Kurland, J Spratlin, J Gagnier, P Amin, A AF Hammers, H. Plimack, E. R. Infante, J. R. Ernstoff, M. Rini, B. I. McDermott, D. F. Razak, A. Pal, S. K. Voss, M. Sharma, P. Kollmannsberger, C. K. Heng, D. Shen, Y. Kurland, J. Spratlin, J. Gagnier, P. Amin, A. TI PHASE I STUDY OF NIVOLUMAB IN COMBINATION WITH IPILIMUMAB IN METASTATIC RENAL CELL CARCINOMA (MRCC) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Hammers, H.] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Plimack, E. R.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Infante, J. R.] Tennessee Oncol Pllc, Sarah Cannon Res Inst, Nashville, TN USA. [Ernstoff, M.] Dartmouth Hitchcock Med Ctr, Geisel Sch Med, Lebanon, NH 03766 USA. [Rini, B. I.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [McDermott, D. F.] Beth Israel Deaconess Med Ctr, Dana Farber Harvard Canc Ctr, Boston, MA 02215 USA. [Razak, A.] Univ Toronto, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Pal, S. K.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Voss, M.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Sharma, P.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kollmannsberger, C. K.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Heng, D.] Univ Calgary, Tom Baker Canc Ctr, Calgary, AB, Canada. [Shen, Y.] Bristol Myers Squibb Co, Biostat, Princeton, NJ USA. [Kurland, J.; Gagnier, P.] Bristol Myers Squibb Co, Bio Res, Princeton, NJ USA. [Spratlin, J.] Univ Alberta, Cross Canc Inst, Edmonton, AB, Canada. [Amin, A.] Levine Canc Inst, Charlotte, NC USA. NR 0 TC 8 Z9 8 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA 1050O DI 10.1093/annonc/mdu342.3 PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000302 ER PT J AU Hutson, T Rathmell, WK Feng, B Robinson, MO Gyuris, J Lin, J Choueiri, T AF Hutson, T. Rathmell, W. K. Feng, B. Robinson, M. O. Gyuris, J. Lin, J. Choueiri, T. TI PHASE 2 CLINICAL EVALUATION OF PRECLINICALLY DEFINED BIOMARKERS FOR VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) TYROSINE KINASE INHIBITOR (TKI) TIVOZANIB IN RENAL CELL CARCINOMA (RCC) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Hutson, T.] Baylor Sammons Canc Ctr, GU Oncol Program, Dallas, TX USA. [Rathmell, W. K.] Univ N Carolina, Lineberger Comprehens Canc Ctr, North Carolina Canc Hosp, Chapel Hill, NC 27599 USA. [Feng, B.; Robinson, M. O.; Gyuris, J.; Lin, J.] AVEO Oncol, Clin Res, Cambridge, MA USA. [Choueiri, T.] Dana Farber Canc Inst, Div Solid Tumor Oncol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA 233P DI 10.1093/annonc/mdu326.66 PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000161 PM 28170687 ER PT J AU Isakoff, SJ Infante, JR Juric, D Chan, WY Jia, S Musib, L Zhu, J Meng, R Patel, PH Bendell, JC AF Isakoff, S. J. Infante, J. R. Juric, D. Chan, W. Y. Jia, S. Musib, L. Zhu, J. Meng, R. Patel, P. H. Bendell, J. C. TI PHASE IB DOSE-ESCALATION STUDY OF THE AKT INHIBITOR IPATASERTIB (IPAT) WITH PACLITAXEL (P) IN PATIENTS (PTS) WITH ADVANCED SOLID TUMORS SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Isakoff, S. J.; Juric, D.] Massachusetts Gen Hosp, Dept Hematol & Med Oncol, Boston, MA 02114 USA. [Infante, J. R.] Sarah Cannon Res Inst, Nashville, TN USA. [Chan, W. Y.; Jia, S.; Musib, L.; Zhu, J.; Meng, R.; Patel, P. H.] Genentech Inc, Exploratory Clin Dev, So San Francisco, CA USA. [Bendell, J. C.] Sarah Cannon Res Inst, Drug Dev Unit, Nashville, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA 446PD PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000204 ER PT J AU Letai, A Chonghaile, TN Hogdal, LJ Bhola, PD Montero, J Touzeau, C Ryan, J AF Letai, A. Chonghaile, T. N. Hogdal, L. J. Bhola, P. D. Montero, J. Touzeau, C. Ryan, J. TI TARGETING THE BCL-2 PATHWAY SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Letai, A.; Chonghaile, T. N.; Hogdal, L. J.; Bhola, P. D.; Montero, J.; Touzeau, C.; Ryan, J.] Dana Farber Canc Inst, Boston, MA 02115 USA. RI Ni Chonghaile, Triona/L-9418-2015 OI Ni Chonghaile, Triona/0000-0002-3041-4031 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA 51IN PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000220 ER PT J AU Motzer, RJ Rini, BI McDermott, DF Redman, B Kuzel, T Harrison, MR Vaishampayan, UN Drabkin, H George, S Logan, T Margolin, K Plimack, ER Waxman, I Lambert, A Hammers, H AF Motzer, R. J. Rini, B. I. McDermott, D. F. Redman, B. Kuzel, T. Harrison, M. R. Vaishampayan, U. N. Drabkin, H. George, S. Logan, T. Margolin, K. Plimack, E. R. Waxman, I. Lambert, A. Hammers, H. TI RANDOMIZED, DOSE-RANGING PHASE II TRIAL OF NIVOLUMAB FOR METASTATIC RENAL CELL CARCINOMA (MRCC) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Motzer, R. J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Rini, B. I.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [McDermott, D. F.] Beth Israel Deaconess Med Ctr, Dana Farber Harvard Canc Ctr, Boston, MA 02215 USA. [Redman, B.] Univ Michigan, Dept Oncol, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Kuzel, T.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Harrison, M. R.] Duke Univ, Med Ctr, Durham, NC USA. [Vaishampayan, U. N.] Wayne State Univ, Karmanos Canc Ctr, Detroit, MI USA. [Drabkin, H.] Med Univ S Carolina, Charleston, SC 29425 USA. [George, S.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Logan, T.] Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA. [Margolin, K.] Seattle Canc Care Alliance, Seattle, WA USA. [Plimack, E. R.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Waxman, I.] Bristol Myers Squibb Co, Oncol, Princeton, NJ USA. [Lambert, A.] Bristol Myers Squibb Co, Biostat, Braine Lalleud, Belgium. [Hammers, H.] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA 810O DI 10.1093/annonc/mdu337.3 PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000252 PM 28172310 ER PT J AU Perez, EA Holmes, E De Azambuja, E Dueck, A Baselga, J Viale, G Zujewski, JA Goldhirsch, A Crescenzo, R Pritchard, K Wolff, AC Jackisch, C Lang, I Untch, M Smith, I Boyle, F Xu, B Gomez, HL Gelber, RD Piccart, M AF Perez, E. A. Holmes, E. De Azambuja, E. Dueck, A. Baselga, J. Viale, G. Zujewski, J. A. Goldhirsch, A. Crescenzo, R. Pritchard, K. Wolff, A. C. Jackisch, C. Lang, I. Untch, M. Smith, I. Boyle, F. Xu, B. Gomez, H. L. Gelber, R. D. Piccart, M. TI DISEASE-FREE SURVIVAL (DFS) IN THE LAPATINIB ALONE ARM AND EXPANDED RESULTS OF THE PHASE III ALTTO TRIAL (BIG 2-06; NCCTG (ALLIANCE) N063D) IN THE ADJUVANT TREATMENT OF HER2-POSITIVE EARLY BREAST CANCER (EBC) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Perez, E. A.] Mayo Clin, Jacksonville, FL 32224 USA. [Holmes, E.] Frontier Sci Scotland Ltd, Stat, Kincraig, Scotland. [De Azambuja, E.] Inst Jules Bordet, B-1000 Brussels, Belgium. [Dueck, A.] Mayo Clin, Biostat Sect, Scottsdale, AZ USA. [Baselga, J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Viale, G.] Ist Europeo Oncol, Dept Pathol, Milan, Italy. [Zujewski, J. A.] NCI, Bethesda, MD 20892 USA. [Goldhirsch, A.] European Inst Oncol, Dept Med, Milan, Italy. [Crescenzo, R.] GlaxoSmithKline, Hematol Oncol, Collegeville, PA USA. [Pritchard, K.] Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Wolff, A. C.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [Jackisch, C.] Klinikum Offenbach GmbH, Oncol, Offenbach, Germany. [Lang, I.] Natl Inst Oncol, Dept Med Oncol, Budapest, Hungary. [Lang, I.] Natl Inst Oncol, Clin Pharmacol B, Budapest, Hungary. [Untch, M.] HELIOS Klinikum Berlin Buch, Frauenklin, Berlin, Germany. [Smith, I.] Royal Marsden Hosp NHS Trust, Sutton, Surrey, England. [Boyle, F.] Univ Sydney, Mater Hosp, Patricia Ritchie Ctr Canc Care & Res, Sydney, NSW, Australia. [Xu, B.] Chinese Acad Med Sci, Canc Hosp, Dept Med, Beijing 100730, Peoples R China. [Gomez, H. L.] Inst Nacl Enfermedades Neoplas, Lima, Peru. [Gelber, R. D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Piccart, M.] Inst Jules Bordet, B-1000 Brussels, Belgium. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA LBA7 DI 10.1093/annonc/mdu438.2 PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000010 ER PT J AU Rabaglio-Poretti, M Giobbie-Hurder, A Thurlimann, B Regan, M Ejlertsen, B Debled, M Colleoni, M Goldhirsch, A Coates, A Gelber, RD AF Rabaglio-Poretti, M. Giobbie-Hurder, A. Thuerlimann, B. Regan, M. Ejlertsen, B. Debled, M. Colleoni, M. Goldhirsch, A. Coates, A. Gelber, R. D. TI PREDICTORS OF HYPERTENSION IN IBCSG 18-98/BIG 1-98: ADJUVANT THERAPY FOR POSTMENOPAUSAL WOMEN WITH HORMONE RECEPTOR-POSITIVE, EARLY BREAST CANCER SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Rabaglio-Poretti, M.] Univ Hosp Inselspital, Int Breast Canc Study Grp Coordinating Ctr, Bern, Switzerland. [Giobbie-Hurder, A.; Regan, M.; Gelber, R. D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Thuerlimann, B.] Kantonsspital St Gallen, Breast Ctr St Gallen, St Gallen, Switzerland. [Ejlertsen, B.] Copenhagen Univ Hosp, Rigshosp, Copenhagen, Denmark. [Debled, M.] Inst Bergonie, Bordeaux, France. [Colleoni, M.] EIO, Milan, Italy. [Goldhirsch, A.] European Inst Oncol, Dept Med, Milan, Italy. [Coates, A.] Int Breast Canc Study Grp, Sydney, NSW, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA 301P DI 10.1093/annonc/mdu327.47 PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000168 PM 28170691 ER PT J AU Robert, C Joshua, AM Weber, JS Ribas, A Hodi, FS Kefford, RF Daud, A Wolchok, JD Hwu, WJ Gangadhar, TC Patnaik, A Hersey, P Dronca, R Zarour, H Ge, Y Lindia, JA Giannotti, M Ebbinghaus, S Kang, SP Hamid, O AF Robert, C. Joshua, A. M. Weber, J. S. Ribas, A. Hodi, F. S. Kefford, R. F. Daud, A. Wolchok, J. D. Hwu, W-J. Gangadhar, T. C. Patnaik, A. Hersey, P. Dronca, R. Zarour, H. Ge, Y. Lindia, J. A. Giannotti, M. Ebbinghaus, S. Kang, S. P. Hamid, O. TI PEMBROLIZUMAB (PEMBRO; MK-3475) FOR ADVANCED MELANOMA (MEL): RANDOMIZED COMPARISON OF TWO DOSING SCHEDULES SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Robert, C.] Inst Gustave Roussy, Villejuif, France. [Robert, C.] INSERM, U981, Villejuif, France. [Joshua, A. M.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Weber, J. S.] Univ S Florida, H Lee Moffitt Canc Ctr, Comprehens Melanoma Res Ctr, Tampa, FL 33682 USA. [Ribas, A.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Hodi, F. S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kefford, R. F.] Westmead Hosp, Crown Princess Mary Canc Ctr, Sydney, NSW, Australia. [Kefford, R. F.] Melanoma Inst Australia, Sydney, NSW, Australia. [Kefford, R. F.] Univ Sydney, Sydney, NSW 2006, Australia. [Daud, A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Wolchok, J. D.] Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY 10021 USA. [Hwu, W-J.] Univ Texas MD Anderson Canc Ctr, Melanoma Med Oncol, Houston, TX 77030 USA. [Gangadhar, T. C.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Patnaik, A.] South Texas Accelerated Res Therapeut, Phase 1, San Antonio, TX USA. [Hersey, P.] Univ Sydney, Sydney, NSW 2006, Australia. [Dronca, R.] Mayo Clin, Rochester, NJ USA. [Zarour, H.] Univ Pittsburgh, Pittsburgh, PA USA. [Ge, Y.] Merck & Co Inc, BARDS, Whitehouse Stn, NJ USA. [Lindia, J. A.; Giannotti, M.; Ebbinghaus, S.; Kang, S. P.] Merck & Co Inc, Clin Oncol, Whitehouse Stn, NJ USA. [Hamid, O.] Angeles Clin & Res Inst, Los Angeles, CA USA. NR 0 TC 2 Z9 2 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA LBA34 DI 10.1093/annonc/mdu438.42 PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000007 ER PT J AU Ryan, CJ Smith, MR Fizazi, K Miller, K Mulders, P Sternberg, CN Saad, F Griffin, T De Porre, P Park, YC Li, J Kheoh, T Naini, V Molina, A Rathkopf, DE AF Ryan, C. J. Smith, M. R. Fizazi, K. Miller, K. Mulders, P. Sternberg, C. N. Saad, F. Griffin, T. De Porre, P. Park, Y. C. Li, J. Kheoh, T. Naini, V. Molina, A. Rathkopf, D. E. TI FINAL OVERALL SURVIVAL (OS) ANALYSIS OF COU-AA-302, A RANDOMIZED PHASE 3 STUDY OF ABIRATERONE ACETATE (AA) IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (MCRPC) PATIENTS (PTS) WITHOUT PRIOR CHEMOTHERAPY SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Ryan, C. J.] Univ Calif San Francisco, Dept Med, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Smith, M. R.] Harvard Univ, Sch Med, Boston, MA USA. [Smith, M. R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Fizazi, K.] Univ Paris Sud, Dept Canc Med, Inst Gustave Roussy, Villejuif, France. [Miller, K.] Charite, Dept Urol, Berlin, Germany. [Mulders, P.] Radboud Univ Nijmegen Med Ctr, Dept Urol, Nijmegen, Netherlands. [Sternberg, C. N.] San Camillo & Forlanini Hosp, Dept Med Oncol, Rome, Italy. [Saad, F.] Univ Montreal, Montreal, PQ, Canada. [Griffin, T.; Naini, V.] Janssen Res & Dev, WC Clin Oncol, Los Angeles, CA USA. [De Porre, P.] Janssen Res & Dev, Oncol Dev, Beerse, Belgium. [Park, Y. C.] Janssen Res & Dev, Biostat, Raritan, NJ USA. [Li, J.] Janssen Res & Dev, PAP, Raritan, NJ USA. [Kheoh, T.] Janssen Res & Dev, Biostat, Los Angeles, CA USA. [Molina, A.] Janssen Res & Dev, Oncol TA Admin PA, Menlo Pk, CA USA. [Rathkopf, D. E.] Mem Sloan Kettering Canc Ctr, Genitourinary Oncol Serv, New York, NY 10021 USA. [Rathkopf, D. E.] Weill Cornell Med Coll, New York, NY USA. RI Mulders, Peter/H-8076-2014 NR 0 TC 5 Z9 5 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA 753O DI 10.1093/annonc/mdu336.1 PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000242 PM 28170514 ER PT J AU Sweeney, C Chen, Y Carducci, M Liu, G Jarrard, D Eisenberger, M Wong, Y Hahn, NM Kohli, M Vogelzang, N Cooney, M Dreicer, R Picus, J Shevrin, D Hussain, M Garcia, J Dipaola, R AF Sweeney, C. Chen, Y. Carducci, M. Liu, G. Jarrard, D. Eisenberger, M. Wong, Y. Hahn, N. M. Kohli, M. Vogelzang, N. Cooney, M. Dreicer, R. Picus, J. Shevrin, D. Hussain, M. Garcia, J. Dipaola, R. TI CHEMOHORMONAL THERAPY VERSUS HORMONAL THERAPY FOR HORMONE NAIVE HIGH VOLUME NEWLY METASTATIC PROSTATE CANCER (PRCA): ECOG LED PHASE III RANDOMIZED TRIAL SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Sweeney, C.] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. [Chen, Y.] Eastern Cooperat Oncol Grp, Boston, MA USA. [Carducci, M.] Kimmel Canc Ctr, Baltimore, MD USA. [Liu, G.; Jarrard, D.] Univ Wisconsin Carbone Canc Ctr, Madison, WI USA. [Eisenberger, M.] Johns Hopkins Med Ctr, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Wong, Y.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Hahn, N. M.] Indiana Univ, Dept Med, Melvin & Bren Simon Canc Ctr, Div Hematol Oncol, Indianapolis, IN USA. [Kohli, M.] Mayo Clin, Rochester, MN USA. [Vogelzang, N.] Comprehens Canc Ctr Nevada, Las Vegas, NV USA. [Cooney, M.] Case Comprehens Canc Ctr, Cleveland, OH USA. [Dreicer, R.; Garcia, J.] Cleveland Clin, Cleveland, OH 44106 USA. [Picus, J.] Alvin J Siteman Canc Ctr, St Louis, MO USA. [Shevrin, D.] NorthShore Univ HealthSyst, Med Oncol, Evanston, IL USA. [Hussain, M.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Dipaola, R.] Rutgers Biomed & Hlth Sci, Med Oncol, New Brunswick, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA 756O DI 10.1093/annonc/mdu336.4 PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000243 PM 28171968 ER PT J AU Templeton, A Knox, J Mitchell, N Broom, R Choueiri, TK McDermott, DF Fay, A Rini, BI Alvarez, A Bjarnason, GA Smoragiewicz, M Kollmannsberger, CK Kanesvaran, R North, S Alimohamed, N Hermanns, T Wells, C Amir, E Heng, D AF Templeton, A. Knox, J. Mitchell, N. Broom, R. Choueiri, T. K. McDermott, D. F. Fay, A. Rini, B. I. Alvarez, A. Bjarnason, G. A. Smoragiewicz, M. Kollmannsberger, C. K. Kanesvaran, R. North, S. Alimohamed, N. Hermanns, T. Wells, C. Amir, E. Heng, D. TI PROGNOSTIC IMPACT OF CHANGE IN NEUTROPHILTO LYMPHOCYTE RATIO (NLR) IN RESPONSE TO TARGETED THERAPY FOR METASTATIC RENAL CELL CARCINOMA (MRCC) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Templeton, A.; Knox, J.; Alimohamed, N.; Amir, E.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Mitchell, N.; Broom, R.] Auckland City Hosp, Auckland, New Zealand. [Choueiri, T. K.; Fay, A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [McDermott, D. F.] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Rini, B. I.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Alvarez, A.] Cleveland Clin, Cleveland, OH 44106 USA. [Bjarnason, G. A.] Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Smoragiewicz, M.; Kollmannsberger, C. K.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Kanesvaran, R.] Natl Canc Ctr, Singapore, Singapore. [North, S.] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Hermanns, T.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Wells, C.; Heng, D.] Tom Baker Canc Clin, Calgary, AB, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA 817P DI 10.1093/annonc/mdu337.10 PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000253 PM 28172100 ER PT J AU Tewari, KS Sill, MW Penson, RT Huang, H Ramondetta, LM Landrum, LM Oaknin, A Reid, TJ Leitao, MM Monk, BJ Michael, HE AF Tewari, K. S. Sill, M. W. Penson, R. T. Huang, H. Ramondetta, L. M. Landrum, L. M. Oaknin, A. Reid, T. J. Leitao, M. M. Monk, B. J. Michael, H. E. TI FINAL OVERALL SURVIVAL ANALYSIS OF THE PHASE III RANDOMIZED TRIAL OF CHEMOTHERAPY WITH AND WITHOUT BEVACIZUMAB FOR ADVANCED CERVICAL CANCER: A NRG ONCOLOGY - GYNECOLOGIC ONCOLOGY GROUP STUDY SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Tewari, K. S.] Univ Calif Irvine, Dept Obstet & Gynecol, Med Ctr, Orange, CA 92668 USA. [Sill, M. W.; Huang, H.] Roswell Pk Canc Inst, Stat & Data Ctr, Buffalo, NY 14263 USA. [Penson, R. T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ramondetta, L. M.] MD Anderson Hosp & Tumor Inst, Houston, TX USA. [Landrum, L. M.] Univ Oklahoma, Oklahoma City, OK USA. [Oaknin, A.] Vall dHebron Univ Hosp, Inst Oncol, Barcelona, Spain. [Reid, T. J.] Univ Cincinnati, Kettering, OH USA. [Leitao, M. M.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Monk, B. J.] Creighton Univ, Sch Med, St Josephs Hosp & Med Ctr, Div Gynecol Oncol, Phoenix, AZ USA. [Michael, H. E.] Indiana Univ, Indianapolis, IN 46204 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA LBA26 DI 10.1093/annonc/mdu438.27 PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000005 ER PT J AU Weber, JS Minor, DR D'Angelo, SP Hodi, FS Gutzmer, R Neyns, B Hoeller, C Khushalani, NI Miller, WH Grob, JJ Lao, C Linette, G Grossmann, K Hassel, JC Lorigan, P Maio, M Sznol, M Lambert, A Yang, A Larkin, J AF Weber, J. S. Minor, D. R. D'Angelo, S. P. Hodi, F. S. Gutzmer, R. Neyns, B. Hoeller, C. Khushalani, N. I. Miller, W. H. Grob, J-J. Lao, C. Linette, G. Grossmann, K. Hassel, J. C. Lorigan, P. Maio, M. Sznol, M. Lambert, A. Yang, A. Larkin, J. TI A PHASE 3 RANDOMIZED, OPEN-LABEL STUDY OF NIVOLUMAB (ANTI-PD-1; BMS-936558; ONO-4538) VERSUS INVESTIGATOR'S CHOICE CHEMOTHERAPY (ICC) IN PATIENTS WITH ADVANCED MELANOMA AFTER PRIOR ANTI-CTLA-4 THERAPY SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 39th ESMO Congress (ESMO) CY SEP 26-30, 2014 CL Madrid, SPAIN SP ESMO C1 [Weber, J. S.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Minor, D. R.] Calif Pacific Med Ctr, San Francisco, CA USA. [D'Angelo, S. P.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Hodi, F. S.] Dana Farber Canc Inst, Melanoma Ctr, Boston, MA 02115 USA. [Gutzmer, R.] Hannover Med Sch, Skin Canc Ctr, Hannover, Germany. [Neyns, B.] Vrije Univ Brussel, Brussels, Belgium. [Hoeller, C.] Med Univ Vienna, Vienna, Austria. [Khushalani, N. I.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Miller, W. H.] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada. [Miller, W. H.] McGill Univ, Jewish Gen Hosp, Segal Canc Ctr, Montreal, PQ H3T 1E2, Canada. [Grob, J-J.] Aix Marseille Univ, Hop Timone, Marseille, France. [Lao, C.] Univ Michigan, Ann Arbor, MI 48109 USA. [Linette, G.] Washington Univ, St Louis, MO USA. [Grossmann, K.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Hassel, J. C.] Univ Heidelberg Hosp, Heidelberg, Germany. [Hassel, J. C.] Natl Ctr Tumor Dis, Heidelberg, Germany. [Lorigan, P.] Christie NHS Fdn Trust, Manchester, Lancs, England. [Maio, M.] Univ Hosp Siena, Ist Toscano Tumori, Div Med Oncol & Immunotherapy, Siena, Italy. [Sznol, M.] Yale Canc Ctr, Sect Med Oncol, New Haven, CT USA. [Lambert, A.] Bristol Myers Squibb, Biostat, Braine Lalleud, Belgium. [Yang, A.] Bristol Myers Squibb Co, Immunooncol, Princeton, NJ USA. [Larkin, J.] Royal Marsden Hosp, Dept Med, London SW3 6JJ, England. RI Lorigan, Paul/J-6898-2015 OI Lorigan, Paul/0000-0002-8875-2164 NR 0 TC 6 Z9 6 U1 2 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2014 VL 25 SU 4 MA LBA3_PR DI 10.1093/annonc/mdu438.34 PG 1 WC Oncology SC Oncology GA AX4KG UT WOS:000346901000006 ER PT J AU Bourdeaut, F Chi, SN Fruhwald, MC AF Bourdeaut, Franck Chi, Susan N. Fruehwald, Michael C. TI Rhabdoid tumors: integrating biological insights with clinical success A report from the SMARCB1 and Rhabdoid Tumor Symposium, Paris, December 12-14, 2013 SO CANCER GENETICS LA English DT Review DE Rhabdoid; ATRT; SMARCB1; INI1; SWI/SNF ID MUTATIONS AB Malignant rhabdoid tumors (MRTs) of the central nervous system (atypical teratoid, rhabdoid tumor (AT/RT)), kidney (rhabdoid tumor of the kidney (RTK)), and soft tissues all share an aggressive clinical behavior and dismal prognosis. The burden of the intensive treatment required to cure patients is a matter of great concern given the young median age at diagnosis, regardless of tumor location. Thus, a greater understanding of the oncogenic properties of SMARCB1 and the SWI/SNF complex, as well as the clinical aspects of malignant rhabdoid tumors is necessary. Towards this aim, the first international SMARCB1 and rhabdoid tumor symposium was held in Paris, France in December 2013, organized by the collaborative efforts of the Dana-Farber Cancer Institute (Susan Chi), Swabian Children's Cancer Center/EU-RHAB Center (Michael Fruhwald) and Curie Institute (Franck Bourdeaut). This workshop of physicians and other scientists fostered the integration of biologic insights towards clinical application in rhabdoid tumors, and other SWI/SNF-related cancers. The following report is a synopsis of the highlights of this meeting. C1 [Bourdeaut, Franck] Inst Curie, Dept Pediat Adolescents & Young Adults Oncol, Paris, France. [Chi, Susan N.] Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA USA. [Fruehwald, Michael C.] Childrens Hosp Augsburg, Swabian Childrens Canc Ctr, Augsburg, Germany. [Fruehwald, Michael C.] EU RHAB Ctr, Augsburg, Germany. RP Bourdeaut, F (reprint author), Inst Curie, Dept Pediat Adolescents & Young Adults Oncol, Site Integrated Res Canc, Paris, France. EM Franck.bourdeaut@curie.fr NR 31 TC 3 Z9 3 U1 3 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2210-7762 EI 2210-7770 J9 CANCER GENET-NY JI Cancer Genet. PD SEP PY 2014 VL 207 IS 9 SI SI BP 346 EP 351 DI 10.1016/j.cancergen.2014.10.004 PG 6 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA AX3DB UT WOS:000346819600002 PM 25468731 ER PT J AU Kim, KH Roberts, CWM AF Kim, Kimberly H. Roberts, Charles W. M. TI Mechanisms by which SMARCB1 loss drives rhabdoid tumor growth SO CANCER GENETICS LA English DT Review DE Rhabdoid tumor; SMARCB1; chromatin-remodeling complex; SWI/SNF; SNF5 ID CHROMATIN-REMODELING COMPLEX; SUPPRESSOR SNF5 LEADS; CANCER CELL-LINES; SWI/SNF COMPLEXES; ONCOGENIC TRANSFORMATION; PATHWAY ALTERATIONS; FREQUENT MUTATIONS; OVARIAN CARCINOMAS; GENETIC LANDSCAPE; SOMATIC MUTATIONS AB SMARCB1 (INI1/SNF5/BAF47), a core subunit of the SWI/SNF (BAF) chromatin-remodeling complex, is inactivated in the large majority of rhabdoid tumors, and germline heterozygous SMARCB1 mutations form the basis for rhabdoid predisposition syndrome. Mouse models validated Smarcb1 as a bona fide tumor suppressor, as Smarcb1 inactivation in mice results in 100% of the animals rapidly developing cancer. SMARCB1 was the first subunit of the SWI/SNF complex found mutated in cancer. More recently, at least seven other genes encoding SWI/SNF sub-units have been identified as recurrently mutated in cancer. Collectively, 20% of all human cancers contain a SWI/SNF mutation. Consequently, investigation of the mechanisms by which SMARCB1 mutation causes cancer has relevance not only for rhabdoid tumors, but also potentially for the wide variety of SWI/SNF mutant cancers. Here we discuss normal functions of SMARCB1 and the SWI/SNF complex as well as mechanistic and potentially therapeutic insights that have emerged. C1 [Kim, Kimberly H.; Roberts, Charles W. M.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Kim, Kimberly H.; Roberts, Charles W. M.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Kim, Kimberly H.; Roberts, Charles W. M.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Kim, Kimberly H.; Roberts, Charles W. M.] Broad Inst Harvard, Boston, MA USA. [Kim, Kimberly H.; Roberts, Charles W. M.] MIT, Boston, MA USA. RP Roberts, CWM (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM Charles_Roberts@dfci.harvard.edu FU Alex's Lemonade Stand Innovation Award; Hyundai Hope on Wheels Award; Garrett B. Smith Foundation; Miles for Mary; Cure AT/RT Now; Avalanna Fund; National Cancer Center; [R01CA113794]; [R01CA172152] FX This work and our efforts described herein were supported in part by R01CA113794 and R01CA172152 (to CWMR); and Alex's Lemonade Stand Innovation and Hyundai Hope on Wheels Awards (CWMR). The Garrett B. Smith Foundation, Miles for Mary, Cure AT/RT Now, and the Avalanna Fund (CWMR) provided additional support. KHK was supported by an award from the National Cancer Center. NR 96 TC 24 Z9 24 U1 3 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2210-7762 EI 2210-7770 J9 CANCER GENET-NY JI Cancer Genet. PD SEP PY 2014 VL 207 IS 9 SI SI BP 365 EP 372 DI 10.1016/j.cancergen.2014.04.004 PG 8 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA AX3DB UT WOS:000346819600005 PM 24853101 ER PT J AU Yeh, S Suhler, EB Smith, JR Bruce, B Fahle, G Bailey, ST Hwang, TS Stout, JT Lauer, AK Wilson, DJ Rosenbaum, JT Flaxel, CJ AF Yeh, Steven Suhler, Eric B. Smith, Justine R. Bruce, Beau Fahle, Gary Bailey, Steven T. Hwang, Thomas S. Stout, J. Timothy Lauer, Andreas K. Wilson, David J. Rosenbaum, James T. Flaxel, Christina J. TI Combination Systemic and Intravitreal Antiviral Therapy in the Management of Acute Retinal Necrosis Syndrome SO OPHTHALMIC SURGERY LASERS & IMAGING RETINA LA English DT Article ID POLYMERASE-CHAIN-REACTION; SIMPLEX-VIRUS TYPE-2; NECROTIZING HERPETIC RETINOPATHY; VITREOUS PENETRATION; ANTIBODY-PRODUCTION; CASE SERIES; RETINITIS; INJECTIONS; ACYCLOVIR; DIAGNOSIS AB BACKGROUND AND OBJECTIVE: Acute retinal necrosis (ARN) may lead to severe visual loss because of its rapid progression and high likelihood of retinal detachment (RD). This study investigates whether combination systemic and intravitreal antiviral therapy is superior to systemic antiviral therapy alone. PATIENTS AND METHODS: Single-center, interventional, comparative case series of patients with ARN treated with combination systemic antiviral and intravitreal foscarnet injection therapy or systemic antiviral therapy alone. Survival analysis and incidence rates of visual acuity (VA) gain of two lines or greater, severe visual loss of 20/200 or worse, and RD were assessed. RESULTS: Twelve patients received combination therapy and 12 received systemic therapy alone. Patients receiving combination therapy were more likely to gain two or more lines of VA and showed decreased incidences of severe visual loss and RD. CONCLUSION: Combination oral and intravitreal antiviral therapy may improve the likelihood for VA gain and decrease the risk of RD in patients with ARN. Clinicians should consider administering combination systemic and intravitreal antiviral therapy for patients with the ARN syndrome. C1 [Bailey, Steven T.; Hwang, Thomas S.; Stout, J. Timothy; Lauer, Andreas K.; Wilson, David J.; Rosenbaum, James T.; Flaxel, Christina J.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Rosenbaum, James T.] Legacy Good Samaritan Hosp, Devers Eye Inst, Portland, OR USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Smith, Justine R.] Flinders Univ S Australia, Adelaide, SA 5001, Australia. [Fahle, Gary] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Yeh, Steven; Bruce, Beau] Emory Univ, Sch Med, Dept Ophthalmol, Emory Eye Ctr, Atlanta, GA 30322 USA. [Bruce, Beau] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Bruce, Beau] Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Bruce, Beau] Emory Univ, Laney Grad Sch, Atlanta, GA 30322 USA. RP Flaxel, CJ (reprint author), Casey Eye Inst, Retina Serv, 3375 SW Terwilliger Blvd, Portland, OR 97239 USA. EM flaxelc@ohsu.edu FU Research to Prevent Blindness; Heed Ophthalmic Foundation; Ronald G. Michels fellowship foundation; William and Mary Bauman Foundation; Stan and Madelle Rosenfeld Family Trust; Fund for Arthritis and Infectious Disease Research; [K23-EY19341] FX Supported in part by unrestricted grants from Research to Prevent Blindness to the Casey Eye Institute and Emory Eye Center. Dr. Yeh has received support from the Heed Ophthalmic Foundation and the Ronald G. Michels fellowship foundation. Dr. Rosenbaum receives support from the William and Mary Bauman Foundation, the Stan and Madelle Rosenfeld Family Trust, and the Fund for Arthritis and Infectious Disease Research. Dr. Bruce has received funding from K23-EY19341. NR 38 TC 4 Z9 5 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 SEP-OCT PY 2014 VL 45 IS 5 BP 399 EP 407 DI 10.3928/23258160-20140908-02 PG 9 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA AY0OY UT WOS:000347297300006 PM 25215870 ER PT J AU Papakostas, TD Yonekawa, Y Wu, D Miller, JB Veldman, PB Chee, YE Husain, D Eliott, D AF Papakostas, Thanos D. Yonekawa, Yoshihiro Wu, David Miller, John B. Veldman, Peter B. Chee, Yewlin E. Husain, Deeba Eliott, Dean TI Retinal Detachment Associated With Traumatic Chorioretinal Rupture SO OPHTHALMIC SURGERY LASERS & IMAGING RETINA LA English DT Article ID SCLOPETARIA AB Traumatic chorioretinal rupture, also known as sclopetaria, is a full-thickness break of the choroid and retina caused by a high-velocity projectile striking or passing adjacent to, but not penetrating, the globe. Previous reports have emphasized that retinal detachment seldom occurs, and observation alone has been the recommended management strategy. However, the authors present herein a series of consecutive patients with retinal detachment associated with sclopetaria and provide a literature review of the topic. They recommend that patients with traumatic chorioretinal rupture be monitored closely for the development of retinal detachment during the first few weeks after the injury. C1 [Papakostas, Thanos D.; Yonekawa, Yoshihiro; Wu, David; Miller, John B.; Veldman, Peter B.; Chee, Yewlin E.; Husain, Deeba; Eliott, Dean] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Eliott, D (reprint author), 243 Charles St, Boston, MA 02114 USA. EM dean_eliott@meei.harvard.edu NR 24 TC 0 Z9 0 U1 0 U2 1 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 SEP-OCT PY 2014 VL 45 IS 5 BP 451 EP 455 DI 10.3928/23258160-20140806-02 PG 5 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA AY0OY UT WOS:000347297300015 PM 25153657 ER PT J AU Reisner, SL Biello, K Perry, NS Gamarel, KE Mimiaga, MJ AF Reisner, Sari L. Biello, Katie Perry, Nicholas S. Gamarel, Kristi E. Mimiaga, Matthew J. TI A Compensatory Model of Risk and Resilience Applied to Adolescent Sexual Orientation Disparities in Nonsuicidal Self-Injury and Suicide Attempts SO AMERICAN JOURNAL OF ORTHOPSYCHIATRY LA English DT Article DE sexual minority; adolescents; mental health; nonsuicidal self-injury ID FULLY CONDITIONAL SPECIFICATION; PSYCHOSOCIAL HEALTH-PROBLEMS; GAY-STRAIGHT ALLIANCES; BISEXUAL YOUTH; HIGH-SCHOOL; YOUNG-ADULTS; MULTIPLE IMPUTATION; CONCEPTUAL ISSUES; MENTAL-HEALTH; MINORITY AB This study investigated and applied a compensatory model of risk and resilience to differences in past-year nonsuicidal self-injury (NSSI) and suicide attempts by sexual orientation using representative data from the 2007 Massachusetts Youth Risk Behavior Survey (n = 3,131). Self-identified lesbian, gay, bisexual, and questioning (LGBQ) adolescents comprised 7% of the sample, but accounted for 67% of NSSI and 80% of suicide attempts. Compared with heterosexuals, LGBQ adolescents had an increased odds of NSSI (adjusted Odds Ratio (aOR) = 2.76; 95% Confidence Interval (CI) [2.00, 3.81] and suicide attempts (aOR = 2.73; 95% CI [1.47, 5.08]. NSSI was highly associated with suicidality (aOR = 10.87; 95% CI [6.17, 19.18]. Family support was independently associated with a decreased odds of both NSSI (aOR = 0.56; 95% CI [0.35, 0.89] and suicidality (aOR = 0.48; 95% CI [0.29, 0.79] supporting a compensatory model of resilience. Screening and preventive interventions for LGBQ adolescents are warranted, including at the family level. Sexual orientation should be included as a standard demographic to monitor health disparities. C1 [Reisner, Sari L.; Biello, Katie] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Reisner, Sari L.; Biello, Katie; Perry, Nicholas S.] Fenway Hlth, Fenway Inst, Boston, MA 02215 USA. [Perry, Nicholas S.] Univ Utah, Dept Psychol, Salt Lake City, UT 84112 USA. [Gamarel, Kristi E.] CUNY, Grad Ctr, New York, NY 10021 USA. [Mimiaga, Matthew J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Fenway Inst,Fenway Hlth, Boston, MA 02115 USA. [Mimiaga, Matthew J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. RP Reisner, SL (reprint author), Fenway Hlth, Fenway Inst, 1340 Boylston St,8th Floor, Boston, MA 02215 USA. EM sreisner@fenwayhealth.org NR 74 TC 9 Z9 9 U1 3 U2 16 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0002-9432 EI 1939-0025 J9 AM J ORTHOPSYCHIAT JI Am. J. Orthopsychiatr. PD SEP PY 2014 VL 84 IS 5 BP 545 EP 556 DI 10.1037/ort0000008 PG 12 WC Psychiatry; Social Work SC Psychiatry; Social Work GA AX4TI UT WOS:000346923700010 PM 25089757 ER PT J AU Williams, W Graham, DP McCurry, K Sanders, A Eiseman, J Chiu, PH King-Casas, B AF Williams, Wright Graham, David P. McCurry, Katherine Sanders, April Eiseman, Jessica Chiu, Pearl H. King-Casas, Brooks TI Group psychotherapy's impact on trust in veterans with PTSD: A pilot study SO BULLETIN OF THE MENNINGER CLINIC LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; COGNITIVE PROCESSING THERAPY; CINGULATE CORTEX; COMBAT VETERANS; PRIMARY-CARE; CHECKLIST; ANGER; COOPERATION; EXCHANGES; RESPONSES AB Interpersonal trust is fundamental for the recovery of trauma survivors and the effectiveness of group psychotherapy. Yet there is limited research on the relationship between interpersonal trust and group psychotherapy. Twenty-one male Vietnam combat veterans with posttraumatic stress disorder (PTSD) (6 in a long-term process group [LTP], 10 in a short-term cognitive processing therapy group [CPT], and 5 treatment-as-usual controls) were evaluated before and after group psychotherapy using the Posttraumatic Stress Disorder Checklist Military Version (PCL-M) and an in-vivo measure of interpersonal trust, the Iterated Trust Game. Three (14.3%) of the veterans were African American, 9 were Caucasian (42.9%), and 9 were Hispanic (42.9%); they averaged 61.9 years of age (SD = 1.8 years). Change in PCL-M scores differed by group (controls: -1.0 +/- 3.7; CPT: -15.5 +/- 6.8; LTP: -1.3 +/- 12.2; p = .003). CPT group subjects improved more than controls (p < .001) and trended toward more improvement than the LTP group (p = .081). Members of the LTP group, compared to nonprocess group participants, showed greater initial (p = .042), and posttherapy trust (p = .003). Posttreatment, interpersonal trust was significantly higher in the LTP than the CPT group (p < .001). These results suggest that CPT treatment may be better than LTP treatment for improving PTSD symptoms, but LTP therapy may be better than CPT therapy for improving interpersonal trust in veterans with PTSD. They suggest important roles for both group treatments and point to the value of interpersonal trust in successful recovery from PTSD. C1 [Williams, Wright; Graham, David P.] Michael E DeBakey Dept Vet Affairs Med Ctr, Houston, TX USA. [Williams, Wright; Graham, David P.] South Cent Mental Illness Res Educ & Clin Ctr, Houston, TX USA. [Williams, Wright; Graham, David P.; Eiseman, Jessica] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Graham, David P.] Michael E DeBakey Dept Vet Affairs Med Ctr, Neurorehabil Neurons Networks Traumat Brain Injur, Houston, TX USA. [McCurry, Katherine; Chiu, Pearl H.; King-Casas, Brooks] Virginia Tech, Virginia Tech Caril Res Inst, Roanoke, VA USA. [McCurry, Katherine; Chiu, Pearl H.; King-Casas, Brooks] Virginia Tech, Dept Psychol, Blacksburg, VA USA. [Chiu, Pearl H.; King-Casas, Brooks] Salem Vet Affairs Med Ctr, Salem, VA USA. [Chiu, Pearl H.; King-Casas, Brooks] Virginia Tech, Caril Sch Med, Dept Psychiat, Roanoke, VA USA. [Sanders, April] Harris Cty Mental Hlth & Mental Retardat Author M, Houston, TX USA. RP Williams, W (reprint author), Michael E DeBakey VAMC, PTSD Clin Team, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM wright.wil-liams@va.gov FU NIMH NIH HHS [MH087692] NR 36 TC 1 Z9 1 U1 2 U2 11 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0025-9284 EI 1943-2828 J9 B MENNINGER CLIN JI Bull. Menninger Clin. PD FAL PY 2014 VL 78 IS 4 BP 335 EP 348 PG 14 WC Psychiatry; Psychology, Psychoanalysis SC Psychiatry; Psychology GA AY0FK UT WOS:000347272800003 PM 25495436 ER PT J AU Haggerty, G Siefert, C Stoycheva, V Sinclair, SJ Baity, M Zodan, J Mehra, A Chand, V Blais, MA AF Haggerty, Greg Siefert, Caleb Stoycheva, Valentina Sinclair, Samuel Justin Baity, Matthew Zodan, Jennifer Mehra, Ashwin Chand, Vijay Blais, Mark A. TI Determining adolescents' suitability for inpatient psychotherapy: Utility of the clinician-rated Readiness for Inpatient Psychotherapy Scale with an adolescent inpatient sample SO BULLETIN OF THE MENNINGER CLINIC LA English DT Article ID SCHWARTZ OUTCOME SCALE-10; MENTAL-HEALTH; GLOBAL ASSESSMENT; TREATMENT MOTIVATION; INITIAL-VALIDATION; AXIS-II; RELIABILITY; RATINGS; DEPRESSION; PREDICTOR AB Growing economic pressure on inpatient services for adolescents has resulted in fewer clinicians to provide individual psychotherapy. As a result, inpatient treatment trends have favored group psychotherapy modalities and psychopharmacological interventions. Currently, no clinician-rated measures exist to assist clinicians in determining who would be able to better utilize individual psychotherapy on inpatient units. The current study sought to demonstrate the utility of the Readiness for Inpatient Psychotherapy Scale with an adolescent inpatient sample. This study also used the RIPS as it is intended to be used in everyday practice. Results from the authors' analyses reveal that the RIPS demonstrates good psychometrics and interrater reliability, as well as construct validity. C1 [Haggerty, Greg; Zodan, Jennifer; Mehra, Ashwin; Chand, Vijay] Nassau Univ, Med Ctr, Von Tauber Inst Global Psychiat, E Meadow, NY USA. [Sinclair, Samuel Justin; Blais, Mark A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sinclair, Samuel Justin; Blais, Mark A.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Siefert, Caleb] Univ Michigan, Dearborn, MI 48128 USA. [Stoycheva, Valentina] Adelphi Univ, Derner Inst Adv Psychol Studies, Garden City, NY USA. [Baity, Matthew] Alliant Int Univ, Alhambra, CA USA. RP Haggerty, G (reprint author), 320 1st Ave, Massapequa Pk, NY 11762 USA. EM Ghag541@aol.com FU NIMH NIH HHS [1R21MH097781-01A1] NR 49 TC 1 Z9 1 U1 1 U2 1 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0025-9284 EI 1943-2828 J9 B MENNINGER CLIN JI Bull. Menninger Clin. PD FAL PY 2014 VL 78 IS 4 BP 349 EP 372 PG 24 WC Psychiatry; Psychology, Psychoanalysis SC Psychiatry; Psychology GA AY0FK UT WOS:000347272800004 PM 25495437 ER PT J AU Landa-Ramirez, E Cardenas-Lopez, G Greer, JA Sanchez-Roman, S Riveros-Rosas, A AF Landa-Ramirez, Edgar Cardenas-Lopez, Georgina Andrew Greer, Joseph Sanchez-Roman, Sofia Riveros-Rosas, Angelica TI Evaluation of depression in patients with terminal cancer and its application in the mexican context : A review SO SALUD MENTAL LA Spanish DT Article DE Depression; cancer; palliative care ID ADVANCED METASTATIC CANCER; PALLIATIVE CARE; HOSPITAL ANXIETY; SCREENING TOOL; BREAST-CANCER; PSYCHIATRIC MORBIDITY; LATIN-AMERICA; PART 1; SCALE; VALIDATION AB Depression is one of the most common emotional problems in palliative patients. Due to the advanced nature of the disease, several physical symptoms presented by patients overlap with symptoms of depression, making it difficult to evaluate and diagnose the problem. The aim of this paper was to conduct a narrative review of the main instruments used to assess depression when it is present in palliative patients, with a special consideration of the Mexican context. Based on the available data and the scholarly literature, it is more appropriate to conduct an assessment of depression focused on emotional aspects than somatics aspects in palliative patients. Internationally, a number of depression assessments place greater emphasis on anhedonia and emotions, such as hopelessness, than on somatic aspects of depression. In Mexico, a considerable gap remains in the development of instruments to identify depression in the palliative setting. Finally, we describe alternative assessments of depression, which could be evaluated and considered in the future in the palliative care setting. C1 [Landa-Ramirez, Edgar] Univ Nacl Autonoma Mexico, Fac Psicol, Programa Med Conductual, Mexico City 04510, DF, Mexico. [Cardenas-Lopez, Georgina] Univ Nacl Autonoma Mexico, Fac Psicol, Mexico City 04510, DF, Mexico. [Andrew Greer, Joseph] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Andrew Greer, Joseph] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Sanchez-Roman, Sofia] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mexico City, DF, Mexico. [Riveros-Rosas, Angelica] Univ Nacl Autonoma Mexico, Fac Contaduria & Adm, Mexico City 04510, DF, Mexico. RP Landa-Ramirez, E (reprint author), Francisco Sarabia 379, Mexico City 02440, DF, Mexico. EM edgar_landa_ramirez@yahoo.com.mx NR 47 TC 0 Z9 0 U1 1 U2 3 PU INST MEX PSIQUIATRIA PI MEXICO CITY PA CALZ MEXICO-XOCHIMILCO #101, MEXICO CITY 22 DF, MEXICO SN 0185-3325 J9 SALUD MENT JI Salud Ment. PD SEP-OCT PY 2014 VL 37 IS 5 BP 415 EP 422 PG 8 WC Psychiatry SC Psychiatry GA AX2DS UT WOS:000346754500008 ER PT J AU Koehler, U Pabst, B Pober, B Kozel, B AF Koehler, Udo Pabst, Brigitte Pober, Barbara Kozel, Beth TI Clinical utility gene card for: Williams-Beuren Syndrome 7q11.23 SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Editorial Material ID DELETIONS; CHILDREN; ELASTIN C1 [Koehler, Udo] MGZ Med Genet Zentrum, D-08335 Munich, Germany. [Pabst, Brigitte] Hannover Med Sch, Inst Hum Genet, Hannover, Germany. [Pober, Barbara] Harvard Med Sch, Mass Gen Hosp, Dept Pediat, Boston, MA USA. [Pober, Barbara] Quinnipiac Univ, Frank H Netter Sch Med, Dept Med Sci, North Haven, CT USA. [Kozel, Beth] Washington Univ Sch Med, Dept Pediat, St Louis, MO USA. RP Koehler, U (reprint author), MGZ Med Genet Zentrum, Bayerstr 3-5, D-08335 Munich, Germany. EM koehler@mgz-muenchen.de NR 10 TC 2 Z9 2 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD SEP PY 2014 VL 22 IS 9 BP E1 EP E3 DI 10.1038/ejhg.2014.28 PG 3 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AN4SA UT WOS:000340577600018 ER PT J AU Kleijn, A Kloezeman, J Treffers-Westerlaken, E Fulci, G Leenstra, S Dirven, C Debets, R Lamfers, M AF Kleijn, Anne Kloezeman, Jenneke Treffers-Westerlaken, Elike Fulci, Giulia Leenstra, Sieger Dirven, Clemens Debets, Reno Lamfers, Martine TI The therapeutic efficacy of the oncolytic virus Delta24-RGD in a murine glioma model depends primarily on antitumor immunity SO ONCOIMMUNOLOGY LA English DT Editorial Material DE adenovirus; virotherapy; immune response; glioma; antitumor immunity ID VIROTHERAPY; CELLS AB Oncolytic viruses selectively lyse tumor cells, making these agents a promising treatment modality for glioma. Accumulating data suggest that the immune system plays an important role in the anti-glioma activity of oncolytic viruses. In an immune competent glioma model, the therapeutic effect of the oncolytic adenovirus Delta24-RGD was found to depend primarily on antitumor immune responses. C1 [Kleijn, Anne; Kloezeman, Jenneke; Leenstra, Sieger; Dirven, Clemens; Lamfers, Martine] ErasmusMC, Brain Tumor Ctr, Dept Neurosurg, Rotterdam, Netherlands. [Treffers-Westerlaken, Elike; Debets, Reno] ErasmusMC, Dept Med Oncol, Lab Expt Tumor Immunol, Rotterdam, Netherlands. [Fulci, Giulia] Massachusetts Gen Hosp, Dept Neurosurg, Brain Tumor Res Ctr, Mol Neurosurg Lab, Boston, MA 02114 USA. RP Lamfers, M (reprint author), ErasmusMC, Brain Tumor Ctr, Dept Neurosurg, Rotterdam, Netherlands. EM m.lamfers@erasmusmc.nl RI Lamfers, Martine/C-6246-2016; OI Lamfers, Martine/0000-0001-7745-9029 NR 9 TC 1 Z9 1 U1 1 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2162-4011 EI 2162-402X J9 ONCOIMMUNOLOGY JI OncoImmunology PD SEP PY 2014 VL 3 IS 9 AR e955697 DI 10.4161/21624011.2014.955697 PG 2 WC Oncology; Immunology SC Oncology; Immunology GA AX4SU UT WOS:000346922400020 ER PT J AU Daley, GQ Lux, SE AF Daley, George Q. Lux, Samuel E. TI Deriving blood stem cells from pluripotent stem cells for research and therapy SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE stem cells; induced pluripotent; hematopoietic stem cells (HSCs); transcription factors; stem cell models ID NUCLEAR TRANSFER AB Embryonic stem cells and induced pluripotent stem cells offer promise for research and treatment of hematologic diseases. While broad clinical application in humans is still a distant prospect, there are promising near-term applications in transfusion of platelets and red blood cells. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Lux, Samuel E.] Childrens Hosp, Stem Cell Transplantat Program, Philadelphia, PA USA. [Lux, Samuel E.] Dana Farber Canc Inst, Boston, MA USA. [Lux, Samuel E.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Lux, Samuel E.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Daley, GQ (reprint author), 300 Longwood Ave, Boston, MA 02115 USA. EM George.Daley@childrens.harvard.edu FU MPM Capital; LLP; Verastem; True North; Solasia; Advanced Cell Therapies FX GQD is a member of advisory boards and holds equity in or receives consulting fees from MPM Capital, LLP, Verastem, True North, Solasia, and Advanced Cell Therapies. NR 12 TC 4 Z9 4 U1 2 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-6926 EI 1532-1924 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD SEP-DEC PY 2014 VL 27 IS 3-4 BP 293 EP 297 DI 10.1016/j.beha.2014.10.013 PG 5 WC Hematology SC Hematology GA AW8YK UT WOS:000346545000014 PM 25455281 ER PT J AU Hawryluk, EB Tsao, H AF Hawryluk, Elena B. Tsao, Hensin TI Melanoma: Clinical Features and Genomic Insights SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID PRIMARY CUTANEOUS MELANOMA; BRAF INHIBITOR RESISTANCE; V600E MUTANT MELANOMA; UVEAL MELANOMA; MALIGNANT-MELANOMA; METASTATIC MELANOMA; MELANOCYTIC NEVI; MEK INHIBITION; MC1R VARIANTS; ULTRAVIOLET-RADIATION AB Recent efforts in genomic research have enabled the characterization of molecular mechanisms underlying many types of cancers, ushering novel approaches for diagnosis and therapeutics. Melanoma is a molecularly heterogeneous disease, as many genetic alterations have been identified and the clinical features can vary. Although discoveries of frequent mutations including BRAF have already made clinically significant impact on patient care, there is a growing body of literature suggesting a role for additional mutations, driver and passenger types, in disease pathophysiology. Although some mutations have been strongly associated with clinical phenotypes of melanomas (such as physical distribution or morphologic subtype), the function or implications of many of the recently identified mutations remains less clear. The phenotypic and clinical impact of genomic mutations in melanoma remains a promising opportunity for progress in the care of melanoma patients. C1 [Hawryluk, Elena B.] Harvard Univ, Sch Med, Boston Childrens Hosp, Dermatol Program, Boston, MA 02115 USA. [Hawryluk, Elena B.; Tsao, Hensin] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. RP Tsao, H (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. EM htsao@partners.org FU Dermatology Foundation; [K24 CA149202] FX The authors gratefully acknowledge Dr. Matthew Hawryluk for his critical review and comments on this work. Funding for this effort is supported in part by K24 CA149202, the generous donors to the Massachusetts General Hospital Millennium Melanoma fund (both to H.T.), and the Dermatology Foundation Fellowship in Pediatric Dermatology (E.B.H.). NR 113 TC 9 Z9 9 U1 1 U2 7 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD SEP PY 2014 VL 4 IS 9 AR a015388 DI 10.1101/cshperspect.a015388 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AW8NZ UT WOS:000346520500002 PM 25183853 ER PT J AU Lindsay, ME Dietz, HC AF Lindsay, Mark E. Dietz, Harry C. TI The Genetic Basis of Aortic Aneurysm SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID EHLERS-DANLOS-SYNDROME; GROWTH-FACTOR-BETA; MARFAN-SYNDROME; TGF-BETA; ANGIOTENSIN-II; LYSYL OXIDASE; CUTIS-LAXA; FILAMIN-A; HYPERTROPHIC CARDIOMYOPATHY; PSEUDOXANTHOMA ELASTICUM AB Gene identification in human aortic aneurysm conditions is proceeding at a rapid pace and the integration of pathogenesis-based management strategies in clinical practice is an emerging reality. Human genetic alterations causing aneurysm involve diverse gene products including constituents of the extracellular matrix, cell surface receptors, intracellular signaling molecules, and elements of the contractile cytoskeleton. Animal modeling experiments and human genetic discoveries have extensively implicated the transforming growth factor-beta (TGF-beta) cytokine-signaling cascade in aneurysm progression, but mechanistic links between many gene products remain obscure. This chapter will integrate human genetic alterations associated with aortic aneurysm with current basic research findings in an attempt to form a reconciling if not unifying model for hereditary aortic aneurysm. C1 [Lindsay, Mark E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Thorac Aort Ctr,Dept Med, Boston, MA 02114 USA. [Lindsay, Mark E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat, Boston, MA 02114 USA. [Dietz, Harry C.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Dept Pediat, Baltimore, MD 21205 USA. [Dietz, Harry C.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Dept Med, Baltimore, MD 21205 USA. [Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [Dietz, Harry C.] Howard Hughes Med Inst, Baltimore, MD 21205 USA. RP Lindsay, ME (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Thorac Aort Ctr,Dept Med, Boston, MA 02114 USA. EM lindsay.mark@mgh.harvard.edu FU Howard Hughes Medical Institute NR 79 TC 11 Z9 11 U1 0 U2 5 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD SEP PY 2014 VL 4 IS 9 AR a015909 DI 10.1101/cshperspect.a015909 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AW8NZ UT WOS:000346520500004 PM 25183854 ER PT J AU Faustman, DL Reinhold, PE Washer, SL Hsu, E Zhao, M Burger, D Zheng, H AF Faustman, D. L. Reinhold, P. E. Washer, S. L. Hsu, E. Zhao, M. Burger, D. Zheng, H. TI Low levels of C-peptide production protect from complications and improve HbA(1c) control in longstanding type 1 diabetes SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Faustman, D. L.; Reinhold, P. E.; Washer, S. L.; Hsu, E.; Zhao, M.; Burger, D.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Immunobiol Lab, Charlestown, MA USA. [Zheng, H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 SEP PY 2014 VL 57 SU 1 MA 91 BP S45 EP S45 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386100091 ER PT J AU Gallwitz, B Ross, SA Caballero, AE Del Prato, S Lewis-D'Agostino, D Bailes, Z Thiemann, S Patel, S Woerle, HJ von Eynatten, M AF Gallwitz, B. Ross, S. A. Caballero, A. E. Del Prato, S. Lewis-D'Agostino, D. Bailes, Z. Thiemann, S. Patel, S. Woerle, H. -J. von Eynatten, M. TI Oral glucose lowering with linagliptin plus metformin is a viable initial treatment strategy in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Gallwitz, B.] Univ Klinikum Tubingen, Dept Med 4, Tubingen, Germany. [Ross, S. A.] Univ Calgary, LMC Endocrinol Ctr, Calgary, AB T2N 1N4, Canada. [Caballero, A. E.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Caballero, A. E.] Harvard Univ, Sch Med, Boston, MA USA. [Del Prato, S.] Univ Pisa, Sect Diabet, Dept Endocrinol & Metab, I-56100 Pisa, Italy. [Lewis-D'Agostino, D.; von Eynatten, M.] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT USA. [Bailes, Z.; Patel, S.] Boehringer Ingelheim Ltd, Bracknell, Berks, England. [Thiemann, S.; Woerle, H. -J.] Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany. RI Del Prato, Stefano/K-3405-2016 OI Del Prato, Stefano/0000-0002-5388-0270 NR 0 TC 0 Z9 0 U1 1 U2 1 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 SEP PY 2014 VL 57 SU 1 MA 894 BP S364 EP S364 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386102157 ER PT J AU Jacobson, AM Brafett, BH Cleary, PA Dunn, RL Holt, S Larkin, ML Wessells, H Sarma, AV AF Jacobson, A. M. Brafett, B. H. Cleary, P. A. Dunn, R. L. Holt, S. Larkin, M. L. Wessells, H. Sarma, A. V. CA DCCT EDIC Res Grp TI Erectile dysfunction and health-related quality of life in type 1 diabetes: longitudinal follow-up of the DCCT/EDIC cohort SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Jacobson, A. M.] Winthrop Univ Hosp, Diabet Obes & Cardiometab Res Ctr, Mineola, NY 11501 USA. [Brafett, B. H.; Cleary, P. A.] George Washington Univ, Biostat Ctr, Rockville, MD USA. [Dunn, R. L.; Sarma, A. V.] Univ Michigan, Ann Arbor, MI 48109 USA. [Holt, S.; Wessells, H.] Univ Washington, Seattle, WA 98195 USA. [Larkin, M. L.] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 SEP PY 2014 VL 57 SU 1 MA 128 BP S61 EP S61 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386100128 ER PT J AU Laffel, L Domenger, C Pilorget, V Candelas, C Danne, T Phillip, M Mazza, C Anderson, B Hanas, R Waldron, S Beck, R Mathieu, C AF Laffel, L. Domenger, C. Pilorget, V. Candelas, C. Danne, T. Phillip, M. Mazza, C. Anderson, B. Hanas, R. Waldron, S. Beck, R. Mathieu, C. TI Glycaemic control and acute complications in children, adolescents, and young adults with type 1 diabetes (T1D): the global TEENs study SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Laffel, L.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Domenger, C.] Sanofi, Paris, France. [Pilorget, V.; Candelas, C.] Sanofi, Chilly Mazarin, France. [Danne, T.] Kinder & Jugendkrankenhaus Auf der Bult, Hannover, Germany. [Phillip, M.] Schneider Childrens Med Ctr Israel, Petah Tiqwa, Israel. [Mazza, C.] Hosp Pediat JP Garrahan, Buenos Aires, DF, Argentina. [Anderson, B.] Baylor Coll Med, Houston, TX 77030 USA. [Hanas, R.] Gothenburg Univ, S-41124 Gothenburg, Sweden. [Waldron, S.] Hosted West Midlands Strateg Clin Network, Birmingham, W Midlands, England. [Beck, R.] Jaeb Ctr Hlth Res, Tampa, FL USA. [Mathieu, C.] Univ Hosp UZ, Leuven, Belgium. NR 0 TC 1 Z9 1 U1 0 U2 0 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 SEP PY 2014 VL 57 SU 1 MA 1257 BP S510 EP S511 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386102520 ER PT J AU Li, G Shao, S Zhang, J Nishimura, W Sharma, A Bee, YM AF Li, G. Shao, S. Zhang, J. Nishimura, W. Sharma, A. Bee, Y-M TI Up-regulation of MafA drives embryonic progenitor-derived insulin-producing cells towards maturation and functional improvement both in vitro and in vivo SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Li, G.; Shao, S.; Zhang, J.; Bee, Y-M] Singapore Gen Hosp, Singapore, Singapore. [Nishimura, W.; Sharma, A.] Joslin Diabet Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 SEP PY 2014 VL 57 SU 1 MA 26 BP S17 EP S17 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386100027 ER PT J AU Marullo, L Kilpelainen, TO Cornes, BK Dupuis, J Scapoli, C Loos, RJF Meigs, JB Morris, AP Prokopenko, I AF Marullo, L. Kilpelainen, T. O. Cornes, B. K. Dupuis, J. Scapoli, C. Loos, R. J. F. Meigs, J. B. Morris, A. P. Prokopenko, I. CA XC-Pleiotropy Grp TI Dissecting the genetic architecture of loci with established effects on multiple cardiometabolic phenotypes and type 2 diabetes SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Marullo, L.; Scapoli, C.] Univ Ferrara, Dept Life Sci & Biotechnol, Genet Sect, I-44100 Ferrara, Italy. [Kilpelainen, T. O.] Univ Copenhagen, Novo Nordisk Fdn, Ctr Basic Metab Res, DK-1168 Copenhagen, Denmark. [Cornes, B. K.; Meigs, J. B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Dupuis, J.] Boston Univ, Sch Publ Hlth, Dept Biostat, New York, NY USA. [Loos, R. J. F.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Morris, A. P.] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England. [Prokopenko, I.] Imperial Coll London, Dept Genom Common Dis, London, England. RI Scapoli, Chiara/E-2268-2015 OI Scapoli, Chiara/0000-0003-4058-4787 NR 0 TC 0 Z9 0 U1 0 U2 2 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 SEP PY 2014 VL 57 SU 1 MA 344 BP S149 EP S149 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386100344 ER PT J AU Mezza, T Sun, AV Conte, C Sorice, G Moffa, S Cefalo, C Kulkarni, RN Mari, A Giaccari, A AF Mezza, T. Sun, A. V. Conte, C. Sorice, G. Moffa, S. Cefalo, C. Kulkarni, R. N. Mari, A. Giaccari, A. TI In vivo beta cell glucose sensitivity regulates ex vivo islet size, transdiferentiation and GLP1 immunoreactivity in the alpha cells in humans SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Mezza, T.; Sun, A. V.; Conte, C.; Sorice, G.; Moffa, S.; Cefalo, C.; Giaccari, A.] Catholic Univ, Rome, Italy. [Kulkarni, R. N.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Mari, A.] CNR, Padua, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP PY 2014 VL 57 SU 1 MA 524 BP S218 EP S218 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386101177 ER PT J AU Phillip, M Lafel, L Domenger, C Pilorget, V Candelas, C Danne, T Mazza, C Anderson, B Hanas, R Waldron, S Beck, R Mathieu, C AF Phillip, M. Lafel, L. Domenger, C. Pilorget, V. Candelas, C. Danne, T. Mazza, C. Anderson, B. Hanas, R. Waldron, S. Beck, R. Mathieu, C. TI Disease management and outcomes in European children, adolescents, and young adults with type 1 diabetes (T1D): the global TEENs study SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Phillip, M.] Schneider Childrens Med Ctr Israel, Petah Tiqwa, Israel. [Lafel, L.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Domenger, C.] Sanofi, Paris, France. [Pilorget, V.; Candelas, C.] Sanofi, Chilly Mazarin, France. [Danne, T.] Kinder & Jugendkrankenhaus Auf der Bult, Hannover, Germany. [Mazza, C.] Hosp Pediat JP Garrahan, Buenos Aires, DF, Argentina. [Anderson, B.] Baylor Coll Med, Houston, TX 77030 USA. [Hanas, R.] Gothenburg Univ, S-41124 Gothenburg, Sweden. [Waldron, S.] Hosted West Midlands Strateg Clin Network, Birmingham, W Midlands, England. [Beck, R.] Jaeb Ctr Hlth Res, Tampa, FL USA. [Mathieu, C.] Univ Hosp UZ, Leuven, Belgium. NR 0 TC 0 Z9 0 U1 0 U2 2 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 SEP PY 2014 VL 57 SU 1 MA 1251 BP S508 EP S509 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386102514 ER PT J AU Prudente, S Prapaporn, J Marucci, A Ludovico, O Mazza, T Hastings, T Mercuri, L Bailetti, D Mendonca, C Carella, M Barbetti, F Trischitta, V Di Paola, R Doria, A AF Prudente, S. Prapaporn, J. Marucci, A. Ludovico, O. Mazza, T. Hastings, T. Mercuri, L. Bailetti, D. Mendonca, C. Carella, M. Barbetti, F. Trischitta, V. Di Paola, R. Doria, A. TI Mutation in APPL1 gene may contribute to familial diabetes mellitus SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Prudente, S.; Mazza, T.; Mercuri, L.; Bailetti, D.] IRCCS CSS Mendel, Rome, Italy. [Prapaporn, J.; Hastings, T.; Mendonca, C.; Doria, A.] Joslin Diabet Ctr, Dept Genet & Epidemiol, Boston, MA 02215 USA. [Marucci, A.; Trischitta, V.; Di Paola, R.] IRCCS Casa Sollievo Soferenza, Res Unit Diabet & Endocrine Dis, San Giovanni Rotondo, Italy. [Ludovico, O.] IRCCS Casa Sollievo Soferenza, Clin Unit Endocrinol, San Giovanni Rotondo, Italy. [Carella, M.] IRCCS Casa Sollievo Soferenza, Med Genet Unit, San Giovanni Rotondo, Italy. [Barbetti, F.] Bambino Gesu Pediat Hosp, Lab Mendelian Diabet, Rome, Italy. [Barbetti, F.] Univ Roma Tor Vergata, Dept Expt Med & Surg, Rome, Italy. [Doria, A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RI Prudente, Sabrina/H-2886-2016; Di Paola, Rosa/G-7813-2011; Trischitta, Vincenzo/K-1487-2016; Mazza, Tommaso/H-6414-2016 OI Prudente, Sabrina/0000-0001-9220-8981; Di Paola, Rosa/0000-0001-5837-9111; Trischitta, Vincenzo/0000-0003-1174-127X; Mazza, Tommaso/0000-0003-0434-8533 NR 0 TC 0 Z9 0 U1 0 U2 2 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 SEP PY 2014 VL 57 SU 1 MA 357 BP S154 EP S154 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386101010 ER PT J AU Ruetten, H Raymond, RH Calle, RA Cao, C Lee, DS Robertson, RP Shankar, SS Staten, M Stefanovski, D Vassileva, MT Vella, A Weir, GC Fryburg, DA AF Ruetten, H. Raymond, R. H. Calle, R. A. Cao, C. Lee, D. S. Robertson, R. P. Shankar, S. S. Staten, M. Stefanovski, D. Vassileva, M. T. Vella, A. Weir, G. C. Fryburg, D. A. CA Beta Cell Team FNIH Biomarkers Con TI Intravenous arginine stimulates GLP-1 release across spectrum of glucose tolerance SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Ruetten, H.] Sanofi Inc, Frankfurt, Germany. [Raymond, R. H.] RSquared Solut, Skillman, NJ USA. [Calle, R. A.; Lee, D. S.] Pfizer Pharmatherapeut R&D, Cambridge, MA 02142 USA. [Cao, C.] Takeda Inc, Chicago, IL USA. [Robertson, R. P.] Pacific Northwest Diabet Res Inst, Seattle, WA USA. [Shankar, S. S.] Eli Lilly Inc, Indianapolis, IN USA. [Staten, M.] NIDDK, NIH, Bethesda, MD 20892 USA. [Stefanovski, D.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Vassileva, M. T.] Fdn NIH Biomarkers Consortium, Bethesda, MD USA. [Vella, A.] Mayo Clin, Rochester, MN USA. [Weir, G. C.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Fryburg, D. A.] ROI BioPharma Consulting, East Lyme, CT USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 SEP PY 2014 VL 57 SU 1 MA 529 BP S220 EP S221 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386101182 ER PT J AU Sun, AV Mezza, T Sorice, G Conte, C Cefalo, C Kulkarni, RN Mari, A Giaccari, A AF Sun, A. V. Mezza, T. Sorice, G. Conte, C. Cefalo, C. Kulkarni, R. N. Mari, A. Giaccari, A. TI Loss of glucose sensitivity and islet neogenesis predict the occurence of diabetes ater acute beta cell reduction SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Sun, A. V.; Mezza, T.; Sorice, G.; Conte, C.; Cefalo, C.; Giaccari, A.] Catholic Univ, Rome, Italy. [Kulkarni, R. N.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Mari, A.] CNR, Padua, Italy. NR 0 TC 0 Z9 0 U1 0 U2 1 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 SEP PY 2014 VL 57 SU 1 MA 515 BP S215 EP S215 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386101168 ER PT J AU Vernochet, C Damilano, F Mourier, A Bezy, O Mori, MA Smith, G Rosenzweig, A Larsson, NG Kahn, RC AF Vernochet, C. Damilano, F. Mourier, A. Bezy, O. Mori, M. A. Smith, G. Rosenzweig, A. Larsson, N. -G. Kahn, R. C. TI Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis and cardiovascular complications SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Vernochet, C.; Damilano, F.; Bezy, O.; Mori, M. A.; Smith, G.; Kahn, R. C.] Max Planck Inst Biol Ageing, Joslin Diabet Ctr, Boston, MA USA. [Mourier, A.; Larsson, N. -G.] Max Planck Inst Biol Ageing, Dept Mitochondrial Biol, Boston, MA USA. [Rosenzweig, A.] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA. [Rosenzweig, A.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP PY 2014 VL 57 SU 1 MA 1332 BP S539 EP S539 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386102595 ER PT J AU Weiss, R Bode, B Bailey, T Schwartz, F Brazg, R Bergenstal, R Thrasher, J Weinstock, R Ahmann, A Klonoff, D Slover, R Garg, S Welsh, J Mao, M AF Weiss, R. Bode, B. Bailey, T. Schwartz, F. Brazg, R. Bergenstal, R. Thrasher, J. Weinstock, R. Ahmann, A. Klonoff, D. Slover, R. Garg, S. Welsh, J. Mao, M. CA ASPIRE In-Home Study Grp TI Effects of automatic insulin pump interruption on duration and weekly rate of nocturnal hypoglycaemic events in the ASPIRE In-Home Study SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Weiss, R.] Hebrew Univ Jerusalem, Jerusalem, Israel. [Bode, B.] Atlanta Diabet Asscociates, Atlanta, GA USA. [Bailey, T.] AMCR Inst, Escondido, CA USA. [Schwartz, F.] Ohio Univ, Athens, OH 45701 USA. [Brazg, R.] Rainier Inst Clin Res, Renton, WA USA. [Bergenstal, R.] Int Diabet Ctr Pk Nicollet, Minneapolis, MN USA. [Thrasher, J.] Arkansas Diabet Clin & Res Ctr, Little Rock, AR USA. [Weinstock, R.] Joslin Diabet Ctr, Syracuse, NY USA. [Ahmann, A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Klonoff, D.] Mills Peninsula Hlth Serv, Diabet Res Inst, San Mateo, CA USA. [Slover, R.; Garg, S.] Univ Colorado, Denver, CO 80202 USA. [Welsh, J.; Mao, M.] Medtronic Inc, Northridge, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP PY 2014 VL 57 SU 1 MA 1003 BP S412 EP S412 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386102266 ER PT J AU Young, AA Brown, KK Williams, JD Pimentel, F Sharp, A Parra, PP Turiel, D Munoz, R Arrese, M Irribarra, V Miguel, JF Kaplan, LM Levine, A Maggs, D Escalona, A AF Young, A. A. Brown, K. K. Williams, J. D. Pimentel, F. Sharp, A. Parra, P. P. Turiel, D. Munoz, R. Arrese, M. Irribarra, V. Miguel, J. F. Kaplan, L. M. Levine, A. Maggs, D. Escalona, A. TI Effects of duodeno-jejunal bypass liner on bile acid homeostasis in patients with severe obesity SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Young, A. A.; Brown, K. K.; Williams, J. D.] GlaxoSmithKline, Res Triangle Pk, NC USA. [Pimentel, F.; Sharp, A.; Parra, P. P.; Turiel, D.; Munoz, R.; Arrese, M.; Irribarra, V.; Miguel, J. F.; Escalona, A.] Pontificia Univ Catolica Chile, Santiago, Chile. [Kaplan, L. M.] Massachusetts Gen Hosp, Obes Metab & Nutr Inst, Boston, MA 02114 USA. [Levine, A.] Harvard Univ, Wyss Inst, Cambridge, MA 02138 USA. [Maggs, D.] GI Dynam, Lexington, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 SEP PY 2014 VL 57 SU 1 MA 982 BP S403 EP S403 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6PX UT WOS:000344386102245 ER PT J AU Okunseri, C Okunseri, E Xiang, Q Thorpe, JM Szabo, A AF Okunseri, Christopher Okunseri, Elaye Xiang, Qun Thorpe, Joshua M. Szabo, Aniko TI Prescription of opioid and nonopioid analgesics for dental care in emergency departments: Findings from the National Hospital Ambulatory Medical Care Survey SO JOURNAL OF PUBLIC HEALTH DENTISTRY LA English DT Article DE nontraumatic dental conditions; dental health services; dental care; emergency physicians; opioid analgesics; nonopioid analgesics; toothache ID ETHNIC DISPARITIES; CONDITION VISITS; PAIN; RACE; FRACTURES; INFERENCE; OFFICES; CANCER AB ObjectivesThe aim of this study was to examine trends and associated factors in the prescription of opioid analgesics, nonopioid analgesics, opioid and nonopioid analgesic combinations, and no analgesics by emergency physicians for nontraumatic dental condition (NTDC)-related visits. Our secondary aim was to investigate whether race/ethnicity is a possible predictor of receiving a prescription for either type of medication for NTDC visits in emergency departments (EDs) after adjustment for potential covariates. MethodsWe analyzed data from the National Hospital Ambulatory Medical Care Survey for 1997-2000 and 2003-2007, and used multinomial multivariate logistic regression to estimate the probability of receiving a prescription for opioid analgesics, nonopioid analgesics, or a combination of both, compared with receiving no analgesics for NTDC-related visits. ResultsDuring 1997-2000 and 2003-2007, prescription of opioid analgesics and combinations of opioid and nonopioid analgesics increased, and that of no analgesics decreased over time. The prescription rates for opioid analgesics, nonopioid analgesics, opioid and nonopioid analgesic combinations, and no analgesics for NTDC-related visits in EDs were 43 percent, 20 percent, 12 percent, and 25 percent, respectively. Majority of patients categorized as having severe pain received prescriptions for opioids for NTDC-related visits in EDs. After adjusting for covariates, patients with self-reported dental reasons for visit and severe pain had a significantly higher probability of receiving prescriptions for opioid analgesics and opioid and nonopioid analgesic combinations. ConclusionsPrescription of opioid analgesics increased over time. ED physicians were more likely to prescribe opioid analgesics and opioid and nonopioid analgesic combinations for NTDC-related visits with reported severe pain. C1 [Okunseri, Christopher; Okunseri, Elaye] Marquette Univ, Sch Dent, Dept Clin Serv, Milwaukee, WI 53201 USA. [Thorpe, Joshua M.] Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15261 USA. [Thorpe, Joshua M.] Univ Pittsburgh, Sch Pharm, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. [Xiang, Qun; Szabo, Aniko] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. RP Okunseri, C (reprint author), Marquette Univ, Sch Dent, Dept Clin Serv, Room 356,POB 1881, Milwaukee, WI 53201 USA. EM christopher.okunseri@marquette.edu FU National Institute of Health [1R15DE021196-01] FX This research was supported by the National Institute of Health grant# 1R15DE021196-01. NR 30 TC 4 Z9 4 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4006 EI 1752-7325 J9 J PUBLIC HEALTH DENT JI J. Public Health Dent. PD FAL PY 2014 VL 74 IS 4 BP 283 EP 292 DI 10.1111/jphd.12055 PG 10 WC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health SC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health GA AW4KH UT WOS:000346249500004 PM 24863407 ER PT J AU Mavroidis, P Giantsoudis, D Awan, MJ Nijkamp, J Rasch, CRN Duppen, JC Thomas, CR Okunieff, P Jones, WE Kachnic, LA Papanikolaou, N Fuller, CD Commit, SOGRO AF Mavroidis, Panayiotis Giantsoudis, Drosoula Awan, Musaddiq J. Nijkamp, Jasper Rasch, Coen R. N. Duppen, Joop C. Thomas, Charles R., Jr. Okunieff, Paul Jones, William E., III Kachnic, Lisa A. Papanikolaou, Niko Fuller, Clifton D. Commit, Southwest Oncology Group Radiation Oncology TI Consequences of anorectal cancer atlas implementation in the cooperative group setting: Radiobiologic analysis of a prospective randomized in silico target delineation study SO RADIOTHERAPY AND ONCOLOGY LA English DT Article DE Anorectal cancer; Target delineation; Radiobiological analysis; Atlas implementation; Inter-observer variation ID DOSE-RESPONSE RELATIONS; VOLUME DELINEATION; RADIATION-THERAPY; RECTAL-CANCER; RADIOTHERAPY; QUALITY; HEAD AB Purpose: The aim of this study is to ascertain the subsequent radiobiological impact of using a consensus guideline target volume delineation atlas. Materials and methods: Using a representative case and target volume delineation instructions derived from a proposed IMRT rectal cancer clinical trial, gross tumor volume (GTV) and clinical/planning target volumes (CTV/PTV) were contoured by 13 physician observers (Phase 1). The observers were then randomly assigned to follow (atlas) or not-follow (control) a consensus guideline/atlas for anorectal cancers, and instructed to re-contour the same case (Phase 2). Results: The atlas group was found to have increased tumor control probability (TCP) after the atlas intervention for both the CTV (p < 0.0001) and PTV1 (p = 0.0011) with decreasing normal tissue complication probability (NTCP) for small intestine, while the control group did not. Additionally, the atlas group had reduced variance in TCP for all target volumes and reduced variance in NTCP for the bowel. In Phase 2, the atlas group had increased TCP relative to the control for CTV (p = 0.03). Conclusions: Visual atlas and consensus treatment guideline usage in the development of rectal cancer IMRT treatment plans reduced the inter-observer radiobiological variation, with clinically relevant TCP alteration for CTV and PTV volumes. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Mavroidis, Panayiotis; Jones, William E., III; Papanikolaou, Niko] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiat Oncol, San Antonio, TX 78229 USA. [Mavroidis, Panayiotis] Karolinska Inst, Dept Oncol Pathol, S-10401 Stockholm, Sweden. [Mavroidis, Panayiotis] Stockholm Univ, Stockholm, Sweden. [Giantsoudis, Drosoula] Massachusetts Gen Hosp, Dept Radiat Oncol, Ctr Canc, Boston, MA 02114 USA. [Awan, Musaddiq J.; Thomas, Charles R., Jr.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Nijkamp, Jasper; Duppen, Joop C.] Netherlands Canc Inst, Dept Radiotherapy, Antoni Van Leeuwenhoek, Netherlands. [Rasch, Coen R. N.] Univ Amsterdam, Acad Med Ctr, Dept Radiotherapy, NL-1105 AZ Amsterdam, Netherlands. [Thomas, Charles R., Jr.] Oregon Hlth & Sci Univ, Dept Radiat Med, Portland, OR 97201 USA. [Okunieff, Paul] Univ Florida, Dept Radiat Oncol, Gainesville, FL USA. [Jones, William E., III] Audie L Murphy Mem Vet Adm Med Ctr, Dept Radiat Oncol, San Antonio, TX USA. [Kachnic, Lisa A.] Boston Univ, Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. RP Mavroidis, P (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Med Phys, Dept Radiol Sci, Canc Therapy & Res Ctr, 7979 Wurzbach Rd,MC 7889, San Antonio, TX 78229 USA. EM mavroidis@uthscsa.edu OI Nijkamp, Jasper/0000-0001-7523-5881; Fuller, Clifton/0000-0002-5264-3994 FU Hope Foundation/Southwest Oncology Group; National Institutes of Health Clinician Scientist Loan Repayment Program [L30 CA136381-01] FX C.D.F. received support from the Hope Foundation/Southwest Oncology Group Dr. Charles A. Coltman, Jr. Fellowship in Clinical Trials and the National Institutes of Health Clinician Scientist Loan Repayment Program (L30 CA136381-01). CDF has served as consultant for GE Medical Systems, Inc. These funders played no role in the study design, collection, analysis, interpretation of data, manuscript writing, or decision to submit the report for publication. Portions of the data were selected for a poster presentation at ESTRO 31, May 9-12, Barcelona, Spain. NR 20 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-8140 J9 RADIOTHER ONCOL JI Radiother. Oncol. PD SEP PY 2014 VL 112 IS 3 BP 418 EP 424 DI 10.1016/j.radonc.2014.05.011 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AW4CL UT WOS:000346228900018 PM 24996454 ER PT J AU Young, RH Ulbright, TM AF Young, Robert H. Ulbright, Thomas M. TI Introduction SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Editorial Material ID GYNECOLOGICAL PATHOLOGY; DIFFERENTIAL-DIAGNOSIS; OVARIAN-TUMORS; HISTORY; IMMUNOHISTOCHEMISTRY C1 [Young, Robert H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright Pathol Labs, Boston, MA 02163 USA. [Ulbright, Thomas M.] Indiana Univ Sch Med, Dept Pathol, Indianapolis, IN 46202 USA. RP Young, RH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright Pathol Labs, Boston, MA 02163 USA. NR 22 TC 0 Z9 0 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0740-2570 EI 1930-1111 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD SEP PY 2014 VL 31 IS 5 BP 319 EP 322 DI 10.1053/j.semdp.2014.08.002 PG 4 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA AX0CY UT WOS:000346622200001 PM 25440721 ER PT J AU Ulbright, TM Young, RH AF Ulbright, Thomas M. Young, Robert H. TI Testicular and paratesticular tumors and tumor-like lesions in the first 2 decades SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE Testicular neoplasms; Children; Adolescents; Germ cell tumor; Yolk sac tumor; Teratoma; Juvenile granulosa cell tumor ID GERM-CELL TUMORS; JUVENILE GRANULOSA-CELL; OF-THE-LITERATURE; YOLK-SAC-TUMOR; MELANOTIC NEUROECTODERMAL TUMOR; PEUTZ-JEGHERS-SYNDROME; CORD-STROMAL TUMORS; DIFFERENTIATED PAPILLARY MESOTHELIOMA; ACUTE LYMPHOBLASTIC-LEUKEMIA; TUNICA VAGINALIS TESTIS AB The spectrum of testicular tumors and tumor-like lesions that affect young patients (defined for purposes of this article as less than 20 years old) differs significantly from that in an older age group. Although germ cell tumors remain the single largest category, they are a smaller proportion than in adults. Furthermore the pathogenesis and behavior of comparably named germ cell tumors differ depending on whether or not they have developed in prepubertal or postpubertal patients. This is most apparent for the teratomas, which are almost uniformly benign in children but, with some notable exceptions, malignant in the older patients. But even the most common malignant tumor of the testis in children, the yolk sac tumor, despite its identical morphology, lacks the association with other germ cell tumor types, including intratubular germ cell neoplasia, and more aggressive behavior that typify the adult tumors. Among the sex cord-stromal tumors, the juvenile granulosa cell tumor predominates in children, mostly occurs in those under 1-year old, and, for all intents and purposes, is not seen in the postpubertal period. It has a distinctive morphology and, to date, a uniformly benign outcome. There are additional tumors in the sex cord-stromal group that are mostly seen in young patients, including the large cell calcifying Sertoli cell tumor and intratubular large cell hyalinizing Sertoli cell neoplasia. The former is sometimes associated with the Carney syndrome and, to date, all of the latter with the Peutz-Jeghers syndrome. The subtypes of lymphomas and leukemias that involve the testis in children are rare in older patients, and similar remarks pertain to the metastatic tumors, where neuroblastoma (especially) and Wilms' tumor are most common but may be mimicked by primary tumors originating in the paratestis. The pseudoneoplastic lesion, the testicular "tumor" of the adrenogenital syndrome, is usually found in young patients and bears a strong resemblance to the Leydig cell tumor, although there are features that allow its distinction, which is important given its frequently bilateral nature and amenability to medical management through glucocorticoid administration. One of the preferential sites for embryonal rhabdomyosarcoma is the paratestis of young patients, where the spindle cell variant predominates. The melanotic neuroectodermal tumor (retinal anlage tumor) usually occurs in the first year of life, typically involves the epididymis, and uncommonly metastasizes. Occasional cases of the desmoplastic small round cell tumor present in the paratestis of teenagers, and some distinctive tumor-like lesions of the paratestis may also be seen, including meconium periorchitis and splenic-gonadal fusion (occupying both testis and paratestis). These tumors and tumor-like lesions and many others are discussed in this review with the hope it will provide the diagnostic pathologist aid in recognizing the lesions and providing some insight into their clinical significance. (C) 2014 Elsevier Inc. All rights reserved. C1 [Ulbright, Thomas M.] Indiana Univ Sch Med, Indiana Pathol Inst, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA. [Young, Robert H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright Pathol Labs, Boston, MA USA. RP Ulbright, TM (reprint author), Indiana Univ, Hlth Pathol Lab, Room 4014,350 W 11th St, Indianapolis, IN 46202 USA. EM tulbrigh@iupui.edu NR 390 TC 10 Z9 11 U1 2 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0740-2570 EI 1930-1111 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD SEP PY 2014 VL 31 IS 5 BP 323 EP 381 DI 10.1053/j.semdp.2014.07.003 PG 59 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA AX0CY UT WOS:000346622200002 PM 25440720 ER PT J AU Young, RH AF Young, Robert H. TI Ovarian tumors and tumor-like lesions in the first three decades SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE Ovarian neoplasms; Children; Adolescents; Pregnancy ID OF-THE-LITERATURE; SERTOLI-LEYDIG-CELL; YOLK-SAC TUMOR; ENDODERMAL SINUS TUMOR; PEUTZ-JEGHERS SYNDROME; MATURE CYSTIC TERATOMA; FEMALE GENITAL-TRACT; MALIGNANT STRUMA OVARII; CORD-STROMAL TUMOR; SOLID PSEUDOPAPILLARY NEOPLASM AB The relative frequency of ovarian tumors and tumor-like lesions that occur in young females (defined in this article as up to 30 years of age) differs considerably from that seen in older patients. The spectrum of lesions encountered is reviewed, with emphasis on those disproportionately seen in younger patients, particularly primitive germ cell tumors, certain tumors in the sex cord-stromal family, the distinctive tumor known as small cell carcinoma of hypercalcemic type, and selected tumor-like lesions. Comments are made initially on the relative frequency of the various well-known categories of ovarian neoplasia in the first three decades, compared to females overall, and differences within the first three decades are noted. Some of the more noteworthy of these include the occurrence of follicular cysts in neonates due to in-utero maternal stimulation, and the often large size of these lesions, with sometimes dramatic clinical Manifestations; the relative rarity of the commonest germ cell tumor of the ovary, the dermoid cyst, in the very early years of life; the peak incidence of all primitive germ cell tumors in the mid to late teens and early 20s; the peak of small cell carcinoma of hypercalcemic type in the early 20s; the preponderance for the juvenile granulosa cell tumor to occur in the first two decades and for one distinctive form of Sertoli-Leydig cell tumor, the retiform variant, to peak at about 15 years of age; the occasional finding of mucinous cystic tumors, usually benign, in the teenage years, and their greater frequency than other surface epithelial neoplasms; a gradual increase in frequency of all types of surface epithelial neoplasia, but particularly mucinous tumors and serous tumors as patients move through the 20s;. and the rarity of metastatic neoplasia in the first three decades in general, but with occasional dramatic examples such as some Krukenberg tumors being seen in these years, as may some of the distinctive tumors of the young such as neuroblastoma. Consideration of the gross and microscopic features, and differential diagnosis, of individual neoplasms follows the introductory remarks and emphasizes the importance of gross pathology. An example of the latter is the marked difference in most cases between a dermoid cyst and an immature teratoma, the former being dominantly cystic and the latter dominantly solid, and the latter on average twice as large as the former. Caution should be exercised in entertaining a diagnosis of immature teratoma if a lesion is grossly a typical dermoid cyst. The treacherous shared gross characteristics and age distribution of the dysgerminoma and small cell carcinoma of hypercalcemic type are noted. The rarity of monodermal teratomas and malignant neoplasms such as squamous cell carcinoma arising in dermoid cysts in the first three decades is noted. The distinctive features of two recently described stromal neoplasms, microcystic stromal tumor and luteinized thecomas of the type associated with sclerosing peritonitis, are emphasized as is the varied differential diagnosis of the juvenile granulosa cell tumor and Sertoli-Leydig cell tumor. Sections on ovarian tumors and tumor-like lesions in pregnant patients and tumor-like lesions overall conclude the article. (C) 2014 Elsevier Inc. All rights reserved. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. RP Young, RH (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Warren 2,55 Fruit St, Boston, MA 02114 USA. EM rhyoung@mgh.harvard.edu NR 308 TC 5 Z9 5 U1 1 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0740-2570 EI 1930-1111 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD SEP PY 2014 VL 31 IS 5 BP 382 EP 426 DI 10.1053/j.semdp.2014.08.001 PG 45 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA AX0CY UT WOS:000346622200003 PM 25440719 ER PT J AU Ulbright, TM Young, RH AF Ulbright, Thomas M. Young, Robert H. TI Gonadoblastoma and selected other aspects of gonadal pathology in young patients with disorders of sex development SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE Disorders of sex development; Intersex; Gonadal dysgenesis; Gonadoblastoma; Androgen insensitivity syndrome; Ovotesticular disorders ID ANDROGEN INSENSITIVITY SYNDROME; GERM-CELL TUMORS; TESTICULAR FEMINIZATION SYNDROME; PEUTZ-JEGHERS SYNDROME; 17-BETA-HYDROXYSTEROID DEHYDROGENASE-DEFICIENCY; Y-CHROMOSOME; MALE PSEUDOHERMAPHRODITISM; OVOTESTICULAR DISORDER; CONSENSUS STATEMENT; OVARIAN DYSGENESIS AB Some patients with disorders of sex development (DSDs), previously known as intersex disorders, have abnormal gonadal development and an increased risk of germ cell tumors. Because of their relative rarity, however, many pathologists are unfamiliar with the morphological findings in the gonads of DSD patients and their clinical significance. This review concentrates on some of the most common DSDs where gonadal specimens may come to the attention of pathologists. It highlights the findings in gonadal dysgenesis, a DSD with a spectrum of clinical, pathologic, and molecular features but with the shared attributes of having both Y chromosomal material (even if in very limited amounts) in the gonad and also having mutations or deletions in genes necessary for normal gonadal development, mostly in those upstream of the SOX9 gene. This situation results in testicular tissue lacking normal Sertoli cells, which are now considered an essential element for the normal maturation of the primordial germ cells that migrate to the gonad from the embryonic yolk sac. Germ cells with delayed maturation mimic neoplastic germ cells, but there are both morphological and immunohistochemical differences. If the gonad having germ cells with delayed maturation also harbors the TSPY gene on the GBY locus of the Y chromosome, the cells may undergo neoplastic transformation and result in the distinctive gonadoblastoma, whose pathologic features are explored at length herein, including its potential for variant morphologies, such as a "dissecting" pattern. Another important DSD, the androgen insensitivity syndrome (AIS), is discussed at length, including the varied appearances of the testis and its distinctive lesions hamartomas and Sertoli cell adenomas. The potential for germ cell neoplasia in the partial AIS is also discussed and contrasted with that of the complete AIS. A third major topic is ovotesticular DSD (true hermaphroditism). The clinical features and morphology of this condition are reviewed, including the arrangements of the tissue components in an ovotestis. Several other DSDs with distinctive gonadal findings are also considered, including Klinefelter syndrome, 5 alpha-reductase deficiency, 17 beta-hydroxysteroid dehydrogenase deficiency, and female adrenogenital syndrome. (C) 2014 Elsevier Inc. All rights reserved. C1 [Ulbright, Thomas M.] Indiana Univ Sch Med, Indiana Pathol Inst, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA. [Young, Robert H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright Pathol Labs, Boston, MA USA. RP Ulbright, TM (reprint author), Indiana Univ, Hlth Pathol Lab, Room 4014,350 W 11th St, Indianapolis, IN 46202 USA. EM tulbrigh@iupui.edu NR 74 TC 5 Z9 6 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0740-2570 EI 1930-1111 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD SEP PY 2014 VL 31 IS 5 BP 427 EP 440 DI 10.1053/j.semdp.2014.07.001 PG 14 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA AX0CY UT WOS:000346622200004 PM 25129544 ER PT J AU Tepsuporn, S Hu, JZ Gostissa, M Alt, FW AF Tepsuporn, Suprawee Hu, Jiazhi Gostissa, Monica Alt, Frederick W. TI Mechanisms That Can Promote Peripheral B-cell Lymphoma in ATM-Deficient Mice SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; DOUBLE-STRAND BREAKS; V(D)J RECOMBINATION; DNA BREAKS; CHROMOSOMAL TRANSLOCATIONS; GENE AMPLIFICATION; SOMATIC HYPERMUTATION; MYC TRANSLOCATIONS; DAMAGE RESPONSE; MANTLE CELL AB The Ataxia Telangiectasia-mutated (ATM) kinase senses DNA double-strand breaks (DSB) and facilitates their repair. In humans, ATM deficiency predisposes to B- and T-cell lymphomas, but in mice it leads only to thymic lymphomas. We tested the hypothesis that increased DSB frequency at a cellular oncogene could promote B-cell lymphoma by generating ATM-deficient mice with a V(D)J recombination target (DJ beta cassette) within c-myc intron 1 ("DA" mice). We also generated ATM-deficient mice carrying an E mu-Bcl-2 transgene (AB mice) to test whether enhanced cellular survival could promote B-cell lymphomas. About 30% of DA or AB mice and nearly 100% of mice harboring the combined genotypes (DAB mice) developed mature B-cell lymphomas. In all genotypes, B-cell tumors harbored oncogenic c-myc amplification generated by breakage-fusion-bridge (BFB) from dicentric chromosomes formed through fusion of IgH V(D) J recombination-associated DSBs on chromosome 12 to sequences downstream of c-myc on chromosome 15. AB tumors demonstrate that B lineage cells harboring spontaneous DSBs leading to IgH/c-myc dicentrics are blocked from progressing to B-cell lymphomas by cellular apoptotic responses. DA and DAB tumor translocations were strictly linked to the cassette, but occurred downstream, frequently in a 6-kb region adjacent to c-myc that harbors multiple cryptic V(D) J recombination targets, suggesting that bona fide V(D) J target sequences may activate linked cryptic targets. Our findings indicate that ATM deficiency allows IgH V(D) J recombination DSBs in developing B cells to generate dicentric translocations that, via BFB cycles, lead to c-myc-activating oncogenic translocations and amplifications in mature B cells. C1 [Tepsuporn, Suprawee; Hu, Jiazhi; Gostissa, Monica; Alt, Frederick W.] Boston Childrens Hosp, Howard Hughes Med Inst, Program Cellular & Mol Med, Boston, MA USA. [Tepsuporn, Suprawee; Hu, Jiazhi; Gostissa, Monica; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Karp RB09216,300 Longwood Ave, Boston, MA 02115 USA. EM Monica.Gostissa2@childrens.harvard.edu; alt@enders.tch.harvard.edu FU National Cancer Institute of the National Institutes of Health [P01CA109901]; Leukemia and Lymphoma Society of America (LLS) SCOR grant; Eleanor and Miles Shore/Boston Children's Hospital Career Development Fellowship Award; Robertson Foundation/Cancer Research Institute Irvington Fellowship FX This work was supported by grant P01CA109901 from the National Cancer Institute of the National Institutes of Health and a Leukemia and Lymphoma Society of America (LLS) SCOR grant (to F.W. Alt). F.W. Alt is an investigator of the Howard Hughes Medical Institute. M. Gostissa was supported by an Eleanor and Miles Shore/Boston Children's Hospital Career Development Fellowship Award. J. Hu is supported by the Robertson Foundation/Cancer Research Institute Irvington Fellowship. NR 48 TC 8 Z9 8 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD SEP PY 2014 VL 2 IS 9 BP 857 EP 866 DI 10.1158/2326-6066.CIR-14-0090 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA AW2QN UT WOS:000346133700005 PM 24913718 ER PT J AU Lee, SA Lee, CT Fu, MM Elmisalati, W Chuang, SK AF Lee, Sung-Ah Lee, Chun-Teh Fu, Martin M. Elmisalati, Waeil Chuang, Sung-Kiang TI Systematic Review and Meta-Analysis of Randomized Controlled Trials for the Management of Limited Vertical Height in the Posterior Region: Short Implants (5 to 8 mm) vs Longer Implants (> 8 mm) in Vertically Augmented Sites SO INTERNATIONAL JOURNAL OF ORAL & MAXILLOFACIAL IMPLANTS LA English DT Review DE complication; dental implant; failure rate; short implant; survival rate; systematic review ID SHORT DENTAL IMPLANTS; PARTIALLY EDENTULOUS PATIENTS; TREATMENT OUTCOMES; BONE AUGMENTATION; TITANIUM SURFACE; SURVIVAL RATES; CLINICAL-TRIAL; FOLLOW-UP; PROSTHESES; MULTICENTER AB Purpose: The aim of this study was to undertake a systematic review with meta-analysis on randomized controlled trials (RCTs) to compare the rates of survival, success, and complications of short implants to those of longer implants in the posterior regions. Materials and Methods: Electronic literature searches were conducted through the MEDLINE (PubMed) and EMBASE databases to locate all relevant articles published between January 1, 1990, and April 30, 2013. Eligible studies were selected based on inclusion criteria, and quality assessments were conducted. After data extraction, meta-analyses were performed. Results: In total, 539 dental implants (265 short implants [length 5 to 8 mm] and 274 control implants [length > 8 mm]) from four RCTs were included. The fixed prostheses of multiple short and control implants were all splinted. The mean follow-up period was 2.1 years. The 1-year and 5-year cumulative survival rates (CSR) were 98.7% (95% confidence interval [CI], 97.8% to 99.5%) and 93.6% (95% CI, 89.8% to 97.5%), respectively, for the short implant group and 98.0% (95% CI, 96.9% to 99.1%) and 90.3% (95% Cl, 85.2% to 95.4%), respectively, for the control implant group. The CSRs of the two groups did not demonstrate a statistically significant difference. There were also no statistically significant differences in success rates, failure rates, or complications between the two groups. Conclusion: Placement of short dental implants could be a predictable alternative to longer implants to reduce surgical complications and patient morbidity in situations where vertical augmentation procedures are needed. However, only four studies with potential risk of bias were selected in this meta-analysis. Within the limitations of this meta-analysis, these results should be confirmed with robust methodology and RCTs with longer follow-up duration. C1 [Lee, Sung-Ah] Harvard Univ, Sch Dent Med, Chestnut Hill, MA 02467 USA. [Lee, Chun-Teh; Elmisalati, Waeil] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Div Periodontol, Chestnut Hill, MA 02467 USA. [Fu, Martin M.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Chestnut Hill, MA 02467 USA. [Chuang, Sung-Kiang] Massachusetts Gen Hosp, Chestnut Hill, MA USA. [Chuang, Sung-Kiang] Harvard Univ, Sch Dent Med, Dept Oral & Maxillofacial Surg, Chestnut Hill, MA 02467 USA. RP Chuang, SK (reprint author), Harvard Univ, Sch Dent Med, Chestnut Hill Stn, POB 67376, Chestnut Hill, MA 02467 USA. EM sungkiangchuang@gmail.com NR 55 TC 17 Z9 17 U1 1 U2 5 PU QUINTESSENCE PUBLISHING CO INC PI HANOVER PARK PA 4350 CHANDLER DRIVE, HANOVER PARK, IL 60133 USA SN 0882-2786 EI 1942-4434 J9 INT J ORAL MAX IMPL JI Int. J. Oral Maxillofac. Implants PD SEP-OCT PY 2014 VL 29 IS 5 BP 1085 EP 1097 PG 13 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AW2LT UT WOS:000346120200010 PM 25216134 ER PT J AU Kaneko, T Newburger, JW Leopold, JA AF Kaneko, Tsuyoshi Newburger, Jane W. Leopold, Jane A. TI Multivessel Giant Coronary Artery Aneurysms in an Adult With an Acute Coronary Syndrome: Latent Finding of Kawasaki Disease SO JOURNAL OF INVASIVE CARDIOLOGY LA English DT Article DE giant coronary artery aneurysms; Kawasaki disease ID NATURAL-HISTORY; RIGHT HEART; LONG; MANAGEMENT; PATIENT; YOUNG AB We present a case of a patient with an acute coronary syndrome who had the exceptionally rare finding of multivessel giant coronary artery aneurysms (>8 mm) involving the left main and ostial right coronary arteries with concomitant atherosclerotic disease. A work-up to diagnose medical conditions that would predispose the patient to giant coronary aneurysms was negative; however, a detailed history recalled a childhood hospitalization with a constellation of signs and symptoms consistent with Kawasaki disease. This demonstrates an unusual anatomy underlying a common cardiac presentation in adults that has implications for the management of the associated atherosclerotic coronary artery disease. C1 [Kaneko, Tsuyoshi] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiac Surg, Boston, MA USA. [Newburger, Jane W.] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [Newburger, Jane W.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Leopold, Jane A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiol, Boston, MA 02115 USA. RP Leopold, JA (reprint author), 77 Ave Louis Pasteur,NRB0630K, Boston, MA 02115 USA. EM jleopold@partners.org NR 15 TC 0 Z9 0 U1 0 U2 1 PU H M P COMMUNICATIONS PI MALVERN PA 83 GENERAL WARREN BLVD, STE 100, MALVERN, PA 19355 USA SN 1042-3931 EI 1557-2501 J9 J INVASIVE CARDIOL JI J. Invasive Cardiol. PD SEP PY 2014 VL 26 IS 9 BP E127 EP E129 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AW2NY UT WOS:000346126400003 PM 25198497 ER PT J AU Manchikanti, L Falco, FJE Benyamin, RM Gharibo, CG Candido, KD Hirsch, JA AF Manchikanti, Laxmaiah Falco, Frank J. E. Benyamin, Ramsin M. Gharibo, Christopher G. Candido, Kenneth D. Hirsch, Joshua A. TI Epidural Steroid Injections Safety Recommendations by the Multi-Society Pain Workgroup (MPW): More Regulations Without Evidence or Clarification SO PAIN PHYSICIAN LA English DT Article ID ACTIVE-CONTROL TRIAL; CERVICAL TRANSFORAMINAL INJECTION; NERVE ROOT BLOCKS; 2-YEAR FOLLOW-UP; LUMBAR DISC HERNIATION; FLAVUM MIDLINE GAPS; DOUBLE-BLIND; PARTICULATE STEROIDS; RADICULAR PAIN; SPINAL-CORD C1 [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Manchikanti, Laxmaiah] Univ Louisville, Louisville, KY 40292 USA. [Falco, Frank J. E.] Mid Atlantic Spine & Pain Phys, Newark, DE USA. [Falco, Frank J. E.] Temple Univ Hosp & Med Sch, Philadelphia, PA 19140 USA. [Benyamin, Ramsin M.] Millennium Pain Ctr, Bloomington, IL USA. [Benyamin, Ramsin M.] Univ Illinois, Urbana, IL USA. [Gharibo, Christopher G.] NYU, Hosp Joint Dis, Sch Med, NYU Langone, New York, NY 10003 USA. [Candido, Kenneth D.] Advocate Illinois Mason Med Ctr, Chicago, IL USA. [Candido, Kenneth D.] Univ Illinois, Coll Med, Chicago, IL USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd Paducah, Paducah, KY USA. EM drlm@thepainmd.com NR 116 TC 15 Z9 17 U1 0 U2 1 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 SEP-OCT PY 2014 VL 17 IS 5 BP E575 EP E588 PG 14 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA AW1EP UT WOS:000346033600003 PM 25247907 ER PT J AU Manchikanti, L Benyamin, RM Hansen, H Swicegood, J Hirsch, JA AF Manchikanti, Laxmaiah Benyamin, Ramsin M. Hansen, Hans Swicegood, John Hirsch, Joshua A. TI Reversal of Epidural Cuts in 2015 Physician Payment Schedule: Two Steps Forward One Step Back SO PAIN PHYSICIAN LA English DT Article ID INTERVENTIONAL PAIN MANAGEMENT; PATTERNS C1 [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Manchikanti, Laxmaiah] Univ Louisville, Louisville, KY 40292 USA. [Benyamin, Ramsin M.] Millennium Pain Ctr, Bloomington, IL USA. [Benyamin, Ramsin M.] Univ Illinois, Urbana, IL 61801 USA. [Hansen, Hans] Pain Relief Ctr, Conover, NC USA. [Swicegood, John] Adv Intervent Pain & Diagnost Western Arkansas, Fort Smith, AR USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com NR 13 TC 3 Z9 3 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 SEP-OCT PY 2014 VL 17 IS 5 BP E565 EP E573 PG 9 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA AW1EP UT WOS:000346033600002 PM 25247906 ER PT J AU Nizamuddin, SL Koury, KM Lau, ME Watt, LD Gulur, P AF Nizamuddin, Sarah L. Koury, Katharine M. Lau, Mary E. Watt, Lisa D. Gulur, Padma TI Use of Targeted Transversus Abdominus Plane Blocks in Pediatric Patients with Anterior Cutaneous Nerve Entrapment Syndrome SO PAIN PHYSICIAN LA English DT Article DE TAP block; pediatric patients; abdominal pain; ACNES ID WALL PAIN; SYNDROME ACNES; DIAGNOSIS; MANAGEMENT; OUTCOMES AB Anterior cutaneous nerve entrapment syndrome (ACNES) is a commonly overlooked source of chronic abdominal wall pain. A diagnosis of ACNES should be considered in cases of severe, localized abdominal pain that is accentuated by physical activity. Providers should consider diagnosing ACNES once a patient has both a positive result from a Carnett's test and precise localization of pain. We describe the use of transversus abdominus plane (TAP) blocks to treat ACNES in the pediatric patient population. TAP blocks are a treatment modality which have been described less frequently in the management of this syndrome, with rectus sheath blocks being used more commonly. TAP blocks can be used effectively for ACNES by targeting the site of maximal tenderness, which was identified using ultrasound guidance. Moreover, TAP blocks are an attractive procedure option for ACNES as they are less invasive than other commonly used techniques. We present 3 case series reports of pediatric patients evaluated at our institution for severe abdominal pain to describe the clinical manifestations, sequelae, and outcome of ACNES. Though the exact incidence of ACNES in the pediatric population is unknown, this condition has significant implications from chronic pain. Chronic pain can lead to significant emotional and social impacts on these pediatric patients, as well as their on their families. Further, the extensive utilization of health care resources is impacted when children with undiagnosed ACNES undergo invasive treatments when ACNES is not in the early differential. The purpose of this case series report is to prompt better recognition of the condition ACNES, and to highlight the efficacy of TAP blocks as a management strategy. C1 [Nizamuddin, Sarah L.; Koury, Katharine M.; Lau, Mary E.; Watt, Lisa D.; Gulur, Padma] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Gulur, P (reprint author), 204 Lonetree, Irvine, CA 92603 USA. EM pgulur@yahoo.com NR 12 TC 3 Z9 3 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 SEP-OCT PY 2014 VL 17 IS 5 BP E623 EP E627 PG 5 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA AW1EP UT WOS:000346033600008 PM 25247912 ER PT J AU Cong, DM Zhu, W Shi, YJ Pointer, KB Clark, PA Shen, HM Kuo, JS Hu, SS Sun, DD AF Cong, Damin Zhu, Wen Shi, Yejie Pointer, Kelli B. Clark, Paul A. Shen, Hongmei Kuo, John S. Hu, Shaoshan Sun, Dandan TI Upregulation of NHE1 protein expression enables glioblastoma cells to escape TMZ-mediated toxicity via increased H+ extrusion, cell migration and survival SO CARCINOGENESIS LA English DT Article ID NA+/H+ EXCHANGER NHE1; PH REGULATION; CANCER-CELLS; STEM-CELLS; MALIGNANT GLIOMAS; APOPTOSIS; ACTIVATION; INHIBITION; ACIDIFICATION; TEMOZOLOMIDE AB Sodium-hydrogen exchanger isoform 1 (NHE1) plays a role in survival and migration/invasion of several cancers and is an emerging new therapeutic target. However, the role of NHE1 in glioblastoma and the interaction of NHE1 expression and function in glioblastoma cells with cytotoxic temozolomide (TMZ) therapy remain unknown. In this study, we detected high levels of NHE1 protein only in primary human glioma cells (GC), glioma xenografts and glioblastoma, but not in human neural stem cells or astrocytes. GC exhibited an alkaline resting pH i (7.46 +/- 0.04) maintained by robust NHE1-mediated H+ extrusion. GC treatment with TMZ for 2-24 h triggered a transient decrease in pH i, which recovered by 48 h and correlated with concurrent upregulation of NHE1 protein expression. NHE1 protein was colocalized with ezrin at lamellipodia and probably involved in GC migration. The TMZ-treated GC exhibited increased migration and invasion, which was attenuated by addition of NHE1 inhibitor HOE-642. Most importantly, NHE1 inhibition prevented prosurvival extracellular signal-regulated kinase activation and accelerated TMZ-induced apoptosis. Taken together, our study provides the first evidence that GC upregulate NHE1 protein to maintain alkaline pH i. Combining TMZ therapy with NHE1 inhibition suppresses GC migration and invasion, and also augments TMZ-induced apoptosis. These findings strongly suggest that NHE1 is an important cytoprotective mechanism in GC and presents a new therapeutic strategy of combining NHE1 inhibition and TMZ chemotherapy. C1 [Cong, Damin; Hu, Shaoshan; Sun, Dandan] Harbin Med Univ, Affiliated Hosp 2, Dept Neurol Surg, Harbin 150086, Peoples R China. [Cong, Damin; Zhu, Wen; Shi, Yejie; Sun, Dandan] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA. [Pointer, Kelli B.; Clark, Paul A.; Kuo, John S.] Univ Wisconsin, Dept Neurol Surg, Madison, WI 53705 USA. [Shen, Hongmei] Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15213 USA. [Kuo, John S.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI 53705 USA. [Kuo, John S.] Univ Wisconsin, Carbone Canc Ctr, Pittsburgh, PA 15213 USA. [Sun, Dandan] Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15213 USA. RP Sun, DD (reprint author), Harbin Med Univ, Affiliated Hosp 2, Dept Neurol Surg, Harbin 150086, Peoples R China. EM shaoshanhu@126.com; sund@upmc.edu OI Shi, Yejie/0000-0001-7502-9201 FU National Institutes of Health [R01NS75995, R01NS48216, T32 GM008692, U L1RR025011, P30CA014520]; UW Carbone Cancer Center; Headrush Brain Tumor Research Professorship; Roger Loff Memorial Fund "Farming against Brain Cancer"; Program for New Century Excellent Talents In University from the Ministry of Education, China [NCET-09-0131]; China National Natural Scientific Fund [30872650] FX National Institutes of Health (R01NS75995 to D.S., J.S.K., K.B.P.; R01NS48216 to D.S.; T32 GM008692 to K.B.P.; U L1RR025011 and P30CA014520); UW Carbone Cancer Center; Headrush Brain Tumor Research Professorship; Roger Loff Memorial Fund "Farming against Brain Cancer" to J.S.K.; the i?1/2Program for New Century Excellent Talents In University?1/2 from the Ministry of Education, China (NCET-09-0131) and China National Natural Scientific Fund (30872650 to S.H.). NR 50 TC 9 Z9 9 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2014 VL 35 IS 9 BP 2014 EP 2024 DI 10.1093/carcin/bgu089 PG 11 WC Oncology SC Oncology GA AU8EL UT WOS:000345829200013 PM 24717311 ER PT J AU Oreskovic, NM Roth, P Charles, SL Tsigaridi, D Shepherd, K Nelson, KP Bar, M AF Oreskovic, Nicolas M. Roth, Pablina Charles, Suzanne Lanyi Tsigaridi, Dido Shepherd, Kathrine Nelson, Kerrie P. Bar, Moshe TI ATTRIBUTES OF FORM IN THE BUILT ENVIRONMENT THAT INFLUENCE PERCEIVED WALKABILITY SO JOURNAL OF ARCHITECTURAL AND PLANNING RESEARCH LA English DT Article ID PHYSICAL-ACTIVITY; UNITED-STATES; URBAN; OBESITY; WALKING; SCENES; PERCEPTION; PREFERENCE; OVERWEIGHT; CHILDHOOD AB A recent focus of design and building regulations, including form-based codes and the Leadership in Energy and Environmental Design for Neighborhood Development rating system, has been on promoting pedestrian activity. This study assessed perceptions of walkability for residential and commercial streetscapes with different design attributes in order to inform form-based regulations and codes that aim to impact walkability. We scored 424 images on four design attributes purported to influence walkability: variation in building height, variation in building plane, presence of ground-floor windows, and presence of a street focal point. We then presented the images to 45 adults, who were asked to rate the images for walkability. The results showed that perceived walkability varied according to the degree to which a particular design attribute was present, with the presence of ground-floor windows and a street focal point most consistently associated with a space's perceived walkability. Understanding if and which design attributes are most related to walkability could allow planners and developers to focus on the most salient built-environment features influencing physical activity, as well as provide empirical scientific evidence for form-based regulations and zoning codes aimed at impacting walkability. C1 [Oreskovic, Nicolas M.; Bar, Moshe] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Roth, Pablina] Heidelberg Univ, Tiffin, OH USA. [Charles, Suzanne Lanyi] Univ Michigan, Taubman Coll Architecture & Urban Planning, Ann Arbor, MI 48109 USA. [Tsigaridi, Dido] Harvard Univ, Grad Sch Design, Cambridge, MA 02138 USA. [Shepherd, Kathrine] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Nelson, Kerrie P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Oreskovic, NM (reprint author), MGH Ctr Child & Adolescent Hlth Res & Policy, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM noreskovic@partners.org RI Charles, Suzanne/C-4466-2016; OI Charles, Suzanne/0000-0002-8880-7014; Oreskovic, Nicolas/0000-0001-8702-8636 FU NCRR NIH HHS [UL1 RR025758] NR 52 TC 1 Z9 1 U1 2 U2 16 PU LOCKE SCIENCE PUBL CO INC PI CHICAGO PA 117 WEST HARRISON BLDG SUITE 640-L221, CHICAGO, IL 60605 USA SN 0738-0895 J9 J ARCHIT PLAN RES JI J. Archit. Plan. Res. PD FAL PY 2014 VL 31 IS 3 BP 218 EP 232 PG 15 WC Environmental Studies; Urban Studies SC Environmental Sciences & Ecology; Urban Studies GA AU5WR UT WOS:000345674900003 PM 25554719 ER PT J AU Patterson, BJ Kaboli, PJ Tubbs, T Alexander, B Lund, BC AF Patterson, Brandon J. Kaboli, Peter J. Tubbs, Traviss Alexander, Bruce Lund, Brian C. TI Rural access to clinical pharmacy services SO JOURNAL OF THE AMERICAN PHARMACISTS ASSOCIATION LA English DT Article DE Rural access; clinical pharmacy services; veterans ID MEDICATION THERAPY MANAGEMENT; BLOOD-PRESSURE CONTROL; GEOGRAPHIC ACCESS; HEALTH-CARE; HOME; VETERANS; INTEGRATION; CHLORTHALIDONE; TELEPHARMACY AB Objectives: To examine the impact of rural residence and primary care site on use of clinical pharmacy services (CPS) and to describe the use of clinical telepharmacy within the Veterans Health Administration (VHA) health care system. Methods: Using 2011 national VHA data, the frequency of patients with CPS encounters was compared across patient residence (urban or rural) and principal site of primary care (medical center, urban clinic, or rural clinic). The likelihood of CPS utilization was estimated with random effects logistic regression. Individual service types (e.g., anticoagulation clinics) and delivery modes (e.g., telehealth) were also examined. Results: Of 3,040,635 patients, 711,348 (23.4%) received CPS. Service use varied by patient residence (urban: 24.9%; rural: 19.7%) and principal site of primary care (medical center: 25.9%; urban clinic: 22.5%; rural clinic: 17.6%). However, in adjusted analyses, urban-rural differences were explained primarily by primary care site and less so by patient residence. Similar findings were observed for individual CPS types. Telehealth encounters were common, accounting for nearly one-half of patients receiving CPS. Video telehealth was infrequent (<0.2%), but more common among patients of rural clinics than those receiving CPS at medical centers (odds ratio [OR] = 9.7; 95% CI 9.0-10.5). Conclusion: We identified a potential disparity between rural and urban patients' access to CPS, which was largely explained by greater reliance on community clinics for primary care than on medical centers. Future research is needed to determine if this disparity will be alleviated by emerging organizational changes, including expanding telehealth capacity and integrating pharmacists into primary care teams, and whether lessons learned at VHA translate to other settings. C1 [Patterson, Brandon J.] Univ Sci, Philadelphia Coll Pharm, Philadelphia, PA 19104 USA. [Patterson, Brandon J.] Univ Iowa, Iowa City, IA USA. [Tubbs, Traviss; Alexander, Bruce] Iowa City Vet Affairs Hlth Care Syst, Serv Pharm, Iowa City, IA USA. [Lund, Brian C.] US Dept Vet Affairs, Ctr Comprehens Access & Delivery Res & Evaluat, Iowa City, IA USA. RP Patterson, BJ (reprint author), Univ Sci, Coll Pharm, Box 34,600 South 43rd St, Philadelphia, PA 19104 USA. EM b.patterson@usciences.edu FU VA Health Services Research and Development Service [CDA 10-017]; Center for Comprehensive Access & Delivery Research and Evaluation [CIN 13-412] FX The Veterans Rural Health Resource Center-Central Region. Additional support from the VA Health Services Research and Development Service (CDA 10-017) and the Center for Comprehensive Access & Delivery Research and Evaluation (CIN 13-412). NR 38 TC 0 Z9 1 U1 2 U2 8 PU AMER PHARMACEUTICAL ASSOC PI WASHINGTON PA 2215 CONSTITUTION AVE NW, WASHINGTON, DC 20037 USA SN 1544-3191 EI 1544-3450 J9 J AM PHARM ASSOC JI J. Am. Pharm. Assoc. PD SEP-OCT PY 2014 VL 54 IS 5 BP 518 EP 525 DI 10.1331/JAPhA.2014.13248 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AU4SC UT WOS:000345600800016 PM 25216881 ER PT J AU Schultze, T Izar, B Qing, X Mannala, GK Hain, T AF Schultze, Tilman Izar, Benjamin Qing, Xiaoxing Mannala, Gopala K. Hain, Torsten TI Current status of antisense RNA-mediated gene regulation in Listeria monocytogenes SO FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY LA English DT Review DE Listeria monocytogenes; antisense RNA; asRNA; regulation; next generation sequencing; bacteria ID MESSENGER-RNA; ESCHERICHIA-COLI; NONCODING RNAS; VIRULENCE GENE; EXPRESSION; BACTERIA; IDENTIFICATION; GADY; TRANSCRIPTOME; PROMOTERS AB Listeria monocytogenes is a Gram-positive human-pathogen bacterium that served as an experimental model for investigating fundamental processes of adaptive immunity and virulence. Recent novel technologies allowed the identification of several hundred non-coding RNAs (ncRNAs) in the Listeria genome and provided insight into an unexpected complex transcriptional machinery. In this review, we discuss ncRNAs that are encoded on the opposite strand of the target gene and are therefore termed antisense RNAs (asRNAs). We highlight mechanistic and functional concepts of asRNAs in L. monocytogenes and put these in context of asRNAs in other bacteria. Understanding asRNAs will further broaden our knowledge of RNA-mediated gene regulation and may provide targets for diagnostic and antimicrobial development. C1 [Schultze, Tilman; Qing, Xiaoxing; Mannala, Gopala K.; Hain, Torsten] Univ Giessen, Inst Med Microbiol, Dept Med, D-35392 Giessen, Germany. [Izar, Benjamin] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Izar, Benjamin] Harvard Univ, Sch Med, Boston, MA USA. RP Hain, T (reprint author), Univ Giessen, Inst Med Microbiol, Dept Med, Schubertstr 81, D-35392 Giessen, Germany. EM torsten.hain@mikrobio.med.uni-giessen.de NR 40 TC 3 Z9 3 U1 3 U2 14 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 2235-2988 J9 FRONT CELL INFECT MI JI Front. Cell. Infect. Microbiol. PD SEP PY 2014 VL 4 AR 135 DI 10.3389/fcimb.2014.00135 PG 6 WC Immunology; Microbiology SC Immunology; Microbiology GA AU3GU UT WOS:000345501300016 PM 25325017 ER PT J AU Thase, ME Fava, M Nierenberg, AA AF Thase, Michael E. Fava, Maurizio Nierenberg, Andrew A. TI Depression: Addressing Partial Response After First-Line Antidepressant Treatment SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Editorial Material ID DISORDER C1 [Thase, Michael E.] Univ Penn, Sch Med, Dept Psychiat, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Thase, Michael E.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15213 USA. [Fava, Maurizio; Nierenberg, Andrew A.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Fava, Maurizio; Nierenberg, Andrew A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nierenberg, Andrew A.] Harvard Univ, Sch Med, Depress Clin Res Program, Boston, MA USA. RP Thase, ME (reprint author), Univ Penn, Sch Med, Dept Psychiat, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. NR 6 TC 1 Z9 1 U1 0 U2 2 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 SEP PY 2014 VL 75 IS 9 BP 978 EP 980 DI 10.4088/JCP.13018co4c PG 3 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AU3SH UT WOS:000345533300016 PM 25295423 ER PT J AU Corp, SA Gitlin, MJ Altshuler, LL AF Corp, Stephanie A. Gitlin, Michael J. Altshuler, Lori L. TI A Review of the Use of Stimulants and Stimulant Alternatives in Treating Bipolar Depression and Major Depressive Disorder SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Review ID TREATMENT-RESISTANT DEPRESSION; SERIOUS CARDIOVASCULAR EVENTS; PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; MODAFINIL AUGMENTATION; METHYLPHENIDATE; FATIGUE; ATOMOXETINE; SLEEPINESS; ADULTS AB Objective: Prescribers often consider the off-label use of stimulants or stimulant alternatives as adjunctive antidepressants. The authors reviewed the available literature on the efficacy of these agents for treatment of refractory unipolar and bipolar depression. Data Sources: PubMed, MEDLINE, and relevant English-language literature from 1988-2013 were searched. Keywords were dopaminergic, stimulant, augmentation, treatment refractory depression, dextroamphetamine, methylphenidate, modafinil, atomoxetine, and cardiovascular safety. Study Selection: All randomized controlled trials (RCTs) published during this time period were included. When RCTs were unavailable, open studies were summarized. Data Extraction: Data on the efficacy of stimulants and stimulant alternatives as treatment augmentation for unipolar and bipolar depression were extracted. Results: Three open studies showed positive findings for dopaminergic stimulants, and, although 2 RCTs showed negative findings, a recent RCT revealed positive results for lisdexamfetamine as an adjunctive agent. To date, dopaminergic stimulants have not been tested in bipolar depression RCTs. Four completed RCTs suggested that modafinil/armodafinil were beneficial as treatment adjuncts for unipolar and bipolar depression, with very low rates of mood switch in bipolar depression. One study was stopped prematurely due to safety concerns of increased suicidality. Conclusions: Modafinil and armodafinil are recommended treatment adjuncts for refractory unipolar and bipolar depression. Until recently, RCT data on dopaminergic stimulants were too limited to warrant their use as first-line treatment adjuncts. However, the promising results of 1 recent lisdexamfetamine RCT, when considered in the context of the deleterious effect of subsyndromal depression, suggest consideration of dopaminergic medications in treatment-refractory unipolar or bipolar depression when modafinil is cost prohibitive or otherwise contraindicated. C1 [Corp, Stephanie A.; Gitlin, Michael J.; Altshuler, Lori L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Corp, Stephanie A.; Gitlin, Michael J.; Altshuler, Lori L.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [Altshuler, Lori L.] VA Greater Los Angeles Healthcare Syst, West Los Angeles Healthcare Ctr, Psychiat Serv, Los Angeles, CA USA. RP Gitlin, MJ (reprint author), 300 UCLA Med Plaza,Ste 2347, Los Angeles, CA 90095 USA. EM mgitlin@mednet.ucla.edu FU Carl and Roberta Deutsch Foundation FX Sponsorship and partial funding for this review were provided by the Carl and Roberta Deutsch Foundation, which provided a gift for the UCLA Mood Disorders Fellowship at the Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA. NR 28 TC 12 Z9 14 U1 2 U2 13 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 SEP PY 2014 VL 75 IS 9 BP 1010 EP 1018 DI 10.4088/JCP.13r08851 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AU3SH UT WOS:000345533300022 PM 25295426 ER PT J AU Gutierrez, PM AF Gutierrez, Peter M. TI Viewing Suicide Risk Through a New Lens: The Benefits of Examining Symptom Trajectories SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Editorial Material C1 [Gutierrez, Peter M.] Univ Colorado, Sch Med, Vet Integrated Serv Network Mental Illness Res Ed, Denver, CO USA. [Gutierrez, Peter M.] Univ Colorado, Sch Med, Dept Psychiat, Denver, CO 80262 USA. RP Gutierrez, PM (reprint author), Denver VA Med Ctr, Mental Illness Res Educ & Clin Ctr, 1055 Clermont St, Denver, CO 80220 USA. EM peter.gutierrez@va.gov NR 2 TC 2 Z9 2 U1 1 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 SEP PY 2014 VL 75 IS 9 BP E945 EP E946 DI 10.4088/JCP.14com09379 PG 2 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AU3SH UT WOS:000345533300007 PM 25295438 ER PT J AU Nazem, S Spitzer, EG Brenner, LA Bahraini, NH AF Nazem, Sarra Spitzer, Elizabeth G. Brenner, Lisa A. Bahraini, Nazanin H. TI Beyond Categorical Classifications: The Importance of Identifying Posttrauma Symptom Trajectories and Associated Negative Outcomes SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Editorial Material ID AFGHANISTAN WAR VETERANS; STRESS-DISORDER; LATENT STRUCTURE; ANXIETY DISORDERS; SUICIDAL IDEATION; IRAQ; BRAIN C1 [Nazem, Sarra; Spitzer, Elizabeth G.; Brenner, Lisa A.; Bahraini, Nazanin H.] US Dept Vet Affairs, Vet Integrated Serv Network Mental Illness Res Ed, Denver, CO USA. [Nazem, Sarra; Brenner, Lisa A.; Bahraini, Nazanin H.] Univ Colorado, Dept Psychiat, Denver, CO 80202 USA. [Brenner, Lisa A.] Univ Colorado, Dept Neurol, Denver, CO 80202 USA. [Brenner, Lisa A.; Bahraini, Nazanin H.] Univ Colorado, Dept Phys Med & Rehabil, Denver, CO 80202 USA. RP Bahraini, NH (reprint author), VISN 19 MIRECC, 1055 Clermont St, Denver, CO 80220 USA. EM Nazanin.Bahraini@va.gov NR 23 TC 2 Z9 2 U1 1 U2 2 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 SEP PY 2014 VL 75 IS 9 BP E947 EP E949 DI 10.4088/JCP.14com09450 PG 3 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AU3SH UT WOS:000345533300020 PM 25295439 ER PT J AU Valentino, MD Foulston, L Sadaka, A Kos, VN Villet, RA Maria, JS Lazinski, DW Camilli, A Walker, S Hooper, DC Gilmore, MS AF Valentino, Michael D. Foulston, Lucy Sadaka, Ama Kos, Veronica N. Villet, Regis A. Maria, John Santa, Jr. Lazinski, David W. Camilli, Andrew Walker, Suzanne Hooper, David C. Gilmore, Michael S. TI Genes Contributing to Staphylococcus aureus Fitness in Abscess- and Infection-Related Ecologies SO MBIO LA English DT Article ID LARGE-SCALE IDENTIFICATION; VIRULENCE GENES; ANTIMICROBIAL PEPTIDES; BURSA-AUREALIS; ANTISENSE RNA; UNITED-STATES; MURINE MODEL; HUMAN BLOOD; RESISTANT; MUTAGENESIS AB Staphylococcus aureus is a leading cause of both community- and hospital-acquired infections that are increasingly antibiotic resistant. The emergence of S. aureus resistance to even last-line antibiotics heightens the need for the development of new drugs with novel targets. We generated a highly saturated transposon insertion mutant library in the genome of S. aureus and used Tn-seq analysis to probe the entire genome, with unprecedented resolution and sensitivity, for genes of importance in infection. We further identified genes contributing to fitness in various infected compartments ( blood and ocular fluids) and compared them to genes required for growth in rich medium. This resulted in the identification of 426 genes that were important for S. aureus fitness during growth in infection models, including 71 genes that could be considered essential for survival specifically during infection. These findings highlight novel as well as previously known genes encoding virulence traits and metabolic pathways important for S. aureus proliferation at sites of infection, which may represent new therapeutic targets. IMPORTANCE Staphylococcus aureus continues to be a leading cause of antibiotic-resistant community and nosocomial infection. With the bacterium's acquisition of resistance to methicillin and, more recently, vancomycin, the need for the development of new drugs with novel targets is urgent. Applying a highly saturated Tn-seq mutant library to analyze fitness and growth requirements in a murine abscess and in various infection-relevant fluids, we identified S. aureus traits that enable it to survive and proliferate during infection. This identifies potential new targeting opportunities for the development of novel therapeutics. C1 [Valentino, Michael D.; Sadaka, Ama; Kos, Veronica N.; Gilmore, Michael S.] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA 02163 USA. [Valentino, Michael D.; Sadaka, Ama; Kos, Veronica N.; Maria, John Santa, Jr.; Walker, Suzanne; Gilmore, Michael S.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Foulston, Lucy] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Villet, Regis A.; Hooper, David C.] Massachusetts Gen Hosp, Div Infect Dis & Med Serv, Boston, MA 02114 USA. [Lazinski, David W.; Camilli, Andrew] Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Gilmore, MS (reprint author), Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA 02163 USA. EM michael_gilmore@meei.harvard.edu FU NIH/NIAID [AI107248]; Harvard-wide Program on Antibiotic Resistance [AI083214]; Harvard Medical School/Massachusetts Eye and Ear Infirmary Molecular Bases of Eye Disease fellowship training grant [T32 EY007145] FX This work was supported by NIH/NIAID grant AI107248 and the Harvard-wide Program on Antibiotic Resistance AI083214. M. D. V. was supported in part by the Harvard Medical School/Massachusetts Eye and Ear Infirmary Molecular Bases of Eye Disease fellowship training grant (T32 EY007145). NR 61 TC 25 Z9 25 U1 2 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD SEP-OCT PY 2014 VL 5 IS 5 AR e01729-14 DI 10.1128/mBio.01729-14 PG 10 WC Microbiology SC Microbiology GA AU2OY UT WOS:000345459000050 PM 25182329 ER PT J AU Liu, YH Diaz, V Fernandez, E Strong, R Ye, L Baur, JA Lamming, DW Richardson, A Salmon, AB AF Liu, Yuhong Diaz, Vivian Fernandez, Elizabeth Strong, Randy Ye, Lan Baur, Joseph A. Lamming, Dudley W. Richardson, Arlan Salmon, Adam B. TI Rapamycin-induced metabolic defects are reversible in both lean and obese mice SO AGING-US LA English DT Article DE rapamycin; glucose; insulin; obesity; mTOR ID EXTENDS LIFE-SPAN; HIGH-FAT DIET; GENETICALLY HETEROGENEOUS MICE; INSULIN-RESISTANCE; MTOR INHIBITION; ADIPOSE-TISSUE; TRANSPLANT RECIPIENTS; MAMMALIAN TARGET; LIPID-METABOLISM; GLUCOSE AB The inhibition of mTOR (mechanistic target of rapamycin) by the macrolide rapamycin has many beneficial effects in mice, including extension of lifespan and reduction or prevention of several age-related diseases. At the same time, chronic rapamycin treatment causes impairments in glucose metabolism including hyperglycemia, glucose intolerance and insulin resistance. It is unknown whether these metabolic effects of rapamycin are permanent or whether they can be alleviated. Here, we confirmed that rapamycin causes glucose intolerance and insulin resistance in both inbred and genetically heterogeneous mice fed either low fat or high fat diets, suggesting that these effects of rapamycin are independent of genetic background. Importantly, we also found that these effects were almost completely lost within a few weeks of cessation of treatment, showing that chronic rapamycin treatment does not induce permanent impairment of glucose metabolism. Somewhat surprisingly, chronic rapamycin also promoted increased accumulation of adipose tissue in high fat fed mice. However, this effect too was lost when rapamycin treatment was ended suggesting that this effect of rapamycin is also not permanent. The reversible nature of rapamycin's alterations of metabolic function suggests that these potentially detrimental side-effects might be managed through alternative dosing strategies or concurrent treatment C1 [Liu, Yuhong; Diaz, Vivian; Fernandez, Elizabeth; Strong, Randy; Salmon, Adam B.] Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78245 USA. [Fernandez, Elizabeth; Strong, Randy; Salmon, Adam B.] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. [Fernandez, Elizabeth; Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78245 USA. [Ye, Lan; Baur, Joseph A.] Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. [Ye, Lan; Baur, Joseph A.] Univ Penn, Perelman Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. [Lamming, Dudley W.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53726 USA. [Richardson, Arlan] Univ Oklahoma, Hlth Sci Ctr, Reynolds Oklahoma Ctr Aging, Oklahoma City, OK 73104 USA. [Richardson, Arlan] Oklahoma City VA Med Ctr, Oklahoma City, OK 73104 USA. [Salmon, Adam B.] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78245 USA. RP Salmon, AB (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78245 USA. EM salmona@uthscsa.edu FU San Antonio Nathan Shock Center of Excellence in the Basic Biology of Aging - NIA [1P30-AG-13319]; National Institutional of Health RC2 Grand Opportunity grant [AG036613]; American Federation for Aging Research; Geriatric Research Education and Clinical Center of the South Texas Veterans Healthcare System; K99/R00 Pathway to Independence Award from the NIH/NIA [AG-041765]; Biomedical Laboratory Research & Development Service of the Veteran's Affairs Office of Research and Development [1I01BX000547] FX This work was funded in part through the San Antonio Nathan Shock Center of Excellence in the Basic Biology of Aging funded by the NIA (1P30-AG-13319) and by a National Institutional of Health RC2 Grand Opportunity grant (AG036613). Animal studies were performed in the Healthspan and Functional Assessment Core of the San Antonio Shock Center. A. B. S. is funded in part by the American Federation for Aging Research and the Geriatric Research Education and Clinical Center of the South Texas Veterans Healthcare System. D. W. L is supported in part by a K99/R00 Pathway to Independence Award from the NIH/NIA (AG-041765). A. R. is supported in part by a grant from the Biomedical Laboratory Research & Development Service of the Veteran's Affairs Office of Research and Development (1I01BX000547). NR 48 TC 26 Z9 26 U1 1 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD SEP PY 2014 VL 6 IS 9 BP 742 EP 754 PG 13 WC Cell Biology SC Cell Biology GA AU2FG UT WOS:000345431200005 PM 25324470 ER PT J AU Brenner, DR Scherer, D Muir, K Schildkraut, J Boffetta, P Spitz, MR Le Marchand, L Chan, AT Goode, EL Ulrich, CM Hung, RJ AF Brenner, Darren R. Scherer, Dominique Muir, Kenneth Schildkraut, Joellen Boffetta, Paolo Spitz, Margaret R. Le Marchand, Loic Chan, Andrew T. Goode, Ellen L. Ulrich, Cornelia M. Hung, Rayjean J. TI A Review of the Application of Inflammatory Biomarkers in Epidemiologic Cancer Research SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Review ID C-REACTIVE PROTEIN; OXIDATIVE DNA-DAMAGE; CELL LUNG-CANCER; FACTOR-KAPPA-B; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; TANDEM MASS-SPECTROMETRY; URINARY 8-HYDROXY-2'-DEOXYGUANOSINE 8-OHDG; PANCREATIC DUCTAL ADENOCARCINOMA; INFILTRATING CD8(+) LYMPHOCYTES; PROSTAGLANDIN E-2 METABOLITE AB Inflammation is a facilitating process for multiple cancer types. It is believed to affect cancer development and progression through several etiologic pathways, including increased levels of DNA adduct formation, increased angiogenesis, and altered antiapoptotic signaling. This review highlights the application of inflammatory biomarkers in epidemiologic studies and discusses the various cellular mediators of inflammation characterizing the innate immune system response to infection and chronic insult from environmental factors. Included is a review of six classes of inflammation-related biomarkers: cytokines/chemokines, immunerelated effectors, acute-phase proteins, reactive oxygen and nitrogen species, prostaglandins and cyclooxygenase-related factors, and mediators such as transcription factors and growth factors. For each of these biomarkers, we provide a brief overview of the etiologic role in the inflammation response and how they have been related to cancer etiology and progression within the literature. We provide a discussion of the common techniques available for quantification of each marker, including strengths, weaknesses, and potential pitfalls. Subsequently, we highlight a few under-studied measures to characterize the inflammatory response and their potential utility in epidemiologic studies of cancer. Finally, we suggest integrative methods for future studies to apply multifaceted approaches to examine the relationship between inflammatory markers and their roles in cancer development. (C) 2014 AACR. C1 [Brenner, Darren R.; Hung, Rayjean J.] Mt Sinai Hosp, Lunenfeld Tannenbaum Res Inst, Toronto, ON M5T 3L9, Canada. [Brenner, Darren R.] Alberta Hlth Serv, Canc Control Alberta, Dept Canc Epidemiol & Prevent, Calgary, AB, Canada. [Scherer, Dominique; Ulrich, Cornelia M.] Natl Ctr Tumor Dis, Div Prevent Oncol, Heidelberg, Germany. [Scherer, Dominique; Ulrich, Cornelia M.] German Canc Res Ctr, Heidelberg, Germany. [Muir, Kenneth] Univ Warwick, Coventry CV4 7AL, W Midlands, England. [Schildkraut, Joellen] Duke Univ, Durham, NC USA. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Spitz, Margaret R.] Baylor Coll Med, Houston, TX 77030 USA. [Le Marchand, Loic] Canc Res Ctr Hawaii, Honolulu, HI USA. [Chan, Andrew T.] Dana Farber Harvard Canc Ctr, Boston, MA USA. [Goode, Ellen L.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Ulrich, Cornelia M.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. RP Hung, RJ (reprint author), Mt Sinai Hosp, Lunenfeld Tannenbaum Res Inst, 60 Murray St Box 18, Toronto, ON M5T 3L9, Canada. EM neli.ulrich@nct-heidelberg.de; rayjean.hung@lunenfeld.ca RI Hung, Rayjean/A-7439-2013 FU Genetic Associations and Mechanisms in Oncology (GAME-ON), an NCI Cancer Post-GWAS Initiative [U19 CA148127]; National Cancer Institute [R01 CA129063]; NIH [R01 CA137178, K24 DK098311, R01-CA-122443, P50-CA-136393]; Canadian Cancer Society Research Institute [020214] FX The scientific development and funding of this project were, in part, supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON), an NCI Cancer Post-GWAS Initiative, and U19 CA148127 (Principal Investigator: Amos). L. Le Marchand is supported by NIH funding: National Cancer Institute (R01 CA129063; Principal Investigator: L. LeMarchand), "Inflammation and Innate Immunity Genes and Colorectal Cancer Risk." A.T. Chan is supported by NIH funding: (R01 CA137178; Principal Investigator: A.T. Chan) and (K24 DK098311; Principal Investigator: A.T. Chan). E.L. Goode is supported by NIH funding: (R01-CA-122443; Principal Investigator: E.L. Goode) and (P50-CA-136393; Principal Investigator: E.L. Goode). R.J. Hung is supported by Canadian Cancer Society Research Institute (no. 020214, Principal Investigator: Hung). NR 283 TC 16 Z9 16 U1 1 U2 21 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 SEP PY 2014 VL 23 IS 9 BP 1729 EP 1751 DI 10.1158/1055-9965.EPI-14-0064 PG 23 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9XC UT WOS:000345276100003 PM 24962838 ER PT J AU Kantor, ED Hutter, CM Minnier, J Berndt, SI Brenner, H Caan, BJ Campbell, PT Carlson, CS Casey, G Chan, AT Chang-Claude, J Chanock, SJ Cotterchio, M Du, MM Duggan, D Fuchs, CS Giovannucci, EL Gong, J Harrison, TA Hayes, RB Henderson, BE Hoffmeister, M Hopper, JL Jenkins, MA Jiao, S Kolonel, LN Le Marchand, L Lemire, M Ma, J Newcomb, PA Ochs-Balcom, HM Pflugeisen, BM Potter, JD Rudolph, A Schoen, RE Seminara, D Slattery, ML Stelling, DL Thomas, F Thornquist, M Ulrich, CM Warnick, GS Zanke, BW Peters, U Hsu, L White, E AF Kantor, Elizabeth D. Hutter, Carolyn M. Minnier, Jessica Berndt, Sonja I. Brenner, Hermann Caan, Bette J. Campbell, Peter T. Carlson, Christopher S. Casey, Graham Chan, Andrew T. Chang-Claude, Jenny Chanock, Stephen J. Cotterchio, Michelle Du, Mengmeng Duggan, David Fuchs, Charles S. Giovannucci, Edward L. Gong, Jian Harrison, Tabitha A. Hayes, Richard B. Henderson, Brian E. Hoffmeister, Michael Hopper, John L. Jenkins, Mark A. Jiao, Shuo Kolonel, Laurence N. Le Marchand, Loic Lemire, Mathieu Ma, Jing Newcomb, Polly A. Ochs-Balcom, Heather M. Pflugeisen, Bethann M. Potter, John D. Rudolph, Anja Schoen, Robert E. Seminara, Daniela Slattery, Martha L. Stelling, Deanna L. Thomas, Fridtjof Thornquist, Mark Ulrich, Cornelia M. Warnick, Greg S. Zanke, Brent W. Peters, Ulrike Hsu, Li White, Emily TI Gene-Environment Interaction Involving Recently Identified Colorectal Cancer Susceptibility Loci SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; DOSE-RESPONSE METAANALYSIS; PANCREATIC-CANCER; SAMPLE-SIZE; RISK LOCUS; 8Q24; VARIANTS; SCAN; BIAS; 12Q13.13 AB Background: Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) that are associated with risk of colorectal cancer. Prior research has evaluated the presence of gene-environment interaction involving the first 10 identified susceptibility loci, but little work has been conducted on interaction involving SNPs at recently identified susceptibility loci, including: rs10911251, rs6691170, rs6687758, rs11903757, rs10936599, rs647161, rs1321311, rs719725, rs1665650, rs3824999, rs7136702, rs11169552, rs59336, rs3217810, rs4925386, and rs2423279. Methods: Data on 9,160 cases and 9,280 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR) were used to evaluate the presence of interaction involving the above-listed SNPs and sex, body mass index (BMI), alcohol consumption, smoking, aspirin use, postmenopausal hormone (PMH) use, as well as intake of dietary calcium, dietary fiber, dietary folate, red meat, processed meat, fruit, and vegetables. Interaction was evaluated using a fixed effects meta-analysis of an efficient Empirical Bayes estimator, and permutation was used to account for multiple comparisons. Results: None of the permutation-adjusted P values reached statistical significance. Conclusions: The associations between recently identified genetic susceptibility loci and colorectal cancer are not strongly modified by sex, BMI, alcohol, smoking, aspirin, PMH use, and various dietary factors. Impact: Results suggest no evidence of strong gene-environment interactions involving the recently identified 16 susceptibility loci for colorectal cancer taken one at a time. (C) 2014 AACR. C1 [Kantor, Elizabeth D.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kantor, Elizabeth D.; Minnier, Jessica; Carlson, Christopher S.; Du, Mengmeng; Gong, Jian; Harrison, Tabitha A.; Jiao, Shuo; Newcomb, Polly A.; Pflugeisen, Bethann M.; Potter, John D.; Stelling, Deanna L.; Thornquist, Mark; Ulrich, Cornelia M.; Warnick, Greg S.; Peters, Ulrike; Hsu, Li; White, Emily] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Kantor, Elizabeth D.; Carlson, Christopher S.; Du, Mengmeng; Newcomb, Polly A.; Potter, John D.; Ulrich, Cornelia M.; Peters, Ulrike; White, Emily] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Hutter, Carolyn M.; Seminara, Daniela] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Minnier, Jessica] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. [Berndt, Sonja I.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Brenner, Hermann; Hoffmeister, Michael] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Consortium DKTK, Heidelberg, Germany. [Caan, Bette J.] Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA. [Campbell, Peter T.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Casey, Graham] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.; Du, Mengmeng; Fuchs, Charles S.; Ma, Jing] Harvard Univ, Sch Med, Boston, MA USA. [Chan, Andrew T.; Du, Mengmeng; Fuchs, Charles S.; Ma, Jing] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Cotterchio, Michelle] Canc Care Ontario, Toronto, ON, Canada. [Duggan, David] Translat Genom Res Inst, Phoenix, AZ USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hayes, Richard B.] NYU, Sch Med, Dept Populat Hlth, Div Epidemiol, New York, NY USA. [Henderson, Brian E.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Hopper, John L.; Jenkins, Mark A.] Univ Melbourne, Melbourne Sch Populat Hlth, Melbourne, Vic 3010, Australia. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Lemire, Mathieu] Ontario Inst Canc Res, Toronto, ON, Canada. [Ochs-Balcom, Heather M.] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Potter, John D.] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [Rudolph, Anja] German Canc Res Ctr, Unit Genet Epidemiol, Div Canc Epidemiol, Heidelberg, Germany. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA. [Slattery, Martha L.] Univ Utah, Hlth Sci Ctr, Dept Internal Med, Salt Lake City, UT USA. [Thomas, Fridtjof] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Ulrich, Cornelia M.] Natl Ctr Tumor Dis, Div Prevent Oncol, Heidelberg, Germany. [Ulrich, Cornelia M.] German Canc Res Ctr, Heidelberg, Germany. [Zanke, Brent W.] Ottawa Hosp, Res Inst, Clin Epidemiol Program, Ottawa, ON, Canada. [Hsu, Li] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. RP Kantor, ED (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM ekantor@hsph.harvard.edu RI Hoffmeister, Michael/B-5745-2012; Jenkins, Mark/P-7803-2015; Brenner, Hermann/B-4627-2017; OI Hoffmeister, Michael/0000-0002-8307-3197; Jenkins, Mark/0000-0002-8964-6160; Brenner, Hermann/0000-0002-6129-1572; Kantor, Elizabeth/0000-0002-9124-5323; Potter, John/0000-0001-5439-1500; Minnier, Jessica/0000-0002-3527-2757; Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute, NIH, U.S. Department of Health and Human Services [U01 CA137088, R01 CA059045]; NIH [R01 CA60987, CA-95-011, R01 CA48998, P01 CA 055075, UM1 CA167552, R01 137178, P50 CA 127003, R37 CA54281, P01 CA033619, R01 CA63464, U01 CA074783, U01 HG004446, GEI U01 HG 004438, R01 CA076366]; National Cancer Institute, NIH [U01 CA122839, R25CA94880, T32CA009001]; NIH: Australasian Colorectal Cancer Family Registry [U01 CA097735]; Ontario Registry for Studies of Familial Colorectal Cancer [U01 CA074783]; Seattle Colorectal Cancer Family Registry [U01 CA074794]; German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; NHS by the NIH [P50 CA 127003, R01 CA137178, P01 CA 087969]; PHS by the NIH [CA42182]; Ontario Research Fund; Canadian Institutes of Health Research; Ontario Institute for Cancer Research; Ontario Ministry of Research and Innovation; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention; National Cancer Institute; DHHS; Genes; Environment and Health Initiative (GEI) [Z01 CP 010200]; NIH from the National Cancer Institute and Office of Dietary Supplements; National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; ACS; GECCO [R01 CA059045] FX C.S. Carlson, M. Du, J. Gong, T.A. Harrison, L. Hsu, C.M. Hutter, S. Jiao, J. Minnier, B.M. Pflugeisen, U. Peters, D.L. Stelling, M. Thornquist, G.S. Warnick, and C.M. Ulrich are affiliated with GECCO, which is supported by the following grants from the National Cancer Institute, NIH, U.S. Department of Health and Human Services: U01 CA137088 and R01 CA059045. L. Le Marchand is affiliated with Colo2&3, which is supported by the NIH (R01 CA60987). G. Casey, J.L. Hopper, M.A. Jenkins, and P.A. Newcomb are affiliated with CCFR, which is supported by the NIH (RFA #CA-95-011) and through cooperative agreements with members of the CCFR and P.I.s. This genome wide scan was supported by the National Cancer Institute, NIH by U01 CA122839. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CFRs, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFR. The following Colon CFR centers contributed data to this manuscript and were supported by NIH: Australasian Colorectal Cancer Family Registry (U01 CA097735), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), and Seattle Colorectal Cancer Family Registry (U01 CA074794). H. Brenner, J. Chang-Claude, M. Hoffmeister, and A. Rudolph are affiliated with DACHS, which was supported by grants from the German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). B.J. Caan, J.D. Potter, and M.L. Slattery are affiliated with DALS, which was supported by the NIH (R01 CA48998 to M.L. Slattery). A.T. Chan, C.S. Fuchs, E.L. Giovannucci, and J. Ma are affiliated with HPFS, NHS, and PHS. HPFS was supported by the NIH (P01 CA 055075, UM1 CA167552, R01 137178, and P50 CA 127003), NHS by the NIH (R01 CA137178, P01 CA 087969, and P50 CA 127003) and PHS by the NIH (CA42182). B.E. Henderson, L.N. Kolonel, and L. Le Marchand are affiliated with MEC, which is supported by the following grants from the NIH: R37 CA54281, P01 CA033619, and R01 CA63464. M. Cotterchio, M. Lemire, and B.W. Zanke are affiliated with OFCCR, which is supported by the NIH, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. S.I. Berndt, S.J. Chanock, R.B. Hayes, and R.E. Schoen are affiliated with PLCO, which was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Funding for the Lung Cancer and Smoking study was provided by NIH, Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. P.A. Newcomb is affiliated with PMH, which is supported by the NIH (R01 CA076366 to P.A. Newcomb). E. White is affiliated with VITAL, which is supported in part by the NIH (K05 CA154337) from the National Cancer Institute and Office of Dietary Supplements. H.M. Ochs-Balcom and F. Thomas are affiliated with WHI. The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, U.S.; Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. P. Campbell is at the American Cancer Society (ACS) and supported through ACS. M. Du is supported by the National Cancer Institute, NIH (R25CA94880). D. Duggan is affiliated with TGEN and funded through a subaward with GECCO (R01 CA059045). E.D. Kantor is supported by the National Cancer Institute, NIH (R25CA94880 and T32CA009001). D. Seminara is a Senior Scientist and Consortia Coordinator at the Epidemiology and Genetics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, NIH. NR 48 TC 11 Z9 11 U1 0 U2 9 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 SEP PY 2014 VL 23 IS 9 BP 1824 EP 1833 DI 10.1158/1055-9965.EPI-14-0062 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9XC UT WOS:000345276100011 PM 24994789 ER PT J AU Chandler, PD Giovannucci, EL Scott, JB Bennett, GG Ng, K Chan, AT Hollis, BW Emmons, KM Fuchs, CS Drake, BF AF Chandler, Paulette D. Giovannucci, Edward L. Scott, Jamil B. Bennett, Gary G. Ng, Kimmie Chan, Andrew T. Hollis, Bruce W. Emmons, Karen M. Fuchs, Charles S. Drake, Bettina F. TI Null Association between Vitamin D and PSA Levels among Black Men in a Vitamin D Supplementation Trial SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID INDEPENDENT PROSTATE-CANCER; CHOLECALCIFEROL; CALCITRIOL; THERAPY; BIOPSY AB Background: Black men exhibit a high prevalence of vitamin D deficiency as well as a higher incidence of prostate cancer and higher mortality rates from prostate cancer than Whites. There are few data about the effect of vitamin D3 (cholecalciferol) supplementation on prostate-specific antigen (PSA) in healthy Black men. Methods: During three winters from 2007 to 2010, 105 Black men (median age, 48.9 years) of Boston, MA were randomized into a four-arm, double-blind trial for 3 months of placebo, 1,000, 2,000, or 4,000 U of vitamin D3. At baseline and 3 months, free and total PSA was measured. Results: With vitamin D supplementation, no significant differences in free and total PSA were observed; free PSA, -0.0004 ng/mL (P = 0.94) and total PSA, -0.004 ng/mL (P = 0.92) for each additional 1,000 U/d of vitamin D3. Conclusion: Within an unselected population of healthy Black men without a cancer diagnosis, we found no effect of vitamin D supplementation on free or total PSA. Impact: These findings support prior findings of no change in PSA with vitamin D supplementation and emphasize the need for new methods to assess the influence of vitamin D supplementation on prostate cancer prevention. (C) 2014 AACR. C1 [Chandler, Paulette D.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Chandler, Paulette D.; Giovannucci, Edward L.; Ng, Kimmie; Chan, Andrew T.; Emmons, Karen M.; Fuchs, Charles S.] Harvard Univ, Sch Med, Boston, MA USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward L.; Scott, Jamil B.] Michigan State Univ, Coll Human Med, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Emmons, Karen M.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Bennett, Gary G.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. [Ng, Kimmie; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. [Hollis, Bruce W.] Med Univ S Carolina, Div Pediat, Charleston, SC 29425 USA. [Drake, Bettina F.] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci, St Louis, MO 63110 USA. RP Chandler, PD (reprint author), Brigham & Womens Hosp, Div Prevent Med, 900 Commonwealth Ave,Third Floor, Boston, MA 02215 USA. EM pchandler@partners.org OI Drake, Bettina/0000-0001-9340-5848 FU National Cancer Institute [U01CA138962, K24DK098311, P50CA127003, K07CA148894, K22CA126992, 5K05CA124415]; DF/HCC SPORE [CA127003]; Department of Defense Prostate Cancer Research Program [PC081669]; American Society of Clinical Oncology Career Development Award; Pharmavite LLC (Mission Hill, CA) FX This trial was funded by the National Cancer Institute (U01CA138962 to P.D. Chandler; K24DK098311 to A.T. Chan; P50CA127003 and K07CA148894 to K. Ng; K22CA126992 and 5K05CA124415 to K.M. Emmons); CA127003 (DF/HCC SPORE to E.L. Giovannucci), the Department of Defense Prostate Cancer Research Program (PC081669 to B.F. Drake), the American Society of Clinical Oncology Career Development Award (K. Ng), and Pharmavite LLC (Mission Hill, CA). This trial has been registered at www.clinicaltrials.gov (identifier NCT00585637). NR 15 TC 7 Z9 7 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 SEP PY 2014 VL 23 IS 9 BP 1944 EP 1947 DI 10.1158/1055-9965.EPI-14-0522 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9XC UT WOS:000345276100025 PM 24974387 ER PT J AU Schachter, SC Garcia-Cairasco, N Kanner, AM AF Schachter, Steven C. Garcia-Cairasco, Norberto Kanner, Andres M. TI Introduction to Epilepsies: Complexity and Comorbidities SO EPILEPSY & BEHAVIOR LA English DT Editorial Material C1 [Schachter, Steven C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Garcia-Cairasco, Norberto] Univ Sao Paulo, Dept Physiol, Ribeirao Preto Sch Med, BR-14049 Ribeirao Preto, SP, Brazil. [Kanner, Andres M.] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. RP Schachter, SC (reprint author), 165 Cambridge St,Suite 702, Boston, MA 02114 USA. EM sschacht@bidmc.harvard.edu NR 5 TC 1 Z9 1 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-5050 EI 1525-5069 J9 EPILEPSY BEHAV JI Epilepsy Behav. PD SEP PY 2014 VL 38 SI SI BP 1 EP 2 DI 10.1016/j.yebeh.2014.06.035 PG 2 WC Behavioral Sciences; Clinical Neurology; Psychiatry SC Behavioral Sciences; Neurosciences & Neurology; Psychiatry GA AT9FJ UT WOS:000345233000001 PM 25260239 ER PT J AU Ehrlichman, LK Toussaint, RJ Kwon, JY AF Ehrlichman, Lauren K. Toussaint, R. James Kwon, John Y. TI Surgical Relocation of Peroneal Tendon Dislocation With Calcaneal Open Reduction and Internal Fixation: Technique Tip SO FOOT & ANKLE INTERNATIONAL LA English DT Editorial Material DE peroneal tendon dislocation; calcaneus fracture; extensile lateral approach; sinus tarsi approach ID RECURRENT DISLOCATION; OPERATIVE TREATMENT; FRACTURES; SUBLUXATION; REPAIR; RETINACULOPLASTY; DISORDERS C1 [Ehrlichman, Lauren K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Toussaint, R. James] OrthoCarolina, Foot & Ankle Inst, Charlotte, NC USA. [Kwon, John Y.] Mercy Med Ctr, Inst Foot & Ankle Reconstruct, Baltimore, MD USA. RP Ehrlichman, LK (reprint author), Massachusetts Gen Hosp, 55 Fruit St,YAW 3F, Boston, MA 02114 USA. EM lehrlichman@partners.org NR 23 TC 1 Z9 1 U1 1 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1071-1007 EI 1944-7876 J9 FOOT ANKLE INT JI Foot Ankle Int. PD SEP PY 2014 VL 35 IS 9 BP 938 EP 942 DI 10.1177/1071100714537478 PG 5 WC Orthopedics SC Orthopedics GA AT8NI UT WOS:000345189400013 PM 25049367 ER PT J AU Fitzpatrick, EP Kwon, JY AF Fitzpatrick, Ellen P. Kwon, John Y. TI Use of a Pointed Reduction Clamp Placed on the Distal Fibula to Ensure Proper Restoration of Fibular Length and Rotation and Anatomic Reduction of the Syndesmosis: A Technique Tip SO FOOT & ANKLE INTERNATIONAL LA English DT Editorial Material DE trauma; syndesmosis ID ANKLE FRACTURES; TIBIOFIBULAR SYNDESMOSIS; RADIOGRAPHIC EVALUATION; SCREW FIXATION; MALREDUCTION; DISRUPTIONS; INJURIES; CADAVER C1 [Fitzpatrick, Ellen P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kwon, John Y.] Mercy Med Ctr, Inst Foot & Ankle Reconstruct Mercy, Baltimore, MD USA. RP Fitzpatrick, EP (reprint author), Massachusetts Gen Hosp, 55 Fruit St,WHT 5-53, Boston, MA 02114 USA. EM epfitzpatrick@partners.org NR 27 TC 1 Z9 1 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1071-1007 EI 1944-7876 J9 FOOT ANKLE INT JI Foot Ankle Int. PD SEP PY 2014 VL 35 IS 9 BP 943 EP 948 DI 10.1177/1071100714537628 PG 6 WC Orthopedics SC Orthopedics GA AT8NI UT WOS:000345189400014 PM 24958765 ER PT J AU Kinaci, A Neuhaus, V Ring, DC AF Kinaci, Ahmet Neuhaus, Valentin Ring, David C. TI Trends in Bone Graft Use in the United States SO ORTHOPEDICS LA English DT Article ID FEMORAL-SHAFT FRACTURES; INDIRECT REDUCTION; INTERNAL-FIXATION; PLATE FIXATION; ILIAC CREST; NONUNIONS; REHABILITATION AB Bone graft and bone graft substitutes are used to provide structural support and enhance bone healing. Autogenous, allogeneic, and artificial bone grafts each have advantages and drawbacks. The development of allografts, synthetic bone grafts, and new operative techniques may have influenced the use of bone grafts in recent years. The goal of this study was to analyze the use of bone grafts and bone graft substitutes in the United States during a 16-year period. Using data from the National Hospital Discharge Survey, the authors analyzed the use of autogenous and artificial bone grafts in almost 2 million patients in the United States between 1992 and 2007 using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes in 4 periods (1992-1995, 1996-1999, 2000-2003, and 2004-2007). Among an estimated almost 2 million bone graft procedures (83% autogenous, 17% artificial), the use of both types of grafts decreased. The main diagnoses for which bone grafts were used did not change; however, cervical spine diseases and lower-limb fractures decreased more remarkably. Although sex (52% male in the early 1990s to 47% in 2000-2003) and discharge status (more discharges to a short-term or long-term-care facility) significantly changed, age increased from 47 to 53 years and inpatient days decreased significantly from 6 to 5 days during the study period. The use of bone grafts and bone graft substitutes is decreasing in the United States, with a slight shift from autogenous to substitute grafts. C1 [Kinaci, Ahmet; Neuhaus, Valentin; Ring, David C.] Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. [Neuhaus, Valentin] Univ Zurich Hosp, Div Trauma Surg, CH-8091 Zurich, Switzerland. RP Ring, DC (reprint author), Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Yawkey Ctr, Ste 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org OI Neuhaus, Valentin/0000-0003-4012-5628 NR 23 TC 4 Z9 4 U1 0 U2 2 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0147-7447 EI 1938-2367 J9 ORTHOPEDICS JI Orthopedics PD SEP PY 2014 VL 37 IS 9 DI 10.3928/01477447-20140825-54 PG 6 WC Orthopedics SC Orthopedics GA AT5GP UT WOS:000344972400012 PM 25350620 ER PT J AU Moussa, ME Malchau, H Freiberg, AA Kwon, YM AF Moussa, Mohamed E. Malchau, Henrik Freiberg, Andrew A. Kwon, Young-Min TI Effect of Immediate Postoperative Portable Radiographs on Reoperation in Primary Total Knee Arthroplasty SO ORTHOPEDICS LA English DT Article ID RECOVERY ROOM RADIOGRAPHS; TOTAL HIP AB Cost-containment strategies are of increasing importance in total knee arthroplasty (TKA). Obtaining immediate postoperative radiographs following primary TKA is common practice, but their usefulness is controversial. The goal of this study was to evaluate the effect of immediate postoperative radiographs on reoperation within 60 days, assess film quality, and determine the cost associated with these radiographs. Using a billing registry at the authors' institution, the number of TKAs performed from 2000 to 2011 was determined. Of those, the authors determined which had undergone reoperation within 60 days. They evaluated those who had immediate postoperative radiographs following their primary TKA, and determined those who had been reoperated on as a result of information obtained from these radiographs. Of 6603 patients who underwent primary TKA from 2000 to 2011, 136 (2%) underwent reoperation within the first 60 days. The causes leading to reoperation were arthrofibrosis, infection, wound-healing complications, and hematoma. Of the 136 who underwent reoperation, 76 had immediate postoperative radiographs. None of them underwent reoperation as a result of findings noted in the radiographs. Of the radiographs reviewed, only 43% were deemed adequate by predetermined criteria. The results of the current study demonstrate that these radiographs do not affect the decision for reoperations that occur within 60 days of the index procedure. Although there may be a benefit to immediate postoperative radiographs in selected clinical situations, the decision for routine use needs to be weighed in light of significant cost and limited clinical usefulness. C1 [Moussa, Mohamed E.; Malchau, Henrik; Freiberg, Andrew A.; Kwon, Young-Min] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Moussa, Mohamed E.] Hosp Special Surg, Harvard Combined Orthopaed Residency Program, New York, NY 10021 USA. RP Moussa, ME (reprint author), Hosp Special Surg, 535 E 71st St, New York, NY 10021 USA. EM momoussa1@gmail.com NR 11 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0147-7447 EI 1938-2367 J9 ORTHOPEDICS JI Orthopedics PD SEP PY 2014 VL 37 IS 9 DI 10.3928/01477447-20140825-59 PG 5 WC Orthopedics SC Orthopedics GA AT5GP UT WOS:000344972400017 PM 25350625 ER PT J AU Saidi, RF Khaksari, S Ko, DSC AF Saidi, Reza F. Khaksari, Sahriar Ko, Dicken S. C. TI Effect of staff migration on kidney transplant activity in United Network for Organ Sharing region 1 transplant centers SO PROGRESS IN TRANSPLANTATION LA English DT Article ID CARDIAC DEATH; DONATION; STATES AB Organ shortage is unquestionably the greatest challenge facing the field of transplantation today. Transplant centers are constantly competing with one another for limited numbers of organs for their recipients. Recruitment of specialized transplant surgical expertise and leadership is thought to enable a center to grow in volume and thus profitability in the increasingly difficult world of health care reimbursement. In this study, the pattern of kidney transplants at 13 different centers in the United Network for Organ Sharing's region 1 is examined: the comparison is between transplant volume before and after changes in the centers' leadership between 2000 and 2011. Each center's kidney transplant volume showed a significant increase after a leadership change that ultimately regressed to the center's baseline. This study is the first to show that behavioral changes in transplant center competition cause transient increases in transplant volume that quickly regress back to mean levels. (C) 2014 NATCO, The Organization for Transplant Professionals C1 [Saidi, Reza F.] Brown Univ, Alpert Med Sch, Providence, RI 02903 USA. [Khaksari, Sahriar] Suffolk Univ, Boston, MA 02114 USA. [Ko, Dicken S. C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ko, Dicken S. C.] Harvard Univ, Sch Med, Boston, MA USA. RP Saidi, RF (reprint author), Brown Univ, Alpert Med Sch, 222 Richmond St, Providence, RI 02903 USA. EM rsaidi@lifespan.org NR 17 TC 1 Z9 1 U1 0 U2 0 PU INNOVISION COMMUNICATIONS PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 1526-9248 J9 PROG TRANSPLANT JI Prog. Transplant. PD SEP PY 2014 VL 24 IS 3 BP 298 EP 301 DI 10.7182/pit2014644 PG 4 WC Surgery; Transplantation SC Surgery; Transplantation GA AT5LH UT WOS:000344984100013 PM 25193733 ER PT J AU Mitsis, EM Riggio, S Kostakoglu, L Dickstein, DL Machac, J Delman, B Goldstein, M Jennings, D D'Antonio, E Martin, J Naidich, TP Aloysi, A Fernandez, C Seibyl, J DeKosky, ST Elder, GA Marek, K Gordon, W Hof, PR Sano, M Gandy, S AF Mitsis, E. M. Riggio, S. Kostakoglu, L. Dickstein, D. L. Machac, J. Delman, B. Goldstein, M. Jennings, D. D'Antonio, E. Martin, J. Naidich, T. P. Aloysi, A. Fernandez, C. Seibyl, J. DeKosky, S. T. Elder, G. A. Marek, K. Gordon, W. Hof, P. R. Sano, M. Gandy, S. TI Tauopathy PET and amyloid PET in the diagnosis of chronic traumatic encephalopathies: studies of a retired NFL player and of a man with FTD and a severe head injury SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID FOOTBALL-LEAGUE PLAYER; ALZHEIMERS-DISEASE; BRAIN-INJURY; RISK-FACTOR; DEMENTIA; ASSOCIATION; BIOMARKERS; LIFE AB Single, severe traumatic brain injury (TBI) which elevates CNS amyloid, increases the risk of Alzheimer's disease (AD); while repetitive concussive and subconcussive events as observed in athletes and military personnel, may increase the risk of chronic traumatic encephalopathy (CTE). We describe two clinical cases, one with a history of multiple concussions during a career in the National Football League (NFL) and the second with frontotemporal dementia and a single, severe TBI. Both patients presented with cognitive decline and underwent [F-18]-Florbetapir positron emission tomography (PET) imaging for amyloid plaques; the retired NFL player also underwent [F-18]-T807 PET imaging, a new ligand binding to tau, the main constituent of neurofibrillary tangles (NFT). Case 1, the former NFL player, was 71 years old when he presented with memory impairment and a clinical profile highly similar to AD. [F-18]-Florbetapir PET imaging was negative, essentially excluding AD as a diagnosis. CTE was suspected clinically, and [F-18]-T807 PET imaging revealed striatal and nigral [F-18]-T807 retention consistent with the presence of tauopathy. Case 2 was a 56-year-old man with personality changes and cognitive decline who had sustained a fall complicated by a subdural hematoma. At 1 year post injury, [F-18]-Florbetapir PET imaging was negative for an AD pattern of amyloid accumulation in this subject. Focal [F-18]-Florbetapir retention was noted at the site of impact. In case 1, amyloid imaging provided improved diagnostic accuracy where standard clinical and laboratory criteria were inadequate. In that same case, tau imaging with [F-18]-T807 revealed a subcortical tauopathy that we interpret as a novel form of CTE with a distribution of tauopathy that mimics, to some extent, that of progressive supranuclear palsy (PSP), despite a clinical presentation of amnesia without any movement disorder complaints or signs. A key distinguishing feature is that our patient presented with hippocampal involvement, which is more frequently seen in CTE than in PSP. In case 2, focal [F-18]-Florbetapir retention at the site of injury in an otherwise negative scan suggests focal amyloid aggregation. In each of these complex cases, a combination of [F-18]-fluorodeoxyglucose, [F-18]-Florbetapir and/or [F-18]-T807 PET molecular imaging improved the accuracy of diagnosis and prevented inappropriate interventions. C1 [Mitsis, E. M.; Riggio, S.; Martin, J.; Aloysi, A.; Fernandez, C.; Elder, G. A.; Sano, M.; Gandy, S.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Mitsis, E. M.; Dickstein, D. L.; Fernandez, C.; Hof, P. R.; Sano, M.; Gandy, S.] Icahn Sch Med Mt Sinai, Mt Sinais Alzheimers Dis Res Ctr, New York, NY 10029 USA. [Mitsis, E. M.; Riggio, S.; Fernandez, C.; Elder, G. A.; Sano, M.; Gandy, S.] James J Peters VA Med Ctr, Bronx, NY USA. [Riggio, S.; Goldstein, M.; Elder, G. A.; Gandy, S.] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Riggio, S.; Gordon, W.; Gandy, S.] Icahn Sch Med Mt Sinai, NFL Neurol Program, New York, NY 10029 USA. [Kostakoglu, L.; Machac, J.] Icahn Sch Med Mt Sinai, Dept Nucl Med, New York, NY 10029 USA. [Dickstein, D. L.; Hof, P. R.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. [Delman, B.; Naidich, T. P.] Icahn Sch Med Mt Sinai, Dept Radiol, New York, NY 10029 USA. [Jennings, D.; Seibyl, J.; Marek, K.] Yale Univ, Inst Neurodegenerat Disorders, New Haven, CT USA. [D'Antonio, E.; Gordon, W.] Icahn Sch Med Mt Sinai, Dept Rehabil Med, New York, NY 10029 USA. [DeKosky, S. T.] Univ Virginia, Dept Neurol, Charlottesville, VA USA. RP Gandy, S (reprint author), James J Peters VA Med Ctr, Mt Sinais Alzheimers Dis Res Ctr, One Gustave L Levy Pl,Box 1187, New York, NY 10029 USA. EM samuel.gandy@mssm.edu FU Veterans Affairs Administration; Icahn School of Medicine Clinical Research Center.; Cure Alzheimer's Fund; Department of Veteran Affairs; Gideon and Sarah Gartner Foundation; Louis B. Mayer Foundation; NIA; NINDS; Baxter Pharmaceuticals; Polyphenolics; Amicus Pharmaceuticals; Icahn School of Medicine Alzheimer's Disease Research Center [P50 AG005138] FX We gratefully acknowledge Ash Rafique for technical support. EMM received grants from the Veterans Affairs Administration and the Icahn School of Medicine Clinical Research Center. SG thanks the Cure Alzheimer's Fund, the Department of Veteran Affairs, the Gideon and Sarah Gartner Foundation and the Louis B. Mayer Foundation. SG has received grants from NIA, NINDS, Baxter Pharmaceuticals, Polyphenolics and Amicus Pharmaceuticals. He has served as a member of the Data and Safety Monitoring Board for the Pfizer-Janssen Alzheimer's Immunotherapy Alliance, as a member of the Scientific Advisory Board of DiaGenic and as a consultant to Amicus Pharmaceuticals and to Cerora. This research was supported in part by the Icahn School of Medicine Alzheimer's Disease Research Center grant P50 AG005138. NR 29 TC 28 Z9 29 U1 5 U2 27 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD SEP PY 2014 VL 4 AR e441 DI 10.1038/tp.2014.91 PG 8 WC Psychiatry SC Psychiatry GA AT3HS UT WOS:000344827000011 PM 25226550 ER PT J AU Hara, H Lin, YJ Tai, HC Ezzelarab, M Quader, MA Houser, SL Nakao, A Cooper, DKC AF Hara, Hidetaka Lin, Yih Jyh Tai, Hao-Chih Ezzelarab, Mohamed Quader, Mubina A. Houser, Stuart L. Nakao, Atsunori Cooper, David K. C. TI Hematopoietic chimerism following allotransplantation of the spleen, splenocytes or kidney in pigs SO TRANSPLANT IMMUNOLOGY LA English DT Article DE Hematopoietic cell chimerism; Pig; Splenocyte; Transplantation, kidney; Transplantation, spleen ID VERSUS-HOST-DISEASE; MINIATURE SWINE; TRANSPLANTATION TOLERANCE; ALLOGRAFT-REJECTION; IMMUNE-RESPONSE; INDUCTION; ENGRAFTMENT; CELLS; RECIPIENT; BABOON AB Background: Mixed chimerism is associated with donor-specific tolerance. Spleen or splenocyte allotransplantation (Tx) is recognized as potentially tolerogenic. There is no definitive report comparing chimerism levels following spleen and splenocyte Tx in a large animal model. We have compared chimerism after spleen, splenocyte, or kidney Tx in pigs. Methods: Outbred (n = 5) and MHC-defined miniature (n = 1) pigs underwent orthotopic spleen Tx. Outbred pigs received splenocytes through a systemic vein (n = 1) or the portal vein (n = 3). Kidney Tx (n = 2) or concomitant Tx of spleen + kidney (n = 2) was carried out All except one recipient pigs were irradiated (700 cGy thymic and 100-125 cGy whole body) on day -2. Cyclosporine or tacrolimus was administered for 42 days. All donors were males and all recipients were females; chimerism in the blood was determined by Quantification-PCR for the donor Y chromosome. Mixed lymphocyte reaction (MLR) was performed before and after Tx. Results: One week after spleen Tx in outbred and MHC-defined pigs, chimerism ranged between 0.8 and 22.5%, and 5.4-20.1%, respectively, and remained between 17.7 and 67.4%, and 2.2-7.4%, respectively, until day 28. One week after splenocyte Tx, chimerism ranged between 0.1 and 8.5%, and decreased to 0.1-0.8% at 3-4 weeks. There was no detectable chimerism 14 days after kidney Tx. The response on MLR of all recipient pigs to donor cells was decreased after Tx, except in one case of splenocyte Tx, indicating that this pig might have become sensitized. After discontinuation of immunosuppression, most isolated spleen or kidney grafts were not rejected, but the kidney was rejected after concomitant spleen + kidney Tx. Conclusions: There was a significantly higher level of blood chimerism following spleen Tx compared to splenocyte or kidney Tx. However, concomitant Tx of spleen + kidney may be associated with accelerated kidney graft rejection. (C) 2014 Elsevier B.V. All rights reserved. C1 [Hara, Hidetaka; Lin, Yih Jyh; Tai, Hao-Chih; Ezzelarab, Mohamed; Nakao, Atsunori; Cooper, David K. C.] Univ Pittsburgh, Med Ctr, Thomas E Staal Transplantat Inst, Dept Surg, Pittsburgh, PA 15261 USA. [Quader, Mubina A.] Univ Pittsburgh, Med Ctr, Dept Radiat Oncol, Pittsburgh, PA 15261 USA. [Houser, Stuart L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. RP Cooper, DKC (reprint author), Univ Pittsburgh, Thomas E Starzl Transplantat Inst, Thomas E Starzl Biomed Sci Tower,Room W1543, Pittsburgh, PA 15261 USA. EM cooperdk@upmc.edu OI Ezzelarab, Mohamed/0000-0002-3919-5250 FU Uehara Memorial Foundation, Japan; American Diabetes Association [1-04-RA-15] FX Hidetaka Hara, M.D., Ph.D. was a recipient of a postdoctoral fellowship grant from the Uehara Memorial Foundation, Japan. The authors thank Stacy Cashman and Michael Nakon for their invaluable technical assistance. This work was carried out with a grant from the American Diabetes Association #1-04-RA-15 (DKCC). NR 34 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0966-3274 EI 2210-3384 J9 TRANSPL IMMUNOL JI Transpl. Immunol. PD SEP PY 2014 VL 31 IS 3 BP 125 EP 133 DI 10.1016/j.trim.2014.09.006 PG 9 WC Immunology; Transplantation SC Immunology; Transplantation GA AT6OE UT WOS:000345057900002 PM 25245436 ER PT J AU Scalea, JR Torabi, R Tena, A Tasaki, M Gillon, BC Moran, S Cormack, T Villani, V Shimizu, A Sachs, DH Yamada, K AF Scalea, Joseph R. Torabi, Radbeh Tena, Aseda Tasaki, Masayuki Gillon, Bradford C. Moran, Shannon Cormack, Taylor Villani, Vincenzo Shimizu, Akira Sachs, David H. Yamada, Kazuhiko TI The rejuvenating effects of leuprolide acetate on the aged baboon's thymus SO TRANSPLANT IMMUNOLOGY LA English DT Article DE LHRH agonist; Thymic rejuvenation; Baboons ID MISMATCHED RENAL-ALLOGRAFTS; PRIMARILY VASCULARIZED ALLOGRAFTS; MINIATURE SWINE; TRANSPLANTATION TOLERANCE; CLASS-I; STABLE INDUCTION; PROSTATE-CANCER; LHRH AGONIST; T-CELLS; CYCLOSPORINE AB Background: We have previously demonstrated that the juvenile thymus plays an essential role in tolerance induced by both renal transplantation and a short course of calcineurin inhibitors. Aged thymi have a decreased ability to induce tolerance. Luteinizing hormone-releasing hormone (LHRH) is known to pharmacologically rejuvenate the thymus in rodents. In order to develop a clinically applicable regimen of transplantation tolerance in adults, we sought to determine if thymic rejuvenation would occur with LHRH agonism in non-human primates. Methods and results: Thymic rejuvenation was evaluated by magnetic resonance imaging (MRI), histology, as well as in-vitro cellular and molecular tests. Four aged male hamadryas baboons underwent subcutaneous injection of a 3-month depot of Lupron (11.25 mg; LI) and were followed for 3 months. Thymi increased volumetrically by MRI. After LI, thymic cellularity markedly increased within the cortical and medullary thymus. Additionally, a significant increase in the CD+/CD45RA(h1+) population in the peripheral blood occurred for 50 days after LI, and flow cytometry of thymic tissue revealed a large increase in the percentage of CD4(+)/CD8(+) cells. TREC assay corroborated enhancement in thymic function. Conclusion: These data indicate that LI is associated with thymic rejuvenation in baboons, and further confirm that extrinsic factors play an important role in thymic rejuvenation in a non-human primate model. (C) 2014 Elsevier B.V. All rights reserved. C1 [Yamada, Kazuhiko] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Yamada, K (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, MGH East,CNY 149-9019,13th St, Boston, MA 02129 USA. OI Villani, Vincenzo/0000-0002-6078-9766 FU Opp round 6 (NIH) FX The authors would like to thank Dr. David Leonard for his helpful advice and review of this manuscript and Dr. Jeanne B. Ackman for her critical review of the magnetic resonance images. We thank Norwood Abbey Ltd. (Melbourne, Australia) for providing Lupron for this research. This research was supported by the Opp round 6 (NIH) (KY). NR 30 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0966-3274 EI 2210-3384 J9 TRANSPL IMMUNOL JI Transpl. Immunol. PD SEP PY 2014 VL 31 IS 3 BP 134 EP 139 DI 10.1016/j.trim.2014.09.001 PG 6 WC Immunology; Transplantation SC Immunology; Transplantation GA AT6OE UT WOS:000345057900003 PM 25240733 ER PT J AU Ford, AC Quigley, EMM Lacy, BE Lembo, AJ Saito, YA Schiller, LR Soffer, EE Spiegel, BMR Moayyedi, P AF Ford, Alexander C. Quigley, Eamonn M. M. Lacy, Brian E. Lembo, Anthony J. Saito, Yuri A. Schiller, Lawrence R. Soffer, Edy E. Spiegel, Brennan M. R. Moayyedi, Paul TI Effect of Antidepressants and Psychological Therapies, Including Hypnotherapy, in Irritable Bowel Syndrome: Systematic Review and Meta-Analysis SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; COGNITIVE-BEHAVIOR THERAPY; PLACEBO-CONTROLLED TRIAL; FUNCTIONAL GASTROINTESTINAL DISORDERS; DOUBLE-BLIND; SELF-MANAGEMENT; CLINICAL-TRIALS; PRIMARY-CARE; WHOLE GUT; HEALTH AB OBJECTIVES: Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder. Evidence relating to the treatment of this condition with antidepressants and psychological therapies continues to accumulate. METHODS: We performed an updated systematic review and meta-analysis of randomized controlled trials (RCTs). MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to December 2013). Trials recruiting adults with IBS, which compared antidepressants with placebo, or psychological therapies with control therapy or "usual management," were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). RESULTS: The search strategy identified 3,788 citations. Forty-eight RCTs were eligible for inclusion: thirty-one compared psychological therapies with control therapy or " usual management, " sixteen compared antidepressants with placebo, and one compared both psychological therapy and antidepressants with placebo. Ten of the trials of psychological therapies, and four of the RCTs of antidepressants, had been published since our previous meta-analysis. The RR of IBS symptom not improving with antidepressants vs. placebo was 0.67 (95% CI = 0.58-0.77), with similar treatment effects for both tricyclic antidepressants and selective serotonin reuptake inhibitors. The RR of symptoms not improving with psychological therapies was 0.68 (95% CI = 0.61-0.76). Cognitive behavioral therapy, hypnotherapy, multicomponent psychological therapy, and dynamic psychotherapy were all beneficial. CONCLUSIONS: Antidepressants and some psychological therapies are effective treatments for IBS. Despite the considerable number of studies published in the intervening 5 years since we last examined this issue, the overall summary estimates of treatment effect have remained remarkably stable. C1 [Ford, Alexander C.] St James Univ Hosp, Leeds Gastroenterol Inst, Leeds LS9 7TF, W Yorkshire, England. [Ford, Alexander C.] Univ Leeds, Leeds Inst Biomed & Clin Sci, Leeds, W Yorkshire, England. [Quigley, Eamonn M. M.] Houston Methodist Hosp, Dept Med, Div Gastroenterol & Hepatol, Houston, TX USA. [Lacy, Brian E.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Lembo, Anthony J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Saito, Yuri A.] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. [Schiller, Lawrence R.] Baylor Univ, Med Ctr, Digest Hlth Associates Texas, Dallas, TX USA. [Soffer, Edy E.] Univ So Calif, Div Gastroenterol Cedars Sinai, Los Angeles, CA USA. [Spiegel, Brennan M. R.] VA Greater Los Angeles Healthcare Syst, Dept Gastroenterol, Los Angeles, CA USA. [Moayyedi, Paul] McMaster Univ, Hlth Sci Ctr, Div Gastroenterol, Hamilton, ON, Canada. RP Ford, AC (reprint author), St James Univ Hosp, Leeds Gastroenterol Inst, Beckett St,Room 125,4th Floor, Leeds LS9 7TF, W Yorkshire, England. EM alexf12399@yahoo.com RI Ford, Alexander/K-5491-2012; Moayyedi, Paul/M-6178-2014 OI Ford, Alexander/0000-0001-6371-4359; Moayyedi, Paul/0000-0002-3616-9292 NR 75 TC 78 Z9 82 U1 5 U2 32 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD SEP PY 2014 VL 109 IS 9 BP 1350 EP 1365 DI 10.1038/ajg.2014.148 PG 16 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS7UJ UT WOS:000344459800006 PM 24935275 ER EF