FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Pisapia, JM Nayak, NR Salinas, RD Macyszyn, L Lee, JYK Lucas, TH Malhotra, NR Chen, HI Schuster, JM AF Pisapia, Jared M. Nayak, Nikhil R. Salinas, Ryan D. Macyszyn, Luke Lee, John Y. K. Lucas, Timothy H. Malhotra, Neil R. Chen, H. Isaac Schuster, James M. TI Navigated odontoid screw placement using the O-arm: technical note and case series SO JOURNAL OF NEUROSURGERY-SPINE LA English DT Article DE odontoid; O-arm navigation; screw fixation; cervical spine ID SPINE SURGERY; IMAGE GUIDANCE; CERVICAL-SPINE; FRACTURES; FIXATION; MANAGEMENT; FLUOROSCOPY; SYSTEM; AXIS; DENS AB OBJECTIVE As odontoid process fractures become increasingly common in the aging population, a technical understanding of treatment approaches is critical. 3D image guidance can improve the safety of posterior cervical hardware placement, but few studies have explored its utility in anterior approaches. The authors present in a stepwise fashion the technique of odontoid screw placement using the Medtronic O-arm navigation system and describe their initial institutional experience with this surgical approach. METHODS The authors retrospectively reviewed all cases of anterior odontoid screw fixation for Type II fractures at an academic medical center between 2006 and 2015. Patients were identified from a prospectively collected institutional database of patients who had suffered spine trauma. A standardized protocol for navigated odontoid screw placement was generated from the collective experience at the authors' institution. Secondarily, the authors compared collected variables, including presenting symptoms, injury mechanism, surgical complications, blood loss, operative time, radiographically demonstrated nonunion rate, and clinical outcome at most recent follow-up, between navigated and nonnavigated cases. RESULTS Ten patients (three female; mean age 61) underwent odontoid screw placement. Most patients presented with neck pain without a neurological deficit after a fall. O-arm navigation was used in 8 patients. An acute neck hematoma and screw retraction, each requiring surgery, occurred in 2 patients in whom navigation was used. Partial vocal cord paralysis occurred after surgery in one patient in whom no navigation was used. There was no difference in blood loss or operative time with or without navigation. One patient from each group had radiographic nonunion. No patient reported.a worsening of symptoms at follow-up (mean duration 9 months). CONCLUSIONS The authors provide a detailed step-by-step guide to the navigated placement of an odontoid screw. Their surgical experience suggests that 0-arm assisted odontoid screw fixation is a viable approach. Future studies will be needed to rigorously compare the accuracy and efficiency of navigated versus nonnavigated odontoid screw placement. C1 [Pisapia, Jared M.; Nayak, Nikhil R.; Salinas, Ryan D.; Lee, John Y. K.; Lucas, Timothy H.; Malhotra, Neil R.; Chen, H. Isaac; Schuster, James M.] Univ Penn, Dept Neurosurg, 3400 Spruce St,3rd Fl Silverstein Pavil, Philadelphia, PA 19104 USA. [Macyszyn, Luke] Univ Calif Los Angeles, Med Ctr, Dept Neurosurg, Santa Monica, CA USA. [Macyszyn, Luke] Univ Calif Los Angeles, Med Ctr, Dept Orthoped, Santa Monica, CA USA. [Chen, H. Isaac] Philadelphia VA Med Ctr, Dept Neurosurg, Philadelphia, PA USA. RP Pisapia, JM (reprint author), Univ Penn, Dept Neurosurg, 3400 Spruce St,3rd Fl Silverstein Pavil, Philadelphia, PA 19104 USA. EM jared.pisapia@uphs.upenn.edu NR 29 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1547-5654 EI 1547-5646 J9 J NEUROSURG-SPINE JI J. Neurosurg.-Spine PD JAN PY 2017 VL 26 IS 1 BP 10 EP 18 DI 10.3171/2016.5.SPINE151412 PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA EG0LV UT WOS:000390725200004 PM 27517526 ER PT J AU Al-Sukaini, A Pereira, NRP Yu, EW Chebib, I Bredella, MA Schwab, J AF Al-Sukaini, Ahmad Pereira, Nuno Rui Paulino Yu, Elaine W. Chebib, Ivan Bredella, Miriam A. Schwab, Joseph TI Idiopathic tumoral calcinosis-like lesion in the lower cervical spine causing acute central cord syndrome: case report SO JOURNAL OF NEUROSURGERY-SPINE LA English DT Article DE tumoral calcinosis; TC-like lesion; calcinosis; oncology ID OF-THE-LITERATURE; PATIENT; CLASSIFICATION; DISEASE AB A 57-year-old male presented with recurrent falls, bilateral lower-limb paresthesia, and severe neck pain. Imaging revealed a mass compressing his spinal cord. He was admitted for further workup for spinal cord compression. Within 24 hours of admission, he developed upper-extremity weakness while maintaining lower-extremity function. He underwent urgent decompression of his spinal cord. During exposure, a white, creamy odorless substance was noted. This same substance was found under pressure within the spinal canal. The mass was grossly removed, and the patient's weakness improved postoperatively. Based on the clinical picture, intraoperative presentation, and final histological examination, idiopathic tumoral calcinosis-like lesion was considered as the most appropriate diagnosis. C1 [Al-Sukaini, Ahmad; Pereira, Nuno Rui Paulino; Schwab, Joseph] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthoped Surg, 55 Fruit St, Boston, MA 02114 USA. [Chebib, Ivan] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Bredella, Miriam A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Yu, Elaine W.] Harvard Med Sch, Massachusetts Gen Hosp, Endocrine Unit, Boston, MA USA. RP Schwab, J (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthoped Surg, 55 Fruit St, Boston, MA 02114 USA. EM jhschwab@mgh.harvard.edu FU Pathological Society; British Medical and Dental Students' Trust FX Dr. Al-Sukaini acknowledges financial awards from the Pathological Society and the British Medical and Dental Students' Trust, which have funded his research elective period during which this case report was written. NR 20 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1547-5654 EI 1547-5646 J9 J NEUROSURG-SPINE JI J. Neurosurg.-Spine PD JAN PY 2017 VL 26 IS 1 BP 97 EP 102 DI 10.3171/2016.6.SPINE151565 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA EG0LV UT WOS:000390725200015 PM 27611507 ER PT J AU Wang, ZJ Wang, XY Liu, J Chen, J Liu, X Nie, GN Jorgenson, K Sohn, KC Huang, RW Liu, M Liu, B Kong, J AF Wang, Zengjian Wang, Xiaoyun Liu, Jian Chen, Jun Liu, Xian Nie, Guangning Jorgenson, Kristen Sohn, Ki Cheul Huang, Ruiwang Liu, Ming Liu, Bo Kong, Jian TI Acupuncture treatment modulates the corticostriatal reward circuitry in major depressive disorder SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Depression; Acupuncture; Striatum; Resting state functional connectivity; Reward; Fluoxetine ID DEFAULT-MODE NETWORK; STATE FUNCTIONAL CONNECTIVITY; VAGUS NERVE-STIMULATION; KNEE OSTEOARTHRITIS PATIENTS; BASAL GANGLIA; HUMAN BRAIN; ELECTROACUPUNCTURE STIMULATION; SUBTHRESHOLD DEPRESSION; ADOLESCENT DEPRESSION; PREFRONTAL CORTEX AB Major depressive disorder (MDD) is a common disorder with a high prevalence and significant social and economic impacts. Nevertheless, the treatment of MDD is far from satisfactory. Acupuncture treatment has emerged as a promising method for treating MDD. However, the neural mechanism by which acupuncture reduces depressive symptoms is not fully understood. Studies have shown that the corticostriatal reward circuitry is associated with the pathophysiology of MDD; thus, we investigated the corticostriatal resting-state functional connectivity (rsFC) before and after real and sham acupuncture treatments combined with the antidepressant fluoxetine. Forty-six female major depressive patients were assigned to either verum acupuncture plus fluoxetine (n = 22) or sham acupuncture plus fluoxetine (n = 24) treatment for 8 weeks, and resting state functional magnetic resonance imaging (fMRI) data were collected before the first and after the last treatment sessions. The results showed that compared with sham acupuncture, the verum acupuncture group showed: (1) significantly increased rsFC between inferior ventral striatum and medial prefrontal cortex, ventral rostral putamen and amygdala/para-hippocampus, as well as dorsal caudate and middle temporal gyrus; (2) significantly decreased rsFC between right ventral rostra] putamen and right dorsolateral prefrontal cortex, and right dorsal caudate and bilateral cerebellar tonsil. The increased rsFC between the inferior ventral striatum and medial prefrontal cortex, ventral rostral putamen and amygdala/parahippocampus were significantly positively associated with decreased clinical scores (Montgomery-Asberg Depression Rating Scale and Self-Rating Depression Scale scores) at the end of the eight-week treatment. Our findings suggest that acupuncture may achieve treatment effects by modulating the corticostriatal reward/motivation circuitry in MDD patients. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Wang, Zengjian; Huang, Ruiwang; Liu, Ming] South China Normal Univ, Sch Psychol, Key Lab Mental Hlth & Cognit Sci Guangdong Prov, Ctr Study Appl Psychol, Guangzhou 510631, Guangdong, Peoples R China. [Wang, Xiaoyun; Liu, Jian; Chen, Jun; Liu, Xian; Nie, Guangning; Liu, Bo] Guangzhou Univ Tradit Chinese Med, Affiliated Hosp 2, Guangzhou 510120, Guangdong, Peoples R China. [Wang, Zengjian; Jorgenson, Kristen; Kong, Jian] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02115 USA. [Sohn, Ki Cheul] Hosp Catholic Univ Daegu, 3056-6 Daemyeong 4 Nam Gu, Daegu 705718, South Korea. RP Liu, B (reprint author), Guangzhou Univ Tradit Chinese Med, Affiliated Hosp 2, Guangzhou 510120, Guangdong, Peoples R China.; Kong, J (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02115 USA. EM lbgdhtcm@163.com; kongj@nmr.mgh.harvard.edu FU South Korean Health Ministry [CIMI-13-01-32]; NIH/NCCIH [R01AT006364, R01 R01AT008563, R21AT008707, P01 AT006663]; Natural Science Foundation of China [31371049]; Planned Science and Technology Project of Guangdong Province, China [2014B020212022] FX The study was funded by 2013 project of South Korean Health Ministry (CIMI-13-01-32). Jian Kong is supported by R01AT006364, R01 R01AT008563, R21AT008707, and P01 AT006663 from NIH/NCCIH. Ming Liu is supported by the Natural Science Foundation of China (No. 31371049). Ruiwang Huang is supported by the Planned Science and Technology Project of Guangdong Province, China (2014B020212022). NR 128 TC 0 Z9 0 U1 8 U2 8 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 JAN PY 2017 VL 84 BP 18 EP 26 DI 10.1016/j.jpsychires.2016.09.014 PG 9 WC Psychiatry SC Psychiatry GA EG0OW UT WOS:000390733100003 PM 27693978 ER PT J AU Dunn, EC Nishimi, K Powers, A Bradley, B AF Dunn, Erin C. Nishimi, Kristen Powers, Abigail Bradley, Bekh TI Is developmental timing of trauma exposure associated with depressive and post-traumatic stress disorder symptoms in adulthood? SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Sensitive periods; Depression; Post-traumatic stress disorder; Child maltreatment; Trauma ID NATIONAL COMORBIDITY SURVEY; AGE-OF-ONSET; CHILD MALTREATMENT; PSYCHOMETRIC PROPERTIES; SENSITIVE PERIODS; MENTAL-DISORDERS; EARLY-LIFE; ADOLESCENT MALTREATMENT; PSYCHIATRIC-DISORDERS; NEURAL DEVELOPMENT AB Background: Trauma exposure is a known risk factor for psychopathology. However, the impact of the developmental timing of exposure remains unclear. This study examined the effect of age at first trauma exposure on levels of adult depressive and posttraumatic stress disorder (PTSD) symptoms. Methods: Lifetime trauma exposure (including age at first exposure and frequency), current psychiatric symptoms, and sociodemographic information were collected during interviews with adults participating in a study at a public urban hospital in Atlanta, GA. Multiple linear regression models assessed the association between timing of first trauma exposure, classified as early childhood (ages 0-5), middle childhood (ages 6-10), adolescence (ages 11-18), and adulthood (ages 19+), on adult psychopathology in 2892 individuals. Results: Participants exposed to trauma (i.e., child maltreatment, other interpersonal violence, non interpersonal violence, and other events) at any age had higher depressive and PTSD symptoms compared to their unexposed peers. However, participants first exposed to child maltreatment during early childhood had depression and PTSD symptoms that were about twice as high as those exposed during later developmental stages. This association was detected even after controlling for sociodemographic characteristics, exposure to other trauma types, and frequency of exposure. Participants first exposed during middle childhood to other interpersonal violence also had depressive symptoms scores that were about twice as high as those first exposed during adulthood. Conclusions: Trauma exposure-at different ages may differentially impact depressive and PTSD symptoms in adulthood. More detailed examination of timing of trauma exposure is warranted to aid in identifying sensitive periods in development. (C) 2016 Published by Elsevier Ltd. C1 [Dunn, Erin C.; Nishimi, Kristen] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, 185 Cambridge St,Simches Res Bldg, Boston, MA 02114 USA. [Dunn, Erin C.] Harvard Med Sch, Dept Psychiat, 401 Pk Dr,2 West,Room 305, Boston, MA 02215 USA. [Dunn, Erin C.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Ted & Vada Stanley Bldg,75 Ames St, Cambridge, MA 02142 USA. [Nishimi, Kristen] Harvard TH Chan Sch Publ Hlth, 677 Huntington Ave, Boston, MA 02115 USA. [Powers, Abigail; Bradley, Bekh] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, 201 Dowman Dr, Atlanta, GA 30322 USA. [Bradley, Bekh] Atlanta VA Med Ctr, 1670 Clairmont Rd, Decatur, GA 30033 USA. RP Dunn, EC (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, 185 Cambridge St,Simches Res Bldg,6th Floor, Boston, MA 02114 USA. EM edunn2@mgh.harvard.edu; kmn920@mail.harvard.edu; abigail.d.powers@emory.edu; rbradl2@emory.edu FU National Institute of Mental Health within the National Institutes of Health [K01MH102403, MH102890]; National Institute of Child Health and Human Development [HD071982] FX Research reported in this publication was supported by the National Institute of Mental Health within the National Institutes of Health under Award Numbers K01MH102403 (Dunn) and MH102890 (Powers) and the National Institute of Child Health and Human Development under Award Number HD071982 (Bradley). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additionally, the contents of this report do not represent the views of the Department of Veterans Affairs or the United States Government. NR 69 TC 0 Z9 0 U1 27 U2 27 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 JAN PY 2017 VL 84 BP 119 EP 127 DI 10.1016/j.jpsychires.2016.09.004 PG 9 WC Psychiatry SC Psychiatry GA EG0OW UT WOS:000390733100016 PM 27728852 ER PT J AU Rosellini, AJ Monahan, J Street, AE Hill, ED Petukhova, M Reis, BY Sampson, NA Benedek, DM Bliese, P Stein, MB Ursano, RJ Kessler, RC AF Rosellini, Anthony J. Monahan, John Street, Amy E. Hill, Eric D. Petukhova, Maria Reis, Ben Y. Sampson, Nancy A. Benedek, David M. Bliese, Paul Stein, Murray B. Ursano, Robert J. Kessler, Ronald C. TI Using administrative data to identify US Army soldiers at high-risk of perpetrating minor violent crimes SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Crime perpetration; Military violence; Prediction model; Risk model; Violence prediction ID AFGHANISTAN WAR VETERANS; MILITARY PERSONNEL; MENTAL-ILLNESS; VARIABLE SELECTION; GUN VIOLENCE; IRAQ; AGGRESSION; BEHAVIOR; ANGER; REGULARIZATION AB Growing concerns exist about violent crimes perpetrated by U.S. military personnel. Although interventions exist to reduce violent crimes in high-risk populations, optimal implementation requires evidence-based targeting. The goal of the current study was to use machine learning methods (stepwise and penalized regression; random forests) to develop models to predict minor violent crime perpetration among U.S. Army soldiers. Predictors were abstracted. from administrative data available for all 975,057 soldiers in the U.S. Army 2004-2009, among whom 25,966 men and 2728 women committed a first founded minor violent crime (simple assault, blackmail-extortion-intimidation, rioting, harassment). Temporally prior administrative records measuring socio-demographic, Army career, criminal justice, medical/pharmacy, and contextual variables were used to build separate male and female prediction models that were then tested in an independent 2011-2013 sample. Final model predictors included young age, low education, early career stage, prior crime involvement, and outpatient treatment for diverse emotional and substance use problems. Area under the receiver operating characteristic curve was 0.79 (for men and women) in the 2004-2009 training sample and 0.74-0.82 (men-women) in the 2011-2013 test sample. 30.5-28.9% (men-women) of all administratively-recorded crimes in 2004 2009 were committed by the 5% of soldiers having highest predicted risk, with similar proportions (28.5-29.0%) when the 2004-2009 coefficients were applied to the 2011-2013 test sample. These results suggest that it may be possible to target soldiers at high-risk of violence perpetration for preventive interventions, although final decisions about such interventions would require weighing predicted effectiveness against intervention costs and competing risks. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Rosellini, Anthony J.; Hill, Eric D.; Petukhova, Maria; Sampson, Nancy A.; Kessler, Ronald C.] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. [Monahan, John] Univ Virginia, Sch Law, Charlottesville, VA 22903 USA. [Street, Amy E.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Street, Amy E.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Reis, Ben Y.] Boston Childrens Hosp, Predict Med Grp, Boston, MA USA. [Reis, Ben Y.] Harvard Med Sch, Boston, MA USA. [Benedek, David M.; Ursano, Robert J.] Uniformed Serv Univ Hlth Sci, Sch Med, Dept Psychiat, Ctr Study Traumat Stress, Bethesda, MD USA. [Bliese, Paul] Univ South Carolina, Darla Moore Sch Business, Columbia, SC USA. [Bliese, Paul] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA. [Stein, Murray B.] VA San Diego Healthcare Syst, San Diego, CA USA. RP Kessler, RC (reprint author), Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. EM Kessler@hcp.med.harvard.edu FU Department of the Army; U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH) [U01MH087981]; Department of Defense, Office of the Assistant Secretary for Defense for Health Affairs, Defense Health Program (OASD/HA); U.S. Army Medical Research & Materiel Command (USAMRMC), at Fort Detrick, MD [W81XWH-12-2-0113] FX The data analyzed in this report were collected as part of the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 with the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH). This research was conducted by Harvard Medical School and is funded by the Department of Defense, Office of the Assistant Secretary for Defense for Health Affairs, Defense Health Program (OASD/HA), awarded and administered by the U.S. Army Medical Research & Materiel Command (USAMRMC), at Fort Detrick, MD, under Contract Number: (Award #W81XWH-12-2-0113). Although a draft of this manuscript was submitted to the Army for review and comment before submission, this was with the understanding that comments would be advisory. NR 57 TC 0 Z9 0 U1 16 U2 16 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 JAN PY 2017 VL 84 BP 128 EP 136 DI 10.1016/j.jpsychires.2016.09.028 PG 9 WC Psychiatry SC Psychiatry GA EG0OW UT WOS:000390733100017 PM 27741501 ER PT J AU Isaacs, K Mota, NP Tsai, J Harpaz-Rotem, I Cook, JM Kirwin, PD Krystal, JH Southwick, SM Pietrzak, RH AF Isaacs, Kayla Mota, Natalie P. Tsai, Jack Harpaz-Rotem, Ilan Cook, Joan M. Kirwin, Paul D. Krystal, John H. Southwick, Steven M. Pietrzak, Robert H. TI Psychological resilience in US military veterans: A 2-year, nationally representative prospective cohort study SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Resilience; Posttraumatic stress disorder; Veterans; Trauma; Depression; Epidemiology ID POSTTRAUMATIC-STRESS-DISORDER; SOCIAL SUPPORT; POTENTIAL TRAUMA; OLDER PERSONS; UNITED-STATES; DSM-IV; PTSD; LIFE; TRAJECTORIES; EXPOSURE AB Although many cross-sectional studies have examined the correlates of psychological resilience in U.S. military veterans, few longitudinal studies have identified long-term predictors of resilience in this population. The current prospective cohort study utilized data from a nationally representative sample of 2157 U.S. military veterans who completed web-based surveys in two waves (2011 and 2013) as part of the National Health and Resilience in Veterans Study (NHRVS). Cluster analysis of cumulative lifetime exposure to potentially traumatic events and Wave 2 measures of current symptoms of posttraumatic stress, major depressive, and generalized anxiety disorders was performed to characterize different profiles of current trauma-related psychological symptoms. Different profiles were compared with respect to sociodemographic, clinical, and psychosocial characteristics. A three-group cluster analysis revealed a Control group with low lifetime trauma exposure and low current psychological distress (59.5%), a Resilient group with high lifetime trauma and low current distress (27.4%), and a Distressed group with both high trauma exposure and current distress symptoms (13.1%). These results suggest that the majority of trauma-exposed veterans (67.7%) are psychologically resilient. Compared with the Distressed group, the Resilient group was younger, more likely to be Caucasian, and scored lower on measures of physical health difficulties, past psychiatric history, and substance abuse. Higher levels of emotional stability, extraversion, dispositional gratitude, purpose in life, and altruism, and lower levels of openness to experiences predicted resilient status. Prevention and treatment efforts designed to enhance modifiable factors such as gratitude, sense of purpose, and altruism may help promote resilience in highly trauma-exposed veterans. Published by Elsevier Ltd. C1 [Isaacs, Kayla; Tsai, Jack; Harpaz-Rotem, Ilan; Cook, Joan M.; Kirwin, Paul D.; Krystal, John H.; Southwick, Steven M.; Pietrzak, Robert H.] Yale Univ, Dept Psychiat, Sch Med, 333 Cedar St, New Haven, CT 06510 USA. [Mota, Natalie P.] Univ Manitoba, Dept Clin Hlth Psychol, Coll Med, 771 Bannatyne Ave, Winnipeg, MB R3E 3N4, Canada. [Tsai, Jack] US Dept Vet Affairs, New England Mental Illness Res Educ & Clin Ctr, VA Connecticut Healthcare Syst, 950 Campbell Ave 161E, West Haven, CT 06516 USA. [Harpaz-Rotem, Ilan; Krystal, John H.; Southwick, Steven M.; Pietrzak, Robert H.] US Dept Vet Affairs, Natl Ctr Posttraumat Stress Disorder, Clin Neurosci Div, VA Connecticut Healthcare Syst, 950 Campbell Ave, West Haven, CT 06516 USA. [Cook, Joan M.] US Dept Vet Affairs, Natl Ctr Posttraumat Stress Disorder, Evaluat Div, VA Connecticut Healthcare Syst, 950 Campbell Ave, West Haven, CT 06516 USA. [Kirwin, Paul D.] VA Connecticut Healthcare Syst, 950 Campbell Ave, West Haven, CT 06516 USA. RP Pietrzak, RH (reprint author), US Dept Vet Affairs, Natl Ctr PTSD, Clin Neurosci Div, VA Connecticut Healthcare Syst, 950 Campbell Ave 161E, West Haven, CT 06516 USA. EM kayla.isaacs@yale.edu; natalie.mota@umanitoba.ca; jack.tsai@yale.edu; ilan.harpaz-rotem@yale.edu; joan.cook@yale.edu; paul.kirwin@yale.edu; john.krystal@yale.edu; steven.southwick@yale.edu; robert.pietrzak@yale.edu OI Tsai, Jack/0000-0002-0329-648X FU U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder FX The National Health and Resilience in Veterans Study was funded by the U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder. This funding source did not play any role in the conduct or publication of the current study. NR 63 TC 0 Z9 0 U1 15 U2 15 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 JAN PY 2017 VL 84 BP 301 EP 309 DI 10.1016/j.jpsychires.2016.10.017 PG 9 WC Psychiatry SC Psychiatry GA EG0OW UT WOS:000390733100037 PM 27814502 ER PT J AU Ross, RA Kaiser, UB AF Ross, Rachel A. Kaiser, Ursula B. TI REPRODUCTIVE ENDOCRINOLOGY The emotional cost of contraception SO NATURE REVIEWS ENDOCRINOLOGY LA English DT Editorial Material ID PREMENSTRUAL DYSPHORIC DISORDER; DEPRESSION; WOMEN; MOOD AB The link between mood disorders and hormonal fluctuations has long been known, but the direction of this correlation has been questioned. New research suggests that initiation of hormonal contraception leads to increased: risk of first-time diagnosis of or treatment for depression over a short time frame, particularly for adolescents. C1 [Ross, Rachel A.] Beth Israel Deaconess Med Ctr, Dept Psychiat, 330 Brookline Ave, Boston, MA 02215 USA. [Ross, Rachel A.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Anxiety & Traumat Stress Disorders, 1 Bowdoin Sq, Boston, MA 02114 USA. [Kaiser, Ursula B.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, 221 Longwood Ave, Boston, MA 02115 USA. [Kaiser, Ursula B.] Harvard Med Sch, 221 Longwood Ave, Boston, MA 02115 USA. RP Kaiser, UB (reprint author), Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, 221 Longwood Ave, Boston, MA 02115 USA.; Kaiser, UB (reprint author), Harvard Med Sch, 221 Longwood Ave, Boston, MA 02115 USA. EM ukaiser@bwh.harvard.edu NR 10 TC 0 Z9 0 U1 17 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5029 EI 1759-5037 J9 NAT REV ENDOCRINOL JI Nat. Rev. Endocrinol. PD JAN PY 2017 VL 13 IS 1 BP 7 EP 9 DI 10.1038/nrendo.2016.194 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EF9DP UT WOS:000390631200003 PM 27929034 ER PT J AU Wang, GY Nazarian, RM Zhao, LL Hristov, AC Patel, RM Fullen, DR Chan, MP AF Wang, Grace Y. Nazarian, Rosalynn M. Zhao, Lili Hristov, Alexandra C. Patel, Rajiv M. Fullen, Douglas R. Chan, May P. TI Protein gene product 9.5 (PGP9.5) expression in benign cutaneous mesenchymal, histiocytic, and melanocytic lesions: comparison with cellular neurothekeoma SO PATHOLOGY LA English DT Article DE Cellular neurothekeoma; immunohistochemistry; PGP9.5 ID PLEXIFORM FIBROHISTIOCYTIC TUMOR; NERVE SHEATH MYXOMA; IMMUNOHISTOCHEMICAL ANALYSIS; SPITZ NEVI; EPITHELIOID VARIANT; S100A6 EXPRESSION; PILAR LEIOMYOMA; NEOPLASMS; MARKER; UPDATE AB Cellular neurothekeoma (CNTK) frequently enters the differential diagnosis of a benign dermal cellular proliferation. Diagnosis often relies on immunohistochemistry including the use of protein gene product 9.5 (PGP9.5). A previous study demonstrated PGP9.5 expression across a wide variety of soft tissue neoplasms. We explored the utility of this antibody in distinguishing CNTK from other benign dermal-based lesions. A cohort of CNTK (n = 7) and benign cutaneous lesions of neural (n = 28), fibrohistiocytic (n = 23), fibroblastic (n = 25), histiocytic (n = 18), myofibroblastic (n = 7), smooth muscle (n = 14), and melanocytic (n = 12) differentiations were immunostained with PGP9.5. Staining was graded by H-score and compared with CNTK. A significantly higher H-score was found in CNTK compared with the fibrohistiocytic (p = 0.0001), histiocytic (p = 0.0016), myofibroblastic (p = 0.0003), smooth muscle (p < 0.0001), and melanocytic (p = 0.0004) groups, with the exceptions of plexiform fibrohistiocytic tumour, xanthoma, and xanthogranuloma. No significant difference was found when comparing CNTK with fibroblastic and neural lesions, with the exceptions of neurofibroma and perineurioma. In conclusion, PGP9.5 is helpful in distinguishing CNTK from most benign cutaneous fibrohistiocytic, histiocytic, myofibroblastic, smooth muscle, and melanocytic lesions. In addition to CNTK and neural lesions, PGP9.5 is also expressed in benign fibroblastic lesions, and therefore distinction of these lesions should not be based on PGP9.5 positivity. C1 [Wang, Grace Y.; Hristov, Alexandra C.; Patel, Rajiv M.; Fullen, Douglas R.; Chan, May P.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Nazarian, Rosalynn M.] Harvard Med Sch, Massachusetts Gen Hosp, Pathol Serv, Boston, MA USA. [Zhao, Lili] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Hristov, Alexandra C.; Patel, Rajiv M.; Fullen, Douglas R.; Chan, May P.] Univ Michigan, Dept Dermatol, Ann Arbor, MI 48109 USA. RP Chan, MP (reprint author), 1301 Catherine St,Med Sci 1,M3261, Ann Arbor, MI 48109 USA. EM mpchan@med.umich.edu FU Anatomic Pathology Projects Committee at the Department of Pathology, University of Michigan FX This project was funded by the Anatomic Pathology Projects Committee at the Department of Pathology, University of Michigan. The authors state there are no conflicts of interest to disclose. NR 51 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0031-3025 EI 1465-3931 J9 PATHOLOGY JI Pathology PD JAN PY 2017 VL 49 IS 1 BP 44 EP 49 DI 10.1016/j.pathol.2016.09.061 PG 6 WC Pathology SC Pathology GA EG1NC UT WOS:000390798500007 PM 27914685 ER PT J AU Efstathiou, JA AF Efstathiou, Jason A. TI Introduction SO SEMINARS IN RADIATION ONCOLOGY LA English DT Editorial Material ID ADVANCED PROSTATE-CANCER; TRIAL C1 [Efstathiou, Jason A.] Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. RP Efstathiou, JA (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. EM jefstathiou@partners.org NR 10 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 1053-4296 EI 1532-9461 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD JAN PY 2017 VL 27 IS 1 BP 1 EP 2 DI 10.1016/j.semradonc.2016.10.001 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EF9GU UT WOS:000390639500001 PM 27986206 ER PT J AU Rebbeck, TR AF Rebbeck, Timothy R. TI Prostate Cancer Genetics: Variation by Race, Ethnicity, and Geography SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; AFRICAN-AMERICAN MEN; LONG-RANGE INTERACTION; SUSCEPTIBILITY LOCI; RADICAL PROSTATECTOMY; PROTEIN EXPRESSION; LINKAGE ANALYSIS; NONCODING RNA; RISK LOCUS; FAMILIES AB Prostate cancer rates vary substantially by race, ethnicity, and geography. These disparities can be explained by variation in access to screening and treatment, variation in exposure to prostate cancer risk factors, and variation in the underlying biology of prostate carcinogenesis (including genomic propensity of some groups to develop biologically aggressive disease). It is clear that access to screening and access to treatment are critical influencing factors of prostate cancer rates; yet, even among geographically diverse populations with similar access to care (eg, low- and medium-income countries), African descent men have higher prostate cancer rates and poorer prognosis. To date, the proportion of prostate cancer that can be explained by environmental exposures is small, and the effect of these factors across different racial, ethnic, or geographical populations is poorly understood. In contrast, prostate cancer has one of the highest heritabilities of all major cancers. Numerous genetic susceptibility markers have been identified from family-based studies, candidate gene association studies, and genome-wide association studies. Some prostate cancer loci, including the risk loci found at chromosome 8q24, have consistent effects in all groups studied to date. However, replication of many susceptibility loci across race, ethnicity, and geography remains limited, and additional studies in certain populations (particularly in men of African descent) are needed to better understand the underlying genetic basis of prostate cancer. (C) 2016 Elsevier Inc. All rights reserved. C1 [Rebbeck, Timothy R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Rebbeck, Timothy R.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Rebbeck, TR (reprint author), Dana Farber Canc Inst, 1101 Dana Bldg,450 Brookline Ave, Boston, MA 02215 USA. EM Timothy_Rebbeck@dfci.harvard.edu FU NIH, United States [P60-MD006900, U01-CA184734] FX This work was supported by NIH, United States Grants P60-MD006900 and U01-CA184734. NR 82 TC 0 Z9 0 U1 8 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1053-4296 EI 1532-9461 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD JAN PY 2017 VL 27 IS 1 BP 3 EP 10 DI 10.1016/j.semradonc.2016.08.002 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EF9GU UT WOS:000390639500002 PM 27986209 ER PT J AU Moghanaki, D Turkbey, B Vapiwala, N Ehdaie, B Frank, SJ McLaughlin, PW Harisinghani, M AF Moghanaki, Drew Turkbey, Baris Vapiwala, Neha Ehdaie, Behfar Frank, Steven J. McLaughlin, Patrick W. Harisinghani, Mukesh TI Advances in Prostate Cancer Magnetic Resonance Imaging and Positron Emission Tomography-Computed Tomography for Staging and Radiotherapy Treatment Planning SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID EXTERNAL-BEAM RADIATION; CLINICALLY LOCALIZED ADENOCARCINOMA; RADICAL RETROPUBIC PROSTATECTOMY; PERMANENT SOURCE BRACHYTHERAPY; PLANAR BONE-SCINTIGRAPHY; PATHOLOGICAL T3 DISEASE; DIFFUSION-WEIGHTED MRI; LYMPH-NODE METASTASES; PHASE-II TRIAL; ACTIVE SURVEILLANCE AB Conventional prostate cancer staging strategies have limited accuracy to define the location, grade, and burden of disease. Evaluations have historically relied upon prostate-specific antigen levels, digital rectal examinations, random systematic biopsies, computed tomography, pelvic lymphadenectomy, or (99m)technetium methylene diphosphonate bone scans. Today, risk stratification tools incorporate these data in a weighted format to guide management. However, the limitations and potential consequences of their uncertainties are well known. Inaccurate information may contribute to understaging and undertreatment, or overstaging and overtreatment. Meanwhile, advances in multiparametric magnetic resonance imaging (MRI), whole-body MRI, lymphotropic nanoparticle-enhanced MRI, and positron emission tomography are now available to improve the accuracy of risk stratification to facilitate more informed medical decisions. They also guide radiation oncologists to develop more accurate treatment plans. This review provides a primer to incorporate these advances into routine clinical workflow. Published by Elsevier Inc. C1 [Moghanaki, Drew] Hunter Holmes McGuire VA Med Ctr, Radiat Oncol Serv, Richmond, VA USA. [Moghanaki, Drew] Virginia Commonwealth Univ, Dept Radiat Oncol, Richmond, VA USA. [Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Vapiwala, Neha] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Ehdaie, Behfar] Mem Sloan Kettering Canc Ctr, Dept Surg, Urol Serv, New York, NY 10021 USA. [Frank, Steven J.] Univ Texas MD Anderson Canc Ctr, Div Radiat Oncol, Houston, TX 77030 USA. [McLaughlin, Patrick W.] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. [Harisinghani, Mukesh] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. RP Moghanaki, D (reprint author), Hunter Holmes McGuire VA Med Ctr, Radiat Oncol Serv, 1201 Broad Rock Blvd, Richmond, VA 23249 USA. EM drew.moghanaki@gmail.com NR 76 TC 0 Z9 0 U1 2 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 1053-4296 EI 1532-9461 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD JAN PY 2017 VL 27 IS 1 BP 21 EP 33 DI 10.1016/j.semradonc.2016.08.008 PG 13 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EF9GU UT WOS:000390639500004 PM 27986208 ER PT J AU Nguyen, PL AF Nguyen, Paul L. TI Optimization of the Radiation Management of High-Risk Prostate Cancer SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID ANDROGEN-DEPRIVATION THERAPY; PHASE-III TRIAL; PELVIC LYMPH-NODES; RANDOMIZED-TRIALS; RADICAL PROSTATECTOMY; BRACHYTHERAPY BOOST; SHORT-TERM; RADIOTHERAPY; SUPPRESSION; METAANALYSIS AB Radiation and androgen-deprivation therapy (ADD are mainstays of treatment for men with high-risk prostate cancer. High-risk disease is heterogeneous and subcategories of "favorable" high risk and very high risk can identify subgroups with particularly good or poor prognosis to help personalize treatment. Overall, randomized trials show that the combination of radiation and ADT improves survival when compared with either by itself. The optimum duration of ADT remains controversial, but for most healthy men with aggressive disease, approximately 2-3 years of ADT is well supported by the literature. The role of prophylactic pelvic nodal irradiation remains controversial, and there is an ongoing trial testing whether it improves overall survival. The use of brachytherapy boost appears to improve recurrence-free survival without yet improving survival, and may come at the cost of slightly higher toxicity. The addition of docetaxel to radiation and ADT may also improve failure-free survival, but a meta analysis did not find that it improved overall survival. Retrospective data about the relative value of surgery vs radiation for high-risk disease have yielded varied conclusions and are ultimately hampered by the major issue of selection bias in retrospective series. (C) 2016 Elsevier Inc. All rights reserved. C1 [Nguyen, Paul L.] Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. RP Nguyen, PL (reprint author), Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu NR 38 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 1053-4296 EI 1532-9461 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD JAN PY 2017 VL 27 IS 1 BP 43 EP 49 DI 10.1016/j.semradonc.2016.08.009 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EF9GU UT WOS:000390639500006 PM 27986211 ER PT J AU Pitt, SC Lubitz, CC AF Pitt, Susan C. Lubitz, Carrie C. TI Editorial: Complex decision making in thyroid cancer: Costs and consequences-is less more? SO SURGERY LA English DT Editorial Material ID PRACTICE GUIDELINES; SURGERY; MICROCARCINOMA C1 [Pitt, Susan C.] Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, 600 Highland Ave,CSC K4-738, Madison, WI 53792 USA. [Lubitz, Carrie C.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Lubitz, Carrie C.] Inst Technol Assessment, Boston, MA USA. RP Pitt, SC (reprint author), Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, 600 Highland Ave,CSC K4-738, Madison, WI 53792 USA. EM pitt@surgery.wisc.edu NR 10 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD JAN PY 2017 VL 161 IS 1 BP 134 EP 136 DI 10.1016/j.surg.2016.09.014 PG 3 WC Surgery SC Surgery GA EG2AR UT WOS:000390836000031 PM 27855971 ER PT J AU Phitayakorn, R Kelz, RR Petrusa, E Sippel, RS Sturgeon, C Patel, KN Perrier, ND AF Phitayakorn, Roy Kelz, Rachel R. Petrusa, Emil Sippel, Rebecca S. Sturgeon, Cord Patel, Kepal N. Perrier, Nancy D. TI Expert consensus of general surgery residents' proficiency with common endocrine operations SO SURGERY LA English DT Article; Proceedings Paper CT 37th Annual Meeting of the American-Association-of-Endocrine-Surgeons CY APR 10-12, 2016 CL Baltimore, MD SP Amer Assoc Endocrine Surg ID PROGRAM-DIRECTORS; AUTONOMY; ROOM; ENTRUSTMENT; BEHAVIORS AB Background. Proficiency with common endocrine operations is expected of graduating, general surgery residents. However, no expert consensus guidelines exist about these expectations. Methods. Members of the American Association of Endocrine Surgeons were surveyed about their opinions on resident proficiency with common endocrine operations. Results. Overall response rate was 38 %. A total of 92% of the respondents operate with residents. On average, they believed that the steps of a total thyroidectomy for benign disease and a well-localized parathyroidectomy could be performed by a postgraduate year 4 surgery resident. Specific steps that they thought might require more training included decisions to divide the strap muscles or leaving a drain. Approximately 66% of respondents thought that a postgraduate year 5 surgery resident could independently perform a total thyroidectomy for benign disease, but only 45% felt similarly for malignant thyroid disease; 79% thought that a postgraduate year 5 surgery resident could independently perform a parathyroidectomy. Respondents' years of experience correlated with their opinions about resident autonomy for total thyroidectomy (benign r = 0.38, P < .001; malignant r = 0.29, P = .001) but not parathyroidectomy. On multivariate analysis, sex and years of experience of the respondents were independently associated with opinions on autonomy but only for total thyroidectomy for benign disease (P = .001). Annual endocrine volume of the respondents did not correlate with beliefs in autonomy. Conclusion. There was general agreement among responding members of the AAES about resident proficiency and autonomy with common endocrine operations. As postgraduate year 5 residents may not be proficient in advanced endocrine operations, opportunities exist to improve training prior to the transition to independent practice for graduates that anticipate performing endocrine operations routinely. C1 [Phitayakorn, Roy; Petrusa, Emil] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Phitayakorn, Roy; Petrusa, Emil] Harvard Med Sch, Boston, MA USA. [Kelz, Rachel R.] Hosp Univ Penn, Dept Surg, Ctr Surg & Hlth Econ, 3400 Spruce St, Philadelphia, PA 19104 USA. [Sippel, Rebecca S.] Univ Wisconsin, Sect Endocrine Surg, Madison, WI USA. [Sturgeon, Cord] Northwestern Univ, Dept Surg, Feinberg Sch Med, Chicago, IL 60611 USA. [Patel, Kepal N.] NYU, Langone Med Ctr, New York, NY USA. [Perrier, Nancy D.] MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX USA. RP Phitayakorn, R (reprint author), Massachusetts Gen Hosp, Dept Surg, Wang ACC, Suite 460,15 Parkman St, Boston, MA 02114 USA. EM rphitayakorn@mgh.harvard.edu OI patel, kepal/0000-0002-9088-4844 NR 22 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD JAN PY 2017 VL 161 IS 1 BP 280 EP 287 DI 10.1016/j.surg.2016.06.067 PG 8 WC Surgery SC Surgery GA EG2AR UT WOS:000390836000066 PM 27865597 ER PT J AU Danger, R Chesneau, M Paul, C Guerif, P Durand, M Newell, KA Turka, LA Kanaparthi, S Soulillou, JP Sykes, M Houlgatte, R Giral, M Ramstein, G Brouard, S AF Danger, R. Chesneau, M. Paul, C. Guerif, P. Durand, M. Newell, K. A. Turka, L. A. Kanaparthi, S. Soulillou, J. P. Sykes, M. Houlgatte, R. Giral, M. Ramstein, G. Brouard, S. TI A COMPOSITE SCORE ASSOCIATED WITH CLINICAL OPERATIONAL TOLERANCE IN KIDNEY TRANSPLANT RECIPIENTS SO TRANSPLANT INTERNATIONAL LA English DT Meeting Abstract C1 [Houlgatte, R.] CHU Nancy, DRCI, Nancy, France. [Houlgatte, R.] INSERM, UMR 954, Nancy, France. [Giral, M.; Brouard, S.] CHU Nantes, CIC Biotherapy, Nantes, France. [Danger, R.; Chesneau, M.; Paul, C.; Guerif, P.; Durand, M.; Soulillou, J. P.; Giral, M.; Brouard, S.] CHU Nantes, ITUN, Nantes, France. [Danger, R.; Chesneau, M.; Paul, C.; Guerif, P.; Durand, M.; Soulillou, J. P.; Giral, M.; Brouard, S.] INSERM, UMR1064, Nantes, France. [Giral, M.] Univ Nantes, Fac Med, Nantes, France. [Ramstein, G.] Univ Nantes, Ecole Mines Nantes, LINA DUKe, UMR 6241, Nantes, France. [Ramstein, G.] CNRS, Nantes, France. [Newell, K. A.] Emory Univ, Dept Surg, Atlanta, GA 30322 USA. [Kanaparthi, S.] Immune Tolerance Network, Bethesda, MD USA. [Turka, L. A.] Massachusetts Gen Hosp, Dept Surg, Ctr Transplantat Sci, Boston, MA 02114 USA. [Turka, L. A.] Harvard Med Sch, Boston, MA USA. [Sykes, M.] Columbia Univ, Med Ctr, Columbia Ctr Translat Immunol, New York, NY 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 0934-0874 EI 1432-2277 J9 TRANSPL INT JI Transpl. Int. PD JAN PY 2017 VL 30 SU 1 MA O66 BP 21 EP 21 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA EG0AE UT WOS:000390692000067 ER PT J AU Rahman, F Himali, JJ Yin, XY Beiser, AS Ellinor, PT Lubitz, SA Vasan, RS Magnani, JW McManus, DD Seshadri, S Benjamin, EJ AF Rahman, Faisal Himali, Jayandra J. Yin, Xiaoyan Beiser, Alexa S. Ellinor, Patrick T. Lubitz, Steven A. Vasan, Ramachandran S. Magnani, Jared W. McManus, David D. Seshadri, Sudha Benjamin, Emelia J. TI Serum brain-derived neurotrophic factor and risk of atrial fibrillation SO AMERICAN HEART JOURNAL LA English DT Article ID CORONARY-ARTERY-DISEASE; COMMUNITY-BASED COHORT; NECROSIS-FACTOR-ALPHA; MYOCARDIAL-INFARCTION; CADHERIN EXPRESSION; ENDOTHELIAL-CELLS; INFLAMMATION; PREVALENCE; PREDICTION; PREVENTS AB Background and objective Brain-derived neurotrophic factor (BDNF) is expressed by endothelial cells and can affect cardiovascular function. We examined if serum BDNF was associated with risk of incident atrial fibrillation (AF) in the Framingham Heart Study. Methods We studied individuals without an AF diagnosis at baseline from the Framingham original and offspring cohorts. We used age-and sex-adjusted, and multivariable-adjusted Cox proportional hazards regression models to examine the association of serum BDNF concentrations with 10-year risk of incident AF. Results We studied 3,457 participants (mean age 65 +/- 11 years, 58% women). During follow-up, 395 participants developed AF. In unadjusted analysis, higher mean serum BDNF concentration was associated with lower incidence of AF (hazard ratio 0.89 per SD, 95% CI 0.80-0.99). In multivariable-adjusted analyses, serum BDNF concentration was not significantly associated with incident AF (hazard ratio 0.98 per SD, 95% CI 0.88-1.09). Compared with the lowest quartile, BDNF levels in the other quartiles were not associated with risk of AF in multivariable-adjusted analyses. No interactions between sex or age with serum BDNF concentrations and risk of AF were found. Conclusions In our prospective, community-based sample, we did not find a statistically significant association of serum BDNF levels with risk of incident AF. C1 [Rahman, Faisal] Boston Univ, Med Ctr, Dept Med, Boston, MA USA. [Himali, Jayandra J.; Yin, Xiaoyan; Beiser, Alexa S.; Vasan, Ramachandran S.; McManus, David D.; Seshadri, Sudha; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Himali, Jayandra J.; Yin, Xiaoyan; Beiser, Alexa S.; Vasan, Ramachandran S.; McManus, David D.; Seshadri, Sudha; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Himali, Jayandra J.; Beiser, Alexa S.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Himali, Jayandra J.; Yin, Xiaoyan; Beiser, Alexa S.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Yin, Xiaoyan; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med Prevent Med & Epidemiol, Boston, MA 02118 USA. [Ellinor, Patrick T.; Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Magnani, Jared W.] Univ Pittsburgh, Dept Med, UPMC Heart & Vasc Inst, Div Cardiol, Pittsburgh, PA USA. [McManus, David D.] Univ Massachusetts, Dept Med, Worcester, MA 01605 USA. [McManus, David D.] Univ Massachusetts, Dept Quantitat Hlth Sci, Worcester, MA 01605 USA. [McManus, David D.] Worcester Polytech Inst, Dept Biomed Engn, Worcester, MA 01609 USA. RP Benjamin, EJ (reprint author), Boston Univ, Framingham Heart Study, Sch Med, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA.; Benjamin, EJ (reprint author), Boston Univ, Framingham Heart Study, Sch Publ Hlth, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM emelia@bu.edu OI /0000-0003-1391-9481 FU National Institutes of Health [R03AG045075, K23HL114724, 6RO1NS17950, 2R01HL092577, 1R01HL128914, R01HL101056, 1P50HL120163, R01HL104156, K24HL105780, KL2RR031981, 5R01HL126911-02, 1R15HL121761-01A1, 1UH2TR000921-02]; Doris Duke Charitable Foundation [2015084, 2014105]; American Heart Association Award [13EIA14220013]; Evans Scholar Award from the Department of Medicine, Boston University School of Medicine; Fondation Leducg [14CVD01]; [HHSN268201500001I]; [N01-HC-25195] FX This work was supported by contracts HHSN268201500001I and N01-HC-25195 (Vasan) and National Institutes of Health Grants R03AG045075 (Magnani); K23HL114724 (Lubitz); 6RO1NS17950 (Seshadri); 2R01HL092577 and 1R01HL128914 (Ellinor and Benjamin); R01HL101056 and 1P50HL120163 (Benjamin); R01HL104156 and K24HL105780 (Ellinor); and KL2RR031981, 5R01HL126911-02, 1R15HL121761-01A1, and 1UH2TR000921-02 (McManus). This work was also supported by Grant 2015084 from the Doris Duke Charitable Foundation (Magnani), Grant 2014105 from the Doris Duke Charitable Foundation (Lubitz), American Heart Association Award 13EIA14220013 (Ellinor), Evans Scholar Award from the Department of Medicine, Boston University School of Medicine (Vasan), and the Fondation Leducg 14CVD01 (Ellinor). NR 38 TC 0 Z9 0 U1 3 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD JAN PY 2017 VL 183 BP 69 EP 73 DI 10.1016/j.ahj.2016.07.027 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EF3XX UT WOS:000390259600010 PM 27979044 ER PT J AU Dhabangi, A Ainomugisha, B Cserti-Gazdewich, C Ddungu, H Kyeyune, D Musisi, E Opoka, R Stowell, CP Dzik, WH AF Dhabangi, Aggrey Ainomugisha, Brenda Cserti-Gazdewich, Christine Ddungu, Henry Kyeyune, Dorothy Musisi, Ezra Opoka, Robert Stowell, Christopher P. Dzik, Walter H. TI B-type natriuretic peptide and plasma hemoglobin levels following transfusion of shorter-storage versus longer-storage red blood cells: Results from the TOTAL randomized trial SO AMERICAN HEART JOURNAL LA English DT Article ID IN-VITRO MARKERS; NITRIC-OXIDE; PULMONARY-HYPERTENSION; SICKLE-CELL; HEMOLYSIS; DISEASE; LESION; MALARIA; DEATH; RISK AB Background Prior studies have suggested that transfusion of stored red blood cells (RBCs) with increased levels of cell-free hemoglobin might reduce the bioavailability of recipient nitric oxide (NO) and cause myocardial strain. Methods Ugandan children (ages6-60months) with severe anemia and lactic acidosis were randomly assigned to receive RBCs stored 1-10 days versus 25-35 days. B-type natriuretic peptide (BNP), vital signs, renal function test results, and plasma hemoglobin were measured. Most children had either malaria or sickle cell disease and were thus at risk for reduced NO bioavailability. Results Seventy patients received RBCs stored 1-10 days, and 77 received RBCs stored 25-35 days. The median (interquartile range) cell-free hemoglobin was nearly 3 times higher in longer-storage RBCs (26.4 [15.5-43.4] mu mol/L) than in shorter-storage RBCs (10.8 [7.8-18.6] mu mol/L), P<.0001. Median (interquartile range) BNP 2 hours posttransfusion was 156 (59-650) pg/mL (shorter storage) versus 158 (59-425) pg/mL (longer storage), P=.76. BNP values 22 hours posttransfusion were 110 (46-337) pg/mL (shorter storage) versus 96 (49-310) pg/mL (longer storage), P=.76. Changes in BNP within individuals from pretransfusion to 2 hours (or 22 hours) posttransfusion were not significantly different between the study groups. BNP change following transfusion did not correlate with the concentration of cell-free hemoglobin in the RBC supernatant. Blood pressure, blood urea nitrogen, creatinine, and change in plasma hemoglobin were not significantly different in the 2 groups. Conclusion In a randomized trial among children at risk for reduced NO bioavailability, we found that BNP, blood pressure, creatinine, and plasma hemoglobin were not higher in patients receiving RBCs stored for 25-35 versus 1-10 days. C1 [Dhabangi, Aggrey] Makerere Univ, Child Hlth & Dev Ctr, Kampala, Uganda. [Ainomugisha, Brenda] Mulago Hosp, Kampala, Uganda. [Cserti-Gazdewich, Christine] Univ Toronto, Lab Med Program, Univ Hlth Network, Toronto, ON, Canada. [Ddungu, Henry] Makerere Univ, Uganda Canc Inst, Kampala, Uganda. [Kyeyune, Dorothy; Musisi, Ezra] Uganda Natl Blood Transfus Serv, Kampala, Uganda. [Opoka, Robert] Makerere Univ, Mulago Hosp, Dept Paediat, Kampala, Uganda. [Stowell, Christopher P.] Harvard Med Sch, Massachusetts Gen Hosp, Blood Transfus Serv, Boston, MA USA. [Dzik, Walter H.] Massachusetts Gen Hosp, Blood Transfus Serv, Room J-224, Boston, MA 02114 USA. RP Dzik, WH (reprint author), Massachusetts Gen Hosp, Blood Transfus Serv, Room J-224, Boston, MA 02114 USA. EM sdzik@mgh.harvard.edu FU National Heart, Lung, and Blood Institute [NIH 1R21HL109518-01A1] FX This study was fully funded by a grant from the National Heart, Lung, and Blood Institute: NIH 1R21HL109518-01A1. NR 35 TC 1 Z9 1 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD JAN PY 2017 VL 183 BP 129 EP 136 DI 10.1016/j.ahj.2016.01.007 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EF3XX UT WOS:000390259600018 PM 27302626 ER PT J AU Cordella, C Dickerson, BC Quimby, M Yunusova, Y Green, JR AF Cordella, Claire Dickerson, Bradford C. Quimby, Megan Yunusova, Yana Green, Jordan R. TI Slowed articulation rate is a sensitive diagnostic marker for identifying non-fluent primary progressive aphasia SO APHASIOLOGY LA English DT Article DE PPA; subtyping; fluency; speech rate; articulation rate ID CONNECTED SPEECH; SPEAKING RATE; 3 VARIANTS; CLASSIFICATION; AGRAMMATISM; SEVERITY; SUBTYPES; FLUENCY; APRAXIA; ANATOMY AB Background: Primary progressive aphasia (PPA) is a neurodegenerative aphasic syndrome with three distinct clinical variants: non-fluent (nfvPPA), logopenic (lvPPA), and semantic (svPPA). Speech (non-) fluency is a key diagnostic marker used to aid identification of the clinical variants, and researchers have been actively developing diagnostic tools to assess speech fluency. Current approaches reveal coarse differences in fluency between subgroups, but often fail to clearly differentiate nfvPPA from the variably fluent lvPPA. More robust subtype differentiation may be possible with finer-grained measures of fluency.Aims: We sought to identify the quantitative measures of speech rate - including articulation rate and pausing measures - that best differentiated PPA subtypes, specifically the non-fluent group (nfvPPA) from the more fluent groups (lvPPA, svPPA). The diagnostic accuracy of the quantitative speech rate variables was compared to that of a speech fluency impairment rating made by clinicians.Methods & Procedures: Automatic estimates of pause and speech segment durations and rate measures were derived from connected speech samples of participants with PPA (N=38; 11 nfvPPA, 14 lvPPA, 13 svPPA) and healthy age-matched controls (N=8). Clinician ratings of fluency impairment were made using a previously validated clinician rating scale developed specifically for use in PPA. Receiver operating characteristic (ROC) analyses enabled a quantification of diagnostic accuracy.Outcomes & Results: Among the quantitative measures, articulation rate was the most effective for differentiating between nfvPPA and the more fluent lvPPA and svPPA groups. The diagnostic accuracy of both speech and articulation rate measures was markedly better than that of the clinician rating scale, and articulation rate was the best classifier overall. Area under the curve (AUC) values for articulation rate were good to excellent for identifying nfvPPA from both svPPA (AUC=.96) and lvPPA (AUC=.86). Cross-validation of accuracy results for articulation rate showed good generalisability outside the training dataset.Conclusions: Results provide empirical support for (1) the efficacy of quantitative assessments of speech fluency and (2) a distinct non-fluent PPA subtype characterised, at least in part, by an underlying disturbance in speech motor control. The trend towards improved classifier performance for quantitative rate measures demonstrates the potential for a more accurate and reliable approach to subtyping in the fluency domain, and suggests that articulation rate may be a useful input variable as part of a multidimensional clinical subtyping approach. C1 [Cordella, Claire; Green, Jordan R.] MGH Inst Hlth Profess, Dept Commun Sci & Disorders, Boston, MA 02129 USA. [Cordella, Claire; Green, Jordan R.] Harvard Univ, Harvard MIT Program Speech & Hearing Biosci & Tec, Cambridge, MA 02138 USA. [Dickerson, Bradford C.; Quimby, Megan] Massachusetts Gen Hosp, MGH Frontotemporal Disorders Unit, Charlestown, MA USA. [Dickerson, Bradford C.; Quimby, Megan] Harvard Med Sch, Charlestown, MA USA. [Yunusova, Yana] Univ Toronto, Dept Speech Language Pathol, Toronto, ON, Canada. RP Green, JR (reprint author), MGH Inst Hlth Profess, Dept Commun Sci & Disorders, Boston, MA 02129 USA.; Green, JR (reprint author), Harvard Univ, Harvard MIT Program Speech & Hearing Biosci & Tec, Cambridge, MA 02138 USA. EM jgreen2@mghihp.edu FU NIH-NINDS [R21-NS077051]; NIH-NIDCD [1R01DC009890, R01 DC0135470, 5T32DC000038-23]; Harvard Catalyst \The Harvard Clinical and Translational Science Center (National Center for Research Resources, National Institutes of Health) [UL1 TR001102]; Harvard Catalyst \The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [UL1 TR001102]; Harvard University and its affiliated academic healthcare centers FX This research was supported by NIH-NINDS [grant R21-NS077051 (to BCD)], NIH-NIDCD [grants 1R01DC009890 and R01 DC0135470 (to JRG & YY)], and by NIH-NIDCD training [grant 5T32DC000038-23] (supporting CC) and also from 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 Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic healthcare centers. NR 47 TC 0 Z9 0 U1 3 U2 3 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0268-7038 EI 1464-5041 J9 APHASIOLOGY JI Aphasiology PY 2017 VL 31 IS 2 BP 241 EP 260 DI 10.1080/02687038.2016.1191054 PG 20 WC Clinical Neurology SC Neurosciences & Neurology GA EF2OA UT WOS:000390162800007 ER PT J AU Spencer, NY Stanton, RC AF Spencer, Netanya Y. Stanton, Robert C. TI Glucose 6-phosphate dehydrogenase and the kidney SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE cancer; diabetes; G6PD; kidney; pentose phosphate pathway ID PENTOSE-PHOSPHATE PATHWAY; GLUCOSE INHIBITS GLUCOSE-6-PHOSPHATE-DEHYDROGENASE; HEXOSE-MONOPHOSPHATE SHUNT; OXIDATIVE STRESS; NITRIC-OXIDE; NADPH OXIDASES; CELL APOPTOSIS; MOUSE MODEL; DEFICIENCY; CANCER AB Purpose of reviewGlucose 6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway. G6PD is the main source of the essential cellular reductant, NADPH. The purpose of this review is to describe the biochemistry of G6PD and NADPH, cellular factors that regulate G6PD, normal physiologic roles of G6PD, and the pathogenic role altered G6PD/NADPH plays in kidney disease.Recent findingsNADPH is required for many essential cellular processes such as the antioxidant system, nitric oxide synthase, cytochrome p450 enzymes, and NADPH oxidase. Decreased G6PD activity and, as a result, decreased NADPH level have been associated with diabetic kidney disease, altered nitric oxide production, aldosterone-mediated endothelial dysfunction, and dialysis-associated anemia. Increased G6PD activity is associated with all cancers including kidney cancer. Inherited G6PD deficiency is the most common mutation in the world that is thought to be a relatively mild disorder primarily associated with anemia. Yet, intriguing studies have shown an increased prevalence of diabetes mellitus in G6PD-deficient people. It is not known if G6PD-deficient people are at more risk for other diseases.SummaryMuch more research needs to be done to determine the role of altered G6PD activity (inherited or acquired) in the pathogenesis of kidney disease. C1 [Spencer, Netanya Y.; Stanton, Robert C.] Joslin Diabet Ctr, Boston, MA 02215 USA. RP Spencer, NY (reprint author), Harvard Med Sch, Kidney & Hypertens Sect, Joslin Diabet Ctr, Med, 1 Joslin Pl, Boston, MA 02215 USA. EM robert.stanton@joslin.harvard.edu FU Joslin Diabetes Center FX Joslin Diabetes Center. NR 83 TC 1 Z9 1 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1062-4821 EI 1473-6543 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD JAN PY 2017 VL 26 IS 1 BP 43 EP 49 DI 10.1097/MNH.0000000000000294 PG 7 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA EF3QI UT WOS:000390238900008 PM 27755120 ER PT J AU Scharpf, J Kamani, D Sadow, PM Randolph, GW AF Scharpf, Joseph Kamani, Dipti Sadow, Peter M. Randolph, Gregory W. TI The follicular variant of papillary thyroid cancer and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE active surveillance; diagnostic criteria for EFVPTC; EFVPTC; NIFTP ID BRAF V600E; CARCINOMA; ASSOCIATION; TUMORS AB Purpose of reviewNoninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a new terminology proposed for encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). Recently, thyroid cancer incidence has increased dramatically, without affecting related mortality rate. This increase is widely attributed to the intensified surveillance leading to a substantial increase in the diagnosis of small classic papillary thyroid cancers and EFVPTCs. Recent studies emphasize the indolent behavior of the EFVPTC. Recently, there has been a reclassification of EFVPTC as NIFTP, a benign entity. The financial and emotional burden of cancer' diagnosis and treatment can be significant.Recent findingsThis review recapitulates the literature supporting the reclassification of EFVPTC as NIFTP, a benign entity, and reviews standardized diagnostic criteria for EFVPTC.SummaryThe information highlighted in this review will affect surgical decision making and may promote the offering of hemithyroidectomy over a total thyroidectomy to some patients with indeterminate' cytopathological category; postoperative radioiodine ablation will not be required for NIFTP patients. C1 [Scharpf, Joseph] Cleveland Clin, Dept Otolaryngol, Head & Neck Inst, Cleveland, OH 44106 USA. [Kamani, Dipti; Randolph, Gregory W.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Div Thyroid & Parathyroid Surg, 243 Charles St, Boston, MA 02114 USA. [Sadow, Peter M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Randolph, Gregory W.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, Boston, MA USA. RP Randolph, GW (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Div Thyroid & Parathyroid Surg, 243 Charles St, Boston, MA 02114 USA. EM Gregory_Randolph@meei.harvard.edu NR 19 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8746 EI 1531-703X J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD JAN PY 2017 VL 29 IS 1 BP 20 EP 24 DI 10.1097/CCO.0000000000000341 PG 5 WC Oncology SC Oncology GA EF3ST UT WOS:000390245400004 PM 27845971 ER PT J AU Micali, N Crous-Bou, M Treasure, J Lawson, EA AF Micali, Nadia Crous-Bou, Marta Treasure, Janet Lawson, Elizabeth A. TI Association Between Oxytocin Receptor Genotype, Maternal Care, and Eating Disorder Behaviours in a Community Sample of Women SO EUROPEAN EATING DISORDERS REVIEW LA English DT Article DE ALSPAC; eating disorders; oxytocin; gene-environment interaction ID PARENTAL BONDING INSTRUMENT; ANOREXIA-NERVOSA; GENE OXTR; BULIMIA-NERVOSA; FOOD-INTAKE; POLYMORPHISMS; PSYCHOPATHOLOGY; TEMPERAMENT; DEPRESSION; SECRETION AB This study aimed to investigate associations between oxytocin receptor gene (OXT-R) polymorphisms (rs53576 and rs2254298), their interaction with maternal care (GxE), and ED behaviours in a community sample. We studied 3698 women from the Avon Longitudinal Study of Parents and Children (ALSPAC) who participated in a two-phase prevalence study of lifetime ED and had genotype data. The GG rs53576 genotype was associated with binge eating and purging, and the rs2254298 AG/AA genotype with restrictive eating lifetime. In addition, the rs2254298 AG/AA genotype interacted with poor maternal care to increase the odds of binge eating and purging (odds ratio=4.40 (95% confidence intervals: 1.11-17.4)). This study replicates previous findings of an association between OXT-R polymorphisms and ED, and it is the first to show an interaction between OXT-R genotype and poor maternal care. As such, these findings highlight the important role of oxytocin in understanding the pathophysiology of ED. (c) 2016 The Authors European Eating Disorders Review published by Eating Disorders Association and John Wiley & Sons Ltd C1 [Micali, Nadia] Icahn Sch Med Mt Sinai, Dept Psychiat, Eating & Weight Disorders Program, New York, NY 10029 USA. [Micali, Nadia] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Micali, Nadia] UCL, Inst Child Hlth, London, England. [Crous-Bou, Marta] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Crous-Bou, Marta; Lawson, Elizabeth A.] Harvard Med Sch, Boston, MA USA. [Crous-Bou, Marta] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Treasure, Janet] Kings Coll London, Inst Psychiat, Eating Disorders Res Unit, Psychol Med, London, England. [Lawson, Elizabeth A.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. RP Micali, N (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, Eating & Weight Disorders Program, New York, NY 10029 USA. EM nadia.micali@mssm.edu OI Crous-Bou, Marta/0000-0003-1493-4288; Treasure, Janet/0000-0003-0871-4596 FU Wellcome Trust [092731]; Dowager Countess Eleanor Peel Trust; NIHR [DHCS/08/08/012]; Guy's and St Thomas' Charity; Swiss Anorexia FX We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The UK Medical Research Council and the Wellcome Trust (Grant ref: 092731) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors, and Nadia Micali will serve as guarantor for the contents of this paper. This research was funded by a travel fellowship from the Dowager Countess Eleanor Peel Trust and an NIHR Clinician Scientist award (DHCS/08/08/012) to Dr Nadia Micali. Prof. Treasure was funded by grants from: Guy's and St Thomas' Charity and Swiss Anorexia. NR 46 TC 0 Z9 0 U1 29 U2 29 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1072-4133 EI 1099-0968 J9 EUR EAT DISORD REV JI Eur. Eat. Disord. Rev. PD JAN PY 2017 VL 25 IS 1 BP 19 EP 25 DI 10.1002/erv.2486 PG 7 WC Psychology, Clinical SC Psychology GA EF5SP UT WOS:000390390200003 PM 27862641 ER PT J AU Bonora, G Mancini, M Carpinella, I Chiari, L Horak, FB Ferrarin, M AF Bonora, Gianluca Mancini, Martina Carpinella, Ilaria Chiari, Lorenzo Horak, Fay B. Ferrarin, Maurizio TI Gait initiation is impaired in subjects with Parkinson's disease in the OFF state: Evidence from the analysis of the anticipatory postural adjustments through wearable inertial sensors SO GAIT & POSTURE LA English DT Article DE Inertial sensors; Force plate; Accelerometry; Spatio-temporal parameters; APA phases; Levodopa ID STEP INITIATION; LEVODOPA; BALANCE AB People with Parkinson's disease (PD) typically demonstrate impaired anticipatory postural adjustments (APAs) that shift the body center of mass forward (imbalance) and over the stance leg (unloading) prior to gait initiation. APAs are known to be smallest when people with PD are in their OFF-medication state compared to ON-medication or healthy controls. The aim of this pilot study is to validate a previously developed method for the assessment of gait initiation on PD patients in OFF state with body-worn, inertial sensors. Ten subjects with mild-to-moderate idiopathic PD and twelve healthy controls of similar age performed three gait initiation trials. The spatio-temporal parameters of APAs were extracted from three wearable sensors, placed on the shins and on the lower back, and validated with two force plates. Temporal parameters extracted from sensors and force plates, as well as the trunk medio-lateral acceleration and the correspondent displacement of the center of pressure, were significantly correlated. Subjects with PD showed hypometric adjustments in the medio-lateral direction (p-value < 0.003) and increased duration of the unloading phase (p-value = 0.04). The unloading phase was significantly longer than the imbalance (p-value = 0.003) only in subjects with PD. The validity of the method of quantifying APAs from inertial sensors was confirmed in PD subjects by comparison with force plates. Sensitivity in discriminating PD patients from healthy controls was proven by both spatial and temporal parameters. Objective measures of gait initiation deficits with wearable technology provides valuable instrument for the assessment of gait initiation in clinical environments. (C) 2016 Elsevier B.V. All rights reserved. C1 [Bonora, Gianluca; Carpinella, Ilaria; Ferrarin, Maurizio] IRCCS Fdn Don Gnocchi Onlus, Biomed Technol Dept, Via Capecelatro 66, I-20148 Milan, Italy. [Mancini, Martina; Horak, Fay B.] Oregon Hlth & Sci Univ, Dept Neurol, Sch Med, 3181 Sam Jackson Pk Rd, Portland, OR 97239 USA. [Chiari, Lorenzo] Univ Bologna, Dept Elect Elect & Informat Engn Guglielmo Marcon, Viale Risorgimento 2, I-40136 Bologna, Italy. [Horak, Fay B.] Portland VA Med Ctr, Dept Res, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. RP Carpinella, I (reprint author), IRCCS Fdn Don Gnocchi Onlus, Biomed Technol Dept, Via Capecelatro 66, I-20148 Milan, Italy. EM icarpinella@dongnocchi.it FU Italian Ministry of Health [Ricerca Corrente and Ricerca Finalizzata] [GR-2009-1604984]; NIH [RC1 NS068678, R42 HD071760-03] FX This publication was mainly funded by the Italian Ministry of Health [Ricerca Corrente and Ricerca Finalizzata: grant no. GR-2009-1604984] with the support from NIH [grant RC1 NS068678 and R42 HD071760-03] for data collection. NR 15 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0966-6362 EI 1879-2219 J9 GAIT POSTURE JI Gait Posture PD JAN PY 2017 VL 51 BP 218 EP 221 DI 10.1016/j.gaitpost.2016.10.017 PG 4 WC Neurosciences; Orthopedics; Sport Sciences SC Neurosciences & Neurology; Orthopedics; Sport Sciences GA EF6TF UT WOS:000390463000035 PM 27816900 ER PT J AU Roka, A Borgquist, R Singh, J AF Roka, Attila Borgquist, Rasmus Singh, Jagmeet TI Coronary Sinus Lead Positioning SO HEART FAILURE CLINICS LA English DT Article DE Cardiac resynchronization therapy; Heart failure; Pacing; Targeted lead placement; Coronary sinus ID CARDIAC-RESYNCHRONIZATION THERAPY; LEFT-VENTRICULAR LEAD; BUNDLE-BRANCH BLOCK; ACUTE HEMODYNAMIC-RESPONSE; CONGESTIVE-HEART-FAILURE; ROTATIONAL VENOGRAPHY; CONDUCTION DELAY; CRT TRIAL; IMPLANTATION; PLACEMENT AB Although cardiac resynchronization therapy improves morbidity and mortality in patients with cardiomyopathy, heart failure, and electrical dyssynchrony, the rate of nonresponders using standard indications and implant techniques is still high. Optimal coronary sinus lead positioning is important to increase the chance of successful resynchronization. Patient factors such as cause of heart failure, type of dyssynchrony, scar burden, coronary sinus anatomy, and phrenic nerve capture may affect the efficacy of the therapy. Several modalities are under investigation. Alternative left ventricular lead implantation strategies are occasionally required when the transvenous route is not feasible or would result in a suboptimal lead position. C1 [Roka, Attila; Borgquist, Rasmus; Singh, Jagmeet] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Div Cardiol, 55 Fruit St, Boston, MA 02114 USA. RP Singh, J (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Div Cardiol, 55 Fruit St, Boston, MA 02114 USA. EM jsingh@mgh.harvard.edu FU Biotronik; Boston Scientific; Medtronic; St. Jude Medical; Sorin Group FX Consulting and research grants from Biotronik, Boston Scientific, Medtronic, St. Jude Medical, and Sorin Group; consulting for Respicardia & Cardiolnsight (J. Singh). None (A. Roka and R. Borgquist). NR 55 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 1551-7136 J9 HEART FAIL CLIN JI Heart Fail. Clin. PD JAN PY 2017 VL 13 IS 1 BP 79 EP + DI 10.1016/j.hfc.2016.07.007 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EF1IO UT WOS:000390078700007 PM 27886934 ER PT J AU Eickhoff, SB Laird, AR Fox, PM Lancaster, JL Fox, PT AF Eickhoff, Simon B. Laird, Angela R. Fox, P. Mickle Lancaster, Jack L. Fox, Peter T. TI Implementation errors in the GingerALE Software: Description and recommendations SO HUMAN BRAIN MAPPING LA English DT Article DE fMRI; statistics; false positives; cluster inference; meta-analysis ID FALSE DISCOVERY RATE; PET IMAGES; METAANALYSIS; CONNECTIVITY; FMRI; NEUROSCIENCE; FAILURE; SCIENCE; SINGLE; POWER AB Neuroscience imaging is a burgeoning, highly sophisticated field the growth of which has been fostered by grant-funded, freely distributed software libraries that perform voxel-wise analyses in anatomically standardized three-dimensional space on multi-subject, whole-brain, primary datasets. Despite the ongoing advances made using these non-commercial computational tools, the replicability of individual studies is an acknowledged limitation. Coordinate-based meta-analysis offers a practical solution to this limitation and, consequently, plays an important role in filtering and consolidating the enormous corpus of functional and structural neuroimaging results reported in the peer-reviewed literature. In both primary data and meta-analytic neuroimaging analyses, correction for multiple comparisons is a complex but critical step for ensuring statistical rigor. Reports of errors in multiple-comparison corrections in primary-data analyses have recently appeared. Here, we report two such errors in GingerALE, a widely used, US National Institutes of Health (NIH)-funded, freely distributed software package for coordinate-based meta-analysis. These errors have given rise to published reports with more liberal statistical inferences than were specified by the authors. The intent of this technical report is threefold. First, we inform authors who used GingerALE of these errors so that they can take appropriate actions including re-analyses and corrective publications. Second, we seek to exemplify and promote an open approach to error management. Third, we discuss the implications of these and similar errors in a scientific environment dependent on third-party software. Hum Brain Mapp 38:7-11, 2017. (c) 2016 Wiley Periodicals, Inc. C1 [Eickhoff, Simon B.] Res Ctr Julich, Inst Neurosci & Med INM 1, Julich, Germany. [Eickhoff, Simon B.] Heinrich Heine Univ, Inst Clin Neurosci & Med Psychol, Dusseldorf, Germany. [Laird, Angela R.] Florida Int Univ, Dept Phys, Miami, FL 33199 USA. [Fox, P. Mickle; Lancaster, Jack L.; Fox, Peter T.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX USA. [Lancaster, Jack L.; Fox, Peter T.] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX USA. [Fox, Peter T.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Fox, PT (reprint author), 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. EM fox@uthscsa.edu FU US National Institute of Mental Health [RO1-MH074457]; Helmholtz Portfolio Theme "Supercomputing and Modelling for the Human Brain"; European Union [604102] FX Contract grant sponsor: US National Institute of Mental Health; Contract grant number: RO1-MH074457 (to P.T.F.); Contract grant sponsor: Helmholtz Portfolio Theme "Supercomputing and Modelling for the Human Brain" and the European Union Seventh Framework Program; Contract grant number: FP7/2007-2013 under grant agreement no. 604102. NR 35 TC 4 Z9 4 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD JAN PY 2017 VL 38 IS 1 BP 7 EP 11 DI 10.1002/hbm.23342 PG 5 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EF3XY UT WOS:000390259700001 PM 27511454 ER PT J AU Braga, RM Hellyer, PJ Wise, RJS Leech, R AF Braga, Rodrigo M. Hellyer, Peter J. Wise, Richard J. S. Leech, Robert TI Auditory and visual connectivity gradients in frontoparietal cortex SO HUMAN BRAIN MAPPING LA English DT Article DE auditory; visual; functional; structural; connectivity; gradients; frontoparietal cortex; tractograpy; resting-state; functional magnetic resonance imaging ID RESTING-STATE CONNECTIVITY; SPATIAL ATTENTION SHIFTS; HUMAN PARIETAL CORTEX; HUMAN CEREBRAL-CORTEX; FRONTAL-CORTEX; FUNCTIONAL CONNECTIVITY; CORTICAL ACTIVATION; DIRECTED ATTENTION; POSTERIOR PARIETAL; EXECUTIVE CONTROL AB A frontoparietal network of brain regions is often implicated in both auditory and visual information processing. Although it is possible that the same set of multimodal regions subserves both modalities, there is increasing evidence that there is a differentiation of sensory function within frontoparietal cortex. Magnetic resonance imaging (MRI) in humans was used to investigate whether different frontoparietal regions showed intrinsic biases in connectivity with visual or auditory modalities. Structural connectivity was assessed with diffusion tractography and functional connectivity was tested using functional MRI. A dorsal-ventral gradient of function was observed, where connectivity with visual cortex dominates dorsal frontal and parietal connections, while connectivity with auditory cortex dominates ventral frontal and parietal regions. A gradient was also observed along the posterior-anterior axis, although in opposite directions in prefrontal and parietal cortices. The results suggest that the location of neural activity within frontoparietal cortex may be influenced by these intrinsic biases toward visual and auditory processing. Thus, the location of activity in frontoparietal cortex may be influenced as much by stimulus modality as the cognitive demands of a task. It was concluded that stimulus modality was spatially encoded throughout frontal and parietal cortices, and was speculated that such an arrangement allows for top-down modulation of modality-specific information to occur within higher-order cortex. This could provide a potentially faster and more efficient pathway by which top-down selection between sensory modalities could occur, by constraining modulations to within frontal and parietal regions, rather than long-range connections to sensory cortices. Hum Brain Mapp 38:255-270, 2017. (c) 2016 Wiley Periodicals, Inc. C1 [Braga, Rodrigo M.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Braga, Rodrigo M.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA USA. [Braga, Rodrigo M.] Harvard Med Sch, Charlestown, MA USA. [Braga, Rodrigo M.; Hellyer, Peter J.; Wise, Richard J. S.; Leech, Robert] Imperial Coll London, Div Brain Sci, Computat Cognit & Clin Neuroimaging Lab, Hammersmith Hosp Campus, London, England. [Hellyer, Peter J.] Kings Coll London, Inst Psychiat Psychol & Neurosci, Ctr Neuroimaging Sci, London, England. RP Braga, RM (reprint author), Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. EM rbraga@fas.harvard.edu FU Medical Research Council of the UK; Wellcome Trust FX Contract grant sponsor: Medical Research Council of the UK and the Wellcome Trust NR 80 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD JAN PY 2017 VL 38 IS 1 BP 255 EP 270 DI 10.1002/hbm.23358 PG 16 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EF3XY UT WOS:000390259700018 PM 27571304 ER PT J AU Fjell, AM Sneve, MH Grydeland, H Storsve, AB Amlien, IK Yendiki, A Walhovd, KB AF Fjell, Anders M. Sneve, Markus H. Grydeland, Hakon Storsve, Andreas B. Amlien, Inge K. Yendiki, Anastasia Walhovd, Kristine B. TI Relationship between structural and functional connectivity change across the adult lifespan: A longitudinal investigation SO HUMAN BRAIN MAPPING LA English DT Article DE structural connectivity; functional connectivity; longitudinal; magnetic resonance imaging; aging; resting-state; tractography ID DEFAULT-MODE NETWORK; HUMAN CEREBRAL-CORTEX; RESTING-STATE FMRI; WHITE-MATTER MICROSTRUCTURE; MAGNETIC-RESONANCE IMAGES; EPISODIC MEMORY CHANGES; SURFACE-BASED ANALYSIS; MULTIPLE-SCLEROSIS; ALZHEIMERS-DISEASE; AGING BRAIN AB Extensive efforts are devoted to understand the functional (FC) and structural connections (SC) of the brain. FC is usually measured by functional magnetic resonance imaging (fMRI), and conceptualized as degree of synchronicity in brain activity between different regions. SC is typically indexed by measures of white matter (WM) properties, for example, by diffusion weighted imaging (DWI). FC and SC are intrinsically related, in that coordination of activity across regions ultimately depends on fast and efficient transfer of information made possible by structural connections. Convergence between FC and SC has been shown for specific networks, especially the default mode network (DMN). However, it is not known to what degree FC is constrained by major WM tracts and whether FC and SC change together over time. Here, 120 participants (20-85 years) were tested at two time points, separated by 3.3 years. Resting-state fMRI was used to measure FC, and DWI to measure WM microstructure as an index of SC. TRACULA, part of FreeSurfer, was used for automated tractography of 18 major WM tracts. Cortical regions with tight structural couplings defined by tractography were only weakly related at the functional level. Certain regions of the DMN showed a modest relationship between change in FC and SC, but for the most part, the two measures changed independently. The main conclusions are that anatomical alignment of SC and FC seems restricted to specific networks and tracts, and that changes in SC and FC are not necessarily strongly correlated. Hum Brain Mapp 38:561-573, 2017. (c) 2016 Wiley Periodicals, Inc. C1 [Fjell, Anders M.; Sneve, Markus H.; Grydeland, Hakon; Storsve, Andreas B.; Amlien, Inge K.; Walhovd, Kristine B.] Univ Oslo, Dept Psychol, Ctr Lifespan Changes Brain & Cognit, Pb 1094 Blindern, N-0317 Oslo, Norway. [Fjell, Anders M.; Walhovd, Kristine B.] Oslo Univ Hosp, Dept Phys Med & Rehabil, Unit Neuropsychol, N-0450 Oslo, Norway. [Yendiki, Anastasia] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Yendiki, Anastasia] Harvard Med Sch, Boston, MA USA. RP Fjell, AM (reprint author), Univ Oslo, Dept Psychol, Ctr Lifespan Changes Brain & Cognit, Pb 1094 Blindern, N-0317 Oslo, Norway.; Fjell, AM (reprint author), Dept Psychol, Pb 1094 Blindern, N-0317 Oslo, Norway. EM andersmf@psykologi.uio.no FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health [P41EB015896]; NIH [S10RR023401, S10RR019307, S10RR 019254, S10RR023043] FX This research was carried out in whole or in part at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies, P41EB015896, a P41 Biotechnology Resource Grant supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health. This work also involved the use of instrumentation supported by the NIH Shared Instrumentation Grant Program and/or High-End Instrumentation Grant Program; specifically, grant number(s) S10RR023401, S10RR019307, S10RR 019254, S10RR023043. NR 78 TC 1 Z9 1 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD JAN PY 2017 VL 38 IS 1 BP 561 EP 573 DI 10.1002/hbm.23403 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EF3XY UT WOS:000390259700038 PM 27654880 ER PT J AU Drawz, PE Pajewski, NM Bates, JT Bello, NA Cushman, WC Dwyer, JP Fine, LJ Goff, DC Haley, WE Krousel-Wood, M McWilliams, A Rifkin, DE Slinin, Y Taylor, A Townsend, R Wall, B Wright, JT Rahman, M AF Drawz, Paul E. Pajewski, Nicholas M. Bates, Jeffrey T. Bello, Natalie A. Cushman, William C. Dwyer, Jamie P. Fine, Lawrence J. Goff, David C., Jr. Haley, William E. Krousel-Wood, Marie McWilliams, Andrew Rifkin, Dena E. Slinin, Yelena Taylor, Addison Townsend, Raymond Wall, Barry Wright, Jackson T. Rahman, Mahboob TI Effect of Intensive Versus Standard Clinic-Based Hypertension Management on Ambulatory Blood Pressure: Results From the SPRINT (Systolic Blood Pressure Intervention Trial) Ambulatory Blood Pressure Study SO HYPERTENSION LA English DT Article DE blood pressure; circadian rhythm; goals; hypertension; stroke ID LEFT-VENTRICULAR HYPERTROPHY; SERVICES TASK-FORCE; RESISTANT HYPERTENSION; MASKED HYPERTENSION; EUROPEAN-SOCIETY; PROGNOSTIC VALUE; CKD; VARIABILITY; RECOMMENDATIONS; POPULATION AB The effect of clinic-based intensive hypertension treatment on ambulatory blood pressure (BP) is unknown. The goal of the SPRINT (Systolic Blood Pressure Intervention Trial) ambulatory BP ancillary study was to evaluate the effect of intensive versus standard clinic-based BP targets on ambulatory BP. Ambulatory BP was obtained within 3 weeks of the 27-month study visit in 897 SPRINT participants. Intensive treatment resulted in lower clinic systolic BP (mean difference between groups=16.0 mmHg; 95% confidence interval, 14.1-17.8 mmHg), nighttime systolic BP (mean difference=9.6 mmHg; 95% confidence interval, 7.7-11.5 mmHg), daytime systolic BP (mean difference=12.3 mmHg; 95% confidence interval, 10.6-13.9 mmHg), and 24-hour systolic BP (mean difference=11.2 mmHg; 95% confidence interval, 9.7-12.8 mmHg). The night/day systolic BP ratio was similar between the intensive (0.920.09) and standard-treatment groups (0.91 +/- 0.09). There was considerable lack of agreement within participants between clinic systolic BP and daytime ambulatory systolic BP with wide limits of agreement on Bland-Altman plots. In conclusion, targeting a systolic BP of <120 mmHg, when compared with <140 mmHg, resulted in lower nighttime, daytime, and 24-hour systolic BP, but did not change the night/day systolic BP ratio. Ambulatory BP monitoring may be required to assess the effect of targeted hypertension therapy on out of office BP. Further studies are needed to assess whether targeting hypertension therapy based on ambulatory BP improves clinical outcomes. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01835249. C1 [Drawz, Paul E.] Univ Minnesota, Div Renal Dis & Hypertens, 717 Delaware St SE,Suite 353, Minneapolis, MN 55414 USA. [Pajewski, Nicholas M.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Bates, Jeffrey T.; Taylor, Addison] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Bates, Jeffrey T.] Baylor Coll Med, Div Gen Internal Med, Houston, TX 77030 USA. [Bello, Natalie A.] Cornell Univ, Med Ctr, Div Cardiol, New York, NY 10021 USA. [Cushman, William C.] Vet Affairs Med Ctr, Dept Med, Memphis, TN USA. [Dwyer, Jamie P.] Vanderbilt Univ, Med Ctr, Div Nephrol & Hypertens, Nashville, TN USA. [Fine, Lawrence J.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Goff, David C., Jr.] Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA. [Haley, William E.] Mayo Clin, Div Nephrol & Hypertens, Jacksonville, FL 32224 USA. [Krousel-Wood, Marie] Tulane Univ, Dept Med, Ochsner Hlth Syst, New Orleans, LA 70118 USA. [Krousel-Wood, Marie] Tulane Univ, Dept Epidemiol, Ochsner Hlth Syst, New Orleans, LA 70118 USA. [McWilliams, Andrew] Carolinas HealthCare Syst, Dept Family Med, Charlotte, NC USA. [Rifkin, Dena E.] Vet Affairs Hlth Syst, Div Nephrol, San Diego, CA USA. [Rifkin, Dena E.] Univ Calif San Diego, San Diego, CA 92103 USA. [Slinin, Yelena] Vet Affairs Hlth Syst, Div Nephrol, Minneapolis, MN USA. [Slinin, Yelena] Univ Minnesota, Minneapolis, MN USA. [Taylor, Addison] Baylor Coll Med, Div Hypertens & Clin Pharmacol, Houston, TX 77030 USA. [Townsend, Raymond] Univ Penn, Med Ctr, Nephrol & Hypertens, Philadelphia, PA 19104 USA. [Wall, Barry] Vet Affairs Med Ctr, Memphis, TN USA. [Wall, Barry] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Wright, Jackson T.] Case Western Reserve Univ, Univ Hosp Cleveland Med Ctr, Div Nephrol & Hypertens, Cleveland, OH 44106 USA. [Rahman, Mahboob] Case Western Reserve Univ, Div Nephrol & Hypertens, Univ Hosp Cleveland Med Ctr, Louis Stokes Cleveland VAMC, Cleveland, OH 44106 USA. RP Drawz, PE (reprint author), Univ Minnesota, Div Renal Dis & Hypertens, 717 Delaware St SE,Suite 353, Minneapolis, MN 55414 USA. EM draw0003@umn.edu FU National Institutes of Health (NIH) [R03DK100530, K12HD043451, K23DK091521, R03DK105314]; University of Minnesota Chronic Kidney Disease Research Fund; Federal funds from the NIH; National Heart, Lung, and Blood Institute (NHLBI); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute on Aging (NIA); National Institute of Neurological Disorders and Stroke (NINDS) [HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN2682009 00049C]; Clinical and Translational Science Awards - National Center for Advancing Translational Sciences (NCATS)-Case Western Reserve University [UL1TR000439]; Ohio State University [UL1RR025755]; University of Pennsylvania [UL1RR024134, UL1TR000003]; University of Illinois [UL1TR000050]; University of Pittsburgh [UL1TR000005]; University of Texas Southwestern [9U54TR000017-06]; University of Utah [UL1TR000105-05]; Vanderbilt University [UL1TR000445]; George Washington University [UL1TR000075]; University of CA, Davis [UL1TR000002]; University of Florida [UL1TR000064]; University of Michigan [UL1TR000433]; Tulane University Center of Biomedical Research Excellence Award, National Institute of General Medical Sciences [P30GM103337]; [A-HL-13-002-001]; [UL1RR025771]; [UL1TR000093]; [UL1RR025752]; [UL1TR000073]; [UL1TR001064] FX The SPRINT ambulatory blood pressure ancillary study was supported by grants R03DK100530 (P.E. Drawz), K12HD043451 (M. Krousel-Wood), K23DK091521 (D.E. Rifkin), and R03DK105314 (D.E. Rifkin) from the National Institutes of Health (NIH) and funds from the University of Minnesota Chronic Kidney Disease Research Fund. The SPRINT (Systolic Blood Pressure Intervention Trial) is funded with Federal funds from the NIH, including the National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute on Aging (NIA), and the National Institute of Neurological Disorders and Stroke (NINDS), under Contract Numbers HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN2682009 00049C, and Inter-Agency Agreement Number A-HL-13-002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals International, Inc. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, NHLBI, the US Department of Veterans Affairs, the US Department of Health and Human Services, the University of Minnesota, or the United States Government. We also acknowledge the support from the following: Clinical and Translational Science Awards funded by National Center for Advancing Translational Sciences (NCATS)-Case Western Reserve University: UL1TR000439; Ohio State University: UL1RR025755; University of Pennsylvania: UL1RR024134 and UL1TR000003; Boston: UL1RR025771; Stanford: UL1TR000093; Tufts: UL1RR025752, UL1TR000073, and UL1TR001064; University of Illinois: UL1TR000050; University of Pittsburgh: UL1TR000005; University of Texas Southwestern: 9U54TR000017-06; University of Utah: UL1TR000105-05; Vanderbilt University: UL1TR000445; George Washington University: UL1TR000075; University of CA, Davis: UL1TR000002; University of Florida: UL1TR000064; University of Michigan: UL1TR000433; and Tulane University: P30GM103337 Center of Biomedical Research Excellence Award, National Institute of General Medical Sciences. All components of the SPRINT study protocol were designed and implemented by the investigators. The investigative team collected, analyzed, and interpreted the data. All aspects of article writing and revision were performed by the coauthors. Scientists at the National Institutes of Health participated in the design of the study and as a group had 1 vote on the steering committee of the trial. NR 30 TC 5 Z9 5 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD JAN PY 2017 VL 69 IS 1 BP 42 EP 50 DI 10.1161/HYPERTENSIONAHA.116.08076 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF5IA UT WOS:000390362700009 PM 27849563 ER PT J AU Calverley, PM Eriksson, G Jenkins, CR Anzueto, AR Make, BJ Persson, A Fageras, M Postma, DS AF Calverley, Peter M. Eriksson, Goran Jenkins, Christine R. Anzueto, Antonio R. Make, Barry J. Persson, Anders Fageras, Malin Postma, Dirkje S. TI Early efficacy of budesonide/formoterol in patients with moderate-to-very-severe COPD SO INTERNATIONAL JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE LA English DT Article DE bronchodilator agents; clinical respiratory medicine; clinical trials; COPD ID OBSTRUCTIVE PULMONARY-DISEASE; METERED-DOSE INHALER; FLUTICASONE PROPIONATE; CLINICAL-TRIAL; DOUBLE-BLIND; EXACERBATIONS; MANAGEMENT; TIOTROPIUM; FORMOTEROL; BUDESONIDE AB Background and objective: Large clinical trials have confirmed the long-term efficacy of inhaled corticosteroid/long-acting beta(2)-agonist combinations in patients with chronic obstructive pulmonary disease (COPD). It was hypothesized that significant treatment effects would already be present within 3 months after the initiation of treatment across a range of clinical outcomes, irrespective of COPD severity. Methods: Post hoc analysis of 3-month post-randomization outcomes, including exacerbation rates, dropouts, symptoms, reliever use, and lung function, from three studies with similar inclusion criteria of moderate-to-very-severe COPD. Patients (n=1,571) were treated with budesonide/formoterol (B/F) 320/9 mu g or placebo, twice daily; in one study, tiotropium 18 mu g once daily was also given. Results: Over the first 3 months of treatment, fewer patients randomized to B/F experienced exacerbations versus the placebo group (111 and 196 patients with >= 1 exacerbation, respectively). This was true in each COPD severity group. Compared with placebo, B/F treatment led to significantly lower 3-month exacerbation rates in the moderate and severe COPD severity groups (46% and 57% reduction, respectively), with a nonsignificant reduction (29%) in very severe COPD. Fewer dropouts occurred among patients treated with B/F versus placebo, this effect being greater with increasing COPD severity. B/F was associated with improved forced expiratory volume in 1 s, morning peak expiratory flow rate, total reliever use, and total symptom score versus placebo. Conclusion: Treatment with B/F decreased exacerbations in patients with moderate-to-very-severe COPD within 3 months of commencing treatment. This effect was paralleled by improved lung function, less reliever medication use, and fewer symptoms, irrespective of disease severity. C1 [Calverley, Peter M.] Aintree Univ Hosp NHS Fdn Trust, Pulm & Rehabil Res Grp, Liverpool, Merseyside, England. [Eriksson, Goran] Univ Hosp, Dept Resp Med & Allergol, Lund, Sweden. [Jenkins, Christine R.] Univ Sydney, George Inst Global Hlth, Sydney, NSW, Australia. [Jenkins, Christine R.] Concord Clin Sch, Sydney, NSW, Australia. [Anzueto, Antonio R.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pulm Med & Allergol, San Antonio, TX 78229 USA. [Anzueto, Antonio R.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Make, Barry J.] Univ Colorado, Natl Jewish Hlth, Div Pulm Sci & Crit Care Med, Denver, CO 80202 USA. [Persson, Anders; Fageras, Malin] AstraZeneca R&D, Gothenburg, Sweden. [Postma, Dirkje S.] Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Dept Pulm Med & TB, Groningen, Netherlands. RP Calverley, PM (reprint author), Aintree Univ Hosp NHS Fdn Trust, Pulm & Rehabil Res Grp, Liverpool, Merseyside, England.; Calverley, PM (reprint author), Aintree Univ Hosp NHS Fdn Trust, Dept Clin Sci, Inst Aging & Chron Dis, Lower Lane, Liverpool L9 7AL, Merseyside, England. EM pmcal@liverpool.ac.uk FU AstraZeneca; Chiesi FX The authors would like to thank Thomas Similowski and Ian Naya for their contributions to this manuscript. We also thank Katharine Williams and Ash Dunne of inScience Communications, Springer Healthcare, who provided medical writing support funded by AstraZeneca. The sponsor (AstraZeneca) funded this analysis and was involved in the analysis, design, and interpretation of the data, always in conjunction with the authors. The University of Groningen has received money for research by unrestricted educational grants from AstraZeneca and Chiesi. AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Nycomed have provided support for travel to meetings. NR 26 TC 0 Z9 0 U1 4 U2 4 PU DOVE MEDICAL PRESS LTD PI ALBANY PA PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND SN 1178-2005 J9 INT J CHRONIC OBSTR JI Int. J. Chronic Obstr. Pulm. Dis. PY 2017 VL 12 BP 13 EP 25 DI 10.2147/COPD.S114209 PG 13 WC Respiratory System SC Respiratory System GA EF5NZ UT WOS:000390378200001 PM 28031707 ER PT J AU Simoni, JM Smith, L Oost, KM Lehavot, K Fredriksen-Goldsen, K AF Simoni, Jane M. Smith, Laramie Oost, Kathryn M. Lehavot, Keren Fredriksen-Goldsen, Karen TI Disparities in Physical Health Conditions Among Lesbian and Bisexual Women: A Systematic Review of Population-Based Studies SO JOURNAL OF HOMOSEXUALITY LA English DT Article DE Bisexual women; lesbian; LGBT; physical health disparities; systematic review ID SEXUAL MINORITY WOMEN; OF-THE-LITERATURE; RANDOMIZED-TRIALS; ORIENTATION; GAY; OVERWEIGHT; OBESITY; STRESS; MODEL AB We conducted a systematic review to assess evidence for disparities for lesbian and bisexual women (i.e., sexual minority women [SMW]) in comparison with heterosexual women across a range of nine physical health conditions. Among the k=11 studies meeting eligibility criteria, almost every comparison (i.e., heterosexual vs. (a) lesbian, (b) bisexual, or (c) both lesbian and bisexual women) was in a direction indicating SMW disparities. Despite limited power due to small samples of SMW, we found evidence of disparities as indicated by a statistically significant adjusted odds ratios for asthma (5 of 7 comparisons), obesity (8 of 12), arthritis (2 of 3), global ratings of physical health (4 of 7), and cardiovascular disease (1 of 1). Evidence was lacking for cancer (1 of 4), diabetes and hypertension (both 1 of 5), and high cholesterol (0 of 3). Future work should confirm findings in more diverse, larger samples and should examine potential explanatory factors. C1 [Simoni, Jane M.] Univ Washington, Dept Psychol, 3909 Stevens Way NE,Campus Box 351525, Seattle, WA 98195 USA. [Smith, Laramie] Univ Calif San Diego, Sch Med, Div Global Publ Hlth, San Diego, CA 92103 USA. [Oost, Kathryn M.] Univ Montana, Dept Psychol, Missoula, MT 59812 USA. [Lehavot, Keren] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. [Lehavot, Keren] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Fredriksen-Goldsen, Karen] Univ Washington, Sch Social Work, Seattle, WA 98195 USA. RP Simoni, JM (reprint author), Univ Washington, Dept Psychol, 3909 Stevens Way NE,Campus Box 351525, Seattle, WA 98195 USA. EM jsimoni@uw.edu FU NIA [R01AG026526]; VA Career Development Award from CSRD [1K2 CX000867]; [K24MH093243]; [P30AI27757] FX Simoni was supported by K24MH093243 and P30AI27757. Fredriksen-Goldsen was supported by NIA (R01AG026526). Smith was supported by the Fogarty International Center of NIH (D43TW008633) as a T32 postdoctoral fellow. Lehavot was supported by a VA Career Development Award from CSR&D (1K2 CX000867). NR 26 TC 0 Z9 0 U1 4 U2 4 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0091-8369 EI 1540-3602 J9 J HOMOSEXUAL JI J. Homosex. PY 2017 VL 64 IS 1 BP 32 EP 44 DI 10.1080/00918369.2016.1174021 PG 13 WC Psychology, Multidisciplinary; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA EF2RH UT WOS:000390171500002 PM 27074088 ER PT J AU Johnson, DB Pectasides, E Feld, E Ye, F Zhao, SL Johnpulle, R Merritt, R McDermott, DF Puzanov, I Lawrence, D Sosman, JA Buchbinder, E Sullivan, RJ AF Johnson, Douglas B. Pectasides, Eirini Feld, Emily Ye, Fei Zhao, Shilin Johnpulle, Romany Merritt, Ryan McDermott, David F. Puzanov, Igor Lawrence, Donald Sosman, Jeffrey A. Buchbinder, Elizabeth Sullivan, Ryan J. TI Sequencing Treatment in BRAF(V600) Mutant Melanoma: Anti-PD-1 Before and After BRAF Inhibition SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE BRAF; melanoma; anti-PD-1; nivolumab; pembrolizumab; vemurafenib; dabrafenib; trametinib; sequence; immune ID RANDOMIZED CONTROLLED-TRIAL; METASTATIC MELANOMA; UNTREATED MELANOMA; IPILIMUMAB; DABRAFENIB; NIVOLUMAB; SURVIVAL; VEMURAFENIB; TRAMETINIB; PEMBROLIZUMAB AB Novel agents targeting immune checkpoint molecules or mutated BRAF are active therapeutic options for patients with BRAF(V600)-mutant melanoma. However, the most effective first-line treatment and the optimal sequencing of these agents have not been well characterized. To explore this, we retrospectively assessed 114 patients from 4 centers with advanced, BRAF(V600)-mutant melanoma who received anti-programmed cell death-1 (PD-1)/PD-L1 antibodies. We evaluated clinical outcomes, including objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) to initial and subsequent therapies in patients that received anti-PD-1 first (n = 56) versus those that received BRAF +/- MEK inhibitors (BRAFi) first (n = 58). Median OS was similar between these groups (27.5 vs. 40.3 mo, P = 0.71). Patients who progressed on anti-PD-1 during the study timeframe had worse outcomes after starting subsequent BRAFi than those who had not received prior anti-PD-1 (median PFS 5 vs. 7.4 mo, median OS 10.6 vs. 40.3 mo). Similarly, patients who previously progressed on BRAFi had seemingly inferior outcomes after starting anti-PD 1 compared with those without prior BRAFi, including ORR (25% vs. 41%), median PFS (2.8 vs. 10.6 mo) and median OS (8.2 vs. 27.6 mo). Notably, patients who benefited > 6 months from BRAFi had superior ORR to subsequent anti-PD-1 compared with those with more rapid progression (< 6 mo) on BRAFi (34% vs. 15%, P = 0.04). We conclude that either BRAFi or anti-PD-1 may be effective regardless of treatment sequence in patients with BRAF(V600)-mutant melanoma, but clinical outcomes to front-line therapy are superior. In addition, we suggest a shared "responder phenotype" between BRAFi and anti-PD-1. C1 [Johnson, Douglas B.; Feld, Emily; Ye, Fei; Zhao, Shilin; Johnpulle, Romany; Puzanov, Igor; Sosman, Jeffrey A.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Pectasides, Eirini] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Pectasides, Eirini; Buchbinder, Elizabeth] Dana Farber Canc Inst, Boston, MA 02115 USA. [Merritt, Ryan; McDermott, David F.; Lawrence, Donald; Sullivan, Ryan J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Johnson, DB (reprint author), 777 PRB,2220 Pierce Ave, Nashville, TN 37232 USA. EM douglas.b.johnson@vanderbilt.edu FU [K12 CA 0906525] FX Supported by K12 CA 0906525 (D.B.J.). NR 22 TC 1 Z9 1 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1524-9557 EI 1537-4513 J9 J IMMUNOTHER JI J. Immunother. PD JAN PY 2017 VL 40 IS 1 BP 31 EP 35 PG 5 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA EF4KC UT WOS:000390293200004 PM 27846054 ER PT J AU Osier, ND Bales, JW Pugh, B Shin, S Wyrobek, J Puccio, AM Okonkwo, DO Ren, DX Alexander, S Conley, YP Dixon, CE AF Osier, Nicole D. Bales, James W. Pugh, Bunny Shin, Samuel Wyrobek, Julie Puccio, Ava M. Okonkwo, David O. Ren, Dianxu Alexander, Sheila Conley, Yvette P. Dixon, C. Edward TI Variation in PPP3CC Genotype Is Associated with Long-Term Recovery after Severe Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE cognitive function; outcome measures; recovery; traumatic brain injury ID MITOCHONDRIAL PERMEABILITY TRANSITION; FLUID PERCUSSION INJURY; FULL-LENGTH HUMAN; CYCLOSPORINE-A; CALCINEURIN-A; GAMMA-SUBUNIT; CATALYTIC SUBUNIT; SYNAPTIC FUNCTION; RAT HIPPOCAMPUS; NEURONAL CELLS AB After experimental traumatic brain injury (TBI), calcineurin is upregulated; blocking calcineurin is associated with improved outcomes. In humans, variation in the calcineurin A-gamma gene (PPP3CC) has been associated with neuropsychiatric disorders, though any role in TBI recovery remains unknown. This study examines associations between PPP3CC genotype and mortality, as well as gross functional status assessed at admission using the Glasgow Coma Scale (GCS) and at 3, 6, and 12 months after severe TBI using the Glasgow Outcome Score (GOS). The following tagging single nucleotide polymorphisms (tSNPs) in PPP3CC were genotyped: rs2443504, rs2461491, rs2469749, and rs10108011. The rs2443504 AA genotype was univariately associated with GCS (p = 0.022), GOS at 3, 6, and 12 months (p = 0.002, p = 0.034, and p = 0.004, respectively), and mortality (p = 0.007). In multivariate analysis controlling for age, sex, and GCS, the AA genotype of rs2443504 was associated with GOS at 3 (p = 0.02), and 12 months (p = 0.01), with a trend toward significance at 6 months (p = 0.05); the AA genotype also was associated with mortality in the multivariate model (p = 0.04). Further work is warranted to better understand the role of calcineurin, as well as the genes encoding it and their relevance to outcomes after brain injury. C1 [Osier, Nicole D.; Pugh, Bunny; Shin, Samuel; Dixon, C. Edward] Univ Pittsburgh, Safar Ctr Resuscitat Res, Pittsburgh, PA USA. [Osier, Nicole D.; Ren, Dianxu; Alexander, Sheila; Conley, Yvette P.] Univ Pittsburgh, Sch Nursing, Pittsburgh, PA 15261 USA. [Alexander, Sheila] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Conley, Yvette P.] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. [Bales, James W.] Univ Washington, Dept Neurosurg, Seattle, WA 98195 USA. [Pugh, Bunny] Seton Hill Univ, Safar Ctr Resuscitat Res, Greensburg, PA USA. [Wyrobek, Julie] Johns Hopkins Univ, Dept Anesthesiol & Crit Care Med, Baltimore, MD USA. [Puccio, Ava M.; Okonkwo, David O.; Dixon, C. Edward] Univ Pittsburgh, Dept Neurol Surg, Med Ctr, Pittsburgh, PA 15260 USA. [Dixon, C. Edward] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Bales, James W.; Wyrobek, Julie] Univ Pittsburgh, 201 Hill Bldg,3434 Fifth Ave, Pittsburgh, PA 15260 USA. RP Dixon, CE (reprint author), Univ Pittsburgh, 201 Hill Bldg,3434 Fifth Ave, Pittsburgh, PA 15260 USA. EM dixonec@upmc.edu FU PPG Grant [30315, P50NS030318]; VA RRD [B6761R]; NIH [R01NR008424, R01NR13342, F31NR014957, T32NR009759]; Pittsburgh Foundation; Sigma Theta Tau International Eta Chapter; International Society for Nurses in Genetics; American Association of Neuroscience Nursing/Neuroscience Nursing Foundation FX This work was generously supported by several grants, including: PPG Grant 30315, P50NS030318, VA RR&D#B6761R, NIH R01NR008424, R01NR13342, F31NR014957, and T32NR009759. Additional support for this work was provided by grants from the following foundations and professional societies: the Pittsburgh Foundation, Sigma Theta Tau International Eta Chapter, the International Society for Nurses in Genetics, and the American Association of Neuroscience Nursing/Neuroscience Nursing Foundation. The authors would like to thank Marilyn K. Farmer, Amanda Savarese, and Lan Pham for their continued editorial support and Michael D. Farmer for his assistance with the figures. NR 81 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 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JAN 1 PY 2017 VL 34 IS 1 BP 86 EP 96 DI 10.1089/neu.2015.4343 PG 11 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA EF6DE UT WOS:000390420100011 PM 27225880 ER PT J AU Coats, B Binenbaum, G Smith, C Peiffer, RL Christian, CW Duhaime, AC Margulies, SS AF Coats, Brittany Binenbaum, Gil Smith, Colin Peiffer, Robert L. Christian, Cindy W. Duhaime, Ann-Christine Margulies, Susan S. TI Cyclic Head Rotations Produce Modest Brain Injury in Infant Piglets SO JOURNAL OF NEUROTRAUMA LA English DT Article DE abusive head trauma; biomechanics; pediatric traumatic brain injury; shaken baby syndrome ID SHAKEN BABY SYNDROME; TRAUMATIC AXONAL INJURY; YOUNG-CHILDREN; NEONATAL PIG; RETINAL HEMORRHAGES; OVINE MODEL; AGE; FALLS; DIRECTION; RESPONSES AB Repetitive back-and-forth head rotation from vigorous shaking is purported to be a central mechanism responsible for diffuse white matter injury, subdural hemorrhage, and retinal hemorrhage in some cases of abusive head trauma (AHT) in young children. Although animal studies have identified mechanisms of traumatic brain injury (TBI) associated with single rapid head acceleration-decelerations at levels experienced in a motor vehicle crash, few experimental studies have investigated TBI from repetitive head rotations. The objective of this study was to systematically investigate the post-injury pathological time-course after cyclic, low-velocity head rotations in the piglet and compare them with single head rotations. Injury metrics were the occurrence and extent of axonal injury (AI), extra-axial hemorrhage (EAH), red cell neuronal/axonal change (RCNAC), and ocular injury (OI). Hyperflexion/extension of the neck were purposefully avoided in the study, resulting in unscaled angular accelerations at the lower end of reported infant surrogate shaking kinematics. All findings were at the mild end of the injury spectrum, with no significant findings at 6 h post-injury. Cyclic head rotations, however, produced modest AI that significantly increased with time post-injury (p < 0.035) and had significantly greater amounts of RCNAC and EAH than noncyclic head rotations after 24 h post-injury (p < 0.05). No OI was observed. Future studies should investigate the contributions of additional physiological and mechanical features associated with AHT (e.g., hyperflexion/extension, increased intracranial pressure from crying or thoracic compression, and more than two cyclic episodes) to enhance our understanding of the causality between proposed mechanistic factors and AHT in infants. C1 [Coats, Brittany] Univ Utah, Dept Mech Engn, 1495 E 100 St,2157 MEK, Salt Lake City, UT 84112 USA. [Binenbaum, Gil] Childrens Hosp Philadelphia, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Binenbaum, Gil; Peiffer, Robert L.] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Smith, Colin] Univ Edinburgh, Dept Pathol, Edinburgh, Midlothian, Scotland. [Christian, Cindy W.] Univ Penn, Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Duhaime, Ann-Christine] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Duhaime, Ann-Christine] Harvard Univ, Boston, MA 02115 USA. [Margulies, Susan S.] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. RP Coats, B (reprint author), Univ Utah, Dept Mech Engn, 1495 E 100 St,2157 MEK, Salt Lake City, UT 84112 USA. EM brittany.coats@utah.edu FU NIH NINDS [T32 NS043126, K12 EY015398, R01 NS39679]; ARRA administrative supplemental award FX Research funding was provided by NIH NINDS T32 NS043126, K12 EY015398, R01 NS39679 and its associated ARRA administrative supplemental award. The authors are grateful to Jill Ralston for assistance with animal handling, tissue processing, and scoring of axonal injury and red cell neuronal/axonal change; Sarah Sullivan for assistance with extra-axial hemorrhage scoring and statistical analysis; Justin Jones for assistance with data analysis; and Dr. Andrew Merryweather for using data motion capture to evaluate head motion during surrogate shaking. NR 66 TC 0 Z9 0 U1 6 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JAN 1 PY 2017 VL 34 IS 1 BP 235 EP 247 DI 10.1089/neu.2015.4352 PG 13 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA EF6DE UT WOS:000390420100025 PM 26953505 ER PT J AU Ramos, KJ Sack, CS Mitchell, KH Goss, CH Starr, JR AF Ramos, Kathleen J. Sack, Coralynn S. Mitchell, Kristina H. Goss, Christopher H. Starr, Jacqueline R. TI Cystic Fibrosis is Associated with Adverse Neonatal Outcomes in Washington State, 1996-2013 SO JOURNAL OF PEDIATRICS LA English DT Article ID BIRTH-WEIGHT; AMNIOTIC-FLUID; CHILDREN; GROWTH; NUTRITION; IVACAFTOR; PANCREAS; SURVIVAL; MUTATION; INFANTS AB Objective To determine whether cystic fibrosis (CF) is associated with adverse neonatal outcomes in a recent birth cohort in the US. Study design A retrospective matched cohort study of infants born in Washington State from 1996 to 2013 was identified through birth certificate data and linked to statewide hospital discharge data. Infants with CF were identified by hospitalization (through age 5 years) in which a CF-specific International Classification of Diseases, Ninth Revision code was recorded. "Unexposed" infants lacked CF-related International Classification of Diseases, Ninth Revision codes and were randomly selected among births, frequency-matched to "exposed" infants on birth year. Associations of CF with adverse neonatal outcomes (low birth weight [LBW], small for gestational age [SGA], preterm birth, and infant mortality) were estimated through Poisson regression. We performed extreme value imputation to address possible ascertainment bias. Results We identified 170 infants with CF and 3400 unexposed infants. CF was associated with increased relative risk (95% CI) of 3.5 (2.5-4.9), 1.6 (1.1-2.4), 3.0 (2.2-4.0), and 6.8 (1.7-26.5) for LBW, SGA, preterm birth, and infant death, respectively. The estimated relative risks were similar among infants born from 2006 to 2013, except SGA was no longer associated with CF diagnosis. Results were robust to extreme value imputation and exclusion of infants with meconium ileus. Conclusions Observed associations of CF with LBW, preterm birth, and infant death are unlikely to be due to ascertainment bias. Further work is needed to determine how to prevent these adverse neonatal outcomes. C1 [Ramos, Kathleen J.; Sack, Coralynn S.; Mitchell, Kristina H.; Starr, Jacqueline R.] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. [Ramos, Kathleen J.; Sack, Coralynn S.; Mitchell, Kristina H.; Goss, Christopher H.] Univ Washington, Dept Med, Div Pulm & Crit Care Med, Seattle, WA USA. [Goss, Christopher H.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Goss, Christopher H.] Seattle Childrens Hosp, Seattle, WA USA. [Starr, Jacqueline R.] Forsyth Inst, Cambridge, MA USA. RP Ramos, KJ (reprint author), Univ Washington, Div Pulm & Crit Care Med, Med Ctr, Box 356522 1959 NE Pacific St, Seattle, WA 98195 USA. EM ramoskj@uw.edu OI Mitchell, Kristina/0000-0002-1743-7976 FU University of Washington Pulmonary and Critical Care Medicine [T32 HL007287]; Cystic Fibrosis Foundation; National Institutes of Health [R01HL103965, R01AI101307, U M1HL119073, P30DK089507]; US Food and Drug Administration [R01FD003704] FX K.R., C.S., and K.M. receive funding by University of Washington Pulmonary and Critical Care Medicine (T32 HL007287). C.G. receives funding from the Cystic Fibrosis Foundation, the National Institutes of Health (R01HL103965, R01AI101307, U M1HL119073, P30DK089507), and the US Food and Drug Administration (R01FD003704). The authors declare no conflicts of interest. NR 33 TC 0 Z9 0 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JAN PY 2017 VL 180 BP 206 EP + DI 10.1016/j.jpeds.2016.09.069 PG 7 WC Pediatrics SC Pediatrics GA EF0PL UT WOS:000390028100041 PM 27793338 ER PT J AU Walcott, ME Daniels, SD Sinz, NJ Field, LD Higgins, LD AF Walcott, Marie E. Daniels, Stephen D. Sinz, Nathan J. Field, Larry D. Higgins, Laurence D. TI Traumatic full-thickness transtendinous rotator cuff tears: a case series SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Article DE Transtendinous; traumatic rotator cuff tear; full thickness; rotator cuff repair; side-to-side repair; outcomes; case series ID SHOULDER; REPAIR; CABLE; EPIDEMIOLOGY; OUTCOMES; DISEASE; INJURY; TENDON; MUSCLE; MODEL AB Hypothesis: Our purpose was to describe an arthroscopic repair technique for and outcomes of traumatic transtendinous rotator cuff tears affecting the supraspinatus tendon. Materials and methods: A retrospective review was performed on a series of patients between January 2009 and January 2012. Demographic data, as well as preoperative and postoperative clinical data including strength, visual analog scale pain score, Subjective Shoulder Value, American Shoulder and Elbow Surgeons score, and Simple Shoulder Test score, were obtained. Results: Seven patients were identified with magnetic resonance imaging showing full-thickness, transtendon supraspinatus tears with extension into the infraspinatus, which were consistent with physical examination and arthroscopic findings. The mechanism of injury was traumatic in all cases, usually a fall with the arm abducted. The mean remaining stump of tendon measured 1.3 cm. All patients underwent open or arthroscopic repair by a side-to-side (tendon-to-tendon) technique with additional suture anchor augmentation. At an average follow-up of 41.5 months (range, 33-50 months), all patients had postoperative improvements in strength and visual analog scale pain scores (range, 0-1), as well as Subjective Shoulder Value, Simple Shoulder Test, and American Shoulder and Elbow Surgeons scores greater than 90. Conclusion: We have described the occurrence of a rare rotator cuff tear in the purely tendinous portion of the muscle, leaving at least 1 cm of tendon attached to an intact footprint. We also have presented an arthroscopic side-to-side repair technique and postoperative outcomes. To our knowledge, this is the first article describing this uncommon rotator cuff tear. (C) 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved. C1 [Walcott, Marie E.; Daniels, Stephen D.; Sinz, Nathan J.; Higgins, Laurence D.] Brigham & Womens Hosp, Dept Orthopaed Surg, 75 Francis St, Boston, MA 02215 USA. [Walcott, Marie E.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Field, Larry D.] Mississippi Sports Med & Orthoped Ctr, Jackson, MS USA. RP Higgins, LD (reprint author), Brigham & Womens Hosp, Dept Orthopaed Surg, 75 Francis St, Boston, MA 02215 USA. EM ldhiggins@partners.org NR 20 TC 0 Z9 0 U1 6 U2 6 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 JAN PY 2017 VL 26 IS 1 BP 62 EP 67 DI 10.1016/j.jse.2016.04.023 PG 6 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA EF0QB UT WOS:000390029700014 PM 27424248 ER PT J AU Orbay, JL Ring, D Kachooei, AR Santiago-Figueroa, J Bolano, L Pirela-Cruz, M Hausman, M Papandrea, RF AF Orbay, Jorge L. Ring, David Kachooei, Amir R. Santiago-Figueroa, Jose Bolano, Luis Pirela-Cruz, Miguel Hausman, Michael Papandrea, Rick F. TI Multicenter trial of an internal joint stabilizer for the elbow SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Article DE Internal joint stabilizer; elbow fracture dislocation; persistent instability; recurrent instability; hinged; subluxation ID HINGED EXTERNAL FIXATION; FRACTURE-DISLOCATION; PERSISTENT INSTABILITY; COMPLEX INSTABILITY; MANAGEMENT; COMPLICATIONS; HEAD AB Background: Our primary efficacy objective was to evaluate the effectiveness of the internal joint stabilizer of the elbow (IJS-E) in maintaining concentric location of the elbow during and after removal of the device in the treatment of persistent or recurrent instability after elbow fracture or dislocations, or both. The secondary study objectives were to assess range of motion, Broberg-Morrey functional score, Broberg-Morrey categorical rating, the Disabilities of the Arm, Shoulder and Hand score, and the rate of complications and adverse events after the use of IJS-E. Methods: Twenty-four patients were studied in a multicenter, nonrandomized, prospective, single-arm study. The IJS-E was used to provide temporary stabilization of the elbow joint and allow a functional range of motion while ligaments and fractures healed. Results: The elbow remained concentrically aligned in 23 of 24 patients. One coronoid-deficient elbow did not maintain concentric reduction. At the last evaluation a minimum of 6 months after device removal, the mean arc of elbow flexion was 119 degrees (range, 80 degrees-150 degrees; standard deviation [SD], 18 degrees), and the mean arc of forearm rotation was 151 degrees (range, 90 degrees-190 degrees; SD, 24 degrees). The mean and median Broberg-Morrey scores were 93 and 97, respectively. Categorically the results were excellent in 14, good in 8, fair in 1, and poor in 1. The mean Disabilities of the Arm, Shoulder and Hand score was 16 (range, 0-68; SD, 18). Conclusion: The IJS-E maintains concentric reduction, allows elbow motion, and avoids the inconveniences and pin problems of percutaneous fixation. (C) 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved. C1 [Orbay, Jorge L.] Miami Hand & Upper Extrem Inst, Miami, FL USA. [Ring, David] Univ Texas Austin, Dell Med Sch, Dept Surg & Perioperat Care, Austin, TX 78712 USA. [Kachooei, Amir R.] Mashhad Univ Med Sci, Orthoped Res Ctr, Mashhad, Iran. [Kachooei, Amir R.] Harvard Med Sch, Massachusetts Gen Hosp, Hand & Upper Extrem Serv, Boston, MA USA. [Santiago-Figueroa, Jose] Univ Puerto Rico, Dept Orthopaed Surg, San Juan, PR 00936 USA. [Bolano, Luis] Three Gables Surg Hosp, Dept Orthoped, Proctorville, OH USA. [Pirela-Cruz, Miguel] Texas Tech Univ Hlth Sci, Dept Orthopaed Surg & Rehabil, El Paso, TX USA. [Hausman, Michael] Mt Sinai Med Ctr, Dept Orthoped, New York, NY 10029 USA. [Papandrea, Rick F.] Orthoped Assoc Wisconsin, Waukesha, WI USA. RP Kachooei, AR (reprint author), Mashhad Univ Med Sci, Hand & Elbow Surg Serv, Orthoped Res Ctr, Ghaem Hosp, Ahmad Abad St, Mashhad, Iran. EM arkachooei@gmail.com OI Kachooei, Amir Reza/0000-0001-7795-1830 FU Skeletal Dynamics LLC; Skeletal Dynamics, LLC; Biomet FX Skeletal Dynamics LLC provided funding support to the Massachusetts General Hospital to run the study.; Jorge L. Orbay discloses patents 8506606 and 8608741 issued to Skeletal Dynamics, LLC. David Ring discloses study-specific grants: Skeletal Dynamics, LLC and Biomet; consultant: Wright Medical, Skeletal Dynamics, and Acumed; honoraria: AO North America, AO International; royalties: Wright Medical; royalties contracted: Biomet, Skeletal Dynamics, LLC; stock options: Illuminos; editorial: Deputy Editor for Review Articles, Journal of Hand Surgery, American; Deputy Editor for Hand and Wrist, Journal of Orthopaedic Trauma; and Assistant Editor, Journal of Shoulder and Elbow Surgery. Rick F. Papandrea, consultant: Skeletal Dynamics, LLC. The other authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article. NR 17 TC 0 Z9 0 U1 1 U2 1 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 JAN PY 2017 VL 26 IS 1 BP 125 EP 132 DI 10.1016/j.jse.2016.09.023 PG 8 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA EF0QB UT WOS:000390029700023 PM 27939280 ER PT J AU Pederson, H Royer, EL Regen, D Ruan, A Pagoto, SL Dellavalle, RP AF Pederson, Hannah Royer, Eryn L. Regen, Donna Ruan, Allen Pagoto, Sherry L. Dellavalle, Robert P. TI A proactive approach to ending the use of university debit cards for indoor tanning SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter C1 [Pederson, Hannah; Royer, Eryn L.; Ruan, Allen] Univ Colorado, Sch Med, Aurora, CO USA. [Pagoto, Sherry L.] Univ Massachusetts, Sch Med, Dept Med, Div Prevent & Behav Med, Worcester, MA USA. [Dellavalle, Robert P.] Univ Colorado Anschutz Med Campus, Dept Epidemiol, Colorado Sch Publ Hlth, Aurora, CO USA. [Dellavalle, Robert P.] Univ Colorado Anschutz Med Campus, Dept Dermatol, Aurora, CO USA. [Dellavalle, Robert P.] US Dept Vet Affairs, Dermatol Serv, Eastern Colorado Hlth Care Syst, Denver, CO USA. RP Dellavalle, RP (reprint author), Dept Vet Affairs Med Ctr, 1055 Clermont St,Box 165, Denver, CO 80220 USA. EM robert.dellavalle@ucdenver.edu OI Pederson, Hannah/0000-0003-0240-8395 NR 5 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 JAN PY 2017 VL 76 IS 1 BP E35 EP E36 DI 10.1016/j.jaad.2016.09.044 PG 2 WC Dermatology SC Dermatology GA EF0TC UT WOS:000390037900019 PM 27986162 ER PT J AU Bouchard, D Perrault, LP Kron, IL Hung, JW AF Bouchard, Denis Perrault, Louis P. Kron, Irving L. Hung, Judy W. TI PREDICTING RECURRENT MITRAL REGURGITATION AFTER MITRALVALVE REPAIR: A DIFFICULT ENDEAVOR AND A NECESSITY SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Letter C1 [Bouchard, Denis; Perrault, Louis P.] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Kron, Irving L.] Univ Virginia, Sch Med, Div Thorac & Cardiovasc Surg, Charlottesville, VA 22908 USA. [Hung, Judy W.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Bouchard, D (reprint author), Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. FU NHLBI NIH HHS [U01 HL088942] 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 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD JAN PY 2017 VL 153 IS 1 BP 145 EP 146 DI 10.1016/j.jtcvs.2016.09.054 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA EF0WZ UT WOS:000390048300041 PM 27986248 ER PT J AU Czerniecki, JM Turner, AP Williams, RM Thompson, ML Landry, G Hakimi, K Speckman, R Norvell, DC AF Czerniecki, Joseph M. Turner, Aaron P. Williams, Rhonda M. Thompson, Mary Lou Landry, Greg Hakimi, Kevin Speckman, Rebecca Norvell, Daniel C. TI The development and validation of the AMPREDICT model for predicting mobility outcome after dysvascular lower extremity amputation SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID LOWER-LIMB AMPUTATION; SELF-RATED HEALTH; ACUTE MYOCARDIAL-INFARCTION; TRANSMETATARSAL AMPUTATIONS; FUNCTIONAL OUTCOMES; DISEASE; MORTALITY; AMPUTEES; DETERMINANTS; LIMITATIONS AB Objective: The objective of this study was the development of AMPREDICT-Mobility, a tool to predict the probability of independence in either basic or advanced (iBASIC or iADVANCED) mobility 1 year after dysvascular major lower extremity amputation. Methods: Two prospective cohort studies during consecutive 4-year periods (2005-2009 and 2010-2014) were conducted at seven medical centers. Multiple demographic and biopsychosocial predictors were collected in the periamputation period among individuals undergoing their first major amputation because of complications of peripheral arterial disease or diabetes. The primary outcomes were iBASIC and iADVANCED mobility, as measured by the Locomotor Capabilities Index. Combined data from both studies were used for model development and internal validation. Backwards stepwise logistic regression was used to develop the final prediction models. The discrimination and calibration of each model were assessed. Internal validity of each model was assessed with bootstrap sampling. Results: Twelve-month follow-up was reached by 157 of 200 (79%) participants. Among these, 54 (34%) did not achieve iBASIC mobility, 103 (66%) achieved at least iBASIC mobility, and 51 (32%) also achieved iADVANCED mobility. Predictive factors associated with reduced odds of achieving iBASIC mobility were increasing age, chronic obstructive pulmonary disease, dialysis, diabetes, prior history of treatment for depression or anxiety, and very poor to fair self-rated health. Those who were white, were married, and had at least a high-school degree had a higher probability of achieving iBASIC mobility. The odds of achieving iBASIC mobility increased with increasing body mass index up to 30 kg/m(2) and decreased with increasing body mass index thereafter. The prediction model of iADVANCED mobility included the same predictors with the exception of diabetes, chronic obstructive pulmonary disease, and education level. Both models showed strong discrimination with C statistics of 0.85 and 0.82, respectively. The mean difference in predicted probabilities for those who did and did not achieve iBASIC and iADVANCED mobility was 33% and 29%, respectively. Tests for calibration and observed vs predicted plots suggested good fit for both models; however, the precision of the estimates of the predicted probabilities was modest. Internal validation through bootstrapping demonstrated some overoptimism of the original model development, with the optimism-adjusted C statistic for iBASIC and iADVANCED mobility being 0.74 and 0.71, respectively, and the discrimination slope 19% and 16%, respectively. Conclusions: AMPREDICT-Mobility is a user-friendly prediction tool that can inform the patient undergoing a dysvascular amputation and the patient's provider about the probability of independence in either basic or advanced mobility at each major lower extremity amputation level. C1 [Czerniecki, Joseph M.; Turner, Aaron P.; Williams, Rhonda M.; Hakimi, Kevin; Speckman, Rebecca] Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Czerniecki, Joseph M.; Turner, Aaron P.; Williams, Rhonda M.; Hakimi, Kevin; Speckman, Rebecca] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Thompson, Mary Lou] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Landry, Greg] Oregon Hlth & Sci Univ, Dept Surg, Div Vasc Surg, Portland, OR 97201 USA. [Norvell, Daniel C.] Spectrum Res Inc, 705 S 9th St,Ste 203, Tacoma, WA 98405 USA. RP Norvell, DC (reprint author), Spectrum Res Inc, 705 S 9th St,Ste 203, Tacoma, WA 98405 USA. EM dan@specri.com FU U.S. Department of Veterans Affairs, Office of Research and Development, Rehabilitation Research and Development [A41241]; [B4927W] FX This material is based on work supported by the U.S. Department of Veterans Affairs, Office of Research and Development, Rehabilitation Research and Development (Merit Review A41241 [J.M.C., principal investigator] and Career Development Award B4927W [A.P.T., principal investigator]). The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States government. NR 43 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JAN PY 2017 VL 65 IS 1 BP 162 EP + DI 10.1016/j.jvs.2016.08.078 PG 13 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA EF0VT UT WOS:000390045100048 PM 27751738 ER PT J AU Salinas, HM Khan, SI McCormack, MC Fernandes, JR Gfrerer, L Watkins, MT Redmond, RW Austen, WG AF Salinas, Harry M. Khan, Saiqa I. McCormack, Michael C. Fernandes, Justin R. Gfrerer, Lisa Watkins, Michael T. Redmond, Robert W. Austen, William G., Jr. TI Prevention of vein graft intimal hyperplasia with photochemical tissue passivation SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT 59th Annual Meeting of the Plastic-Surgery-Research-Council CY MAR 07-09, 2014 CL New York, NY SP Plast Surg Res Council ID GREATER SAPHENOUS-VEIN; CLINICAL-OUTCOMES; RANDOMIZED-TRIAL; BYPASS; REVASCULARIZATION; RAPAMYCIN; DISEASE; LIGHT; SKIN AB Objective: Saphenous vein is the conduit of choice for bypass grafting. Saphenous vein grafts have poor long-term patency rates because of intimal hyperplasia (IH) and subsequent accelerated atherosclerosis. One of the primary triggers of IH is endothelial injury resulting from excessive dilation of the vein after exposure to arterial pressures. Photochemical tissue passivation (PTP) is a technology that cross-links adventitial collagen by a light-activated process, which limits dilation by improving vessel compliance. The objective of this study was to investigate whether PTP limits the development of IH in a rodent venous interposition graft model. Methods: PTP is accomplished by coating venous adventitia with a photosensitizing dye and exposing it to light. To assess the degree of collagen cross-linking after PTP treatment, a biodegradation assay was performed. Venous interposition grafts were placed in the femoral artery of Sprague-Dawley rats. Rats were euthanized after 4 weeks, and intimal thickness was measured histologically. Vein dilation at the time of the initial procedure was also measured. Results: Time to digestion was 63 +/- 7 minutes for controls, 101 +/- 2.4 minutes for rose bengal (RB), and 300 +/- 0 minutes for PTP (P < .001 PTP vs control). A total of 37 animals underwent the procedure: 12 PTP, 12 RB only, and 13 untreated controls. Dilation of the graft after clamp release was 99% for control, 65% for RB only, and 19% for PTP-treated (P < .001 PTP vs control). Intimal thickness was 77 +/- 59 mm in controls, 60 +/- 27 mm in RB only, and 33 +/- 28 mm in PTP-treated grafts. There was a statistically significant 57% reduction in intimal thickness after treatment with PTP compared with untreated controls (P = .03). Conclusions: PTP treatment of venous interposition grafts in a rat model resulted in significant collagen cross-linking, decreased vessel compliance, and significant reduction in IH. C1 [Salinas, Harry M.; Khan, Saiqa I.; McCormack, Michael C.; Fernandes, Justin R.; Gfrerer, Lisa; Austen, William G., Jr.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Div Plast & Reconstruct Surg, Boston, MA USA. [Watkins, Michael T.] Harvard Med Sch, Massachusetts Gen Hosp, Div Vasc & Endovasc Surg, Boston, MA USA. [Redmond, Robert W.] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Dept Dermatol, Boston, MA USA. RP Austen, WG (reprint author), Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, 15 Parkman St,WAC 435, Boston, MA 02114 USA.; Austen, WG (reprint author), Massachusetts Gen Hosp, Div Burn Surg, 15 Parkman St,WAC 435, Boston, MA 02114 USA. EM wausten@partners.org NR 28 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JAN PY 2017 VL 65 IS 1 BP 190 EP 196 DI 10.1016/j.jvs.2015.11.049 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA EF0VT UT WOS:000390045100053 PM 27066947 ER PT J AU Lacagnina, MJ Rivera, PD Bilbo, SD AF Lacagnina, Michael J. Rivera, Phillip D. Bilbo, Staci D. TI Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse SO NEUROPSYCHOPHARMACOLOGY LA English DT Review ID VENTRAL TEGMENTAL AREA; FIBRILLARY ACIDIC PROTEIN; CENTRAL-NERVOUS-SYSTEM; TOLL-LIKE RECEPTORS; INDUCED MICROGLIAL ACTIVATION; ASTROCYTE-SECRETED PROTEINS; MORPHINE-INDUCED ANALGESIA; HEMATOPOIETIC STEM-CELLS; ALCOHOL-INDUCED SEDATION; INNATE IMMUNE-RESPONSES AB Drugs of abuse cause persistent alterations in synaptic plasticity that may underlie addiction behaviors. Evidence suggests glial cells have an essential and underappreciated role in the development and maintenance of drug abuse by influencing neuronal and synaptic functions in multifaceted ways. Microglia and astrocytes perform critical functions in synapse formation and refinement in the developing brain, and there is growing evidence that disruptions in glial function may be implicated in numerous neurological disorders throughout the lifespan. Linking evidence of function in health and under pathological conditions, this review will outline the glial and neuroimmune mechanisms that may contribute to drug-abuse liability, exploring evidence from opioids, alcohol, and psychostimulants. Drugs of abuse can activate microglia and astrocytes through signaling at innate immune receptors, which in turn influence neuronal function not only through secretion of soluble factors (eg, cytokines and chemokines) but also potentially through direct remodeling of the synapses. In sum, this review will argue that neural-glial interactions represent an important avenue for advancing our understanding of substance abuse disorders. C1 [Lacagnina, Michael J.; Rivera, Phillip D.; Bilbo, Staci D.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. RP Bilbo, SD (reprint author), Harvard Med Sch, Massachusetts Gen Hosp East, Dept Pediat, CNY 114, Charlestown, MA 02129 USA. EM sbilbo@mgh.harvard.edu FU NIH [DA034185, R01DA034185-03S1] FX This work is supported by NIH grants DA034185 (SBD) and R01DA034185-03S1 (PDR). NR 262 TC 2 Z9 2 U1 12 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JAN PY 2017 VL 42 IS 1 BP 156 EP 177 DI 10.1038/npp.2016.121 PG 22 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EF1KI UT WOS:000390083300011 PM 27402494 ER PT J AU Kumar, DKV Moir, RD AF Kumar, Deepak Vijaya Kumar Moir, Robert D. TI The Emerging Role of Innate Immunity in Alzheimer's Disease SO NEUROPSYCHOPHARMACOLOGY LA English DT Editorial Material C1 [Kumar, Deepak Vijaya Kumar; Moir, Robert D.] Massachusetts Gen Hosp, Dept Neurol, Genet & Aging Res Unit, Boston, MA 02114 USA. [Kumar, Deepak Vijaya Kumar; Moir, Robert D.] Harvard Med Sch, Boston, MA 02115 USA. RP Moir, RD (reprint author), Massachusetts Gen Hosp, Dept Neurol, Genet & Aging Res Unit, Boston, MA 02114 USA.; Moir, RD (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM moir@helix.mgh.harvard.edu NR 5 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JAN PY 2017 VL 42 IS 1 BP 362 EP 363 DI 10.1038/npp.2016.226 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EF1KI UT WOS:000390083300024 ER PT J AU Prerau, MJ Brown, RE Bianchi, MT Ellenbogen, JM Purdon, PL AF Prerau, Michael J. Brown, Ritchie E. Bianchi, Matt T. Ellenbogen, Jeffrey M. Purdon, Patrick L. TI Sleep Neurophysiological Dynamics Through the Lens of Multitaper Spectral Analysis SO PHYSIOLOGY LA English DT Review ID HUMAN REM-SLEEP; LESS-THAN-1 HZ OSCILLATION; PIG THALAMIC NEURONS; ALPHA OSCILLATIONS; BAND OSCILLATIONS; ATTENTIONAL MODULATION; PARVALBUMIN NEURONS; DROWSINESS PERIOD; SPINDLES; RHYTHM AB During sleep, cortical and subcortical structures within the brain engage in highly structured oscillatory dynamics that can be observed in the electroencephalogram (EEG). The ability to accurately describe changes in sleep state from these oscillations has thus been a major goal of sleep medicine. While numerous studies over the past 50 years have shown sleep to be a continuous, multifocal, dynamic process, long-standing clinical practice categorizes sleep EEG into discrete stages through visual inspection of 30-s epochs. By representing sleep as a coarsely discretized progression of stages, vital neurophysiological information on the dynamic interplay between sleep and arousal is lost. However, by using principled timefrequency spectral analysis methods, the rich dynamics of the sleep EEG are immediately visible-elegantly depicted and quantified at time scales ranging from a full night down to individual microevents. In this paper, we review the neurophysiology of sleep through this lens of dynamic spectral analysis. We begin by reviewing spectral estimation techniques traditionally used in sleep EEG analysis and introduce multitaper spectral analysis, a method that makes EEG spectral estimates clearer and more accurate than traditional approaches. Through the lens of the multitaper spectrogram, we review the oscillations and mechanisms underlying the traditional sleep stages. In doing so, we will demonstrate how multitaper spectral analysis makes the oscillatory structure of traditional sleep states instantaneously visible, closely paralleling the traditional hypnogram, but with a richness of information that suggests novel insights into the neural mechanisms of sleep, as well as novel clinical and research applications. C1 [Prerau, Michael J.; Purdon, Patrick L.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA 02129 USA. [Brown, Ritchie E.] VA Boston Healthcare Syst, Dept Psychiat, Lab Neurosci, Brockton, MA USA. [Brown, Ritchie E.] Harvard Med Sch, Brockton, MA USA. [Bianchi, Matt T.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Ellenbogen, Jeffrey M.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. RP Prerau, MJ (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA 02129 USA. EM prerau@nmr.mgh.harvard.edu; patrickp@nmr.mgh.harvard.edu FU VA; National Institutes of Health (NIH) [R21 NS-093000, R01 MH-039683, HL-095491]; National Institute Of Neurological Disorders And Stroke [R01 NS-096177]; NIH [DP2-OD006454]; Department of Neurology, Massachusetts General Hospital; Center for Integration of Medicine and Innovative Technology; Milton Family Foundation; MGH-MIT Grand Challenge; Servier; MC10, Inc.; Insomnisolv, Inc. FX This work was supported by VA and by National Institutes of Health (NIH) Grants R21 NS-093000 (R.E.B.), R01 MH-039683 and HL-095491(R.E.B), National Institute Of Neurological Disorders And Stroke Grant R01 NS-096177 (M.J.P.), and by NIH New Innovator Award DP2-OD006454 (P.L.P.).; M.T.B. receives funding from the Department of Neurology, Massachusetts General Hospital, the Center for Integration of Medicine and Innovative Technology, the Milton Family Foundation, and the MGH-MIT Grand Challenge. M.T.B. has a pending patent on a sleep wearable device, received travel funds from Servier, served on the advisory board of Foramis, received research funding from MC10, Inc. and Insomnisolv, Inc., has consulting agreements with McKesson and with International Flavors and Fragrances, and has provided expert testimony in sleep medicine. NR 102 TC 1 Z9 1 U1 13 U2 13 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1548-9213 EI 1548-9221 J9 PHYSIOLOGY JI Physiology PD JAN PY 2017 VL 32 IS 1 BP 60 EP 92 DI 10.1152/physiol.00062.2015 PG 33 WC Physiology SC Physiology GA EF1YH UT WOS:000390120600009 PM 27927806 ER PT J AU Chasser, Y Kim, AY Freudenreich, O AF Chasser, Yvonne Kim, Arthur Y. Freudenreich, Oliver TI Hepatitis C Treatment: Clinical Issues for Psychiatrists in the Post-Interferon Era SO PSYCHOSOMATICS LA English DT Review DE hepatitis C; epidemiology; integrated care; barriers to care; serious mental illness; schizophrenia ID SEVERE MENTAL-ILLNESS; HCV GENOTYPE 1; COST-EFFECTIVENESS; VIRUS-INFECTION; SUBSTANCE USE; SOFOSBUVIR; PREVALENCE; VELPATASVIR; CARE; SCHIZOPHRENIA AB Background: Hepatitis C virus ( HCV) is a widespread and costly cause of morbidity and mortality globally and in the United States. The treatment of HCV has been revolutionized with the recent development of direct acting antiviral medications. These new treatments are substantially better tolerated and more efficacious than previously used interferon-based therapies. Despite these innovations, sustained virologic response has remained low, hovering at approximately 9% of all infected persons. The reasons for this failure include lack of screening, low rates of linkage to care, cost of direct-acting antivirals, and barriers in access to care for patients. Psychiatrists work with patients at a disproportionately high risk for HCV infection yet many do not currently assume an active role in the HCV epidemic. Objective: The purpose of this clinical review is to familiarize psychiatrists with currently available hepatitis C treatments and discuss the remaining treatment challenges, including the high cost of treatment. Methods: The authors used information from the Centers for Disease Control and Food and Drug Administration on the most current estimates of HCV epidemiology, risk factors, and approved interferon free treatments. PUBMED was searched for examples of HCV treatment in community psychiatry settings. Conclusions: The mental health community is well positioned to take on a more active role in HCV treatment and engage patients' trust in the treatment process. However, many barriers still exist. We encourage psychiatrists to assume a collaborative role in caring for psychiatric patients infected with HCV. C1 [Chasser, Yvonne] Massachusetts Gen Hosp, MGH McLean Adult Psychiat Residency Training Prog, Boston, MA 02114 USA. [Kim, Arthur Y.] Massachusetts Gen Hosp, Div Infect Dis, Dept Child Psychiat, Boston, MA 02114 USA. [Freudenreich, Oliver] Massachusetts Gen Hosp, Schizophrenia Clin & Res Program, Boston, MA 02114 USA. [Chasser, Yvonne; Kim, Arthur Y.; Freudenreich, Oliver] Harvard Med Sch, Boston, MA USA. RP Chasser, Y (reprint author), Massachusetts Gen Hosp, Dept Child Psychiat, Yawkey Bldg,6th Floor,55 Fruit St, Boston, MA 02114 USA. EM ychasser@partners.org NR 39 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 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD JAN-FEB PY 2017 VL 58 IS 1 BP 1 EP 10 PG 10 WC Psychiatry; Psychology SC Psychiatry; Psychology GA EF2AD UT WOS:000390125600001 PM 27871760 ER PT J AU Fishman, D Beach, S Quinn, D Roy, D AF Fishman, Daniel Beach, Scott Quinn, Davin Roy, Durga TI Special Interest Group-sponsored Updates in Psychosomatics (SIG-UPs): Understanding the Pathophysiology of Catatonia Through Associated Neurological Insults (Neuropsychiatry SIG) SO PSYCHOSOMATICS LA English DT Letter ID DEPRESSION; THERAPY C1 [Fishman, Daniel] Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA 15260 USA. [Beach, Scott] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Quinn, Davin] Univ New Mexico, Dept Psychiat & Behav Sci, Albuquerque, NM 87131 USA. [Roy, Durga] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. RP Fishman, D (reprint author), Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA 15260 USA. NR 9 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD JAN-FEB PY 2017 VL 58 IS 1 BP 90 EP 91 PG 2 WC Psychiatry; Psychology SC Psychiatry; Psychology GA EF2AD UT WOS:000390125600012 PM 28010749 ER PT J AU Josa, S Seruggia, D Fernandez, A Montoliu, L AF Josa, Santiago Seruggia, Davide Fernandez, Almudena Montoliu, Lluis TI Concepts and tools for gene editing SO REPRODUCTION FERTILITY AND DEVELOPMENT LA English DT Article; Proceedings Paper CT Annual Conference of the International-Embryo-Technology-Society (IETS) CY JAN 14-17, 2017 CL Austin, TX SP Int Embryo Technol Soc DE genetically modified animals; genome-edited animals; knockin; knockout; transgenic animals ID ZINC-FINGER NUCLEASES; ONE-STEP GENERATION; CRISPR-CAS SYSTEM; HOMOLOGOUS RECOMBINATION; EMBRYO MICROINJECTION; GENOME MODIFICATION; MAMMALIAN-CELLS; KNOCKOUT RATS; MICE; TALEN AB Gene editing is a relatively recent concept in the molecular biology field. Traditional genetic modifications in animals relied on a classical toolbox that, aside from some technical improvements and additions, remained unchanged for many years. Classical methods involved direct delivery of DNA sequences into embryos or the use of embryonic stem cells for those few species (mice and rats) where it was possible to establish them. For livestock, the advent of somatic cell nuclear transfer platforms provided alternative, but technically challenging, approaches for the genetic alteration of loci at will. However, the entire landscape changed with the appearance of different classes of genome editors, from initial zinc finger nucleases, to transcription activator-like effector nucleases and, most recently, with the development of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas). Gene editing is currently achieved by CRISPR-Cas-mediated methods, and this technological advancement has boosted our capacity to generate almost any genetically altered animal that can be envisaged. C1 [Josa, Santiago; Seruggia, Davide; Fernandez, Almudena; Montoliu, Lluis] CSIC, CNB, Dept Bioli Mol & Celular, Darwin 3, Madrid 28049, Spain. [Josa, Santiago; Seruggia, Davide; Fernandez, Almudena; Montoliu, Lluis] Inst Salud Carlos III, CIBERER, Madrid 28029, Spain. [Seruggia, Davide] Harvard Med Sch, Dana Farber Canc Inst, Boston Childrens Hosp, Boston, MA 02215 USA. RP Montoliu, L (reprint author), CSIC, CNB, Dept Bioli Mol & Celular, Darwin 3, Madrid 28049, Spain.; Montoliu, L (reprint author), Inst Salud Carlos III, CIBERER, Madrid 28029, Spain. EM montoliu@cnb.csic.es NR 86 TC 0 Z9 0 U1 42 U2 42 PU CSIRO PUBLISHING PI CLAYTON PA UNIPARK, BLDG 1, LEVEL 1, 195 WELLINGTON RD, LOCKED BAG 10, CLAYTON, VIC 3168, AUSTRALIA SN 1031-3613 EI 1448-5990 J9 REPROD FERT DEVELOP JI Reprod. Fertil. Dev. PY 2017 VL 29 IS 1 BP 1 EP 7 DI 10.1071/RD16396 PG 7 WC Developmental Biology; Reproductive Biology; Zoology SC Developmental Biology; Reproductive Biology; Zoology GA EF6CW UT WOS:000390419100002 ER PT J AU Stone, JA Lester, CA Aboneh, EA Phelan, CH Welch, LL Chui, MA AF Stone, Jamie A. Lester, Corey A. Aboneh, Ephrem A. Phelan, Cynthia H. Welch, Lauren L. Chui, Michelle A. TI A preliminary examination of over-the-counter medication misuse rates in older adults SO RESEARCH IN SOCIAL & ADMINISTRATIVE PHARMACY LA English DT Article DE Drugs; Medication; Health; Sleep; Community pharmacy ID ADVERSE DRUG EVENTS; UNITED-STATES; CARE AB Background: Older adults are the largest consumers of over the counter (OTC) medications. Of the older adults who are at risk of a major adverse drug event, more than 50% of these events involve an OTC medication. Objective: To explore how older adults select and hypothetically use OTC medications and if the selected medications would be considered safe for use. Methods: Walking interviews were conducted with 20 community-dwelling older adults in a community pharmacy. Each participant selected an OTC medication for a hypothetical pain and sleep scenario. Data were analyzed for four types of misuse: drug drug interaction, drug disease interaction, drug age interaction, and excess usage. Results: At least one instance of potential misuse was found in 95% of participants. For sleep medications, drug-drug interactions and drug-age interactions were more common, affecting 50% and 65% of participants respectively. The most common type of misuse noted in the pain products selected was that of drug-drug interaction, with a total of 39 occurrences, affecting 60% of the participants. Conclusions: OTC misuse is common among older adults, and it is important for older adults to seek out resources, such as a pharmacist, to help them make safe OTC decisions. (C) 2016 Elsevier Inc. All rights reserved. C1 [Stone, Jamie A.; Lester, Corey A.; Aboneh, Ephrem A.; Chui, Michelle A.] Univ Wisconsin, Sch Pharm, 777 Highland Ave, Madison, WI 53705 USA. [Phelan, Cynthia H.; Welch, Lauren L.] William S Middleton Mem Vet Adm Med Ctr, Dept Vet Affairs, 2500 Overlook Terrace, Madison, WI 53705 USA. RP Chui, MA (reprint author), Univ Wisconsin, Sch Pharm, 777 Highland Ave, Madison, WI 53705 USA. EM michelle.chui@wisc.edu FU Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS) [UL1TR000427]; U.S. Department of Veterans Affairs Clinical Science Research & Development Service [1K2CX000535] FX The project described was supported by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR000427 and Career Development Award #1K2CX000535 from the U.S. Department of Veterans Affairs Clinical Science Research & Development Service (Phelan). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the U.S. Department of Veterans Affairs, or the United States Government. NR 17 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7411 EI 1934-8150 J9 RES SOC ADMIN PHARM JI Res. Soc. Adm. Pharm. PD JAN-FEB PY 2017 VL 13 IS 1 BP 187 EP 192 DI 10.1016/j.sapharm.2016.01.004 PG 6 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA EE8GM UT WOS:000389863700014 PM 26853833 ER PT J AU Itagaki, T Bennett, DJ Chenelle, CT Fisher, DF Kacmarek, RM AF Itagaki, Taiga Bennett, Desmond J. Chenelle, Christopher T. Fisher, Daniel F. Kacmarek, Robert M. TI Performance of Leak Compensation in All-Age ICU Ventilators During Volume-Targeted Neonatal Ventilation: A Lung Model Study SO RESPIRATORY CARE LA English DT Article DE neonates; mechanical ventilation; acute care ventilator; leak compensation; volume-targeted ventilation; patient-ventilator interaction ID PRESSURE SUPPORT VENTILATION; NONINVASIVE VENTILATION; BRONCHOPULMONARY DYSPLASIA; MECHANICAL VENTILATION; RESPIRATORY MECHANICS; GUARANTEE VENTILATION; LIMITED VENTILATION; PRETERM INFANTS; NASAL CANNULA; CHILDREN AB BACKGROUND: Volume-targeted ventilation is increasingly used in low birthweight infants because of the potential for reducing volutrauma and avoiding hypocapnea. However, it is not known what level of air leak is acceptable during neonatal volume-targeted ventilation when leak compensation is activated concurrently. METHODS: Four ICU ventilators (Servo-i, PB980, V500, and Avea) were compared in available invasive volume-targeted ventilation modes (pressure control continuous spontaneous ventilation [PC-CSV] and pressure control continuous mandatory ventilation [PC-CMV]). The Servo-i and PB980 were tested with (+) and without (-) their proximal flow sensor. The V500 and Avea were tested with their proximal flow sensor as indicated by their manufacturers. An ASL 5000 lung model was used to simulate 4 neonatal scenarios (body weight 0.5, 1, 2, and 4 kg). The ASL 5000 was ventilated via an endotracheal tube with 3 different leaks. Two minutes of data were collected after each change in leak level, and the asynchrony index was calculated. Tidal volume (V-T) before and after the change in leak was assessed. RESULTS: The differences in delivered V-T between before and after the change in leak were within +/-5% in all scenarios with the PB980 (-/+) and V500. With the Servo-i (-/+), baseline V-T was >= 10% greater than set V-T during PC-CSV, and delivered V-T markedly changed with leak. The Avea demonstrated persistent high V-T in all leak scenarios. Across all ventilators, the median asynchrony index was 1% (interquartile range 0-27%) in PC-CSV and 1.8% (0-45%) in PC-CMV. The median asynchrony index was significantly higher in the Servo-i (-/+) than in the PB980 (-/+) and V500 in 1 and 2 kg scenarios during PC-CSV and PC-CMV. CONCLUSIONS: The PB980 and V500 were the only ventilators to acclimate to all leak scenarios and achieve targeted V-T. Further clinical investigation is needed to validate the use of leak compensation during neonatal volume-targeted ventilation. (C) 2017 Daedalus Enterprises C1 [Itagaki, Taiga; Bennett, Desmond J.; Chenelle, Christopher T.; Fisher, Daniel F.; Kacmarek, Robert M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Resp Care, Boston, MA USA. [Itagaki, Taiga; Kacmarek, Robert M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. RP Kacmarek, RM (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM rkacmarek@mgh.harvard.edu FU Covidien FX This study was funded in part by a research grant from Covidien. Dr Kacmarek has disclosed relationships with Covidien, Venner Medical, and Orange Medical. The other authors have disclosed no conflicts of interest. NR 40 TC 0 Z9 0 U1 1 U2 1 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 JAN PY 2017 VL 62 IS 1 BP 10 EP 21 DI 10.4187/respcare.05012 PG 12 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EF6FW UT WOS:000390427500003 PM 27879380 ER PT J AU Itagaki, T Chenelle, CT Bennett, DJ Fisher, DF Kacmarek, RM AF Itagaki, Taiga Chenelle, Christopher T. Bennett, Desmond J. Fisher, Daniel F. Kacmarek, Robert M. TI Effects of Leak Compensation on Patient-Ventilator Synchrony During Premature/Neonatal Invasive and Noninvasive Ventilation: A Lung Model Study SO RESPIRATORY CARE LA English DT Article DE leak compensation; neonatal ventilation; acute care ventilator; invasive ventilation; noninvasive ventilation ID PRESSURE SUPPORT VENTILATION; ADULT ICU VENTILATORS; BRONCHOPULMONARY DYSPLASIA; MECHANICAL VENTILATION; PULMONARY MECHANICS; NASAL CANNULA; INFANTS; CHILDREN; ASYNCHRONY; RESISTANCE AB BACKGROUND: During both nasal noninvasive ventilation (NIV) and invasive ventilation of neonates, the presence of air leaks causes triggering and cycling asynchrony. METHODS: Five ICU ventilators (PB840, PB980, Servo-i, V500, and Avea) were compared in available invasive ventilation and NIV ventilator modes (pressure control continuous spontaneous ventilation [PC-CSV] and pressure control continuous mandatory ventilation [PC-CMV]). The V500 and Avea do not provide PC-CSV and PC-CMV in NIV. The Servo-i and Avea were tested with and without their proximal flow sensor. The ASL 5000 lung model (version 3.5) was used to simulate 4 neonatal scenarios (body weight 0.5, 1, 2, and 4 kg). The ASL 5000 was ventilated via endotracheal tube (invasive ventilation) or nasal cannula (NIV) with 4 different leaks. RESULTS: The Avea (without flow sensor) during invasive ventilation and Servo-i and PB840 during NIV were not triggered by inspiratory efforts of the ASL 5000 at the baseline leak in the 0.5 kg scenario. In invasive ventilation, overall (median) asynchrony index was significantly lower with the PB980 (1%) and V500 (3%) than with the Servo-i (with flow sensor, 50%; without flow sensor, 50%) and Avea (with sensor, 50%; without sensor, 62%) (P <. 05 for all comparisons). The PB840 (33%) was significantly different from all ventilators (P <. 05). In NIV, the asynchrony index was significantly lower in PB980 (2%) than in the Servo-i (with sensor, 100%; without sensor, 100%) and PB840 (75%) (P < .05 for both). There was no difference in asynchrony index between PC-CSV and PC-CMV in all tested conditions and ventilators. CONCLUSIONS: The ability of leak compensation to prevent asynchronous breathing varied widely between ventilators and lung mechanics. The PB980 and V500 were the only two ventilators to acclimate to all leak scenarios in invasive ventilation, and PB980 was the only ventilator to acclimate to all leak scenarios in NIV. (C) 2017 Daedalus Enterprises C1 [Itagaki, Taiga; Chenelle, Christopher T.; Bennett, Desmond J.; Fisher, Daniel F.; Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Itagaki, Taiga; Kacmarek, Robert M.] Harvard Med Sch, Dept Anesthesia Crit Care & Pain Med, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. RP Kacmarek, RM (reprint author), Harvard Med Sch, Dept Anesthesia Crit Care & Pain Med, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM rkacmarek@mgh.harvard.edu FU Covidien FX This study was partially funded by a research grant from Covidien. Dr Kacmarek has disclosed relationships with Covidien, Venner Medical, and Orange Medical. The other authors have disclosed no conflicts of interest. NR 39 TC 2 Z9 2 U1 1 U2 1 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 JAN PY 2017 VL 62 IS 1 BP 22 EP 33 DI 10.4187/respcare.04825 PG 12 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EF6FW UT WOS:000390427500004 PM 27651525 ER PT J AU Chenelle, CT Itagaki, T Fisher, DF Berra, L Kacmarek, RM AF Chenelle, Christopher T. Itagaki, Taiga Fisher, Daniel F. Berra, Lorenzo Kacmarek, Robert M. TI Performance of the PneuX System: A Bench Study Comparison With 4 Other Endotracheal Tube Cuffs SO RESPIRATORY CARE LA English DT Article DE intubation; intratracheal; ventilator-associated pneumonia; respiratory aspiration ID VENTILATOR-ASSOCIATED PNEUMONIA; CRITICALLY-ILL PATIENTS; REDUCES PULMONARY ASPIRATION; TRACHEAL TUBE; FLUID LEAKAGE; EXPIRATORY PRESSURE; INTUBATED PATIENTS; POLYURETHANE CUFF; PREVENT LEAKAGE; MICROASPIRATION AB BACKGROUND: Cuff design affects microaspiration, a risk factor for pneumonia. We questioned whether the PneuX low-volume fold-free cuff design would prevent cuff leakage and maintain the same tracheal wall pressure as high-volume, low-pressure (HVLP) cuffs. METHODS: We evaluated 4 HVLP-cuffed endotracheal tubes (ETTs), Hi-Lo (polyvinyl chloride [PVC]), Microcuff (polyurethane [PU]), SealGuard (PU + tapered), and TaperGuard (PVC + tapered), and the PneuX with its dedicated tracheal seal monitor. In Part 1, we determined tracheal wall pressure using each cuff's capacity to support water columns across recommended intracuff pressures. In Part 2, we evaluated the tracheal seal monitor function at recommended settings. In Part 3, we compared leakage volumes of all ETTs during 30 min of simulated mechanical ventilation or during 8 h if no leak occurred. Parts 1 and 3 were performed with/without lubrication and PEEP. RESULTS: In Part 1, PneuX cuffs exerted an average tracheal wall pressure of 27.4 +/- 2.4 cm H2O at the recommended intracuff pressure of approximately 80 cm H2O. Tracheal wall pressure did not differ among HVLP cuffs (19.6 +/- 1.4 to 29.5 +/- 1.4 cm H2O). In Part 2, preinflation intracuff pressure affected the time to obtain tracheal seal monitor pressure attainment (P <.01). The tracheal seal monitor generated average calculated tracheal wall pressure of 33.4 +/- 1.2 cm H2O. In Part 3, PneuX ETT showed no leak across 8 h for all trials. Overall, leakage volume was lower with PU (P <.01) and PneuX (P <.01) than with PVC cuffs, regardless of shape, and lower with lubrication and/or PEEP (all P <.01). In each HVLP cuff, lubrication alone eliminated leak at an intracuff pressure of <= 30 cm H2O. CONCLUSIONS: The PneuX cuff generally exerted acceptable tracheal wall pressure, but the tracheal wall pressure monitor allowed pressures exceeding 30 cm H2O in some trials and was the only ETT to prevent leak in all tests. For HVLP cuffs, leak was reduced by PU and PEEP and eliminated by lubrication. C1 [Chenelle, Christopher T.; Fisher, Daniel F.; Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Itagaki, Taiga; Berra, Lorenzo; Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Itagaki, Taiga; Berra, Lorenzo; Kacmarek, Robert M.] Harvard Med Sch, Warren Bldg 1225,55 Fruit St, Boston, MA 02114 USA. RP Kacmarek, RM (reprint author), Harvard Med Sch, Warren Bldg 1225,55 Fruit St, Boston, MA 02114 USA.; Kacmarek, RM (reprint author), Massachusetts Gen Hosp, Resp Care Serv, Dept Anesthesia Crit Care & Pain Med, Warren Bldg 1225,55 Fruit St, Boston, MA 02114 USA. EM rkacmarek@partners.org FU Venner Medical FX This study was financed in part by a grant from Venner Medical. Dr Kacmarek has disclosed relationships with Orange Medical, Covidien, and Venner Medical. Dr Berra has disclosed relationships with EndOclear LLC and Venner Medical. The other authors have disclosed no conflicts of interest. NR 42 TC 1 Z9 1 U1 0 U2 0 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD JAN PY 2017 VL 62 IS 1 BP 102 EP 112 DI 10.4187/respcare.04996 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EF6FW UT WOS:000390427500014 PM 27879379 ER PT J AU Kashiwagi, S Khan, MAS Yasuhara, S Goto, T Kem, WR Tompkins, RG Kaneki, M Martyn, JAJ AF Kashiwagi, Shizuka Khan, Mohammed A. S. Yasuhara, Shingo Goto, Takahisa Kem, William R. Tompkins, Ronald G. Kaneki, Masao Martyn, J. A. Jeevendra TI Prevention of Burn-Induced Inflammatory Responses and Muscle Wasting by GTS-21, a Specific Agonist for 7 Nicotinic Acetylcholine Receptors SO SHOCK LA English DT Article DE 7 acetylcholine receptor; burn injury; GTS-21; inflammation; muscle atrophy; muscle wasting ID ENDOTHELIAL-CELL ACTIVATION; KAPPA-B ACTIVATION; SKELETAL-MUSCLE; STIMULATION; ATROPHY; INHIBITION; MICE; PHOSPHORYLATION; EXPRESSION; ATROGIN-1 AB Introduction:Muscle wasting (MW) in catabolic conditions (e.g., burn injury [BI]) is a major risk factor affecting prognosis. Activation of interleukin-1 (IL-1)/nuclear factor-kappa B (NF-B), interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3), and/or forkhead box O transcriptional factor (FOXO)-mediated gene transcription pathways is the pivotal trigger of inflammatory response-induced protein catabolic processes in muscle. The 7 acetylcholine receptors (7AChRs) are upregulated in macrophages and peripheral tissues including skeletal muscle during MW conditions. Stimulation of 7AChRs mitigates inflammatory responses. Hypothesis tested is that attenuation of inflammation by 7AChR stimulation with specific 7AChR agonist, GTS-21, will reverse BI-induced body mass and MW by modulating inflammatory and proteolytic signals.Methods:Body surface area (30%) BI or sham BI mice were treated with GTS-21 or saline. Tibialis anterior (TA) muscle was harvested at 6h, day 1 or 3 to examine inflammatory and proteolytic signals.Results:GTS-21 significantly ameliorated the BI-induced increased expression of inflammatory cytokines IL-6, IL-1, C-X-C motif chemokine ligand 2 (6h), phosphorylated STAT3, and NF-B (day 1) in TA muscle. GTS-21 also significantly inhibited BI-induced increase of MuRF1 and FOXO1 (day 1). Consistent with the cytokine and inflammatory mediator changes, BI-induced body weight and TA muscle mass loss at day 3 were mitigated by GTS-21 treatment. The beneficial effect of GTS-21 on BI changes was absent in methyllycaconitine (7AChR antagonist)-treated wild-type and 7AChR knockout mice.Conclusion:GTS-21 stimulation of 7AChRs, by modulating multiple molecular signals related to inflammation and proteolysis, attenuates protein wasting, evidenced by maintenance of body weight and attenuation of distant muscle mass loss after BI. GTS-21 can be a novel, potent therapeutic option for reversal of BI-induced MW. C1 [Kashiwagi, Shizuka; Khan, Mohammed A. S.; Yasuhara, Shingo; Kaneki, Masao; Martyn, J. A. Jeevendra] Shriners Hosp Children, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Kashiwagi, Shizuka; Khan, Mohammed A. S.; Yasuhara, Shingo; Tompkins, Ronald G.; Kaneki, Masao; Martyn, J. A. Jeevendra] Harvard Med Sch, Boston, MA USA. [Kashiwagi, Shizuka; Goto, Takahisa] Yokohama City Univ, Grad Sch Med, Dept Anesthesiol & Crit Care Med, Yokohama, Kanagawa, Japan. [Tompkins, Ronald G.; Kaneki, Masao; Martyn, J. A. Jeevendra] Shriners Hosp Children, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Kem, William R.] Univ Florida, Coll Med, Dept Pharmacol & Therapeut, Gainesville, FL 32610 USA. RP Kashiwagi, S (reprint author), Shriners Hosp Children Boston, Boston, MA 02114 USA. EM shizuka0312@gmail.com FU Shriners Hospital for Children, Tampa, Fla [86100]; NIH [P-50 GM2500, RO1 GM118947] FX This study was supported in part by grants from Shriners Hospital for Children (#86100), Tampa, Fla, and from the NIH, P-50 GM2500 Project 1 and RO1 GM118947 (to JAJM). NR 38 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1073-2322 EI 1540-0514 J9 SHOCK JI Shock PD JAN PY 2017 VL 47 IS 1 BP 61 EP 69 DI 10.1097/SHK.0000000000000729 PG 9 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA EF3QP UT WOS:000390239800008 PM 27529131 ER PT J AU Fantaneanu, TA Tillman, G Garcia, E Grady, T Dworetzky, BA AF Fantaneanu, T. A. Tillman, G. Garcia, E. Grady, T. Dworetzky, B. A. TI Preserved vagus nerve stimulator function after radiation therapy SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Article DE vagus nerve stimulator; radiation ID EPILEPSY AB Background - Epilepsy and breast cancer are both prevalent conditions. A subset of women with medically refractory epilepsy and vagus nerve stimulators (VNS) may later develop breast cancer and may require adjuvant radiation as part of their treatment regimen. However, to date, little data are available on the effects of radiation on VNS function. Case Presentation - We present a young woman with tuberous sclerosis, developmental delay, and medically refractory epilepsy who developed left-sided breast cancer. Her epilepsy became controlled with a recent addition of a VNS implanted in her left chest wall. She required adjuvant radiation therapy to her left breast, and this raised the novel question of the safety of radiation on the integrity and functioning of the device, which we explore in this article. Conclusion - This case is the first report of a patient with VNS for epilepsy and breast cancer who received radiation therapy proximal to the device. The device continued to function properly despite the exposure. C1 [Fantaneanu, T. A.; Dworetzky, B. A.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Tillman, G.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Garcia, E.] Newton Wellesley Hosp, Dept Neurol, Newton, MA USA. [Grady, T.] Newton Wellesley Hosp, Dept Surg, Newton, MA USA. RP Fantaneanu, TA (reprint author), Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. EM tfantaneanu@partners.org NR 7 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-6314 EI 1600-0404 J9 ACTA NEUROL SCAND JI Acta Neurol. Scand. PD JAN PY 2017 VL 135 IS 1 BP 142 EP 144 DI 10.1111/ane.12584 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA EE2NM UT WOS:000389421400016 PM 26968442 ER PT J AU Mao, EJ Hazlewood, GS Kaplan, GG Peyrin-Biroulet, L Ananthakrishnan, AN AF Mao, E. J. Hazlewood, G. S. Kaplan, G. G. Peyrin-Biroulet, L. Ananthakrishnan, A. N. TI Systematic review with meta-analysis: comparative efficacy of immunosuppressants and biologics for reducing hospitalisation and surgery in Crohn's disease and ulcerative colitis SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; POPULATION-BASED COHORT; FACTOR-ALPHA AGENTS; NETWORK METAANALYSIS; UNITED-STATES; WESTERN COUNTRIES; CONTROLLED-TRIALS; NAIVE PATIENTS; INFLIXIMAB; THERAPY AB Introduction Crohn's disease (CD) and ulcerative colitis (UC) have a progressive course leading to hospitalisation and surgery. The ability of existing therapies to alter disease course is not clearly defined. Aim To investigate the comparative efficacy of currently available inflammatory bowel disease (IBD) therapies to reduce hospitalisation and surgery. Methods We conducted a systematic review in MEDLINE/PubMed for randomised controlled trials (RCT) published between January 1980 and May 2016 examining efficacy of biological or immunomodulator therapy in IBD. We performed direct comparisons of pooled proportions of hospitalisation and surgery. Pair-wise comparisons using a random-effects Bayesian network meta-analysis were performed to assess comparative efficacy of different treatments. Results We identified seven randomised controlled trials (5 CD; 2 UC) comparing three biologics and one immunomodulator with placebo. In CD, anti-TNF biologics significantly reduced hospitalisation [Odds ratio (OR) 0.46, 95% confidence interval (CI) 0.36-0.60] and surgery (OR 0.23, 95% CI 0.13-0.42) compared to placebo. No statistically significant reduction was noted with azathioprine or vedolizumab. Azathioprine was inferior to both infliximab and adalimumab in preventing CD-related hospitalisation (>97.5% probability). Anti-TNF biologics significantly reduced hospitalisation (OR 0.48, 95% CI 0.29-0.80) and surgery (OR 0.67, 95% CI 0.46-0.97) in UC. There were no statistically significant differences in the pair-wise comparisons between active treatments. Conclusions In CD and UC, anti-TNF biologics are efficacious in reducing the odds of hospitalisation by half and surgery by 33-77%. Azathioprine and vedolizumab were not associated with a similar improvement, but robust conclusions may be limited due to paucity of RCTs. C1 [Mao, E. J.] Brown Univ, Alpert Med Sch, Div Gastroenterol, Providence, RI 02912 USA. [Hazlewood, G. S.; Kaplan, G. G.] Univ Calgary, Dept Med, Calgary, AB, Canada. [Hazlewood, G. S.; Kaplan, G. G.] Univ Calgary, Dept Community Hlth Sci, Calgary, AB, Canada. [Hazlewood, G. S.] Univ Calgary, McCaig Inst Bone & Joint Hlth, Calgary, AB, Canada. [Peyrin-Biroulet, L.] Univ Lorraine, Nancy Univ Hosp, INSERM, U954, Vandoeuvre Les Nancy, France. [Peyrin-Biroulet, L.] Univ Lorraine, Nancy Univ Hosp, Dept Gastroenterol, Vandoeuvre Les Nancy, France. [Ananthakrishnan, A. N.] Harvard Med Sch, Massachusetts Gen Hosp, Gastroenterol Unit, Boston, MA USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@mgh.harvard.edu FU UCB Pharma; Canadian Institute of Health Research; Alberta-Innovates Health-Solutions; Abbvie; Shire; GlaxoSmithKline; Merck; Janssen; Genentech; Mitsubishi; Ferring; Norgine; Tillots; Vifor; Therakos; Pharmacosmos; Pilege; BMS; UCB-pharma; Hospira; Celltrion; Takeda; Biogaran; Boerhinger-Ingelheim; Lilly; Pfizer; HAC-Pharma; Index Pharmaceuticals; Amgen; Sandoz; Forward Pharma GmbH; Celgene; Biogen; Lycera; Samsung Bioepis; US National Institutes of Health FX Dr Mao has no conflicts of interest to declare. Dr Hazlewood has received fellowship funding partially supported by UCB Pharma, honorariums and travel expenses from Abbott, and honorariums from UCB Pharma and has participated in an advisory board meeting for Amgen. Dr Kaplan is supported through a New Investigator Award from the Canadian Institute of Health Research and a Population Health Investigator Award from Alberta-Innovates Health-Solutions. Dr Kaplan has served as a speaker for Janssen and Abbvie. He has participated in advisory board meetings for Abbvie, Janssen, and Shire. Dr Kaplan has received research support from Abbvie, Shire, and GlaxoSmithKline. Dr Peyrin-Biroulet has received consulting fees from Merck, Abbvie, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Therakos, Pharmacosmos, Pilege, BMS, UCB-pharma, Hospira, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, Pfizer, HAC-Pharma, Index Pharmaceuticals, Amgen, Sandoz, Forward Pharma GmbH, Celgene, Biogen, Lycera, Samsung Bioepis. Lecture fees from Merck, Abbvie, Takeda, Janssen, Takeda, Ferring, Norgine, Tillots, Vifor, Therakos, Mitsubishi, HAC-pharma. Dr Ananthakrishnan has received funding from the US National Institutes of Health, served on scientific advisory boards for Abbvie, Cubist and Exact Sciences, and received research funding from Merck and Amgen. NR 62 TC 0 Z9 0 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JAN PY 2017 VL 45 IS 1 BP 3 EP 13 DI 10.1111/apt.13847 PG 11 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA EE2UF UT WOS:000389439600002 PM 27862107 ER PT J AU Mouli, VP Munot, K Ananthakrishnan, A Kedia, S Addagalla, S Garg, SK Benjamin, J Singla, V Dhingra, R Tiwari, V Bopanna, S Hutfless, S Makharia, G Ahuja, V AF Mouli, V. Pratap Munot, K. Ananthakrishnan, A. Kedia, S. Addagalla, S. Garg, S. K. Benjamin, J. Singla, V. Dhingra, R. Tiwari, V. Bopanna, S. Hutfless, S. Makharia, G. Ahuja, V. TI Endoscopic and clinical responses to anti-tubercular therapy can differentiate intestinal tuberculosis from Crohn's disease SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; SACCHAROMYCES-CEREVISIAE ANTIBODY; ANTIMYCOBACTERIAL THERAPY; DIAGNOSIS; BIOPSY; INDIA; ASIA; PARATUBERCULOSIS; EPIDEMIOLOGY; CLOFAZIMINE AB Background Differentiation between intestinal tuberculosis and Crohn's disease is difficult and may require therapeutic trial with anti-tubercular therapy in tuberculosis-endemic regions. Aim To evaluate the role of therapeutic trial with anti-tubercular therapy in patients with diagnostic confusion between intestinal tuberculosis and Crohn's disease. Methods We performed retrospective-comparative (n = 288: 131 patients who received anti-tubercular therapy before being diagnosed as Crohn's disease and 157 intestinal tuberculosis patients) and prospective-validation study (n = 55 patients with diagnostic confusion of intestinal tuberculosis/Crohn's disease). Outcomes assessed were global symptomatic response and endoscopic mucosal healing. Results In the derivation cohort, among those eventually diagnosed as Crohn's disease, global symptomatic response with anti-tubercular therapy was seen in 38% at 3 months and in 37% who completed 6 months of anti-tubercular therapy. Ninety-four per cent of intestinal tuberculosis patients showed global symptomatic response by 3 months. Endoscopic mucosal healing was seen in only 5% of patients with Crohn's disease compared with 100% of intestinal tuberculosis patients. In the validation cohort, all the patients with intestinal tuberculosis had symptomatic response and endoscopic mucosal healing after 6 months of antitubercular therapy. Among the patients with an eventual diagnosis of Crohn's disease, symptomatic response was seen in 64% at 2 months and in 31% who completed 6 months of anti-tubercular therapy, none had mucosal healing. Conclusions Disproportionately lower mucosal healing rate despite an overall symptom response with 6 months of anti-tubercular therapy in patients with Crohn's disease suggests a need for repeat colonoscopy for diagnosing Crohn's disease. Patients with intestinal tuberculosis showing significant symptomatic response after 2-3 months of anti-tubercular therapy, suggest that symptom persistence after a therapeutic trial of 3 months of anti-tubercular therapy may indicate the diagnosis of Crohn's disease. C1 [Mouli, V. Pratap; Munot, K.; Kedia, S.; Addagalla, S.; Garg, S. K.; Benjamin, J.; Singla, V.; Dhingra, R.; Tiwari, V.; Bopanna, S.; Makharia, G.; Ahuja, V.] All India Inst Med Sci, Dept Gastroenterol, New Delhi, India. [Mouli, V. Pratap; Munot, K.; Kedia, S.; Addagalla, S.; Garg, S. K.; Benjamin, J.; Singla, V.; Dhingra, R.; Tiwari, V.; Bopanna, S.; Makharia, G.; Ahuja, V.] All India Inst Med Sci, Human Nutr Unit, New Delhi, India. [Ananthakrishnan, A.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Hutfless, S.] Johns Hopkins Univ, Div Gastroenterol, Baltimore, MA USA. RP Ahuja, V (reprint author), All India Inst Med Sci, Dept Gastroenterol, New Delhi, India.; Ahuja, V (reprint author), All India Inst Med Sci, Human Nutr Unit, New Delhi, India. EM vins_ahuja@hotmail.com FU Amgen; Merck; National Institutes of Health FX Dr Ananthakrishnan is, or has been, a member of advisory boards for AbbVie, Exact Sciences, Takeda, and Merck. He has received research grant support from Amgen and Merck. His research is funded by the National Institutes of Health. NR 51 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JAN PY 2017 VL 45 IS 1 BP 27 EP 36 DI 10.1111/apt.13840 PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA EE2UF UT WOS:000389439600004 ER PT J AU Butt, AA Ren, Y Marks, K Shaikh, OS Sherman, KE AF Butt, A. A. Ren, Y. Marks, K. Shaikh, O. S. Sherman, K. E. CA ERCHIVES Study TI Do directly acting antiviral agents for HCV increase the risk of hepatic decompensation and decline in renal function? Results from ERCHIVES SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID C VIRUS-INFECTION; CIRRHOSIS; DASABUVIR; ABT-450/R-OMBITASVIR; RIBAVIRIN; PARITAPREVIR; OMBITASVIR; RITONAVIR; SURVIVAL; THERAPY AB Background Directly acting antiviral agents (DAA) have been associated with hepatic decompensation, especially in patients with pre-treatment cirrhosis, but this risk is not well defined. Aim To determine the incidence of hepatic decompensation, liver transplantation, death and worsening renal function in patients treated with a Paritaprevir/ritonavir, Ombitasvir, Dasabuvir (PrOD), sofosbuvir/simeprevir or sofosbuvir/ledipasvir regimen. Methods We followed ERCHIVES participants treated with the above regimens for up to 12 weeks post-treatment. We excluded those with HIV, HBsAg+ and pre-existing diagnosis of hepatic decompensation and hepatocellular carcinoma. Results Of 3728 persons on PrOD, 1578 on sofosbuvir/simeprevir and 10 440 on sofosbuvir/ledipasvir, incidence rates (95% CI) of hepatic decompensation/1000 patient-years were 10.6 (5.89-17.36) for the PrOD, 32.4 (20.74-48.16) for the sofosbuvir/simeprevir and 13.0 (9.74-17.10) for the sofosbuvir/ledipasvir. Among those with baseline cirrhosis, these rates were 36.9 (19.1-64.5), 61.8 (38.2-94.5) and 41.1 (29.9-55.2) respectively, while among those without cirrhosis at baseline, these rates were 2.7 (0.6-8.0), 7.5 (1.5-21.8) and 2.7 (1.2-5.4). Advanced fibrosis was associated with increased risk of hepatic decompensation in all groups [HR (95% CI) per 0.5 unit increase in FIB-4 score: PrOD 1.11 (1.07-1.16); sofosbuvir/simeprevir 1.03 (1.01-1.05); sofosbuvir/ledipasvir 1.02 (1.01-1.03)]. There were no deaths. Proportion of persons with eGFR decrease >30 ml/min/1.73 m(2) was higher among the PrOD group, but presence of cirrhosis did not appear to affect this. Conclusions The incidence of hepatic decompensation in persons treated with PrOD, up to 12 weeks after completion of treatment, was comparable to those treated with sofosbuvir/ledipasvir regimen, and was lower than among those treated with a sofosbuvir/simeprevir regimen. Such risk was predominantly observed in those with pre-treatment cirrhosis. C1 [Butt, A. A.; Ren, Y.; Shaikh, O. S.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Butt, A. A.] Weill Cornell Med Coll, Doha, Qatar. [Butt, A. A.] Weill Cornell Med Coll, New York, NY USA. [Butt, A. A.; Marks, K.] Hamad Med Corp, Hamad Healthcare Qual Inst, Doha, Qatar. [Shaikh, O. S.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Sherman, K. E.] Univ Cincinnati, Cincinnati, OH USA. RP Butt, AA (reprint author), Univ Dr C,Bldg 30,Mailstop 151, Pittsburgh, PA 15240 USA. EM aab2005@qatar-med.cornell.edu FU AbbVie Inc.; Gilead; AbbVie FX This work was supported in part by an investigator initiated grant from AbbVie Inc. to Veterans Research Foundation of Pittsburgh (Principal Investigator Dr Butt). Dr Butt has received grant support (to the institution) from Gilead and AbbVie. Dr Shaikh has received grant support (to the institution) from Gilead. Dr Sherman reports grants from AbbVie, Anadys, Genentech, Gilead, Merck, Novartis, Vertex, personal fees from Bioline, MedImmune, Merck, Kadmon, personal fees from Janssen, MedPace, Synteract, outside the submitted work. Dr Marks and Ms. Ren have nothing to disclose. NR 30 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JAN PY 2017 VL 45 IS 1 BP 150 EP 159 DI 10.1111/apt.13837 PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA EE2UF UT WOS:000389439600015 PM 27813162 ER PT J AU Sonnenberg, A Turner, KO Spechler, SJ Genta, RM AF Sonnenberg, A. Turner, K. O. Spechler, S. J. Genta, R. M. TI The influence of Helicobacter pylori on the ethnic distribution of Barrett's metaplasia SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID ESOPHAGEAL ADENOCARCINOMA; UNITED-STATES; INFECTION; PREVALENCE; DIAGNOSIS; DISEASE; RISK; CLASSIFICATION; EPIDEMIOLOGY; METAANALYSIS AB Background Environmental risk factors associated with ethnicity may contribute to the occurrence of Barrett's metaplasia. Aim To investigate the interaction between ethnicity and Helicobacter pylori infection in the occurrence of Barrett's metaplasia among patients undergoing oesophago-gastro-duodenoscopy. Methods The Miraca Life Sciences Database is an electronic repository of histopathological patient records. A case-control study evaluated the influence of age, gender, ethnicity and histological diagnosis of H. pylori on the occurrence of Barrett's metaplasia. Results The total study population comprised 596 479 subjects, of whom 76 475 harboured a diagnosis of Barrett's metaplasia. Male sex, age and H. pylori infection in declining order exerted the strongest influence on the occurrence of BM. In comparison with the population comprising Caucasians and African Americans, Barrett's metaplasia was less common among subjects of African (OR = 0.09, 95% CI = 0.01-0.43), Middle Eastern (0.26, 0.20-0.34), East Asian (0.35, 0.31-0.40), Indian (0.39, 0.32-0.47), Hispanic (0.62, 0.59-0.64) or Jewish descent (0.50, 0.45-0.54), but more common among subjects of Northern European descent (1.14, 1.03-1.26). With the exception of Jews and Northern Europeans, all other ethnic subgroups were characterised by a higher prevalence of H. pylori than the comparison group. A low prevalence of H. pylori was significantly associated with a high prevalence of Barrett's metaplasia (R-2 = 0.82, P < 0.001), as well as dysplasia or oesophageal adenocarcinoma (R-2 = 0.81, P < 0.001). Conclusion Our analysis reveals an inverse relationship between the prevalence of Barrett's metaplasia and H. pylori gastritis among different ethnic groups within the United States. C1 [Sonnenberg, A.; Turner, K. O.; Genta, R. M.] Miraca Life Sci, Irving, TX USA. [Sonnenberg, A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Spechler, S. J.] VA North Texas Hlth Care Syst, Dallas, TX USA. [Genta, R. M.] Baylor Coll Med, Houston, TX 77030 USA. RP Sonnenberg, A (reprint author), Portland VA Med Ctr, P3 GI, Portland, OR 97239 USA. EM sonnenbe@ohsu.edu NR 32 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JAN PY 2017 VL 45 IS 2 BP 283 EP 290 DI 10.1111/apt.13854 PG 8 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA EE2VA UT WOS:000389441900008 PM 27862104 ER PT J AU Goyal, N Yarlagadda, BB Deschler, DG Emerick, KS Lin, DT Rich, DL Rocco, JW Durand, ML AF Goyal, Neerav Yarlagadda, Bharat B. Deschler, Daniel G. Emerick, Kevin S. Lin, Derrick T. Rich, Debbie L. Rocco, James W. Durand, Marlene L. TI Surgical Site Infections in Major Head and Neck Surgeries Involving Pedicled Flap Reconstruction SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE pedicled flaps; surgical site infections; fistula; head and neck cancer; reconstructive surgery ID FREE TISSUE TRANSFER; MYOCUTANEOUS FLAPS; CONTAMINATED HEAD; SALVAGE LARYNGECTOMY; RISK-FACTORS; COMPLICATIONS; PROPHYLAXIS; DEFECTS; FISTULA; RATES AB Objective: To evaluate surgical site infections (SSI) after pedicled reconstruction in head and neck surgery. Methods: Records of patients with pedicled flap reconstructions between 2009 and 2014 at Massachusetts Eye and Ear were reviewed. Onset of SSI or fistula 30 days postoperatively was noted. A free flap cohort was reviewed for comparison. Results: Two hundred and eight pedicled reconstructions were performed for cancer (83%), osteoradionecrosis (7%), and other reasons (10%). Most (72%) cases were clean-contaminated and American Society of Anesthesiologists classification 3 or higher (73%); 63% of patients had prior radiation. The SSIs occurred in 9.1% and were associated with a longer length of stay (P = .004) but no particular risk factors. Seventeen patients developed a fistula (11 without SSI). The SSI rates were not significantly different between pedicled and free flaps, but pedicled flap patients were older, more likely to have had prior surgery and/or radiation, and be methicillin-resistant Staphylococcus aureus positive. In the combined population, multivariate analysis demonstrated clean-contaminated wound classification (P = .03), longer operating time (P = .03), and clindamycin prophylaxis (P = .009) as SSI risk factors. Conclusions: The SSI rate following pedicled flap surgeries was low and similar to free flap surgeries despite a significantly different population. No specific risk factors were associated with developing a pedicled flap SSI. C1 [Goyal, Neerav; Yarlagadda, Bharat B.; Deschler, Daniel G.; Emerick, Kevin S.; Lin, Derrick T.] Harvard Med Sch, Dept Otolaryngol, Massachusetts Eye & Ear, Boston, MA 02115 USA. [Goyal, Neerav] Penn State Univ, Div Otolaryngol Head & Neck Surg, Dept Surg, Coll Med, 500 Univ Dr,POB 850, Hershey, PA 17033 USA. [Yarlagadda, Bharat B.] Lahey Hosp Med Ctr, Dept Otolaryngol, Burlington, MA USA. [Rich, Debbie L.] Massachusetts Eye & Ear, Dept Nursing, Boston, MA USA. [Rocco, James W.] Ohio State Univ, Wexner Med Ctr, Dept Otolaryngol Head & Neck Surg, Columbus, OH USA. [Durand, Marlene L.] Massachusetts Gen Hosp, Dept Med, Infect Dis Unit, Boston, MA 02114 USA. [Durand, Marlene L.] Massachusetts Eye & Ear, Infect Dis Serv, Boston, MA 02114 USA. RP Goyal, N (reprint author), Penn State Univ, Div Otolaryngol Head & Neck Surg, Dept Surg, Coll Med, 500 Univ Dr,POB 850, Hershey, PA 17033 USA. EM ngoyal1@hmc.psu.edu NR 22 TC 0 Z9 0 U1 2 U2 2 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 JAN PY 2017 VL 126 IS 1 BP 20 EP 28 DI 10.1177/0003489416672871 PG 9 WC Otorhinolaryngology SC Otorhinolaryngology GA EF0CD UT WOS:000389992200005 PM 27913719 ER PT J AU Chen, JX Howell, C Haller, CA Patel, MS Ayala, P Moravec, KA Dai, EB Liu, LY Sotiri, I Aizenberg, M Aizenberg, J Chaikof, EL AF Chen, Jiaxuan Howell, Caitlin Haller, Carolyn A. Patel, Madhukar S. Ayala, Perla Moravec, Katherine A. Dai, Erbin Liu, Liying Sotiri, Irini Aizenberg, Michael Aizenberg, Joanna Chaikof, Elliot L. TI An immobilized liquid interface prevents device associated bacterial infection in vivo SO BIOMATERIALS LA English DT Article DE SLIPS; Perfluorocarbon liquids; Polytetrafluoroethylene; Implant; Infection; In vivo ID BIOMATERIAL-ASSOCIATED INFECTION; SUBCUTANEOUS ABSCESS FORMATION; FOREIGN-BODY INFECTION; STAPHYLOCOCCUS-EPIDERMIDIS; HERNIA REPAIR; ANTIBIOTIC-RESISTANCE; SUBCLINICAL INFECTION; TITANIUM IMPLANTS; OXYGEN CARRIERS; MEDICAL DEVICES AB Virtually all biomaterials are susceptible to biofilm formation and, as a consequence, device-associated infection. The concept of an immobilized liquid surface, termed slippery liquid-infused porous surfaces (SLIPS), represents a new framework for creating a stable, dynamic, omniphobic surface that displays ultralow adhesion and limits bacterial biofilm formation. A widely used biomaterial in clinical care, expanded polytetrafluoroethylene (ePTFE), infused with various perfluorocarbon liquids generated SLIPS surfaces that exhibited a 99% reduction in S. aureus adhesion with preservation of macrophage viability, phagocytosis, and bactericidal function. Notably, SLIPS modification of ePTFE prevents device infection after S. aureus challenge in vivo, while eliciting a significantly attenuated innate immune response. SLIPS-modified implants also decrease macrophage inflammatory cytokine expression in vitro, which likely contributed to the presence of a thinner fibrous capsule in the absence of bacterial challenge. SLIPS is an easily implementable technology that provides a promising approach to substantially reduce the risk of device infection and associated patient morbidity, as well as health care costs. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Chen, Jiaxuan; Haller, Carolyn A.; Patel, Madhukar S.; Ayala, Perla; Moravec, Katherine A.; Dai, Erbin; Liu, Liying; Chaikof, Elliot L.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA. [Chen, Jiaxuan; Howell, Caitlin; Haller, Carolyn A.; Patel, Madhukar S.; Ayala, Perla; Sotiri, Irini; Aizenberg, Michael; Aizenberg, Joanna; Chaikof, Elliot L.] Harvard Univ, Wyss Inst Biol Inspired Engn, 3 Blackfan Circle, Boston, MA 02115 USA. [Howell, Caitlin; Sotiri, Irini; Aizenberg, Joanna] Harvard Univ, John A Paulson Sch Engn & Appl Sci, 29 Oxford St, Cambridge, MA 02138 USA. [Patel, Madhukar S.] Harvard Med Sch, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. [Aizenberg, Joanna] Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA. [Aizenberg, Joanna] Harvard Univ, Kavli Inst Bionano Sci & Technol, 29 Oxford St, Cambridge, MA 02138 USA. [Chaikof, Elliot L.] Harvard MIT Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02138 USA. RP Chaikof, EL (reprint author), Beth Israel Deaconess Med Ctr, Dept Surg, 110 Francis St,Suite 9F, Boston, MA 02115 USA.; Aizenberg, J (reprint author), Harvard Univ, Sch Engn & Appl Sci, 29 Oxford St,Pierce 229, Cambridge, MA 02138 USA. EM jaiz@seas.harvard.edu; echaikof@bidmc.harvard.edu OI Howell, Caitlin/0000-0002-9345-6642 FU Defense Advanced Research Projects Agency [N66001-11-1-4180, HR0011-13-C-0025]; NIH [T32 HL 008843-21A1, T35 HL 110843]; American College of Surgeons Resident Research Scholarship FX The authors acknowledge support from the Defense Advanced Research Projects Agency Grant N66001-11-1-4180 and Contract HR0011-13-C-0025. This work was also in part funded by NIH T32 HL 008843-21A1 and the American College of Surgeons Resident Research Scholarship to Madhukar S. Patel as well as NIH T35 HL 110843 to Katherine A. Moravec. We thank the members of the Dr. Chaikof and Dr. Aizenberg lab for helpful discussions, as well as Jaakko' Timonen and Thomas Ferrante for confocal microscopy assistance. We also thank the research and animal facilities at BIDMC and the Wyss Institute. NR 79 TC 0 Z9 0 U1 20 U2 20 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD JAN PY 2017 VL 113 BP 80 EP 92 DI 10.1016/j.biomaterials.2016.09.028 PG 13 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA EE2EK UT WOS:000389396300007 PM 27810644 ER PT J AU Chen, QX Osada, K Ge, ZS Uchida, S Tockary, TA Dirisala, A Matsui, A Toh, K Takeda, KM Liu, XY Nomoto, T Ishii, T Oba, M Matsumoto, Y Kataoka, K AF Chen, Qixian Osada, Kensuke Ge, Zhishen Uchida, Satoshi Tockary, Theofilus A. Dirisala, Anjaneyulu Matsui, Akitsugu Toh, Kazuko Takeda, Kaori M. Liu, Xueying Nomoto, Takahiro Ishii, Tekihiko Oba, Makoto Matsumoto, Yu Kataoka, Kazunori TI Polyplex micelle installing intracellular self-processing functionalities without free catiomers for safe and efficient systemic gene therapy through tumor vasculature targeting SO BIOMATERIALS LA English DT Article DE Polyplex micelle; Toxicity; Endosome escape; Systemic administration; Tumor vasculature targeting; Tumor gene therapy ID PANCREATIC-CANCER; PEGYLATED POLYPLEX; BETA(3) INTEGRIN; SOLUBLE FLT-1; PLASMID DNA; DELIVERY; EXPRESSION; ANGIOGENESIS; MANAGEMENT; CARCINOMA AB Both efficiency and safety profiles are crucial for promotion of gene delivery systems towards practical applications. A promising template system was previously developed based on block catiomer of poly(ethylene glycol) (PEG)-b-poly{N'-N-(2-aminoethyl)-2-aminoehtyllaspartamide)-cholesteryl [PEG-PAsp(DET)-cholesteryl] with strategies of ligand conjugation at the alpha-terminus for specific affinity to the targeted cells and cholesteryl conjugation at the omega-terminus for structural stabilization to obtain systemic retention. Aiming for advocating this formulation towards practical applications, in the current study, the binding profile of this polymer to plasmid DNA (pDNA) was carefully studied to address an issue of toxicity origin. Quantification of free polymer composition confirmed that the toxicity mainly results from unbound polymer and polyplex micelle itself has negligible toxicity. This evaluation allowed for identifying an optimal condition to prepare safe polyplex micelles for systemic application that possess maximal polymer-binding but exclude free polymers. The identified polyplex micelles then faced a drawback of limited transfection efficiency due to the absence of free polymer, which is an acknowledged tendency found in various synthetic gene carriers. Thus, series of functional components was strategically compiled to improve the transfection efficiency such as attachment of cyclic (Arg-Gly-Asp) (cRGD) peptide as a ligand onto the polyplex micelles to facilitate cellular uptake, use of endosome membrane disruptive catiomer of PAsp(DET) for facilitating endosome escape along with use of the conjugated cholesteryl group to amplify the effect of PAsp(DET) on membrane disruption, so as to obtain efficient transfection. The mechanistic investigation respecting the appreciated pH dependent protonation behavior of PAsp(DET) permitted to depict an intriguing scenario how the block catiomers manage to escape from the endosome entrapment in response to the pH gradient. Subsequent systemic application to the pancreatic tumor demonstrated a capability of vascular targeting mediated by the cRGD ligand, which was directly confirmed based on in situ confocal laser scanning microscopy observation. Encouraging this result, the vascular targeting to transfect a secretable anti-angiogenic gene was attempted to treat the intractable pancreatic tumor with anticipation that the strategy could circumvent the intrinsic physiological barriers derived from hypovascular and fibrotic characters. The obtained therapeutic efficiency demonstrates promising utilities of the proposed formulation as a safe systemic gene delivery carrier in practical use. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Chen, Qixian; Ge, Zhishen; Tockary, Theofilus A.; Takeda, Kaori M.; Kataoka, Kazunori] Univ Tokyo, Grad Sch Engn, Dept Mat Engn, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138656, Japan. [Osada, Kensuke; Dirisala, Anjaneyulu; Ishii, Tekihiko; Kataoka, Kazunori] Univ Tokyo, Grad Sch Engn, Dept Bioengn, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138656, Japan. [Uchida, Satoshi; Matsui, Akitsugu; Toh, Kazuko; Liu, Xueying; Matsumoto, Yu; Kataoka, Kazunori] Univ Tokyo, Grad Sch Med, Div Clin Biotechnol, Ctr Dis Biol & Integrat Med,Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan. [Tockary, Theofilus A.; Dirisala, Anjaneyulu; Toh, Kazuko; Liu, Xueying; Kataoka, Kazunori] Inst Ind Promot KAWASAKI, Innovat Ctr NanoMed ICONM, Kawasaki Ku, 3-25-14 Tonomachi, Kawasaki, Kanagawa 2100821, Japan. [Nomoto, Takahiro] Tokyo Inst Technol, Div Polymer Chem, Lab Chem & Life Sci, Midori Ku, R1-11,4259 Nagatsuta, Yokohama, Kanagawa 2268503, Japan. [Oba, Makoto] Nagasaki Univ, Sch Pharmaceut Sci, Div Pharmaceut Chem, Dept Mol Med Sci, 1-14 Bunkyo Machi, Nagasaki 8528521, Japan. [Osada, Kensuke] Japan Sci & Technol Agcy, PRESTO, Tokyo, Japan. [Ge, Zhishen] Univ Sci & Technol China, Dept Polymer Sci & Engn, CAS Key Lab Soft Matter Chem, Hefei 230026, Peoples R China. [Chen, Qixian] MIT, Dept Chem, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Chen, Qixian] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Chen, Qixian] Massachusetts Gen Hosp, Ctr Canc Res, 55 Fruit St, Boston, MA 02114 USA. RP Kataoka, K (reprint author), Univ Tokyo, Grad Sch Engn, Dept Mat Engn, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138656, Japan.; Osada, K (reprint author), Univ Tokyo, Grad Sch Engn, Dept Bioengn, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138656, Japan. EM osada@bmw.t.u-tokyo.ac.jp; kataoka@bmw.t.u-tokyo.ac.jp RI Nomoto, Takahiro/E-6495-2014 OI Nomoto, Takahiro/0000-0002-0391-0478 FU Center of Innovation (COI); Precursory Research for Embryonic Science and Technology (PRESTO) from the Japan Science and Technology Corporation; Japan Society for the Promotion of Science through its Funding Program for Specially Promoted Research [25000006]; Core to Core Program for A. Advanced Research Networks; Ministry of Education, Science, Sports and Culture, Japan (MEXT) FX This work was financially supported by the Center of Innovation (COI) and Precursory Research for Embryonic Science and Technology (PRESTO) from the Japan Science and Technology Corporation, and by the Japan Society for the Promotion of Science through its Funding Program for Specially Promoted Research (Grant Number 25000006) and Core to Core Program for A. Advanced Research Networks. Q. C. acknowledges a fellowship from Ministry of Education, Science, Sports and Culture, Japan (MEXT). The authors are grateful to Dr. H. Kim and Dr. H. Wu for their intellectual contributions to the discussion. NR 34 TC 0 Z9 0 U1 43 U2 43 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD JAN PY 2017 VL 113 BP 253 EP 265 DI 10.1016/j.biomaterials.2016.10.042 PG 13 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA EE2EK UT WOS:000389396300021 PM 27835820 ER PT J AU Nevarez, MD Malone, JC Rentz, DM Waldinger, RJ AF Nevarez, Michael D. Malone, Johanna C. Rentz, Dorene M. Waldinger, Robert J. TI War and remembrance: Combat exposure in young adulthood and memory function sixty years later SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; COGNITIVE IMPAIRMENT; DEFENSE-MECHANISMS; LATE-LIFE; EMOTIONAL MEMORY; EGO MECHANISMS; OLDER-ADULTS; II COMBAT; RETRIEVAL; HEALTH AB Objective: Identifying adaptive ways to cope with extreme stress is essential to promoting long-term health. Memory systems are highly sensitive to stress, and combat exposure during war has been shown to have deleterious effects on cognitive processes, such as memory, decades later. No studies have examined coping styles used by combat veterans and associations with later-life cognitive functioning. Defenses are coping mechanisms that manage difficult memories and feelings, with some more closely related to memory processes (e.g., suppression, repression). Utilizing a longitudinal database, we assessed how reliance on certain defense mechanisms after World War II combat exposure could affect cognitive health 60 years later. Method: Data spanning 75 years were available on 71 men who had post-war assessment of combat exposure, defense mechanism ratings (ages 19-50), and late-life neuropsychological testing. Interaction models of combat exposure with defenses predicting late-life memory were examined. Results: In bivariate analyses, greater reliance on suppression correlated with worse memory performance (r = 0.30, p = .01), but greater reliance on repression did not. Greater reliance on suppression strengthened the link between combat exposure and worse memory in late life (R-2 = 0.24, p < .001). In contrast, greater reliance on repression attenuated the link between combat exposure and poorer late-life memory (R-2 = 0.19,p < .001). Conclusions: Results suggest that coping styles may affect the relationship between early-adult stress and late-life cognition. Findings highlight the importance of understanding how coping styles may impact cognitive functioning as people move through adult life. (C) 2016 Elsevier Inc. All rights reserved. C1 [Nevarez, Michael D.; Malone, Johanna C.; Waldinger, Robert J.] Harvard Med Sch, Massachusetts Gen Hosp, Harvard Study Adult Dev, Boston, MA USA. [Rentz, Dorene M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Rentz, Dorene M.] Harvard Med Sch, Brigham & Womens Hosp, Dept Neurol, Ctr Alzheimer Res & Treatment, Boston, MA USA. RP Nevarez, MD (reprint author), Massachusetts Gen Hosp, Harvard Study Adult Dev, 151 Merrimac St,2nd Floor, Boston, MA 02114 USA. EM mnevarez@partners.org FU National Institute on Aging [R01AG034554, R01 AG045230] FX The study was supported by grants from the National Institute on Aging R01AG034554 and R01 AG045230. NR 53 TC 0 Z9 0 U1 10 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 0010-440X EI 1532-8384 J9 COMPR PSYCHIAT JI Compr. Psychiat. PD JAN PY 2017 VL 72 BP 97 EP 105 DI 10.1016/j.comppsych.2016.10.003 PG 9 WC Psychiatry SC Psychiatry GA EE5YC UT WOS:000389684500014 PM 27776275 ER PT J AU Beam, CA MacCallum, C Herold, KC Wherrett, DK Palmer, J Ludvigsson, J AF Beam, Craig A. MacCallum, Colleen Herold, Kevan C. Wherrett, Diane K. Palmer, Jerry Ludvigsson, Johnny CA Type 1 Diabet TrialNet Study Grp TI GAD vaccine reduces insulin loss in recently diagnosed type 1 diabetes: findings from a Bayesian meta-analysis SO DIABETOLOGIA LA English DT Article DE Bayes methods; Glutamic acid decarboxylase (GAD); Meta-analysis; Type 1 diabetes; Vaccine ID ANTIGEN-BASED THERAPY; C-PEPTIDE; T-CELLS; P-VALUE; MICE; TRIAL AB GAD is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. Randomised controlled clinical trials of a GAD + alum vaccine in human participants have so far given conflicting results. In this study, we sought to see whether a clearer answer to the question of whether GAD65 has an effect on C-peptide could be reached by combining individual-level data from the randomised controlled trials using Bayesian meta-analysis to estimate the probability of a positive biological effect (a reduction in C-peptide loss compared with placebo approximately 1 year after the GAD vaccine). We estimate that there is a 98% probability that 20 mu g GAD with alum administered twice yields a positive biological effect. The effect is probably a 15-20% reduction in the loss of C-peptide at approximately 1 year after treatment. This translates to an annual expected loss of between -0.250 and -0.235 pmol/ml in treated patients compared with an expected 2 h AUC loss of -0.294 pmol/ml at 1 year for untreated newly diagnosed patients. The biological effect of this vaccination should be developed further in order to reach clinically desirable reductions in insulin loss in patients recently diagnosed with type 1 diabetes. C1 [Beam, Craig A.; MacCallum, Colleen] Western Michigan Univ, Homer Stryker MD Sch Med, Div Epidemiol & Biostat, Dept Biomed Sci, 1000 Oakland Dr, Kalamazoo, MI 49008 USA. [Herold, Kevan C.] Yale Univ, Dept Immunobiol, New Haven, CT USA. [Herold, Kevan C.] Yale Univ, Dept Internal Med, New Haven, CT USA. [Wherrett, Diane K.] Hosp Sick Children, Dept Pediat, Toronto, ON, Canada. [Wherrett, Diane K.] Univ Toronto, Toronto, ON, Canada. [Palmer, Jerry] Univ Washington, Seattle, WA 98195 USA. [Palmer, Jerry] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Ludvigsson, Johnny] Linkoping Univ, Dept Clin & Expt Med, Div Pediat, Linkoping, Sweden. RP Beam, CA (reprint author), Western Michigan Univ, Homer Stryker MD Sch Med, Div Epidemiol & Biostat, Dept Biomed Sci, 1000 Oakland Dr, Kalamazoo, MI 49008 USA. EM craig.beam@med.wmich.edu OI Ludvigsson, Johnny/0000-0003-1695-5234 FU JDRF [1-INO-20140170-A-V] FX This work was supported by JDRF grant 1-INO-20140170-A-V. NR 18 TC 1 Z9 1 U1 3 U2 3 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 JAN PY 2017 VL 60 IS 1 BP 43 EP 49 DI 10.1007/s00125-016-4122-1 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EE5GQ UT WOS:000389634000007 PM 27704166 ER PT J AU Wong, EB Ndung'u, T Kasprowicz, VO AF Wong, Emily B. Ndung'u, Thumbi Kasprowicz, Victoria O. TI The role of mucosal-associated invariant T cells in infectious diseases SO IMMUNOLOGY LA English DT Review DE bacterial; cytotoxic T lymphocytes; mucosa; viral ID MR1-RESTRICTED MAIT CELLS; VITAMIN-B METABOLITES; ANTIBACTERIAL IMMUNITY; RECEPTOR HETEROGENEITY; BACTERIAL-INFECTION; MULTIPLE-SCLEROSIS; MOLECULAR-BASIS; HIV-INFECTION; MR1 TETRAMERS; INNATE AB Mucosal-associated invariant T (MAIT) cells are donor-unrestricted lymphocytes that are surprisingly abundant in humans, representing 1-10% of circulating T cells and further enriched in mucosal tissues. MAIT cells recognize and are activated by small molecule ligands produced by microbes and presented by MR1, a highly conserved MHC-related antigen-presenting protein that is ubiquitously expressed in human cells. Increasing evidence suggests that MAIT cells play a protective role in anti-bacterial immunity at mucosal interfaces. Some fungi are known to produce MAIT-activating ligands, but the role of MAIT cells in fungal infections has not yet been investigated. In viral infections, specifically HIV, which has received the most study, MAIT cell biology is clearly altered, but the mechanisms explaining these alterations and their clinical significance are not yet understood. Many questions remain unanswered about the potential of MAIT cells for protection or pathogenesis in infectious diseases. Because they interact with the universal, donor-unrestricted ligand-presenting MR1 molecule, MAIT cells may be attractive immunotherapy or vaccine targets. New tools, including the development of MR1-ligand tetramers and next-generation T-cell receptor sequencing, have the potential to accelerate MAIT cell research and lead to new insights into the role of this unique set of lymphocytes in infectious diseases. C1 [Wong, Emily B.; Ndung'u, Thumbi; Kasprowicz, Victoria O.] African Hlth Res Inst, Durban, South Africa. [Wong, Emily B.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Wong, Emily B.] Harvard Med Sch, Boston, MA USA. [Ndung'u, Thumbi; Kasprowicz, Victoria O.] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa. [Ndung'u, Thumbi; Kasprowicz, Victoria O.] Harvard Med Sch, Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Ndung'u, Thumbi] Max Planck Inst Infect Biol, Berlin, Germany. RP Wong, EB (reprint author), Nelson R Mandela Sch Med, African Hlth Res Inst, 719 Umbilo Rd, ZA-4001 Durban, South Africa. EM ebwong@mgh.harvard.edu FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID/NIH) [K08 AI118538]; Burroughs Wellcome Fund/ASTMH Postdoctoral Fellowship in Tropical Infectious Diseases; Advancing Care & Treatment for TB/HIV (ACT4TB/HIV) - South African Medical Research Council; South African Research Chairs Initiative; Victor Daitz Foundation; Howard Hughes Medical Institute FX The authors are supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID/NIH) grant K08 AI118538, the Burroughs Wellcome Fund/ASTMH Postdoctoral Fellowship in Tropical Infectious Diseases, the Advancing Care & Treatment for TB/HIV (ACT4TB/HIV) funded by the South African Medical Research Council, the South African Research Chairs Initiative, the Victor Daitz Foundation and the Howard Hughes Medical Institute. NR 74 TC 0 Z9 0 U1 9 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD JAN PY 2017 VL 150 IS 1 BP 45 EP 54 DI 10.1111/imm.12673 PG 10 WC Immunology SC Immunology GA EE2MG UT WOS:000389417800006 PM 27633333 ER PT J AU Singh, R Hui, T Matsui, A Allahem, Z Johnston, CD Ruiz-Torruella, M Rittling, SR AF Singh, Rani Hui, Tommy Matsui, Aritsune Allahem, Ziyad Johnston, Christopher D. Ruiz-Torruella, Montserrat Rittling, Susan R. TI Modulation of infection-mediated migration of neutrophils and CXCR2 trafficking by osteopontin SO IMMUNOLOGY LA English DT Article DE CXCR2; endodontic infection; integrin-av; osteopontin; receptor recycling ID RESORPTION IN-VIVO; BONE DESTRUCTION; CELL-MIGRATION; POSTTRANSLATIONAL MODIFICATIONS; INTEGRIN ALPHA-9-BETA-1; RHEUMATOID-ARTHRITIS; ENDODONTIC INFECTION; OSTEOCLAST FORMATION; CHEMOKINE RECEPTORS; IL-17 RECEPTOR AB Osteopontin (OPN) is a pro-inflammatory protein that paradoxically protects against inflammation and bone destruction in a mouse model of endodontic infection. Here we have tested the hypothesis that this effect of OPN is mediated by effects on migration of innate immune cells to the site of infection. Using the air pouch as a model of endodontic infection in mice, we showed that neutrophil accumulation at the site of infection with a mixture of endodontic pathogens is significantly reduced in OPNdeficient mice. Reduced neutrophil accumulation in the absence of OPN was accompanied by an increase in bacterial load. OPN-deficiency did not affect neutrophil survival, CXCR2 ligand expression, or the production of inflammatory cytokines in the air pouch. In vitro, OPN enhanced neutrophil migration to CXCL1, whereas in vivo, inhibition of CXCR2 suppressed cellular infiltration in air pouches of infected wild-type mice by > 50%, but had no effect in OPN-deficient mice. OPN increased cell surface expression of CXCR2 on bone marrow neutrophils in an integrinav-dependent manner, and suppressed the internalization of CXCR2 in the absence of ligand. Together, these results support a model where the protective effect of OPN results from enhanced initial neutrophil accumulation at sites of infection resulting in optimal bacterial killing. We describe a novel mechanism for this effect of OPN: integrin-alpha(v)-dependent suppression of CXCR2 internalization in neutrophils, which increases the ability of these cells to migrate to sites of infection in response to CXCR2 ligands. C1 [Singh, Rani; Hui, Tommy; Matsui, Aritsune; Allahem, Ziyad; Johnston, Christopher D.; Ruiz-Torruella, Montserrat; Rittling, Susan R.] Forsyth Inst, Dept Immunol & Infect Dis, 245 First St, Cambridge, MA 02142 USA. [Singh, Rani; Johnston, Christopher D.; Rittling, Susan R.] Harvard Sch Dent Med, Dept Dev Biol, Boston, MA USA. [Matsui, Aritsune] Tohoku Univ, Grad Sch Dent, Dept Oral Med & Surg, Div Oral & Maxillofacial Surg, Sendai, Miyagi, Japan. [Allahem, Ziyad] King Saud Univ, Coll Dent, Riyadh, Saudi Arabia. RP Rittling, SR (reprint author), Forsyth Inst, Dept Immunol & Infect Dis, 245 First St, Cambridge, MA 02142 USA. EM srittling@forsyth.org FU National Institute of Dental and Craniofacial Research of the NIH [RO1-DE022380]; American Association of Immunologists (AAI) FX The authors thank members of the Rittling laboratory for helpful discussions and Adam Lacy-Hulbert for the gift of the avfl/-Tie2Cre mice. Supported by the National Institute of Dental and Craniofacial Research of the NIH under grant no RO1-DE022380. RS was supported by a Career Development Award from the American Association of Immunologists (AAI). TH, RS, AM, ZA, MR-T and CDJ designed and performed experiments. SRR designed experiments, and RS and SRR wrote the manuscript. NR 57 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD JAN PY 2017 VL 150 IS 1 BP 74 EP 86 DI 10.1111/imm.12668 PG 13 WC Immunology SC Immunology GA EE2MG UT WOS:000389417800009 PM 27599164 ER PT J AU Sullivan, KM Rose, CD Phillips, JC Holzemer, WL Webel, AR Nicholas, P Corless, IB Kirksey, K Eller, LS Voss, J Tyer-Viola, L Portillo, C Johnson, MO Brion, J Sefcik, E Nokes, K Reid, P Rivero-Mendez, M Chen, WT AF Sullivan, Kathleen M. Rose, Carol Dawson Phillips, J. Craig Holzemer, William L. Webel, Allison R. Nicholas, Patrice Corless, Inge B. Kirksey, Kenn Eller, Lucille Sanzero Voss, Joachim Tyer-Viola, Lynda Portillo, Carmen Johnson, Mallory O. Brion, John Sefcik, Elizabeth Nokes, Kathleen Reid, Paula Rivero-Mendez, Marta Chen, Wei-Ti TI Sexual transmission-risk behaviour among HIV-positive persons: a multisite study using social action theory SO JOURNAL OF ADVANCED NURSING LA English DT Article DE condom use; HIV prevention; HIV self-management; HIV-positive adults; HIV-transmission risk; nursing; self-efficacy; sexual behaviour; Social Action Theory ID AFRICAN-AMERICAN MEN; NATIONAL PROBABILITY SAMPLE; CONDOM USE; UNITED-STATES; BISEXUAL MEN; TREATMENT OPTIMISM; SUBSTANCE-ABUSE; SELF-ESTEEM; LIFE EVENTS; GAY AB AimSexual risk behaviour was explored and described using Social Action Theory. BackgroundThe sexual transmission of HIV is complex and multi-factorial. Social Action Theory provides a framework for viewing self-regulation of modifiable behaviour such as condom use. Condom use is viewed within the context of social interaction and interdependence. DesignCross-sectional survey. MethodsSelf-report questionnaire administered to adults living with HIV/AIDS, recruited from clinics, service organizations and by active outreach, between 2010 - 2011. FindingsHaving multiple sex partners with inconsistent condom use during a 3-month recall period was associated with being male, younger age, having more years of education,substance use frequency and men having sex with men being a mode of acquiring HIV. In addition, lower self-efficacy for condom use scores were associated with having multiple sex partners and inconsistent condom use. ConclusionSocial Action Theory provided a framework for organizing data from an international sample of seropositive persons. Interventions for sexually active, younger, HIV positive men who have sex with men, that strengthen perceived efficacy for condom use, and reduce the frequency of substance use, may contribute to reducing HIV-transmission risk. C1 [Sullivan, Kathleen M.] Univ Hawaii, Manoa Sch Nursing & Dent Hyg, Honolulu, HI 96822 USA. [Rose, Carol Dawson; Portillo, Carmen; Johnson, Mallory O.] Univ Calif San Francisco, Sch Nursing, San Francisco, CA 94143 USA. [Phillips, J. Craig] Univ Ottawa, Sch Nursing, Sch Nursing, Ottawa, ON, Canada. [Holzemer, William L.; Eller, Lucille Sanzero] Rutgers State Univ, Coll Nursing, Newark, NJ 07102 USA. [Webel, Allison R.] Case Western Reserve Univ, Sch Nursing, Cleveland, OH 44106 USA. [Nicholas, Patrice; Corless, Inge B.] Massachusetts Gen Hosp, Inst Hlth Profess, Boston, MA 02114 USA. [Kirksey, Kenn] Harris Hlth Syst, Nursing Strateg Initiat, Houston, TX USA. [Voss, Joachim] Frances Payne Bolton Sch Nursing, Cleveland, OH USA. [Tyer-Viola, Lynda] Baylor Coll Med, Houston, TX 77030 USA. [Tyer-Viola, Lynda] AVP Texas Childrens Hosp, Houston, TX 77030 USA. [Brion, John] Ohio State Univ, Coll Nursing, Columbus, OH 43210 USA. [Sefcik, Elizabeth] Texas A&M Univ Corpus Christi, Christi, TX USA. [Nokes, Kathleen] CUNY Hunter Coll, Sch Nursing, New York, NY 10021 USA. [Reid, Paula] Univ N Carolina, Wilmington, NC USA. [Rivero-Mendez, Marta] Univ Puerto Rico, San Juan, PR 00936 USA. [Chen, Wei-Ti] Yale Univ, Sch Nursing, New Haven, CT 06536 USA. RP Sullivan, KM (reprint author), Univ Hawaii, Manoa Sch Nursing & Dent Hyg, Honolulu, HI 96822 USA. EM ksulliva@hawaii.edu NR 62 TC 1 Z9 1 U1 11 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0309-2402 EI 1365-2648 J9 J ADV NURS JI J. Adv. Nurs. PD JAN PY 2017 VL 73 IS 1 BP 162 EP 176 DI 10.1111/jan.13087 PG 15 WC Nursing SC Nursing GA EE7VF UT WOS:000389832100014 PM 27485796 ER PT J AU Chi, W Morgan, O Wu, E Morgan, BA AF Chi, Woo Morgan, Odysseas Wu, Eleanor Morgan, Bruce A. TI Stabilization of beta-Catenin Does Not Increase Dermal Papilla Cell Number in the Hair Follicle SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Letter ID CYCLE C1 [Chi, Woo; Morgan, Odysseas; Wu, Eleanor; Morgan, Bruce A.] Harvard Med Sch, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Dept Dermatol, Boston, MA 02115 USA. RP Morgan, BA (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Dept Dermatol, Boston, MA 02115 USA. EM bmorgan@mgh.harvard.edu FU NIAMS NIH HHS [R01 AR055256] NR 8 TC 1 Z9 1 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JAN PY 2017 VL 137 IS 1 BP 245 EP 246 DI 10.1016/j.jid.2016.08.014 PG 2 WC Dermatology SC Dermatology GA EF4QE UT WOS:000390316300034 PM 27592798 ER PT J AU Asgari, MM Toland, AE Arron, ST AF Asgari, Maryam M. Toland, Amanda E. Arron, Sarah T. TI IRF4 Polymorphism Is Associated with Cutaneous Squamous Cell Carcinoma in Organ Transplant Recipients: A Pigment-Independent Phenomenon SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Letter ID GENOME-WIDE ASSOCIATION; SKIN-CANCER; VORICONAZOLE; EXPOSURE; THERAPY; RISK C1 [Asgari, Maryam M.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Toland, Amanda E.] Ohio State Univ, Ctr Comprehens Canc, Dept Canc Biol & Genet, Columbus, OH 43210 USA. [Toland, Amanda E.] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA. [Arron, Sarah T.] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. RP Arron, ST (reprint author), Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. EM sarah.arron@ucsf.edu NR 13 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 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JAN PY 2017 VL 137 IS 1 BP 251 EP 253 DI 10.1016/j.jid.2016.07.038 PG 3 WC Dermatology SC Dermatology GA EF4QE UT WOS:000390316300037 PM 27566401 ER PT J AU Morris, SE Dole, OR Joselow, M Duncan, J Renaud, K Branowicki, P AF Morris, Sue E. Dole, Olivia R. Joselow, Marsha Duncan, Janet Renaud, Kristen Branowicki, Patricia TI The Development of a Hospital-Wide Bereavement Program: Ensuring Bereavement Care for All Families of Pediatric Patients SO JOURNAL OF PEDIATRIC HEALTH CARE LA English DT Article DE Bereavement; death; child; pediatrics; hospital-wide; program ID MENTAL-HEALTH-SERVICES; PALLIATIVE CARE; CHILD; PARENTS; GRIEF; CANCER; DEATH; ADJUSTMENT AB Although grief is a normal response to loss, the death of a child is believed to be one of the most difficult losses a person can endure, and bereaved parents are considered to be an "at-risk'' group. Even though most deaths of children in the United States occur in hospitals, bereavement care provided by hospitals is highly variable, and little attention has been directed to how hospitals can best support grieving parents. In this article, we describe the development of a hospital-wide bereavement program at Boston Children's Hospital, where we conceptualize bereavement care as a preventive model of care. We identify the primary constructs of the program as education, guidance, and support and outline a template for use by other hospitals. We recommend that all pediatric hospitals implement basic, coordinated bereavement programs as the standard of care to ensure that all families receive bereavement care after the death of a patient. C1 [Morris, Sue E.] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Dana Farber Brigham & Womens Canc Ctr, Bereavement Serv, 450 Brookline Ave,DA 2016A, Boston, MA 02215 USA. [Dole, Olivia R.] Boston Childrens Hosp, Hale Family Ctr Families, Boston, MA USA. [Joselow, Marsha; Duncan, Janet] Boston Childrens Hosp, Pediat Adv Care Team, Boston, MA USA. [Joselow, Marsha; Duncan, Janet] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave,DA 2016A, Boston, MA 02215 USA. [Renaud, Kristen; Branowicki, Patricia] Boston Childrens Hosp, Med Patient Serv, Boston, MA USA. [Branowicki, Patricia] Dana Farber Canc Inst, Pediat Oncol, 450 Brookline Ave,DA 2016A, Boston, MA 02215 USA. RP Morris, SE (reprint author), Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave,DA 2016A, Boston, MA 02215 USA. EM sue_morris@dfci.harvard.edu NR 32 TC 0 Z9 0 U1 8 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5245 EI 1532-656X J9 J PEDIATR HEALTH CAR JI J. Pediatr. Health Care PD JAN-FEB PY 2017 VL 31 IS 1 BP 88 EP 95 DI 10.1016/j.pedhc.2016.04.013 PG 8 WC Health Policy & Services; Nursing; Pediatrics SC Health Care Sciences & Services; Nursing; Pediatrics GA EE3XV UT WOS:000389536500013 PM 27236573 ER PT J AU Kahn, JM Athale, UH Clavell, LA Cole, PD Leclerc, JM Laverdiere, C Michon, B Schorin, MA Welch, JJG Sallan, SE Silverman, LB Kelly, KM AF Kahn, Justine M. Athale, Uma H. Clavell, Luis A. Cole, Peter D. Leclerc, Jean-Marie Laverdiere, Caroline Michon, Bruno Schorin, Marshall A. Welch, Jennifer J. G. Sallan, Stephen E. Silverman, Lewis B. Kelly, Kara M. TI How Variable Is Our Delivery of Information? Approaches to Patient Education About Oral Chemotherapy in the Pediatric Oncology Clinic SO JOURNAL OF PEDIATRIC HEALTH CARE LA English DT Article DE Pediatric; leukemia; adherence; cancer care delivery; patient education ID ACUTE LYMPHOBLASTIC-LEUKEMIA; MEDICATION DOSING ERRORS; CHILDREN; COMMUNICATION; SATISFACTION; NONADHERENCE; CHILDHOOD; ADHERENCE; CANCER AB In pediatric patients with acute lymphoblastic leukemia, adherence to oral chemotherapy relies largely on a parent's comprehension of the drug's indication and administration guidelines. We assessed how pediatric oncology providers educate families about oral chemotherapy. We conducted a cross-sectional survey of 68 physicians and nurses from 9 institutions in the Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium. The inter-individual approach to patient education is variable and may consist of handouts, treatment calendars, and discussions. The extent of teaching often varies depending on a provider's subjective assessment of a family's needs. Twenty-five percent of providers suggested standardizing patient teaching. When developing educational models, care teams should consider approaches that (a) objectively identify families in need of extensive teaching, (b) designate allotted teaching time by nursing staff during clinic visits, and (c) maintain the variation and dynamism that informs a successful provider-patient relationship. C1 [Kahn, Justine M.] Columbia Univ, Med Ctr, Div Pediat Hematol Oncol Stem Cell Transplantat, Pediat,Dept Pediat, 161 Ft Washington,7th Floor, New York, NY 10032 USA. [Athale, Uma H.] McMaster Childrens Hosp, Hamilton Hlth Sci, Div Hematol Oncol, Hamilton, ON, Canada. [Clavell, Luis A.] San Jorge Childrens Hosp, San Juan, PR USA. [Cole, Peter D.] Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA. [Leclerc, Jean-Marie; Laverdiere, Caroline] Univ Montreal, St Justine Univ Hosp, Charles Bruneau Canc Ctr, Hematol Oncol Div, Montreal, PQ, Canada. [Michon, Bruno] Ctr Hosp Univ Quebec, Ste Foy, PQ, Canada. [Schorin, Marshall A.] Inova Childrens Hosp, Falls Church, VA USA. [Welch, Jennifer J. G.] Brown Univ, Hasbro Childrens Hosp, Alpert Med Sch, Providence, RI 02912 USA. [Sallan, Stephen E.; Silverman, Lewis B.] Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA USA. [Kelly, Kara M.] Columbia Univ, Med Ctr, Dept Pediat, Div Pediat Hematol Oncol Stem Cell Transplantat, 161 Ft Washington,7th Floor, New York, NY 10032 USA. [Kelly, Kara M.] SUNY Buffalo, Sch Med, Roswell Pk Canc Inst, Buffalo, NY USA. [Kelly, Kara M.] SUNY Buffalo, Sch Med, Womens & Childrens Hosp, Buffalo, NY USA. RP Kahn, JM (reprint author), Columbia Univ, Med Ctr, New York Presbyterian, 161 Ft Washington,7th Floor, New York, NY 10032 USA. EM jmk9015@nyp.org OI Kahn, Justine/0000-0003-3330-6754 FU National Cancer Institute [R25 CA094061] FX Justine M. Kahn is supported in part by a fellowship from the National Cancer Institute (R25 CA094061). NR 21 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5245 EI 1532-656X J9 J PEDIATR HEALTH CAR JI J. Pediatr. Health Care PD JAN-FEB PY 2017 VL 31 IS 1 BP E1 EP E6 DI 10.1016/j.pedhc.2016.06.004 PG 6 WC Health Policy & Services; Nursing; Pediatrics SC Health Care Sciences & Services; Nursing; Pediatrics GA EE3XV UT WOS:000389536500001 PM 27461368 ER PT J AU Schaller, SJ Alam, SM Mao, JR Zhao, YL Blobner, M Greenblatt, DJ Martyn, JAJ AF Schaller, Stefan J. Alam, Saad M. Mao, Jianren Zhao, Yanli Blobner, Manfred Greenblatt, David J. Martyn, J. A. Jeevendra TI Pharmacokinetics cannot explain the increased effective dose requirement for morphine and midazolam in rats during their extended administration alone or in combination SO JOURNAL OF PHARMACY AND PHARMACOLOGY LA English DT Article DE drug disposition; pharmacokinetics ID HUMAN LIVER-MICROSOMES; UDP-GLUCURONOSYLTRANSFERASES; INTRATHECAL MIDAZOLAM; DRUG GLUCURONIDATION; IN-VITRO; TOLERANCE; METABOLISM; TRIAZOLAM; SEDATION; HUMANS AB ObjectivesChronic administration of morphine and midazolam, alone or in combination, can induce tolerance to their effects. Data showed that co-administration of morphine and midazolam increased effective dose requirement of morphine, exceeding that observed with morphine alone. MethodsTo elucidate the pharmacokinetic component to the tolerance, we administered midazolam (2 mg/kg) and morphine (10 mg/kg) alone or their combination daily to rats for 12 days followed by a pharmacokinetic study on day 13. On the study day, each animal received a single bolus dose of 5 mg/kg morphine, and 2 mg/kg of midazolam 30 s later. Multiple blood samples were obtained for 6 h. Plasma drug concentrations were assayed by mass spectrometry optimized for small samples. Key findingsMean morphine clearance was as follows: 22.2, 27.2, 26.0 and 23.4 l/h per kg in the saline-saline, saline-midazolam, saline-morphine and midazolam-morphine groups, respectively. Corresponding midazolam clearances were 32.8, 23.0, 22.2 and 31.1 l/h per kg. ANOVA indicated no significant differences among the four groups in the clearances, half-lives, and volumes of distribution. Morphine and midazolam clearances were significantly correlated (R-2 = 0.48, P < 0.001). ConclusionsThis animal model suggests that altered pharmacokinetics cannot explain tolerance evidenced as increased dose requirement for morphine or midazolam, when administered alone or combination, for extended periods. C1 [Schaller, Stefan J.; Alam, Saad M.; Mao, Jianren; Martyn, J. A. Jeevendra] Shriners Hosp Children, Massachusetts Gen Hosp, Dept Anesthesiol Crit Care & Pain Med, 51 Blossom St,Room 206, Boston, MA 02114 USA. [Schaller, Stefan J.; Alam, Saad M.; Mao, Jianren; Martyn, J. A. Jeevendra] Harvard Med Sch, Boston, MA USA. [Schaller, Stefan J.; Blobner, Manfred] Tech Univ Munich, Klinikum Rechts Isar, Klin Anaesthesiol, Munich, Germany. [Zhao, Yanli; Greenblatt, David J.] Tufts Univ, Sch Med, Program Pharmacol & Expt Therapeut, Boston, MA 02111 USA. RP Martyn, JAJ (reprint author), Shriners Hosp Children, Massachusetts Gen Hosp, Dept Anesthesiol Crit Care & Pain Med, 51 Blossom St,Room 206, Boston, MA 02114 USA. EM JMARTYN@mgh.harvard.edu OI Schaller, Stefan/0000-0002-6683-9584 FU Klinikum fur Anaesthesiologie; Technische Universitat, Munich, Germany FX This work was supported by institutional funds of the Klinikum fur Anaesthesiologie, Klinikum rechts der Isar, Technische Universitat, Munich, Germany, to Dr. Schaller. NR 43 TC 0 Z9 0 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3573 EI 2042-7158 J9 J PHARM PHARMACOL JI J. Pharm. Pharmacol. PD JAN PY 2017 VL 69 IS 1 BP 82 EP 88 DI 10.1111/jphp.12663 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EE7WF UT WOS:000389835000009 PM 27891611 ER PT J AU Falgas, I Ramos, Z Herrera, L Qureshi, A Chavez, L Bonal, C McPeck, S Wang, Y Cook, B Alegria, M AF Falgas, Irene Ramos, Zorangeli Herrera, Lizbeth Qureshi, Adil Chavez, Ligia Bonal, Covadonga McPeck, Samantha Wang, Ye Cook, Benjamin Alegria, Margarita TI Barriers to and Correlates of Retention in Behavioral Health Treatment Among Latinos in 2 Different Host Countries: The United States and Spain SO JOURNAL OF PUBLIC HEALTH MANAGEMENT AND PRACTICE LA English DT Article DE barriers; behavioral health; cross-national; ethnic; immigrants; international; Latinos ID MENTAL-HEALTH; LANGUAGE BARRIERS; PSYCHOMETRIC PROPERTIES; PSYCHOLOGICAL DISTRESS; PSYCHIATRIC-DISORDERS; DEPRESSION TREATMENT; SERVICE UTILIZATION; SCALE-UP; CARE; IMMIGRANT AB Context: Latino immigrants constitute a large portion of the Spanish and US immigrant populations, yet a dearth of research exists regarding barriers to retention in behavioral health care. Objectives: To identify and compare perceived barriers related to behavioral health care among first-and second-generation Latinos in Boston, Madrid, and Barcelona, and evaluate whether the frequency of behavioral health care use in the last year was related to these barriers. Design, Setting, and Participants: Data were obtained from the International Latino Research Partnership project. First- or second-generation self-identified Latino immigrants aged 18 years and more who resided more than 1 year in the host country were recruited from community agencies and primary care, mental health, substance abuse, and HIV clinics. Main Outcome Measures: Eleven barriers were assessed and compared across sites. The relationship between barriers and behavioral services visits within the last yearwas evaluated, adjusting for sociodemographics, clinical measures, degree of health literacy, cultural, and social factors. Results: Wanting to handle the problem on one's own, thinking that treatment would not work, and being unsure of where to go or who to see were the most frequently reported barriers for Latino immigrants. Previous treatment failure, difficulties in transportation or scheduling, and linguistic barriers were more likely to be reported in Boston; trying to deal with mental health problems on one's own was more commonly reported in Barcelona and Madrid. Two barriers associated with the number of visits were concerns about the cost of services and uncertainty about where to go or who to see. Conclusions: After adjusting for sociodemographics, clinical measures, degree of health literacy, cultural, and social factors, barriers still differed significantly across sites. Efforts to improve behavioral health services must be tailored to immigrants' context, with attention to changing attitudes of self-reliance and outreach to improve access to and retention in care. C1 [Falgas, Irene; Qureshi, Adil] Univ Autonoma Barcelona, Dept Psychiat & Forens Med, Vall dHebron Univ Hosp, Barcelona, Spain. [Falgas, Irene; Ramos, Zorangeli; Herrera, Lizbeth; McPeck, Samantha; Wang, Ye; Alegria, Margarita] Massachusetts Gen Hosp, Dept Med, Dispar Res Unit, Boston, MA 02114 USA. [Falgas, Irene; Ramos, Zorangeli; Herrera, Lizbeth; McPeck, Samantha; Wang, Ye; Alegria, Margarita] Harvard Med Sch, Boston, MA 02114 USA. [Chavez, Ligia] Univ Puerto Rico, San Juan, PR 00936 USA. [Bonal, Covadonga] Univ Hosp Fdn Jimenez Diaz, Madrid, Spain. [Cook, Benjamin] Cambridge Hlth Alliance, Hlth Equ Res Lab, Cambridge, MA USA. [Cook, Benjamin] Harvard Med Sch, Cambridge, MA USA. RP Alegria, M (reprint author), Massachusetts Gen Hosp, Dept Med, Dispar Res Unit, Boston, MA 02114 USA.; Alegria, M (reprint author), Harvard Med Sch, Boston, MA 02114 USA. EM malegria@mgh.harvard.edu FU NIDA [5R01DA034952-02]; NIMH [3R01MH100155-01S1] FX Work supported by NIDA Grant 5R01DA034952-02; NIMH supplement 3R01MH100155-01S1. NR 73 TC 0 Z9 0 U1 8 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-4659 EI 1550-5022 J9 J PUBLIC HEALTH MAN JI J. Public Health Manag. Pract. PD JAN-FEB PY 2017 VL 23 IS 1 BP E20 EP E27 DI 10.1097/PHH.0000000000000391 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EE3BY UT WOS:000389462800003 PM 26910867 ER PT J AU Davis, JP Bergman, BG Smith, DC Kelly, JF AF Davis, Jordan P. Bergman, Brandon G. Smith, Douglas C. Kelly, John F. TI Testing a Matching Hypothesis for Emerging Adults in Project MATCH: During-Treatment and One-Year Outcomes SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID MANAGED CARE PROGRAM; YOUNG-ADULTS; SUBSTANCE USE; PSYCHOMETRIC PROPERTIES; COGNITIVE-DEVELOPMENT; ADDICTION TREATMENT; TREATMENT RETENTION; MULTILEVEL SEM; ADOLESCENTS; PREDICTORS AB Objective: Compared with older adults, emerging adults (18-29 years old) entering treatment typically have less severe alcohol use consequences. Also, their unique clinical presentations (e.g., modest initial abstinence motivation) and developmental contexts (e.g., drinking rich social networks) may make a straightforward implementation of treatments developed for adults less effective. Yet, this has seldom been examined empirically. This study was a secondary analysis of Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity) data examining (a) overall differences between emerging adults and older adults (>= 30 years old) on outcomes during treatment and at 1-year follow-up, and (b) whether emerging adults had poorer outcomes on any of the three Project MATCH treatments in particular. Method: Participants were 267 emerging adults and 1,459 older adults randomly assigned to individually delivered cognitive-behavioral therapy (CBT), motivational enhancement therapy (MET), or 12-step facilitation (TSF). Multilevel growth curve models tested differences on percentage of days abstinent (PDA) and drinks per drinking day (DDD) by age group and treatment assignment. Results: During treatment, compared with older adults, emerging adults reported more DDD but similar PDA. Further, emerging adults assigned to TSF had less PDA and more DDD than emerging adults and older adults assigned to CBT or MET during treatment (i.e., emerging adults in TSF has poorer outcomes initially), but this matching effect was not evident at 1-year follow-up. Conclusions: This study is among the first to test age group differences across three psychosocial interventions shown to be efficacious treatments for alcohol use disorder. Although emerging adults generally did as well as their older counterparts, they may require a more developmentally sensitive approach to bolster TSF effects during treatment. C1 [Davis, Jordan P.; Smith, Douglas C.] Univ Illinois, 1010 W Nevada St MC-082, Urbana, IL 61801 USA. [Bergman, Brandon G.; Kelly, John F.] Massachusetts Gen Hosp, Ctr Addict Med, Boston, MA 02114 USA. [Bergman, Brandon G.; Kelly, John F.] Harvard Med Sch, Boston, MA USA. RP Davis, JP (reprint author), Univ Illinois, 1010 W Nevada St MC-082, Urbana, IL 61801 USA. EM jdavis37@illinois.edu FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) [K23AA017702, K24AA022136-02] FX This study was supported by National Institute on Alcohol Abuse and Alcoholism (NIAAA) Grants K23AA017702 (to Douglas C. Smith) and K24AA022136-02 (to John F. Kelly). The NIAAA had no role in the study design, collection, or analysis; interpretation of results; writing of the manuscript; or decisions on publication outlet. NR 50 TC 0 Z9 0 U1 1 U2 1 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 EI 1938-4114 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD JAN PY 2017 VL 78 IS 1 BP 140 EP 145 PG 6 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA EE5XW UT WOS:000389683900018 PM 27936374 ER PT J AU Irwin, D Grossman, M Weintraub, D Hurtig, HI Duda, JE Xie, SX Lee, EB Van Deerlin, VM Lopez, OL Kofler, JK Nelson, PT Jicha, GA Woltjer, R Quinn, JF Kaye, J Leverenz, JB Tsuang, D Longfellow, K Yearout, D Kukull, W Keene, CD Montine, TJ Zabetian, CP Trojanowski, JQ AF Irwin, David Grossman, Murray Weintraub, Daniel Hurtig, Howard I. Duda, John E. Xie, Sharon X. Lee, Edward B. Van Deerlin, Vivianna M. Lopez, Oscar L. Kofler, Julia K. Nelson, Peter T. Jicha, Gregory A. Woltjer, Randy Quinn, Joseph F. Kaye, Jeffery Leverenz, James B. Tsuang, Debby Longfellow, Katelan Yearout, Dora Kukull, Walter Keene, C. Dirk Montine, Thomas J. Zabetian, Cyrus P. Trojanowski, John Q. TI Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis SO LANCET NEUROLOGY LA English DT Article ID ALZHEIMERS ASSOCIATION GUIDELINES; PARKINSONS-DISEASE DEMENTIA; LEWY BODY; ALPHA-SYNUCLEIN; DIAGNOSTIC-CRITERIA; NATIONAL INSTITUTE; PATHOLOGY; TAU; PREVALENCE; BODIES AB Background Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synudeinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of dinical heterogeneity in synudeinopathies. Methods In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed a synudeinopathy (as of Oct 1, 2015) who were previously induded in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, alpha-synudein indusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synudeinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex. Findings On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Levey body disorder with autopsy-confirmed a synudeinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral a-synudein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<0.0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (beta -4.0, 95% CI -5.5 to -2.6; p<0.0001; R-2 0.22, p<0.0001) and with survival (-2.0, -3.2 to -0.8; 0.003; 0.15, <0.0001) in models that induded age at death, sex, cerebral neuritic plaque scores, cerebral alpha-synudein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates. Interpretation Alzheimer's disease neuropathology is common in synudeinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to a-synudein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synudeinopathies should help to identify the most appropriate patients for dinical trials of emerging therapies targeting tau, amyloid-beta or alpha synudein, and to stratify them by level of Alzheimer's disease neuropathology. C1 [Irwin, David; Grossman, Murray; Weintraub, Daniel; Hurtig, Howard I.; Xie, Sharon X.; Lee, Edward B.; Van Deerlin, Vivianna M.; Trojanowski, John Q.] Univ Penn, Perelman Sch Med, Ctr Neurodegenerat Dis Res, Dept Pathol, Philadelphia, PA 19104 USA. [Irwin, David; Grossman, Murray; Weintraub, Daniel; Hurtig, Howard I.; Xie, Sharon X.; Lee, Edward B.; Van Deerlin, Vivianna M.; Trojanowski, John Q.] Univ Penn, Perelman Sch Med, Lab Med, Morris K Udall Parkinsons Dis Ctr Excellence,Inst, Philadelphia, PA 19104 USA. [Irwin, David; Grossman, Murray; Weintraub, Daniel; Hurtig, Howard I.; Duda, John E.] Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Xie, Sharon X.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Weintraub, Daniel; Duda, John E.] Michael J Crescenz VA Med Ctr, Educ & Clin Ctr, Parkinsons Dis Res, Philadelphia, PA USA. [Lopez, Oscar L.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Kofler, Julia K.] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. [Nelson, Peter T.; Jicha, Gregory A.] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. [Nelson, Peter T.] Univ Kentucky, Dept Pathol, Lexington, KY USA. [Woltjer, Randy] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. [Quinn, Joseph F.; Kaye, Jeffery] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Leverenz, James B.] Cleveland Clin Fdn, Cleveland Clin, Lou Ruvo Ctr Brain Hlth, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Montine, Thomas J.] Standford Univ, Dept Pathol, Stanford, CA USA. [Kukull, Walter] Univ Washington, Sch Med, Dept Epidemiol, Seattle, WA USA. [Tsuang, Debby] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA USA. [Longfellow, Katelan; Yearout, Dora; Zabetian, Cyrus P.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. [Keene, C. Dirk] Univ Washington, Sch Med, Dept Pathol, Seattle, WA USA. [Quinn, Joseph F.; Leverenz, James B.; Yearout, Dora; Keene, C. Dirk; Montine, Thomas J.; Zabetian, Cyrus P.] Univ Washington, Sch Med, Pacific Udall Ctr, Seattle, WA USA. [Tsuang, Debby; Yearout, Dora; Zabetian, Cyrus P.] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Longfellow, Katelan; Zabetian, Cyrus P.] VA Puget Sound Hlth Care Syst, Northwest Parkinsons Dis Res Educ & Clin Ctr, Seattle, WA USA. RP Irwin, D (reprint author), Univ Penn, Perelman Sch Med, Ctr Neurodegenerat Dis Res, Dept Pathol, Philadelphia, PA 19104 USA.; Irwin, D (reprint author), Univ Penn, Perelman Sch Med, Lab Med, Morris K Udall Parkinsons Dis Ctr Excellence,Inst, Philadelphia, PA 19104 USA.; Irwin, D (reprint author), Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19104 USA.; Irwin, D (reprint author), Univ Penn, Hosp Univ Penn, Perelman Sch Med, Frontotemporal Degenerat Ctr, 3600 Spruce St, Philadelphia, PA 19104 USA.; Irwin, D (reprint author), Univ Penn, Hosp Univ Penn, Perelman Sch Med, Ctr Neurodegenerat Dis Res, 3600 Spruce St, Philadelphia, PA 19104 USA. EM dirwin@mail.med.upenn.edu FU US National Institutes of Health (National Institute on Aging); US National Institutes of Health (National Institute of Neurological Disorders and Stroke) FX US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke). NR 30 TC 2 Z9 2 U1 8 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD JAN PY 2017 VL 16 IS 1 BP 55 EP 65 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA EE8IP UT WOS:000389869200027 PM 27979356 ER PT J AU Schrag, A Siddiqui, UF Anastasiou, Z Weintraub, D Schott, JM AF Schrag, Anette Siddiqui, Uzma Faisal Anastasiou, Zacharias Weintraub, Daniel Schott, Jonathan M. TI Clinical variables and biomarkers in prediction of cognitive CrossMark impairment in patients with newly diagnosed Parkinson's disease: a cohort study SO LANCET NEUROLOGY LA English DT Article ID CEREBROSPINAL-FLUID; ALPHA-SYNUCLEIN; ALZHEIMER-DISEASE; DATATOP COHORT; AMYLOID-BETA; DEMENTIA; DECLINE; PROGRESSION; TAU; INSTRUMENT AB Background Parkinson's disease is associated with an increased incidence of cognitive impairment and dementia. Predicting who is at risk of cognitive decline early in the disease course has implications for clinical prognosis and for stratification of participants in clinical trials. We assessed the use of clinical information and biomarkers as predictive factors for cognitive decline in patients with newly diagnosed Parkinson's disease. Methods The Parkinson's Progression Markers Initiative (PPMI) study is a cohort study in patients with newly diagnosed Parkinson's disease. We evaluated cognitive performance (Montreal Cognitive Assessment [MoCA] scores), demographic and clinical data, APOE status, and biomarkers (CSF and dopamine transporter [DAT] imaging results). Using change in MoCA scores over 2 years, MoCA scores at 2 years' follow-up, and a diagnosis of cognitive impairment (combined mild cognitive impairment or dementia) at 2 years as outcome measures, we assessed the predictive values of baseline clinical variables and separate or combined additions of APOE status, DAT imaging, and CSF biomarkers. We did univariate and multivariate linear analyses with MoCA change scores between baseline and 2 years, and with MoCA scores at 2 years as dependent variables, using backwards linear regression analysis. Additionally, we constructed a prediction model for diagnosis of cognitive impairment using logistic regression analysis. Findings 390 patients with Parkinson's disease recruited between July 1,2010, and May 31,2013, and for whom data on MoCA scores at baseline and 2 years were available. In multivariate analyses, baseline age, University of Pennsylvania Smell Inventory Test (UP SIT) scores, CSF amyloid (A beta(42)) to t-tau ratio, and APOE status were associated with change in MoCA scores over time. Baseline age, MoCA and UPSIT scores, and CSF A beta(42) to t-tau ratio were associated with MoCA score at 2 years (using a backwards p-removal threshold of 0.1). Accuracy of prediction of cognitive impairment using age alone (area under the curve 0-68,95% CI 0.60-0.76) significantly improved by addition of clinical scores (UP SIT, Rapid Eye Movement Sleep Behaviour Disorder Screening Questionnaire [RBDSQ], Geriatric Depression Scale, and Movement Disorder Society Unified Parkinson's Disease Rating Scale motor scores; 0.76, 0.68-0.83), CSF variables (0.74, 0.68-0.81), or DAT imaging results (0.76, 0.68-0.83). In combination, the five variables showing the most significant associations with cognitive impairment (age, UP SIT, RBDSQ, CSF AR, and caudate uptake on DAT imaging) allowed prediction of cognitive impairment at 2 years (0.80, 0.74-0.87; p=0.0003 compared to age alone). Interpretation In newly diagnosed Parkinson's disease, the occurrence of cognitive impairment at 2 year follow-up can be predicted with good accuracy using a model combining information on age, non-motor assessments, DAT imaging, and CSF biomarkers. C1 [Schrag, Anette; Siddiqui, Uzma Faisal; Anastasiou, Zacharias] UCL, UCL Inst Neurol, Dept Clin Neurosci, Royal Free Campus, London NW3 2PF, England. [Schott, Jonathan M.] UCL, UCL Inst Neurol, Dementia Res Ctr, Dept Neurodegenerat Dis, London, England. [Weintraub, Daniel] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Schrag, A (reprint author), UCL, UCL Inst Neurol, Dept Clin Neurosci, Royal Free Campus, London NW3 2PF, England. EM a.schrag@ucl.ac.uk FU Michael J Fox Foundation for Parkinson's Research; AbbVie; Avid; Biogen; Bristol-Myers Squibb; Covance; GE Healthcare; Genentech; GlaxoSmithKline; Lilly; Lundbeck; Merck; Meso Scale Discovery; Pfizer; Piramal; Roche; Servier; Teva; UCB; National Institute for Health Research Queen Square Dementia Biomedical Research Unit; National Institute for Health Research University College London Hospital Biomedical Research Centre; Wolfson Foundation; Engineering and Physical Sciences Research Council [EP/J020990/1]; Medical Research Council [CSUB19166]; Arthritis Research UK [ARUK-Network 2012-6-ICE, ARUK-PG2014-1946]; European Union [666992] FX This project relied mainly on publicly available data without specific funding for the analysis. PPMI (a public-private partnership) is funded by the Michael J Fox Foundation for Parkinson's Research and funding partners, including AbbVie, Avid, Biogen, Bristol-Myers Squibb, Covance, GE Healthcare, Genentech, GlaxoSmithKline, Lilly, Lundbeck, Merck, Meso Scale Discovery, Pfizer, Piramal, Roche, Servier, Teva, and UCB. This study was not supported by additional funding. JMS was supported by the National Institute for Health Research Queen Square Dementia Biomedical Research Unit, the National Institute for Health Research University College London Hospital Biomedical Research Centre, Wolfson Foundation, Engineering and Physical Sciences Research Council (EP/J020990/1), Medical Research Council (CSUB19166), Arthritis Research UK (ARUK-Network 2012-6-ICE; ARUK-PG2014-1946), and the European Union's Horizon 2020 research and innovation programme (grant 666992). NR 36 TC 2 Z9 2 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD JAN PY 2017 VL 16 IS 1 BP 66 EP 75 DI 10.1016/S1474-4422(16)30328-3 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA EE8IP UT WOS:000389869200028 PM 27866858 ER PT J AU Wolkow, N Jakobiec, FA Stagner, AM Cunnane, ME Piantadosi, AL Basgoz, N Lefebvre, D AF Wolkow, Natalie Jakobiec, Frederick A. Stagner, Anna M. Cunnane, Mary E. Piantadosi, Anne L. Basgoz, Nesli Lefebvre, Daniel TI Chronic orbital and calvarial fungal infection with Apophysomyces variabilis in an immunocompetent patient SO SURVEY OF OPHTHALMOLOGY LA English DT Review DE Apophysomyces; Saksenaea; mucor; rhino-orbito-cerebral mucormycosis; fungus; calvarial lytic lesions; amphotericin B; posaconazole; diploic venous system ID VITRO ANTIFUNGAL SUSCEPTIBILITY; SKULL-BASE OSTEOMYELITIS; SAKSENAEA-VASIFORMIS; RHINOCEREBRAL MUCORMYCOSIS; CEREBRAL MUCORMYCOSIS; REFRACTORY MYCOSES; HYPERBARIC-OXYGEN; HEALTHY PATIENT; ELEGANS; ZYGOMYCOSIS AB Apophysomyces is a rare fungal organism causing rhino-orbito-cerebral mycotic infections with high morbidity and mortality, typically in immunocompetent individuals. Several cases of Apophysomyces elegans orbital disease have been reported. Herein, we report a case of Apophysomyces variabilis infection involving the orbit, sinuses, and calvarium in an immunocompetent 74-year-old woman, with a review of the literature. Unlike prior cases of A. elegans classic rhino-orbito-cerebral infection, our case included diffuse calvarial lytic lesions and overlying soft tissue nodules, but without parenchymal intracranial involvement. There was radiographic and clinical evidence of infarction of the orbital contents and cavernous sinus thrombosis. Anastomoses between the superior orbital (ophthalmic) vein and diploic veins of the calvarium are believed to be primarily responsible for the unusual mode of spread on the extradural surface of the brain. Although the patient stabilized without definitive surgical intervention, her disease slowly and intermittently progressed for over a year after presentation, requiring multiple courses of antifungal treatment. (C) 2016 Elsevier Inc. All rights reserved. C1 [Wolkow, Natalie; Jakobiec, Frederick A.; Stagner, Anna M.; Cunnane, Mary E.; Lefebvre, Daniel] Harvard Med Sch, Dept Ophthalmol, Boston, MA USA. [Wolkow, Natalie; Jakobiec, Frederick A.; Stagner, Anna M.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Jakobiec, Frederick A.; Stagner, Anna M.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, David G Cogan Lab Ophthalm Pathol, Suite 328,243 Charles St, Boston, MA 02114 USA. [Cunnane, Mary E.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA USA. [Piantadosi, Anne L.; Basgoz, Nesli] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA USA. [Lefebvre, Daniel] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Div Ophthalm Plast Surg, Boston, MA 02114 USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, David G Cogan Lab Ophthalm Pathol, Suite 328,243 Charles St, Boston, MA 02114 USA. EM Fred_Jakobiec@meei.harvard.edu NR 65 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 0039-6257 EI 1879-3304 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD JAN-FEB PY 2017 VL 62 IS 1 BP 70 EP 82 DI 10.1016/j.survophthal.2016.05.006 PG 13 WC Ophthalmology SC Ophthalmology GA EE5AN UT WOS:000389617200005 PM 27256687 ER PT J AU Baud'huin, M Lamoureux, F Jacques, C Calleja, LR Quillard, T Charrier, C Amiaud, J Berreur, M Brounais-LeRoyer, B Owen, R Reilly, GC Bradner, JE Heymann, D Ory, B AF Baud'huin, Marc Lamoureux, Francois Jacques, Camille Calleja, Lidia Rodriguez Quillard, Thibaut Charrier, Celine Amiaud, Jerome Berreur, Martine Brounais-LeRoyer, Benedicte Owen, Robert Reilly, Gwendolen C. Bradner, James E. Heymann, Dominique Ory, Benjamin TI Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis SO BONE LA English DT Article DE Osteoporosis; Epigenetic; Bromodomain; Inhibitor; Osteoblast; Osteoclast ID AUTOSOMAL-DOMINANT OSTEOPETROSIS; OSTEOCLAST DIFFERENTIATION; BROMODOMAIN INHIBITION; SELECTIVE-INHIBITION; ONCOSTATIN-M; BONE; CELLS; OSTEOSARCOMA; TARGET; MECHANISMS AB Histone modifications are important for maintaining the transcription program. BET proteins, an important class of "histone reading proteins", have recently been described as essential in bone biology. This study presents the therapeutic opportunity of BET protein inhibition in osteoporosis. We find that the pharmacological BET protein inhibitor JQ1 rescues pathologic bone loss in a post-ovariectomy osteoporosis model by increasing the trabecular bone volume and restoring mechanical properties. The BET protein inhibition suppresses osteoclast differentiation and activity as well as the osteoblastogenesis in vitro. Moreover, we show that treated non-resorbing osteoclasts could still activate osteoblast differentiation. In addition, specific inhibition of BRD4 using RNA interference inhibits osteoclast differentiation but strongly activates osteoblast mineralization activity. Mechanistically, JQ1 inhibits expression of the master osteoclast transcription factor NFATc1 and the transcription factor of osteoblast Runx2. These findings strongly support that targeting epigenetic chromatin regulators such as BET proteins may offer a promising alternative for the treatment of bone-related disorders such as osteoporosis. (C) 2016 Elsevier Inc. All rights reserved. C1 [Baud'huin, Marc; Lamoureux, Francois; Jacques, Camille; Calleja, Lidia Rodriguez; Quillard, Thibaut; Charrier, Celine; Amiaud, Jerome; Berreur, Martine; Brounais-LeRoyer, Benedicte; Heymann, Dominique; Ory, Benjamin] INSERM, UMR 957, Equipe Labellisee Ligue 2012, 1 Rue Gaston Veil, F-44035 Nantes, France. [Baud'huin, Marc; Lamoureux, Francois; Jacques, Camille; Calleja, Lidia Rodriguez; Quillard, Thibaut; Charrier, Celine; Amiaud, Jerome; Berreur, Martine; Brounais-LeRoyer, Benedicte; Heymann, Dominique; Ory, Benjamin] Univ Nantes, Physiopathol Resorpt Osseuse & Therapie Tumeurs O, Nantes Atlantique Univ, EA3822, 1 Rue Gaston Veil, F-44035 Nantes, France. [Baud'huin, Marc; Heymann, Dominique] Nantes Univ Hosp, Nantes, France. [Owen, Robert; Reilly, Gwendolen C.] Univ Sheffield, Dept Mat Sci & Engn, INSIGNEO, Inst In Silico Med, Sheffield, S Yorkshire, England. [Bradner, James E.] Harvard Med Sch, Dept Med Oncol, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Bradner, James E.] Harvard Med Sch, Dept Med, 25 Shattuck St, Boston, MA 02115 USA. RP Ory, B (reprint author), INSERM, UMR 957, 1 Rue Gaston Veil, F-44035 Nantes, France. EM Benjamin.ory@univ-nantes.fr OI Quillard, Thibaut/0000-0002-8096-2597 FU Seventh Framework Programme [FP7] [264817]; Region Pays de la Loire [000381794] FX This paper was written as a part of research project which received funding from the Seventh Framework Programme ([FP7/2007-2013]) under grant agreement no. 264817 - BONE-NET.; Camille Jacques is founded by INSERM (Institut National de la Sante et de la Recherche Medicale) and Region Pays de la Loire (grant no. 000381794). NR 34 TC 1 Z9 1 U1 15 U2 15 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 JAN PY 2017 VL 94 BP 10 EP 21 DI 10.1016/j.bone.2016.09.020 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EE0QC UT WOS:000389283000002 PM 27669656 ER PT J AU Joseph, P Ishai, A Mani, V Kallend, D Rudd, JHF Fayad, ZA Tawakol, A AF Joseph, Philip Ishai, Amorina Mani, Venkatesh Kallend, David Rudd, James H. F. Fayad, Zahi A. Tawakol, Ahmed TI Short-term changes in arterial inflammation predict long-term changes in atherosclerosis progression SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE Positron emission tomography; Magnetic resonance imaging; Inflammation; Atherosclerosis ID RANDOMIZED CLINICAL-TRIAL; ACUTE CORONARY SYNDROME; PLAQUE INFLAMMATION; FDG-PET/CT; DAL-PLAQUE; DISEASE; PROTEIN; EVENTS; DALCETRAPIB; MANAGEMENT AB Purpose It remains unclear whether changes in arterial wall inflammation are associated with subsequent changes in the rate of structural progression of atherosclerosis. Methods In this sub-study of the dal-PLAQUE clinical trial, multi-modal imaging was performed using 18-fludeoxyglucose (FDG) positron emission tomography (PET, at 0 and 6 months) and magnetic resonance imaging (MRI, at 0 and 24 months). The primary objective was to determine whether increasing FDG uptake at 6 months predicted atherosclerosis progression on MRI at 2 years. Arterial inflammation was measured by the carotid FDG target-to-background ratio (TBR), and atherosclerotic plaque progression was defined as the percentage change in carotid mean wall area (MWA) and mean wall thickness (MWT) on MRI between baseline and 24 months. Results A total of 42 participants were included in this sub-study. The mean age of the population was 62.5 years, and 12 (28.6 %) were women. In participants with (vs. without) any increase in arterial inflammation over 6 months, the long-term changes in both MWT (% change MWT: 17.49 % vs. 1.74 %, p = 0.038) and MWA (% change MWA: 25.50 % vs. 3.59 %, p = 0.027) were significantly greater. Results remained significant after adjusting for clinical and biochemical covariates. Individuals with no increase in arterial inflammation over 6 months had no significant structural progression of atherosclerosis over 24 months as measured by MWT (p = 0.616) or MWA (p = 0.373). Conclusions Short-term changes in arterial inflammation are associated with long-term structural atherosclerosis progression. These data support the concept that therapies that reduce arterial inflammation may attenuate or halt progression of atherosclerosis. C1 [Joseph, Philip; Ishai, Amorina; Tawakol, Ahmed] Massachusetts Gen Hosp, Div Cardiol, Suite 400-165,Cambridge St, Boston, MA 02114 USA. [Joseph, Philip; Ishai, Amorina; Tawakol, Ahmed] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Suite 400-165,Cambridge St, Boston, MA 02114 USA. [Joseph, Philip; Ishai, Amorina; Tawakol, Ahmed] Harvard Med Sch, Suite 400-165,Cambridge St, Boston, MA 02114 USA. [Joseph, Philip] McMaster Univ, Dept Med, Populat Hlth Res Inst, Hamilton, ON, Canada. [Joseph, Philip] McMaster Univ, Dept Radiol, Hamilton, ON, Canada. [Mani, Venkatesh; Fayad, Zahi A.] Icahn Sch Med Mt Sinai, Sch Med, Translat & Mol Imaging Inst, Hess CSM Bldg Floor TMII,Rm S1-104, New York, NY 10029 USA. [Mani, Venkatesh; Fayad, Zahi A.] Icahn Sch Med Mt Sinai, Sch Med, Dept Radiol, Hess CSM Bldg Floor TMII,Rm S1-104, New York, NY 10029 USA. [Kallend, David] Med Co, Parsippany, NJ USA. [Rudd, James H. F.] Univ Cambridge, Div Cardiovasc Med, Cambridge, England. RP Tawakol, A (reprint author), Massachusetts Gen Hosp, Div Cardiol, Suite 400-165,Cambridge St, Boston, MA 02114 USA.; Tawakol, A (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, Suite 400-165,Cambridge St, Boston, MA 02114 USA.; Tawakol, A (reprint author), Harvard Med Sch, Suite 400-165,Cambridge St, Boston, MA 02114 USA.; Fayad, ZA (reprint author), Icahn Sch Med Mt Sinai, Sch Med, Translat & Mol Imaging Inst, Hess CSM Bldg Floor TMII,Rm S1-104, New York, NY 10029 USA.; Fayad, ZA (reprint author), Icahn Sch Med Mt Sinai, Sch Med, Dept Radiol, Hess CSM Bldg Floor TMII,Rm S1-104, New York, NY 10029 USA. EM zahi.fayad@mssm.edu; atawakol@mgh.harvard.edu FU McMaster University Early Career Investigator award; F. Hoffmann-La Roche Ltd; NIHR Cambridge Biomedical Research Centre; British Heart Foundation; Wellcome Trust FX This study was funded by F. Hoffmann-La Roche Ltd. Dr. Joseph is supported in part by a McMaster University Early Career Investigator award. Dr. Rudd is supported in part by the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation and the Wellcome Trust. NR 29 TC 1 Z9 1 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 EI 1619-7089 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD JAN PY 2017 VL 44 IS 1 BP 141 EP 150 DI 10.1007/s00259-016-3524-0 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EE0CX UT WOS:000389242200018 PM 27738728 ER PT J AU Rabinak, CA Mori, S Lyons, M Milad, MR Phan, KL AF Rabinak, Christine A. Mori, Shoko Lyons, Maryssa Milad, Mohammed R. Phan, K. Luan TI Acquisition of CS-US contingencies during Pavlovian fear conditioning and extinction in social anxiety disorder and posttraumatic stress disorder SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Social phobia; PTSD; Aversive; Classical conditioning; Threat expectancy ID POTENTIATED STARTLE PARADIGM; BECK DEPRESSION INVENTORY; PSYCHOMETRIC PROPERTIES; PREFRONTAL CORTEX; METAANALYSIS; PHOBIA; PTSD; HUMANS; VALIDATION; INHIBITION AB Background: Fear-based disorders, like social anxiety disorder (SAD) and posttraumatic stress disorder (PTSD), are characterized by an exaggerated fear response and avoidance to trigger cues, suggesting transdiagnostic mechanism of psychopathology. Current theories suggest that abnormalities in conditioned fear is a primary contributor to the pathophysiology of these disorders. The primary goal of this study was to compare acquisition of conditioned stimulus (CS) and aversive unconditioned stimulus (US) contingencie, during fear learning and extinction in individuals with SAD and PTSD. Methods: In a standard Pavlovian fear conditioning-extinction paradigm we measured subjective UF expectancy ratings to different CSs in patients with SAD (n=16) compared to patients with PTSD (n=13) am healthy controls (n=15) Results: Both patient groups (SAD, PTSD) acquired differential conditioning between a CS that predicted UP (CS+) and a CS that never predicted the US (CS-), however, both groups reported an increased expectancy tha the US would occur following the CS-. Additionally, the PTSD group overestimated that the US would occur in general. Neither patient group showed evidence of successful extinction of the CS+-US contingency nor differentiated their expectation of US occurrence between the CS+ and CS- during extinction learning. Limitations: Group sample sizes were small and we did not include a trauma-exposed group without PTSD Conclusions: Both SAD and PTSD generalize expectations of an aversive outcome across CSs, even when a CSs never signals an aversive outcome and PTSD may tend to over-expect threat. Fear learning and extinction abnormalities may be a core feature underlying shared symptoms across fear-based disorders. C1 [Rabinak, Christine A.] Wayne State Univ, Dept Pharm Practice, 259 Mack Ave,Suite 2190, Detroit, MI 48201 USA. [Rabinak, Christine A.] Wayne State Univ, Psychiat & Behav Neurosci, Detroit, MI USA. [Rabinak, Christine A.] Wayne State Univ, Pharmaceut Sci, Detroit, MI USA. [Rabinak, Christine A.] Wayne State Univ, Translat Neurosci Program, Detroit, MI USA. [Rabinak, Christine A.; Mori, Shoko; Lyons, Maryssa; Phan, K. Luan] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Mori, Shoko] SUNY Downstate Coll Med, Brooklyn, NY USA. [Milad, Mohammed R.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Milad, Mohammed R.] Harvard Med Sch, Boston, MA USA. [Phan, K. Luan] Univ Illinois, Dept Psychiat, Chicago, IL USA. [Phan, K. Luan] Univ Illinois, Anat & Cell Biol, Chicago, IL USA. [Phan, K. Luan] Univ Illinois, Grad Program Neurosci, Chicago, IL USA. [Phan, K. Luan] Jesse Brown VA Med Ctr, Mental Hlth Serv Line, Chicago, IL USA. RP Rabinak, CA (reprint author), Wayne State Univ, Dept Pharm Practice, 259 Mack Ave,Suite 2190, Detroit, MI 48201 USA. EM rabinak@wayne.edu FU National Center for Research Resources [UL1RR024986]; National Center for Advancing Translational Sciences [UL1TR000433] FX The project described was supported by the National Center for Research Resources, Grant UL1RR024986, and is now at the National Center for Advancing Translational Sciences, Grant UL1TR000433. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. These funding sources were not directly involved in the study design; collection, analysis and interpretation of the data; writing of the report; or the decision to submit the article for publication. NR 76 TC 0 Z9 0 U1 17 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD JAN 1 PY 2017 VL 207 BP 76 EP 85 DI 10.1016/j.jad.2016.09.018 PG 10 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA ED7YM UT WOS:000389088600012 PM 27716541 ER PT J AU Egede, LE Gebregziabher, M Walker, RJ Payne, EH Acierno, R Frueh, BC AF Egede, Leonard E. Gebregziabher, Mulugeta Walker, Rebekah J. Payne, Elizabeth H. Acierno, Ron Frueh, B. Christopher TI Trajectory of cost overtime after psychotherapy for depression in older Veterans via telemedicine SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Telemedicine; Depression; Cost; Behavioral activation; Telepsychology; Elderly ID BEHAVIORAL ACTIVATION TREATMENT; COLLABORATIVE CARE; ADULTS; TRIAL; TELEPSYCHIATRY; DISORDER AB Background: Little evidence exists regarding the costs of telemedicine, especially considering changes over time. This analysis aimed to analyze trajectory of healthcare cost before, during, and after a behavioral activation intervention delivered via telepsychology and same-room delivery to elderly Veterans with depression. Methods: 241 participants were randomly assigned into one of two study groups: behavioral activation for depression via telemedicine or via same-room treatment. Patients received 8 weeks of weekly 60-min individual sessions of behavioral activation for depression. Primary outcomes were collected at 12-months. Inpatient, outpatient, pharmacy, and total costs were collected from VA Health Economics Resource Center (HERC) datasets for FY 1998-2014 and compared between the two treatment groups. Generalized mixed models were used to investigate the trajectories over time. Results: Overall cost, as well as, outpatient and pharmacy cost show increasing trend over time. Unadjusted and adjusted trajectories over time for any cost were not different between the two treatment groups. There was a significant overall increasing trend over time for outpatient (p < 0.001) and total cost (p < 0.001) but not for inpatient (p=0.543) or pharmacy cost (p=0.084). Limitations: Generalizability to younger, healthier populations may be limited due to inclusion criteria for study participants. Conclusion: Healthcare costs before, during, and after intervention did not differ between the telemedicine and in-person delivery methods. Outpatient costs accounted for most of the increasing trend of cost over time. These results support policies to use both telehealth and in-person treatment modalities to effectively and efficiently provide high quality care. C1 [Egede, Leonard E.; Gebregziabher, Mulugeta; Walker, Rebekah J.; Payne, Elizabeth H.; Acierno, Ron] Ralph H Johnson Vet Affairs Med Ctr, HEROIC, Charleston, SC USA. [Egede, Leonard E.; Walker, Rebekah J.] Med Univ South Carolina, Dept Med, Div Gen Internal Med & Geriatr, Charleston, SC 29425 USA. [Gebregziabher, Mulugeta; Payne, Elizabeth H.] Med Univ South Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Acierno, Ron] Med Univ South Carolina, Coll Nursing, Charleston, SC 29425 USA. [Frueh, B. Christopher] Univ Hawaii, Dept Psychol, Hilo, HI 96720 USA. [Frueh, B. Christopher] Menninger Clin, Dept Psychol, Houston, TX USA. RP Egede, LE (reprint author), Med Univ South Carolina, Ctr Hlth Dispar Res, 35 Rutledge Ave,Room 280G, Charleston, SC 29425 USA. EM egedel@musc.edu OI Gebregziabher, Mulugeta/0000-0002-4826-481X FU Veterans Affairs Health Services Research and Development (VA HSR D) program [IIR 04-421] FX This study was supported by Grant #IIR 04-421 funded by the Veterans Affairs Health Services Research and Development (VA HSR & D) program (PI: Leonard Egede). NR 30 TC 0 Z9 0 U1 8 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD JAN 1 PY 2017 VL 207 BP 157 EP 162 DI 10.1016/j.jad.2016.09.044 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA ED7YM UT WOS:000389088600023 PM 27721190 ER PT J AU Post, RM Altshuler, LL Kupka, R McElroy, SL Frye, MA Rowe, M Grunze, H Suppes, T Keck, PE Nolen, WA AF Post, Robert M. Altshuler, Lori L. Kupka, Ralph McElroy, Susan L. Frye, Mark A. Rowe, Michael Grunze, Heinz Suppes, Trisha Keck, Paul E., Jr. Nolen, Willem A. TI Illnesses in siblings of US patients with bipolar disorder relate to multigenerational family history and patients severity of illness SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Depression; Alcohol abuse/dependence; Substance abuse/dependence; Suicide attempts; Anxiety disorder; Transgenerational vulnerability; Illness differences across countries ID PSYCHIATRIC-DISORDERS; UNITED-STATES; EARLY-ONSET; EARLY AGE; CLINICAL-FEATURES; SEXUAL-ABUSE; CHILDHOOD; PARENTS; RISK; ADOLESCENTS AB Background: Patients with bipolar disorder from the US have more early-onset illness and a greater familial loading for psychiatric problems than those from the Netherlands or Germany (abbreviated here as Europe). We hypothesized that these regional differences in illness burden would extend to the patients siblings. Methods: Outpatients with bipolar disorder gave consent for participation in a treatment outcome network and for filling out detailed questionnaires. This included a family history of unipolar depression, bipolar disorder, suicide attempt, alcohol abuse/dependence, drug abuse/dependence, and "other" illness elicited for the patients' grandparents, parents, spouses, offspring, and siblings. Problems in the siblings were examined as a function of parental and grandparental problems and the patients' adverse illness characteristics or poor prognosis factors (PPFs). Results: Each problem in the siblings was significantly (p < 0.001) more prevalent in those from the US than in those from Europe. In the US, problems in the parents and grandparents were almost uniformly associated with the same problems in the siblings, and sibling problems were related to the number of PPFs observed in the patients. Limitations: Family history was based on patient report. Conclusions: Increased familial loading for psychiatric problems extends through 4 generations of patients with bipolar disorder from the US compared to Europe, and appears to "breed true" into the siblings of the patients. In addition to early onset, a variety of PPFs are associated with the burden of psychiatric problems in the patients' siblings and offspring. Greater attention to the multigenerational prevalence of illness in patients from the US is indicated. C1 [Post, Robert M.; Rowe, Michael] Bipolar Collaborat Network, Bethesda, MD 20814 USA. [Post, Robert M.] George Washington Univ, Dept Psychiat & Behav Sci, Washington, DC USA. [Altshuler, Lori L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Altshuler, Lori L.] West Los Angeles Healthcare Ctr, VA Greater Los Angeles Healthcare Syst, Dept Psychiat, Los Angeles, CA USA. [Kupka, Ralph; Keck, Paul E., Jr.] Univ Cincinnati, Dept Psychiat & Behav Neurosci, Coll Med, Cincinnati, OH USA. [McElroy, Susan L.; Keck, Paul E., Jr.] Lindner Ctr HOPE, Mason, OH USA. [McElroy, Susan L.] Univ Cincinnati, Coll Med, Biol Psychiat Program, Cincinnati, OH USA. [Frye, Mark A.] Mayo Clin, Dept Psychiat, Rochester, MI USA. [Grunze, Heinz] Paracelsus Med Univ Salzburg, Christian Doppler Klin, Dept Psychiat & Psychotherapy, Salzburg, Austria. [Suppes, Trisha] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. [Suppes, Trisha] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Nolen, Willem A.] Univ Groningen, Univ Med Ctr, Groningen, Netherlands. RP Post, RM (reprint author), Bipolar Collaborat Network, Bethesda, MD 20814 USA. OI Grunze, Heinz/0000-0003-4712-8979 NR 44 TC 0 Z9 0 U1 9 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 JAN 1 PY 2017 VL 207 BP 313 EP 319 DI 10.1016/j.jad.2016.09.042 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA ED7YM UT WOS:000389088600044 PM 27741468 ER PT J AU Hom, MA Stanley, IH Gutierrezb, PM Joiner, TE AF Hom, Melanie A. Stanley, Ian H. Gutierrez, Peter M. Joiner, Thomas E., Jr. TI Exploring the association between exposure to suicide and suicide risk among military service members and veterans SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Suicide; Bereavement; Survivor; Military service member; Veteran ID INTERPERSONAL NEEDS QUESTIONNAIRE; FAMILIAL TRANSMISSION; BEREAVEMENT; VALIDITY; BEHAVIOR; RELIABILITY; PREVALENCE; PEER; ADOLESCENTS; POPULATION AB Background: Past research suggests that suicide has a profound impact on surviving family members and friends; yet, little is known about experiences with suicide bereavement among military populations. This study aimed to characterize experiences with suicide exposure and their associations with lifetime and current psychiatric symptoms among military service members and veterans. Methods: A sample of 1753 United States military service members and veterans completed self-report questionnaires assessing experiences with suicide exposure, lifetime history of suicidal thoughts and behaviors, current suicidal symptoms, and perceived likelihood of making a future suicide attempt. Results: The majority of participants (57.3%) reported knowing someone who had died by suicide, and of these individuals, most (53.1%) reported having lost a friend to suicide. Chi-square tests, one-way ANOVAs, and logistic regression analyses revealed that those who reported knowing a suicide decedent were more likely to report more severe current suicidal symptoms and a history of suicidal thoughts and behaviors compared to those who did not know a suicide decedent. Hierarchical linear regression analyses indicated that greater self reported interpersonal closeness to a suicide decedent predicted greater self-reported likelihood of a future suicide attempt, even after controlling for current suicidal symptoms and prior suicidal thoughts and behaviors. Limitations: This study utilized cross-sectional data, and information regarding degree of exposure to suicide was not collected. Conclusions: Military personnel and veterans who have been bereaved by suicide may themselves be at elevated risk for suicidal thoughts and behaviors. Additional work is needed to delineate the relationship between these experiences. C1 [Hom, Melanie A.; Stanley, Ian H.; Joiner, Thomas E., Jr.] Florida State Univ, Dept Psychol, 1107 West Call St, Tallahassee, FL 32306 USA. [Gutierrez, Peter M.] Denver Vet Affairs Med Ctr, Rocky Mt Mental Illness Res Educ & Clin Ctr, Denver, CO USA. [Gutierrez, Peter M.] Univ Colorado, Sch Med, Dept Psychiat, Boulder, CO 80309 USA. RP Hom, MA (reprint author), Florida State Univ, Dept Psychol, 1107 West Call St, Tallahassee, FL 32306 USA. EM hom@psy.fsu.edu FU Department of Defense [W81XWH-10-2-0181, W81XWH-10-2-0178]; Office of the Assistant Secretary of Defense for Health Affairs FX This work was supported, in part, by grants awarded to Florida State University (W81XWH-10-2-0181) and the Rocky Mountain Mental Illness Research, Education and Clinical Center (W81XWH-10-2-0178) by the Department of Defense. The Department of Defense had no further role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. The content of this paper is solely the responsibility of the authors and the views and opinions expressed do not necessarily represent those of the Military Suicide Research Consortium, Department of Defense, or the United States Government.; The authors would like to thank the Military Suicide Research Consortium (MSRC), an effort supported by the Office of the Assistant Secretary of Defense for Health Affairs, for being the funding source of the provided data and to express their gratitude to the following principal investigators (PIs) for providing data used in this submission: Dr. Michael D. Anestis, PI of the study "Predicting Suicide Risk in a Military Population"; Dr. Sean M. Barnes, PI of the study "Behaviorally Assessing Suicide Risk"; Dr. Rebecca A. Bernert, PI of the study "Behavioral Sleep Intervention for the Prevention of Suicidal Behaviors in Military Veterans"; Dr. Nigel E. Bush, PI of the studies "Usability and Utility of a Virtual Hope Box (VHB) for Reducing Suicidal Ideation" and "Effectiveness of VHB Smartphone App in Enhancing Veterans' Coping with Suicidal Ideation"; Dr. Katherine A. Comtois, PI of the study "Continuity Contacts via Text Message: Testing a Brief Intervention to Prevent Suicidal Ideation and Behavior"; Drs. Peter M. Gutierrez and Thomas E. Joiner, PIs of the study "Toward a Gold Standard for Suicide Risk Assessment for Military Personnel"; Dr. Lori Johnson, PI of the study, "Suicide Risk Assessments within Suicide-Specific Group Therapy Treatment for Veterans"; Dr. Matthew K. Nock, PI of the study "Looking for Cognitive Differences in Suicidal Veterans"; Dr. Gina M. Signoracci, PI of the study "Assessment of Cognitive Functioning as It Relates to Risk for Suicide in Veterans with HIV/AIDS"; and Drs. Deborah A. Yurgelun-Todd and Perry F. Renshaw, PIs of the study "Neuroimaging Correlates of Suicide." This data is the property of the stated PIs and cannot be used without prior written approval. NR 49 TC 0 Z9 0 U1 5 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 JAN 1 PY 2017 VL 207 BP 327 EP 335 DI 10.1016/j.jad.2016.09.043 PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA ED7YM UT WOS:000389088600047 PM 27743535 ER PT J AU Nierenbereg, AA Montana, R Kinrys, G Deckersbach, T Dufour, S Baek, JH AF Nierenbereg, Andrew A. Montana, Rebecca Kinrys, Gustavo Deckersbach, Thilo Dufour, Steven Baek, Ji Hyun TI L-Methylfolate For Bipolar I depressive episodes: An open trial proof-of-concept registry SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder; Depression; Deplin; L-methylfolate ID FOLIC-ACID; DOUBLE-BLIND; FUNCTIONAL IMPAIRMENT; MAJOR DEPRESSION; SELF-REPORT; DISORDERS; HOMOCYSTEINE; RELIABILITY; VALPROATE; VALIDITY AB Background: L-methylfolate is a compelling candidate to treat bipolar I major depressive episodes. While approved as an adjunct for unipolar major depressive disorder, no studies have been done to assess the tolerability, safety, and efficacy of L-methylfolate for bipolar depression. As a first step, we developed a registry of bipolar patients treated with L-methylfolate to examine tolerability and outcomes. Methods: Subjects (N=10) received treatment as usual plus daily L-methylfolate 15 mg for 6 weeks in this open-label registry. Depressive symptoms were assessed with the Montgomery Asberg Depression Rating Scale (MADRS) and manic symptoms with the Young Mania Rating Scale (YMRS). Effect size was measured with Cohen's d to provide an estimate of potential efficacy. Results: The pre-treatment mean (SD) MADRS score was 23.4 (4.34); the post-treatment score was 13.9 (8.24). Cohen's d was 1.19. At post-treatment, 6/10 patients had at least 50% MADRS improvement, and 4/10 patients exhibited remission with MADRS <= 10. The pre-treatment YMRS score was 3.2 (3.0); the post-treatment score was 2.7 (5.2). Cohen's d was 0.17. Limitations: This registry was a small open-label clinical trial for a fluctuating disorder. We cannot rule out that our results are due to regression to the mean. A controlled trial is warranted. Conclusions: This first proof-of-concept open registry suggests that L-methylfolate in combination with treatment as usual has potential to treat bipolar depression. C1 [Nierenbereg, Andrew A.; Montana, Rebecca; Kinrys, Gustavo; Deckersbach, Thilo; Dufour, Steven; Baek, Ji Hyun] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Nierenbereg, Andrew A.; Kinrys, Gustavo; Deckersbach, Thilo] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Baek, Ji Hyun] Samsung Med Ctr, Dept Psychiat, Seoul, South Korea. RP Nierenbereg, AA (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Bipolar Clin, 50 Staniford St,Suite 580, Boston, MA 02114 USA.; Nierenbereg, AA (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Res Program, 50 Staniford St,Suite 580, Boston, MA 02114 USA. EM anierenberg@partners.org NR 37 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD JAN 1 PY 2017 VL 207 BP 429 EP 433 DI 10.1016/j.jad.2016.09.053 PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA ED7YM UT WOS:000389088600060 PM 27794238 ER PT B AU Kammer, RE Goldsmith, T AF Kammer, Rachael E. Goldsmith, Tessa BE Friberg, JC Vinney, LA TI Nutrition and Swallowing Challenges Laryngeal Cancer SO LARYNGEAL CANCER: AN INTERDISCIPLINARY RESOURCE FOR PRACTITIONERS LA English DT Article; Book Chapter ID SQUAMOUS-CELL CARCINOMA; QUALITY-OF-LIFE; SUPRACRICOID PARTIAL LARYNGECTOMY; VS. TOTAL LARYNGECTOMY; NECK-CANCER; ORGAN-PRESERVATION; INDUCTION CHEMOTHERAPY; NONSURGICAL TREATMENT; SUPRAGLOTTIC LARYNGECTOMY; RADIATION-THERAPY C1 [Kammer, Rachael E.; Goldsmith, Tessa] Massachusetts Gen Hosp, Dept Speech Language & Swallowing Disorders, Boston, MA 02114 USA. RP Kammer, RE (reprint author), Massachusetts Gen Hosp, Dept Speech Language & Swallowing Disorders, Boston, MA 02114 USA. NR 64 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE ROAD, THOROFARE, NJ 08086-9447 USA BN 978-1-63091-159-1 PY 2017 BP 91 EP 110 PG 20 WC Oncology SC Oncology GA BG2OI UT WOS:000387517000006 ER PT J AU Chang, CY Kattapuram, SV Huang, AJ Simeone, FJ Torriani, M Bredella, MA AF Chang, Connie Y. Kattapuram, Susan V. Huang, Ambrose J. Simeone, F. Joseph Torriani, Martin Bredella, Miriam A. TI Treatment of aneurysmal bone cysts by percutaneous CT-guided injection of calcitonin and steroid SO SKELETAL RADIOLOGY LA English DT Article DE Sclerotherapy; Aneurysmal bone cyst; ABC; CT; Percutaneous; Calcitonin; Steroid ID ETHIBLOC INJECTION; INTRALESIONAL INJECTION; METHYLPREDNISOLONE ACETATE; MOBILE SPINE; FOLLOW-UP; CHILDREN; SCLEROTHERAPY; RECURRENCE; LESIONS AB To determine the efficacy and safety of percutaneous calcitonin and steroid injection in the treatment of aneurysmal bone cysts (ABCs). Our study was IRB-approved and HIPAA-compliant. We reviewed pre- and post-procedural imaging studies and medical records of all CT-guided percutaneous injections of ABCs with calcitonin and steroid performed at our institution between 2003 and 2015. Treatment success based on imaging was categorized as substantial (51-100 %), partial (1-50 %), or none (0 %) by comparing radiographs of the lesion before and after treatment. Our study group comprised 9 patients (7 female, 2 male; mean age 19 +/- 5 (range 12-25) years). ABCs were located in the pubis (n = 3), femur (n = 2), and humerus/scapula/ilium/sacrum (n = 1 for each). One patient did not have any clinical or imaging follow-up. For the other 8 patients, clinical and imaging follow-up ranged from 1 to 93 months (mean 16 +/- 29 months). One patient had two injections, and 1 patient had three injections. Six out of eight patients (75 %) had complete symptomatic relief and 2 patients (25 %) had partial symptomatic relief after initial injection. Imaging follow-up revealed substantial imaging response in 4 out of 8 patients (50 %). There was a partial imaging response in 2 patients (25 %) and no imaging response in 2 out of 8 patients (25 %), and all 4 of these patients had local recurrence. There were no complications. Percutaneous CT-guided injection of ABCs with calcitonin and steroid is a safe and effective treatment. Lack of imaging response may necessitate more aggressive treatment to minimize local recurrence. C1 [Chang, Connie Y.; Kattapuram, Susan V.; Huang, Ambrose J.; Simeone, F. Joseph; Torriani, Martin; Bredella, Miriam A.] Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, 55 Fruit St Yawkey 6E, Boston, MA 02114 USA. RP Chang, CY (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, 55 Fruit St Yawkey 6E, Boston, MA 02114 USA. EM cychang@mgh.harvard.edu NR 31 TC 0 Z9 0 U1 2 U2 2 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 JAN PY 2017 VL 46 IS 1 BP 35 EP 40 DI 10.1007/s00256-016-2503-7 PG 6 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA EE0GY UT WOS:000389253500005 PM 27743037 ER PT J AU Huang, AJ Bos, SA Torriani, M Simeone, FJ Chang, CY Pomerantz, SR Bredella, MA AF Huang, Ambrose J. Bos, Stijn A. Torriani, Martin Simeone, F. Joseph Chang, Connie Y. Pomerantz, Stuart R. Bredella, Miriam A. TI Long-term outcomes of percutaneous lumbar facet synovial cyst rupture SO SKELETAL RADIOLOGY LA English DT Article DE Lumbar facet synovial cyst; Percutaneous rupture; CT; Fluoroscopy; MRI; Outcome ID 10-YEAR EXPERIENCE; STEROID INJECTIONS; CT; SPINE AB To evaluate the therapeutic value, safety, and long-term clinical outcomes of percutaneous lumbar facet synovial cyst (LFSC) rupture. Our study was institutional review board (IRB)-approved and Health Insurance Portability and Accountability Act (HIPAA)-compliant. The study group comprised 71 patients (44 women, mean age: 65 +/- 17 years) who underwent CT- or fluoroscopy-guided percutaneous LFSC rupture. The technical success of LFSC rupture, the long-term clinical outcome, including repeat procedures or surgery, and imaging findings on MRI and CT were recorded. Seventy-nine LFSC ruptures were performed in 71 patients. CT guidance was used in 57 cases and fluoroscopy guidance in 22 cases. LFSC rupture was technically successful in 58 out of 79 cases (73 %). Mean injection volume for cyst rupture was 3.6 +/- 2.2 mL and a combination of steroid and anesthetic was injected in all cases. Over a mean follow-up time of 44 months, 12 % of patients underwent repeat cyst rupture, and 46 % eventually underwent surgery, whereas the majority of patients (55 %) experienced symptomatic relief and did not undergo surgery. There was no significant association between a successful outcome and age, sex, level, or size of LFSC (p > 0.1). LFSCs with T2 hypointensity were more likely to require surgery (p = 0.02). There was one complication, a bacterial skin infection that completely resolved following antibiotic therapy. Percutaneous LFSC rupture is an effective and safe nonsurgical treatment option for LFSC. More than half of treated patients were able to avoid subsequent surgery. Therefore, percutaneous LFSC rupture should be considered before surgical intervention. C1 [Huang, Ambrose J.; Bos, Stijn A.; Torriani, Martin; Simeone, F. Joseph; Chang, Connie Y.; Pomerantz, Stuart R.; Bredella, Miriam A.] Massachusetts Gen Hosp, Dept Radiol, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. [Huang, Ambrose J.; Bos, Stijn A.; Torriani, Martin; Simeone, F. Joseph; Chang, Connie Y.; Pomerantz, Stuart R.; Bredella, Miriam A.] Harvard Med Sch, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. RP Bredella, MA (reprint author), Massachusetts Gen Hosp, Dept Radiol, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA.; Bredella, MA (reprint author), Harvard Med Sch, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. EM mbredella@mgh.harvard.edu NR 20 TC 0 Z9 0 U1 2 U2 2 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 JAN PY 2017 VL 46 IS 1 BP 75 EP 80 DI 10.1007/s00256-016-2513-5 PG 6 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA EE0GY UT WOS:000389253500010 PM 27771754 ER PT J AU Eajazi, A Kheterpal, A Kattapuram, S Nielsen, GP Rosenthal, DI AF Eajazi, Alireza Kheterpal, Arvin Kattapuram, Susan Nielsen, Gunnlaugur Petur Rosenthal, Daniel Ira TI Multiple giant cell tumors of bone arising from multiple fatty tumors SO SKELETAL RADIOLOGY LA English DT Article DE Giant cell tumor (GCT); Fatty tumor; Bone; Recurrent; Multifocal ID INTRAOSSEOUS LIPOMA; RARE PRESENTATION; RADIOTHERAPY; MANAGEMENT; EFFICACY; THERAPY; MARROW AB We describe a patient with a history of giant cell tumor who over the course of 18 years developed multiple fat containing osseous lesions in the pelvis and spine. Two of these lesions subsequently evolved into biopsy proven giant cell tumor of bone. To our knowledge, this phenomenon of giant cell tumors evolving from fat containing lesions has not been described. C1 [Eajazi, Alireza; Kheterpal, Arvin; Kattapuram, Susan; Rosenthal, Daniel Ira] Massachusetts Gen Hosp, Dept Radiol, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. [Eajazi, Alireza; Kheterpal, Arvin; Kattapuram, Susan; Rosenthal, Daniel Ira] Harvard Med Sch, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. [Nielsen, Gunnlaugur Petur] Massachusetts Gen Hosp, Dept Pathol, Warren 2,55 Fruit St, Boston, MA 02114 USA. [Nielsen, Gunnlaugur Petur] Harvard Med Sch, Warren 2,55 Fruit St, Boston, MA USA. RP Kheterpal, A (reprint author), Massachusetts Gen Hosp, Dept Radiol, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA.; Kheterpal, A (reprint author), Harvard Med Sch, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. EM akheterpal@mgh.harvard.edu NR 43 TC 0 Z9 0 U1 2 U2 2 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 JAN PY 2017 VL 46 IS 1 BP 117 EP 121 DI 10.1007/s00256-016-2498-0 PG 5 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA EE0GY UT WOS:000389253500017 PM 27771752 ER PT J AU Moye, J AF Moye, Jennifer TI Theory, Science, and Practice for Advancing Capacity Evaluation in Older Adults SO CLINICAL GERONTOLOGIST LA English DT Editorial Material C1 [Moye, Jennifer] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Moye, Jennifer] Harvard Med Sch, Boston, MA 02115 USA. RP Moye, J (reprint author), VA Boston Healthcare Syst, Boston, MA 02130 USA.; Moye, J (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM Jennifer.moye@va.gov RI Moye, Jennifer/F-2240-2017 OI Moye, Jennifer/0000-0002-3434-347X NR 9 TC 0 Z9 0 U1 1 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0731-7115 EI 1545-2301 J9 CLIN GERONTOLOGIST JI Clin. Gerontol. PY 2017 VL 40 IS 1 SI SI BP 1 EP 2 DI 10.1080/07317115.2016.1238676 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EC0PZ UT WOS:000387804400001 ER PT J AU Page, KS Hinrichs, KLM AF Page, Kyle S. Hinrichs, Kate L. M. TI Swimming against the Tide: A Case Study on the Removal of Conservatorship and Guardianship SO CLINICAL GERONTOLOGIST LA English DT Article DE Capacity; conservatorship; dementia; financial; guardianship; medical AB Objective: This article evaluates the role healthcare providers play in balancing safety versus autonomy among elders when performing capacity evaluations.Methods: Presentation of a case study consisting of an 85-year-old, Caucasian, widowed, male, post-stroke veteran, residing in long-term care. He was assigned a permanent court-appointed joint guardian and conservator, but wanted to remove both of these as he felt he had the ability to manage his own affairs. This case study specifically addresses the issue of financial capacity.Results: After completion of the evaluation, a case was made for the least restrictive means balancing patient autonomy and protection, opting for a limited conservatorship. The court, using the evaluation as evidence, completely removed the guardianship and conservatorship.Conclusions: This article outlines how providers can navigate multiple roles, team dynamics, and advocate for enhancing the capacity of an older adult. C1 [Page, Kyle S.] Cheyenne VA Med Ctr, Cheyenne, WY USA. [Hinrichs, Kate L. M.] VA Boston Healthcare Syst, Boston, MA USA. RP Page, KS (reprint author), Cheyenne VA Med Ctr, Mental Hlth Serv 116, 2360 East Pershing Blvd, Cheyenne, WY 82001 USA. EM kyle.page@va.gov NR 14 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0731-7115 EI 1545-2301 J9 CLIN GERONTOLOGIST JI Clin. Gerontol. PY 2017 VL 40 IS 1 SI SI BP 35 EP 42 DI 10.1080/07317115.2016.1177767 PG 8 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EC0PZ UT WOS:000387804400005 ER PT J AU Feng, MC Murphy, MR Mlinac, M AF Feng, Michelle C. Murphy, Margaret R. Mlinac, Michelle TI Independent Living Capacity Evaluation in Home-Based Primary Care: Considerations and Outcomes of a Quality Improvement Project SO CLINICAL GERONTOLOGIST LA English DT Article DE Decision-making capacity; home-based primary care; home-based services; independent living capacity; interdisciplinary ID MENTAL-HEALTH; OLDER-ADULTS; VETERANS; MODEL; GUARDIANSHIP; TRANSITIONS; COMMUNITY; SYSTEM; NEEDS AB Objectives: This article describes results of a quality improvement project review of 5years of capacity evaluations for independent living conducted in one Home-Based Primary Care (HBPC) Program.Methods: A retrospective chart review was conducted for all patients evaluated for independent living capacity through the Boston VA HBPC Program (N=25) to identify differences in outcomes for those with and without capacity. Descriptive information included referral sources, capacity decisions, time remaining in the home, and trajectory of patients following evaluation.Results: All patients evaluated had been diagnosed with a cognitive disorder, and on average, a relatively lower prevalence of mental illness compared with the national HBPC population. Referrals were made primarily by the HBPC team. Patients with capacity were found to have remained in their home longer than those who lacked capacity.Conclusions: Referral for a higher level of care was typically only recommended when no further intervention could be implemented and active risk in the home could not be managed.Clinical Implications: In home capacity evaluations are complex and challenging, yet results help family and HBPC team support patients' preferences for staying in their own home as long as possible. C1 [Feng, Michelle C.] Execut Mental Hlth, Los Angeles, CA USA. [Murphy, Margaret R.; Mlinac, Michelle] Harvard Med Sch, VA Boston Healthcare Syst, Boston, MA USA. RP Feng, MC (reprint author), 10801 Natl Blvd,Suite 601, Los Angeles, CA 90025 USA. EM mfeng@emhla.com NR 26 TC 0 Z9 0 U1 3 U2 3 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0731-7115 EI 1545-2301 J9 CLIN GERONTOLOGIST JI Clin. Gerontol. PY 2017 VL 40 IS 1 SI SI BP 51 EP 62 DI 10.1080/07317115.2016.1210272 PG 12 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EC0PZ UT WOS:000387804400007 PM 28111494 ER PT J AU Maeng, LY Cover, KK Taha, MB Landau, AJ Milad, MR Lebron-Milad, K AF Maeng, Lisa Y. Cover, Kara K. Taha, Mohamad B. Landau, Aaron J. Milad, Mohammed R. Lebron-Milad, Kelimer TI Estradiol Shifts Interactions Between the Infralimbic Cortex and Central Amygdala To Enhance Fear Extinction Memory in Female Rats SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE sex differences; estradiol; infralimbic cortex; central amygdala; c-fos; fear extinction; estrous cycle; centromedial amygdala; female; PTSD; anxiety; fear; ventromedial prefrontal cortex ID POSTTRAUMATIC-STRESS-DISORDER; MEDIAL PREFRONTAL CORTEX; CONDITIONED FEAR; SEX-DIFFERENCES; FUNCTIONAL CONNECTIVITY; BASOLATERAL AMYGDALA; INHIBITORY CIRCUITS; LEARNED FEAR; ESTROGEN; EXPRESSION AB There is growing evidence that estradiol (E2) enhances fear extinction memory consolidation. However, it is unclear how E2 influences the nodes of the fear extinction network to enhance extinction memory. This study begins to delineate the neural circuits underlying the influence of E2 on fear extinction acquisition and consolidation in female rats. After fear conditioning (day 1), naturally cycling female rats underwent extinction learning (day 2) in a low-E2 state, receiving a systemic administration of either E2 or vehicle prior to extinction training. Extinction memory recall was then tested 24 hr later (day 3). We measured immediate early gene c-fos expression within the extinction network during fear extinction learning and extinction recall. During extinction learning, E2 treatment increased centrolateral amygdala c-fos activity and reduced lateral amygdala activity relative to vehicle. During extinction recall, E2-treated rats exhibited reduced cfos expression in the centromedial amygdala. There were no group differences in c-fos expression within the medial prefrontal cortex or dorsal hippocampus. Examining c-fos ratios with the infralimbic cortex (IL) revealed that, despite the lack of group differences within the IL, E2 treatment induced greater IL activity relative to both prelimbic cortex and central amygdala (CeA) activity during extinction memory recall. Only the relationship between IL and CeA activity positively correlated with extinction retention. In conclusion, E2 appears to modify interactions between the IL and the CeA in females, shifting from stronger amygdalar modulation of fear during extinction learning to stronger IL control during extinction recall. (C) 2016 Wiley Periodicals, Inc. C1 [Maeng, Lisa Y.; Cover, Kara K.; Taha, Mohamad B.; Landau, Aaron J.; Milad, Mohammed R.; Lebron-Milad, Kelimer] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. [Maeng, Lisa Y.; Taha, Mohamad B.; Milad, Mohammed R.; Lebron-Milad, Kelimer] Harvard Med Sch, Dept Psychiat, Boston, MA USA. RP Maeng, LY (reprint author), 149 13th St,Room 2510, Charlestown, MA 02129 USA. EM lmaeng@mgh.harvard.edu FU National Institute of Mental Health [R01 MH097880-001] FX Contract grant sponsor: National Institute of Mental Health; Contract grant number: R01 MH097880-001 (to M.R.M.) NR 46 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0360-4012 EI 1097-4547 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JAN-FEB PY 2017 VL 95 IS 1-2 BP 163 EP 175 DI 10.1002/jnr.23826 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EC9DI UT WOS:000388443900018 PM 27870439 ER PT J AU Pavlovic, JM Akcali, D Bolay, H Bernstein, C Maleki, N AF Pavlovic, Jelena M. Akcali, Didem Bolay, Hayrunnisa Bernstein, Carolyn Maleki, Nasim TI Sex-Related Influences in Migraine SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Review DE hormones; estrogen; menstrual migraine; menopause; cortical spreading depression; trigeminal pathway; neuroimaging ID CORTICAL SPREADING DEPRESSION; FREELY MOVING RATS; MENSTRUAL-CYCLE; UNITED-STATES; SOCIODEMOGRAPHIC FACTORS; HORMONAL CYCLE; HUMAN BRAIN; HEADACHE; PREVALENCE; PAIN AB Migraine is a common neurological disorder with significantly higher incidence and prevalence in women than men. The presentation of the disease in women is modulated by changes in sex hormones from adolescence to pregnancy and menopause. Yet, the effect of sex influences has often been neglected in both basic and clinical and in clinical management of the disease. In this review, evidence from epidemiological, clinical, animal, and neuroimaging studies on the significance of the sex-related influences in migraine is presented, and the unmet needs in each area are discussed. (C) 2016 Wiley Periodicals, Inc. C1 [Pavlovic, Jelena M.] Albert Einstein Coll Med, Dept Neurol, 1575 Blondell Ave,Room 225, Bronx, NY 10461 USA. [Pavlovic, Jelena M.] Montefiore Headache Ctr, Bronx, NY USA. [Akcali, Didem; Bolay, Hayrunnisa] Gazi Univ, Sch Med, Dept Neurol, Ankara, Turkey. [Akcali, Didem; Bolay, Hayrunnisa] Gazi Univ, Sch Med, Neuropsychiat Ctr, Ankara, Turkey. [Bernstein, Carolyn] Harvard Med Sch, Brigham & Womens Hosp, Dept Neurol, Boston, MA USA. [Maleki, Nasim] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Psychiat Neuroimaging, Charlestown, MA USA. RP Pavlovic, JM (reprint author), Albert Einstein Coll Med, Dept Neurol, 1575 Blondell Ave,Room 225, Bronx, NY 10461 USA. EM jpavlovi@montefiore.org NR 92 TC 0 Z9 0 U1 11 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0360-4012 EI 1097-4547 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JAN-FEB PY 2017 VL 95 IS 1-2 BP 587 EP 593 DI 10.1002/jnr.23903 PG 7 WC Neurosciences SC Neurosciences & Neurology GA EC9DI UT WOS:000388443900055 PM 27870430 ER PT J AU Kalkstein, S Scott, JC Biester, R Brownlow, JA Harpaz-Rotem, I Gur, RC AF Kalkstein, Solomon Scott, J. Cobb Biester, Rosette Brownlow, Janeese A. Harpaz-Rotem, Ilan Gur, Ruben C. TI Comparison of blast-exposed OEF/OIF veterans with and without a history of TBI symptoms on a brief computerized neuropsychological battery SO APPLIED NEUROPSYCHOLOGY-ADULT LA English DT Article DE Blast; cognitive; neuropsychological; posttraumatic stress disorder; traumatic brain injury ID TRAUMATIC BRAIN-INJURY; TEST-PERFORMANCE; NEUROCOGNITIVE BATTERY; MILD TBI; METAANALYSIS; DISORDER; SEQUELAE; MODERATE; OUTCOMES AB Mild traumatic brain injuries (mild TBIs) resulting from exposure to Improvised Explosive Devices (IEDs) are highly prevalent among veterans of the wars in Iraq and Afghanistan. This exploratory study compared the neurocognitive performance of blast-exposed veterans with (n=19) and without (n=15) reported symptoms of mild TBI. All subjects had diagnoses of posttraumatic stress disorder (PTSD). Neurocognitive testing was administered using a well-established computerized battery, the Penn Computerized Neuropsychological Battery (CNB), and groups were well matched on age, race, education, and time since most recent blast exposure. Although differences were not observed on CNB accuracy scores, MANOVAs revealed slower processing speed in the mTBI group when answering correctly on tests of simple and sustained attention, with large effect sizes. Results suggest a potential speed-accuracy tradeoff in blast-related mild TBI, which should be further examined in larger samples. C1 [Kalkstein, Solomon; Scott, J. Cobb; Biester, Rosette; Brownlow, Janeese A.; Gur, Ruben C.] Philadelphia Vet Affairs Med Ctr, 3900 Woodland Ave, Philadelphia, PA 19104 USA. [Kalkstein, Solomon; Scott, J. Cobb; Biester, Rosette; Brownlow, Janeese A.; Gur, Ruben C.] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Scott, J. Cobb; Gur, Ruben C.] Philadelphia Vet Affairs Med Ctr, VISN4 Mental Illness Res Educ & Clin Ctr, Philadelphia, PA USA. [Harpaz-Rotem, Ilan] Yale Univ, Sch Med, New Haven, CT USA. [Harpaz-Rotem, Ilan] Natl Ctr PTSD, Vet Affairs Connecticut Hlth Care Syst, Clin Neurosciences Div, West Haven, CT USA. RP Kalkstein, S (reprint author), Philadelphia Vet Affairs Med Ctr, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM solomon.kalkstein@va.gov FU Philadelphia VA Parkinson's Disease Research, Education, & Clinical Center; Department of Veterans Affairs [IK2CX000772] FX This work was supported by a Pilot Project Award from the Philadelphia VA Parkinson's Disease Research, Education, & Clinical Center. Dr. Scott's participation was supported by a Department of Veterans Affairs Career Development Award (IK2CX000772). NR 26 TC 0 Z9 0 U1 7 U2 7 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 2327-9095 EI 2327-9109 J9 APPL NEUROPSYCH-ADUL JI Appl. Neuropsychol.-Adult PY 2017 VL 24 IS 1 BP 92 EP 97 DI 10.1080/23279095.2015.1119693 PG 6 WC Clinical Neurology; Psychology SC Neurosciences & Neurology; Psychology GA EC3KW UT WOS:000388026000010 PM 27045712 ER PT J AU Brunner, C Davies, NM Martin, RM Eeles, R Easton, D Kote-Jarai, Z Al Olama, AA Benlloch, S Muir, K Giles, G Wiklund, F Gronberg, H Haiman, CA Schleutker, J Nordestgaard, BG Travis, RC Neal, D Donovan, J Hamdy, FC Pashayan, N Khaw, KT Stanford, JL Blot, WJ Thibodeau, S Maier, C Kibel, AS Cybulski, C Cannon-Albright, L Brenner, H Park, J Kaneva, R Batra, J Teixeira, MR Pandha, H Zuccolo, L AF Brunner, Clair Davies, Neil M. Martin, Richard M. Eeles, Rosalind Easton, Doug Kote-Jarai, Zsofia Al Olama, Ali Amin Benlloch, Sara Muir, Kenneth Giles, Graham Wiklund, Fredrik Gronberg, Henrik Haiman, Christopher A. Schleutker, Johanna Nordestgaard, Borge G. Travis, Ruth C. Neal, David Donovan, Jenny Hamdy, Freddie C. Pashayan, Nora Khaw, Kay-Tee Stanford, Janet L. Blot, William J. Thibodeau, Stephen Maier, Christiane Kibel, Adam S. Cybulski, Cezary Cannon-Albright, Lisa Brenner, Hermann Park, Jong Kaneva, Radka Batra, Jyotsna Teixeira, Manuel R. Pandha, Hardev Zuccolo, Luisa CA the PRACTICAL Consortium, TI Alcohol consumption and prostate cancer incidence and progression: A Mendelian randomisation study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE alcohol; prostate cancer; alcohol metabolising genes; Mendelian randomisation ID ALDEHYDE DEHYDROGENASE; GENETIC POLYMORPHISMS; SUSCEPTIBILITY LOCI; TUMOR-SUPPRESSOR; RETINOIC ACID; NECK-CANCER; RISK; METAANALYSIS; ALDH2; ADH AB Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In this study, we investigated the associations of genetic variants in alcohol-metabolising genes with prostate cancer incidence and survival. We analysed data from 23,868 men with prostate cancer and 23,051 controls from 25 studies within the international PRACTICAL Consortium. Study-specific associations of 68 single nucleotide polymorphisms (SNPs) in 8 alcohol-metabolising genes (Alcohol Dehydrogenases (ADHs) and Aldehyde Dehydrogenases (ALDHs)) with prostate cancer diagnosis and prostate cancer-specific mortality, by grade, were assessed using logistic and Cox regression models, respectively. The data across the 25 studies were meta-analysed using fixed-effect and random-effects models. We found little evidence that variants in alcohol metabolising genes were associated with prostate cancer diagnosis. Four variants in two genes exceeded the multiple testing threshold for associations with prostate cancer mortality in fixed-effect meta-analyses. SNPs within ALDH1A2 associated with prostate cancer mortality were rs1441817 (fixed effects hazard ratio, HRfixed=0.78; 95% confidence interval (95%CI):0.66,0.91; p values=0.002); rs12910509, HRfixed=0.76; 95%CI:0.64,0.91; p values=0.003); and rs8041922 (HRfixed=0.76; 95%CI:0.64,0.91; p values=0.002). These SNPs were in linkage disequilibrium with each other. In ALDH1B1, rs10973794 (HRfixed=1.43; 95%CI:1.14,1.79; p values=0.002) was associated with prostate cancer mortality in men with low-grade prostate cancer. These results suggest that alcohol consumption is unlikely to affect prostate cancer incidence, but it may influence disease progression. What's new? Alcohol may spur prostate cancer progression, though it does not appear to affect incidence, according to new analysis. Variation in genes involved in alcohol metabolism affect how much the body is exposed to carcinogenic metabolites. These authors examined 68 genetic variants in alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes, seeking a link with prostate cancer risk. While they found no evidence that these variants alter prostate cancer incidence, they did show that SNPs in the ALDH1A2 gene affect prostate cancer mortality. From a public health standpoint, these results suggest reducing alcohol consumption could slow prostate cancer disease progression. C1 [Brunner, Clair; Davies, Neil M.; Martin, Richard M.; Donovan, Jenny; Zuccolo, Luisa] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Brunner, Clair; Davies, Neil M.; Martin, Richard M.; Zuccolo, Luisa] Univ Bristol, MRC Univ Bristol Integrat Epidemiol Unit, Bristol, Avon, England. [Martin, Richard M.] Univ Bristol, NIHR Bristol Nutr Biomed Res Unit, Univ Hosp Bristol NHS Fdn Trust, Bristol, Avon, England. [Eeles, Rosalind; Kote-Jarai, Zsofia] Inst Canc Res, London SM2 5NG, England. [Eeles, Rosalind] Royal Marsden NHS Fdn Trust, London SW3 6JJ, England. [Easton, Doug; Al Olama, Ali Amin; Benlloch, Sara] Univ Cambridge, Strangeways Lab, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Giles, Graham] Canc Council Victoria, Canc Epidemiol Ctr, 1 Rathdowne St, Carlton, Vic, Australia. [Giles, Graham] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Wiklund, Fredrik; Gronberg, Henrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Haiman, Christopher A.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Schleutker, Johanna] Univ Turku, Dept Med Biochem & Genet, Turku, Finland. [Schleutker, Johanna] Univ Tampere, Inst Biomed Technol BioMediTech, FimLab Labs, Tampere, Finland. [Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev Ringvej 75, DK-2730 Herlev, Denmark. [Travis, Ruth C.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Neal, David] Univ Cambridge, Surg Oncol Uro Oncol S4, Addenbrookes Hosp, Box 279,Hills Rd, Cambridge, England. [Neal, David] Canc Res UK Cambridge Res Inst, Li Ka Shing Ctr, Cambridge, England. [Hamdy, Freddie C.] Univ Oxford, Nuffield Dept Surg, Oxford, England. [Pashayan, Nora] Univ Cambridge, Strangeways Lab, Dept Oncol, Ctr Canc Genet Epidemiol, Worts Causeway, Cambridge, England. [Pashayan, Nora] UCL, Dept Appl Hlth Res, London, England. [Khaw, Kay-Tee] Univ Cambridge, Cambridge Inst Publ Hlth, Forvie Site,Robinson Way, Cambridge CB2 0SR, England. [Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Thibodeau, Stephen] Mayo Clin, Rochester, MN USA. [Maier, Christiane] Univ Hosp Ulm, Dept Urol, Ulm, Germany. [Maier, Christiane] Univ Hosp Ulm, Inst Human Genet, Ulm, Germany. [Kibel, Adam S.] Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St,ASB II 3, Boston, MA 02115 USA. [Kibel, Adam S.] Washington Univ, St Louis, MO USA. [Cybulski, Cezary] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Cannon-Albright, Lisa] Univ Utah, Sch Med, Dept Med, Div Genet Epidemiol, Salt Lake City, UT USA. [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Park, Jong] H Lee Moffitt Canc Ctr & Res Inst, Div Canc Prevent & Control, 12902 Magnolia Dr, Tampa, FL USA. [Kaneva, Radka] Med Univ Sofia, Dept Med Chem & Biochem, Mol Med Ctr, 2 Zdrave St, Sofia 1431, Bulgaria. [Batra, Jyotsna] Queensland Univ Technol, Sch Life Sci & Publ Hlth, Inst Hlth & Biomed Innovat, Australian Prostate Canc Res Ctr Qld, Brisbane, Qld 4001, Australia. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. [Pandha, Hardev] Univ Surrey, Guildford GU2 7XH, Surrey, England. RP Zuccolo, L (reprint author), Univ Bristol, MRC Univ Bristol Integrat Epidemiol Unit, Bristol, Avon, England. EM l.zuccolo@bristol.ac.uk RI Brenner, Hermann/B-4627-2017 OI Brenner, Hermann/0000-0002-6129-1572 FU UK MRC Special Training Fellowship [G0501864/76656]; UK MRC Population Health Scientist fellowship [G0902144]; UK MRC [G0600705]; University of Bristol [MC_UU_12013/1,9]; European Commission's Seventh Framework Programme [HEALTH-F2-2009-223175]; Cancer Research UK [C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, C16913/A6135, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C18281/A19169]; National Institutes of Health [CA128978]; National Institute of Health (NIH) Cancer Post-Cancer GWAS [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Canadian Department of Defence [W81XWH-10-1-0341]; UK Health Technology Assessment (HTA) Programme of the NIH Research [HTA 96/20/99, ISRCTN20141297]; National Cancer Research Institute (Department of Health, the Medical Research Council and Cancer Research UK) [G0500966/75466] FX Grant sponsor: UK MRC Special Training Fellowship; Grant number: G0501864/76656; Grant sponsor: UK MRC Population Health Scientist fellowship; Grant number: G0902144; Grant sponsor: UK MRC; Grant number: G0600705; Grant sponsor: University of Bristol; Grant number: MC_UU_12013/1,9; Grant sponsor: The European Commission's Seventh Framework Programme; Grant number: HEALTH-F2-2009-223175; Grant sponsor: Cancer Research UK; Grant number(s): C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, C16913/A6135, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C18281/A19169; Grant sponsor: National Institutes of Health; Grant number: CA128978; Grant sponsor: National Institute of Health (NIH) Cancer Post-Cancer GWAS; Grant number(s): 1U19 CA148537, 1U19 CA148065, 1U19 CA148112; Grant sponsor: Canadian Department of Defence; Grant number: W81XWH-10-1-0341; Grant sponsor: UK Health Technology Assessment (HTA) Programme of the NIH Research; Grant number(s): HTA 96/20/99, ISRCTN20141297; Grant sponsor: National Cancer Research Institute (Department of Health, the Medical Research Council and Cancer Research UK); Grant number: G0500966/75466. NR 51 TC 0 Z9 0 U1 16 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JAN PY 2017 VL 140 IS 1 BP 75 EP 85 DI 10.1002/ijc.30436 PG 11 WC Oncology SC Oncology GA EB8DG UT WOS:000387620600009 PM 27643404 ER PT J AU Fried, PJ Schilberg, L Brem, AK Saxena, S Wong, B Cypess, AM Horton, ES Pascual-Leone, A AF Fried, Peter J. Schilberg, Lukas Brem, Anna-Katharine Saxena, Sadhvi Wong, Bonnie Cypess, Aaron M. Horton, Edward S. Pascual-Leone, Alvaro TI Humans with Type-2 Diabetes Show Abnormal Long-Term Potentiation-Like Cortical Plasticity Associated with Verbal Learning Deficits SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Article DE Cognitive aging; neuroplasticity; transcranial magnetic stimulation; type 2 diabetes mellitus; verbal learning ID THETA-BURST-STIMULATION; MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE PATIENTS; HUMAN MOTOR CORTEX; NMDA RECEPTOR BLOCKADE; INTRANASAL INSULIN; CEREBRAL-CORTEX; PHYSIOLOGICAL-BASIS; HEALTHY HUMANS; MEMORY AB Background: Type-2 diabetes mellitus (T2DM) accelerates cognitive aging and increases risk of Alzheimer's disease. Rodent models of T2DM show altered synaptic plasticity associated with reduced learning and memory. Humans with T2DM also show cognitive deficits, including reduced learning and memory, but the relationship of these impairments to the efficacy of neuroplastic mechanisms has never been assessed. Objective: Our primary objective was to compare mechanisms of cortical plasticity in humans with and without T2DM. Our secondary objective was to relate plasticity measures to standard measures of cognition. Methods: A prospective cross-sectional cohort study was conducted on 21 adults with T2DM and 15 demographically similar non-diabetic controls. Long-term potentiation-like plasticity was assessed in primary motor cortex by comparing the amplitude of motor evoked potentials (MEPs) from single-pulse transcranial magnetic stimulation before and after intermittent theta-burst stimulation (iTBS). Plasticity measures were compared between groups and related to neuropsychological scores. Results: In T2DM, iTBS-induced modulation of MEPs was significantly less than controls, even after controlling for potential confounds. Furthermore, in T2DM, modulation of MEPs 10-min post-iTBS was significantly correlated with Rey Auditory Verbal Learning Task (RAVLT) performance. Conclusion: Humans with T2DM show abnormal cortico-motor plasticity that is correlated with reduced verbal learning. Since iTBS after-effects and the RAVLT are both NMDA receptor-dependent measures, their relationship in T2DM may reflect brain-wide alterations in the efficacy of NMDA receptors. These findings offer novel mechanistic insights into the brain consequences of T2DM and provide a reliable means to monitor brain health and evaluate the efficacy of clinical interventions. C1 [Fried, Peter J.; Schilberg, Lukas; Brem, Anna-Katharine; Saxena, Sadhvi; Wong, Bonnie; Pascual-Leone, Alvaro] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Intervent Cognit Neurol, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA USA. [Schilberg, Lukas] Maastricht Univ, Fac Psychol & Neurosci, Dept Cognit Neurosci, Maastricht, Netherlands. [Brem, Anna-Katharine] Univ Oxford, Dept Expt Psychol, Oxford, England. [Saxena, Sadhvi] Johns Hopkins Med Sch, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Cypess, Aaron M.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA. [Cypess, Aaron M.; Horton, Edward S.] Harvard Med Sch, Joslin Diabet Ctr, Res Div, Boston, MA USA. [Wong, Bonnie] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Frontotemporal Dementia Unit, Charlestown, MA USA. RP Fried, PJ; Pascual-Leone, A (reprint author), Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, 330 Brookline Ave,KS 158, Boston, MA 02215 USA. EM pfried@bidmc.harvard.edu; apleone@bidmc.harvard.edu FU Young Academics Support; Stiefel-Zangger Foundation of the University of Zurich, Switzerland; Swiss National Foundation [PBZHP1_147196]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Sidney R. Baer Jr. Foundation; National Institutes of Health (NIH) [R21 NS082870, R01 HD069776, R01 NS073601, R21 MH099196, R21 NS085491, R21 HD07616]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (NCRR and the NCATS NIH) [UL1 RR025758] FX This study was primarily funded by the National Institutes of Health (NIH R21 NS082870). Dr. Brem was further supported by the Young Academics Support and the Stiefel-Zangger Foundation of the University of Zurich, Switzerland, and the Swiss National Foundation (PBZHP1_147196). Dr. Cypess was further supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Dr. Pascual-Leone was further supported in part by the Sidney R. Baer Jr. Foundation, the NIH (R01 HD069776, R01 NS073601, R21 MH099196, R21 NS085491, R21 HD07616), and Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (NCRR and the NCATS NIH, UL1 RR025758). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the National Institutes of Health, or the Sidney R. Baer Jr. Foundation. NR 58 TC 0 Z9 0 U1 2 U2 2 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1387-2877 EI 1875-8908 J9 J ALZHEIMERS DIS JI J. Alzheimers Dis. PY 2017 VL 55 IS 1 BP 89 EP 100 DI 10.3233/JAD-160505 PG 12 WC Neurosciences SC Neurosciences & Neurology GA EB8WI UT WOS:000387671600009 PM 27636847 ER PT J AU Banks, WA Kovac, A Majerova, P Bullock, KM Shi, M Zhang, J AF Banks, William A. Kovac, Andrej Majerova, Petra Bullock, Kristin M. Shi, Min Zhang, Jing TI Tau Proteins Cross the Blood-Brain Barrier SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Article DE Alzheimer's disease; blood-brain barrier; tau protein; tauopathy ID PAIRED HELICAL FILAMENT; ALZHEIMERS-DISEASE; P-GLYCOPROTEIN; ALPHA-SYNUCLEIN; DISORDERED PROTEINS; CEREBROSPINAL-FLUID; EFFLUX TRANSPORT; CLEARANCE; PEPTIDE; ALBUMIN AB Tauopathies are a hallmark of many neurodegenerative diseases, including Alzheimer's disease and traumatic brain injuries. It has been demonstrated that amyloid-beta peptides, alpha-synuclein, and prion proteins cross the blood-brain barrier (BBB), contributing to their abilities to induce disease. Very little is known about whether tau proteins can cross the BBB. Here we systematically characterized several key forms of tau proteins to cross the BBB, including Tau-441 (2N4R), Tau-410 (2N3R), truncated tau 151-391 (0N4R), and truncated tau 121-227. All of these tau proteins crossed the BBB readily and bidirectonally; however, only Tau-410 had a saturable component to its influx. The tau proteins also entered the blood after their injection into the brain, with Tau 121-227 having the slowest exit from brain. The tau proteins varied in regards to their enzymatic stability in brain and blood and in their peripheral pharmacokinetics. These results show that blood-borne tau proteins could contribute to brain tauopathies. The result also suggest that the CNS can contribute to blood levels of tau, raising the possibility that, as suggested for other misfolded proteins, blood levels of tau proteins could be used as a biomarker of CNS disease. C1 [Banks, William A.; Bullock, Kristin M.] Vet Affairs Puget Sound Hlth Care Syst, Res & Dev, Seattle, WA USA. [Banks, William A.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. [Kovac, Andrej; Majerova, Petra] Slovak Acad Sci, Inst Neuroimmunol, Bratislava, Slovakia. [Kovac, Andrej] Univ Vet Med & Pharm, Dept Pharmacol & Toxicol, Kosice, Slovakia. [Majerova, Petra] AXON Neurosci SE, Bratislava, Slovakia. [Shi, Min; Zhang, Jing] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. [Zhang, Jing] Peking Univ, Hlth Sci Ctr, Dept Pathol, Beijing, Peoples R China. [Zhang, Jing] Peking Univ, Hosp 3, Beijing, Peoples R China. RP Banks, WA (reprint author), VAPSHCS, 1660S ColumbianWay, Seattle, WA 98108 USA. EM wabanks1@uw.edu FU NIH [R01 AG046619]; Alzheimer's Association grant [2015-NIRG-342009]; Veterans Affairs; APVV-14-0547 FX Supported by APVV-14-0547, Veterans Affairs, Alzheimer's Association grant 2015-NIRG-342009, and NIH R01 AG046619. NR 48 TC 0 Z9 0 U1 10 U2 10 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1387-2877 EI 1875-8908 J9 J ALZHEIMERS DIS JI J. Alzheimers Dis. PY 2017 VL 55 IS 1 BP 411 EP 419 DI 10.3233/JAD-160542 PG 9 WC Neurosciences SC Neurosciences & Neurology GA EB8WI UT WOS:000387671600032 PM 27662303 ER PT J AU Bui, E Anderson, E Goetter, EM Campbell, AA Fischer, LE Barrett, LF Simon, NM AF Bui, Eric Anderson, Eric Goetter, Elizabeth M. Campbell, Allison A. Fischer, Laura E. Barrett, Lisa Feldman Simon, Naomi M. TI Heightened sensitivity to emotional expressions in generalised anxiety disorder, compared to social anxiety disorder, and controls SO COGNITION & EMOTION LA English DT Article DE Anxiety; anxiety disorders; generalised anxiety disorder; social anxiety disorder; social phobia; cognition; assessment; diagnosis ID COMORBIDITY SURVEY REPLICATION; FACIAL EXPRESSIONS; PHOBIA; DEPRESSION; RECOGNITION; ADOLESCENTS; UNCERTAINTY; INTOLERANCE; PERCEPTION; THREAT AB Few studies have examined potential differences between social anxiety disorder (SAD) and generalised anxiety disorder (GAD) in the sensitivity to detect emotional expressions. The present study aims to compare the detection of emotional expressions in SAD and GAD. Participants with a primary diagnosis of GAD (n=46), SAD (n=70), and controls (n=118) completed a morph movies task. The task presented faces expressing increasing degrees of emotional intensity, slowly changing from a neutral to a full-intensity happy, sad, or angry expressions. Participants used a slide bar to view the movie frames from left to right, and to stop at the first frame where they perceived an emotion. The frame selected thus indicated the intensity of emotion required to identify the facial expression. Participants with GAD detected the onset of facial emotions at lower intensity of emotion than participants with SAD (p=0.002) and controls (p=0.039). In a multiple regression analysis controlling for age, race, and depressive symptom severity, lower frame at which the emotion was detected was independently associated and GAD diagnosis (B=-5.73, SE=1.74, p<0.01). Our findings suggest that individuals with GAD exhibit enhanced detection of facial emotions compared to those with SAD or controls. C1 [Bui, Eric; Goetter, Elizabeth M.; Campbell, Allison A.; Fischer, Laura E.; Barrett, Lisa Feldman; Simon, Naomi M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bui, Eric; Goetter, Elizabeth M.; Simon, Naomi M.] Harvard Med Sch, Boston, MA USA. [Anderson, Eric; Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA USA. RP Bui, E (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA.; Bui, E (reprint author), Harvard Med Sch, Boston, MA USA. EM tebui@mgh.harvard.edu FU Highland Street Foundation; National Institute of Health Director's Pioneer Award [DP1OD003312]; US Army Research Institute for the Behavioral and Social Sciences [W5J9CQ-11-C-0049]; [R01 AG030311]; [R01 MH093394] FX The present study was funded by a grant from the Highland Street Foundation. In addition, preparation of this manuscript was supported by a National Institute of Health Director's Pioneer Award [grant number DP1OD003312], by the US Army Research Institute for the Behavioral and Social Sciences (contract W5J9CQ-11-C-0049), and by grant R01 AG030311 awarded to LFB, as well as grant R01 MH093394 awarded to NMS. NR 37 TC 1 Z9 1 U1 25 U2 25 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0269-9931 EI 1464-0600 J9 COGNITION EMOTION JI Cogn. Emot. PY 2017 VL 31 IS 1 BP 119 EP 126 DI 10.1080/02699931.2015.1087973 PG 8 WC Psychology, Experimental SC Psychology GA EB3JD UT WOS:000387259500011 PM 26395075 ER PT J AU Abramson, JS AF Abramson, Jeremy S. TI Bone marrow biopsies for staging of diffuse large B-cell lymphoma: are we looking too closely? SO LEUKEMIA & LYMPHOMA LA English DT Editorial Material ID PET/CT C1 [Abramson, Jeremy S.] Massachusetts Gen Hosp, Dept Med, Ctr Canc, Ctr Lymphoma, Boston, MA 02114 USA. [Abramson, Jeremy S.] Harvard Med Sch, Dept Med, Boston, MA USA. RP Abramson, JS (reprint author), Massachusetts Gen Hosp, Ctr Canc, Ctr Lymphoma, 32 Fruit St,Yawkey 9A, Boston, MA 02114 USA. EM jabramson@mgh.harvard.edu NR 8 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PY 2017 VL 58 IS 1 BP 4 EP 5 DI 10.1080/10428194.2016.1246731 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA EB6ID UT WOS:000387484400002 PM 27778520 ER PT J AU Bhatt, S Sarosiek, KA Lossos, IS AF Bhatt, Shruti Sarosiek, Kristopher A. Lossos, Izidore S. TI Interleukin 21-its potential role in the therapy of B-cell lymphomas SO LEUKEMIA & LYMPHOMA LA English DT Review DE Interleukin-21; B-cell lymphoma therapy; NK-cell mediated cytotoxicity; STAT3; cMyc ID RECOMBINANT HUMAN INTERLEUKIN-21; LYMPHOCYTIC-LEUKEMIA CELLS; NON-HODGKINS-LYMPHOMA; COMMON GAMMA-CHAIN; PHASE-I TRIAL; METASTATIC MELANOMA; IL-21 RECEPTOR; FOLLICULAR LYMPHOMA; T-CELLS; NKT CELLS AB Interleukin-21 (IL-21), a member of IL-2 cytokine family, has pleotropic biological effects on lymphoid and myeloid cells. During the past 15 years, since the discovery of IL-21, great advances have been made regarding its biological activity and the mechanisms controlling IL-21-mediated cellular responses, especially in hematological malignancies. Preclinical studies have shown that IL-21R is expressed on healthy and neoplastic B-cells and exogenous IL-21 can induce direct apoptosis of IL-21R expressing B-cell non-Hodgkin lymphomas (NHL), making it a potentially attractive anti-lymphoma therapy. However, in some hematological malignancies such as multiple myeloma, Hodgkin lymphoma and Burkitt lymphoma, IL-21 can induce proliferation of neoplastic B-cells. In NHL, the underlying mechanism of cell death was found to be different between the various subtypes, including activation of different JAK/STAT signal transduction pathways or other factors. Immunomodulatory effects of IL-21 have also been reported to contribute to its antitumor effects as described by earlier studies in solid tumors and B-cell associated malignancies. These effects are predominantly mediated by IL-21' s ability to activate cytolytic activities by NKcells and CD4(+)/CD8(+)-cells. In this review, we provide an overview of IL-21' s effects in NHL, results from clinical trials utilizing IL-21, and propose how IL-21 can be therapeutically exploited for treating these lymphomas. C1 [Bhatt, Shruti; Sarosiek, Kristopher A.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Lossos, Izidore S.] Univ Miami, Miller Sch Med, Dept Mol & Cellular Pharmacol, Miami, FL 33136 USA. [Lossos, Izidore S.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Dept Med,Div Hematol Oncol, Miami, FL 33136 USA. RP Lossos, IS (reprint author), Univ Miami, Sylvester Comprehens Canc Ctr, Div Hematol & Oncol, 1475 NW 12th Ave D8-4, Miami, FL 33136 USA. EM ilossos@med.miami.edu FU Sylvester Comprehensive Cancer Center; Dwoskin Family Foundation; Recio Family Foundation; Anthony Rizzo Family Foundation FX I.S.L. is supported by the Sylvester Comprehensive Cancer Center and by the Dwoskin, Recio and Anthony Rizzo Family Foundations. NR 79 TC 0 Z9 0 U1 8 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PY 2017 VL 58 IS 1 BP 17 EP 29 DI 10.1080/10428194.2016.1201568 PG 13 WC Oncology; Hematology SC Oncology; Hematology GA EB6ID UT WOS:000387484400005 PM 27405876 ER PT J AU von Tresckow, B Morschhauser, F Szer, J Eichenauer, DA Abramson, JS Sureda, A Engert, A AF von Tresckow, Bastian Morschhauser, Franck Szer, Jeffrey Eichenauer, Dennis A. Abramson, Jeremy S. Sureda, Anna Engert, Andreas TI Panobinostat consolidation in patients with Hodgkin lymphoma at risk for relapse after high dose chemotherapy and autologous stem cell transplant: final results after early trial discontinuation SO LEUKEMIA & LYMPHOMA LA English DT Letter C1 [von Tresckow, Bastian; Eichenauer, Dennis A.; Engert, Andreas] Univ Hosp, GHSG, Dept Internal Med 1, Kerpener Str 62, Cologne, Germany. [Morschhauser, Franck] CHRU Lille, Hop Claude Huriez, Dept Hematol, Lille, France. [Szer, Jeffrey] Royal Melbourne Hosp, Bone Marrow Transplant Unit, Parkville, Vic, Australia. [Abramson, Jeremy S.] Massachusetts Gen Hosp, Yawkey Ctr, Suite 9A, Boston, MA 02114 USA. [Sureda, Anna] Hosp De La Santa Creu & Sant Pau, Dept Hematol, Barcelona, Spain. [Sureda, Anna] Inst Catala Oncol LHosp, Dept Hematol, Gran Via, Barcelona, Spain. RP von Tresckow, B (reprint author), Cologne Univ Hosp, Dept Internal Med 1, Kerpener Str 62, D-50937 Cologne, Germany. EM bastian.von-tresckow@uk-koeln.de NR 7 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PY 2017 VL 58 IS 1 BP 222 EP 225 DI 10.1080/10428194.2016.1182164 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA EB6ID UT WOS:000387484400033 PM 27184350 ER PT J AU Mason, EF Brown, RD Szeto, DP Gibson, CJ Jia, YH Garcia, EP Jacobson, CA Dal Cin, P Kuo, FC Pinkus, GS Lindeman, NI Sholl, LM Aster, JC Morgan, EA AF Mason, Emily F. Brown, Ronald D. Szeto, David P. Gibson, Christopher J. Jia, Yonghui Garcia, Elizabeth P. Jacobson, Caron A. Dal Cin, Paola Kuo, Frank C. Pinkus, Geraldine S. Lindeman, Neal I. Sholl, Lynette M. Aster, Jon C. Morgan, Elizabeth A. TI Detection of activating MAP2K1 mutations in atypical hairy cell leukemia and hairy cell leukemia variant SO LEUKEMIA & LYMPHOMA LA English DT Letter ID LYMPHOMA; NOTCH1; GENES C1 [Mason, Emily F.; Brown, Ronald D.; Szeto, David P.; Jia, Yonghui; Garcia, Elizabeth P.; Dal Cin, Paola; Kuo, Frank C.; Pinkus, Geraldine S.; Lindeman, Neal I.; Sholl, Lynette M.; Aster, Jon C.; Morgan, Elizabeth A.] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA. [Gibson, Christopher J.; Jacobson, Caron A.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. RP Morgan, EA (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St,Amory 3, Boston, MA 02115 USA. EM eamorgan@partners.org NR 15 TC 2 Z9 2 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PY 2017 VL 58 IS 1 BP 233 EP 236 DI 10.1080/10428194.2016.1185786 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA EB6ID UT WOS:000387484400036 PM 27241017 ER PT J AU Tanaka, T Ikegami, Y Nakazawa, H Kuriyama, N Oki, M Hanai, JI Sukhatme, VP Kaneki, M AF Tanaka, Tomokazu Ikegami, Yuichi Nakazawa, Harumasa Kuriyama, Naohide Oki, Miwa Hanai, Jun-Ichi Sukhatme, Vikas P. Kaneki, Masao TI Low-Dose Farnesyltransferase Inhibitor Suppresses HIF-1 alpha and Snail Expression in Triple-Negative Breast Cancer MDA-MB-231 Cells In Vitro SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID FARNESYL TRANSFERASE INHIBITOR; HYPOXIA-INDUCIBLE FACTOR; TRANSCRIPTION FACTOR SNAIL; TO-MESENCHYMAL TRANSITION; ACUTE MYELOID-LEUKEMIA; E-CADHERIN EXPRESSION; PHASE-II TRIAL; TUMOR-GROWTH; MYELODYSPLASTIC SYNDROME; ENDOTHELIAL-CELLS AB The aggressiveness of triple-negative breast cancer (TNBC), which lacks estrogen receptor, progesterone receptor and epidermal growth factor receptor 2 (HER2), represents a major challenge in breast cancer. Migratory and self-renewal capabilities are integral components of invasion, metastasis and recurrence of TNBC. Elevated hypoxia-inducible factor-1 alpha (HIF-1 alpha) expression is associated with aggressiveness of cancer. Nonetheless, how HIF-1 alpha expression is regulated and how HIF-1 alpha induces aggressive phenotype are not completely understood in TNBC. The cytotoxic effects of farnesyltransferase (FTase) inhibitors (FTIs) have been studied in cancer and leukemia cells. In contrast, the effect of FTIs on HIF-1 alpha expression has not yet been studied. Here, we show that clinically relevant low-dose FTI, tipifarnib (300 nM), decreased HIF-1 alpha expression, migration and tumorsphere formation in human MDA-MB-231 TNBC cells under a normoxic condition. In contrast, the low-dose FTIs did not inhibit cell growth and activity of the Ras pathway in MDA-MB 231 cells. Tipifarnib-induced decrease in HIF-1 alpha expression was associated with amelioration of the Warburg effect, hypermetabolic state, increases in Snail expression and ATP release, and suppressed E-cadherin expression, major contributors to invasion, metastasis and recurrence of TBNC. These data suggest that FTIs may be capable of ameliorating the aggressive phenotype of TNBC by suppressing the HIF-1 alpha-Snail pathway. (C) 2016 Wiley Periodicals, Inc. C1 [Tanaka, Tomokazu; Ikegami, Yuichi; Nakazawa, Harumasa; Kuriyama, Naohide; Kaneki, Masao] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA USA. [Nakazawa, Harumasa; Kuriyama, Naohide; Kaneki, Masao] Shriners Hosp Children, Boston, MA USA. [Oki, Miwa; Hanai, Jun-Ichi; Sukhatme, Vikas P.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Interdisciplinary Med & Biotechnol, Dept Med,Div Nephrol, Boston, MA USA. RP Kaneki, M (reprint author), Harvard Med Sch, Shriners Hosp Children, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 149 Thirteenth St,Rm 6604, Charlestown, MA 02129 USA. EM mkaneki@helix.mgh.harvard.edu FU National Institutes of Health [R01 DK05827] FX Contract grant sponsor: National Institutes of Health;; Contract grant number: R01 DK05827. NR 55 TC 1 Z9 1 U1 37 U2 37 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9541 EI 1097-4652 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD JAN PY 2017 VL 232 IS 1 BP 192 EP 201 DI 10.1002/jcp.25411 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA EB0OI UT WOS:000387043000013 PM 27137755 ER PT J AU Krieger, M Mayrhofer, T AF Krieger, Miriam Mayrhofer, Thomas TI Prudence and prevention: an economic laboratory experiment SO APPLIED ECONOMICS LETTERS LA English DT Article DE Self-protection; prevention; prudence; risk preferences; laboratory experiment; I10; C91; D81 ID RISK-AVERSION; SELF-PROTECTION; PREFERENCES; INSURANCE; TEMPERANCE; BEHAVIOR AB In an economic laboratory experiment, we study the relationship between prudence and prevention in general decision situations. Previous theoretical research on this relationship posits a negative impact of prudence on the optimal level of prevention. Overall, we find both risk-averse and prudent behaviour among our subjects. Moreover, prudent subjects chose significantly less prevention than nonprudent subjects, confirming the theoretical results of one-period models in the literature. Our findings might have implications for health policy if prudence - rather than irrational decision behaviour, as previously assumed - is responsible for low levels of preventive effort. C1 [Krieger, Miriam] Univ Duisburg Essen, CINCH Hlth Econ Res Ctr, Essen, Germany. [Mayrhofer, Thomas] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Mayrhofer, Thomas] Harvard Univ, Harvard Med Sch, Boston, MA 02115 USA. [Mayrhofer, Thomas] Stralsund Univ Appl Sci, Sch Business Studies, Schwedenschanze 15, D-18345 Stralsund, Germany. RP Mayrhofer, T (reprint author), Stralsund Univ Appl Sci, Sch Business Studies, Schwedenschanze 15, D-18345 Stralsund, Germany. EM thomas.mayrhofer@fh-stralsund.de FU German Research Foundation (DFG) [FOR 655] FX Financial support from the German Research Foundation (DFG) [FOR 655] is gratefully acknowledged. NR 28 TC 1 Z9 1 U1 5 U2 5 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1350-4851 EI 1466-4291 J9 APPL ECON LETT JI Appl. Econ. Lett. PD JAN PY 2017 VL 24 IS 1 BP 19 EP 24 DI 10.1080/13504851.2016.1158909 PG 6 WC Economics SC Business & Economics GA EA2TC UT WOS:000386446600005 ER PT J AU Banks, HT Hu, SH Rosenberg, E AF Banks, H. T. Hu, Shuhua Rosenberg, Eric TI A dynamical modeling approach for analysis of longitudinal clinical trials in the presence of missing endpoints SO APPLIED MATHEMATICS LETTERS LA English DT Article DE HIV; Hypothesis testing; Ordinary differential equation; Inverse problems ID STRATEGIES AB Randomized longitudinal clinical trials are the gold standard to evaluate the effectiveness of interventions among different patient treatment groups. However, analysis of such clinical trials becomes difficult in the presence of missing data, especially in the case where the study endpoints become difficult to measure because of subject dropout rates or/and the time to discontinue the assigned interventions are different among the patient groups. Here we report on using a validated mathematical model combined with an inverse problem approach to predict the values for the missing endpoints. A small randomized HIV clinical trial where endpoints for most of patients are missing is used to demonstrate this approach. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Banks, H. T.; Hu, Shuhua; Rosenberg, Eric] North Carolina State Univ, Ctr Res Sci Computat, Raleigh, NC 27695 USA. [Hu, Shuhua] Certara Inc, Cary, NC 27518 USA. [Rosenberg, Eric] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Rosenberg, Eric] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Rosenberg, Eric] Harvard Med Sch, Boston, MA 02114 USA. RP Banks, HT (reprint author), North Carolina State Univ, Ctr Res Sci Computat, Raleigh, NC 27695 USA. EM htbanks@ncsu.edu FU National Institute of Allergy and Infectious Diseases [NIAID R01AI071915-10]; Air Force Office of Scientific Research [AFOSR FA9550-12-1-0188] FX This research was supported in part by grant number NIAID R01AI071915-10 from the National Institute of Allergy and Infectious Diseases, and in part by the Air Force Office of Scientific Research under grant number AFOSR FA9550-12-1-0188. NR 7 TC 0 Z9 0 U1 15 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0893-9659 J9 APPL MATH LETT JI Appl. Math. Lett. PD JAN PY 2017 VL 63 BP 109 EP 117 DI 10.1016/j.aml.2016.07.002 PG 9 WC Mathematics, Applied SC Mathematics GA DX5CS UT WOS:000384398000017 PM 28344385 ER PT B AU Davis, CM AF Davis, Carol M. BE Davis, CM TI INTEGRATIVE THERAPIES IN REHABILITATION Evidence for Efficacy in Therapy, Prevention, and Wellness Introduction to the Fourth Edition SO INTEGRATIVE THERAPIES IN REHABILITATION: EVIDENCE FOR EFFICACY IN THERAPY, PREVENTION, AND WELLNESS, FOURTH EDITION LA English DT Editorial Material; Book Chapter C1 [Davis, Carol M.] Univ Miami, Sch Med, Miami, FL 33136 USA. [Davis, Carol M.] Dept Phys Therapy, Miami, FL USA. [Davis, Carol M.] Univ Miami, Miller Sch Med, Dept Phys Therapy, Coral Gables, FL 33124 USA. [Davis, Carol M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Davis, Carol M.] Univ Alabama Birmingham, Birmingham, AL USA. [Davis, Carol M.] Boston Univ, Sargent Coll, Phys Therapy, Boston, MA 02215 USA. RP Davis, CM (reprint author), Univ Miami, Sch Med, Miami, FL 33136 USA. NR 1 TC 0 Z9 0 U1 1 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE ROAD, THOROFARE, NJ 08086-9447 USA BN 978-1-63091-043-3 PY 2017 BP 3 EP 4 PG 2 WC Rehabilitation SC Rehabilitation GA BF5WR UT WOS:000382708500001 ER PT B AU Davis, CM AF Davis, Carol M. BE Davis, CM TI Energy Techniques as a Way of Returning Healing to Health Care SO INTEGRATIVE THERAPIES IN REHABILITATION: EVIDENCE FOR EFFICACY IN THERAPY, PREVENTION, AND WELLNESS, FOURTH EDITION LA English DT Article; Book Chapter C1 [Davis, Carol M.] Univ Miami, Sch Med, Miami, FL 33136 USA. [Davis, Carol M.] Dept Phys Therapy, Miami, FL USA. [Davis, Carol M.] Univ Miami, Miller Sch Med, Dept Phys Therapy, Coral Gables, FL 33124 USA. [Davis, Carol M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Davis, Carol M.] Univ Alabama Birmingham, Birmingham, AL USA. [Davis, Carol M.] Boston Univ, Sargent Coll, Phys Therapy, Boston, MA 02215 USA. RP Davis, CM (reprint author), Univ Miami, Sch Med, Miami, FL 33136 USA. NR 13 TC 0 Z9 0 U1 1 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE ROAD, THOROFARE, NJ 08086-9447 USA BN 978-1-63091-043-3 PY 2017 BP 5 EP 12 PG 8 WC Rehabilitation SC Rehabilitation GA BF5WR UT WOS:000382708500002 ER PT B AU Davis, CM AF Davis, Carol M. BE Davis, CM TI Psychoneuroimmunology The Bridge to the Coexistence of Two Paradigms SO INTEGRATIVE THERAPIES IN REHABILITATION: EVIDENCE FOR EFFICACY IN THERAPY, PREVENTION, AND WELLNESS, FOURTH EDITION LA English DT Article; Book Chapter ID UNCONVENTIONAL MEDICINE; EMPATHY C1 [Davis, Carol M.] Univ Miami, Sch Med, Miami, FL 33136 USA. [Davis, Carol M.] Dept Phys Therapy, Miami, FL USA. [Davis, Carol M.] Univ Miami, Miller Sch Med, Dept Phys Therapy, Coral Gables, FL 33124 USA. [Davis, Carol M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Davis, Carol M.] Univ Alabama Birmingham, Birmingham, AL USA. [Davis, Carol M.] Boston Univ, Sargent Coll, Phys Therapy, Boston, MA 02215 USA. RP Davis, CM (reprint author), Univ Miami, Sch Med, Miami, FL 33136 USA. NR 38 TC 0 Z9 0 U1 2 U2 2 PU SLACK INC PI THOROFARE PA 6900 GROVE ROAD, THOROFARE, NJ 08086-9447 USA BN 978-1-63091-043-3 PY 2017 BP 15 EP 25 PG 11 WC Rehabilitation SC Rehabilitation GA BF5WR UT WOS:000382708500003 ER PT B AU Davis, CM AF Davis, Carol M. BE Davis, CM TI Quantum Physics and Systems Theory The Science Behind Complementary and Alternative Therapies SO INTEGRATIVE THERAPIES IN REHABILITATION: EVIDENCE FOR EFFICACY IN THERAPY, PREVENTION, AND WELLNESS, FOURTH EDITION LA English DT Article; Book Chapter ID THERAPEUTIC TOUCH C1 [Davis, Carol M.] Univ Miami, Sch Med, Miami, FL 33136 USA. [Davis, Carol M.] Dept Phys Therapy, Miami, FL USA. [Davis, Carol M.] Univ Miami, Miller Sch Med, Dept Phys Therapy, Coral Gables, FL 33124 USA. [Davis, Carol M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Davis, Carol M.] Univ Alabama Birmingham, Birmingham, AL USA. [Davis, Carol M.] Boston Univ, Sargent Coll, Phys Therapy, Boston, MA 02215 USA. RP Davis, CM (reprint author), Univ Miami, Sch Med, Miami, FL 33136 USA. NR 37 TC 0 Z9 0 U1 6 U2 6 PU SLACK INC PI THOROFARE PA 6900 GROVE ROAD, THOROFARE, NJ 08086-9447 USA BN 978-1-63091-043-3 PY 2017 BP 27 EP 34 PG 8 WC Rehabilitation SC Rehabilitation GA BF5WR UT WOS:000382708500004 ER PT B AU Davis, CM AF Davis, Carol M. BE Davis, CM TI Advances in the Science of Energy Medicine Vibration, Photons, and the Zero Point Field SO INTEGRATIVE THERAPIES IN REHABILITATION: EVIDENCE FOR EFFICACY IN THERAPY, PREVENTION, AND WELLNESS, FOURTH EDITION LA English DT Article; Book Chapter C1 [Davis, Carol M.] Univ Miami, Sch Med, Miami, FL 33136 USA. [Davis, Carol M.] Dept Phys Therapy, Miami, FL USA. [Davis, Carol M.] Univ Miami, Miller Sch Med, Dept Phys Therapy, Coral Gables, FL 33124 USA. [Davis, Carol M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Davis, Carol M.] Univ Alabama Birmingham, Birmingham, AL USA. [Davis, Carol M.] Boston Univ, Sargent Coll, Phys Therapy, Boston, MA 02215 USA. RP Davis, CM (reprint author), Univ Miami, Sch Med, Miami, FL 33136 USA. NR 27 TC 0 Z9 0 U1 7 U2 7 PU SLACK INC PI THOROFARE PA 6900 GROVE ROAD, THOROFARE, NJ 08086-9447 USA BN 978-1-63091-043-3 PY 2017 BP 35 EP 42 PG 8 WC Rehabilitation SC Rehabilitation GA BF5WR UT WOS:000382708500005 ER PT B AU Davis, CM AF Davis, Carol M. BE Davis, CM TI Fascia and the Extracellular Matrix Latest Science Discoveries That Forecast the Importance of This Tissue to Health and Healing SO INTEGRATIVE THERAPIES IN REHABILITATION: EVIDENCE FOR EFFICACY IN THERAPY, PREVENTION, AND WELLNESS, FOURTH EDITION LA English DT Article; Book Chapter ID GELS C1 [Davis, Carol M.] Univ Miami, Sch Med, Miami, FL 33136 USA. [Davis, Carol M.] Dept Phys Therapy, Miami, FL USA. [Davis, Carol M.] Univ Miami, Miller Sch Med, Dept Phys Therapy, Coral Gables, FL 33124 USA. [Davis, Carol M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Davis, Carol M.] Univ Alabama Birmingham, Birmingham, AL USA. [Davis, Carol M.] Boston Univ, Sargent Coll, Phys Therapy, Boston, MA 02215 USA. RP Davis, CM (reprint author), Univ Miami, Sch Med, Miami, FL 33136 USA. NR 37 TC 0 Z9 0 U1 5 U2 5 PU SLACK INC PI THOROFARE PA 6900 GROVE ROAD, THOROFARE, NJ 08086-9447 USA BN 978-1-63091-043-3 PY 2017 BP 43 EP 53 PG 11 WC Rehabilitation SC Rehabilitation GA BF5WR UT WOS:000382708500006 ER PT J AU Gregory, KE Samuel, BS Houghteling, P Shan, G Ausubel, FM Sadreyev, RI Walker, WA AF Gregory, Katherine E. Samuel, Buck S. Houghteling, Pearl Shan, Guru Ausubel, Frederick M. Sadreyev, Ruslan I. Walker, W. Allan TI Influence of maternal breast milk ingestion on acquisition of the intestinal microbiome in preterm infants SO MICROBIOME LA English DT Article DE Preterm infant; Intestinal colonization; Microbiome; Breast milk; Nutrition; Newborn intensive care ID GUT MICROBIOTA; NECROTIZING ENTEROCOLITIS; PREMATURE-INFANTS; DISEASE; HEALTH; OLIGOSACCHARIDES; INFLAMMATION; PROGRESSION; EPITHELIUM; PROBIOTICS AB Background: The initial acquisition and early development of the intestinal microbiome during infancy are important to human health across the lifespan. Mode of birth, antibiotic administration, environment of care, and nutrition have all been shown to play a role in the assembly of the intestinal microbiome during early life. For preterm infants, who are disproportionately at risk of inflammatory intestinal disease (i.e., necrotizing enterocolitis), a unique set of clinical factors influence the establishment of the microbiome. The purpose of this study was to establish the influence of nutritional exposures on the intestinal microbiome in a cohort of preterm infants early in life. Results: Principal component analysis of 199 samples from 30 preterm infants (<32 weeks) over the first 60 days following birth showed that the intestinal microbiome was influenced by postnatal time (p < 0.001, R-2 = 0.13), birth weight (p < 0.001, R-2 = 0.08), and nutrition (p < 0.001, R-2 = 0.21). Infants who were fed breast milk had a greater initial bacterial diversity and a more gradual acquisition of diversity compared to infants who were fed infant formula. The microbiome of infants fed breast milk were more similar regardless of birth weight (p = 0.049), in contrast to the microbiome of infants fed infant formula, which clustered differently based on birth weight (p < 0.001). By adjusting for differences in gut maturity, an ordered succession of microbial phylotypes was observed in breast milk-fed infants, which appeared to be disrupted in those fed infant formula. Supplementation with pasteurized donor human milk was partially successful in promoting a microbiome more similar to breast milk-fed infants and moderating rapid increases in bacterial diversity. Conclusions: The preterm infant intestinal microbiome is influenced by postnatal time, birth weight, gestational age, and nutrition. Feeding with breast milk appears to mask the influence of birth weight, suggesting a protective effect against gut immaturity in the preterm infant. These findings suggest not only a microbial mechanism underpinning the body of evidence showing that breast milk promotes intestinal health in the preterm infant but also a dynamic interplay of host and dietary factors that facilitate the colonization of and enrichment for specific microbes during establishment of the preterm infant microbiota. C1 [Gregory, Katherine E.] Brigham & Womens Hosp, Dept Pediat Newborn Med, 75 Francis St, Boston, MA 02115 USA. [Samuel, Buck S.] Baylor Coll Med, Dept Mol Virol & Microbiol, Alkek Ctr Metagen & Microbiome Res, Houston, TX 77030 USA. [Houghteling, Pearl] Yale Sch Med, Dept Pediat, New Haven, CT USA. [Shan, Guru] Cooper Med Sch, Camden, NJ USA. [Ausubel, Frederick M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Genet, Dept Mol Biol, Boston, MA USA. [Sadreyev, Ruslan I.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Mol Biol, Dept Pathol, Boston, MA USA. [Walker, W. Allan] Harvard Med Sch, Massachusetts Gen Hosp Children, Dept Pediat, Mucosal Immunol & Biol Res Ctr, Boston, MA USA. RP Gregory, KE (reprint author), Brigham & Womens Hosp, Dept Pediat Newborn Med, 75 Francis St, Boston, MA 02115 USA. EM kgregory1@partners.org FU National Institutes of Health, Bethesda, MD [R01 HD059126, R01 HD012437, P01 DK033506, P30 DK040561, K23 NR 011320] FX This study was supported by grants from the National Institutes of Health, Bethesda, MD (R01 HD059126; R01 HD012437, P01 DK033506, P30 DK040561 to WAW) (K23 NR 011320 to KEG). NR 58 TC 0 Z9 0 U1 21 U2 21 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2049-2618 J9 MICROBIOME JI Microbiome PD DEC 30 PY 2016 VL 4 AR 68 DI 10.1186/s40168-016-0214-x PG 15 WC Microbiology SC Microbiology GA EG8SA UT WOS:000391326000001 PM 28034306 ER PT J AU Shrime, MG Sekidde, S Linden, A Cohen, JL Weinstein, MC Salomon, JA AF Shrime, Mark G. Sekidde, Serufusa Linden, Allison Cohen, Jessica L. Weinstein, Milton C. Salomon, Joshua A. TI Sustainable Development in Surgery: The Health, Poverty, and Equity Impacts of Charitable Surgery in Uganda SO PLOS ONE LA English DT Article ID SURGICAL SERVICES; CARE; MANAGEMENT; EFFICIENCY; HOSPITALS; COUNTRIES; OUTCOMES; PROGRAM; MODEL; KENYA AB Background The recently adopted Sustainable Development Goals call for the end of poverty and the equitable provision of healthcare. These goals are often at odds, however: health seeking can lead to catastrophic spending, an outcome for which cancer patients and the poor in resource-limited settings are at particularly high risk. How various health policies affect the additional aims of financial wellbeing and equity is poorly understood. This paper evaluates the health, financial, and equity impacts of governmental and charitable policies for surgical oncology in a resource-limited setting. Methods Three charitable platforms for surgical oncology delivery in Uganda were compared to six governmental policies aimed at improving healthcare access. An extended cost-effectiveness analysis using an agent-based simulation model examined the numbers of lives saved, catastrophic expenditure averted, impoverishment averted, costs, and the distribution of benefits across the wealth spectrum. Findings Of the nine policies and platforms evaluated, two were able to provide simultaneous health and financial benefits efficiently and equitably: mobile surgical units and governmental policies that simultaneously address surgical scaleup, the cost of surgery, and the cost of transportation. Policies that only remove user fees are dominated, as is the commonly employed short-term "surgical mission trip". These results are robust to scenario and sensitivity analyses. Interpretation The most common platforms for increasing access to surgical care appear unable to provide health and financial risk protection equitably. On the other hand, mobile surgical units, to date an underutilized delivery platform, are able to deliver surgical oncology in a manner that meets sustainable development goals by improving health, financial solvency, and equity. These platforms compare favorably with policies that holistically address surgical delivery and should be considered as countries strengthen health systems. C1 [Shrime, Mark G.] Harvard Med Sch, Dept Global Hlth & Social Med, Program Global Surg & Social Change, Boston, MA 02115 USA. [Shrime, Mark G.] Massachusetts Eye & Ear Infirm, Off Global Surg, Boston, MA 02114 USA. [Sekidde, Serufusa] Aspen Inst, Aspen Global Hlth & Dev, Aspen, CO USA. [Linden, Allison] Childrens Hosp Los Angeles, Div Pediat Surg, Los Angeles, CA 90027 USA. [Cohen, Jessica L.; Salomon, Joshua A.] Harvard TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA USA. [Weinstein, Milton C.] Harvard TH Chan Sch Publ Hlth, Ctr Hlth Decis Sci, Boston, MA USA. [Weinstein, Milton C.; Salomon, Joshua A.] Harvard TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. RP Shrime, MG (reprint author), Harvard Med Sch, Dept Global Hlth & Social Med, Program Global Surg & Social Change, Boston, MA 02115 USA.; Shrime, MG (reprint author), Massachusetts Eye & Ear Infirm, Off Global Surg, Boston, MA 02114 USA. EM shrime@mail.harvard.edu FU National Cancer Institute [R25 CA92203] FX This work was supported by National Cancer Institute: R25 CA92203 (MGS). NR 61 TC 0 Z9 0 U1 10 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 30 PY 2016 VL 11 IS 12 AR e0168867 DI 10.1371/journal.pone.0168867 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG7LN UT WOS:000391229300035 PM 28036357 ER PT J AU Sher, L Fisher, AM Kelliher, CH Penner, JD Goodman, M Koenigsberg, HW New, AS Siever, LJ Hazlett, EA AF Sher, Leo Fisher, Amanda M. Kelliher, Caitlin H. Penner, Justin D. Goodman, Marianne Koenigsberg, Harold W. New, Antonia S. Siever, Larry J. Hazlett, Erin A. TI Clinical features and psychiatric comorbidities of borderline personality disorder patients with versus without a history of suicide attempt SO PSYCHIATRY RESEARCH LA English DT Article DE Suicide; Borderline personality disorder; Narcissistic personality disorder; Depression; Affective lability ID SUBSTANCE USE DISORDERS; NONSUICIDAL SELF-INJURY; MAJOR DEPRESSIVE EPISODE; II COMPARISON SUBJECTS; NARCISSISTIC PERSONALITY; FUNCTIONAL IMPAIRMENT; EMOTIONAL PICTURES; BIPOLAR DISORDER; MOOD DISORDERS; YOUNG-ADULTS AB Patients with borderline personality disorder (BPD) are at high risk for suicidal behavior. However, many BPD patients do not engage in suicidal behavior. In this study, we compared clinical features of BPD patients with or without a history of suicide attempts and healthy volunteers. Compared with healthy volunteers, both BPD groups had higher Affective Lability Scale (ALS), ALS - Depression-Anxiety Subscale, Barratt Impulsivity Scale (BIS), and Lifetime History of Aggression (LHA) scores and were more likely to have a history of temper tantrums. BPD suicide attempters had higher ALS, ALS - Depression-Anxiety Subscale and LHA scores and were more likely to have a history of non-suicidal self-injury or temper tantrums compared to BPD nonattempters. Also, BPD suicide attempters were more likely to have a history of comorbid major depressive disorder and less likely to have comorbid narcissistic personality disorder (NPD) in comparison to BPD nonattempters. About 50% of study participants in each BPD group had a history of comorbid substance use disorder (SUD). Our study indicates that BPD patients with a history of suicide attempt are more aggressive, affectively dysregulated and less narcissistic than BPD suicide non-attempters. C1 [Sher, Leo; Fisher, Amanda M.; Kelliher, Caitlin H.; Penner, Justin D.; Goodman, Marianne; Koenigsberg, Harold W.; New, Antonia S.; Siever, Larry J.; Hazlett, Erin A.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Sher, Leo; Penner, Justin D.; Goodman, Marianne; Koenigsberg, Harold W.; Siever, Larry J.] James J Peters VA Med Ctr, Inpatient & Outpatient Psychiat, Bronx, NY USA. [Hazlett, Erin A.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Penner, Justin D.; Goodman, Marianne; Siever, Larry J.; Hazlett, Erin A.] James J Peters VA Med Ctr, MIRECC, VISN South 2, Bronx, NY USA. RP Sher, L (reprint author), James J Peters Vet Adm Med Ctr, 130 West Kingsbridge Rd, New York, NY 10468 USA. EM leo.sher@mssm.edu FU VA Merit award [I01CX000609]; Mental Illness Research, Education, and Clinical Center (MIRECC; VISN 2 South) at the James J. Peters VA Medical Center FX This work was supported by a VA Merit award (I01CX000609) to EAH and the Mental Illness Research, Education, and Clinical Center (MIRECC; VISN 2 South) at the James J. Peters VA Medical Center. NR 76 TC 1 Z9 1 U1 10 U2 10 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 DEC 30 PY 2016 VL 246 BP 261 EP 266 DI 10.1016/j.psychres.2016.10.003 PG 6 WC Psychiatry SC Psychiatry GA EG3TT UT WOS:000390968300039 PM 27728869 ER PT J AU Talaei-Khoei, M Mohamadi, A Mellema, JJ Tourjee, SM Ring, D Vranceanu, AM AF Talaei-Khoei, Mojtaba Mohamadi, Amin Mellema, Jos J. Tourjee, Stephen M. Ring, David Vranceanu, Ana-Maria TI The direct and indirect effects of the negative affectivity trait on self reported physical function among patients with upper extremity conditions SO PSYCHIATRY RESEARCH LA English DT Article DE Negative affectivity; Pain; Physical function; Upper extremity ID MEASUREMENT INFORMATION-SYSTEM; FEAR-AVOIDANCE MODEL; EMOTIONAL DISORDERS; TRANSDIAGNOSTIC TREATMENT; UNIFIED PROTOCOL; MUSCULOSKELETAL PAIN; D PERSONALITY; DEPRESSION; PROMIS; SAMPLE AB Negative affectivity is a personality trait that predisposes people to psychological distress and low life satisfaction. Negative affectivity may also affect pain intensity and physical function in patients with musculoskeletal conditions. We explored the association of negative affectivity to pain intensity and self reported physical function, and tested whether pain intensity mediates the effect of negative affectivity on physical function. In a cross-sectional study, 102 patients with upper extremity musculoskeletal conditions presenting to an orthopedic surgeon completed self-report measures of negative affectivity, pain intensity, and physical function in addition to demographic and injury information. We used the Preacher and Hayes' bootstrapping approach to quantify the indirect effect of negative affectivity on physical function through pain intensity. Negative affectivity correlated with greater pain intensity and lower self-reported physical function significantly. Also, pain intensity mediated the association of negative affectivity with physical function. The indirect effect accounted for one-third of the total effect. To conclude, negative affectivity is associated with decreased engagement in daily life activities both directly, but also indirectly through increased pain intensity. Treatments targeting negative affectivity may be more economical and efficient for alleviation of pain and limitations associated with musculoskeletal illness than those addressing coping strategies or psychological distress. C1 [Talaei-Khoei, Mojtaba; Mohamadi, Amin; Mellema, Jos J.] Harvard Med Sch, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Boston, MA USA. [Tourjee, Stephen M.; Vranceanu, Ana-Maria] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Ring, David] Univ Texas Austin, Dept Surg & Perloperat Care, Dell Med Sch, Austin, TX 78712 USA. RP Vranceanu, AM (reprint author), Massachusetts Gen Hosp, Behav Med Serv, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM mtalaeikhoei@mgh.harvard.edu; amohamadi@mgh.harvard.edu; josjmellema@gmail.com; stourjee@partners.org; david.ring@austin.utexas.edu; avranceanu@mgh.harvard.edu OI Mohamadi, Amin/0000-0003-0958-0091 NR 30 TC 0 Z9 0 U1 5 U2 5 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 DEC 30 PY 2016 VL 246 BP 568 EP 572 DI 10.1016/j.psythres.2016.10.040 PG 5 WC Psychiatry SC Psychiatry GA EG3TT UT WOS:000390968300090 PM 27825044 ER PT J AU Aljabri, A Huckleberry, Y Karnes, JH Gharaibeh, M Kutbi, HI Raz, Y Yun, S Abraham, I Erstad, B AF Aljabri, Ahmed Huckleberry, Yvonne Karnes, Jason H. Gharaibeh, Mahdi Kutbi, Hussam I. Raz, Yuval Yun, Seongseok Abraham, Ivo Erstad, Brian TI Cost-effectiveness of anticoagulants for suspected heparin-induced thrombocytopenia in the United States SO BLOOD LA English DT Article ID SEROTONIN-RELEASE ASSAY; ARGATROBAN ANTICOAGULATION; VENOUS THROMBOEMBOLISM; INITIAL TREATMENT; FONDAPARINUX; MANAGEMENT; BIVALIRUDIN; DIAGNOSIS; EFFICACY; FAILURE AB Despite the availability of multiple nonheparin anticoagulants for the treatment of heparin-induced thrombocytopenia (HIT), few data are available comparing the cost-effectiveness of these agents. This analysis is particularly important when considering differences in the risk of adverse effects, routes of administration, requirements for phlebotomy and laboratory monitoring, and overall drug costs. We conducted a cost-effectiveness analysis of argatroban, bivalirudin, and fondaparinux for the treatment of suspected HIT from the institutional perspective. A 3-arm decision-tree model was developed that employs standard practices for anticoagulation monitoring. We incorporated published data on drug efficacy and probability of HIT-related thromboembolism and major bleeding. We considered both institutional costs and average wholesale price (AWP) and performed probabilistic sensitivity analyses (PSA) to address any uncertainty in model parameters. Using institutional costs, fondaparinux prevailed over both argatroban and bivalirudin in terms of cost ($151 vs $1250 and $1466, respectively) and adverse events averted (0.9989 vs 0.9957 and 0.9947, respectively). Results were consistent when AWP was used, with fondaparinux being less expensive ($555 vs $3081 and $2187, respectively) and more effective in terms of adverse events averted (0.9989 vs 0.9957 and 0.9947, respectively). The PSA confirmed our findings using both institutional costs and AWP. In conclusion, fondaparinux subcutaneous injection afforded significant advantages in terms of cost savings and adverse events averted compared with IV argatroban or bivalirudin infusions. Our data strongly suggest potential cost savings with fondaparinux and underscore the critical need for larger clinical studies of fondaparinux in the treatment of suspected HIT. C1 [Aljabri, Ahmed; Gharaibeh, Mahdi; Kutbi, Hussam I.; Abraham, Ivo; Erstad, Brian] Univ Arizona, Ctr Hlth Outcomes & PharmacoEcon Res, Drachman Hall B-306,1295 N Martin, Tucson, AZ 85721 USA. [Aljabri, Ahmed; Kutbi, Hussam I.] King Abdulaziz Univ, Coll Pharm, Jeddah, Saudi Arabia. [Huckleberry, Yvonne] Banner Univ, Med Ctr, Tucson, AZ USA. [Karnes, Jason H.; Abraham, Ivo; Erstad, Brian] Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci, Tucson, AZ 85721 USA. [Karnes, Jason H.] Univ Arizona, Sarver Heart Ctr, Tucson, AZ USA. [Raz, Yuval] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Pulm & Crit Care, Boston, MA USA. [Yun, Seongseok] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. EM abraham@pharmacy.arizona.edu FU Futures Grant from the American College of Clinical Pharmacy Research Institute (Lenexa, KS) FX The authors thank the members of the postdoctoral fellowship programs in (1) Clinical Research in Human Therapeutics and (2) Health Outcomes, Effectiveness, and Economics Research at the University of Arizona for their comments on this study; these programs funded the work reported here. J.H.K. is supported by a Futures Grant from the American College of Clinical Pharmacy Research Institute (Lenexa, KS). NR 48 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD DEC 29 PY 2016 VL 128 IS 26 BP 3043 EP 3051 DI 10.1182/blood-2016-07-728030 PG 9 WC Hematology SC Hematology GA EI7CZ UT WOS:000392656400009 PM 27793877 ER PT J AU Moss, HE Samelson, M Mohan, G Jiang, QL AF Moss, Heather E. Samelson, Monica Mohan, Girish Jiang, Qin Li TI High and Low Contrast Visual Acuity Are Not Affected in Amyotrophic Lateral Sclerosis SO PLOS ONE LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; MULTIPLE-SCLEROSIS; INVOLVEMENT; ABNORMALITIES; DIAGNOSIS; CRITERIA; VISION; CHARTS AB The afferent visual system may be affected by neuro-degeneration in amyotrophic lateral sclerosis (ALS) based on observations of visual function impairment and retinal inclusions on histopathology in ALS patients. To test the hypothesis that visual acuity is impaired in ALS, we compared three measures of visual acuity in ALS patients (n = 25) attending a multidisciplinary ALS clinic and age matched control subjects (n = 25). Bilateral monocular and binocular visual acuities were assessed using high contrast (black letters on white background) and low contrast (2.5%, 1.25% grey letters on white background) visual acuity charts under controlled lighting conditions following refraction. Binocular summation was calculated as the difference between binocular and best monocular acuity scores. There were no associations between binocular or monocular high contrast visual acuity or low contrast visual acuity and amyotrophic lateral sclerosis diagnosis (generalized estimating equation models accounting for age). Binocular summation was similar in both amyotrophic lateral sclerosis and control subjects. There was a small magnitude association between increased duration of ALS symptoms and reduced 1.25% low contrast visual acuity. This study does not confirm prior observations of impaired visual acuity in patients with amyotrophic lateral sclerosis and does not support this particular measure of visual function for use in broad scale assessment of visual pathway involvement in ALS patients. C1 [Moss, Heather E.; Samelson, Monica; Mohan, Girish] Univ Illinois, Dept Ophthalmol & Visual Sci, Div Neuroophthalmol, Chicago, IL 60607 USA. [Moss, Heather E.; Jiang, Qin Li] Univ Illinois, Dept Neurol & Rehabil, Chicago, IL 60607 USA. [Moss, Heather E.] Stanford Univ, Dept Ophthalmol, Palo Alto, CA 94304 USA. [Samelson, Monica] Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. [Mohan, Girish] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. RP Moss, HE (reprint author), Univ Illinois, Dept Ophthalmol & Visual Sci, Div Neuroophthalmol, Chicago, IL 60607 USA.; Moss, HE (reprint author), Univ Illinois, Dept Neurol & Rehabil, Chicago, IL 60607 USA.; Moss, HE (reprint author), Stanford Univ, Dept Ophthalmol, Palo Alto, CA 94304 USA. EM hemoss@stanford.edu OI Moss, Heather/0000-0003-4373-447X FU US National Institute of Health [K12 EY02147, K23 EY 024345, UL1TR000050]; Research to Prevent Blindness FX This work was supported by the US National Institute of Health (nih.gov) grants numbered K12 EY02147, K23 EY 024345 and UL1TR000050; Research to Prevent Blindness (www.rpbusa.org) unrestricted grant to the UIC Department of Ophthalmology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 21 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 29 PY 2016 VL 11 IS 12 AR e0168714 DI 10.1371/journal.pone.0168714 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG7KQ UT WOS:000391226900038 PM 28033389 ER PT J AU Asch, DA Rosin, R AF Asch, David A. Rosin, Roy TI Engineering Social Incentives for Health SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID RANDOMIZED-TRIAL; FINANCIAL INCENTIVES C1 [Asch, David A.; Rosin, Roy] Univ Penn, Ctr Hlth Care Innovat, Philadelphia, PA 19104 USA. [Asch, David A.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equity Res & Promot, Philadelphia, PA USA. RP Asch, DA (reprint author), Univ Penn, Ctr Hlth Care Innovat, Philadelphia, PA 19104 USA.; Asch, DA (reprint author), Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equity Res & Promot, Philadelphia, PA USA. NR 5 TC 0 Z9 0 U1 4 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 29 PY 2016 VL 375 IS 26 BP 2511 EP 2513 DI 10.1056/NEJMp1603978 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EG6SC UT WOS:000391175300002 PM 28029924 ER PT J AU Kaplan, JL Rincon, SP Duhaime, AC AF Kaplan, Jess L. Rincon, Sandra P. Duhaime, Ann-Christine TI Case 40-2016: A 14-Month-Old Girl with Recurrent Vomiting SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID NORTH-AMERICAN SOCIETY; PEDIATRIC GASTROENTEROLOGY; 3RD VENTRICULOSTOMY; CHILDREN; HEPATOLOGY; DIAGNOSIS C1 [Kaplan, Jess L.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Rincon, Sandra P.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Duhaime, Ann-Christine] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Kaplan, Jess L.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Rincon, Sandra P.] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Duhaime, Ann-Christine] Harvard Med Sch, Dept Neurosurg, Boston, MA USA. RP Kaplan, JL (reprint author), Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA.; Kaplan, JL (reprint author), Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. FU Harvard Medical School Department of Continuing Education FX This case was presented at the postgraduate course, "Primary Care Pediatrics," codirected by Peter Greenspan, M.D., John Patrick T. Co, M.D., M.P.H., Ronni L. Goldsmith, M.D., Janice A. Lowe, M.D., and Benjamin A. Nelson, M.D., and sponsored by the Harvard Medical School Department of Continuing Education. NR 10 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 DEC 29 PY 2016 VL 375 IS 26 BP 2583 EP 2593 DI 10.1056/NEJMcpc1613468 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EG6SC UT WOS:000391175300013 PM 28029921 ER PT J AU Damien, P Lanham, HJ Parthasarathy, M Shah, NL AF Damien, Paul Lanham, Holly J. Parthasarathy, Murali Shah, Nikhil L. TI Assessing key cost drivers associated with caring for chronic kidney disease patients SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Chronic kidney disease; Total costs drivers; Co-morbid conditions ID STAGE RENAL-DISEASE; UNITED-STATES; HEALTH-CARE; TRADE-OFF; MEDICARE; PREVALENCE; QUALITY; PAYMENT; RATES AB Background: To examine key factors influencing chronic kidney disease (CKD) patients' total expenditure and offer recommendations on how to reduce total cost of CKD care without compromising quality. Methods: Using the 2002-2011 Medical Expenditure Panel Survey (MEPS) data, our cross-sectional study analyzed 197 patient records-79 patients with one record and 59 with two entries per patient (138 unique patients). We used three patient groups, based on international statistical classification of diseases version 9 code for condition (ICD9CODX) classification, to focus inference from the analysis: (a) non-dialysis dependent CKD, (b) dialysis and (c) transplant. Covariate information included region, demographic, co-morbid conditions and types of services. We used descriptive methods and multivariate generalized linear models to understand the impact of cost drivers. We compared actual and predicted CKD cost of care data using a hold-out sample of nine, randomly selected patients to validate the models. Results: Total costs were significantly affected by treatment type, with dialysis being significantly higher than non-dialysis and transplant groups. Costs were highest in the West region of the U.S. Average costs for patients with public insurance were significantly higher than patients with private insurance (p < .0743), and likewise, for patients with co-morbid conditions over those without co-morbid conditions (p < .001). Conclusions: Managing CKD patients both before and after the onset of dialysis treatment and managing co-morbid conditions in individuals with CKD are potential sources of substantial cost savings in the care of CKD patients. Comparing total costs pre and post the United States Affordable Care Act could provide invaluable insights into managing the cost-quality tradeoff in CKD care. C1 [Damien, Paul; Lanham, Holly J.] Univ Texas Austin, McCombs Sch Business, Austin, TX 78712 USA. [Lanham, Holly J.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Lanham, Holly J.] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Parthasarathy, Murali] Saaraa Med Solut, Whitehouse Stn, NJ USA. [Shah, Nikhil L.] Piedmont Clin, Atlanta, GA USA. [Shah, Nikhil L.] Georgia Inst Technol, Atlanta, GA 30332 USA. RP Lanham, HJ (reprint author), Univ Texas Austin, McCombs Sch Business, Austin, TX 78712 USA.; Lanham, HJ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA.; Lanham, HJ (reprint author), South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. EM lanham@uthscsa.com FU Department of Information, Risk and Operations Management at the McCombs School of Business, The University of Texas at Austin FX The Department of Information, Risk and Operations Management at the McCombs School of Business, The University of Texas at Austin provided funding for PD. NR 29 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD DEC 28 PY 2016 VL 16 AR 690 DI 10.1186/s12913-016-1922-4 PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EH6LS UT WOS:000391885200001 PM 28031020 ER PT J AU Izgu, EC Bjorkbom, A Kamat, NP Lelyveld, VS Zhang, WC Jia, TZ Szostak, JW AF Izgu, Enver Cagri Bjorkbom, Anders Kamat, Neha P. Lelyveld, Victor S. Zhang, Weicheng Jia, Tony Z. Szostak, Jack W. TI N-Carboxyanhydride-Mediated Fatty Acylation of Amino Acids and Peptides for Functionalization of Protocell Membranes SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MONOCARBOXYLIC ACIDS; PREBIOTIC FORMATION; CARBONYL SULFIDE; RNA; PROTEINS; VESICLES; MECHANISM; POLYPEPTIDES; ANHYDRIDES; GROWTH AB Early protocells are likely to have arisen from the self-assembly of RNA, peptide, and lipid molecules that were generated and concentrated within geologically favorable environments on the early Earth. The reactivity of these components in a prebiotic environment that supplied sources of chemical energy could have produced additional species with properties favorable to the emergence of protocells. The geochemically plausible activation of amino acids by carbonyl sulfide has been shown to generate short peptides via the formation of cyclic amino acid N-carboxyanhydrides (NCAs). Here, we show that the polymerization of valine-NCA in the presence of fatty acids yields acylated amino acids and peptides via a mixed anhydride intermediate. Notably, N-alpha-oleoylarginine, a product of the reaction between arginine and oleic acid in the presence of valine-NCA, partitions spontaneously into vesicle membranes and mediates the association of RNA with the vesicles. Our results suggest a potential mechanism by which activated amino acids could diversify the chemical functionality of fatty acid membranes and colocalize RNA with vesicles during the formation of early protocells. C1 [Izgu, Enver Cagri; Bjorkbom, Anders; Kamat, Neha P.; Lelyveld, Victor S.; Zhang, Weicheng; Jia, Tony Z.; Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, 185 Cambridge St, Boston, MA 02114 USA. [Izgu, Enver Cagri; Bjorkbom, Anders; Kamat, Neha P.; Lelyveld, Victor S.; Zhang, Weicheng; Jia, Tony Z.; Szostak, Jack W.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, 185 Cambridge St, Boston, MA 02114 USA. [Izgu, Enver Cagri; Bjorkbom, Anders; Kamat, Neha P.; Lelyveld, Victor S.; Zhang, Weicheng; Jia, Tony Z.; Szostak, Jack W.] Harvard Med Sch, Dept Genet, 77 Ave Louis Pasteur, Boston, MA 02115 USA. [Bjorkbom, Anders] Abo Akad Univ, Dept Biosci, FI-20520 Turku, Finland. [Zhang, Weicheng; Jia, Tony Z.; Szostak, Jack W.] Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA. [Bjorkbom, Anders] Statens Serum Inst, Artillerivej 5, DK-2300 Copenhagen S, Denmark. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, 185 Cambridge St, Boston, MA 02114 USA.; Szostak, JW (reprint author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, 185 Cambridge St, Boston, MA 02114 USA.; Szostak, JW (reprint author), Harvard Med Sch, Dept Genet, 77 Ave Louis Pasteur, Boston, MA 02115 USA.; Szostak, JW (reprint author), Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA. EM szostak@molbio.mgh.harvard.edu FU Academy of Finland; Simons Foundation [290363] FX We thank Prof. Sheref Mansy, Dr. Lijun Zhou, Dr. Li Li, and Ms. Claudia Bonfio for critical discussions and technical insights. We also thank Dr. Daniel Duzdevich for helpful comments on the manuscript. J.W.S. is an Investigator of the Howard Hughes Medical Institute. A.B. was supported by a fellowship from the Academy of Finland. This work was supported in part by a grant (290363) from the Simons Foundation to J.W.S. NR 47 TC 0 Z9 0 U1 20 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD DEC 28 PY 2016 VL 138 IS 51 BP 16669 EP 16676 DI 10.1021/jacs.6b08801 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA EG5KD UT WOS:000391081800019 PM 27959544 ER PT J AU Zhang, W Tam, CP Wang, JW Szostak, JW AF Zhang, Wen Tam, Chun Pong Wang, Jiawei Szostak, Jack W. TI Unusual Base-Pairing Interactions in Monomer-Template Complexes SO ACS CENTRAL SCIENCE LA English DT Article ID HAIRPIN OLIGONUCLEOTIDES; OLIGOGUANYLATE SYNTHESIS; DIRECTED SYNTHESIS; STRUCTURAL BASIS; RNA; BROMOTRIMETHYLSILANE; CRYSTALLOGRAPHY; OLIGOMERIZATION; NUCLEOTIDES; REPLICATION AB Many high-resolution crystal structures have contributed to our understanding of the reaction pathway for catalysis by DNA and RNA polymerases, but the structural basis of nonenzymatic template-directed RNA replication has not been studied in comparable detail. Here we present crystallographic studies of the binding of ribonucleotide monomers to RNA primer-template complexes, with the goal of improving our understanding of the mechanism of nonenzymatic RNA copying, and of catalysis by polymerases. To explore how activated ribonucleotides recognize and bind to RNA templates, we synthesized an unreactive phosphonate-linked pyrazole analogue of guanosine 5'-phosphoro-2-methylimidazolide (2-MeImpG), a highly activated nucleotide that has been used extensively to study nonenzymatic primer extension. We cocrystallized this analogue with structurally rigidified RNA primer-template complexes carrying single or multiple monomer binding sites, and obtained high-resolution X-ray structures of these complexes. In addition to Watson-Crick base pairing, we repeatedly observed noncanonical guanine: cytidine base pairs in our crystal structures. In most structures, the phosphate and leaving group moieties of the monomers were highly disordered, while in others the distance from O3' of the primer to the phosphorus of the incoming monomer was too great to allow for reaction. We suggest that these effects significantly influence the rate and fidelity of nonenzymatic RNA replication, and that even primitive ribozyme polymerases could enhance RNA replication by enforcing Watson-Crick base pairing between monomers and primer-template complexes, and by bringing the reactive functional groups into closer proximity. C1 [Zhang, Wen; Tam, Chun Pong; Szostak, Jack W.] Massachusetts Gen Hosp, Dept Mol Biol, Howard Hughes Med Inst, 185 Cambridge St, Boston, MA 02114 USA. [Zhang, Wen; Tam, Chun Pong; Szostak, Jack W.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, 185 Cambridge St, Boston, MA 02114 USA. [Zhang, Wen; Szostak, Jack W.] Harvard Med Sch, Dept Genet, 77 Ave Louis Pasteur, Boston, MA 02115 USA. [Tam, Chun Pong; Szostak, Jack W.] Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA. [Wang, Jiawei] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Howard Hughes Med Inst, 185 Cambridge St, Boston, MA 02114 USA.; Szostak, JW (reprint author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, 185 Cambridge St, Boston, MA 02114 USA.; Szostak, JW (reprint author), Harvard Med Sch, Dept Genet, 77 Ave Louis Pasteur, Boston, MA 02115 USA.; Szostak, JW (reprint author), Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA. EM szostak@molbio.mgh.harvard.edu FU DOE Office of Biological and Environmental Research; National Institutes of Health; National Institute of General Medical Sciences; Howard Hughes Medical Institute; Simons Foundation [290363] FX We thank Drs. Albert Fahrenbach, Tony Jia, Li Li, Derek O'Flaherty, Tivoli Olsen, and Lijun Zhou, as well as Travis Walton, Constantin Giurgiu, and Liuchuan Tong for helpful discussions and insightful commentaries on the manuscript. Xray diffraction data were collected at the Advanced Light Source (ALS) SIBYLS beamlines 821 and 822, a national user facility operated by Lawrence Berkeley National Laboratory on behalf of the Department of Energy, Office of Basic Energy Sciences, through the Integrated Diffraction Analysis Technologies (IDAT) program, supported by DOE Office of Biological and Environmental Research. The Berkeley Center for Structural Biology is supported in part by the National Institutes of Health, National Institute of General Medical Sciences, and the Howard Hughes Medical Institute. We thank Dr. Gabriel Birrane from the X-ray Crystallography Core, Beth Israel Deaconess Medical Center, for the use of their X-ray source and help during data collection. J.W.S. is an Investigator of the Howard Hughes Medical Institute. This work was supported in part by a grant (290363) from the Simons Foundation to J.W.S. NR 48 TC 2 Z9 2 U1 7 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2374-7943 EI 2374-7951 J9 ACS CENTRAL SCI JI ACS Central Sci. PD DEC 28 PY 2016 VL 2 IS 12 BP 916 EP 926 DI 10.1021/acscentsci.6b00278 PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA EG2HW UT WOS:000390865300009 PM 28058281 ER PT J AU Zachrison, KS Iwashyna, TJ Gebremariam, A Hutchins, M Lee, JM AF Zachrison, Kori Sauser Iwashyna, Theodore J. Gebremariam, Achamyeleh Hutchins, Meghan Lee, Joyce M. TI Can longitudinal generalized estimating equation models distinguish network influence and homophily? An agent-based modeling approach to measurement characteristics SO BMC MEDICAL RESEARCH METHODOLOGY LA English DT Article DE Network Analysis; GEE Models; Network Influence ID LARGE SOCIAL NETWORK; INSTRUMENTAL VARIABLES; DYNAMIC NETWORKS; CONTAGION; OBESITY AB Background: Connected individuals (or nodes) in a network are more likely to be similar than two randomly selected nodes due to homophily and/or network influence. Distinguishing between these two influences is an important goal in network analysis, and generalized estimating equation (GEE) analyses of longitudinal dyadic network data are an attractive approach. It is not known to what extent such regressions can accurately extract underlying data generating processes. Therefore our primary objective is to determine to what extent, and under what conditions, does the GEE-approach recreate the actual dynamics in an agent-based model. Methods: We generated simulated cohorts with pre-specified network characteristics and attachments in both static and dynamic networks, and we varied the presence of homophily and network influence. We then used statistical regression and examined the GEE model performance in each cohort to determine whether the model was able to detect the presence of homophily and network influence. Results: In cohorts with both static and dynamic networks, we find that the GEE models have excellent sensitivity and reasonable specificity for determining the presence or absence of network influence, but little ability to distinguish whether or not homophily is present. Conclusions: The GEE models are a valuable tool to examine for the presence of network influence in longitudinal data, but are quite limited with respect to homophily. C1 [Zachrison, Kori Sauser] Massachusetts Gen Hosp, Dept Emergency Med, Zero Emerson Pl Suite 3B,55 Fruit St, Boston, MA 02114 USA. [Zachrison, Kori Sauser] Harvard Med Sch, Zero Emerson Pl Suite 3B,55 Fruit St, Boston, MA 02114 USA. [Iwashyna, Theodore J.] VA HSR&D Ctr Excellence, Ann Arbor, MI USA. [Iwashyna, Theodore J.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Gebremariam, Achamyeleh; Lee, Joyce M.] Univ Michigan, Dept Pediat, Div Pediat Endocrinol, Child Hlth Evaluat & Res Unit CHEAR, Ann Arbor, MI 48109 USA. [Hutchins, Meghan] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI USA. RP Zachrison, KS (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Zero Emerson Pl Suite 3B,55 Fruit St, Boston, MA 02114 USA.; Zachrison, KS (reprint author), Harvard Med Sch, Zero Emerson Pl Suite 3B,55 Fruit St, Boston, MA 02114 USA. EM ksauser@mgh.harvard.edu FU Center for Social Epidemiology and Population Health; Clinical Sciences Scholars Program at the University of Michigan; NIH grants from NIDDK [K08DK082386]; NHLBI [K08HL091249]; AHRQ [K08HS024561] FX This work was supported by the Center for Social Epidemiology and Population Health and the Clinical Sciences Scholars Program at the University of Michigan, as well as by NIH grants from NIDDK via K08DK082386 (Dr. Lee) and from NHLBI via K08HL091249 (Dr. Iwashyna) and by AHRQ via K08HS024561 (Dr. Sauser Zachrison). NR 26 TC 0 Z9 0 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2288 J9 BMC MED RES METHODOL JI BMC Med. Res. Methodol. PD DEC 28 PY 2016 VL 16 AR 174 DI 10.1186/s12874-016-0274 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EG2XS UT WOS:000390908000001 ER PT J AU Emdin, CA Khera, AV Natarajan, P Klarin, D Won, HH Peloso, GM Stitziel, NO Nomura, A Zekavat, SM Bick, AG Gupta, N Asselta, R Duga, S Merlini, PA Correa, A Kessler, T Wilson, JG Bown, MJ Hall, AS Braund, PS Samani, NJ Schunkert, H Marrugat, J Elosua, R McPherson, R Farrall, M Watkins, H Willer, C Abecasis, GR Felix, JF Vasan, RS Lander, E Rader, DJ Danesh, J Ardissino, D Gabriel, S Saleheen, D Kathiresan, S AF Emdin, Connor A. Khera, Amit V. Natarajan, Pradeep Klarin, Derek Won, Hong-Hee Peloso, Gina M. Stitziel, Nathan O. Nomura, Akihiro Zekavat, Seyedeh M. Bick, Alexander G. Gupta, Namrata Asselta, Rosanna Duga, Stefano Merlini, Piera Angelica Correa, Adolfo Kessler, Thorsten Wilson, James G. Bown, Matthew J. Hall, Alistair S. Braund, Peter S. Samani, Nilesh J. Schunkert, Heribert Marrugat, Jaume Elosua, Roberto McPherson, Ruth Farrall, Martin Watkins, Hugh Willer, Cristen Abecasis, Goncalo R. Felix, Janine F. Vasan, Ramachandran S. Lander, Eric Rader, Daniel J. Danesh, John Ardissino, Diego Gabriel, Stacey Saleheen, Danish Kathiresan, Sekar CA CHARGE Heart Failure Consortium CARDIoGRAM Exome Consortium TI Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE coronary heart disease; genetics; phenome-wide association study; single nucleotide polymorphism ID CORONARY-HEART-DISEASE; ATHEROSCLEROSIS RISK; LARGE-SCALE; ELEVATED LIPOPROTEIN(A); CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; BIOLOGICAL PATHWAYS; GENOME-WIDE; APOLIPOPROTEIN(A); ASSOCIATION AB BACKGROUND Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose-response curve of target perturbation. OBJECTIVES The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose-response curve between genetically altered plasma Lp(a) and risk for CHD. METHODS We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD. RESULTS One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk. CONCLUSIONS Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases. (C) 2016 by the American College of Cardiology Foundation. C1 [Emdin, Connor A.; Khera, Amit V.; Natarajan, Pradeep; Klarin, Derek; Nomura, Akihiro; Zekavat, Seyedeh M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA USA. [Emdin, Connor A.; Khera, Amit V.; Natarajan, Pradeep; Klarin, Derek; Nomura, Akihiro; Zekavat, Seyedeh M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Massachusetts Gen Hosp, Boston, MA USA. [Emdin, Connor A.; Khera, Amit V.; Natarajan, Pradeep; Klarin, Derek; Peloso, Gina M.; Nomura, Akihiro; Zekavat, Seyedeh M.; Bick, Alexander G.; Gupta, Namrata; Lander, Eric; Gabriel, Stacey; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Won, Hong-Hee] Sungkyunkwan Univ, Samsung Med Ctr, Samsung Adv Inst Hlth Sci & Technol, Seoul, South Korea. [Peloso, Gina M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO USA. [Asselta, Rosanna; Duga, Stefano] Humanitas Univ, Dept Biomed Sci, Milan, Italy. [Asselta, Rosanna; Duga, Stefano] Humanitas Clin & Res Ctr, Milan, Italy. [Merlini, Piera Angelica] Osped Niguarda Ca Granda, Milan, Italy. [Correa, Adolfo] Univ Mississippi, Med Ctr, Dept Med, Jackson Heart Study, Jackson, MS 39216 USA. [Kessler, Thorsten] Tech Univ Munich, Deutsch Herzzentrum munchen, Deutsch Zentrum Herz Kreislauf Forsch, Munich, Germany. [Kessler, Thorsten] Munich Heart Alliance, Munich, Germany. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Bown, Matthew J.; Braund, Peter S.; Samani, Nilesh J.; Schunkert, Heribert] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Bown, Matthew J.; Braund, Peter S.; Samani, Nilesh J.; Schunkert, Heribert] Univ Leicester, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Hall, Alistair S.] Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Leeds, W Yorkshire, England. [Marrugat, Jaume; Elosua, Roberto] IMIM Hosp del Mar Res Inst, Cardiovasc Epidemiol & Genet, Barcelona, Spain. [McPherson, Ruth] Univ Ottawa, Inst Heart, Ottawa, ON, Canada. [Farrall, Martin; Watkins, Hugh] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England. [Farrall, Martin; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Willer, Cristen] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Willer, Cristen] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Willer, Cristen] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Abecasis, Goncalo R.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Felix, Janine F.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Vasan, Ramachandran S.] Natl Heart Lung & Blood Inst & Boston Univ Framin, Framingham, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Cardiol, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Epidemiol, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Med, Sect Cardiol, Boston, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Med, Sect Prevent Med, Boston, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Med, Sect Epidemiol, Boston, MA USA. [Rader, Daniel J.] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Danesh, John] Univ Cambridge, Publ Hlth & Primary Care, Cambridge, England. [Danesh, John] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge, England. [Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, Natl Inst Hlth Res, Blood & Transplant Res Unit Donor Hlth & Gen, Cambridge, England. [Ardissino, Diego] Univ Parma, Azienda Osped Univ Parma, Div Cardiol, Parma, Italy. [Ardissino, Diego] ASTC, Pavia, Italy. [Saleheen, Danish] Univ Penn, Perelman Sch Med, Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 185 Cambridge St,CPZN 5-252, Boston, MA 02114 USA.; Kathiresan, S (reprint author), Massachusetts Gen Hosp, Ctr Human Genet, 185 Cambridge St,CPZN 5-252, Boston, MA 02114 USA. EM skathiresan1@mgh.harvard.edu OI Watkins, Hugh/0000-0002-5287-9016 FU Spanish Ministry of Economy and Innovation through the Carlos III Health Institute (Red Investigacion Cardiovascular) [RD12/0042, PI09/90506]; European Funds for Development (ERDF-FEDER); Catalan Research and Technology Innovation Interdepartmental Commission [2014SGR240]; British Heart Foundation (British Heart Foundation Family Heart Study) [RG2000010]; British Heart Foundation (U.K. Aneurysm Growth Study) [CS/14/2/30841]; National Institute for Health Research (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Centre for Cardiovascular Science) [IS_BRU_0211_20033]; German Federal Ministry of Education and Research (BMBF); FP7 European Union project CVgenes@target [261123]; Fondation Leducq [12CVD02]; Deutsche Forschungsgemeinschaft; Programma di ricerca Regione-Universita Area 1-Strategic Programmes-Regione Emilia-Romagna; Rhodes Trust; John S. Ladue Memorial Fellowship in Cardiology; Harvard Catalyst [TR001100]; Merck; Amarin; National Research Foundation of Korea - Ministry of Science, ICT & Future Planning [2016R1C1B2007920]; National Heart, Lung, and Blood Institute of the National Institutes of Health [K01HL125751]; AstraZeneca; Regeneron; British Heart Foundation Centre of Research Excellence, Oxford [RE/13/1/30181]; Wellcome Trust [090532/Z/09/Z]; Aegerion Pharmaceuticals; Alnylam Pharmaceuticals; Eli Lilly and Company; Pfizer; Sanofi; Novartis; British Heart Foundation; BUPA Foundation; diaDexus; European Research Council; European Union; Evelyn Trust; Fogarty International Centre; GlaxoSmithKline; National Heart, Lung, and Blood Institute; National Health Service Blood and Transplant; National Institute for Health Research; National Institute of Neurological Disorders and Stroke; Roche; Takeda; Wellcome Trust, U. K.; Biobank; University of British Columbia; U. K. Medical Research Council; Boehringer Ingelheim; Johnson Johnson; Bayer; Daiichi-Sankyo; Boston Scientific; Bristol-Myers Squibb; Menarini Group; National Institutes of Health; Massachusetts General Hospital; Donovan Family Foundation; Bayer Healthcare; Leerink Partners; Noble Insights; Quest Diagnostics; Genomics PLC; [SFB 1123]; [RFPS-2007-3-644382]; [RC2 HL103010]; [RC2 HL102923]; [RC2 HL102924]; [5U54HG003067]; [K08HL114642]; [R01HL131961]; [R01 HL127564] FX The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the U.S. Department of Health and Human Services. The REGICOR study was supported by the Spanish Ministry of Economy and Innovation through the Carlos III Health Institute (Red Investigacion Cardiovascular RD12/0042, PI09/90506), European Funds for Development (ERDF-FEDER), and by the Catalan Research and Technology Innovation Interdepartmental Commission (2014SGR240). Samples for the Leicester cohort were collected as part of projects funded by the British Heart Foundation (British Heart Foundation Family Heart Study, RG2000010; U.K. Aneurysm Growth Study, CS/14/2/30841) and the National Institute for Health Research (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Centre for Cardiovascular Science, IS_BRU_0211_20033). The Munich MI Study is supported by the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed) and the FP7 European Union project CVgenes@target (261123). Additional grants were received from the Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes, 12CVD02). This study was also supported through the Deutsche Forschungsgemeinschaft cluster of excellence "Inflammation at Interfaces" and SFB 1123. The Italian Atherosclerosis, Thrombosis, and Vascular Biology (ATVB) Study was supported by a grant from RFPS-2007-3-644382 and Programma di ricerca Regione-Universita 2010-2012 Area 1-Strategic Programmes-Regione Emilia-Romagna. Funding for the exome sequencing project was provided by RC2 HL103010 (HeartGO), RC2 HL102923 (LungGO), and RC2 HL102924 (WHISP). Exome sequencing was performed through RC2 HL102925 (BroadGO) and RC2 HL102926 (SeattleGO). Exome sequencing in ATVB, PROCARDIS, Ottawa, and the Southern German Myocardial Infarction Study was supported by 5U54HG003067 (to Drs. Lander and Gabriel). For a full list of CHARGE-HF (Cohorts for Heart and Aging Research in Genomic Epidemiology-Heart Failure) working group members contributing to this work and for CHARGE-HF acknowledgements, please see PMID 20445134. Mr. Emdin is supported by the Rhodes Trust. Dr. Khera is supported by a John S. Ladue Memorial Fellowship in Cardiology and a KL2/Catalyst Medical Research Investigator Training award (an appointed KL2 award: TR001100) from Harvard Catalyst and has received consulting fees from Merck and Amarin. Dr. Won was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (2016R1C1B2007920). Dr. Peloso is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number K01HL125751. Dr. Stitziel has received funding from K08HL114642 and R01HL131961; has received a research grant from AstraZeneca; and has received consulting fees from Regeneron. Dr. Farrall has received the British Heart Foundation Centre of Research Excellence, Oxford (RE/13/1/30181), award; the Wellcome Trust core award (090532/Z/09/Z); and funding from the Wellcome Trust Institutional Support Scheme. Dr. Abecasis has served as a consultant for Regeneron. Dr.; Rader has received consulting fees from Aegerion Pharmaceuticals, Alnylam Pharmaceuticals, Eli Lilly and Company, Pfizer, Sanofi, and Novartis; is an inventor on a patent related to lomitapide that is owned by the University of Pennsylvania and licensed to Aegerion Pharmaceuticals; and is a cofounder of Vascular Strategies and Staten Biotechnology. Dr. Danesh has served as a consultant for Takeda; has been a member of the Novartis Cardiovascular & Metabolic Advisory Board, the International Cardiovascular and Metabolism Research and Development portfolio committee for Novartis, the Merck Sharp & Dohme UK Atherosclerosis Advisory Board, the Pfizer Population Research Advisory Panel, and the Sanofi Advisory Board; and has received funding from the British Heart Foundation, the BUPA Foundation, diaDexus, European Research Council, the European Union, Evelyn Trust, Fogarty International Centre, GlaxoSmithKline, Merck, the National Heart, Lung, and Blood Institute, the National Health Service Blood and Transplant, the National Institute for Health Research, the National Institute of Neurological Disorders and Stroke, Novartis, Pfizer, Roche, Sanofi, Takeda, The Wellcome Trust, U. K. Biobank, the University of British Columbia, and the U. K. Medical Research Council. Dr. Ardissino has received speaker fees from AstraZeneca, Boehringer Ingelheim, Johnson & Johnson, Bayer, Daiichi-Sankyo, GlaxoSmithKline, Eli Lilly and Company, Boston Scientific, Bristol-Myers Squibb, Menarini Group, Novartis, and Sanofi; and research grants from GlaxoSmithKline, Eli Lilly and Company, Pfizer, and Novartis. Dr. Saleheen has received grants from Pfizer, Regeneron, and the National Institutes of Health. Dr. Kathiresan is supported by a research scholar award from the Massachusetts General Hospital, the Donovan Family Foundation, and R01 HL127564; has received grants from Bayer Healthcare, Aegerion Pharmaceuticals, and Regeneron Pharmaceuticals; has received consulting fees from Merck, Novartis, Sanofi, AstraZeneca, Alnylam Pharmaceuticals, Leerink Partners, Noble Insights, Quest Diagnostics, Genomics PLC, and Eli Lilly and Company; and holds equity in San Therapeutics and Catabasis Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Emdin and Khera contributed equally to this work. NR 39 TC 2 Z9 2 U1 10 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD DEC 27 PY 2016 VL 68 IS 25 BP 2761 EP 2772 DI 10.1016/j.jacc.2016.10.033 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ1SN UT WOS:000392990600007 PM 28007139 ER PT J AU Ussher, JR Elmariah, S Gerszten, RE Dyck, JRB AF Ussher, John R. Elmariah, Sammy Gerszten, Robert E. Dyck, Jason R. B. TI The Emerging Role of Metabolomics in the Diagnosis and Prognosis of Cardiovascular Disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE diabetes mellitus; diagnostics; energy metabolism; heart failure; ischemic heart disease; obesity ID CORONARY-ARTERY-DISEASE; CHAIN AMINO-ACIDS; MAGNETIC-RESONANCE-SPECTROSCOPY; PRESERVED EJECTION FRACTION; HUMAN HEART-FAILURE; INSULIN-RESISTANCE; FAILING HEART; KETONE-BODIES; MYOCARDIAL-METABOLISM; HUMANS AB Perturbations in cardiac energy metabolism are major contributors to a number of cardiovascular pathologies. In addition, comorbidities associated with cardiovascular disease (CVD) can alter systemic and myocardial metabolism, often contributing to the worsening of cardiac function and health outcomes. State-of-the-art metabolomic technologies give us the ability to measure thousands of metabolites in biological fluids or biopsies, providing us with a metabolic fingerprint of individual patients. These metabolic profiles may serve as diagnostic and/or prognostic tools that have the potential to significantly alter the management of CVD. Herein, the authors review how metabolomics can assist in the interpretation of perturbed metabolic processes, and how this has improved our ability to understand the pathology of ischemic heart disease, atherosclerosis, and heart failure. Taken together, the integration of metabolomics with other "omics" platforms will allow us to gain insight into pathophysiological interactions of metabolites, proteins, genes, and disease states, while advancing personalized medicine. (C) 2016 by the American College of Cardiology Foundation. C1 [Ussher, John R.; Dyck, Jason R. B.] Univ Alberta, Fac Med & Dent, Mazankowski Alberta Heart Inst, Cardiovasc Res Ctr,Dept Pediat, 458 Heritage Med Res Ctr, Edmonton, AB T6G 2S2, Canada. [Ussher, John R.] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB, Canada. [Elmariah, Sammy] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA USA. [Gerszten, Robert E.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc Med, Boston, MA USA. RP Dyck, JRB (reprint author), Univ Alberta, Fac Med & Dent, Mazankowski Alberta Heart Inst, Cardiovasc Res Ctr,Dept Pediat, 458 Heritage Med Res Ctr, Edmonton, AB T6G 2S2, Canada. EM jason.dyck@ualberta.ca FU American Heart Association [4FTF20440012]; Massachusetts General Hospital Heart Center Hassenfeld Scholar Award; NIH [R01-DK081572]; Heart and Stroke Foundation of Canada; CDA; Canadian Institutes for Health Research FX Dr. Ussher is a New Investigator of the Heart and Stroke Foundation of Alberta, NWT & Nunavut, and is a Scholar of the Canadian Diabetes Association (CDA). Dr. Elmariah is supported by the American Heart Association (4FTF20440012) and by the Massachusetts General Hospital Heart Center Hassenfeld Scholar Award. Dr. Gerszten is supported by NIH grant R01-DK081572. Dr. Dyck is a Canada Research Chair in Molecular Medicine, and is supported by the Heart and Stroke Foundation of Canada, the CDA, and the Canadian Institutes for Health Research. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 84 TC 1 Z9 1 U1 11 U2 11 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 DEC 27 PY 2016 VL 68 IS 25 BP 2850 EP 2870 DI 10.1016/j.jacc.2016.09.972 PG 21 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ1SN UT WOS:000392990600014 PM 28007146 ER PT J AU Sandholm, J Lehtimaki, J Ishizu, T Velu, SE Clark, J Harkonen, P Jukkola-Vuorinen, A Schrey, A Harris, KW Tuomela, JM Selander, KS AF Sandholm, Jouko Lehtimaki, Jaakko Ishizu, Tamiko Velu, Sadanandan E. Clark, Jeremy Harkonen, Pirkko Jukkola-Vuorinen, Arja Schrey, Aleksi Harris, Kevin W. Tuomela, Johanna M. Selander, Katri S. TI Toll-like receptor 9 expression is associated with breast cancer sensitivity to the growth inhibitory effects of bisphosphonates in vitro and in vivo SO ONCOTARGET LA English DT Article DE breast cancer; bisphosphonate; biomarker; TLR9; ApppI ID NITROGEN-CONTAINING BISPHOSPHONATES; ADJUVANT ZOLEDRONIC ACID; MEVALONATE PATHWAY; NLRP3 INFLAMMASOME; CELLULAR INVASION; CELLS; MACROPHAGES; ALENDRONATE; ACTIVATION; CLODRONATE AB Bisphosphonates are standard treatments for bone metastases. When given in the adjuvant setting, they reduce breast cancer mortality and recurrence in bone but only among post-menopausal patients. Optimal drug use would require biomarker-based patient selection. Such biomarkers are not yet in clinical use. Based on the similarities in inflammatory responses to bisphosphonates and Toll-like receptor (TLR) agonists, we hypothesized that TLR9 expression may affect bisphosphonate responses in cells. We compared bisphosphonate effects in breast cancer cell lines with low or high TLR9 expression. We discovered that cells with decreased TLR9 expression are significantly more sensitive to the growth-inhibitory effects of bisphosphonates in vitro and in vivo. Furthermore, cancer growth-promoting effects seen with some bisphosphonates in some control shRNA cells were not detected in TLR9 shRNA cells. These differences were not associated with inhibition of Rap1A prenylation or p38 phosphorylation, which are known markers for bisphosphonate activity. However, TLR9 shRNA cells exhibited increased sensitivity to ApppI, a metabolite that accumulates in cells after bisphosphonate treatment. We conclude that decreased TLR9-expression sensitizes breast cancer cells to the growth inhibitory effects of bisphosphonates. Our results suggest that TLR9 should be studied as a potential biomarker for adjuvant bisphosphonate sensitivity among breast cancer patients. C1 [Sandholm, Jouko] Univ Turku, Turku Ctr Biotechnol, Cell Imaging Core, Turku, Finland. [Sandholm, Jouko] Abo Akad Univ, Turku, Finland. [Lehtimaki, Jaakko; Ishizu, Tamiko; Harkonen, Pirkko; Tuomela, Johanna M.] Univ Turku, Dept Cell Biol & Anat, Turku, Finland. [Ishizu, Tamiko] Univ Turku, Turku PET Ctr, MediCity Res Lab PET, Turku, Finland. [Velu, Sadanandan E.; Clark, Jeremy; Selander, Katri S.] Univ Alabama Birmingham, Dept Chem, Birmingham, AL 35294 USA. [Jukkola-Vuorinen, Arja] Oulu Univ Hosp, Dept Oncol, Oulu, Finland. [Schrey, Aleksi] Turku Univ Hosp, Dept Otorhinolaryngol Head & Neck Surg, Turku, Finland. [Harris, Kevin W.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Harris, Kevin W.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Harris, Kevin W.] UAB, Ctr Comprehens Canc, Birmingham, AL USA. [Selander, Katri S.] Lapland Cent Hosp, Dept Pathol, Rovaniemi, Finland. RP Selander, KS (reprint author), Univ Alabama Birmingham, Dept Chem, Birmingham, AL 35294 USA.; Selander, KS (reprint author), Lapland Cent Hosp, Dept Pathol, Rovaniemi, Finland. EM Katriselander@uabmc.edu OI Schrey, Aleksi/0000-0002-5985-0259; Tuomela, Johanna/0000-0003-4390-4563 FU DOD [W81XWH-10-1-0310, W81XWH-04-1-0479]; Jane and Aatos Erkko Foundation FX This research was funded by DOD grants W81XWH-10-1-0310 and W81XWH-04-1-0479 (K.S.S), and Jane and Aatos Erkko Foundation (J.T.). NR 65 TC 0 Z9 0 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD DEC 27 PY 2016 VL 7 IS 52 BP 87373 EP 87389 DI 10.18632/oncotarget.13570 PG 17 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EG9ZT UT WOS:000391422500136 PM 27888633 ER PT J AU Bajaj, S Housley, SN Wu, D Dhamala, M James, GA Butler, AJ AF Bajaj, Sahil Housley, Stephen N. Wu, David Dhamala, Mukesh James, G. A. Butler, Andrew J. TI Dominance of the Unaffected Hemisphere Motor Network and Its Role in the Behavior of Chronic Stroke Survivors SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE functional magnetic resonance imaging(fMRI); effective connectivity; dynamic causal modeling (DCM); motor task; stroke; affected hemisphere; unaffected hemisphere ID TEST-RETEST RELIABILITY; BAYESIAN MODEL SELECTION; FUGL-MEYER ASSESSMENT; CEREBRAL INFARCTION; FUNCTIONAL MRI; EFFECTIVE CONNECTIVITY; LONGITUDINAL FMRI; HAND MOVEMENTS; RECOVERY; ACTIVATION AB Balance of motor network activity between the two brain hemispheres after stroke is crucial for functional recovery. Several studies have extensively studied the role of the affected brain hemisphere to better understand changes in motor network activity following stroke. Very few studies have examined the role of the unaffected brain hemisphere and confirmed the testretest reliability of connectivity measures on unaffected hemisphere. We recorded blood oxygenation level dependent functional magnetic resonance imaging (fMRI) signals from nine stroke survivors with hemiparesis of the left or right hand. Participants performed a motor execution task with affected hand, unaffected hand, and both hands simultaneously. Participants returned for a repeat fMRI scan 1 week later. Using dynamic causal modeling (DCM), we evaluated effective connectivity among three motor areas: the primary motor area (M1), the premotor cortex (PMC) and the supplementary motor area for the affected and unaffected hemispheres separately. Five participants manual motor ability was assessed by Fugl-Meyer Motor Assessment scores and root-mean square error of participants tracking ability during a robot-assisted game. We found (i) that the task performance with the affected hand resulted in strengthening of the connectivity pattern for unaffected hemisphere, (ii) an identical network of the unaffected hemisphere when participants performed the task with their unaffected hand, and (iii) the pattern of directional connectivity observed in the affected hemisphere was identical for tasks using the affected hand only or both hands. Furthermore, paired t-test comparison found no significant differences in connectivity strength for any path when compared with one-week follow-up. Brain-behavior linear correlation analysis showed that the connectivity patterns in the unaffected hemisphere more accurately reflected the behavioral conditions than the connectivity patterns in the affected hemisphere. Above findings enrich our knowledge of unaffected brain hemisphere following stroke, which further strengthens our neurobiological understanding of stroke-affected brain and can help to effectively identify and apply stroke-treatments. C1 [Bajaj, Sahil; Dhamala, Mukesh] Georgia State Univ, Dept Phys & Astron, Atlanta, GA 30303 USA. [Bajaj, Sahil] Univ Arizona, Coll Med, Dept Psychiat, Tucson, AZ 85721 USA. [Housley, Stephen N.; Wu, David; Butler, Andrew J.] Georgia State Univ, Byrdine F Lewis Sch Nursing & Hlth Profess, Atlanta, GA 30303 USA. [Dhamala, Mukesh] Georgia State Univ, Ctr Diagnost & Therapeut, Ctr Nanoopt, Joint Ctr Adv Brain Imaging,Ctr Behav Neurosci, Atlanta, GA USA. [Dhamala, Mukesh; Butler, Andrew J.] Georgia State Univ, Inst Neurosci, Atlanta, GA 30303 USA. [James, G. A.] Univ Arkansas Med Sci, Inst Psychiat Res, Little Rock, AR 72205 USA. [Butler, Andrew J.] US Dept Vet Affairs, Atlanta Rehabil Res & Dev Ctr Excellence, Decatur, GA USA. RP Bajaj, S (reprint author), Georgia State Univ, Dept Phys & Astron, Atlanta, GA 30303 USA.; Bajaj, S (reprint author), Univ Arizona, Coll Med, Dept Psychiat, Tucson, AZ 85721 USA. EM sahil.neuro@gmail.com FU U.S. Department of Veterans Affairs, Rehabilitation Research & Development Service [5I21RX000561 (B7676-P)] FX This study was supported by 5I21RX000561 (B7676-P) U.S. Department of Veterans Affairs, Rehabilitation Research & Development Service to AB. The authors would also like to thank Dr. Daniel Drake and Kimberly Richards for their assistance in data collection. NR 76 TC 0 Z9 0 U1 3 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD DEC 27 PY 2016 VL 10 AR 650 DI 10.3389/fnhum.2016.00650 PG 14 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA EG0VS UT WOS:000390751000001 PM 28082882 ER PT J AU Karreci, ES Fan, H Uehara, M Mihali, AB Singh, PK Kurdi, AT Solhjou, Z Riella, LV Ghobrial, I Laragione, T Routray, S Assaker, JP Wang, R Sukenick, G Shi, L Barrat, FJ Nathan, CF Lin, G Azzi, J AF Karreci, Esilida Sula Fan, Hao Uehara, Mayuko Mihali, Albana B. Singh, Pradeep K. Kurdi, Ahmed T. Solhjou, Zhabiz Riella, Leonardo V. Ghobrial, Irene Laragione, Teresina Routray, Sujit Assaker, Jean Pierre Wang, Rong Sukenick, George Shi, Lei Barrat, Franck J. Nathan, Carl F. Lin, Gang Azzi, Jamil TI Brief treatment with a highly selective immunoproteasome inhibitor promotes long-term cardiac allograft acceptance in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE allograft; effector T cells; immunoproteasome; memory T cells; T-cell exhaustion ID T-CELL EXHAUSTION; CONSTITUTIVE PROTEASOME; HUMAN PROTEOME; INTERFERON; DEGRADATION; RECEPTORS; SUBSTRATE; DRAFT; LUPUS AB Constitutive proteasomes (c-20S) are ubiquitously expressed cellular proteases that degrade polyubiquitinated proteins and regulate cell functions. An isoform of proteasome, the immunoproteasome (i-20S), is highly expressed in human T cells, dendritic cells (DCs), and B cells, suggesting that it could be a potential target for inflammatory diseases, including those involving auto-immunity and alloimmunity. Here, we describe DPLG3, a rationally designed, noncovalent inhibitor of the immunoproteasome chymotryptic subunit beta 5i that has thousands-fold selectivity over constitutive beta 5c. DPLG3 suppressed cytokine release from blood mononuclear cells and the activation of DCs and T cells, diminished accumulation of effector T cells, promoted expression of exhaustion and coinhibitory markers on T cells, and synergized with CTLA4-Ig to promote long-term acceptance of cardiac allografts across a major histocompatibility barrier. These findings demonstrate the potential value of using brief posttransplant immunoproteasome inhibition to entrain a long-term response favorable to allograft survival as part of an immunomodulatory regimen that is neither broadly immunosuppressive nor toxic. C1 [Karreci, Esilida Sula; Uehara, Mayuko; Mihali, Albana B.; Solhjou, Zhabiz; Riella, Leonardo V.; Routray, Sujit; Assaker, Jean Pierre; Azzi, Jamil] Harvard Med Sch, Brigham & Womens Hosp, Div Renal, Transplantat Res Ctr, Boston, MA 02115 USA. [Fan, Hao; Nathan, Carl F.; Lin, Gang] Weill Cornell Med, Dept Microbiol & Immunol, New York, NY 10065 USA. [Singh, Pradeep K.] Weill Cornell Med, Dept Biochem, Milstein Chem Core Facil, New York, NY 10065 USA. [Kurdi, Ahmed T.; Ghobrial, Irene] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Laragione, Teresina; Barrat, Franck J.] Hosp Special Surg, Autoimmun & Inflammat Program, New York, NY 10021 USA. [Wang, Rong; Sukenick, George] Mem Sloan Kettering Canc Ctr, NMR Analyt Core Facil, New York, NY 10065 USA. [Shi, Lei] Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA. [Laragione, Teresina] Icahn Sch Med Mt Sinai, Dept Med, Div Rheumatol, New York, NY 10029 USA. RP Azzi, J (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Renal, Transplantat Res Ctr, Boston, MA 02115 USA.; Nathan, CF; Lin, G (reprint author), Weill Cornell Med, Dept Microbiol & Immunol, New York, NY 10065 USA. EM cnathan@med.cornell.edu; gal2005@med.cornell.edu; jazzi@rics.bwh.harvard.edu RI Singh, Pradeep/E-6481-2010 OI Singh, Pradeep/0000-0002-3570-1005 FU American Heart Association grant; Milstein Program in Translational Medicine and Chemical Biology; Alliance for Lupus Research; Daedalus Fund for Innovation at Weill Cornell Medicine; William Randolph Hearst Trust FX We thank Dr. J. David Warren at The Abby and Howard P. Milstein Synthetic Chemistry Core Facility at Weill Cornell Medicine for assistance and Drs. Jane Salmon and Xiaoping Qing at Hospital for Special Surgery for discussions. This work was supported by an American Heart Association grant (to J. A.), by the Milstein Program in Translational Medicine and Chemical Biology (C.F.N.), by the Alliance for Lupus Research (G.L.), and by the Daedalus Fund for Innovation at Weill Cornell Medicine (G.L.). The Department of Microbiology and Immunology at Weill Cornell Medicine is supported by the William Randolph Hearst Trust. NR 33 TC 0 Z9 0 U1 3 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 27 PY 2016 VL 113 IS 52 BP E8425 EP E8432 DI 10.1073/pnas.1618548114 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG5NL UT WOS:000391090800008 ER PT J AU Yang, MH Abashin, M Saisan, PA Tian, PF Ferri, CGL Devor, A Fainman, Y AF Yang, Mu-Han Abashin, Maxim Saisan, Payam A. Tian, Peifang Ferri, Christopher G. L. Devor, Anna Fainman, Yeshaiahu TI Non-degenerate 2-photon excitation in scattering medium for fluorescence microscopy SO OPTICS EXPRESS LA English DT Article ID IMAGING IN-VIVO; MULTIPHOTON MICROSCOPY; CROSS-SECTIONS; BRAIN; RESOLUTION; BEAMS; SUPERRESOLUTION; ABERRATION; NEURONS; WINDOWS AB Non-degenerate 2-photon excitation (ND-2PE) of a fluorophore with two laser beams of different photon energies offers an independent degree of freedom in tuning of the photon flux for each beam. This feature takes advantage of the infrared wavelengths used in degenerate 3-photon excitation (D-3PE) microscopy to achieve increased penetration depths, while preserving a relatively high 2-photon excitation cross section in comparison to that of D-3PE. Here, using spatially and temporally aligned Ti:Sapphire laser and optical parametric oscillator beams operating at near infrared (NIR) and short-wavelength infrared (SWIR) optical frequencies, we employ ND-2PE and provide a practical demonstration that a constant fluorophore emission intensity is achievable deeper into a scattering medium using ND-2PE as compared to the commonly used degenerate 2-photon excitation (D-2PE). (C) 2016 Optical Society of America C1 [Yang, Mu-Han; Abashin, Maxim; Fainman, Yeshaiahu] Univ Calif San Diego, Dept Elect & Comp Engn, La Jolla, CA 92093 USA. [Saisan, Payam A.; Tian, Peifang; Ferri, Christopher G. L.; Devor, Anna] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Tian, Peifang] John Carroll Univ, Dept Phys, Cleveland, OH 44118 USA. [Devor, Anna] Univ Calif San Diego, Dept Radiol, San Diego, CA 92093 USA. [Devor, Anna] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Yang, MH (reprint author), Univ Calif San Diego, Dept Elect & Comp Engn, La Jolla, CA 92093 USA. EM muy003@eng.ucsd.edu FU NIH BRAIN Initiative [U01 NS090491, R01NS057198]; UCSD Center for Brain Activity Mapping (CBAM); NSF [CBET 1445158, ECCS 1405234, ECCS 1507146]; ONR [ECE4509]; Cymer Corporation FX NIH BRAIN Initiative (U01 NS090491, R01NS057198); UCSD Center for Brain Activity Mapping (CBAM); NSF (CBET 1445158, ECCS 1405234, ECCS 1507146); ONR (ECE4509); Cymer Corporation. NR 48 TC 0 Z9 0 U1 0 U2 0 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD DEC 26 PY 2016 VL 24 IS 26 BP 30173 EP 30187 DI 10.1364/OE.24.030173 PG 15 WC Optics SC Optics GA EG1RE UT WOS:000390809100088 PM 28059294 ER PT J AU Jaff, MR Weinberg, I AF Jaff, Michael R. Weinberg, Ido TI How to Treat Critical Limb Ischemia The Critical Need for High-Grade Evidence SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material DE critical limb ischemia; gangrene; peripheral artery disease ID REVASCULARIZATION; PREVALENCE; DISEASE C1 [Jaff, Michael R.] Newton Wellesley Hosp, Dept Med, Boston, MA USA. [Weinberg, Ido] Massachusetts Gen Hosp, Fireman Vasc Ctr, Boston, MA 02114 USA. [Weinberg, Ido] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. EM mjaff@partners.org NR 11 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 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD DEC 26 PY 2016 VL 9 IS 24 BP 2566 EP 2567 DI 10.1016/j.jcin.2016.10.005 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI6QA UT WOS:000392619400015 PM 28007206 ER PT J AU Martin, MBC Santos-Lozano, A Martin-Hernandez, J Lopez-Miguel, A Maldonado, M Baladron, C Bauer, CM Merabet, LB AF Martin, Maria B. C. Santos-Lozano, Alejandro Martin-Hernandez, Juan Lopez-Miguel, Alberto Maldonado, Miguel Baladron, Carlos Bauer, Corinna M. Merabet, Lotfi B. TI Cerebral versus Ocular Visual Impairment: The Impact on Developmental Neuroplasticity SO FRONTIERS IN PSYCHOLOGY LA English DT Review DE cortical; cerebral; visual impairment; ocular blindness; connectivity ID CONGENITALLY BLIND HUMANS; PERIVENTRICULAR LEUKOMALACIA; BRAIN-INJURY; CHILDHOOD BLINDNESS; OCCIPITAL CORTEX; GESTATIONAL-AGE; CHILDREN; DISORDERS; SPECTRUM; ACTIVATION AB Cortical/cerebral visual impairment (CVI) is clinically defined as significant visual dysfunction caused by injury to visual pathways and structures occurring during early perinatal development. Depending on the location and extent of damage, children with CVI often present with a myriad of visual deficits including decreased visual acuity and impaired visual field function. Most striking, however, are impairments in visual processing and attention which have a significant impact on learning, development, and independence. Within the educational arena, current evidence suggests that strategies designed for individuals with ocular visual impairment are not effective in the case of CVI. We propose that this variance may be related to differences in compensatory neuroplasticity related to the type of visual impairment, as well as underlying alterations in brain structural connectivity. We discuss the etiology and nature of visual impairments related to CVI, and how advanced neuroimaging techniques (i.e., diffusion-based imaging) may help uncover differences between ocular and cerebral causes of visual dysfunction. Revealing these differences may help in developing future strategies for the education and rehabilitation of individuals living with visual impairment. C1 [Martin, Maria B. C.; Santos-Lozano, Alejandro; Martin-Hernandez, Juan; Baladron, Carlos] European Univ Miguel de Cervantes, GIDFYS, Valladolid, Spain. [Santos-Lozano, Alejandro] Hosp 12 Octubre I 12, Res Inst, Madrid, Spain. [Lopez-Miguel, Alberto; Maldonado, Miguel] Inst Eye, Inst Univ Oftalmobiol Aplicada, Ophthalmol, Refract Surg & Visual Rehabil, Valladolid, Spain. [Bauer, Corinna M.; Merabet, Lotfi B.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Lab Visual Neuroplast, Boston, MA USA. RP Martin, MBC (reprint author), European Univ Miguel de Cervantes, GIDFYS, Valladolid, Spain. EM lobabego@gmail.com FU NIH/NEI [RO1 EY019924]; Low Vision Research Award from Research to Prevent Blindness (RPB); Lions Clubs International Foundation (LCIF) FX This work was supported by grants from the NIH/NEI (RO1 EY019924) and the Low Vision Research Award from Research to Prevent Blindness (RPB) and the Lions Clubs International Foundation (LCIF) to LM. NR 84 TC 0 Z9 0 U1 3 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD DEC 26 PY 2016 VL 7 AR 1958 DI 10.3389/fpsyg.2016.01958 PG 9 WC Psychology, Multidisciplinary SC Psychology GA EF6FK UT WOS:000390426300001 PM 28082927 ER PT J AU Collier, JB Whitaker, RM Eblen, ST Schnellmann, RG AF Collier, Justin B. Whitaker, Ryan M. Eblen, Scott T. Schnellmann, Rick G. TI Rapid Renal Regulation of Peroxisome Proliferator-activated Receptor gamma Coactivator-1 alpha by Extracellular Signal-Regulated Kinase 1/2 in Physiological and Pathological Conditions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR RECEPTOR; ACUTE KIDNEY INJURY; FOXO TRANSCRIPTION FACTORS; MITOCHONDRIAL DYSFUNCTION; FACTOR FKHR; IN-VITRO; PHOSPHORYLATION; CELLS; TRANSACTIVATION; PGC-1-ALPHA AB Previous studies have shown that extracellular signal-regulated kinase 1/2 (ERK1/2) directly inhibits mitochondrial function during cellular injury. We evaluated the role of ERK1/2 on the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) gene, a master regulator of mitochondrial function. The potent and specific MEK1/2 inhibitor trametinib rapidly blocked ERK1/2 phosphorylation, decreased cytosolic and nuclear FOXO3a/1 phosphorylation, and increased PGC-1 alpha gene expression and its downstream mitochondrial biogenesis (MB) targets under physiological conditions in the kidney cortex and in primary renal cell cultures. The epidermal growth factor receptor (EGFR) inhibitor erlotinib blocked ERK1/2 phosphorylation and increased PGC-1 alpha gene expression similar to treatment with trametinib, linking EGFR activation and FOXO3a/1 inactivation to the down-regulation of PGC-1 alpha and MB through ERK1/2. Pretreatment with trametinib blocked early ERK1/2 phosphorylation following ischemia/reperfusion kidney injury and attenuated the downregulation of PGC-1 alpha and downstream target genes. These results demonstrate that ERK1/2 rapidly regulates mitochondrial function through a novel pathway, EGFR/ERK1/2/FOXO3a/1/PGC-1 alpha, under physiological and pathological conditions. As such, ERK1/2 down-regulates mitochondrial function directly by phosphorylation of upstream regulators of PGC-1 alpha and subsequently decreasing MB. C1 [Collier, Justin B.; Whitaker, Ryan M.; Schnellmann, Rick G.] Med Univ South Carolina, Dept Drug Discovery & Biomed Sci, Charleston, SC 29425 USA. [Eblen, Scott T.] Med Univ South Carolina, Dept Cell & Mol Pharmacol, Charleston, SC 29425 USA. [Schnellmann, Rick G.] Ralph H Johnson Vet Adm Med Ctr, Charleston, SC 29425 USA. [Collier, Justin B.; Schnellmann, Rick G.] Univ Arizona, Drachman Hall,1295 N Martin Ave,POB 210202, Tucson, AZ 85721 USA. RP Schnellmann, RG (reprint author), Univ Arizona, Drachman Hall,1295 N Martin Ave,POB 210202, Tucson, AZ 85721 USA. EM schnell@pharmacy.arizona.edu FU National Institutes of Health National Center for Research Resources [C06-RR015455] FX Animal facilities were funded by the National Institutes of Health National Center for Research Resources (Grant C06-RR015455). NR 44 TC 0 Z9 0 U1 0 U2 0 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 DEC 23 PY 2016 VL 291 IS 52 BP 26850 EP 26859 DI 10.1074/jbc.M116.754762 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EH2BE UT WOS:000391571400022 PM 27875304 ER PT J AU Inomata, T Hua, J Di Zazzo, A Dana, R AF Inomata, Takenori Hua, Jing Di Zazzo, Antonio Dana, Reza TI Impaired Function of Peripherally Induced Regulatory T Cells in Hosts at High Risk of Graft Rejection SO SCIENTIFIC REPORTS LA English DT Article ID SOLID-ORGAN TRANSPLANTATION; DRAINING LYMPH-NODES; CORNEAL TRANSPLANTATION; TGF-BETA; IMMUNE HOMEOSTASIS; AUTOIMMUNE-DISEASE; ALLOGRAFT SURVIVAL; DENDRITIC CELLS; SELF-TOLERANCE; IN-VIVO AB Regulatory T cells (Tregs) are crucial for allograft survival. Tregs can be divided into thymus-derived natural Tregs (tTregs) and peripherally-derived induced Tregs (pTregs). Here, we determine whether the suppressive function of Treg subsets is hampered in hosts who are at high risk for rejecting their graft. To induce graft beds that promote high risk of transplant rejection, intrastromal corneal sutures were placed two weeks prior to the transplant procedure in mice. We demonstrate that in high-risk recipients the frequencies and function of pTregs (but not tTregs) are suppressed. Reduced function of pTregs correlated with decreased expression of CTLA-4, interleukin-10, and transforming growth factor-beta. Adoptive transfer of pTregs from mice at low risk of subsequent graft rejection is able to rescue graft survival in recipients that are at high risk of rejecting their grafts. Our data suggest that impaired function of pTregs, but not tTregs, mediates the loss of immune tolerance and promotes allograft rejection. C1 [Inomata, Takenori; Hua, Jing; Di Zazzo, Antonio; Dana, Reza] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Dept Ophthalmol, Boston, MA 02114 USA. RP Dana, R (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Dept Ophthalmol, Boston, MA 02114 USA. EM Reza_Dana@meei.harvard.edu OI Inomata, Takenori/0000-0003-3435-1055 FU National Institutes of Health/National Eye Institute Grant [EY012963]; National Eye Institute Core Grant [P30EY003790] FX This study was supported by the National Institutes of Health/National Eye Institute Grant EY012963 (RD) and the National Eye Institute Core Grant P30EY003790. We thank Dr. Susanne Eiglmeier for assistance in preparing the manuscript. NR 40 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 23 PY 2016 VL 6 AR 39924 DI 10.1038/srep39924 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF5MY UT WOS:000390375500001 PM 28008995 ER PT J AU Cooney, JD Aguiar, RCT AF Cooney, Jeffrey D. Aguiar, Ricardo C. T. TI Phosphodiesterase 4 inhibitors have wide-ranging activity in B-cell malignancies SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NON-HODGKIN-LYMPHOMA; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; MICROVESSEL DENSITY; PDE4 INHIBITORS; TARGETING BTK; EXPRESSION; IDELALISIB; ROFLUMILAST; RECEPTOR AB Phosphodiesterase 4 (PDE4) inhibition restores the suppressive effects of 3',5'-cyclic adenosine monophosphate in lymphocytes. In this concise review, we detail how PDE4 inhibition downmodulates the B-cell receptor (BCR)-related kinases spleen tyrosine kinase and phosphatidylinositol 3-kinase and inhibits vascular endothelial growth factor A secretion by tumor cells, inducing cancer cell apoptosis and blocking angiogenesis in the microenvironment. We describe the successful clinical repurposing of PDE4 inhibitors in B-cell malignancies, and propose that given their anti-inflammatory/immunomodulatory activity, these agents will suppress BCR signals without the toxicity associated with other targeted biological doublets. C1 [Cooney, Jeffrey D.; Aguiar, Ricardo C. T.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Hematol & Med Oncol, San Antonio, TX 78229 USA. [Cooney, Jeffrey D.] Univ Texas Hlth Sci Ctr San Antonio, MD PhD Program, San Antonio, TX 78229 USA. [Aguiar, Ricardo C. T.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78284 USA. [Aguiar, Ricardo C. T.] Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA. [Aguiar, Ricardo C. T.] South Texas Vet Hlth Care Syst, Audie L Murphy Mem VA Hosp, San Antonio, TX USA. EM aguiarr@uthscsa.edu FU National Institutes of Health, National Cancer Institute [1F30CA206343-01]; Cancer Prevention and Research Institute of Texas (CPRIT) [RP15077]; Owens' Foundation; Leukemia & Lymphoma Society [TRP-6524] FX J.D.C. was supported by the National Institutes of Health, National Cancer Institute (1F30CA206343-01). R.C.T.A. was supported in part by an award from the Cancer Prevention and Research Institute of Texas (CPRIT; RP15077), the Owens' Foundation, and the Leukemia & Lymphoma Society (TRP-6524). NR 54 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD DEC 22 PY 2016 VL 128 IS 25 BP 2886 EP 2890 DI 10.1182/blood-2016-09-737676 PG 5 WC Hematology SC Hematology GA EI7CO UT WOS:000392655100007 PM 27756749 ER PT J AU Ryan, CE Sahaf, B Logan, AC O'Brien, S Byrd, JC Hillmen, P Brown, JR Dyer, MJS Mato, AR Keating, MJ Jaglowski, S Clow, F Rezvani, AR Styles, L Coutre, SE Miklos, DB AF Ryan, Christine E. Sahaf, Bita Logan, Aaron C. O'Brien, Susan Byrd, John C. Hillmen, Peter Brown, Jennifer R. Dyer, Martin J. S. Mato, Anthony R. Keating, Michael J. Jaglowski, Samantha Clow, Fong Rezvani, Andrew R. Styles, Lori Coutre, Steven E. Miklos, David B. TI Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; MINIMAL RESIDUAL DISEASE; HEMATOPOIETIC-CELL TRANSPLANTATION; BTK INHIBITOR IBRUTINIB; T-CELLS; LYMPHOMA; CLL; RESPONSES; THERAPY; BLOOD AB Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD. C1 [Ryan, Christine E.; Sahaf, Bita; Rezvani, Andrew R.; Coutre, Steven E.; Miklos, David B.] Stanford Univ, Sch Med, Stanford Canc Ctr, Stanford, CA 94305 USA. [Logan, Aaron C.] Univ Calif San Francisco, Helen Diller Comprehens Canc Ctr, San Francisco, CA 94143 USA. [O'Brien, Susan] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Byrd, John C.; Jaglowski, Samantha] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. [Hillmen, Peter] Leeds Teaching Hosp, St James Inst Oncol, Leeds, W Yorkshire, England. [Brown, Jennifer R.] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Dyer, Martin J. S.] Univ Leicester, Ernest & Helen Scott Haematol Res Inst, Leicester, Leics, England. [Mato, Anthony R.] Univ Penn, Ctr CLL, Philadelphia, PA 19104 USA. [Mato, Anthony R.] Hackensack Univ Med Ctr, Hackensack, NJ USA. [Clow, Fong; Styles, Lori] Pharmacycl LLC, Sunnyvale, CA USA. EM dmiklos@stanford.edu FU Pharmacyclics, LLC, an AbbVie Company; Pharmacyclics, LLC; National Institutes of Health National Cancer Institute [P01 CA049605]; Stanford University Cancer Institute [1P030CA124435-01]; Stanford Medical Scholars Fellowship Program FX The authors thank the patients who participated in this study, and their families, as well as all the Bone Marrow Transplant nurses, patient coordinators, and staff. The Pharmacyclics clinical trial data analysis was sponsored by Pharmacyclics, LLC, an AbbVie Company. Supriya Srinivasan provided editorial assistance, for which funding was provided by Pharmacyclics, LLC.; The Stanford work was supported by National Institutes of Health National Cancer Institute grant P01 CA049605 and Stanford University Cancer Institute-supported grant 1P030CA124435-01. D.B.M. and B.S. received research support from Pharmacyclics, LLC. C.E.R. received research support from the Stanford Medical Scholars Fellowship Program. NR 44 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD DEC 22 PY 2016 VL 128 IS 25 BP 2899 EP 2908 DI 10.1182/blood-2016-06-715284 PG 10 WC Hematology SC Hematology GA EI7CO UT WOS:000392655100009 PM 27802969 ER PT J AU Cui, B Ghia, EM Chen, LG Rassenti, LZ DeBoever, C Widhopf, GF Yu, J Neuberg, DS Wierda, WG Rai, KR Kay, NE Brown, JR Jones, JA Gribben, JG Frazer, KA Kipps, TJ AF Cui, Bing Ghia, Emanuela M. Chen, Liguang Rassenti, Laura Z. DeBoever, Christopher Widhopf, George F., II Yu, Jian Neuberg, Donna S. Wierda, William G. Rai, Kanti R. Kay, Neil E. Brown, Jennifer R. Jones, Jeffrey A. Gribben, John G. Frazer, Kelly A. Kipps, Thomas J. TI High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia SO BLOOD LA English DT Article ID RECEPTOR TYROSINE KINASE; CLL CELLS; MONOCLONAL-ANTIBODIES; CD38 EXPRESSION; MUTATION STATUS; TARGETING ROR1; OVARIAN-CANCER; B-CELLS; APOPTOSIS; CHEMOTAXIS AB ROR1 is an oncoembryonic orphan receptor found on chronic lymphocytic leukemia (CLL) B cells, but not on normal postpartum tissues. ROR1 is a receptor for Wnt5a that may complex with TCL1, a coactivator of AKT that is able to promote development of CLL. We found the CLL cells of a few patients expressed negligible ROR1 (ROR1(Neg)), but expressed TCL1A at levels comparable to those of samples that expressed ROR1 (ROR1 Pos). Transcriptome analyses revealed that ROR1(Neg) cases generally could be distinguished from those that were ROR1 Pos in unsupervised gene-expression clustering analysis. Gene-set enrichment analyses demonstrated that ROR1(Neg) CLL had lower expression and activation of AKT signaling pathways relative to ROR1 Pos CLL, similar to what was noted for leukemia that respectively developed in TCL1 vs ROR1xTCL1 transgenicmice. In contrast to its effect on ROR1 Pos CLL, Wnt5a did not enhance the proliferation, chemotaxis, or survival of ROR1(Neg) CLL. We examined the CLL cells from 1568 patients, which we randomly assigned to a training or validation set of 797 or 771 cases, respectively. Using recursive partitioning, we defined a threshold for ROR1surfaceexpressionthatcouldsegregatesamplesof thetrainingset intoROR1-Hi vsROR1-Losubgroupsthatdiffered significantly in theirmedian treatment-free survival (TFS). Using this threshold, we found thatROR1-Hi cases had a significantly shorter medianTFSandoverallsurvival thanROR1-Locasesin the validationset. Thesedatademonstrate that expressionofROR1maypromote leukemia-cell activation and survival and enhance disease progression in patients with CLL. C1 [Cui, Bing; Ghia, Emanuela M.; Chen, Liguang; Rassenti, Laura Z.; Widhopf, George F., II; Yu, Jian; Kipps, Thomas J.] Univ Calif San Diego, Dept Med, Moores Canc Ctr, San Diego, CA 92103 USA. [Cui, Bing] Chinese Acad Med Sci, Inst Mat Med, State Key Lab Bioact Substance & Funct Nat Med, Beijing, Peoples R China. [Cui, Bing] Peking Union Med Coll, Beijing, Peoples R China. [DeBoever, Christopher] Univ Calif San Diego, Bioinformat & Syst Biol, San Diego, CA 92103 USA. [Neuberg, Donna S.] Harvard Univ, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA USA. [Wierda, William G.] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Rai, Kanti R.] Hofstra North Shore Long Isl Jewish Sch Med, Dept Med, Hempstead, NY USA. [Kay, Neil E.] Mayo Clin, Div Hematol, Dept Internal Med, Rochester, MN USA. [Brown, Jennifer R.] Harvard Univ, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Jones, Jeffrey A.] Ohio State Univ, Div Hematol, Columbus, OH 43210 USA. [Jones, Jeffrey A.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Gribben, John G.] Queen Mary Univ London, Barts Canc Inst, Dept Haematooncol, London, England. [Frazer, Kelly A.] Univ Calif San Diego, Dept Pediat, Moores Canc Ctr, San Diego, CA 92103 USA. [Frazer, Kelly A.] Univ Calif San Diego, Rady Childrens Hosp, Inst Genom Med, Chron Lymphocyt Leukemia Res Consortium, San Diego, CA 92103 USA. EM tkipps@ucsd.edu OI Cui, Bing/0000-0001-8374-7801 FU CRC [PO1-CA81534)]; Blood Cancer Research Fund; University of California, San Diego (UCSD); Genetics Training Program through an institutional training grant from the National Institute of General Medical Sciences [T32GM008666]; California Institute for Regenerative Medicine Interdisciplinary Stem Cell Training Program at UCSD II [TG2-01154]; National Cancer Institute [R37-CA049870]; National Institutes of Health FX This work was supported in part by the National Institutes of Health, National Cancer Institute (grant R37-CA049870) (T.J.K.), CRC (grant PO1-CA81534) (L.Z.R. and T.J.K.), and the Blood Cancer Research Fund. C.D. is supported in part by the University of California, San Diego (UCSD), Genetics Training Program through an institutional training grant from the National Institute of General Medical Sciences (T32GM008666) and the California Institute for Regenerative Medicine Interdisciplinary Stem Cell Training Program at UCSD II (TG2-01154). NR 34 TC 1 Z9 1 U1 3 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 DEC 22 PY 2016 VL 128 IS 25 BP 2931 EP 2940 DI 10.1182/blood-2016-04712562 PG 10 WC Hematology SC Hematology GA EI7CO UT WOS:000392655100012 PM 27815263 ER PT J AU Lupo, F Tibaldi, E Matte, A Sharma, AK Brunati, AM Alper, SL Zancanaro, C Benati, D Siciliano, A Bertoldi, M Zonta, F Storch, A Walker, RH Danek, A Bader, B Hermann, A De Franceschi, L AF Lupo, Francesca Tibaldi, Elena Matte, Alessandro Sharma, Alok K. Brunati, Anna Maria Alper, Seth L. Zancanaro, Carlo Benati, Donatella Siciliano, Angela Bertoldi, Mariarita Zonta, Francesca Storch, Alexander Walker, Ruth H. Danek, Adrian Bader, Benedikt Hermann, Andreas De Franceschi, Lucia TI A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ANION TRANSPORT ACTIVITY; RED-CELLS; NEUROACANTHOCYTOSIS SYNDROMES; MITOCHONDRIAL CLEARANCE; PROTEIN-PHOSPHORYLATION; MEMBRANE ASSOCIATION; SELECTIVE AUTOPHAGY; OXIDATIVE STRESS; MOUSE MODEL AB Chorea-acanthocytosis is one of the hereditary neurodegenerative disorders known as the neuroacanthocytoses. Chorea-acanthocytosis is characterized by circulating acanthocytes deficient in chorein, a protein of unknown function. We report here for the first time that chorea-acanthocytosis red-cells are characterized by impaired autophagy, with cytoplasmic accumulation of active Lyn and of autophagy-related proteins Ulk1, Atg7. In chorea-acanthocytosis erythrocytes, active Lyn is sequestered by HSP90-70 to form high-molecular-weight complexes that stabilize and protect Lyn from its proteasomal degradation, contributing to toxic Lyn accumulation. An interplay between accumulation of active Lyn and autophagy was found in chorea-acanthocytosis based on Lyn co-immunoprecipitation with Ulk1 and Atg7 and on the presence of Ulk1 in Lyn-containing high-molecular-weight complexes. In addition, chorein associated with Atg7 in healthy but not in chorea-acanthocytosis erythrocytes. Electron-microscopic detected multivesicular bodies and membrane remnants only in circulating chorea-acanthocytosis red cells. In addition, reticulocyte-enriched chorea-acanthocytosis red cell fractions exhibited delayed clearance of mitochondria and lysosomes, further supporting the impairment of authophagic flux. Since autophagy is also important in erythropoiesis, we studied in vitro CD34(+) derived erythroid precursors. In chorea-acanthocytosis, we found (1) dyserythropoiesis; (2) increased active Lyn, (3) accumulation of, a marker of autophagic flux and autolysososme degradation; (4) accumlation of Lamp1, a lysosmal membrane protein, and LAMP1 positive aggregates; (5) reduced clearance of lysosomes and mitochondria. Our results uncover in chorea-acanthocytosis erythroid cells an association between accumulation of active Lyn and impaired autophagy, suggesting a link between chorein and autophagic vesicle trafficking in erythroid maturation. C1 [Lupo, Francesca; Matte, Alessandro; Siciliano, Angela; De Franceschi, Lucia] Univ Verona, Dept Med, Verona, Italy. [Lupo, Francesca; Matte, Alessandro; Siciliano, Angela; De Franceschi, Lucia] Azienda Osped Univ Integrata Verona, Verona, Italy. [Tibaldi, Elena; Brunati, Anna Maria; Zonta, Francesca] Univ Padua, Dept Mol Med, Padua, Italy. [Sharma, Alok K.; Alper, Seth L.] Beth Israel Deaconess Med Ctr, Div Nephrol, Boston, MA 02215 USA. [Sharma, Alok K.; Alper, Seth L.] Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Boston, MA 02215 USA. [Sharma, Alok K.; Alper, Seth L.] Harvard Med Sch, Boston, MA USA. [Zancanaro, Carlo; Benati, Donatella; Bertoldi, Mariarita] Univ Verona, Dept Neurosci Biomed & Movement, Verona, Italy. [Storch, Alexander] Tech Univ Dresden, Ctr Regenerat Therapies, Dresden, Germany. [Storch, Alexander; Hermann, Andreas] Tech Univ Dresden, Div Neurodegenerat Dis, Dept Neurol, Dresden, Germany. [Storch, Alexander] Ctr Neurodegenerat Dis, Dresden, Germany. [Walker, Ruth H.] James J Peters VA Med Ctr, Dept Neurol, Bronx, NY USA. [Walker, Ruth H.] Mt Sinai Sch Med, New York, NY USA. [Danek, Adrian; Bader, Benedikt] Ludwig Maximilians Univ Munchen, Dept Neurol, Munich, Germany. EM lucia.defranceschi@univr.it RI Danek, Adrian/G-7339-2011 OI Danek, Adrian/0000-0001-8857-5383 FU Telethon [GPP13005]; NA advocacy; Fondo Universitario di Ricerca; Federal Ministry of research and education Germany-European Multidisciplinary Initiative on Neuroacantocytosis (EMINA)-2 [ERARE12-081]; ERA-Net for Research on Rare Diseases; Doris Duke Charitable Foundation; European Agency-net E-Rare consortium EMINA [BMBF01 GM1003] FX This work was supported by Telethon grant GPP13005 (L.D.F.); an NA advocacy grant (L.D.F.); Fondo Universitario di Ricerca (L.D.F.); Federal Ministry of research and education Germany grant ERARE12-081-European Multidisciplinary Initiative on Neuroacantocytosis (EMINA)-2, under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases (A.H.); and the Doris Duke Charitable Foundation (S.L.A.). Western blot analysis of chorein was performed by G. Kwiatkowski and B. Bader, with financial support of NA advocacy and European Agency-net E-Rare consortium EMINA (BMBF01 GM1003) in the laboratories of H. Kretzschmar/A. Giese (Neuropathology) and A. Danek (Neurology) at Ludwing-Maximilians-Universitat Munich (Germany). NR 72 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD DEC 22 PY 2016 VL 128 IS 25 BP 2976 EP 2987 DI 10.1182/blood-2016-07727321 PG 12 WC Hematology SC Hematology GA EI7CO UT WOS:000392655100016 PM 27742708 ER PT J AU Ward, RE Beauchamp, MK Latham, NK Leveille, SG Percac-Lima, S Kurlinski, L Ni, PS Goldstein, R Jette, AM Bean, JF AF Ward, Rachel E. Beauchamp, Marla K. Latham, Nancy K. Leveille, Suzanne G. Percac-Lima, Sanja Kurlinski, Laura Ni, Pengsheng Goldstein, Richard Jette, Alan M. Bean, Jonathan F. TI A Novel Approach to Identifying Trajectories of Mobility Change in Older Adults SO PLoS One LA English DT Article ID LOWER-EXTREMITY FUNCTION; PHYSICAL PERFORMANCE BATTERY; CONFIDENCE ABC SCALE; MINI-MENTAL-STATE; SUBSEQUENT DISABILITY; LATE-LIFE; HEALTH; BALANCE; INDEPENDENCE; POPULATION AB Objectives To validate trajectories of late-life mobility change using a novel approach designed to overcome the constraints of modest sample size and few follow-up time points. Methods Using clinical reasoning and distribution-based methodology, we identified trajectories of mobility change (Late Life Function and Disability Instrument) across 2 years in 391 participants age >= 65 years from a prospective cohort study designed to identify modifiable impairments predictive of mobility in late-life. We validated our approach using model fit indices and comparing baseline mobility-related factors between trajectories. Results Model fit indices confirmed that the optimal number of trajectories were between 4 and 6. Mobility-related factors varied across trajectories with the most unfavorable values in poor mobility trajectories and the most favorable in high mobility trajectories. These factors included leg strength, trunk extension endurance, knee flexion range of motion, limb velocity, physical performance measures, and the number and prevalence of medical conditions including osteoarthritis and back pain. Conclusions Our findings support the validity of this approach and may facilitate the investigation of a broader scope of research questions within aging populations of varied sizes and traits. C1 [Ward, Rachel E.; Bean, Jonathan F.] Boston VA Healthcare Syst, New England GRECC, Boston, MA 02130 USA. [Ward, Rachel E.; Leveille, Suzanne G.; Percac-Lima, Sanja; Kurlinski, Laura; Goldstein, Richard; Bean, Jonathan F.] Harvard Med Sch, Cambridge, MA USA. [Ward, Rachel E.; Kurlinski, Laura; Goldstein, Richard; Bean, Jonathan F.] Spaulding Rehabil Hosp, Cambridge, MA 02138 USA. [Beauchamp, Marla K.] McMaster Univ, Sch Rehabil Sci, Hamilton, ON, Canada. [Latham, Nancy K.; Ni, Pengsheng; Jette, Alan M.] Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, Boston, MA USA. [Leveille, Suzanne G.] Univ Massachusetts, Coll Nursing & Hlth Sci, Boston, MA 02125 USA. [Percac-Lima, Sanja] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ward, RE (reprint author), Boston VA Healthcare Syst, New England GRECC, Boston, MA 02130 USA.; Ward, RE (reprint author), Harvard Med Sch, Cambridge, MA USA.; Ward, RE (reprint author), Spaulding Rehabil Hosp, Cambridge, MA 02138 USA. EM reward@partners.org RI Bean, Jonathan/F-5798-2017 OI Bean, Jonathan/0000-0001-8385-8210 FU National Institute on Aging [R01 AG032052-03]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [1K24HD070966-01]; National Center for Research Resources [1 UL1 RR025758-01]; National Institute on Disability, Independent Living, and Rehabilitation Research [H133P120001]; Canadian Institutes of Health Research FX This work was supported by the National Institute on Aging (R01 AG032052-03, https://www.nia.nih.gov/); the Eunice Kennedy Shriver National Institute of Child Health and Human Development (1K24HD070966-01 to JFB, https://www.nichd.nih.gov/Pages/index.aspx); and the National Center for Research Resources in a grant to the Harvard Clinical and Translational Science Center (1 UL1 RR025758-01, http://sdminutes.cit.nih.gov/about/almanac/organization/NCRR.htm). REW is supported by the National Institute on Disability, Independent Living, and Rehabilitation Research (H133P120001, http://www.acl.gov/programs/NIDILRR/). MKB is supported by a fellowship from the Canadian Institutes of Health Research (http://cihr-irsc.gc.ca/e/193.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 0 Z9 0 U1 1 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 DEC 22 PY 2016 VL 11 IS 12 AR e0169003 DI 10.1371/journal.pone.0169003 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI9QH UT WOS:000392843200121 PM 28006024 ER PT J AU Pavasini, R Guralnik, J Brown, JC di Bari, M Cesari, M Landi, F Vaes, B Legrand, D Verghese, J Wang, CL Stenholm, S Ferrucci, L Lai, JC Bartes, AA Espaulella, J Ferrer, M Lim, JY Ensrud, KE Cawthon, P Turusheva, A Frolova, E Rolland, Y Lauwers, V Corsonello, A Kirk, GD Ferrari, R Volpato, S Campo, G AF Pavasini, Rita Guralnik, Jack Brown, Justin C. di Bari, Mauro Cesari, Matteo Landi, Francesco Vaes, Bert Legrand, Delphine Verghese, Joe Wang, Cuiling Stenholm, Sari Ferrucci, Luigi Lai, Jennifer C. Arnau Bartes, Anna Espaulella, Joan Ferrer, Montserrat Lim, Jae-Young Ensrud, Kristine E. Cawthon, Peggy Turusheva, Anna Frolova, Elena Rolland, Yves Lauwers, Valerie Corsonello, Andrea Kirk, Gregory D. Ferrari, Roberto Volpato, Stefano Campo, Gianluca TI Short Physical Performance Battery and all-cause mortality: systematic review and meta-analysis SO BMC MEDICINE LA English DT Review DE Short Physical Performance Battery; All-cause mortality; Physical function; Meta-analysis ID LOWER-EXTREMITY PERFORMANCE; LOWER-LIMB FUNCTION; OLDER-ADULTS; MOBILITY DISABILITY; MUSCLE STRENGTH; HEART-FAILURE; FRAILTY; HOSPITALIZATION; PREDICTORS; SURVIVAL AB Background: The Short Physical Performance Battery (SPPB) is a well-established tool to assess lower extremity physical performance status. Its predictive ability for all-cause mortality has been sparsely reported, but with conflicting results in different subsets of participants. The aim of this study was to perform a meta-analysis investigating the relationship between SPPB score and all-cause mortality. Methods: Articles were searched in MEDLINE, the Cochrane Library, Google Scholar, and BioMed Central between July and September 2015 and updated in January 2016. Inclusion criteria were observational studies; > 50 participants; stratification of population according to SPPB value; data on all-cause mortality; English language publications. Twenty-four articles were selected from available evidence. Data of interest (i.e., clinical characteristics, information after stratification of the sample into four SPPB groups [0-3, 4-6, 7-9, 10-12]) were retrieved from the articles and/or obtained by the study authors. The odds ratio (OR) and/or hazard ratio (HR) was obtained for all-cause mortality according to SPPB category (with SPPB scores 10-12 considered as reference) with adjustment for age, sex, and body mass index. Results: Standardized data were obtained for 17 studies (n = 16,534, mean age 76 +/- 3 years). As compared to SPPB scores 10-12, values of 0-3 (OR 3.25, 95% CI 2.86-3.79), 4-6 (OR 2.14, 95% CI 1.92-2.39), and 7-9 (OR 1.50, 95% CI 1. 32-1.71) were each associated with an increased risk of all-cause mortality. The association between poor performance on SPPB and all-cause mortality remained highly consistent independent of follow-up length, subsets of participants, geographic area, and age of the population. Random effects meta-regression showed that OR for all-cause mortality with SPPB values 7-9 was higher in the younger population, diabetics, and men. Conclusions: An SPPB score lower than 10 is predictive of all-cause mortality. The systematic implementation of the SPPB in clinical practice settings may provide useful prognostic information about the risk of all-cause mortality. Moreover, the SPPB could be used as a surrogate endpoint of all-cause mortality in trials needing to quantify benefit and health improvements of specific treatments or rehabilitation programs. C1 [Pavasini, Rita; Ferrari, Roberto; Campo, Gianluca] Univ S Anna, Azienda Osped, Cardiol Unit, Via Aldo Moro 8, I-44124 Ferrara, Italy. [Guralnik, Jack] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Brown, Justin C.] Dana Farber Canc Inst, Dept Med Oncol, Div Populat Sci, Boston, MA 02115 USA. [di Bari, Mauro] Univ Florence, Dept Crit Care Med & Surg, Unit Gerontol & Geriatr Med, Florence, Italy. [di Bari, Mauro] Univ Careggi, Azienda Osped, Florence, Italy. [Cesari, Matteo; Rolland, Yves] Ctr Hosp Univ Toulouse, Gerontopole, Toulouse, France. [Cesari, Matteo; Rolland, Yves] Univ Toulouse III Paul Sabatier, INSERM UMR1027, Toulouse, France. [Landi, Francesco] Univ Cattolica Sacro Cuore, Dept Geriatr Neurosci & Orthopaed, Rome, Italy. [Vaes, Bert] Catholic Univ Louvain, Inst Hlth & Soc, Brussels, Belgium. [Vaes, Bert] Katholieke Univ Leuven, Dept Publ Hlth & Primary Care, Leuven, Belgium. [Legrand, Delphine; Turusheva, Anna] Catholic Univ Louvain, Inst Rech Sante & Soc, Brussels, Belgium. [Verghese, Joe] Albert Einstein Coll Med, Dept Neurol & Med, Bronx, NY 10467 USA. [Wang, Cuiling] Albert Einstein Coll Med, Dept Epidemiol, Bronx, NY 10467 USA. [Stenholm, Sari] Univ Turku, Dept Publ Hlth, Turku, Finland. [Ferrucci, Luigi] Harbor Hosp, NIA, Longitudinal Studies Sect, Clin Res Branch,NIA ASTRA Unit, Baltimore, MD USA. [Lai, Jennifer C.] Univ Calif San Francisco, Dept Med, Div Gastroenterol & Hepatol, San Francisco, CA USA. [Arnau Bartes, Anna] Althaia Xarxa Assistencial Univ Manresa, Clin Res Unit, Manresa, Barcelona, Spain. [Espaulella, Joan] Hosp Univ Santa Creu, Serv Geriatria & Cures Palliat, Vic, Barcelona, Spain. [Ferrer, Montserrat] Hosp del Mar, Med Res Inst, IMIM, Hlth Serv Res Grp, Barcelona, Spain. [Ferrer, Montserrat] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain. [Lim, Jae-Young] Seoul Natl Univ, Seoul Natl Univ Bundang Hosp, Coll Med, Dept Rehabil Med, Seongnam, Gyeonggi, South Korea. [Ensrud, Kristine E.] Univ Minnesota, Med & Epidemiol & Community Hlth, Minneapolis, MN USA. [Ensrud, Kristine E.] Minneapolis VA Hlth Care Syst, Gen Internal Med, Minneapolis, MN USA. [Cawthon, Peggy] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Frolova, Elena] North Western State Med Univ, Dept Family Med, St Petersburg, Russia. [Lauwers, Valerie] Fac Med, Lab Epidemiol & Sante Commun, Unite Inserm 558, Allees Jules Guesde, Toulouse, France. [Corsonello, Andrea] Res Hosp Cosenza, INRCA, Unit Geriatr Pharmacoepidemiol, Cosenza, Italy. [Kirk, Gregory D.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Kirk, Gregory D.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Ferrari, Roberto] Maria Cecilia Hosp, ES Hlth Sci Fdn, GVM Care & Res, Cotignola, Italy. [Volpato, Stefano] Univ Ferrara, Dept Med Sci, Sect Internal & Cardiorespiratory Med, Ferrara, Italy. RP Pavasini, R (reprint author), Univ S Anna, Azienda Osped, Cardiol Unit, Via Aldo Moro 8, I-44124 Ferrara, Italy. EM pvsrti@unife.it RI Cesari, Matteo/A-4649-2008; OI Cesari, Matteo/0000-0002-0348-3664; ARNAU, ANNA/0000-0001-8939-3469; Frolova, Elena/0000-0002-5569-5175 FU Fondation Louvain [B40320084685]; US National Institute on Aging [P01 AGO3949, R01 AGO25119]; National Institute on Aging [P01 AGO3949, R01 AG039330, R01 AGO44007, AGO44829, R01 AG036921, R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576]; Fund for Health Research of Spain [PI042370]; European Regional Development Fund (FEDER); National Institutes of Health [U01-DA-036297, R01-DA-04334, R01-DA-12568, RC1-AI-086053, K24-AI118591]; Russian Federation [192-RP] FX B. Vaes and D. Legrand participated in the BELFRAIL study (B40320084685), which was supported by an unconditional grant from the Fondation Louvain. The Fondation Louvain is the support unit of the Universite catholique de Louvain and is charged with developing the educational and research projects of the university by collecting gifts from corporations, foundations, and alumni.; J. Verghese participated in The Einstein Aging Study, which was supported by US National Institute on Aging grants (P01 AGO3949 and R01 AGO25119). Dr. Verghese received funding support from National Institute on Aging grants (R01 AG039330, R01 AGO44007, AGO44829, and R01 AG036921). C. Wang received funding support from National Institute on Aging grants (P01 AGO3949, R01 AG039330, R01 AGO44007, AGO44829, and R01 AG036921).; A. Arnau Bartes received a grant from the Fund for Health Research of Spain (PI042370) and the European Regional Development Fund (FEDER). K. Ensrud and P. Cawthon participated in the Study of Osteoporotic Fractures (SOF), which is supported by National Institutes of Health funding. The National Institute on Aging provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576.; A. Turusheva and E. Frolova received a Grant of the President of the Russian Federation (grant 192-RP) and the Foundation Louvain.; G. Kirk participated in the AIDS Linked to the IntraVenous Experience (ALIVE) study, which was supported by the National Institutes of Health (grants U01-DA-036297, R01-DA-04334, R01-DA-12568, RC1-AI-086053, and K24-AI118591). NR 41 TC 0 Z9 0 U1 8 U2 8 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 DEC 22 PY 2016 VL 14 AR 215 DI 10.1186/s12916-016-0763-7 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EG5FX UT WOS:000391070100001 PM 28003033 ER PT J AU Lee, REC Qasaimeh, MA Xia, XF Juncker, D Gaudet, S AF Lee, Robin E. C. Qasaimeh, Mohammad A. Xia, Xianfang Juncker, David Gaudet, Suzanne TI NF-kappa B signalling and cell fate decisions in response to a short pulse of tumour necrosis factor SO SCIENTIFIC REPORTS LA English DT Article ID TNF-ALPHA; GENE-EXPRESSION; SINGLE CELLS; CASPASE-8 EXPRESSION; MEDIATED APOPTOSIS; CANCER-PATIENTS; PHASE-I; RECEPTOR; DEATH; TRANSCRIPTION AB In tissues and tumours, cell behaviours are regulated by multiple time-varying signals. While in the laboratory cells are often exposed to a stimulus for the duration of the experiment, in vivo exposures may be much shorter. In this study, we monitored NF-kappa B and caspase signalling in human cancer cells treated with a short pulse of Tumour Necrosis Factor (TNF). TNF is an inflammatory cytokine that can induce both the pro-survival NF-kappa B-driven gene transcription pathway and the pro-apoptotic caspase pathway. We find that a few seconds of exposure to TNF is sufficient to activate the NF-kappa B pathway in HeLa cells and induce apoptotic cell death in both HeLa and Kym-1 cells. Strikingly, a 1-min pulse of TNF can be more effective at killing than a 1-hour pulse, indicating that in addition to TNF concentration, duration of exposure also coordinates cell fate decisions. C1 [Lee, Robin E. C.; Qasaimeh, Mohammad A.; Xia, Xianfang; Gaudet, Suzanne] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Lee, Robin E. C.; Qasaimeh, Mohammad A.; Xia, Xianfang; Gaudet, Suzanne] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA. [Lee, Robin E. C.; Qasaimeh, Mohammad A.; Xia, Xianfang; Gaudet, Suzanne] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Qasaimeh, Mohammad A.; Juncker, David] McGill Univ, Biomed Engn Dept, Montreal, PQ H3A 2B4, Canada. [Juncker, David] McGill Univ, Montreal, PQ H3A 0G1, Canada. [Juncker, David] Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada. [Juncker, David] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada. [Lee, Robin E. C.] Univ Pittsburgh, Sch Med, Dept Computat & Syst Biol, Pittsburgh, PA 15260 USA. [Qasaimeh, Mohammad A.] New York Univ Abu Dhabi, Div Engn, POB 129188, Abu Dhabi, U Arab Emirates. RP Gaudet, S (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.; Gaudet, S (reprint author), Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA.; Gaudet, S (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. EM Suzanne_Gaudet@dfci.harvard.edu FU NIH [CA139980, R01-GM104247]; Barr investigator award; NSERC; CIHR; FQRNT (International Training Scholarship); McGill Faculty of Medicine International Travel Award FX We thank Matthew S. Owen and Colin T. Waters for advice on the manuscript and many helpful discussions, Kate Savery for technical assistance and the Harvard Medical School Quad Machine Shop for assistance in designing a custom device holder for microscopy. This work was funded by NIH grants CA139980 and R01-GM104247, and a Barr investigator award to SG. DJ acknowledges a Canada Research Chair and funding from NSERC and CIHR. SG is a Kimmel Scholar, RECL is a CIHR research fellow and MAQ acknowledges the FQRNT (International Training Scholarship), The Center for Biorecognition and Biosensors (CBB), and McGill Faculty of Medicine International Travel Award and he is an Alexander Graham Bell NSERC Fellow. NR 56 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 22 PY 2016 VL 6 AR 39519 DI 10.1038/srep39519 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF4OI UT WOS:000390309100001 PM 28004761 ER PT J AU Hong, TS Gray, PJ Allen, JN Shellito, PC Lowry, KP Zukerberg, LR AF Hong, Theodore S. Gray, Phillip J. Allen, Jill N. Shellito, Paul C. Lowry, Kathryn P. Zukerberg, Lawrence R. TI Case 39-2016: A 74-Year-Old Man with Rectal Bleeding and a History of Prostate Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS; RANDOMIZED-TRIAL; RADIOTHERAPY; CHEMOTHERAPY; RADIATION; RISK; CHEMORADIATION; BRACHYTHERAPY; MITOMYCIN C1 [Hong, Theodore S.; Gray, Phillip J.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Allen, Jill N.] Massachusetts Gen Hosp, Dept Hematol, Boston, MA 02114 USA. [Shellito, Paul C.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Lowry, Kathryn P.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Zukerberg, Lawrence R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hong, Theodore S.; Gray, Phillip J.] Harvard Med Sch, Dept Radiat Oncol, Boston, MA 02115 USA. [Allen, Jill N.] Harvard Med Sch, Dept Hematol, Boston, MA 02115 USA. [Shellito, Paul C.] Harvard Med Sch, Dept Surg, Boston, MA 02115 USA. [Lowry, Kathryn P.] Harvard Med Sch, Dept Radiol, Boston, MA 02115 USA. [Zukerberg, Lawrence R.] Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA. RP Hong, TS (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA.; Hong, TS (reprint author), Harvard Med Sch, Dept Radiat Oncol, Boston, MA 02115 USA. NR 16 TC 0 Z9 0 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 22 PY 2016 VL 375 IS 25 BP 2481 EP 2488 DI 10.1056/NEJMcpc1613458 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA EF1NL UT WOS:000390091500012 PM 28002705 ER PT J AU Zhang, Q Shi, LL Ravella, KC Koh, JL Wang, SB Liu, CL Li, GA Wang, JH AF Zhang, Qiang Shi, Lewis L. Ravella, Krishna C. Koh, Jason L. Wang, Shaobai Liu, Cailong Li, Guoan Wang, Jianhua TI Distinct Proximal Humeral Geometry in Chinese Population and Clinical Relevance SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID TOTAL SHOULDER ARTHROPLASTY; PROSTHETIC DESIGN; 3-DIMENSIONAL ANALYSIS; SURGICAL TECHNIQUE; MR ARTHROGRAPHY; GLENOID CAVITY; HEAD; RETROVERSION; REPLACEMENT; CURVATURE AB Background: Replicating humeral anatomy during shoulder arthroplasty is important for good patient outcomes. The proximal humeral geometry of the Chinese population has been rarely reported. We analyzed the geometry of the proximal part of the humerus in Chinese subjects and compared it with that of Western populations and the dimensions of available prostheses. Methods: Eighty healthy Chinese subjects underwent computed tomography (CT)-arthrography. Three-dimensional (3D) digital humeral and glenoid models were reconstructed, and geometric parameters were measured. Humeral measurements included the radius of curvature, articular surface diameter and thickness, anterior-posterior/superior-inferior (AP/SI) articular surface diameter ratio, articular surface thickness/radius of curvature ratio, surface arc, inclination angle, retroversion angle, and medial and posterior offsets. Glenoid measurements included SI length, AP length, SI radius, and AP radius. Results: The average radius of curvature (and standard deviation) of the humeral head was 22.1 +/- 1.9 mm, the articular surface diameter averaged 42.9 +/- 3.6 mm, and the articular surface thickness averaged 16.9 +/- 1.5 mm. There was strong linear correlation between the articular surface diameter and thickness (r(2) = 0.696, p = 0.001), with a linear regression relationship of thickness = 0.357 x diameter + 1.615. The AP/SI articular surface diameter ratio averaged 0.93 +/- 0.03; the articular surface thickness/radius of curvature ratio, 0.77 +/- 0.05; the surface arc, 153 degrees +/- 5.6 degrees; the inclination angle, 133 degrees +/- 3.1 degrees; and the retroversion angle, 22.6 degrees +/- 10.2 degrees. The medial and posterior offsets averaged 6.3 +/- 0.9 mm and 0.4 +/- 0.78 mm, respectively; the SI and AP lengths, 30.15 +/- 3.70 mm and 20.35 +/- 2.56 mm; and the SI and AP radii, 23.49 +/- 2.48 mm and 25.54 +/- 3.07 mm. Compared with the Western population, the Chinese cohort had a smaller radius of curvature (p < 0.001), smaller articular surface diameter (p = 0.009), larger articular surface thickness/ radius of curvature ratio (p < 0.001), larger surface arc (p < 0.001), smaller inclination angle (p < 0.001), and smaller posterior offset (p < 0.001). Unlike the Western population, the Chinese population had higher glenohumeral conformity in the coronal plane than in the axial plane. Many manufacturers' shoulder prostheses do not adequately cover the range of humeral head dimensions in our Chinese cohort. Conclusions: The geometric parameters of the humeri in the Chinese population differ from those in other populations. These differences have clinical relevance with regard to implant design and arthroplasty technique and likely affect clinical outcomes. C1 [Zhang, Qiang; Shi, Lewis L.; Ravella, Krishna C.; Koh, Jason L.; Wang, Shaobai; Liu, Cailong; Li, Guoan; Wang, Jianhua] Shanghai Jiao Tong Univ, Sch Med, Xin Hua Hosp, Shanghai, Peoples R China. [Zhang, Qiang; Liu, Cailong; Wang, Jianhua] Shanghai Jiao Tong Univ, Sch Med, Dept Orthopaed Surg, Xin Hua Hosp, Shanghai, Peoples R China. [Shi, Lewis L.; Ravella, Krishna C.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Koh, Jason L.] NorthShore Univ HealthSyst, Dept Orthopaed Surg, Evanston, IL USA. [Wang, Shaobai; Li, Guoan] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Wang, JH (reprint author), Shanghai Jiao Tong Univ, Sch Med, Xin Hua Hosp, Shanghai, Peoples R China.; Wang, JH (reprint author), Shanghai Jiao Tong Univ, Sch Med, Dept Orthopaed Surg, Xin Hua Hosp, Shanghai, Peoples R China. EM shwangjianhua@gmail.com FU National Natural Science Foundation of China [81171706]; Shanghai Municipal Natural Science Foundation [11ZR1427400] FX Funding from the National Natural Science Foundation of China (81171706) and Shanghai Municipal Natural Science Foundation (11ZR1427400) supported this research. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article. NR 31 TC 0 Z9 0 U1 0 U2 0 PU JOURNAL BONE JOINT SURGERY PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02492 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD DEC 21 PY 2016 VL 98 IS 24 BP 2071 EP 2081 DI 10.2106/JBJS.15.01232 PG 11 WC Orthopedics; Surgery SC Orthopedics; Surgery GA EN4AO UT WOS:000395949800011 PM 28002370 ER PT J AU Eisen, A Cannon, CP Blazing, MA Bohula, EA Park, JG Murphy, SA White, JA Giugliano, RP Braunwald, E AF Eisen, Alon Cannon, Christopher P. Blazing, Michael A. Bohula, Erin A. Park, Jeong-Gun Murphy, Sabina A. White, Jennifer A. Giugliano, Robert P. Braunwald, Eugene CA IMPROVE-IT IMProved Reduction TI The benefit of adding ezetimibe to statin therapy in patients with prior coronary artery bypass graft surgery and acute coronary syndrome in the IMPROVE-IT trial SO EUROPEAN HEART JOURNAL LA English DT Article DE coronary artery bypass graft; ezetimibe; statin; acute coronary syndrome; cardiovascular events ID MYOCARDIAL-INFARCTION; UNSTABLE ANGINA; PLAQUE REGRESSION; OUTCOMES; ATORVASTATIN; INTERVENTION; INHIBITION; REDUCTION; STRATEGY AB Aims To examine the efficacy and safety of ezetimibe added to statin in patients with prior coronary artery bypass graft surgery (CABG) following hospitalization for an acute coronary syndrome (ACS). Methods and results In the IMPROVE-IT trial, post-ACS patients with mean low density lipoprotein cholesterol (LDL-C) of 93.8 mg/dL at presentation were randomized to simvastatin/ezetimibe or simvastatin/placebo. The primary endpoint was cardiovascular death, major coronary event or stroke, and the median follow-up was 6 years. Efficacy and safety endpoints were examined by prior CABG status. Among 18 134 patients, 1684 (9.3%) had a prior CABG (median age 69 years, 82% male). During the trial, the median time-weighted LDL-C level was 55.0 mg/dL with simvastatin/ezetimibe vs. 69.9 mg/dL with simvastatin/placebo in patients with prior CABG (P < 0.001), and it was 53.6 mg/dL vs. 69.5 mg/dL, respectively, in patients without prior CABG (P < 0.001). The rate of the primary endpoint was higher in patients with vs. without prior CABG [56% vs. 32%, adj. hazard ratio 1.45, 95% confidence interval (CI) 1.33-1.58]. Patients with prior CABG receiving simvastatin/ezetimibe had an 8.8% (95% CI 3.1-14.6%) lower absolute risk over simvastatin/placebo in the primary endpoint, whereas patients without prior CABG had a 1.3% (95% CI 0-2.6%) lower absolute risk (P-interaction = 0.02). There were no between-group significant differences in safety endpoints. Conclusion The clinical benefit of adding ezetimibe to statin appears to be enhanced in patients with prior CABG, supporting the use of intensive lipid lowering therapy in these high-risk patients following ACS. C1 [Eisen, Alon; Cannon, Christopher P.; Bohula, Erin A.; Park, Jeong-Gun; Murphy, Sabina A.; Giugliano, Robert P.; Braunwald, Eugene] Brigham & Womens Hosp, Cardiovasc Div, TIMI Study Grp, 350 Longwood Ave,1st Floor Off, Boston, MA 02115 USA. [Eisen, Alon; Cannon, Christopher P.; Bohula, Erin A.; Park, Jeong-Gun; Murphy, Sabina A.; Giugliano, Robert P.; Braunwald, Eugene] Harvard Med Sch, 350 Longwood Ave,1st Floor Off, Boston, MA 02115 USA. [Blazing, Michael A.; White, Jennifer A.] Duke Clin Res Inst, Durham, NC USA. RP Braunwald, E (reprint author), Brigham & Womens Hosp, Cardiovasc Div, TIMI Study Grp, 350 Longwood Ave,1st Floor Off, Boston, MA 02115 USA.; Braunwald, E (reprint author), Harvard Med Sch, 350 Longwood Ave,1st Floor Off, Boston, MA 02115 USA. EM ebraunwald@partners.org FU Merck FX The IMPROVE-IT trial was supported by Merck. NR 23 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD DEC 21 PY 2016 VL 37 IS 48 BP 3576 EP 3584 DI 10.1093/eurheartj/ehw377 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EK5YP UT WOS:000394002400011 PM 27569841 ER PT J AU Rittiner, JE Caffall, ZF Hernandez-Martinez, R Sanderson, SM Pearson, JL Tsukayama, KK Liu, AY Xiao, CR Tracy, S Shipman, MK Hickey, P Johnson, J Scott, B Stacy, M Saunders-Pullman, R Bressman, S Simonyan, K Sharma, N Ozelius, LJ Cirulli, ET Calakos, N AF Rittiner, Joseph E. Caffall, Zachary F. Hernandez-Martinez, Ricardo Sanderson, Sydney M. Pearson, James L. Tsukayama, Kaylin K. Liu, Anna Y. Xiao, Changrui Tracy, Samantha Shipman, Miranda K. Hickey, Patrick Johnson, Julia Scott, Burton Stacy, Mark Saunders-Pullman, Rachel Bressman, Susan Simonyan, Kristina Sharma, Nutan Ozelius, Laurie J. Cirulli, Elizabeth T. Calakos, Nicole TI Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2 alpha Signaling as a Generalizable Mechanism for Dystonia SO NEURON LA English DT Article ID ONSET TORSION DYSTONIA; ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; TERM SYNAPTIC PLASTICITY; KNOCK-IN MOUSE; NUCLEAR-ENVELOPE; DYT1 DYSTONIA; TRANSLATIONAL CONTROL; MUTANT TORSINA; SECRETORY PATHWAY AB Dystonia is a brain disorder causing involuntary, often painful movements. Apart from a role for dopamine deficiency in some forms, the cellular mechanisms underlying most dystonias are currently unknown. Here, we discover a role for deficient eIF2 alpha signaling in DYT1 dystonia, a rare inherited generalized form, through a genome-wide RNAi screen. Subsequent experiments including patient-derived cells and a mouse model support both a pathogenic role and therapeutic potential for eIF2 alpha pathway perturbations. We further find genetic and functional evidence supporting similar pathway impairment in patients with sporadic cervical dystonia, due to rare coding variation in the eIF2 alpha effector ATF4. Considering also that another dystonia, DYT16, involves a gene upstream of the eIF2 alpha pathway, these results mechanistically link multiple forms of dystonia and put forth a new overall cellular mechanism for dystonia pathogenesis, impairment of eIF2 alpha signaling, a pathway known for its roles in cellular stress responses and synaptic plasticity. C1 [Rittiner, Joseph E.; Caffall, Zachary F.; Hernandez-Martinez, Ricardo; Sanderson, Sydney M.; Tsukayama, Kaylin K.; Liu, Anna Y.; Xiao, Changrui; Tracy, Samantha; Shipman, Miranda K.; Hickey, Patrick; Johnson, Julia; Scott, Burton; Stacy, Mark; Calakos, Nicole] Duke Univ, Dept Neurol, Durham, NC 27708 USA. [Calakos, Nicole] Duke Univ, Dept Neurobiol, Durham, NC 27708 USA. [Pearson, James L.; Cirulli, Elizabeth T.] Duke Univ, Dept Mol Genet & Microbiol, Durham, NC 27708 USA. [Pearson, James L.] Duke Univ, Dept RNAi Screening Facil, Durham, NC 27708 USA. [Cirulli, Elizabeth T.] Duke Univ, Ctr Appl Genom & Precis Med, Durham, NC 27708 USA. [Saunders-Pullman, Rachel; Bressman, Susan] Mt Sinai Beth Israel Med Ctr, Dept Neurol, New York, NY 10003 USA. [Saunders-Pullman, Rachel; Bressman, Susan; Simonyan, Kristina] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Simonyan, Kristina] Icahn Sch Med Mt Sinai, Dept Otolaryngol, New York, NY 10029 USA. [Sharma, Nutan; Ozelius, Laurie J.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02114 USA. [Sharma, Nutan; Ozelius, Laurie J.] Harvard Med Sch, Boston, MA 02115 USA. RP Calakos, N (reprint author), Duke Univ, Dept Neurol, Durham, NC 27708 USA.; Calakos, N (reprint author), Duke Univ, Dept Neurobiol, Durham, NC 27708 USA. EM nicole.calakos@dm.duke.edu FU Tyler's Hope Foundation for a Dystonia Cure; Bachmann Strauss Parkinson Dystonia Center of Excellence; Duke University School of Medicine; [NS079860]; [NS051156]; [NS095653]; [GM007105]; [R01DC011805]; [R01NS088160]; [R56AI098588]; [RC2NS070342]; [UO1AIO67854] FX The authors wish to thank: Drs. Xandra Breakefield and Flavia Nery for advice on the luciferase secretion assay; Dr. William Dauer for sharing cDNA, DYT1 knockin mouse lines, and insightful discussions; Dr. Takashi Kudo for providing BiX; Dr. So Young Kim for high-content imaging expertise; Dr. David Corcoran for bioinformatics and microarray expertise; Drs. Chris Nicchitta and Dennis Thiele for insightful discussions and critical reading of the manuscript; Jessi Cruger for technical laboratory assistance; the Tyler's Hope Foundation for a Dystonia Cure, Bachmann Strauss Parkinson Dystonia Center of Excellence, and Duke University School of Medicine for critical financial support (N.C.); and foremost, the many individuals who participated in the clinical research that enabled these studies. This work was funded in part by NS079860 (N.C.), NS051156 and NS095653 (J.E.R.), GM007105 (S.M.S.), R01DC011805 and R01NS088160 (collection of dystonia patient DNA samples by K.S.), and R56AI098588, RC2NS070342, and UO1AIO67854 (collection of exome sequencing control samples). NR 71 TC 1 Z9 1 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD DEC 21 PY 2016 VL 92 IS 6 BP 1238 EP 1251 DI 10.1016/j.neuron.2016.11.012 PG 14 WC Neurosciences SC Neurosciences & Neurology GA EJ3MV UT WOS:000393117200013 PM 27939583 ER PT J AU Cai, XL Zhang, CJ Lim, FTW Chan, SJ Bandla, A Chuan, CK Hu, F Xu, SD Thakor, NV Liao, LD Liu, B AF Cai, Xiaolei Zhang, Chong-Jing Lim, Frances Ting Wei Chan, Su Jing Bandla, Aishwarya Chuan, Chan Kim Hu, Fang Xu, Shidang Thakor, Nitish V. Liao, Lun-De Liu, Bin TI Organic Nanoparticles with Aggregation-Induced Emission for Bone Marrow Stromal Cell Tracking in a Rat PTI Model SO SMALL LA English DT Article ID MESENCHYMAL STEM-CELLS; ACUTE ISCHEMIC-STROKE; IN-VIVO; SECONDARY PREVENTION; THERAPEUTIC BENEFIT; CANCER-CELLS; DOTS; VITRO; INFARCTION; BIOPROBE AB Stem-cell based therapy is an emerging therapeutic approach for ischemic stroke treatment. Bone marrow stromal cells (BMSCs) are in common use as a cell source for stem cell therapy and show promising therapeutic outcomes for stroke treatment. One challenge is to develop a reliable tracking strategy to monitor the fate of BMSCs and assess their therapeutic effects in order to improve the success rate of such treatment. Herein, TPEEP, a fluorogen with aggregation-induced emission characteristics and near-infrared emission are designed and synthesized and further fabricated into organic nanoparticles (NPs). The obtained NPs show high fluorescence quantum yield, low cytotoxicity with good physical and photostability, which display excellent tracking performance of BMSCs in vitro and in vivo. Using a rat photothrombotic ischemia model as an example, the NP-labeled BMSCs are able to migrate to the stroke lesion site to yield bright red fluorescence. Immunofluorescence staining shows that the NP labeling does not affect the normal function of BMSCs, proving their good biocompatibility in vivo. These merits make TPEEP NP a potential cell tracker to evaluate the fate of BMSCs in cell therapy. C1 [Cai, Xiaolei; Zhang, Chong-Jing; Hu, Fang; Xu, Shidang; Liu, Bin] Natl Univ Singapore, Dept Biomol & Chem Engn, 4 Engn Dr 4, Singapore 117585, Singapore. [Cai, Xiaolei] Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, 28 Med Dr,05-01, Singapore 117456, Singapore. [Lim, Frances Ting Wei; Bandla, Aishwarya; Chuan, Chan Kim; Thakor, Nitish V.; Liao, Lun-De] Natl Univ Singapore, Singapore Inst Neurotechnol SINAPSE, 28 Med Dr, Singapore 117456, Singapore. [Chan, Su Jing] Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Radiol, Charlestown, MA USA. [Chan, Su Jing] Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Neurol, Charlestown, MA USA. [Chan, Su Jing] Harvard Med Sch, Charlestown, MA USA. [Liao, Lun-De] Natl Hlth Res Inst, Inst Biomed Engn & Nanomed, 35 Keyan Rd, Zhunan Town 35053, Miaoli County, Taiwan. RP Liu, B (reprint author), Natl Univ Singapore, Dept Biomol & Chem Engn, 4 Engn Dr 4, Singapore 117585, Singapore.; Liao, LD (reprint author), Natl Univ Singapore, Singapore Inst Neurotechnol SINAPSE, 28 Med Dr, Singapore 117456, Singapore.; Liao, LD (reprint author), Natl Hlth Res Inst, Inst Biomed Engn & Nanomed, 35 Keyan Rd, Zhunan Town 35053, Miaoli County, Taiwan. EM ldliao@nhri.org.tw; cheliub@nus.edu.sg OI Bandla, Aishwarya/0000-0002-6705-1318 FU Singapore National Research Foundation [R279-000-444-281]; Institute of Materials Research and Engineering of Singapore [IMRE/14-8P1110] FX X.C., C.-J.Z., and F.T.W.L. contributed equally to this work. The authors thank the Singapore National Research Foundation (R279-000-444-281) and Institute of Materials Research and Engineering of Singapore (IMRE/14-8P1110) for financial support. The authors declare no competing financial interest. NR 49 TC 1 Z9 1 U1 3 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1613-6810 EI 1613-6829 J9 SMALL JI Small PD DEC 21 PY 2016 VL 12 IS 47 BP 6576 EP 6585 DI 10.1002/smll.201601630 PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EJ4XN UT WOS:000393220700014 PM 27592863 ER PT J AU Forcino, RC Bustamante, N Thompson, R Percac-Lima, S Elwyn, G Perez-Arechaederra, D Barr, PJ AF Forcino, Rachel C. Bustamante, Nitzy Thompson, Rachel Percac-Lima, Sanja Elwyn, Glyn Perez-Arechaederra, Diana Barr, Paul J. TI Developing and Pilot Testing a Spanish Translation of CollaboRATE for Use in the United States SO PLoS One LA English DT Article ID SHARED DECISION-MAKING; CROSS-CULTURAL ADAPTATION; HEALTH-CARE; LANGUAGE BARRIERS; COMMUNICATION; SATISFACTION; DISPARITIES; ETHNICITY; PHYSICIAN; SPEAKING AB Background/Aim Given the need for access to patient-facing materials in multiple languages, this study aimed to develop and pilot test an accurate and understandable translation of CollaboRATE, a three-item patient-reported measure of shared decision-making, for Spanish-speaking patients in the United States (US). Method We followed the Translate, Review, Adjudicate, Pre-test, Document (TRAPD) survey translation protocol. Cognitive interviews were conducted with Spanish-speaking adults within an urban Massachusetts internal medicine clinic. For the pilot test, all patients with weekday appointments between May 1 and May 29, 2015 were invited to complete CollaboRATE in either English or Spanish upon exit. We calculated the proportion of respondents giving the best score possible on CollaboRATE and compared scores across key patient subgroups. Results Four rounds of cognitive interviews with 26 people were completed between January and April 2015. Extensive, iterative refinements to survey items between interview rounds led to final items that were generally understood by participants with diverse educational backgrounds. Pilot data collection achieved an overall response rate of 73 percent, with 606 (49%) patients completing Spanish CollaboRATE questionnaires and 624 (51%) patients completing English CollaboRATE questionnaires. The proportion of respondents giving the best score possible on CollaboRATE was the same (86%) for both the English and Spanish versions of the instrument. Discussion Our translation method, guided by emerging best practices in survey and health measurement translation, encompassed multiple levels of review. By conducting four rounds of cognitive interviews with iterative item refinement between each round, we arrived at a Spanish language version of CollaboRATE that was understandable to a majority of cognitive interview participants and was completed by more than 600 pilot questionnaire respondents. C1 [Forcino, Rachel C.; Thompson, Rachel; Elwyn, Glyn; Barr, Paul J.] Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH 03766 USA. [Bustamante, Nitzy; Percac-Lima, Sanja] Harvard Med Sch, Boston, MA USA. [Percac-Lima, Sanja] Massachusetts Gen Hosp, Chelsea HealthCare Ctr, Chelsea, MA USA. [Perez-Arechaederra, Diana] Biomed Res Inst Salamanca IBSAL, Primary Care Res Unit, Alamedilla Hlth Ctr, Salamanca, Spain. [Perez-Arechaederra, Diana] Ctr Univ San Rafael Nebrija, Madrid, Spain. RP Barr, PJ (reprint author), Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH 03766 USA. EM paul.j.barr@dartmouth.edu FU Gordon and Betty Moore Foundation [3929]; Regional Health Management of the Castilla and Leon, Spain [BIO/SA02/15] FX The Gordon and Betty Moore Foundation (httos://www.moore.org/) funded this study (#3929). This work was also supported by a grant from the Regional Health Management of the Castilla and Leon, Spain (BIO/SA02/15). NR 27 TC 0 Z9 0 U1 1 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 DEC 21 PY 2016 VL 11 IS 12 AR e0168538 DI 10.1371/journal.pone.0168538 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI9TW UT WOS:000392853100050 PM 28002422 ER PT J AU Magnotti, EL Hughes, SA Dillard, RS Wang, SY Hough, L Karumbamkandathil, A Lian, TQ Wall, JS Zuo, XB Wright, ER Conticello, VP AF Magnotti, Elizabeth L. Hughes, Spencer A. Dillard, Rebecca S. Wang, Shengyuan Hough, Lillian Karumbamkandathil, Arshad Lian, Tianquan Wall, Joseph S. Zuo, Xiaobing Wright, Elizabeth R. Conticello, Vincent P. TI Self-Assembly of an alpha-Helical Peptide into a Crystalline Two-Dimensional Nanoporous Framework SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID SUPRAMOLECULAR ORGANIC FRAMEWORK; ANGSTROM RESOLUTION STRUCTURE; PACKING ANGLE PREFERENCES; COILED-COIL ASSEMBLIES; COMPUTATIONAL DESIGN; PROTEIN NANOMATERIALS; DIMERIZATION DOMAIN; COMPLEX NANOSHEET; ATP SYNTHASE; SHEETS AB Sequence-specific peptides have been demonstrated to self-assemble into structurally defined nanoscale objects including nanofibers, nanotubes, and nanosheets. The latter structures display significant promise for the construction of hybrid materials for functional devices due to their extended planar geometry. Realization of this objective necessitates the ability to control the structural features of the resultant assemblies through the peptide sequence. The design of a amphiphilic peptide, 3FD-IL, is described that comprises two repeats of a canonical 18 amino acid sequence associated with straight a-helical structures. Peptide 3FD-IL displays 3-fold screw symmetry in a helical conformation and self-assembles into nanosheets based on hexagonal packing of helices. Biophysical evidence from TEM, cryo-TEM, SAXS, AFM, and STEM measurements on the 3FD-IL nanosheets support a structural model based on a honeycomb lattice, in which the length of the peptide determines the thickness of the nanosheet and the packing of helices defines the presence of nanoscale channels that permeate the sheet. The honeycomb structure can be rationalized on the basis of geometrical packing frustration in which the channels occupy defect sites that define a periodic superlattice. The resultant 2D materials may have potential as materials for nanoscale transport and controlled release applications. C1 [Magnotti, Elizabeth L.; Hughes, Spencer A.; Wang, Shengyuan; Hough, Lillian; Karumbamkandathil, Arshad; Lian, Tianquan; Conticello, Vincent P.] Emory Univ, Dept Chem, Atlanta, GA 30322 USA. [Dillard, Rebecca S.; Wright, Elizabeth R.] Emory Univ, Sch Med, Dept Pediat, Childrens Healthcare Atlanta, Atlanta, GA 30322 USA. [Wall, Joseph S.] Brookhaven Natl Lab, POB 5000, Upton, NY 11973 USA. [Zuo, Xiaobing] Argonne Natl Lab, Xray Sci Div, 9700 South Cass Ave, Argonne, IL 60439 USA. [Magnotti, Elizabeth L.] Harvard Med Sch, Dept Canc Immunol & Virol, Dana Farber Canc Inst, Dept Med, 450 Brookline Ave, Boston, MA 02215 USA. RP Conticello, VP (reprint author), Emory Univ, Dept Chem, Atlanta, GA 30322 USA. EM vcontic@emory.edu FU National Science Foundation [0923395, CHE-1309817]; National Institutes of Health [S10 RR025679]; Robert P. Apkarian Integrated Electron Microscopy Core (RPAIEMC); Emory College of Arts and Sciences; Emory University School of Medicine; National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR000454]; U.S. D.O.E. Office of Basic Energy Sciences, Division of Material Sciences [W-31-109-Eng-38]; NSF [CHE-1012620, CHE-1412580]; Emory University; Children's Healthcare of Atlanta; Georgia Research Alliance; Center for AIDS Research at Emory University [P30 AI050409]; James B. Pendleton Charitable Trust; NIH [R01GM104540] FX The electron microscopy data described here were gathered on either a JEOL JEM-2200FS 200 kV TEM (supported by a National Science Foundation Major Research Instrumentation Grant 0923395) or on a JEOL JEM-1400 120 kV TEM (supported by a National Institutes of Health Grant S10 RR025679). This study was supported in part by the Robert P. Apkarian Integrated Electron Microscopy Core (RPAIEMC), which is subsidized by the Emory College of Arts and Sciences and the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR000454. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. This work benefited from the use of the A.P.S. funded by U.S. D.O.E. Office of Basic Energy Sciences, Division of Material Sciences, under contract W-31-109-Eng-38. We acknowledge the assistance of Dr. Anil Mehta for the construction of the molecular model of the honeycomb structure. V.P.C. acknowledges financial support from NSF grants CHE-1012620 and CHE-1412580. T.L. acknowledges the financial support from the National Science Foundation (CHE-1309817). E.R.W. acknowledges support from Emory University, Children's Healthcare of Atlanta, the Georgia Research Alliance, the Center for AIDS Research at Emory University (P30 AI050409), the James B. Pendleton Charitable Trust, and NIH grant R01GM104540. NR 79 TC 0 Z9 0 U1 34 U2 34 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD DEC 21 PY 2016 VL 138 IS 50 BP 16274 EP 16282 DI 10.1021/jacs.6b06592 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA EG0NM UT WOS:000390729500021 PM 27936625 ER PT J AU Benmansour, S Arroyo, LD Frazer, A AF Benmansour, Saloua Arroyo, Luis D. Frazer, Alan TI Comparison of the Antidepressant-Like Effects of Estradiol and That of Selective Serotonin Reuptake Inhibitors in Middle-Aged Ovariectomized Rats SO FRONTIERS IN AGING NEUROSCIENCE LA English DT Article DE middle age; OVX rats; estradiol; SSRI; FST; SERT function; critical period ID ESTROGEN-RECEPTOR-ALPHA; LATE-LIFE DEPRESSION; POSTMENOPAUSAL WOMEN; FEMALE RATS; HUMAN-BRAIN; MENOPAUSAL TRANSITION; CONTROLLED-TRIAL; CREB PHOSPHORYLATION; IMIPRAMINE BINDING; ALZHEIMERS-DISEASE AB This study investigated the effect of age and that of the post-ovariectomy (OVX) time interval on the antidepressant (AD)-like effects of estradiol (E-2) and selective serotonin reuptake inhibitors (SSR1s) in middle-aged (10 month) OVX rats (10m-OVX). Acute or chronic effects of these treatments in 10m-OVX were compared with those (1) in young adult (4-month) OVX rats (4m-OVX) or with older (14-month) OVX rats (14m-OVX), at a short time: 2 weeks post-OVX (+2w) and (2) in 10m-OVX rats after a longer times: 4 or 8 months post-OVX (+4m or +8m). Using in vivo chronoamperometry in the CA3 region of the hippocampus. E-2 at 20 pmol, a dose shown previously to inhibit the serotonin transporter (SERT) in 4m-OVX, had no effect in 10m-OVX+2w. A higher dose of E-2 (40 pmol) increased T80 value, a measure of serotonin or 5-hydroxytryptamine (5 HT) clearance, and also blocked the ability of fluvoxamine to increase T80. By contrast, estradiol had no effects on SERT function in 10m-OVX+4m, even at a higher dose than 40 pmol. Fluvoxamine slowed 5-HT clearance in 10m-OVX at +2w, +4m and +8m post-OVX as it did in the 4m-OVX. Using the forced swim test, 2 weeks treatment with E-2 (5 mu g/day), a dose shown previously to induce AD-like effects in 4m-OVX, had no effect in 10m-OVX+2w. However, a higher dose (10 mu g/day) of E-2 induced an AD-like effect as demonstrated by significantly increased swimming behavior and decreased immobility. This effect was not seen in 10m-OVX+4m. By contrast, significant AD-like effects were obtained in 14m-OVX+2w, thereby demonstrating that the lack of an AD effect of E-2 is due to the 4-month hormone withdrawal and not to an age effect. After 2 weeks treatment with the SSRI sertraline, similar AD-like effects were obtained in 10m-OVX tested at +2w, +4m or +8m post-OVX as those found in 4m-OVX. Thus, the potency of estradiol to produce effects consistent with inhibition of the SERT was not only decreased in older rats but its effects were markedly diminished the longer hormonal depletion occurred. By contrast, the ability of SSRIs to inhibit the SERT was not affected either by age or the length of hormonal depletion. C1 [Benmansour, Saloua; Arroyo, Luis D.; Frazer, Alan] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Frazer, Alan] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Benmansour, S (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. EM benmansour@uthscsa.edu FU NARSAD; Department of Veterans Affairs FX This research was supported by funds from NARSAD and the Department of Veterans Affairs. NR 88 TC 0 Z9 0 U1 1 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1663-4365 J9 FRONT AGING NEUROSCI JI Front. Aging Neurosci. PD DEC 21 PY 2016 VL 8 AR 311 DI 10.3380/fnagi.2016.00311 PG 13 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA EF2JF UT WOS:000390150000001 PM 28066235 ER PT J AU Sitek, A AF Sitek, Arkadiusz TI Comment on 'Imaging of prompt gamma rays emitted during delivery of clinical proton beams with a Compton camera: feasibility studies for range verification' SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Editorial Material DE proton therapy; image reconstruction; origin ensemble; statistics ID EMISSION-TOMOGRAPHY; RECONSTRUCTION AB The origin ensemble (OE) algorithm is a new method used for image reconstruction from nuclear tomographic data. The main advantage of this algorithm is the ease of implementation for complex tomographic models and the sound statistical theory. In this comment, the author provides the basics of the statistical interpretation of OE and gives suggestions for the improvement of the algorithm in the application to prompt gamma imaging as described in Polf et al (2015 Phys. Med. Biol. 60 7085). C1 [Sitek, Arkadiusz] Harvard Med Sch, Massachusetts Gen Hosp, Gordon Ctr Med Imaging, 55 Fruit St, Boston, MA 02114 USA. RP Sitek, A (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Gordon Ctr Med Imaging, 55 Fruit St, Boston, MA 02114 USA. EM sarkadiu@gmail.com NR 10 TC 0 Z9 0 U1 0 U2 0 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD DEC 21 PY 2016 VL 61 IS 24 BP 8941 EP 8944 DI 10.1088/1361-6560/61/24/8941 PG 4 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA EF4ZF UT WOS:000390339800006 PM 27910819 ER PT J AU Hao, Y Yasmin-Karim, S Moreau, M Sinha, N Sajo, E Ngwa, W AF Hao, Yao Yasmin-Karim, Sayeda Moreau, Michele Sinha, Neeharika Sajo, Erno Ngwa, Wilfred TI Enhancing radiotherapy for lung cancer using immunoadjuvants delivered in situ from new design radiotherapy biomaterials: a preclinical study SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE abscopal effect; SBRT; nanoparticles; immunoadjuvants; multifunctional radiotherapy biomaterials ID GOLD NANOPARTICLES; SOLID TUMORS; CTLA-4 BLOCKADE; PROSTATE-CANCER; LOCAL RADIATION; THERAPY; IMMUNOTHERAPY; ANTIBODY; GUIDANCE; ANTI-CTLA-4 AB Studies show that radiotherapy of a primary tumor in combination with immunoadjuvants (IA) can result in increased survival or immune-mediated regression of metastasis outside the radiation field, a phenomenon known as abscopal effect. However, toxicities due to repeated systematic administration of IA have been shown to be a major obstacle in clinical trials. To minimize the toxicities and prime a more potent immune response, Ngwa et al have proposed that inert radiotherapy biomaterials such as fiducials could be upgraded to multifunctional ones loaded with IA for in situ delivery directly into the tumor sub-volume at no additional inconvenience to patients. In this preliminary study, the potential of such an approach is investigated for lung cancer using anti-CD40 antibody. First the benefit of using the anti-CD40 delivered in situ to enhance radiotherapy was tested in mice with subcutaneous tumors generated with the Lewis Lung cancer cell line LL/2 (LLC-1). The tumors were implanted on both flanks of the mice to simulate metastasis. Tumors on one flank were treated with and without anti-CD40 and the survival benefits compared. An experimentally determined in vivo diffusion coefficient for nanoparticles was then employed to estimate the time for achieving intratumoral distribution of the needed minimal concentrations of anti-CD40 nanoparticles if released from a multifuntional radiotherapy biomaterials. The studies show that the use of anti-CD40 significantly enhanced radiotherapy effect, slowing the growth of the treated and untreated tumors, and increasing survival. Meanwhile our calculations indicate that for a 2-4 cm tumor and 7 mg g(-1) IA concentrations, it would take 4.4-17.4 d, respectively, following burst release, for the required concentration of IA nanoparticles to accumulate throughout the tumor during image-guided radiotherapy. The distribution of IA could be customized as a function of loading concentrations or nanoparticle size to fit current Stereotactic Body Radiotherapy schedules. Overall, the preliminary results support ongoing work in developing multifunctional radiotherapy biomaterials for in situ delivery of immunoadjuvants such as anti-CD40 to leverage the abscopal effect, while minimizing systemic toxicities. The potential of extending such an approach to other cancer types is discussed. C1 [Hao, Yao; Moreau, Michele; Sajo, Erno; Ngwa, Wilfred] Univ Massachusetts, Dept Phys & Appl Phys, Lowell, MA 01854 USA. [Yasmin-Karim, Sayeda; Ngwa, Wilfred] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. [Yasmin-Karim, Sayeda; Ngwa, Wilfred] Harvard Med Sch, Boston, MA 02115 USA. [Sinha, Neeharika] Wentworth Inst Technol, Dept Sci, Boston, MA USA. RP Ngwa, W (reprint author), Univ Massachusetts, Dept Phys & Appl Phys, Lowell, MA 01854 USA.; Ngwa, W (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA.; Ngwa, W (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM wngwa@lroc.harvard.edu FU BWH Biomedical Research Institute; National Institutes of Health National Cancer Institute [1 K01 CA172478-01] FX The authors acknowledge funding support from BWH Biomedical Research Institute and National Institutes of Health National Cancer Institute grant 1 K01 CA172478-01. NR 41 TC 1 Z9 1 U1 12 U2 12 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD DEC 21 PY 2016 VL 61 IS 24 DI 10.1088/1361-6560/61/24/N697 PG 11 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA EF4ZK UT WOS:000390340300001 ER PT J AU Bility, MT Nio, K Li, F McGivern, DR Lemon, SM Feeney, ER Chung, RT Su, LS AF Bility, Moses T. Nio, Kouki Li, Feng McGivern, David R. Lemon, Stanley M. Feeney, Eoin R. Chung, Raymond T. Su, Lishan TI Chronic hepatitis C infection-induced liver fibrogenesis is associated with M2 macrophage activation SO SCIENTIFIC REPORTS LA English DT Article ID VIRUS-INFECTIONS; SOLUBLE CD163; FIBROSIS; CELLS; INTERLEUKIN-12; MONOCYTES; RESPONSES AB The immuno-pathogenic mechanisms of chronic hepatitis C virus (HCV) infection remain to be elucidated and pose a major hurdle in treating or preventing chronic HCV-induced advanced liver diseases such as cirrhosis. Macrophages are a major component of the inflammatory milieu in chronic HCV-induced liver disease, and are generally derived from circulating inflammatory monocytes; however very little is known about their role in liver diseases. To investigate the activation and role of macrophages in chronic HCV-induced liver fibrosis, we utilized a recently developed humanized mouse model with autologous human immune and liver cells, human liver and blood samples and cell culture models of monocyte/macrophage and/or hepatic stellate cell activation. We showed that M2 macrophage activation was associated with liver fibrosis during chronic HCV infection in the livers of both humanized mice and patients, and direct-acting antiviral therapy attenuated M2 macrophage activation and associated liver fibrosis. We demonstrated that supernatant from HCV-infected liver cells activated human monocytes/macrophages with M2-like phenotypes. Importantly, HCV-activated monocytes/macrophages promoted hepatic stellate cell activation. These results suggest a critical role for M2 macrophage induction in chronic HCV-associated immune dysregulation and liver fibrosis. C1 [Bility, Moses T.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Infect Dis & Microbiol, Pittsburgh, PA 15261 USA. [Nio, Kouki; Li, Feng; McGivern, David R.; Lemon, Stanley M.; Su, Lishan] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27514 USA. [Nio, Kouki; Li, Feng; McGivern, David R.; Lemon, Stanley M.; Su, Lishan] Univ North Carolina Chapel Hill, Dept Microbiol & Immunol, Chapel Hill, NC 27514 USA. [Lemon, Stanley M.] Univ North Carolina Chapel Hill, Div Infect Dis, Dept Med, Chapel Hill, NC USA. [Feeney, Eoin R.] Univ Coll Dublin, Dublin, Ireland. [Feeney, Eoin R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chung, Raymond T.] Harvard Med Sch, Boston, MA USA. RP Bility, MT (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Infect Dis & Microbiol, Pittsburgh, PA 15261 USA.; Su, LS (reprint author), Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27514 USA.; Su, LS (reprint author), Univ North Carolina Chapel Hill, Dept Microbiol & Immunol, Chapel Hill, NC 27514 USA. EM mtbility@upitt.edu; lsu@med.unc.edu FU UNC UCRF innovation grant; NIH: UNC SPORE grants [AI076142, AA018009, R01CA164029-04, R01AI095690-05, DK098079, DK108370]; Harvard University CFAR [5P30AI060354-09, R21AI115207-01A1]; UNC Lineberger Comprehensive Cancer Center; UNC Infectious Disease Pathogenesis Postdoctoral Training Grants; [P30 AI50410/UNC CFAR] FX This work was supported in part by grants from UNC UCRF innovation grant, from NIH: UNC SPORE grants, AI076142, AA018009, R01CA164029-04 (L. S.), R01CA164029-04, R01AI095690-05 (S.M.L.), DK098079, DK108370 (RTC), Harvard University CFAR 5P30AI060354-09 (E.R.F), R21AI115207-01A1 (D.R.M), and UNC Lineberger Comprehensive Cancer Center and UNC Infectious Disease Pathogenesis Postdoctoral Training Grants and P30 AI50410/UNC CFAR Administrative Supplement (M.T.B.). NR 31 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 21 PY 2016 VL 6 AR 39520 DI 10.1038/srep39520 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF4LK UT WOS:000390298400001 PM 28000758 ER PT J AU Kim, RS Hasegawa, D Goossens, N Tsuchida, T Athwal, V Sun, XC Robinson, CL Bhattacharya, D Chou, HI Zhang, DY Fuchs, BC Lee, YM Hoshida, Y Friedman, SL AF Kim, Rosa S. Hasegawa, Daisuke Goossens, Nicolas Tsuchida, Takuma Athwal, Varinder Sun, Xiaochen Robinson, Christopher L. Bhattacharya, Dipankar Chou, Hsin-I Zhang, David Y. Fuchs, Bryan C. Lee, Youngmin Hoshida, Yujin Friedman, Scott L. TI The XBP1 Arm of the Unfolded Protein Response Induces Fibrogenic Activity in Hepatic Stellate Cells Through Autophagy SO SCIENTIFIC REPORTS LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; EXPRESSION PROFILES; FIBROSIS; LIVER; GENE; ER; INFLAMMATION; DEGRADATION; ACTIVATION; DISEASE AB Autophagy and the unfolded protein response (UPR) both promote activation of hepatic stellate cells (HSC), however the link between the two stimuli remains unclear. Here we have explored the role of X-box binding protein 1 (XBP1), one of three UPR effector pathways and sought to establish the interdependence between autophagy and the UPR during HSC activation. XBP1 induction accompanied both culture-based HSC activation and ER stress induced by tunicamycin. Ectopic overexpression of XBP1 induced collagen 1-alpha expression in HSCs, which was inhibited by knockdown of ATG7, a critical autophagy mediator. Genome-wide transcriptomic profiling indicated an upregulation of collagen synthesis pathways, but not of the transforming growth factor (TGF)-beta pathway, a canonical fibrogenic driver, suggesting that XBP1 activates a specific subset of fibrogenesis pathways independent of TGF-beta 1. XBP1 target gene signatures were significantly induced in rodent liver fibrosis models (n = 3-5) and in human samples of non-alcoholic fatty liver disease (NAFLD) (n = 72-135). Thus, XBP1-mediated UPR contributes to fibrogenic HSC activation and is functionally linked to cellular autophagy. C1 [Kim, Rosa S.; Hasegawa, Daisuke; Goossens, Nicolas; Tsuchida, Takuma; Athwal, Varinder; Sun, Xiaochen; Bhattacharya, Dipankar; Chou, Hsin-I; Zhang, David Y.; Lee, Youngmin; Hoshida, Yujin; Friedman, Scott L.] Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, Tisch Canc Inst, Div Liver Dis,Dept Med,Liver Canc Program, New York, NY 10029 USA. [Hasegawa, Daisuke] St Marianna Univ, Sch Med, Div Gastroenterol, Kawasaki, Kanagawa, Japan. [Hasegawa, Daisuke] St Marianna Univ, Sch Med, Div Hepatol, Kawasaki, Kanagawa, Japan. [Goossens, Nicolas] Univ Hosp Geneva, Div Gastroenterol, Geneva, Switzerland. [Goossens, Nicolas] Univ Hosp Geneva, Div Hepatol, Geneva, Switzerland. [Tsuchida, Takuma] Mitsubishi Tanabe Pharma Corp, Div Res, Saitama, Japan. [Athwal, Varinder] Univ Manchester, Inst Human Dev, Manchester, Lancs, England. [Robinson, Christopher L.] Weill Cornell Med Coll, Dept Surg, New York, NY USA. [Fuchs, Bryan C.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, Boston, MA USA. RP Hoshida, Y; Friedman, SL (reprint author), Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, Tisch Canc Inst, Div Liver Dis,Dept Med,Liver Canc Program, New York, NY 10029 USA. EM yujin.hoshida@mssm.edu; Scott.Friedman@mssm.edu FU NIH [R01DK56621, R01AA020709, T32GM007280, T32GM007739, DP2DK098093]; Irma T. Hirschl Trust; U.S. Department of Defense [W81XWH-16-1-0363]; Astellas Foundation for Research on Metabolic Disorders; Nuovo-Soldati Cancer Research Foundation; Geneva University Hospital; NIHR Academic Clinical Lectureship; FLAGS foundation; [R01DK099558] FX This work was supported by NIH grants R01DK56621 and R01AA020709 (to SLF), R01DK099558 and the Irma T. Hirschl Trust, and U.S. Department of Defense grant W81XWH-16-1-0363 (to YH), fellowship from the Astellas Foundation for Research on Metabolic Disorders (to DH) the FLAGS foundation, the Nuovo-Soldati Cancer Research Foundation, an advanced training grant from Geneva University Hospital (to NG), the NIHR Academic Clinical Lectureship (to VA), and the NIH awards T32GM007280 (to DZ), and T32GM007739 and DP2DK098093 (to CLR). NR 34 TC 1 Z9 1 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 20 PY 2016 VL 6 AR 39342 DI 10.1038/srep39342 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF0ZG UT WOS:000390054200002 PM 27996033 ER PT J AU Richard, NP Pippa, R Cleary, MM Puri, A Tibbitts, D Mahmood, S Christensen, DJ Jeng, S McWeeney, S Look, AT Chang, BH Tyner, JW Vitek, MP Odero, MD Sears, R Agarwal, A AF Richard, Nameeta P. Pippa, Raffaella Cleary, Megan M. Puri, Alka Tibbitts, Deanne Mahmood, Shawn Christensen, Dale J. Jeng, Sophia McWeeney, Shannon Look, A. Thomas Chang, Bill H. Tyner, Jeffrey W. Vitek, Michael P. Odero, Maria D. Sears, Rosalie Agarwal, Anupriya TI Combined targeting of SET and tyrosine kinases provides an effective therapeutic approach in human T-cell acute lymphoblastic leukemia SO ONCOTARGET LA English DT Article DE T-ALL; c-MYC; SET; PP2A; tyrosine kinases ID PROTEIN PHOSPHATASE 2A; ACUTE MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; C-MYC; TUMOR-SUPPRESSOR; LYMPHOCYTIC-LEUKEMIA; ANTICANCER THERAPY; PATHWAY DEPENDENCE; SIGNALING AXIS; LUNG-CANCER AB Recent evidence suggests that inhibition of protein phosphatase 2A (PP2A) tumor suppressor activity via the SET oncoprotein contributes to the pathogenesis of various cancers. Here we demonstrate that both SET and c-MYC expression are frequently elevated in T-ALL cell lines and primary samples compared to healthy T cells. Treatment of T-ALL cells with the SET antagonist OP449 restored the activity of PP2A and reduced SET interaction with the PP2A catalytic subunit, resulting in a decrease in cell viability and c-MYC expression in a dose-dependent manner. Since a tight balance between phosphatases and kinases is required for the growth of both normal and malignant cells, we sought to identify a kinase inhibitor that would synergize with SET antagonism. We tested various T-ALL cell lines against a small-molecule inhibitor screen of 66 compounds targeting two-thirds of the tyrosine kinome and found that combined treatment of T-ALL cells with dovitinib, an orally active multi-targeted small-molecule receptor tyrosine kinase inhibitor, and OP449 synergistically reduced the viability of all tested T-ALL cell lines. Mechanistically, combined treatment with OP449 and dovitinib decreased total and phospho c-MYC levels and reduced ERK1/2, AKT, and p70S6 kinase activity in both NOTCH-dependent and independent T-ALL cell lines. Overall, these results suggest that combined targeting of tyrosine kinases and activation of serine/threonine phosphatases may offer novel therapeutic strategies for the treatment of T-ALL. C1 [Richard, Nameeta P.] Randall Childrens Hosp Legacy Emanuel, Childrens Canc & Blood Disorders Program, Portland, OR 97227 USA. [Pippa, Raffaella; Odero, Maria D.] Univ Navarra, Ctr Appl Med Res CIMA, Div Oncol, Pio XII-55, Pamplona 31008, Spain. [Cleary, Megan M.; Puri, Alka; Mahmood, Shawn; Agarwal, Anupriya] Oregon Hlth & Sci Univ, Div Hematol & Med Oncol, Portland, OR 97239 USA. [Tibbitts, Deanne; Sears, Rosalie; Agarwal, Anupriya] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA. [Christensen, Dale J.; Vitek, Michael P.] Oncotide Pharmaceut, Res & Dev, Res Triangle Pk, NC 27710 USA. [Jeng, Sophia; McWeeney, Shannon] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Div Bioinformat & Computat Biol, Portland, OR 97239 USA. [Richard, Nameeta P.; Chang, Bill H.] Oregon Hlth & Sci Univ, Div Pediat Hematol Oncol, Portland, OR 97239 USA. [Look, A. Thomas] Dana Farber Canc Inst, Harvard Canc Ctr, Boston, MA 02215 USA. [Tyner, Jeffrey W.] Oregon Hlth & Sci Univ, Dept Cell & Dev Biol, Portland, OR 97239 USA. [Cleary, Megan M.; Puri, Alka; Mahmood, Shawn; Jeng, Sophia; McWeeney, Shannon; Chang, Bill H.; Tyner, Jeffrey W.; Sears, Rosalie; Agarwal, Anupriya] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA. [Christensen, Dale J.] Spyryx Biosci, Durham, NC 27713 USA. RP Agarwal, A (reprint author), Oregon Hlth & Sci Univ, Div Hematol & Med Oncol, Portland, OR 97239 USA.; Agarwal, A (reprint author), Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA.; Agarwal, A (reprint author), Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA. EM agarwala@ohsu.edu FU NCI NIH HHS [R01 CA196228, R00 CA151670] NR 59 TC 0 Z9 0 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD DEC 20 PY 2016 VL 7 IS 51 BP 84214 EP 84227 DI 10.18632/oncotarget.12394 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EG9BT UT WOS:000391353200034 PM 27705940 ER PT J AU Li, QL Yin, LJ Jones, LW Chu, GCY Wu, JBY Huang, JM Li, QL You, SY Kim, J Lu, YT Mrdenovic, S Wang, RX Freeman, MR Garraway, I Lewis, MS Chung, LWK Zhau, HE AF Li, Qinlong Yin, Lijuan Jones, Lawrence W. Chu, Gina C-Y Wu, Jason B-Y. Huang, Jen-Ming Li, Quanlin You, Sungyong Kim, Jayoung Lu, Yi-Tsung Mrdenovic, Stefan Wang, Ruoxiang Freeman, Michael R. Garraway, Isla Lewis, Michael S. Chung, Leland W. K. Zhau, Haiyen E. TI Keratin 13 expression reprograms bone and brain metastases of human prostate cancer cells SO ONCOTARGET LA English DT Article DE bone and brain metastases; RANKL-independent; targeting; biomarker; cell signal network ID EPITHELIAL-MESENCHYMAL TRANSITION; BREAST-CANCER; GENE-EXPRESSION; DIFFERENTIATION; CARCINOMA; PROGRESSION; INVASION; SURVIVAL; SITES AB Lethal progression of prostate cancer metastasis can be improved by developing animal models that recapitulate the clinical conditions. We report here that cytokeratin 13 (KRT13), an intermediate filament protein, plays a directive role in prostate cancer bone, brain, and soft tissue metastases. KRT13 expression was elevated in bone, brain, and soft tissue metastatic prostate cancer cell lines and in primary and metastatic clinical prostate, lung, and breast cancer specimens. When KRT13 expression was determined at a single cell level in primary tumor tissues of 44 prostate cancer cases, KRT13 level predicted bone metastasis and the overall survival of prostate cancer patients. Genetically enforced KRT13 expression in human prostate cancer cell lines drove metastases toward mouse bone, brain and soft tissues through a RANKLindependent mechanism, as KRT13 altered the expression of genes associated with EMT, stemness, neuroendocrine/neuromimicry, osteomimicry, development, and extracellular matrices, but not receptor activator NF-kappa B ligand (RANKL) signaling networks in prostate cancer cells. Our results suggest new inhibitors targeting RANKLindependent pathways should be developed for the treatment of prostate cancer bone and soft tissue metastases. C1 [Li, Qinlong; Yin, Lijuan; Chu, Gina C-Y; Wu, Jason B-Y.; Huang, Jen-Ming; Mrdenovic, Stefan; Wang, Ruoxiang; Chung, Leland W. K.; Zhau, Haiyen E.] Cedars Sinai Med Ctr, Dept Med, Urooncol Res Program, Los Angeles, CA 90048 USA. [Jones, Lawrence W.] Huntington Mem Hosp, Huntington Med Res Inst, Urol Res, Pasadena, CA USA. [Li, Quanlin] Dept Med, Biostat & Bioinformat, Los Angeles, CA USA. [You, Sungyong; Kim, Jayoung; Freeman, Michael R.] Cedars Sinai Med Ctr, Dept Surg, Los Angeles, CA 90048 USA. [Lu, Yi-Tsung] Jr Hosp Cook Cty, Chicago, IL USA. [Garraway, Isla] Univ Calif Los Angeles, Dept Urol, Los Angeles, CA USA. [Garraway, Isla] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Garraway, Isla] Greater Los Angeles Vet Affairs Healthcare Syst, Div Urol, Los Angeles, CA 90073 USA. [Lewis, Michael S.] Sepulveda Res Corp, VA Med Ctr, Los Angeles, CA 90024 USA. [Li, Qinlong] Fourth Mil Med Univ, Xijing Hosp, Dept Pathol, Xian, Shaanxi, Peoples R China. RP Chung, LWK; Zhau, HE (reprint author), Cedars Sinai Med Ctr, Dept Med, Urooncol Res Program, Los Angeles, CA 90048 USA.; Garraway, I (reprint author), Univ Calif Los Angeles, Dept Urol, Los Angeles, CA USA.; Garraway, I (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA.; Garraway, I (reprint author), Greater Los Angeles Vet Affairs Healthcare Syst, Div Urol, Los Angeles, CA 90073 USA.; Lewis, MS (reprint author), Sepulveda Res Corp, VA Med Ctr, Los Angeles, CA 90024 USA. EM igarraway@mednet.ucla.edu; michael.lewis8@va.gov; Leland.Chung@cshs.org; Haiyen.Zhau@cshs.org NR 51 TC 0 Z9 0 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD DEC 20 PY 2016 VL 7 IS 51 BP 84645 EP 84657 DI 10.18632/oncotarget.13175 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EG9BT UT WOS:000391353200069 PM 27835867 ER PT J AU Boyiadzis, M Bishop, MR Abonour, R Anderson, KC Ansell, SM Avigan, D Barbarotta, L Barrett, AJ Van Besien, K Bergsagel, PL Borrello, I Brody, J Brufsky, J Cairo, M Chari, A Cohen, A Cortes, J Forman, SJ Friedberg, JW Fuchs, EJ Gore, SD Jagannath, S Kahl, BS Kline, J Kochenderfer, JN Kwak, LW Levy, R de Lima, M Litzow, MR Mahindra, A Miller, J Munshi, NC Orlowski, RZ Pagel, JM Porter, DL Russell, SJ Schwartz, K Shipp, MA Siegel, D Stone, RM Tallman, MS Timmerman, JM Van Rhee, F Waller, EK Welsh, A Werner, M Wiernik, PH Dhodapkar, MV AF Boyiadzis, Michael Bishop, Michael R. Abonour, Rafat Anderson, Kenneth C. Ansell, Stephen M. Avigan, David Barbarotta, Lisa Barrett, Austin John Van Besien, Koen Bergsagel, P. Leif Borrello, Ivan Brody, Joshua Brufsky, Jill Cairo, Mitchell Chari, Ajai Cohen, Adam Cortes, Jorge Forman, Stephen J. Friedberg, Jonathan W. Fuchs, Ephraim J. Gore, Steven D. Jagannath, Sundar Kahl, Brad S. Kline, Justin Kochenderfer, James N. Kwak, Larry W. Levy, Ronald de Lima, Marcos Litzow, Mark R. Mahindra, Anuj Miller, Jeffrey Munshi, Nikhil C. Orlowski, Robert Z. Pagel, John M. Porter, David L. Russell, Stephen J. Schwartz, Karl Shipp, Margaret A. Siegel, David Stone, Richard M. Tallman, Martin S. Timmerman, John M. Van Rhee, Frits Waller, Edmund K. Welsh, Ann Werner, Michael Wiernik, Peter H. Dhodapkar, Madhav V. TI The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of hematologic malignancies: multiple myeloma, lymphoma, and acute leukemia SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article DE Cancer immunotherapy; Hematologic malignancies; Acute leukemia; Lymphoma; Multiple myeloma; Immunotherapy ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHIMERIC ANTIGEN RECEPTOR; STEM-CELL TRANSPLANTATION; CYTOTOXIC T-LYMPHOCYTES; NATURAL-KILLER-CELLS; COLONY-STIMULATING FACTOR; LOW-DOSE DEXAMETHASONE; LARGE B-CELL; WT1 PEPTIDE VACCINATION; LENALIDOMIDE PLUS DEXAMETHASONE AB Increasing knowledge concerning the biology of hematologic malignancies as well as the role of the immune system in the control of these diseases has led to the development and approval of immunotherapies that are resulting in impressive clinical responses. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a hematologic malignancy Cancer Immunotherapy Guidelines panel consisting of physicians, nurses, patient advocates, and patients to develop consensus recommendations for the clinical application of immunotherapy for patients with multiple myeloma, lymphoma, and acute leukemia. These recommendations were developed following the previously established process based on the Institute of Medicine's clinical practice guidelines. In doing so, a systematic literature search was performed for high-impact studies from 2004 to 2014 and was supplemented with further literature as identified by the panel. The consensus panel met in December of 2014 with the goal to generate consensus recommendations for the clinical use of immunotherapy in patients with hematologic malignancies. During this meeting, consensus panel voting along with discussion were used to rate and review the strength of the supporting evidence from the literature search. These consensus recommendations focus on issues related to patient selection, toxicity management, clinical endpoints, and the sequencing or combination of therapies. Overall, immunotherapy is rapidly emerging as an effective therapeutic strategy for the management of hematologic malignances. Evidence-based consensus recommendations for its clinical application are provided and will be updated as the field evolves. C1 [Boyiadzis, Michael] Univ Pittsburgh, Div Hematol Oncol, Sch Med, Dept Med,Canc Inst,Med Ctr, 5150 Ctr Ave,Suite 564, Pittsburgh, PA 15232 USA. [Bishop, Michael R.] Univ Chicago, Hematopoiet Cellular Therapy Program, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Abonour, Rafat] Indiana Univ Sch Med, 980 W Walnut St,Walther Hall R3,C400, Indianapolis, IN 46202 USA. [Anderson, Kenneth C.; Stone, Richard M.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Ansell, Stephen M.; Russell, Stephen J.] Mayo Clin, 200 First St SW, Rochester, MN 55905 USA. [Avigan, David] Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA. [Barbarotta, Lisa] Yale New Haven, Smilow Canc Hosp, 35 Pk St, New Haven, CT 06519 USA. [Barrett, Austin John] NIH, Bldg 10 CRC Room 3-5330, Bethesda, MD 20814 USA. [Van Besien, Koen] Weill Cornell Med Coll, 407 E 71st St, New York, NY 10065 USA. [Bergsagel, P. Leif] Mayo Clin, 13400 E Shea Blvd, Scottsdale, AZ 85259 USA. [Borrello, Ivan] Johns Hopkins Sch Med, 1650 Orleans St, Baltimore, MD 21231 USA. [Brody, Joshua; Chari, Ajai; Jagannath, Sundar] Icahn Sch Med Mt Sinai, One Gustave L Levy Pl, New York, NY 10029 USA. [Brufsky, Jill] Univ Pittsburgh, Inst Canc, 5150 Ctr Ave, Pittsburgh, PA 15232 USA. [Cairo, Mitchell] Maria Fareri Childrens Hosp, New York Med Coll, 100 Woods Rd, Valhalla, NY 10595 USA. [Chari, Ajai] Univ Penn, Abramson Canc Ctr, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. [Cortes, Jorge] Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd, Houston, TX 77030 USA. [Forman, Stephen J.] City Hope Natl Med Ctr, 1500 East Duarte Rd, Duarte, CA 91010 USA. [Friedberg, Jonathan W.] Univ Rochester, Wilmot Canc Inst, 601 Elmwood Ave,Box 704, Rochester, NY 14642 USA. [Fuchs, Ephraim J.] Johns Hopkins Univ, Sch Med, 401 N Broadway, Baltimore, MD 21231 USA. [Gore, Steven D.] Yale Canc Ctr, 333 Cedar St, New Haven, CT 06511 USA. [Kahl, Brad S.] Washington Univ, Sch Med, 660 S Euclid Ave, St Louis, MO 63110 USA. [Kline, Justin] Univ Chicago, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Kochenderfer, James N.] NCI, NIH, 8500 Roseweood Dr, Bethesda, MD 20814 USA. [Kwak, Larry W.] City Hope Natl Med Ctr, 1500 E Duarte Rd,Beckman Bldg,Room 4117, Duarte, CA 91010 USA. [Levy, Ronald] Stanford Univ, Div Med Oncol, Sch Med, 269 Campus Dr, Stanford, CA 94305 USA. [de Lima, Marcos] Case Western Reserve Univ, Dept Med Hematol & Oncol, 11100 Euclid Ave, Cleveland, OH 44106 USA. [Litzow, Mark R.] Mayo Clin, Ctr Canc, Dept Hematol, 200 First St SW, Rochester, MN 55905 USA. [Mahindra, Anuj] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Box 0324, San Francisco, CA 94143 USA. [Miller, Jeffrey] Univ Minnesota, Div Hematol Oncol, 420 Delaware St SE, Minneapolis, MN 55455 USA. [Munshi, Nikhil C.] Dana Farber Canc Inst, 450 Brookline Ave,Dana B106, Boston, MA 02215 USA. [Orlowski, Robert Z.] Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd,Unit 429, Houston, TX 77030 USA. [Pagel, John M.] Swedish Canc Inst, 1221 Madison St,Suite 1020, Seattle, WA 98104 USA. [Porter, David L.] Univ Penn, 3400 Civ Ctr Blvd,PCAM 12 South Pavil, Philadelphia, PA 19104 USA. [Schwartz, Karl] Patients Lymphoma, 3774 Buckwampum Rd, Riegelsville, PA 18077 USA. [Shipp, Margaret A.] Dana Farber Canc Inst, 450 Brookline Ave,Mayer 513, Boston, MA 02215 USA. [Siegel, David] Hackensack Univ, Med Ctr, 92 2nd St, Hackensack, NJ 07601 USA. [Tallman, Martin S.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA. [Timmerman, John M.] Univ Calif Los Angeles, 10833 LeConte Ave, Los Angeles, CA 90095 USA. [Van Rhee, Frits] Univ Arkansas Med Sci, Myeloma Inst, 4301 W Markham 816, Little Rock, AR 72205 USA. [Waller, Edmund K.] Emory Univ, Winship Canc Inst, 1365B Clifton Rd NE, Atlanta, GA 30322 USA. [Welsh, Ann] Univ Pittsburgh, Med Ctr, 200 Lothrop St, Pittsburgh, PA 15213 USA. [Werner, Michael] Patient Advocate, 33 East Bellevue Pl, Chicago, IL 60611 USA. [Wiernik, Peter H.] Canc Res Fdn New York, 43 Longview Lane, Chappaqua, NY 10514 USA. [Dhodapkar, Madhav V.] Yale Univ, Dept Hematol & Immunobiol, 333 Cedar St,Box 208021, New Haven, CT 06510 USA. RP Dhodapkar, MV (reprint author), Yale Univ, Dept Hematol & Immunobiol, 333 Cedar St,Box 208021, New Haven, CT 06510 USA. EM madhav.dhodapkar@yale.edu FU Bristol-Myers Squibb; Cellplex; Seattle Genetics; Novartis; Millennium (Takeda); Celgene; Array BioPharma; Onyx; Janssen Pharmaceuticals; Pharmacylics; Pfizer; Janssen; Dynavax; Pharmacyclics; Amgen; Fate Therapeutics; Oxis Biotech; Onyx (Amgen); Spectrum Pharma; FORMA Therapeutics; Merck; Valor Biotherapeutics; Kite Pharma FX RA acts as a consultant to Celgene. KCA participates on an advisory board for Celgene, Millennium (Takeda), and Gilead. He is also the scientific founder of Acetlyon, Oncopep, and C4Therapies. SMA has received research funding from Bristol-Myers Squibb, Cellplex, and Seattle Genetics. DA participates On scientific advisory boards for Celgene and Seattle Genetics. LB selves on the speaker's bureau for Celgene and Bristol-Myers Squibb. PLB acts as a consultant and has received research funding from Novartis. MC acts as a consultant for Sanofi, Celgene, Roche, Gilead, and Jazz Pharmaceuticals. AC1 participates on an advisory board and has received research funding from Millennium (Takeda), Celgene, Array BioPharma, Novartis, and Onyx. In addition, he am as a consultant for Janssen Pharmaceuticals as well as Bristol-Myers Squibb and has received research funding from Janssen Pharmaceuticals and Pharmacylics. AC2 participates on an advisory, board and has receive research funding from Bristol-Myers Squibb. In addition he acts on an advisory board for Janssen Pharmaceuticals and has received institutional research funding from Novartis. JC has received research support. from Bristol-Myers Squibb, Pfizer, and Janssen and acts as a consultant to Bristol-Meyers Squibb, Pfizer, Janssen, Amphivena, and Merus. JWF participates on an advisory board for Bayer. SJ has received he and participates on an advisory board for Celgene, Bristol-Myers Squibb, and Janssen Pharmaceuticals. BBK acts as a consultant to Genentech (Roche), Juno, and Celgene. Through the National Cancer Institute, INK has cooperative research and development agreements with Kite Pharma and Bluebird Bio. LWK is a founder of XEME Biopharma and acts as a consultant for Sellas and Celltrion. RL has received research funding from Bristol-Myers Squibb, Dynavax, Pfizer, and Pharmacyclics. MRL has received research funding from Amgen. AM participates on an advisory board for Novartis. JM acts as a consultant and has received research funding from Fate Therapeutics and Oxis Biotech. He also participates on a scientific advisory Board for Celegene. NCM has ownership interest in Oncopep and acts as a consultant for Celgene, Merck, Pfizer, Takeda, and Janssen Pharmaceuticals. RZO has receive research funding from Bristol-Myers Squibb, Celgene, Millennium (Takeda), Onyx (Amgen), and Spectrum Pharma. In addition, he participates on advisory boards for Array BioPharma, Bristol-Myers Squibb, Celgene, FORMA Therapeutics, Janssen Pharmaceuticals, Millennium (Takeda), and Onyx (Amgen). DLP has received research funding and holds royalties as well as intellectual property interests with Novartis. DLP's spouse is also employed by Genentech (Roche). SJR is the co-founder/co-owner as well as CEO and Board Member of Vyriad, Inc. MAS has received research funding and participates on a scientific advisory board for Bristol-Myers Squibb and Merck. DS acts on advisory boards and on speaker's bureaus nor Celgene, Millennium (Takeda), Amgen, and Bristol-Myers Squibb. RMS acts as a consultant or on an advisory board for AbbVie, Abios, Amgen, Pfizer, Roche, Celator, Celgene, Janssen, Novartis, Sunesis, Juno, Kaypharm, Merck, Seattle Genetics, and Xenetic. JWT acts as a consultant for Celgene as well as Genmab and has received research funding from Bristol-Myers Squibb, Janssen Pharmaceuticals, Valor Biotherapeutics, and Kite Pharma. AJB, KVB, MRB, IB, MB, JB1, JB2, JC, MVD, SJF, EJF, SDG, JK, MdL, JP, KS, MST, EKW, AW, MW, PHW, and FVR declare no competing interests. NR 219 TC 0 Z9 0 U1 7 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD DEC 20 PY 2016 VL 4 AR 90 DI 10.1186/s40425-016-0188-z PG 25 WC Oncology SC Oncology GA EG8WW UT WOS:000391338800007 PM 28018601 ER PT J AU Deming, DA AF Deming, Dustin A. TI Advances in immunotherapeutic strategies for colorectal cancer commentary on: tumoral immune cell exploitation in colorectal cancer metastases can be targeted effectively by anti-CCR5 therapy in cancer patients by Halama et al SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Editorial Material ID DENSITY AB Colorectal cancer is a leading cause of cancer-related death in the United States, despite recent advances in treatment strategies. The immune system has been implicated in the pathogenesis of colorectal cancer, with numerous studies identifying either antagonistic or pro-tumorigenic effects of infiltrating immune cells. Therapeutic strategies harnessing the immune system to target cancers have evolved expediently over the last 5 years, especially the use of checkpoint inhibitors. Recently, a subset of patients whose colorectal cancers harbor a deficiency in mismatch repair proteins have demonstrated dramatic and durable response to checkpoint blockade. Unfortunately, the vast majority of colorectal cancers are mismatch repair proficient and resistant to these inhibitors. The tumor microenvironment has been implicated in the resistance to checkpoint block and ways to overcome these resistance mechanisms would be a major advance for the treatment of colorectal cancer. Here we provide commentary on a manuscript from Halama et al. examining CCL5/CCR5 as an immune biomarker and the potential role of anti-CCR5 agents for the treatment of patients with colorectal cancer. C1 [Deming, Dustin A.] Univ Wisconsin, Dept Med, Div Hematol & Oncol, Madison, WI 53706 USA. [Deming, Dustin A.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI 53705 USA. [Deming, Dustin A.] Univ Wisconsin, Dept Oncol, McArdle Lab Canc Res, Madison, WI 53705 USA. [Deming, Dustin A.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. RP Deming, DA (reprint author), Univ Wisconsin, Dept Med, Div Hematol & Oncol, Madison, WI 53706 USA.; Deming, DA (reprint author), Univ Wisconsin, Carbone Canc Ctr, Madison, WI 53705 USA.; Deming, DA (reprint author), Univ Wisconsin, Dept Oncol, McArdle Lab Canc Res, Madison, WI 53705 USA.; Deming, DA (reprint author), William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. EM ddeming@medicine.wisc.edu FU University of Wisconsin Carbone Cancer Center [NCI P30 CA014520] FX NCI P30 CA014520 (Core Grant, University of Wisconsin Carbone Cancer Center). NR 10 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD DEC 20 PY 2016 VL 4 AR 93 DI 10.1186/s40425-016-0197-y PG 3 WC Oncology SC Oncology GA EG8WY UT WOS:000391339000002 PM 28031821 ER PT J AU Nishino, M Ramaiya, NH Chambers, ES Adeni, AE Hatabu, H Janne, PA Hodi, FS Awad, MM AF Nishino, Mizuki Ramaiya, Nikhil H. Chambers, Emily S. Adeni, Anika E. Hatabu, Hiroto Janne, Pasi A. Hodi, F. Stephen Awad, Mark M. TI Immune-related response assessment during PD-1 inhibitor therapy in advanced non-small-cell lung cancer patients SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article DE PD-1 inhibitor; Immunotherapy; Non-small-cell lung cancer; Computed tomography; Tumor response evaluation ID GUIDELINE VERSION 1.1; LONG-TERM SAFETY; ADVANCED MELANOMA; SOLID TUMORS; HEPATOCELLULAR-CARCINOMA; NIVOLUMAB; PEMBROLIZUMAB; IPILIMUMAB; CRITERIA; RECIST AB Background: Tumor response characteristics using immune-related RECIST1.1 (irRECIST1.1) in advanced non-small-cell lung cancer (NSCLC) patients treated with nivolumab monotherapy in the clinical setting have not been previously described with a direct comparison with the assessments according to the conventional RECIST1.1. Methods: Fifty-six advanced NSCLC patients treated with nivolumab monotherapy after its Food and Drug Administration (FDA) approval were retrospectively studied. Tumor burden was quantified on serial CT scans during therapy using irRECIST1.1, which uses unidimensional measurements and includes new lesion measurements in total tumor burden. Response assessments by irRECIST1.1 were compared with assessments by RECIST1.1. Responses of individual lesions in different organs were also compared. Results: Tumor burden change at best overall response ranged from -66.8 to +278.1% (median: +3.9%). Response rate was 14% (8/56; 8 partial responses, 0 complete responses) by irRECIST1.1 and by RECIST1.1. Time-to-progression (TTP) by irRECIST1.1 was longer than TTP by RECIST1.1 (median TTP: not reached vs. 1.9 months, respectively). No patients experienced pseudoprogression during the study. Among 128 target lesions, the lesion-based size change at best response differed significantly across different organs, with adrenal lesions and lymph nodes having greater size decrease, followed by lung, while liver and other miscellaneous lesions had lesser degree of size decrease (p = 0.002). Conclusions: Immune-related response evaluations using irRECIST1.1 in advanced NSCLC patients treated with nivolumab resulted in the identical response rate and longer TTP compared to RECIST1.1. No pseudoprogression cases were observed during the study. Adrenal lesions and lymph nodes were more responsive and liver lesions were less responsive to nivolumab. C1 [Nishino, Mizuki; Ramaiya, Nikhil H.; Hatabu, Hiroto] Brigham & Womens Hosp, Dept Radiol, 450 Brookline Ave, Boston, MA 02215 USA. [Nishino, Mizuki; Ramaiya, Nikhil H.; Hatabu, Hiroto] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Chambers, Emily S.; Adeni, Anika E.; Janne, Pasi A.; Hodi, F. Stephen; Awad, Mark M.] Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Chambers, Emily S.; Adeni, Anika E.; Janne, Pasi A.; Hodi, F. Stephen; Awad, Mark M.] Dana Farber Canc Inst, Dept Med, 450 Brookline Ave, Boston, MA 02215 USA. [Chambers, Emily S.; Adeni, Anika E.; Janne, Pasi A.; Hodi, F. Stephen; Awad, Mark M.] Brigham & Womens Hosp, 450 Brookline Ave, Boston, MA 02215 USA. RP Nishino, M (reprint author), Brigham & Womens Hosp, Dept Radiol, 450 Brookline Ave, Boston, MA 02215 USA.; Nishino, M (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM Mizuki_Nishino@DFCI.HARVARD.EDU FU NCI [1K23CA157631] FX The investigator, M.N., was supported by 1K23CA157631 (NCI). NR 35 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD DEC 20 PY 2016 VL 4 AR 84 DI 10.1186/s40425-016-0193-2 PG 10 WC Oncology SC Oncology GA EG8WW UT WOS:000391338800001 PM 28018599 ER PT J AU Liu, JF Ray-Coquard, I Selle, F Poveda, AM Cibula, D Hirte, H Hilpert, F Raspagliesi, F Gladieff, L Harter, P Siena, S del Campo, JM Tabah-Fisch, I Pearlberg, J Moyo, V Riahi, K Nering, R Kubasek, W Adiwijaya, B Czibere, A Naumann, RW Coleman, RL Vergote, I MacBeath, G Pujade-Lauraine, E AF Liu, Joyce F. Ray-Coquard, Isabelle Selle, Frederic Poveda, Andres M. Cibula, David Hirte, Hal Hilpert, Felix Raspagliesi, Francesco Gladieff, Laurence Harter, Philipp Siena, Salvatore del Campo, Josep Maria Tabah-Fisch, Isabelle Pearlberg, Joseph Moyo, Victor Riahi, Kaveh Nering, Rachel Kubasek, William Adiwijaya, Bambang Czibere, Akos Naumann, R. Wendel Coleman, Robert L. Vergote, Ignace MacBeath, Gavin Pujade-Lauraine, Eric TI Randomized Phase II Trial of Seribantumab in Combination With Paclitaxel in Patients With Advanced Platinum-Resistant or - Refractory Ovarian Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; COLORECTAL-CANCER; DEPENDENT ACTIVATION; ACQUIRED-RESISTANCE; ONCOLOGY-GROUP; BREAST-CANCER; DOUBLE-BLIND; ERBB3; CHEMOTHERAPY; GROWTH AB Purpose Seribantumab is a fully human immunoglobulin G2 monoclonal antibody that binds to human epidermal growth factor receptor (HER) 3 (ErbB3), blocking heregulin (HRG) -mediated ErbB3 signaling and inducing ErbB3 receptor downregulation. This open-label randomized phase II study evaluated progression-free survival (PFS) with seribantumab in combination with once-per-week paclitaxel compared with paclitaxel alone in patients with platinum-resistant or -refractory ovarian cancer. A key secondary objective was to determine if any of five prespecified biomarkers predicted benefit from seribantumab. Patients and Methods Patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned at a ratio of two to one to receive seribantumab plus paclitaxel or paclitaxel alone. Patients underwent pretreatment core needle biopsy; archival tumor samples were also obtained to support biomarker analyses. Results A total of 223 patientswere randomly assigned (seribantumab plus paclitaxel, n = 140; paclitaxel alone, n = 83). Median PFS in the unselected intent-to-treat population was 3.75 months with seribantumab plus paclitaxel compared with 3.68 months with paclitaxel alone (hazard ratio [HR], 1.027; 95% CI, 0.741 to 1.425; P =.864). Among patients whose tumors had detectable HRG mRNA and low HER2 (n = 57 [38%] of 151with available biomarker data), increased treatment benefitwas observed in those receiving seribantumab plus paclitaxel compared with paclitaxel alone (PFS HR, 0.37; 95% CI, 0.18 to 0.76; P =.007). The HR in patients notmeeting these criteriawas 1.80 (95% CI, 1.08 to 2.98; P =.023). Conclusion The addition of seribantumab to paclitaxel did not result in improved PFS in unselected patients. Exploratory analyses suggest that detectable HRG and low HER2, biomarkers that link directly to the mechanism of action of seribantumab, identified patients who might benefit from this combination. Future clinical trials are needed to validate this finding and should preselect for HRG expression and focus on cancers with low HER2 levels. (C) 2016 by American Society of Clinical Oncology C1 [Liu, Joyce F.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Ray-Coquard, Isabelle; Pearlberg, Joseph] Sanofi Oncol, Cambridge, MA USA. [Moyo, Victor; Riahi, Kaveh; Nering, Rachel; Kubasek, William; Adiwijaya, Bambang; Czibere, Akos; MacBeath, Gavin] Merrimack Pharmaceut, Cambridge, MA USA. [Naumann, R. Wendel] Carolinas Med Ctr, Levine Canc Inst, Charlotte, NC 28203 USA. [Coleman, Robert L.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Tabah-Fisch, Isabelle] Univ Claude Bernard, Ctr Leon Berard, Lyon, France. [Tabah-Fisch, Isabelle] GINECO, Lyon, France. [Selle, Frederic] Hop Tenon, GINECO, Paris, France. [Selle, Frederic; Pujade-Lauraine, Eric] GINECO, Paris, France. [Pujade-Lauraine, Eric] Hop Hotel Dieu, Paris, France. [Pujade-Lauraine, Eric] Univ Paris 05, Paris, France. [Gladieff, Laurence] Inst Univ Canc Toulouse Oncopole, Inst Claudius Regaud, Toulouse, France. [Gladieff, Laurence] GINECO, Toulouse, France. [Poveda, Andres M.] Inst Valenciano Oncol, Valencia, Spain. [Poveda, Andres M.] GEICO, Valencia, Spain. [del Campo, Josep Maria] Hosp Univ Vall dHebron, Barcelona, Spain. [del Campo, Josep Maria] GEICO, Barcelona, Spain. [Cibula, David] Gen Univ Hosp Prague, Prague, Czech Republic. [Cibula, David] Charles Univ Prague, Prague, Czech Republic. [Hirte, Hal] Hamilton Hlth Sci Juravinski Canc Ctr, Hamilton, ON, Canada. [Hilpert, Felix] Univ Klinikum Schleswig Holstein, Kiel, Germany. [Harter, Philipp] Kliniken Essen Mitte, Essen, Germany. [Harter, Philipp] Arbeitsgemeinschaft Gynakol Onkol, Essen, Germany. [Raspagliesi, Francesco] Fdn Ist Ricovero & Cura Carattere Sci, Ist Nazl Tumori, Milan, Italy. [Siena, Salvatore] Grande Osped Metropolitano Niguarda, Niguarda Canc Ctr, Milan, Italy. [Siena, Salvatore] Univ Milan, Milan, Italy. [Vergote, Ignace] Katholieke Univ Leuven, Univ Hosp, Leuven, Belgium. [Vergote, Ignace] Leuven Canc Inst, Leuven, Belgium. RP Liu, JF (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM joyce_liu@dfci.harvard.edu FU Merrimack Pharmaceuticals FX Supported by Merrimack Pharmaceuticals. NR 36 TC 1 Z9 1 U1 3 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 20 PY 2016 VL 34 IS 36 BP 4345 EP + DI 10.1200/JCO.2016.67.1891 PG 14 WC Oncology SC Oncology GA EG9LO UT WOS:000391380500009 PM 27998236 ER PT J AU Leijen, S van Geel, RMJM Pavlick, AC Tibes, R Rosen, L Razak, ARA Lam, R Demuth, T Rose, S Lee, MA Freshwater, T Shumway, S Liang, LW Oza, AM Schellens, JHM Shapiro, GI AF Leijen, Suzanne van Geel, Robin M. J. M. Pavlick, Anna C. Tibes, Raoul Rosen, Lee Razak, Albiruni R. Abdul Lam, Raymond Demuth, Tim Rose, Shelonitda Lee, Mark A. Freshwater, Tomoko Shumway, Stuart Liang, Li Wen Oza, Amit M. Schellens, Jan H. M. Shapiro, Geoffrey I. TI Phase I Study Evaluating WEE1 Inhibitor AZD1775 As Monotherapy and in Combination With Gemcitabine, Cisplatin, or Carboplatin in Patients With Advanced Solid Tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID DNA-DAMAGING AGENTS; MITOTIC CATASTROPHE; ANTITUMOR-ACTIVITY; KINASE INHIBITOR; CANCER-THERAPY; MK-1775; CELLS; CHK1; VIVO; GLIOBLASTOMA AB Purpose AZD1775 is a WEE1 kinase inhibitor targeting G2 checkpoint control, preferentially sensitizing TP53-deficient tumor cells to DNA damage. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of oral AZD1775 as monotherapy or in combination with chemotherapy in patients with refractory solid tumors. Patients and Methods In part 1, patients received a single dose of AZD1775 followed by 14 days of observation. In part 2, patients received AZD1775 as a single dose (part 2A) or as five twice per day doses or two once per day doses (part 2B) in combination with one of the following chemotherapy agents: gemcitabine (1,000 mg/m(2)), cisplatin (75 mg/m2), or carboplatin (area under the curve, 5 mg/mL.min). Skin biopsies were collected for pharmacodynamic assessments. TP53 status was determined retrospectively in archival tumor tissue. Results Two hundred two patients were enrolled onto the study, including nine patients in part 1, 43 in part 2A (including eight rollover patients from part 1), and 158 in part 2B. AZD1775 monotherapy given as single dose was well tolerated, and the maximum-tolerated dose was not reached. In the combination regimens, the most common adverse events consisted of fatigue, nausea and vomiting, diarrhea, and hematologic toxicity. The maximum-tolerated doses and biologically effective doses were established for each combination. Target engagement, as a predefined 50% pCDK1 reduction in surrogate tissue, was observed in combination with cisplatin and carboplatin. Of 176 patients evaluable for efficacy, 94 (53%) had stable disease as best response, and 17 (10%) achieved a partial response. The response rate in TP53-mutated patients (n = 19) was 21% compared with 12% in TP53 wild-type patients (n = 33). Conclusion AZD1775 was safe and tolerable as a single agent and in combination with chemotherapy at doses associated with target engagement. (C) 2016 by American Society of Clinical Oncology C1 [Leijen, Suzanne; van Geel, Robin M. J. M.; Schellens, Jan H. M.] Netherlands Canc Inst, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. [Schellens, Jan H. M.] Univ Utrecht, Utrecht, Netherlands. [Pavlick, Anna C.] NYU, Med Ctr, New York, NY 10016 USA. [Rosen, Lee] Univ Calif Los Angeles, Santa Monica, CA USA. [Lam, Raymond; Rose, Shelonitda; Lee, Mark A.; Freshwater, Tomoko; Shumway, Stuart] Merck, Kenilworth, NJ USA. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Razak, Albiruni R. Abdul; Oza, Amit M.] Princess Margaret Hosp, Toronto, ON, Canada. [Tibes, Raoul] Univ Hosp Wurzburg, Wurzburg, Germany. [Demuth, Tim] Sandoz AG, Holzkirchen, Germany. [Liang, Li Wen] Merck Sharp & Dohme R&D, Beijing, Peoples R China. RP Schellens, JHM (reprint author), Netherlands Canc Inst, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. EM j.schellens@nki.nl FU Bristol-Myers Squibb; Millennium; Novartis; Merck; Celldex; EntreMed; Boehringer Ingelheim; Cayo Pharmaceutical; Eli Lilly; Genentech; Roche; AstraZeneca; Clovis Oncology; Pfizer; Bayer; Immune Design; Vertex; Puma Biotechnology; Tensha Therapeutics; Covidien; Cellceutix; Sanofi; Cyclacel; Mirati Therapeutics; GlaxoSmithKline; Aileron Therapeutics; PharmaMar; PTC Therapeutics FX Bristol-Myers Squibb (Inst), Millennium (Inst), Novartis (Inst), Merck (Inst), Celldex (Inst); Merck; Merck, Novartis, EntreMed, Boehringer Ingelheim, Bristol-Myers Squibb, Cayo Pharmaceutical, Eli Lilly, Genentech, Roche; Merck; AstraZeneca (Inst), Roche (Inst), Merck (Inst), Clovis Oncology (Inst); Pfizer (Inst), Genentech (Inst), Bayer (Inst), Immune Design (Inst), Vertex (Inst), Millennium (Inst), Puma Biotechnology (Inst), Tensha Therapeutics (Inst), Covidien (Inst), Novartis (Inst), Cellceutix (Inst), Sanofi (Inst), Cyclacel (Inst), Mirati Therapeutics (Inst), AstraZeneca (Inst), GlaxoSmithKline (Inst), Eli Lilly, Aileron Therapeutics (Inst), PharmaMar (Inst), PTC Therapeutics (Inst), Merck (Inst) NR 38 TC 1 Z9 1 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 DEC 20 PY 2016 VL 34 IS 36 BP 4371 EP + DI 10.1200/JCO.2016.67.5991 PG 19 WC Oncology SC Oncology GA EG9LO UT WOS:000391380500012 PM 27601554 ER PT J AU Rowhani-Rahbar, A Fan, MD Simonetti, JA Lyons, VH Wang, J Zatzick, D Rivara, FP AF Rowhani-Rahbar, Ali Fan, Mary D. Simonetti, Joseph A. Lyons, Vivian H. Wang, Jin Zatzick, Douglas Rivara, Frederick P. TI Violence Perpetration Among Patients Hospitalized for Unintentional and Assault-Related Firearm Injury A Case-Control Study and a Cohort Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID URBAN EMERGENCY-DEPARTMENT; SUBSTANCE USE; RISK; YOUTH; INTERVENTION; ADOLESCENTS; CARE; VICTIMIZATION; MORTALITY; REINJURY AB Background: Hospital-based violence intervention programs typically focus on patients whose firearm injury occurred through interpersonal violence (assault). Knowledge of violence perpetration by victims of unintentional (accidental) firearm injury is limited. Objective: To examine violence perpetration before and after a patient becomes hospitalized for firearm injury according to injury intent (intentional [assault] or unintentional [accidental]). Design: A case-control study and a retrospective cohort study. Setting: Hospitals in Washington. Patients: Persons aged 15 years or older hospitalized for a firearm injury, other injuries, or a noninjury reason from 2006 to 2007. Measurements: In the case-control study, the odds of violencerelated arrest from 2001 through hospitalization by injury intent among 3 groups were compared. In the cohort study, the rates of violence-related arrest from hospitalization through 2011 by injury intent among 3 groups were compared. Results: Patients with unintentional firearm injuries (n = 180) were more likely than those with other unintentional injuries (n = 62 795; odds ratio [OR], 2.01 [95% Cl, 1.31 to 3.09]) and no injuries (n = 172 830; OR, 3.43 [Cl, 2.22 to 5.32]) to have been arrested for a violent crime before hospitalization. Prior violencerelated arrest did not differ between patients with assault-related firearm injuries (n = 339) and those with other assault-related injuries (n = 2342; OR, 1.10 [CI, 0.84 to 1.46). During follow-up, the cumulative incidence of violence-related arrest for patients with unintentional and assault-related firearm injuries was 10% and 15% (subhazard ratio, 1.88 [CI, 1.11 to 3.17] and 1.61 [CI, 1.08 to 2.44]), respectively, compared with 1% for those without injuries. Limitation: Exclusion of self-inflicted injuries, misclassification of intent, and ascertainment bias. Conclusion: Some firearm injuries classified as accidental may indicate involvement in the cycle of violence and present an opportunity for intervention. C1 [Rowhani-Rahbar, Ali] Univ Washington, Sch Publ Hlth, Dept Epidemiol, 1959 Northeast Pacific St,Hlth Sci Bldg,F-250D, Seattle, WA 98195 USA. [Zatzick, Douglas] Univ Washington, Dept Psychiat & Behav Sci, Sch Med, 325 Ninth Ave,Box 359911, Seattle, WA 98104 USA. [Fan, Mary D.; Simonetti, Joseph A.; Lyons, Vivian H.; Wang, Jin; Rivara, Frederick P.] Univ Washington, Seattle, WA 98195 USA. [Fan, Mary D.; Lyons, Vivian H.; Wang, Jin; Rivara, Frederick P.] Harborview Injury Prevent & Res Ctr, 325 Ninth Ave,Box 359960, Seattle, WA 98104 USA. [Simonetti, Joseph A.] Vet Affairs Puget Sound Hlth Care Syst, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. RP Rowhani-Rahbar, A (reprint author), Univ Washington, Sch Publ Hlth, Dept Epidemiol, 1959 Northeast Pacific St,Hlth Sci Bldg,F-250D, Seattle, WA 98195 USA. EM rowhani@uw.edu FU City of Seattle [124195] FX Dr. Rivara reports grants from the City of Seattle during the conduct of the study. Dr. Zatzick reports a contract (number 124195) from the City of Seattle during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOflnterestForms.do?msNum=M16-159 6. NR 36 TC 1 Z9 1 U1 1 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD DEC 20 PY 2016 VL 165 IS 12 BP 841 EP U150 DI 10.7326/M16-1596 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA EG7OJ UT WOS:000391236900012 PM 27750282 ER PT J AU Hamedani, A Safdar, B Aaronson, E Lee, TH AF Hamedani, Azita Safdar, Basmah Aaronson, Emily Lee, Thomas H. TI Patient Experience Must Move Beyond Bad Apples SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID HEALTH-CARE C1 [Hamedani, Azita] Univ Wisconsin, Sch Med & Publ Hlth, Univ Wisconsin Hosp & Clin, Dept Emergency Med, 800 Univ Bay Dr,Suite 310,Mail Code 9123, Madison, WI 53705 USA. [Safdar, Basmah] Yale Sch Med, Dept Emergency Med, 464 Congress Ave,Suite 260, New Haven, CT 06519 USA. Harvard Med Sch, Massachusetts Gen Hosp, Massachusetts Gen Phys Org, Boston, MA USA. [Lee, Thomas H.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Press Ganey, South Bend, IN USA. [Aaronson, Emily] Massachusetts Gen Hosp, Dept Emergency Med, Suite 3B, Boston, MA 02115 USA. RP Lee, TH (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM thlee@partners.org NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD DEC 20 PY 2016 VL 165 IS 12 BP 869 EP U192 DI 10.7326/M16-1725 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EG7OJ UT WOS:000391236900016 PM 27750283 ER PT J AU Kansagara, D Wilt, TJ Starkey, M Oaseem, A AF Kansagara, Devan Wilt, Timothy J. Starkey, Melissa Oaseem, Amir TI Management of Chronic Insomnia Disorder in Adults RESPONSE SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 [Kansagara, Devan] Portland Evidence Based Synth Program, Portland, OR 97239 USA. [Kansagara, Devan] Portland VA Med Ctr, Portland, OR 97239 USA. [Wilt, Timothy J.] Minneapolis VA Ctr Chron Dis Outcomes Res, Minneapolis, MN USA. [Wilt, Timothy J.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Starkey, Melissa; Oaseem, Amir] Amer Coll Physicians, Philadelphia, PA USA. RP Kansagara, D (reprint author), Portland Evidence Based Synth Program, Portland, OR 97239 USA.; Kansagara, D (reprint author), Portland VA Med Ctr, Portland, OR 97239 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD DEC 20 PY 2016 VL 165 IS 12 BP 892 EP 892 DI 10.7326/L16-0542 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EG7OJ UT WOS:000391236900029 PM 27992908 ER PT J AU Aeby, E Ahmed, W Redon, S Simanis, V Lingner, J AF Aeby, Eric Ahmed, Wareed Redon, Sophie Simanis, Viesturs Lingner, Joachim TI Peroxiredoxin 1 Protects Telomeres from Oxidative Damage and Preserves Telomeric DNA for Extension by Telomerase SO CELL REPORTS LA English DT Article ID TRIGGERS CELL-DEATH; STRESS; REPLICATION; ANTIOXIDANT; ACTIVATION; MODULATORS; INTEGRITY; REVEALS; FAMILY AB Oxidative damage of telomeres can promote cancer, cardiac failure, and muscular dystrophy. Specific mechanisms protecting telomeres from oxidative damage have not been described. We analyzed telomeric chromatin composition during the cell cycle and show that the antioxidant enzyme peroxiredoxin 1 (PRDX1) is enriched at telomeres during S phase. Deletion of the PRDX1 gene leads to damage of telomeric DNA upon oxidative stress, revealing a protective function of PRDX1 against oxidative damage at telomeres. We also show that the oxidized nucleotide 8-oxo-2' deoxyguanosine-5'-triphosphate (8oxodGTP) causes premature chain termination when incorporated by telomerase and that some DNA substrates terminating in 8oxoG prevent extension by telomerase. Thus, PRDX1 safeguards telomeres from oxygen radicals to counteract telomere damage and preserve telomeric DNA for elongation by telomerase. C1 [Aeby, Eric; Ahmed, Wareed; Redon, Sophie; Simanis, Viesturs; Lingner, Joachim] Ecole Polytech Fed Lausanne, Sch Life Sci, Swiss Inst Expt Canc Res ISREC, CH-1015 Lausanne, Switzerland. [Aeby, Eric] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Aeby, Eric] Harvard Med Sch, Dept Genet, Boston, MA 02114 USA. RP Lingner, J (reprint author), Ecole Polytech Fed Lausanne, Sch Life Sci, Swiss Inst Expt Canc Res ISREC, CH-1015 Lausanne, Switzerland. EM joachim.lingner@epfl.ch FU Swiss National Science Foundation (SNSF) [166675]; SNSF-funded NCCR RNA and disease network [141735]; Initial Training Network (ITN) grant (CodeAge) from the European Commission's Seventh Framework Programme [316354]; Swiss Cancer League [KLS-3824-02-2016]; Ecole Polytechnique Federale de Lausanne (EPFL); SNSF [156769]; EPFL FX We thank F. Armand, R. Hamelin, D. Chappe, and M. Moniatte for mass spectrometry analysis and David Hacker, Sarah Thurnheer, and Larissa Grolimund for advice with cell cultures. Research in J.L.'s laboratory was supported by the Swiss National Science Foundation (SNSF) (grant agreement no. 166675), the SNSF-funded NCCR RNA and disease network (grant agreement no. 141735), an Initial Training Network (ITN) grant (CodeAge) from the European Commission's Seventh Framework Programme (grant agreement number 316354), the Swiss Cancer League (grant agreement no. KLS-3824-02-2016), and Ecole Polytechnique Federale de Lausanne (EPFL. Research in V.S.'s laboratory was supported by the SNSF (grant agreement no. 156769) and EPFL. NR 28 TC 0 Z9 0 U1 3 U2 3 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 DEC 20 PY 2016 VL 17 IS 12 BP 3107 EP 3114 DI 10.1016/j.celrep.2016.11.071 PG 8 WC Cell Biology SC Cell Biology GA EG2SY UT WOS:000390895600003 PM 28009281 ER PT J AU Lu, YF Cahan, P Ross, S Sahalie, J Sousa, PM Hadland, BK Cai, WQ Serrao, E Engelman, AN Bernstein, ID Daley, GQ AF Lu, Yi-Fen Cahan, Patrick Ross, Samantha Sahalie, Julie Sousa, Patricia M. Hadland, Brandon K. Cai, Wenqing Serrao, Erik Engelman, Alan N. Bernstein, Irwin D. Daley, George Q. TI Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity SO CELL REPORTS LA English DT Article ID EMBRYONIC STEM-CELLS; DEFINITIVE HEMATOPOIESIS; HEMOGENIC ENDOTHELIUM; PROGENITOR CELLS; YOLK-SAC; NOTCH; INDUCTION; PROMOTES; DIFFERENTIATION; ACTIVATION AB Hematopoietic stemcell (HSC) transplantationis curative for malignant and genetic blood disorders, but is limited by donor availability and immune-mismatch. Deriving HSCs from patient-matched embryonic/induced-pluripotent stem cells (ESCs/iPSCs) could address these limitations. Prior efforts in murine models exploited ectopic HoxB4 expression to drive self-renewal and enable multi-lineage reconstitution, yet fell short in delivering robust lymphoid engraftment. Here, by titrating exposure of HoxB4-ESC-HSC to Notch ligands, we report derivation of engineered HSCs that self-renew, repopulate multi-lineage hematopoiesis in primary and secondary engrafted mice, and endow adaptive immunity in immune- deficient recipients. Single-cell analysis shows that following engraftment in the bone marrow niche, these engineered HSCs further specify to a hybrid cell type, in which distinct gene regulatory networks of hematopoietic stem/progenitors and differentiated hematopoietic lineages are co-expressed. Our work demonstrates engineering of fully functional HSCs via modulation of genetic programs that govern self-renewal and lineage priming. C1 [Lu, Yi-Fen; Cahan, Patrick; Ross, Samantha; Sahalie, Julie; Sousa, Patricia M.; Cai, Wenqing; Daley, George Q.] Childrens Hosp Boston, Howard Hughes Med Inst, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA. [Lu, Yi-Fen; Cahan, Patrick; Daley, George Q.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Lu, Yi-Fen; Cahan, Patrick; Ross, Samantha; Sahalie, Julie; Sousa, Patricia M.; Daley, George Q.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Cahan, Patrick] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Dept Biomed Engn, Baltimore, MD 21205 USA. [Hadland, Brandon K.; Bernstein, Irwin D.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Hadland, Brandon K.; Bernstein, Irwin D.] Univ Washington, Dept Pediat, Seattle, WA 98105 USA. [Serrao, Erik; Engelman, Alan N.] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA. RP Daley, GQ (reprint author), Childrens Hosp Boston, Howard Hughes Med Inst, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA.; Daley, GQ (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Daley, GQ (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM george.daley@childrens.harvard.edu FU NIH [UO1-HL100001, R24DK092760, NIDDK K01DK096013]; Boston Children's Hospital Stem Cell Program FX We thank members of the Daley laboratory for critical discussions, the flow cytometry core at Boston Children's Hospital for key analytic resources, the Biopolymers facility at Harvard Medical School for single cell RNA-seq service, and the Coriell Institute for microarray processing. G.Q.D. is supported by grants from the NIH (Progenitor Cell Biology Consortium UO1-HL100001 and R24DK092760) and the Boston Children's Hospital Stem Cell Program. P.C. received support from NIH (NIDDK K01DK096013). NR 45 TC 0 Z9 0 U1 4 U2 4 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 DEC 20 PY 2016 VL 17 IS 12 BP 3178 EP 3192 DI 10.1016/j.celrep.2016.11.077 PG 15 WC Cell Biology SC Cell Biology GA EG2SY UT WOS:000390895600010 PM 28009288 ER PT J AU Luo, SX Timbang, L Kim, JI Shang, YL Sandoval, K Tang, AA Whistler, JL Ding, JB Huang, EJ AF Luo, Sarah X. Timbang, Leah Kim, Jae-Ick Shang, Yulei Sandoval, Kadellyn Tang, Amy A. Whistler, Jennifer L. Ding, Jun B. Huang, Eric J. TI TGF-beta Signaling in Dopaminergic Neurons Regulates Dendritic Growth, Excitatory-Inhibitory Synaptic Balance, and Reversal Learning SO CELL REPORTS LA English DT Article ID IN-VIVO; MICE; NEUROGENESIS; EXPRESSION; SURVIVAL; DISRUPTION; RECEPTORS; BEHAVIOR; DEFECTS; APLYSIA AB Neural circuits involving midbrain dopaminergic (DA) neurons regulate reward and goal-directed behaviors. Although local GABAergic input is known to modulate DA circuits, the mechanism that controls excitatory/inhibitory synaptic balance in DA neurons remains unclear. Here, we show that DA neurons use autocrine transforming growth factor beta (TGF-beta) signaling to promote the growth of axons and dendrites. Surprisingly, removing TGF-beta type II receptor in DA neurons also disrupts the balance in TGF-beta 1 expression in DA neurons and neighboring GABAergic neurons, which increases inhibitory input, reduces excitatory synaptic input, and alters phasic firing patterns in DA neurons. Mice lacking TGF-beta signaling in DA neurons are hyperactive and exhibit inflexibility in relinquishing learned behaviors and re-establishing new stimulus-reward associations. These results support a role for TGF-beta in regulating the delicate balance of excitatory/inhibitory synaptic input in local microcircuits involving DA and GABAergic neurons and its potential contributions to neuropsychiatric disorders. C1 [Luo, Sarah X.; Timbang, Leah; Shang, Yulei; Sandoval, Kadellyn; Tang, Amy A.; Huang, Eric J.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [Luo, Sarah X.; Whistler, Jennifer L.; Huang, Eric J.] Univ Calif San Francisco, Neurosci Grad Program, San Francisco, CA 94143 USA. [Kim, Jae-Ick; Ding, Jun B.] Stanford Univ, Dept Neurosurg, Palo Alto, CA 94304 USA. [Kim, Jae-Ick; Ding, Jun B.] Stanford Univ, Dept Neurol & Neurol Sci, Palo Alto, CA 94304 USA. [Whistler, Jennifer L.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Huang, Eric J.] San Francisco VA Med Ctr, Pathol Serv 113B, San Francisco, CA 94121 USA. [Kim, Jae-Ick] Ulsan Natl Inst Sci & Technol, Sch Life Sci, Ulsan 44919, South Korea. RP Huang, EJ (reprint author), Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA.; Huang, EJ (reprint author), Univ Calif San Francisco, Neurosci Grad Program, San Francisco, CA 94143 USA.; Huang, EJ (reprint author), San Francisco VA Med Ctr, Pathol Serv 113B, San Francisco, CA 94121 USA. EM eric.huang2@ucsf.edu RI Ding, Jun/B-2513-2009 OI Ding, Jun/0000-0003-0690-1312 FU NIH [NS081485, NS098516, NS091144, DA037963]; Department of Veterans Affairs [BX001108, RX002133]; Klingenstein Foundation; state of California for medical research on alcohol and substance abuse through UCSF; A*STAR Scholar Program FX We thank Ivy Hsieh for help with the electron microscope (EM), Dr. Linda Noble and UCSF Neurobehavioral Core Facility for help with motor behavioral analyses, and Dr. Michael Kohn and Dr. Isabel Elaine Allen for statistical analyses. This work has been supported by grants from NIH NS081485 and NS098516 (E.J.H.), NS091144 (J.B.D.), DA037963 (J.L.W.), and from the Department of Veterans Affairs BX001108 and RX002133 (E.J.H.), the Klingenstein Foundation (J.B.D.), and funds provided by the state of California for medical research on alcohol and substance abuse through UCSF (J.L.W.). S.X.L. was supported by the A*STAR Scholar Program. NR 41 TC 0 Z9 0 U1 1 U2 1 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 DEC 20 PY 2016 VL 17 IS 12 BP 3233 EP 3245 DI 10.1016/j.celrep.2016.11.068 PG 13 WC Cell Biology SC Cell Biology GA EG2SY UT WOS:000390895600014 PM 28009292 ER PT J AU Hinson, JT Chopra, A Lowe, A Sheng, CC Gupta, RM Kuppusamy, R O'Sullivan, J Rowe, G Wakimoto, H Gorham, J Zhang, KH Musunuru, K Gerszten, RE Wu, SM Chen, CS Seidman, JG Seidman, CE AF Hinson, J. Travis Chopra, Anant Lowe, Andre Sheng, Calvin C. Gupta, Rajat M. Kuppusamy, Rajarajan O'Sullivan, John Rowe, Glenn Wakimoto, Hiroko Gorham, Joshua Zhang, Kehan Musunuru, Kiran Gerszten, Robert E. Wu, Sean M. Chen, Christopher S. Seidman, Jonathan G. Seidman, Christine E. TI Integrative Analysis of PRKAG2 Cardiomyopathy iPS and Microtissue Models Identifies AMPK as a Regulator of Metabolism, Survival, and Fibrosis SO CELL REPORTS LA English DT Article ID PARKINSON-WHITE-SYNDROME; EPITHELIAL-MESENCHYMAL TRANSITION; PROTEIN-KINASE ACTIVITY; HYPERTROPHIC CARDIOMYOPATHY; GLYCOGEN-STORAGE; DILATED CARDIOMYOPATHY; PRESSURE-OVERLOAD; ANGIOTENSIN-II; GROWTH-FACTOR; MOUSE MODEL AB AMP-activated protein kinase (AMPK) is a metabolic enzyme that can be activated by nutrient stress or geneticmutations. Missense mutations in the regulatory subunit, PRKAG2, activate AMPK and cause left ventricular hypertrophy, glycogen accumulation, and ventricular pre-excitation. Using human iPS cell models combined with three-dimensional cardiac microtissues, we show that activating PRKAG2 mutations increase microtissue twitch force by enhancing myocyte survival. Integrating RNA sequencing with metabolomics, PRKAG2 mutations that activate AMPK remodeled global metabolism by regulating RNA transcripts to favor glycogen storage and oxidative metabolism instead of glycolysis. As in patients with PRKAG2 cardiomyopathy, iPS cell and mouse models are protected from cardiac fibrosis, and we define a crosstalk between AMPK and post-transcriptional regulation of TGF beta isoform signaling that has implications in fibrotic forms of cardiomyopathy. Our results establish critical connections among metabolic sensing, myocyte survival, and TGF beta signaling. C1 [Hinson, J. Travis; Lowe, Andre] Jackson Lab Genom Med, Farmington, CT 06032 USA. [Hinson, J. Travis] Univ Connecticut Hlth, Ctr Cardiol, Farmington, CT 06030 USA. [Chopra, Anant; Zhang, Kehan; Chen, Christopher S.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Chopra, Anant; Zhang, Kehan; Chen, Christopher S.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Sheng, Calvin C.; Wakimoto, Hiroko; Gorham, Joshua; Seidman, Jonathan G.; Seidman, Christine E.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Gupta, Rajat M.; Seidman, Christine E.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Kuppusamy, Rajarajan; Wu, Sean M.] Stanford Univ, Sch Med, Cardiovasc Inst, Div Cardiovasc Med, Stanford, CA 94305 USA. [O'Sullivan, John; Gerszten, Robert E.] Massachusetts Gen Hosp, Div Cardiovasc Med, Boston, MA 02114 USA. [Rowe, Glenn] Univ Alabama Birmingham, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Musunuru, Kiran] Univ Penn, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA. [Gerszten, Robert E.] Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, Boston, MA 02115 USA. [Seidman, Christine E.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Hinson, JT (reprint author), Jackson Lab Genom Med, Farmington, CT 06032 USA.; Hinson, JT (reprint author), Univ Connecticut Hlth, Ctr Cardiol, Farmington, CT 06030 USA.; Seidman, CE (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.; Seidman, CE (reprint author), Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA.; Seidman, CE (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. EM travis.hinson@jax.org; cseidman@genetics.med.harvard.edu OI Rowe, Glenn/0000-0002-8195-9605 FU NIH [HL125807, AR062128, UH3EB017103, EB001046, HL080494, HL128810, HL084553]; John S. Ladue Foundation; Leducq Foundation; Sarnoff Foundation; Howard Hughes Medical Institute FX We thank Barbara McDonough, Kaoru Ito, and Gregory Fishbein for their contributions. C.S.C. is the scientific founder of Innolign Biological, which is developing CMTs for commercial applications. This work was supported in part by grants from NIH HL125807 (to J.T.H.), AR062128 (to G.R.), UH3EB017103 (to C.S.C.), EB001046 (to C.S.C.), HL080494 (to J.G.S. and C.S.C.), HL128810 (to R.M.G.), HL084553 (to J.G.S.), John S. Ladue Foundation (to J.T.H.), Leducq Foundation (to J.G.S. and C.E.S.), Sarnoff Foundation (to C.C.S.), and the Howard Hughes Medical Institute (to C.E.S.). NR 49 TC 0 Z9 0 U1 6 U2 6 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 DEC 20 PY 2016 VL 17 IS 12 BP 3292 EP 3304 DI 10.1016/j.celrep.2016.11.066 PG 13 WC Cell Biology SC Cell Biology GA EG2SY UT WOS:000390895600019 PM 28009297 ER PT J AU Pecot, J Maillet, L Le Pen, J Vuillier, C Trecesson, SD Fetiveau, A Sarosiek, KA Bock, FJ Braun, F Letai, A Tait, SWG Gautier, F Juin, PP AF Pecot, Jessie Maillet, Laurent Le Pen, Janic Vuillier, Celine Trecesson, Sophie de Came Fetiveau, Aurelie Sarosiek, Kristopher A. Bock, Florian J. Braun, Frederique Letai, Anthony Tait, Stephen W. G. Gautier, Fabien Juin, Philippe P. TI Tight Sequestration of BH3 Proteins by BCL-xL at Subcellular Membranes Contributes to Apoptotic Resistance SO CELL REPORTS LA English DT Article ID LIVE MCF-7 CELLS; BH3-ONLY PROTEINS; BAX ACTIVATION; FAMILY; DEATH; PUMA; ABT-737; MITOCHONDRIA; BINDING; OLIGOMERIZATION AB Anti-apoptotic BCL-2 family members bind to BH3-only proteins and multidomain BAX/BAK to preserve mitochondrial integrity and maintain survival. Whereas inhibition of these interactions is the biological basis of BH3-mimetic anti-cancer therapy, the actual response of membrane-bound protein complexes to these compounds is currently ill-defined. Here, we find that treatment with BH3 mimetics targeting BCL-xL spares subsets of cells with the highest levels of this protein. In intact cells, sequestration of some pro-apoptotic activators (including PUMA and BIM) by full-length BCL-xL is much more resistant to derepression than previously described in cell-free systems. Alterations in the BCL-xL C-terminal anchor that impacts subcellular membrane-targeting and localization dynamics restore sensitivity. Thus, the membrane localization of BCL-xL enforces its control over cell survival and, importantly, limits the pro-apoptotic effects of BH3 mimetics by selectively influencing BCL-xL binding to key proapoptotic effectors. C1 [Pecot, Jessie; Maillet, Laurent; Le Pen, Janic; Vuillier, Celine; Trecesson, Sophie de Came; Fetiveau, Aurelie; Braun, Frederique; Gautier, Fabien; Juin, Philippe P.] Univ Nantes, Univ Angers, CNRS, CRCNA,INSERM, F-44035 Nantes, France. [Gautier, Fabien; Juin, Philippe P.] ICO Rene Gauducheau, F-44805 St Herblain, France. [Sarosiek, Kristopher A.; Letai, Anthony] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02215 USA. [Bock, Florian J.; Tait, Stephen W. G.] Univ Glasgow, Inst Canc Sci, Canc Res UK Beatson Inst, Garscube Estate,Switchback Rd, Glasgow G61 1BD, Lanark, Scotland. [Trecesson, Sophie de Came] Francis Crick Inst, Oncogene Biol Lab, 1 Midland Rd, London NW1 1AT, England. [Braun, Frederique] Univ Paris Diderot, Sorbonne Paris Cite, CNRS FRE3630, Inst Biol Physiochim, 13 Rue Pierre & Marie Curie, F-75005 Paris, France. RP Gautier, F; Juin, PP (reprint author), Univ Nantes, Univ Angers, CNRS, CRCNA,INSERM, F-44035 Nantes, France.; Gautier, F; Juin, PP (reprint author), ICO Rene Gauducheau, F-44805 St Herblain, France. EM fabien.gautier@univ-nantes.fr; philippe.juin@univ-nantes.fr OI BRAUN, Frederique/0000-0001-5871-6042 FU Ministere de la Recherche et de l'Enseignement Superieur; INSERM Region; Region Pays de la Loire [CIMATH2]; Ligue contre le Cancer [R13137]; ARC [R15083NN]; INCA PLBio [R12134NN] FX We thank members of the "Cell Survival and Tumor Escape in Breast Cancer'' laboratory for their technical advice, fruitful comments, and enthusiasm. We thank C. Couriaud for her technical help in the preparation of lentivirus particles and Dr. F. Edlich for the generous gift of BCL-xL D2 allele. We are grateful for technical support from the Cellular and Tissular Imaging (MicroPICell) and Molecular Interactions and Protein Activities (IMPACT) Core Facilities of Nantes University. J.P. and C.V. are supported by PhD fellowships from the Ministere de la Recherche et de l'Enseignement Superieur, and J.L.P. was supported by a PhD fellowship from INSERM Region. This work was supported by Region Pays de la Loire (CIMATH2), Ligue contre le Cancer (R13137), ARC (R15083NN), and INCA PLBio 2013 (R12134NN). NR 49 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD DEC 20 PY 2016 VL 17 IS 12 BP 3347 EP 3358 DI 10.1016/j.celrep.2016.11.064 PG 12 WC Cell Biology SC Cell Biology GA EG2SY UT WOS:000390895600023 PM 28009301 ER PT J AU Liu, LL Brumbaugh, J Bar-Nur, O Smith, Z Stadtfeld, M Meissner, A Hochedlinger, K Michor, F AF Liu, Lin L. Brumbaugh, Justin Bar-Nur, Ori Smith, Zachary Stadtfeld, Matthias Meissner, Alexander Hochedlinger, Konrad Michor, Franziska TI Probabilistic Modeling of Reprogramming to Induced Pluripotent Stem Cells SO CELL REPORTS LA English DT Article ID SOMATIC-CELLS; IPS CELLS; DYNAMICS; GENERATION; PATHWAYS; REVEALS; FATES AB Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) is typically an inefficient and asynchronous process. A variety of technological efforts have been made to accelerate and/or synchronize this process. To define a unified framework to study and compare the dynamics of reprogramming under different conditions, we developed an in silico analysis platform based on mathematical modeling. Our approach takes into account the variability in experimental results stemming from probabilistic growth and death of cells and potentially heterogeneous reprogramming rates. We suggest that re-programming driven by the Yamanaka factors alone is a more heterogeneous process, possibly due to cell-specific reprogramming rates, which could be homogenized by the addition of additional factors. We validated our approach using publicly available reprogramming datasets, including data on early re-programming dynamics as well as cell count data, and thus we demonstrated the general utility and predictive power of our methodology for investigating reprogramming and other cell fate change systems. C1 [Liu, Lin L.; Michor, Franziska] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Liu, Lin L.; Michor, Franziska] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Brumbaugh, Justin; Bar-Nur, Ori; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Brumbaugh, Justin; Bar-Nur, Ori; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Brumbaugh, Justin; Bar-Nur, Ori; Hochedlinger, Konrad] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Brumbaugh, Justin; Bar-Nur, Ori; Smith, Zachary; Meissner, Alexander; Hochedlinger, Konrad] Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Stadtfeld, Matthias] NYU, Sch Med, Dept Cell Biol, Helen L & Martin S Kimmel Ctr Biol & Med,Skirball, New York, NY 10016 USA. [Hochedlinger, Konrad] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Michor, F (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA.; Michor, F (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. EM michor@jimmy.harvard.edu OI Stadtfeld, Matthias/0000-0002-5852-9906 FU National Institute of General Medical Sciences (NIGMS) [P01GM099117]; National Human Genome Research Institute (NHGRI) [1P50HG006193]; New York Stem Cell Foundation; Dana-Farber Cancer Institute Physical Sciences-Oncology Center [U54CA143798]; NIH [R01HD058013] FX The authors would like to thank the F.M. lab (in particular Thomas O. McDonald and Philipp M. Altrock) and K.H. lab as well as Jacob Hanna, Bruno Di Stefano, James M. Robins, Lam Si Tung Ho, Marc A. Suchard, Lorenzo Trippa, Kai Fu, and Giovanni Parmigiani for insightful discussions. A.M. was supported by the National Institute of General Medical Sciences (NIGMS) (P01GM099117) and the National Human Genome Research Institute (NHGRI) (1P50HG006193). A.M. and F.M. are supported by the New York Stem Cell Foundation, and A.M. is a New York Stem Cell Foundation Robertson Investigator. We gratefully acknowledge support from the Dana-Farber Cancer Institute Physical Sciences-Oncology Center (U54CA143798 to F.M.). K.H. was supported by the NIH (R01HD058013). NR 32 TC 0 Z9 0 U1 9 U2 9 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 DEC 20 PY 2016 VL 17 IS 12 BP 3395 EP 3406 DI 10.1016/j.celrep.2016.11.080 PG 12 WC Cell Biology SC Cell Biology GA EG2SY UT WOS:000390895600027 PM 28009305 ER PT J AU Ficarro, SB Browne, CM Card, JD Alexander, WM Zhang, TH Park, E McNally, R Dhe-Paganon, S Seo, HS Lamberto, I Eck, MJ Buhrlage, SJ Gray, NS Marto, JA AF Ficarro, Scott B. Browne, Christopher M. Card, Joseph D. Alexander, William M. Zhang, Tinghu Park, Eunyoung McNally, Randall Dhe-Paganon, Sirano Seo, Hyuk-Soo Lamberto, Ilaria Eck, Michael J. Buhrlage, Sara J. Gray, Nathanael S. Marto, Jarrod A. TI Leveraging Gas-Phase Fragmentation Pathways for Improved Identification and Selective Detection of Targets Modified by Covalent Probes SO ANALYTICAL CHEMISTRY LA English DT Article ID TYROSINE KINASE INHIBITOR; MASS-SPECTROMETRY; IRREVERSIBLE INHIBITORS; PSEUDOKINASE HER3; CARRIER DOMAINS; SOLID TUMORS; IN-VITRO; DISCOVERY; CANCER; THERAPY AB The recent approval of covalent inhibitors for multiple clinical indications has reignited enthusiasm for this class of drugs. As interest in covalent drugs has increased, so too has the need for analytical platforms that can leverage their mechanism-of-action to characterize modified protein targets. Here we describe novel gas phase dissociation pathways which yield predictable fragment ions during MS/MS of inhibitor-modified peptides. We find that these dissociation pathways are common to numerous cysteine-directed probes as well as the covalent drugs, Ibrutinib and Neratinib. We leverage the predictable nature of these fragment ions to improve the confidence of peptide sequence assignment in proteomic analyses and explore their potential use in selective mass spectrometry-based assays. C1 [Ficarro, Scott B.; Browne, Christopher M.; Card, Joseph D.; Alexander, William M.; Zhang, Tinghu; Park, Eunyoung; McNally, Randall; Dhe-Paganon, Sirano; Seo, Hyuk-Soo; Lamberto, Ilaria; Eck, Michael J.; Buhrlage, Sara J.; Gray, Nathanael S.; Marto, Jarrod A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Ficarro, Scott B.; Card, Joseph D.; Alexander, William M.; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA. [Ficarro, Scott B.; Browne, Christopher M.; Alexander, William M.; Zhang, Tinghu; Park, Eunyoung; McNally, Randall; Dhe-Paganon, Sirano; Seo, Hyuk-Soo; Lamberto, Ilaria; Eck, Michael J.; Buhrlage, Sara J.; Gray, Nathanael S.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Marto, Jarrod A.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Marto, Jarrod A.] Harvard Med Sch, Boston, MA 02115 USA. RP Marto, JA (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA.; Marto, JA (reprint author), Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA.; Marto, JA (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA.; Marto, JA (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM jarrod_marto@dfci.harvard.edu FU Strategic Research Initiative at the Dana-Farber Cancer Institute; National Cancer Institute [CA188881]; National Institutes of Health [CA182736-03, CA179483-03, GM110352, CA201049] FX This work was supported by the Strategic Research Initiative at the Dana-Farber Cancer Institute and the National Cancer Institute (Grant CA188881, to JAM) in addition to the National Institutes of Health Grants CA182736-03 and CA179483-03 (to N.S.G.) and Grants GM110352 and CA201049 (to M.J.E.). NR 51 TC 0 Z9 0 U1 3 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD DEC 20 PY 2016 VL 88 IS 24 BP 12248 EP 12254 DI 10.1021/acs.analchem.6b03394 PG 7 WC Chemistry, Analytical SC Chemistry GA EF8ZR UT WOS:000390621000040 PM 28193034 ER PT J AU Boehmer, JP Hariharan, R Devecchi, FG Smith, AL Giulio, M Capucci, A An, Q Averina, V Thakur, PH Wariar, R Zhang, Y Singh, J AF Boehmer, John P. Hariharan, Ramesh Devecchi, Fausto G. Smith, Andrew L. Giulio, Molon Capucci, Alessandro An, Qi Averina, Viktoria Thakur, Pramodsingh H. Wariar, Ramesh Zhang, Yi Singh, Jagmeet TI A Multi-sensor Algorithm Predicts Heart Failure Events in Patients with Implanted Devices: Results from the MULTISENSE Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium CY NOV 12-16, 2016 CL New Orleans, LA SP Amer Heart Assoc C1 [Boehmer, John P.] Penn State Univ, Coll Med, Hershey, PA USA. [Hariharan, Ramesh] Univ Texas Phys, Clin Cardiac Electrophysiol, Houston, TX USA. [Devecchi, Fausto G.] Lutheran Hlth Network, Cardiac Arrhythmia Serv, Ft Wayne, IN USA. [Smith, Andrew L.] Emory Univ, Atlanta, GA 30322 USA. [Giulio, Molon] Sacro Cuore Hosp, Cardiol, Negrar, Italy. [Capucci, Alessandro] Univ Politecn March, Cardiol & Arrhythmol Clin, Ancona, Italy. [An, Qi; Averina, Viktoria; Thakur, Pramodsingh H.; Wariar, Ramesh; Zhang, Yi] Boston Sci, Marlborough, MA USA. [Singh, Jagmeet] Massachusetts Gen Hosp, Ctr Heart, Boston, MA 02114 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD DEC 20 PY 2016 VL 134 IS 25 MA 24089 BP E708 EP E708 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF8DY UT WOS:000390560100018 ER PT J AU Butler, J Konstam, MA Felker, M Kalogeropoulos, AP Givertz, MM Mann, DL Margulies, KB Redfield, MM Semigran, MJ Tang, W Whellan, DJ McNulty, SE Anstrom, KJ Desvigne-Nickens, P Hernandez, AF Braunwald, E AF Butler, Javed Konstam, Marvin A. Felker, Michael Kalogeropoulos, Andreas P. Givertz, Michael M. Mann, Douglas L. Margulies, Kenneth B. Redfield, Margaret M. Semigran, Marc J. Tang, Wilson Whellan, David J. McNulty, Stephen E. Anstrom, Kevin J. Desvigne-Nickens, Patrice Hernandez, Adrian F. Braunwald, Eugene TI Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure (ATHENA-HF) Trial SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium CY NOV 12-16, 2016 CL New Orleans, LA SP Amer Heart Assoc C1 [Butler, Javed] SUNY Stony Brook, Med, Atlanta, GA USA. [Konstam, Marvin A.] Tufts Univ, Med, Boston, MA 02111 USA. [Felker, Michael] Duke Univ, Med, Durham, NC USA. [Kalogeropoulos, Andreas P.] Emory, Med, Atlanta, GA USA. [Givertz, Michael M.] Brigham & Womens Hosp, Med, Boston, MA 02115 USA. [Mann, Douglas L.; Braunwald, Eugene] Washington Univ, Med, St Louis, MO USA. [Margulies, Kenneth B.] Univ Penn, Med, Philadelphia, PA 19104 USA. [Redfield, Margaret M.] Mayo Clin, Med, Rochester, MN USA. [Semigran, Marc J.; Braunwald, Eugene] Mass Gen Hosp, Med, Boston, MA USA. [Tang, Wilson] Cleveland Clin, Med, Cleveland, OH 44106 USA. [Whellan, David J.] Thomas Jefferson Univ, Med, Philadelphia, PA 19107 USA. [McNulty, Stephen E.] Duke, DCRI, Durham, NC USA. [Anstrom, Kevin J.; Hernandez, Adrian F.] Duke, Med, Durham, NC USA. [Desvigne-Nickens, Patrice] NHLBI, Bethesda, MD 20892 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD DEC 20 PY 2016 VL 134 IS 25 MA 21206 BP E707 EP E708 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF8DY UT WOS:000390560100015 ER PT J AU Lewis, GD Anstrom, KJ McNulty, S Hernandez, AF Braunwald, E AF Lewis, Gregory D. Anstrom, Kevin J. McNulty, Steven Hernandez, Adrian F. Braunwald, Eugene CA NHLBI Heart Failure Network TI Oral Iron Repletion effects on Oxygen Uptake in Heart Failure (IRONOUT HF) SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium CY NOV 12-16, 2016 CL New Orleans, LA SP Amer Heart Assoc C1 [Lewis, Gregory D.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Anstrom, Kevin J.; McNulty, Steven] Duke Univ, Div Cardiol, Durham, NC USA. [Hernandez, Adrian F.] Duke Univ, Div Cardiol, Durham, MA USA. [Braunwald, Eugene] Harvard Med Sch, Div Cardiol, Boston, MA 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD DEC 20 PY 2016 VL 134 IS 25 MA 21208 BP E708 EP E708 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF8DY UT WOS:000390560100016 ER PT J AU Merchant, RM Volpp, KG Asch, DA AF Merchant, Raina M. Volpp, Kevin G. Asch, David A. TI Learning by Listening-Improving Health Care in the Era of Yelp SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID PATIENT EXPERIENCE C1 [Merchant, Raina M.; Asch, David A.] Univ Penn, Perelman Sch Med, Penn Med Ctr Hlth Care Innovat, Philadelphia, PA 19104 USA. [Merchant, Raina M.] Univ Penn, Perelman Sch Med, Dept Emergency Med, Philadelphia, PA 19104 USA. [Volpp, Kevin G.] Univ Penn, Perelman Sch Med, Ctr Hlth Incent & Behav Econ, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Asch, David A.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Merchant, RM (reprint author), Univ Penn, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM raina.merchant@uphs.upenn.edu NR 5 TC 0 Z9 0 U1 3 U2 3 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 DEC 20 PY 2016 VL 316 IS 23 BP 2483 EP 2484 DI 10.1001/jama.2016.16754 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EG3QH UT WOS:000390959300011 PM 27997663 ER PT J AU Lee, JS Giesler, DL Fine, MJ AF Lee, Jonathan S. Giesler, Daniel L. Fine, Michael J. TI Duration of Antibiotic Therapy for Community-Acquired Pneumonia in the Era of Personalized Medicine SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID GUIDELINES AB IMPORTANCE The optimal duration of antibiotic treatment for community acquired pneumonia (CAP) has not been well established. OBJECTIVE To validate Infectious Diseases Society of America/American Thoracic Society guidelines for duration of antibiotic treatment in hospitalized patients with CAP. DESIGN, SETTING, AND PARTICIPANTS This study was a multicenter, noninferiority randomized clinical trial performed at 4 teaching hospitals in Spain from January 1, 2012, through August 31, 2013. A total of 312 hospitalized patients diagnosed as having CAP were studied. Data analysis was performed from January 1, 2014, through February 28, 2015. INTERVENTIONS Patients were randomized at day 5 to an intervention or control group. Those in the intervention group were treated with antibiotics for a minimum of 5 days, and the antibiotic treatment was stopped at this point if their body temperature was 37.8 degrees C or less for 48 hours and they had no more than 1 CAP-associated sign of clinical instability. Duration of antibiotic treatment in the control group was determined by physicians. MAIN OUTCOMES AND MEASURES Clinical success rate at days 10 and 30 since admission and CAP-related symptoms at days 5 and 10 measured with the 18-item CAP symptom questionnaire score range, 0-90; higher scores indicate more severe symptoms. RESULTS Of the 312 patients included, 150 and 162 were randomized to the control and intervention groups, respectively. The mean (SD) age of the patientswas 66.2 (17.9) years and 64.7 (18.7) years in the control and intervention groups, respectively. Therewere 95 men (63.3%) and 55women (36.7%) in the control group and 101 men (62.3%) and 61 women (37.7%) in the intervention group. In the intent-to-treat analysis, clinical success was 48.6%(71 of 150) in the control group and 56.3% (90 of 162) in the intervention group at day 10 (P =.18) and 88.6%(132 of 150) in the control group and 91.9%(147 of 162) in the intervention group at day 30 (P =.33). The mean (SD) CAP symptom questionnaire scoreswere 24.7 (11.4) vs 27.2 (12.5) at day 5 (P =.10) and 18.6 (9.0) vs 17.9 (7.6) at day 10 (P =.69). In the per-protocol analysis, clinical successwas 50.4%(67 of 137) in the control group and 59.7%(86 of 146) in the intervention group at day 10 (P =.12) and 92.7%(126 of 137) in the control group and 94.4%(136 of 146) in the intervention group at day 30 (P = .54). The mean (SD) CAP symptom questionnaire scores were 24.3 (11.4) vs 26.6 (12.1) at day 5 (P = .16) and 18.1 (8.5) vs 17.6 (7.4) at day 10 (P = .81). CONCLUSIONS AND RELEVANCE The Infectious Diseases Society of America/American Thoracic Society recommendations for duration of antibiotic treatment based on clinical stability criteria can be safely implemented in hospitalized patients with CAP. C1 [Lee, Jonathan S.] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA USA. [Giesler, Daniel L.; Fine, Michael J.] Univ Pittsburgh, Sch Med, Dept Med, Div Gen Internal Med, Pittsburgh, PA 15213 USA. [Fine, Michael J.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, 151C Univ Dr,Bldg 30, Pittsburgh, PA 15240 USA. RP Fine, MJ (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, 151C Univ Dr,Bldg 30, Pittsburgh, PA 15240 USA. EM michael.fine@va.gov NR 6 TC 0 Z9 0 U1 3 U2 3 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 DEC 20 PY 2016 VL 316 IS 23 BP 2544 EP 2545 DI 10.1001/jamainternmed.2016.3633 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EG3QH UT WOS:000390959300022 PM 27997641 ER PT J AU Clark, NE Katolik, A Roberts, KM Taylor, AB Holloway, SP Schuermann, JP Montemayor, EJ Stevens, SW Fitzpatrick, PF Damha, MJ Hart, PJ AF Clark, Nathaniel E. Katolik, Adam Roberts, Kenneth M. Taylor, Alexander B. Holloway, Stephen P. Schuermann, Jonathan P. Montemayor, Eric J. Stevens, Scott W. Fitzpatrick, Paul F. Damha, Masad J. Hart, P. John TI Metal dependence and branched RNA cocrystal structures of the RNA lariat debranching enzyme Dbr1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE RNA debranching; intron lariat; enzyme kinetics; X-ray crystallography; Dbr1 ID WAGR SYNDROME; MECHANISM; SITES; PHOSPHODIESTERASE; 5'-NUCLEOTIDASE; SPLICEOSOME; PROTEINS; TURNOVER; BINDING; REVEAL AB Intron lariats are circular, branched RNAs (bRNAs) produced during pre-mRNA splicing. Their unusual chemical and topological properties arise from branch-point nucleotides harboring vicinal 2', 5'- and 3', 5'-phosphodiester linkages. The 2', 5'-bonds must be hydrolyzed by the RNA debranching enzyme Dbr1 before spliced introns can be degraded or processed into small nucleolar RNA and microRNA derived from intronic RNA. Here, we measure the activity of Dbr1 from Entamoeba histolytica by using a synthetic, dark-quenched bRNA substrate that fluoresces upon hydrolysis. Purified enzyme contains nearly stoichiometric equivalents of Fe and Zn per polypeptide and demonstrates turnover rates of similar to 3 s(-1). Similar rates are observed when apo-Dbr1 is reconstituted with Fe(II)+Zn(II) under aerobic conditions. Under anaerobic conditions, a rate of similar to 4.0 s(-1) is observed when apoenzyme is reconstituted with Fe(II). In contrast, apo-Dbr1 reconstituted with Mn(II) or Fe(II) under aerobic conditions is inactive. Diffraction data from crystals of purified enzyme using X-rays tuned to the Fe absorption edge show Fe partitions primarily to the beta-pocket and Zn to the alpha-pocket. Structures of the catalytic mutant H91A in complex with 7-mer and 16-mer synthetic bRNAs reveal bona fide RNA branchpoints in the Dbr1 active site. A bridging hydroxide is in optimal position for nucleophilic attack of the scissile phosphate. The results clarify uncertainties regarding structure/function relationships in Dbr1 enzymes, and the fluorogenic probe permits high-throughput screening for inhibitors that may hold promise as treatments for retroviral infections and neurodegenerative disease. C1 [Clark, Nathaniel E.; Taylor, Alexander B.; Holloway, Stephen P.; Fitzpatrick, Paul F.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem & Struct Biol, San Antonio, TX 78229 USA. [Katolik, Adam; Damha, Masad J.] McGill Univ, Dept Chem, Montreal, PQ H3A 0B8, Canada. [Roberts, Kenneth M.] Univ Southern Carolina Aiken, Dept Chem & Phys, Aiken, SC 29811 USA. [Taylor, Alexander B.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Xray Crystallog Core Lab, San Antonio, TX 78229 USA. [Schuermann, Jonathan P.] Cornell Univ, Dept Chem & Chem Biol, Northeastern Collaborat Access Team, Ithaca, NY 14853 USA. [Montemayor, Eric J.] Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. [Montemayor, Eric J.] Univ Wisconsin, Dept Biomol Chem, Madison, WI 53706 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, San Antonio, TX 78229 USA. RP Clark, NE (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem & Struct Biol, San Antonio, TX 78229 USA. EM clarkn@uthscsa.edu; fitzpatrickp@uthscsa.edu; masad.damha@mcgill.ca; pjh@biochem.uthscsa.edu FU US Department of Veterans Affairs, Biomedical Laboratory Research and Development Service, S. Texas Veterans Health Care System [I01 BX0025801]; Welch Foundation [AQ-1399, AQ-1245]; Judith and Jean Pape Adams Charitable Foundation; National Sciences and Engineering Research Council of Canada; National Institutes of Health (NIH) [GM084246]; NIH through the Barshop Institute for Longevity and Aging Studies [T-32 AG021890]; National Science Foundation [DBI-0905865]; US Department of Energy [DE-AC02-06CH11357]; Office of the Vice President for Research; San Antonio Cancer Institute [P30 CA054174]; National Center for Advancing Translational Sciences, NIH [UL1 TR001120]; NIH [P41 GM103403] FX P.J.H. was supported in part by Merit Review Award I01 BX0025801 from the US Department of Veterans Affairs, Biomedical Laboratory Research and Development Service, S. Texas Veterans Health Care System, and in part by a Welch Foundation Grant AQ-1399 and by the Judith and Jean Pape Adams Charitable Foundation. M.J.D. was supported by a Discovery Grant from the National Sciences and Engineering Research Council of Canada. S.W.S. was supported by National Institutes of Health (NIH) Grant GM084246. N.E.C. and E.J.M. were supported by NIH Grant T-32 AG021890 through the Barshop Institute for Longevity and Aging Studies. E.J.M. was supported by Grant DBI-0905865 through the National Science Foundation. P.F.F. and K.M.R. were supported by Grant AQ-1245 from The Welch Foundation. Support for NE-CAT beamline 24-ID-E is provided by NIH Grant P41 GM103403 and US Department of Energy Grant DE-AC02-06CH11357. The X-Ray Core Laboratory at University of Texas Health Science Center, San Antonio (UTHSCSA) is supported in part by the Office of the Vice President for Research and by San Antonio Cancer Institute Grant P30 CA054174. Equipment and technical expertise were provided by the Center for Innovative Drug Discovery and High Throughput Screening Facility at UTHSCSA, which is supported by Grant UL1 TR001120 from the National Center for Advancing Translational Sciences, NIH. NR 49 TC 1 Z9 1 U1 1 U2 1 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 DEC 20 PY 2016 VL 113 IS 51 BP 14727 EP 14732 DI 10.1073/pnas.1612729114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF0VR UT WOS:000390044900061 PM 27930312 ER PT J AU Steinberg, BA Shrader, P Thomas, L Ansell, J Fonarow, GC Gersh, BJ Kowey, PR Mahaffey, KW Naccarelli, G Reiffel, J Singer, DE Peterson, ED Piccini, JP AF Steinberg, Benjamin A. Shrader, Peter Thomas, Laine Ansell, Jack Fonarow, Gregg C. Gersh, Bernard J. Kowey, Peter R. Mahaffey, Kenneth W. Naccarelli, Gerald Reiffel, James Singer, Daniel E. Peterson, Eric D. Piccini, Jonathan P. CA ORBIT-AF Investigators Patients TI Off-Label Dosing of Non-Vitamin K Antagonist Oral Anticoagulants and Adverse Outcomes The ORBIT-AF II Registry SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE apixaban; atrial fibrillation; dabigatran; off-label use; outcomes; rivaroxaban ID NONVALVULAR ATRIAL-FIBRILLATION; SERUM CREATININE; WARFARIN; RIVAROXABAN; DABIGATRAN; SAFETY; HEMODIALYSIS; PREDICTION; APIXABAN; EFFICACY AB BACKGROUND Although non-vitamin K antagonist oral anticoagulants (NOACs) do not require frequent laboratory monitoring, each compound requires dose adjustments on the basis of certain clinical criteria. OBJECTIVES This study assessed the frequency of off-label NOAC doses among AF patients and the associations between off-label dose therapy and clinical outcomes in community practice. METHODS We evaluated 5,738 patients treated with a NOAC at 242 ORBIT-AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation phase II) sites. NOAC doses were classified as either underdosed or overdosed, consistent with Food and Drug Administration labeling. Longitudinal outcomes (median follow-up: 0.99 years) included stroke or systemic embolism, myocardial infarction, major bleeding (International Society of Thrombosis and Haemostasis criteria), cause-specific hospitalization, and all-cause mortality. RESULTS Overall, 541 NOAC-treated patients (9.4%) were underdosed, 197 were overdosed (3.4%), and 5,000 were dosed according to U.S. labeling (87%). Compared with patients receiving the recommended dose, those who were receiving off-label doses were older (median: 79 and 80 years of age vs. 70 years of age, respectively; p < 0.0001), more likely female (48% and 67% vs. 40%, respectively; p < 0.0001), less likely to be treated by an electrophysiologist (18% and 19% vs. 27%, respectively; p < 0.0001), and had higher CHA(2)DS(2)-VASc scores (96% and 97% >= 2 vs. 86%, respectively; p < 0.0001) and higher ORBIT bleeding scores (25% and 31% >4 vs. 11%, respectively; p < 0.0001). After dose adjustment, NOAC overdosing was associated with increased all-cause mortality compared with recommended doses (adjusted hazard ratio: 1.91; 95% confidence interval [CI]: 1.02 to 3.60; p = 0.04). Underdosing was associated with increased cardiovascular hospitalization (adjusted hazard ratio: 1.26; 95% CI: 1.07 to 1.50; p = 0.007). CONCLUSIONS A significant minority (almost 1 in 8) of U.S. patients in the community received NOAC doses inconsistent with labeling. NOAC over-and underdosing are associated with increased risk for adverse events. (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II [ORBIT-AF II]; NCT01701817) (C) 2016 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. C1 [Steinberg, Benjamin A.] Univ Utah, Hlth Sci Ctr, Div Cardiovasc Med, 30 North 1900 East,Room 4A100, Salt Lake City, UT 84132 USA. [Steinberg, Benjamin A.; Peterson, Eric D.; Piccini, Jonathan P.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Steinberg, Benjamin A.; Shrader, Peter; Thomas, Laine; Peterson, Eric D.; Piccini, Jonathan P.] Duke Clin Res Inst, Durham, NC USA. [Ansell, Jack] Hofstra Northwell Sch Med, Dept Med, Long Isl City, NY USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Sch Med, Div Cardiol, Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA 90024 USA. [Gersh, Bernard J.] Mayo Clin, Dept Med, Rochester, MN USA. [Kowey, Peter R.] Lankenau Inst Med Res, Wynnewood, PA USA. [Mahaffey, Kenneth W.] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA. [Naccarelli, Gerald] Penn State Univ, Sch Med, Dept Med, Hershey, PA USA. [Reiffel, James] Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY USA. [Singer, Daniel E.] Harvard Med Sch, Dept Med, Boston, MA USA. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Steinberg, BA (reprint author), Univ Utah, Hlth Sci Ctr, Div Cardiovasc Med, 30 North 1900 East,Room 4A100, Salt Lake City, UT 84132 USA. EM benjamin.steinberg@hsc.utah.edu FU Janssen Scientific Affairs, LLC.; Janssen Scientific; Janssen; Amgen; Daiichi; Johnson Johnson; Medtronic; Merck; St. Jude Medical; Tenax; American College of Cardiology; AstraZeneca; BAROnova; Bayer; Bio2Medical; Boehringer Ingelheim; Bristol-Myers Squibb; Cubist; Eli Lilly; Elsevier; Epson; Forest; Eli Lilly Co.; Janssen Pharmaceuticals; American Heart Association; Bayer HealthCare Pharmaceuticals; Boston Scientific FX The ORBITAF registry was sponsored by Janssen Scientific Affairs, LLC. Dr. Steinberg has received research support from Janssen Scientific; and is a consultant for BMS-Pfizer. Dr. Ansell is a consultant for and advisory board member for Bristol-Myers Squibb, Pfizer, Janssen, Daiichi, Boehringer Ingelheim, and Alere. Dr. Fonarow is a consultant for and receives research support from Janssen. Dr. Gersh has received research support from and is an advisory board member of Medtronic, Baxter Healthcare Corporation, InspireMD, Cardiovascular Research Foundation, PPD Development, LP, Boston Scientific, and St. Jude. Dr. Kowey is a consultant for and advisory board member with Boehringer Ingelheim, Bristol-Myers Squibb, Johnson & Johnson, Portola, Merck, Sanofi, and Daiichi-Sankyo. Dr. Mahaffey has received research grants from Amgen, Daiichi, Johnson & Johnson, Medtronic, Merck, St. Jude Medical, Tenax; has received consulting fees from the American College of Cardiology, AstraZeneca, BAROnova, Bayer, Bio2Medical, Boehringer Ingelheim, Bristol-Myers Squibb, Cubist, Eli Lilly, Elsevier, Epson, Forest, Johnson & Johnson, and Medtronic; and has equity in BioPrintFitness. Dr. Peterson has received research support from Eli Lilly & Co., Janssen Pharmaceuticals, and American Heart Association; and is a consultant and advisory board member for Boehringer Ingelheim, Bristol-Myers Squibb, Janssen Pharmaceuticals, Pfizer, and Genentech Inc. Dr. Piccini has received research support from Johnson & Johnson, Janssen Pharmaceuticals, Bayer HealthCare Pharmaceuticals, Boston Scientific, Johnson & Johnson; and is a consultant and advisory board member for Forest Laboratories, Inc., Medtronic, Johnson & Johnson, and Janssen Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 20 TC 1 Z9 1 U1 8 U2 8 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 DEC 20 PY 2016 VL 68 IS 24 BP 2597 EP 2604 DI 10.1016/j.jacc.2016.09.966 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EE4RO UT WOS:000389593000001 PM 27978942 ER PT J AU Vargas, T Moreno-Rubio, J Herranz, J Cejas, P Molina, S Mendiola, M Burgos, E Custodio, AB De Miguel, M Martin-Hernandez, R Reglero, G Feliu, J de Molina, AR AF Vargas, Teodoro Moreno-Rubio, Juan Herranz, Jesus Cejas, Paloma Molina, Susana Mendiola, Marta Burgos, Emilio Custodio, Ana B. De Miguel, Maria Martin-Hernandez, Roberto Reglero, Guillermo Feliu, Jaime Ramirez de Molina, Ana TI 3 ' UTR Polymorphism in ACSL1 Gene Correlates with Expression Levels and Poor Clinical Outcome in Colon Cancer Patients SO PLoS One LA English DT Article ID BODY-MASS INDEX; COLORECTAL-CANCER; ADJUVANT CHEMOTHERAPY; METABOLIC SYNDROME; STAGE-II; LIPID-METABOLISM; RISK; PROGNOSIS; SURVIVAL; CARCINOMA AB Strong evidence suggests that lipid metabolism (LM) has an essential role in tumor growth to support special energetic and structural requirements of tumor cells. Recently, overexpression of LM-related genes, apolipoproteins related to metabolic syndrome, and ACSL/SCD network involved in fatty acid activation have been proposed as prognostic markers of colon cancer (CC). Furthermore, activation of this latter lipid network has been recently demonstrated to confer invasive and stem cell properties to tumor cells promoting tumor aggressiveness and patient relapse. With the aim of elucidating whether any genetic variation within these genes could influence basal expression levels and consequent susceptibility to relapse, we genotype, in 284 CC patients, 57 polymorphisms located in the 7 genes of these lipid networks previously associated with worse clinical outcome of CC patients (ABCA1, ACSL1, AGPAT1, APOA2, APOC1, APOC2 and SCD), some of them related to CC aggressiveness. After adjusting with clinical confounding factors and multiple comparisons, an association between genotype and disease-free survival (DFS) was shown for rs8086 in 3'-UTR of ACSL1 gene (HR 3.08; 95% CI 1.69-5.63; adjusted p = 0.046). Furthermore, the risk T/T genotype had significantly higher ACSL1 gene expression levels than patients carrying C/T or C/C genotype (means = 5.34; 3.73; 2.37 respectively; p-value (ANOVA) = 0.019), suggesting a functional role of this variant. Thus, we have identified a "risk genotype" of ACSL1 gene that confers constitutive high levels of the enzyme, which is involved in the activation of fatty acids through conversion to acyl-CoA and has been recently related to increased invasiveness of tumor cells. These results suggest that rs8086 of ACSL1 could be a promising prognostic marker in CC patients, reinforcing the relevance of LM in the progression of CC. C1 [Vargas, Teodoro; Moreno-Rubio, Juan; Molina, Susana; Reglero, Guillermo; Ramirez de Molina, Ana] CEI UAM CSIC, IMDEA Food Inst, Mol Oncol, Madrid, Spain. [Moreno-Rubio, Juan] Infanta Sofia Univ Hosp, POL, Madrid, Spain. [Moreno-Rubio, Juan; Cejas, Paloma; De Miguel, Maria] La Paz Univ Hosp IdiPAZ, Translat Oncol Lab, Madrid, Spain. [Herranz, Jesus; Martin-Hernandez, Roberto] CEI UAM CSIC, IMDEA Food Inst, Biostat & Bioinformat Unit, Madrid, Spain. [Cejas, Paloma] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Burgos, Emilio] La Paz Univ Hosp IdiPAZ, Dept Pathol, Madrid, Spain. [Custodio, Ana B.; Feliu, Jaime] La Paz Univ Hosp IdiPAZ, Med Oncol, Madrid, Spain. RP de Molina, AR (reprint author), CEI UAM CSIC, IMDEA Food Inst, Mol Oncol, Madrid, Spain. EM ana.ramirez@imdea.org FU Ministerio de Economia y Competitividad (Plan Nacional I+D+i) [AGL2013-48943-C2]; Comunidad de Madrid (ALIBIRD-CM) [P2013/ABI-2728]; European Union Structural Funds FX This work was funded by the Ministerio de Economia y Competitividad (Plan Nacional I+D+i AGL2013-48943-C2); Comunidad de Madrid (P2013/ABI-2728. ALIBIRD-CM); and European Union Structural Funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 19 PY 2016 VL 11 IS 12 AR e0168423 DI 10.1371/journal.pone.0168423 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI9QC UT WOS:000392842600057 PM 27992526 ER PT J AU Fridenson-Hayo, S Berggren, S Lassalle, A Tal, S Pigat, D Bolte, S Baron-Cohen, S Golan, O AF Fridenson-Hayo, Shimrit Berggren, Steve Lassalle, Amandine Tal, Shahar Pigat, Delia Bolte, Sven Baron-Cohen, Simon Golan, Ofer TI Basic and complex emotion recognition in children with autism: cross-cultural findings SO MOLECULAR AUTISM LA English DT Article DE Autism spectrum condition; Emotion recognition; Basic emotions; Complex emotions; Cross-cultural research ID HIGH-FUNCTIONING AUTISM; PERVASIVE DEVELOPMENTAL DISORDER; TYPICALLY DEVELOPING-CHILDREN; FACIAL AFFECT RECOGNITION; DORSAL VISUAL PATHWAY; SPECTRUM DISORDERS; ASPERGER-SYNDROME; BIOLOGICAL MOTION; NORMAL ADULTS; YOUNG-CHILDREN AB Background: Children with autism spectrum conditions (ASC) have emotion recognition deficits when tested in different expression modalities (face, voice, body). However, these findings usually focus on basic emotions, using one or two expression modalities. In addition, cultural similarities and differences in emotion recognition patterns in children with ASC have not been explored before. The current study examined the similarities and differences in the recognition of basic and complex emotions by children with ASC and typically developing (TD) controls across three cultures: Israel, Britain, and Sweden. Methods: Fifty-five children with high-functioning ASC, aged 5-9, were compared to 58 TD children. On each site, groups were matched on age, sex, and IQ. Children were tested using four tasks, examining recognition of basic and complex emotions from voice recordings, videos of facial and bodily expressions, and emotional video scenarios including all modalities in context. Results: Compared to their TD peers, children with ASC showed emotion recognition deficits in both basic and complex emotions on all three modalities and their integration in context. Complex emotions were harder to recognize, compared to basic emotions for the entire sample. Cross-cultural agreement was found for all major findings, with minor deviations on the face and body tasks. Conclusions: Our findings highlight the multimodal nature of ER deficits in ASC, which exist for basic as well as complex emotions and are relatively stable cross-culturally. Cross-cultural research has the potential to reveal both autism-specific universal deficits and the role that specific cultures play in the way empathy operates in different countries. C1 [Fridenson-Hayo, Shimrit; Tal, Shahar; Golan, Ofer] Bar Ilan Univ, Dept Psychol, Ramat Gan, Israel. [Berggren, Steve; Bolte, Sven] Karolinska Inst, Dept Womens & Childrens Hlth, Ctr Neurodev Disorders KIND, Stockholm, Sweden. [Lassalle, Amandine; Pigat, Delia; Baron-Cohen, Simon] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England. [Lassalle, Amandine] Harvard Med Sch, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Bolte, Sven] Stockholm Cty Council, Ctr Psychiat Res, Stockholm, Sweden. RP Golan, O (reprint author), Bar Ilan Univ, Dept Psychol, Ramat Gan, Israel. EM ofer.golan@biu.ac.il FU European Community [289021]; Swedish Research Council [523-2009-7054]; Autism Research Trust; MRC; Wellcome Trust; NIHR CLAHRC EoE FX The research leading to this work has received funding from the European Community's Seventh Framework Programme (FP7) under grant agreement no. [289021]. SvB was supported by the Swedish Research Council (Grant No. 523-2009-7054), and SBC was supported by the Autism Research Trust, the MRC, the Wellcome Trust, and the NIHR CLAHRC EoE during the period of this work. NR 111 TC 0 Z9 0 U1 27 U2 27 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2040-2392 J9 MOL AUTISM JI Mol. Autism PD DEC 19 PY 2016 VL 7 AR 52 DI 10.1186/s13229-016-0113-9 PG 11 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA EF4HS UT WOS:000390286600001 PM 28018573 ER PT J AU Douw, L Wakeman, DG Tanaka, N Liu, HS Stufflebeam, SM AF Douw, Linda Wakeman, Daniel G. Tanaka, Naoaki Liu, Hesheng Stufflebeam, Steven M. TI STATE-DEPENDENT VARIABILITY OF DYNAMIC FUNCTIONAL CONNECTIVITY BETWEEN FRONTOPARIETAL AND DEFAULT NETWORKS RELATES TO COGNITIVE FLEXIBILITY SO NEUROSCIENCE LA English DT Article DE brain dynamics; cognition; resting-state fMRI ID HUMAN CEREBRAL-CORTEX; BRAIN NETWORKS; RESTING-STATE; MODE; INTERFERENCE; TIME; MRI; RECONFIGURATION; MODULATION; ATTENTION AB The brain is a dynamic, flexible network that continuously reconfigures. However, the neural underpinnings of how state-dependent variability of dynamic functional connectivity (vdFC) relates to cognitive flexibility are unclear. We therefore investigated flexible functional connectivity during resting-state and task-state functional magnetic resonance imaging (rs-fMRI and t-fMRI, resp.) and performed separate, out-of-scanner neuropsychological testing. We hypothesize that state-dependent vdFC between the frontoparietal network (FPN) and the default mode network (DMN) relates to cognitive flexibility. Seventeen healthy subjects performed the Stroop color word test and underwent t-fMRI (Stroop computerized version) and rs-fMRI. Time series were extracted from a cortical atlas, and a sliding window approach was used to obtain a number of correlation matrices per subject. vdFC was defined as the standard deviation of connectivity strengths over these windows. Higher task-state FPN-DMN vdFC was associated with greater out-of-scanner cognitive flexibility, while the opposite relationship was present for resting-state FPN-DMN vdFC. Moreover, greater contrast between task-state and resting-state vdFC related to better cognitive performance. In conclusion, our results suggest that not only the dynamics of connectivity between these networks is seminal for optimal functioning, but also that the contrast between dynamics across states reflects cognitive performance. (C) 2016 The Authors. Published by Elsevier Ltd on behalf of IBRO. This is an open access article under the CC BY-NC-ND license. C1 [Douw, Linda; Wakeman, Daniel G.; Tanaka, Naoaki; Liu, Hesheng; Stufflebeam, Steven M.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. [Douw, Linda] Vrije Univ Amsterdam, Med Ctr, Dept Anat & Neurosci, Boechorststr 7, NL-1081 BT Amsterdam, Netherlands. [Wakeman, Daniel G.; Tanaka, Naoaki; Liu, Hesheng; Stufflebeam, Steven M.] Harvard Med Sch, Dept Radiol, 25 Shattuck St, Boston, MA 02115 USA. RP Douw, L (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Anat & Neurosci, O12 Bldg,Boelelaan 1108, NL-1081 HZ Amsterdam, Netherlands. EM l.douw@vumc.nl FU National Center for Research Resources [S10RR014978]; National Institutes of Health [R01-NS069696, 5R01-NS060918, U01MH093765, S10RR023043, S10RR023401]; National Science Foundation [1042134]; Dutch Organization for Scientific Research (Rubicon) [825.11.002, 016.146.086]; Society in Science FX This work was supported by the National Center for Research Resources (grant number S10RR014978), the National Institutes of Health (grant numbers R01-NS069696, 5R01-NS060918, U01MH093765, S10RR023043, S10RR023401), the National Science Foundation (grant number 1042134) to [DGW], the Dutch Organization for Scientific Research (Rubicon; grant number 825.11.002, Veni; grant number 016.146.086) to [LD], and a Branco Weiss Fellowship from Society in Science to [LD]. NR 52 TC 0 Z9 0 U1 8 U2 8 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 DEC 17 PY 2016 VL 339 BP 12 EP 21 DI 10.1016/j.neuroscience.2016.09.034 PG 10 WC Neurosciences SC Neurosciences & Neurology GA ED9CT UT WOS:000389168500002 PM 27687802 ER PT J AU Chiara, DC Jounaidi, Y Zhou, XJ Savechenkov, PY Bruzik, KS Miller, KW Cohen, JB AF Chiara, David C. Jounaidi, Youssef Zhou, Xiaojuan Savechenkov, Pavel Y. Bruzik, Karol S. Miller, Keith W. Cohen, Jonathan B. TI General Anesthetic Binding Sites in Human alpha 4 beta 3 delta gamma-Aminobutyric Acid Type A Receptors (GABAARs) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EXTRASYNAPTIC GABA(A) RECEPTORS; DELTA-SUBUNIT; INTRAVENOUS ANESTHETICS; TRANSMEMBRANE DOMAIN; ALLOSTERIC MODULATION; FUNCTIONAL-PROPERTIES; BETA-3 SUBUNIT; ETOMIDATE; PROPOFOL; STOICHIOMETRY AB Extrasynaptic gamma-aminobutyric acid type A receptors (GABA(A)Rs), which contribute generalized inhibitory tone to the mammalian brain, are major targets for general anesthetics. To identify anesthetic binding sites in an extrasynaptic GABA(A)R, we photolabeled human alpha 4 beta 3 delta GABA(A)Rs purified in detergent with [H-3]azietomidate and a barbiturate, [H-3]R-mTFD-MPAB, photoreactive anesthetics that bind with high selectivity to distinct but homologous intersubunit binding sites in the transmembrane domain of synaptic alpha 1 beta 3 gamma 2 GABA(A)Rs. Based upon H-3 incorporation into receptor subunits resolved by SDS-PAGE, there was etomidate-inhibitable labeling by [H-3] azietomidate in the alpha 4 and beta 3 subunits and barbiturate-inhibitable labeling by [H-3] R-mTFD-MPAB in the beta 3 subunit. These sites did not bind the anesthetic steroid alphaxalone, which enhanced photolabeling, or DS-2, a delta subunit-selective positive allosteric modulator, which neither enhanced nor inhibited photolabeling. The amino acids labeled by [H-3] azietomidate or [H-3] R-mTFD-MPAB were identified by N-terminal sequencing of fragments isolated by HPLC fractionation of enzymatically digested subunits. No evidence was found for a delta subunit contribution to an anesthetic binding site. [H-3] azietomidate photolabeling of beta 3Met-286 in beta M3 and alpha 4Met-269 in alpha M1 that was inhibited by etomidate but not by R-mTFD-MPAB established that etomidate binds to a site at the alpha 3(+)-alpha 4(-) interface equivalent to its site in alpha 1 beta 3 gamma 2 GABA(A)Rs. [H-3] Azietomidate and [H-3] R-mTFD-MPAB photolabeling of beta 3Met-227 in beta M1 established that these anesthetics also bind to a homologous site, most likely at the beta 3(+)-beta 3(-) interface, which suggests a subunit arrangement of beta 3 alpha 4 beta 3 delta beta 3. C1 [Chiara, David C.; Cohen, Jonathan B.] Harvard Med Sch, Dept Neurobiol, 220 Longwood Ave, Boston, MA 02115 USA. [Miller, Keith W.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Jounaidi, Youssef; Zhou, Xiaojuan; Miller, Keith W.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Savechenkov, Pavel Y.; Bruzik, Karol S.] Univ Illinois, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA. RP Cohen, JB (reprint author), Harvard Med Sch, Dept Neurobiol, 220 Longwood Ave, Boston, MA 02115 USA. EM jonathan_cohen@hms.harvard.edu FU National Institutes of Health [GM-58448] FX This work was supported, in whole or in part, by National Institutes of Health Grant GM-58448. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 50 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 16 PY 2016 VL 291 IS 51 BP 26529 EP 26539 DI 10.1074/jbc.M116.753335 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EH1ZY UT WOS:000391568200025 PM 27821594 ER PT J AU Castillo-Quan, JI Blackwell, TK AF Castillo-Quan, Jorge Ivan Blackwell, T. Keith TI Metformin: Restraining Nucleocytoplasmic Shuttling to Fight Cancer and Aging SO CELL LA English DT Editorial Material ID C. ELEGANS; MTORC1; AMPK AB In this issue of Cell, Wu et al. employed C. elegans and human cell experiments to identify a pathway through which metformin increases lifespan and inhibits growth. A key transcriptional target, ACAD10, is activated when metformin induces nuclear exclusion of the GTPase RagC, thereby inhibiting mTORC1 through an unexpected mechanism. C1 [Castillo-Quan, Jorge Ivan; Blackwell, T. Keith] Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. [Castillo-Quan, Jorge Ivan; Blackwell, T. Keith] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Castillo-Quan, Jorge Ivan; Blackwell, T. Keith] Harvard Med Sch, Harvard Stem Cell Inst, Boston, MA 02115 USA. RP Blackwell, TK (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA.; Blackwell, TK (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.; Blackwell, TK (reprint author), Harvard Med Sch, Harvard Stem Cell Inst, Boston, MA 02115 USA. EM keith.blackwell@joslin.harvard.edu OI Castillo-Quan, Jorge Ivan/0000-0002-6324-2854 NR 9 TC 0 Z9 0 U1 4 U2 4 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 DEC 15 PY 2016 VL 167 IS 7 BP 1670 EP 1671 DI 10.1016/j.cell.2016.11.058 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EJ3LW UT WOS:000393114700004 PM 27984715 ER PT J AU Zou, L AF Zou, Lee TI A Zygotic Checkpoint for Unrepaired Lesions SO CELL LA English DT Editorial Material ID COHESIN RING; ATR AB DNA demethylation, a process involving DNA repair, is critical for reprogramming of the paternal genome during the oocyte-to-zygote transition. A new study by Ladstatter and Tachibana-Konwalski shows that a Chk1-mediated zygotic checkpoint monitors the cohesin-dependent repair of DNA lesions arising from DNA demethylation, which prevents zygotes carrying unrepaired lesions from entering mitosis. C1 [Zou, Lee] Harvard Med Sch, Massachusetts Gen Hosp, MGH Canc Ctr, Charlestown, MA 02129 USA. [Zou, Lee] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA 02129 USA. RP Zou, L (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, MGH Canc Ctr, Charlestown, MA 02129 USA.; Zou, L (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA 02129 USA. EM zou.lee@mgh.harvard.edu NR 9 TC 0 Z9 0 U1 6 U2 6 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 DEC 15 PY 2016 VL 167 IS 7 BP 1676 EP 1678 DI 10.1016/j.cell.2016.11.049 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EJ3LW UT WOS:000393114700007 PM 27984718 ER PT J AU Wu, LF Zhou, B Oshiro-Rapley, N Li, M Paulo, JA Webster, CM Mou, F Kacergis, MC Talkowski, ME Carr, CE Gygi, SP Zheng, B Soukas, AA AF Wu, Lianfeng Zhou, Ben Oshiro-Rapley, Noriko Li, Man Paulo, Joao A. Webster, Christopher M. Mou, Fan Kacergis, Michael C. Talkowski, Michael E. Carr, Christopher E. Gygi, Steven P. Zheng, Bin Soukas, Alexander A. TI An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. elegans and Cancer SO CELL LA English DT Article ID NUCLEAR-PORE COMPLEX; CAENORHABDITIS-ELEGANS; SACCHAROMYCES-CEREVISIAE; PANCREATIC-CANCER; MAMMALIAN TARGET; RAG GTPASES; MTOR; PATHWAY; CELLS; GLUCONEOGENESIS AB Metformin has utility in cancer prevention and treatment, though the mechanisms for these effects remain elusive. Through genetic screening in C. elegans, we uncover two metformin response elements: the nuclear pore complex (NPC) and acyl-CoA dehydrogenase family member-10 (ACAD10). We demonstrate that biguanides inhibit growth by inhibiting mitochondrial respiratory capacity, which restrains transit of the RagA-RagC GTPase heterodimer through the NPC. Nuclear exclusion renders RagC incapable of gaining the GDP-bound state necessary to stimulate mTORC1. Biguanide-induced inactivation of mTORC1 subsequently inhibits growth through transcriptional induction of ACAD10. This ancient metformin response pathway is conserved from worms to humans. Both restricted nuclear pore transit and upregulation of ACAD10 are required for biguanides to reduce viability in melanoma and pancreatic cancer cells, and to extend C. elegans lifespan. This pathway provides a unified mechanism by which metformin kills cancer cells and extends lifespan, and illuminates potential cancer targets. C1 [Wu, Lianfeng; Zhou, Ben; Webster, Christopher M.; Kacergis, Michael C.; Soukas, Alexander A.] Massachusetts Gen Hosp, Dept Med, Diabet Unit, Boston, MA 02114 USA. [Wu, Lianfeng; Zhou, Ben; Webster, Christopher M.; Kacergis, Michael C.; Talkowski, Michael E.; Soukas, Alexander A.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Wu, Lianfeng; Zhou, Ben; Webster, Christopher M.; Soukas, Alexander A.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Wu, Lianfeng; Zhou, Ben; Webster, Christopher M.; Soukas, Alexander A.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Oshiro-Rapley, Noriko; Carr, Christopher E.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Li, Man; Mou, Fan; Zheng, Bin] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Li, Man; Mou, Fan; Zheng, Bin] Harvard Med Sch, Charlestown, MA 02129 USA. [Paulo, Joao A.; Gygi, Steven P.] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. [Talkowski, Michael E.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Talkowski, Michael E.] Harvard Med Sch, Boston, MA 02114 USA. [Carr, Christopher E.] MIT, Dept Earth Atmospher & Planetary Sci, Cambridge, MA 02139 USA. RP Soukas, AA (reprint author), Massachusetts Gen Hosp, Dept Med, Diabet Unit, Boston, MA 02114 USA.; Soukas, AA (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.; Soukas, AA (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA.; Soukas, AA (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. EM asoukas@mgh.harvard.edu FU NIH [P40 OD010440, R03DK098436, K08DK087941, R01DK072041, R01CA166717]; Broad Institute SPARC Grant; Ellison Medical Foundation New Scholar in Aging Award; NORC of Harvard [P30DK040561]; Boston Area DERC [P30DK057521] FX We thank the Broad Institute GPP for lentiviral shRNA reagents. Some worm strains were from the CGC, which is funded by the NIH (P40 OD010440). This work was funded by NIH grants R03DK098436 (A.A.S), K08DK087941 (A.A.S), R01DK072041 (A.A.S), and R01CA166717 (B. Zheng), a Broad Institute SPARC Grant (A.A.S.), the Ellison Medical Foundation New Scholar in Aging Award (A.A.S.), and supported by resources from the NORC of Harvard (P30DK040561) and the Boston Area DERC (P30DK057521). We thank Joseph Avruch, Jose Florez, and Geoffrey Walford for critical reading and discussions. NR 47 TC 1 Z9 1 U1 4 U2 4 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 DEC 15 PY 2016 VL 167 IS 7 BP 1705 EP + DI 10.1016/j.cell.2016.11.055 PG 27 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EJ3LW UT WOS:000393114700011 PM 27984722 ER PT J AU Zovoilis, A Cifuentes-Rojas, C Chu, HP Hernandez, AJ Lee, JT AF Zovoilis, Athanasios Cifuentes-Rojas, Catherine Chu, Hsueh-Ping Hernandez, Alfredo J. Lee, Jeannie T. TI Destabilization of B2 RNA by EZH2 Activates the Stress Response SO CELL LA English DT Article ID REPRESSIVE COMPLEX 2; LONG NONCODING RNAS; POLYMERASE-II TRANSCRIPTION; EMBRYONIC STEM-CELLS; HEAT-SHOCK; POLYCOMB; BINDING; GENOME; IDENTIFICATION; PRC2 AB More than 98% of the mammalian genome is non-coding, and interspersed transposable elements account for similar to 50% of noncoding space. Here, we demonstrate that a specific interaction between the polycomb protein EZH2 and RNA made from B2 SINE retrotransposons controls stress-responsive genes in mouse cells. In the heat-shock model, B2 RNA binds stress genes and suppresses their transcription. Upon stress, EZH2 is recruited and triggers cleavage of B2 RNA. B2 degradation in turn upregulates stress genes. Evidence indicates that B2 RNA operates as a "speed bump'' against advancement of RNA polymerase II, and temperature stress releases the brakes on transcriptional elongation. These data attribute a new function to EZH2 that is independent of its histone methyltransferase activity and reconcile how EZH2 can be associated with both gene repression and activation. Our study reveals that EZH2 and B2 together control activation of a large network of genes involved in thermal stress. C1 [Zovoilis, Athanasios; Cifuentes-Rojas, Catherine; Chu, Hsueh-Ping; Lee, Jeannie T.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Zovoilis, Athanasios; Cifuentes-Rojas, Catherine; Chu, Hsueh-Ping; Lee, Jeannie T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Zovoilis, Athanasios; Cifuentes-Rojas, Catherine; Chu, Hsueh-Ping; Lee, Jeannie T.] Harvard Med Sch, Dept Genet, Boston, MA 02114 USA. [Hernandez, Alfredo J.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Lee, JT (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA.; Lee, JT (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Lee, JT (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02114 USA. EM lee@molbio.mgh.harvard.edu FU German Research Foundation [Zo 287-4-1]; National Institutes of Health [R01-GM090278, K99-GM115868-02] FX We thank the Lee Lab for many excellent discussions. Special thanks go to J. Froberg for MiSeq experiments, W. Press for optimizing transfection conditions, B. Del Rosario for GST protein, and R. Kingston for sharing the pfastbac plasmids encoding FLAG-EZH2 and -EED. This study was funded by the German Research Foundation (grant no. Zo 287-4-1) to A.Z. and by National Institutes of Health R01-GM090278 to J.T.L. and K99-GM115868-02 to C.C.R. J.T.L. is also an Investigator of the HHMI. NR 55 TC 0 Z9 0 U1 6 U2 6 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 DEC 15 PY 2016 VL 167 IS 7 BP 1788 EP + DI 10.1016/j.cell.2016.11.041 PG 28 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EJ3LW UT WOS:000393114700017 PM 27984727 ER PT J AU Sanidas, I Dyson, NJ AF Sanidas, Ioannis Dyson, Nicholas J. TI pRB Takes an EZ Path to a Repetitive Task SO MOLECULAR CELL LA English DT Editorial Material ID INSTABILITY AB Repetitive DNA elements are essential for genome function; in this issue of Molecular Cell, Ishak et al. (2016) describe a novel mechanism of epigenetic repression at these elements that requires pRB-dependent recruitment of EZH2. C1 [Sanidas, Ioannis; Dyson, Nicholas J.] Harvard Med Sch, Ctr Canc, Mol Oncol Lab, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Dyson, NJ (reprint author), Harvard Med Sch, Ctr Canc, Mol Oncol Lab, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. EM dyson@helix.mgh.harvard.edu NR 9 TC 0 Z9 0 U1 1 U2 1 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 DEC 15 PY 2016 VL 64 IS 6 BP 1015 EP 1017 DI 10.1016/j.molcel.2016.11.035 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EJ3PV UT WOS:000393125000003 PM 27984740 ER PT J AU Joh, RI Khanduja, JS Calvo, IA Mistry, M Palmieri, CM Savol, AJ Sui, SJH Sadreyev, RI Aryee, MJ Motamedi, M AF Joh, Richard I. Khanduja, Jasbeer S. Calvo, Isabel A. Mistry, Meeta Palmieri, Christina M. Savol, Andrej J. Sui, Shannan J. Ho Sadreyev, Ruslan I. Aryee, Martin J. Motamedi, Mo TI Survival in Quiescence Requires the Euchromatic Deployment of Clr4/SUV39H by Argonaute-Associated Small RNAs SO MOLECULAR CELL LA English DT Article ID STEM-CELL QUIESCENCE; FACULTATIVE HETEROCHROMATIN FORMATION; H3 LYSINE-9 METHYLATION; FISSION YEAST; SCHIZOSACCHAROMYCES-POMBE; HISTONE H3; QUALITY-CONTROL; CAENORHABDITIS-ELEGANS; SILENCING COMPLEX; GENE-EXPRESSION AB Quiescence (G0) is a ubiquitous stress response through which cells enter reversible dormancy, acquiring distinct properties including reduced metabolism, resistance to stress, and long life. G0 entry involves dramatic changes to chromatin and transcription of cells, but the mechanisms coordinating these processes remain poorly understood. Using the fission yeast, here, we track G0-associated chromatin and transcriptional changes temporally and show that as cells enter G0, their survival and global gene expression programs become increasingly dependent on Clr4/SUV39H, the sole histone H3 lysine 9 (H3K9) methyltransferase, and RNAi proteins. Notably, G0 entry results in RNAi-dependent H3K9 methylation of several euchromatic pockets, prior to which Argonaute1-associated small RNAs from these regions emerge. Overall, our data reveal another function for constitutive heterochromatin proteins (the establishment of the global G0 transcriptional program) and suggest that stress-induced alterations in Argonaute-associated sRNAs can target the deployment of transcriptional regulatory proteins to specific sequences. C1 [Joh, Richard I.; Khanduja, Jasbeer S.; Calvo, Isabel A.; Palmieri, Christina M.; Aryee, Martin J.; Motamedi, Mo] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Joh, Richard I.; Khanduja, Jasbeer S.; Calvo, Isabel A.; Palmieri, Christina M.; Aryee, Martin J.; Motamedi, Mo] Harvard Med Sch, Dept Med, Charlestown, MA 02129 USA. [Mistry, Meeta; Sui, Shannan J. Ho] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Bioinformat Core, Boston, MA 02115 USA. [Savol, Andrej J.; Sadreyev, Ruslan I.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Sadreyev, Ruslan I.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Sadreyev, Ruslan I.; Aryee, Martin J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sadreyev, Ruslan I.; Aryee, Martin J.] Harvard Med Sch, Boston, MA 02114 USA. RP Motamedi, M (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA.; Motamedi, M (reprint author), Harvard Med Sch, Dept Med, Charlestown, MA 02129 USA. EM mmotamedi@hms.harvard.edu FU Proton Beam grant [C06 CA059267]; V Scholar and V Scholar Plus grant; Beatriu de Pinos (Generalitat de Catalunya) post-doctoral fellowship; Harvard Catalyst (NIH award) [UL1 RR 025758] FX This work was supported by a Proton Beam grant (C06 CA059267), V Scholar and V Scholar Plus grant to M. Motamedi, and a Beatriu de Pinos (Generalitat de Catalunya) post-doctoral fellowship to I.A.C. Bioinformatics analyses by M. Mistry and S.J.H.S. were conducted with the support of Harvard Catalyst (NIH award # UL1 RR 025758). We thank Daniel Holoch and Ruby Yu of the Moazed lab for sRNA purification advice and protocols. We are grateful to Mario Suva, Shawn Gillespie, and the Broad Institute for sharing deep-sequencing barcodes and thank Daniel Haber, Johnathan Whetstine, and Anders Naar for critical reading of and constructive comments on the manuscript. NR 71 TC 0 Z9 0 U1 1 U2 1 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 DEC 15 PY 2016 VL 64 IS 6 BP 1088 EP 1101 DI 10.1016/j.molcel.2016.11.020 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EJ3PV UT WOS:000393125000011 PM 27984744 ER PT J AU Cortese, S Castellanos, FX Eickhoff, CR D'Acunto, G Masi, G Fox, PT Laird, AR Eickhoff, SB AF Cortese, Samuele Castellanos, F. Xavier Eickhoff, Claudia R. D'Acunto, Giulia Masi, Gabriele Fox, Peter T. Laird, Angela R. Eickhoff, Simon B. TI Functional Decoding and Meta-analytic Connectivity Modeling in Adult Attention-Deficit/Hyperactivity Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Adults; Attention-deficit/hyperactivity disorder; fMRI; Functional decoding; Meta-analysis; Meta-analytic connectivity modeling ID DEFICIT HYPERACTIVITY DISORDER; WORKING-MEMORY; REWARD ANTICIPATION; RESPONSE-INHIBITION; BRAIN ACTIVATION; INTERFERENCE INHIBITION; PREFRONTAL CORTEX; NEURAL ACTIVITY; GRAY-MATTER; FOLLOW-UP AB BACKGROUND: Task-based functional magnetic resonance imaging (fMRI) studies of adult attention-deficit/hyperactivity disorder (ADHD) have revealed various ADHD-related dysfunctional brain regions, with heterogeneous findings across studies. Here, we used novel meta-analytic data-driven approaches to characterize the function and connectivity profile of ADHD-related dysfunctional regions consistently detected across studies. METHODS: We first conducted an activation likelihood estimation meta-analysis of 24 task-based fMRI studies in adults with ADHD. Each ADHD-related dysfunctional region resulting from the activation likelihood estimation meta-analysis was then analyzed using functional decoding based on similar to 7500 fMRI experiments in the BrainMap database. This approach allows mapping brain regions to functions not necessarily tested in individual studies, thus suggesting possible novel functions for those regions. Additionally, ADHD-related dysfunctional regions were clustered based on their functional coactivation profiles across all the experiments stored in BrainMap (meta-analytic connectivity modeling). RESULTS: ADHD-related hypoactivation was found in the left putamen, left inferior frontal gyrus (pars opercularis), left temporal pole, and right caudate. Functional decoding mapped the left putamen to cognitive aspects of music perception/reproduction and the left temporal lobe to language semantics; both these regions clustered together on the basis of their meta-analytic functional connectivity. Left inferior gyrus mapped to executive function tasks; right caudate mapped to both executive function tasks and music-related processes. CONCLUSIONS: Our study provides meta-analytic support to the hypothesis that, in addition to well-known deficits in typical executive functions, impairment in processes related to music perception/reproduction and language semantics may be involved in the pathophysiology of adult ADHD. C1 [Cortese, Samuele] Univ Southampton, Fac Med, Dev Brain Behav Lab, Acad Unit Psychol, Southampton, Hants, England. [Cortese, Samuele] Univ Southampton, Fac Med, Clin & Expt Sci CNS & Psychiat, Southampton, Hants, England. [Castellanos, F. Xavier] NYU Langone Med Ctr, Hassenfeld Childrens Hosp New York, Ctr Child Study, New York, NY USA. [Castellanos, F. Xavier] Nathan S Kline Inst Psychiat Res, Orangeburg, NY USA. [Fox, Peter T.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Fox, Peter T.] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX 78229 USA. [Fox, Peter T.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Laird, Angela R.] Florida Int Univ, Dept Phys, Miami, FL 33199 USA. [Cortese, Samuele; D'Acunto, Giulia; Masi, Gabriele] IRCCS, Stella Maris Sci Inst Child Neurol & Psychiat, Calambrone, Italy. [Eickhoff, Claudia R.; Eickhoff, Simon B.] Res Ctr Julich GmbH, Inst Neurosci & Med INM 1, Julich, Germany. [Eickhoff, Claudia R.] Rhein Westfal TH Aachen, Dept Psychiat Psychotherapy & Psychosomat, Aachen, Germany. [Eickhoff, Simon B.] Heinrich Heine Univ Duesseldorf, Inst Clin Neurosci & Med Psychol, Dusseldorf, Germany. RP Cortese, S (reprint author), Univ Southampton, Dev Brain Behav Lab, Acad Unit Psychol, Southampton, Hants, England. EM samuele.cortese@gmail.com OI Castellanos, Francisco/0000-0001-9192-9437 FU Helmholtz Portfolio Theme "Supercomputing and Modeling for the Human Brain"; European Union Seventh Framework Programme (FP7) [604102]; Eli Lilly; Shire; [R01MH083246]; [R01MH074457] FX This work was supported by Grant Nos. R01MH083246 and R01MH074457, the Helmholtz Portfolio Theme "Supercomputing and Modeling for the Human Brain" and the European Union Seventh Framework Programme (FP7/2007-2013) under Grant No. 604102.; SC has received royalties from Argon Healthcare, Italy (2012-2014). GM was on the advisory boards for Eli Lilly, Shire, and Angelini; has received research grants from Eli Lilly and Shire; and has been a speaker for Eli Lilly, Shire, Lundbeck, and Otsuka. All other authors report no biomedical financial interests or potential conflicts of interest. NR 84 TC 1 Z9 1 U1 7 U2 7 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 DEC 15 PY 2016 VL 80 IS 12 BP 896 EP 904 DI 10.1016/j.biopsych.2016.06.014 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EI8JZ UT WOS:000392754000005 PM 27569542 ER PT J AU Lubitz, CC Sosa, JA AF Lubitz, Carrie C. Sosa, Julie A. TI The Changing Landscape of Papillary Thyroid Cancer: Epidemiology, Management, and the Implications for Patients SO CANCER LA English DT Editorial Material DE active surveillance; financial toxicity; health-related quality of life; papillary thyroid carcinoma; thyroid neoplasms ID QUALITY-OF-LIFE; UNITED-STATES; INCREASING INCIDENCE; ACTIVE SURVEILLANCE; FINANCIAL BURDEN; SURVIVORS; RISK; MICROCARCINOMA; CARCINOMA; SURGERY AB The incidence of thyroid cancer has tripled over the past 3 decades, with the vast majority of the increase noted to be among small, indolent papillary thyroid carcinomas. Substantial overdiagnosis and potential overtreatment have led to a shift in clinical practice toward less aggressive approaches and a focus on improved risk stratification. This shift in practice may be associated with recent evidence suggesting that the increase in the incidence of thyroid cancer is slowing. Because patients are often young when they are diagnosed with thyroid cancer and because there is excellent long-term, disease-specific survival, there is an ever-growing population of survivors of thyroid cancer in the United States who accumulate substantial associated health care costs as they undergo surveillance and/or remedial treatment. Survivors of thyroid cancer can experience significant detriments to their quality of life and endure financial hardship. Future research should focus on the appropriateness of treatment as well as the financial and quality-of-life effects of thyroid cancer survivorship. (C) 2016 American Cancer Society. C1 [Lubitz, Carrie C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, 55 Fruit St,Yawkey 7B, Boston, MA 02114 USA. [Lubitz, Carrie C.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Sosa, Julie A.] Duke Univ, Sch Med, Duke Canc Inst, Dept Surg, Durham, NC USA. [Sosa, Julie A.] Duke Univ, Sch Med, Dept Med, Duke Canc Inst, Durham, NC 27706 USA. [Sosa, Julie A.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. RP Lubitz, CC (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, 55 Fruit St,Yawkey 7B, Boston, MA 02114 USA. EM clubitz@mgh.harvard.edu NR 50 TC 1 Z9 1 U1 5 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 DEC 15 PY 2016 VL 122 IS 24 BP 3754 EP 3759 DI 10.1002/cncr.30201 PG 6 WC Oncology SC Oncology GA EI9KH UT WOS:000392826300005 PM 27517675 ER PT J AU Jimeno, A Machiels, JP Wirth, L Specenier, P Seiwert, TY Mardjuadi, F Wang, XD Kapp, AV Royer-Joo, S Penuel, E McCall, B Pirzkall, A Clement, PM AF Jimeno, Antonio Machiels, Jean-Pascal Wirth, Lori Specenier, Pol Seiwert, Tanguy Y. Mardjuadi, Feby Wang, Xiaodong Kapp, Amy V. Royer-Joo, Stephanie Penuel, Elicia McCall, Bruce Pirzkall, Andrea Clement, Paul M. TI Phase Ib Study of Duligotuzumab (MEHD7945A) Plus Cisplatin/5-Fluorouracil or Carboplatin/Paclitaxel for First-Line Treatment of Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck SO CANCER LA English DT Article DE antibody; clinical trial; duligotuzumab; epidermal growth factor receptor (EGFR); human epidermal growth factor receptor 3 (HER3) ID COOPERATIVE-ONCOLOGY-GROUP; PLATINUM-BASED THERAPY; OPEN-LABEL; LUNG-CANCER; RANDOMIZED-TRIAL; SOLID TUMORS; COPY NUMBER; RECEPTOR; RECURRENT; CETUXIMAB AB BACKGROUND: This open-label, multicenter, phase Ib study assessed the safety and preliminary activity of duligotuzumab, a dualaction antibody that blocks ligand binding to human epidermal growth factor receptor 3 (HER3) and epidermal growth factor receptor, in combination with chemotherapy, in the first-line treatment of patients with recurrent/metastatic squamous cell cancer of the head and neck. METHODS: On day 1, duligotuzumab at a dose of 1650mg intravenously was combined with cisplatin at a dose of 100mg/m(2) and 5-fluorouracil at a dose of 1000mg/m(2) /day on days 1 to 4 in treatment arm A, or carboplatin (area under the curve, 6mg/mL/min) and paclitaxel (at a dose of 200mg/m(2)) in treatment arm B. Up to 6 cycles (21 days/cycle) were followed by duligotuzumab maintenance until disease progression or intolerable toxicity occurred. RESULTS: Nine patients in arm A and 15 patients in arm B received a median of 6 cycles of chemotherapy, and a median of 11 cycles (arm A) and 9 cycles (arm B) of duligotuzumab. Doselimiting toxicities occurred in 3 patients in arm A and 1 patient in arm B. Grade >= 3 treatment-related adverse events (graded according to graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]) in >= 3 patients were neutropenia (5 patients), hypokalemia (4 patients), dehydration (3 patients), anemia (3 patients), and diarrhea (3 patients) in arm A, and neutropenia (8 patients), anemia (5 patients), febrile neutropenia (4 patients), leukopenia (3 patients), thrombocytopenia (3 patients), and hypomagnesemia (3 patients) in arm B. The chemotherapy dose was reduced in 19 of 24 patients. Sixteen patients (67%) demonstrated objective responses regardless of human papillomavirus status or neuregulin 1 (NRG1) mRNA expression (arm A: 2 confirmed complete responses and 4 confirmed partial responses; arm B: 2 confirmed complete responses and 8 confirmed partial responses). CONCLUSIONS: Duligotuzumab in combination with cisplatin/5-fluorouracil or carboplatin/paclitaxel demonstrated encouraging activity in patients with recurrent/metastatic squamous cell cancer of the head and neck; an association with increased frequency and severity of select adverse events relative to historical data was suggestive of the potentiation of chemotherapyrelated adverse events. (C) 2016 American Cancer Society. C1 [Jimeno, Antonio] Univ Colorado, Sch Med, Div Med Oncol, 12801 E 17th Ave, Aurora, CO 80045 USA. [Machiels, Jean-Pascal; Mardjuadi, Feby] Catholic Univ Louvain, King Albert II Inst, Med Oncol Serv, St Luc Univ Clin, Brussels, Belgium. [Machiels, Jean-Pascal; Mardjuadi, Feby] Catholic Univ Louvain, Clin & Expt Res Inst, Pole MIRO, Brussels, Belgium. [Wirth, Lori] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. [Specenier, Pol] Univ Antwerp Hosp, Dept Med Oncol, Edegem, Belgium. [Seiwert, Tanguy Y.] Univ Chicago, Med Ctr, Dept Hematol Oncol, Chicago, IL 60637 USA. [Wang, Xiaodong; Kapp, Amy V.; Royer-Joo, Stephanie; Penuel, Elicia; McCall, Bruce; Pirzkall, Andrea] Genentech Inc, San Francisco, CA 94080 USA. [Clement, Paul M.] Univ Hosp Leuven, Dept Gen Med Oncol, Leuven, Belgium. [Clement, Paul M.] Katholieke Univ Leuven, Dept Oncol, Leuven, Belgium. RP Jimeno, A (reprint author), Univ Colorado, Sch Med, Div Med Oncol, 12801 E 17th Ave, Aurora, CO 80045 USA. EM antonio.jimeno@ucdenver.edu OI Specenier, Pol/0000-0002-2465-5197 FU Genentech Inc. FX Supported by Genentech Inc. NR 35 TC 1 Z9 1 U1 3 U2 3 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 DEC 15 PY 2016 VL 122 IS 24 BP 3803 EP 3811 DI 10.1002/cncr.30256 PG 9 WC Oncology SC Oncology GA EI9KH UT WOS:000392826300012 PM 27525588 ER PT J AU Sherman, SI Clary, DO Elisei, R Schlumberger, MJ Cohen, EEW Schoffski, P Wirth, LJ Mangeshkar, M Aftab, DT Brose, MS AF Sherman, Steven I. Clary, Douglas O. Elisei, Rossella Schlumberger, Martin J. Cohen, Ezra E. W. Schoffski, Patrick Wirth, Lori J. Mangeshkar, Milan Aftab, Dana T. Brose, Marcia S. TI Correlative Analyses of RET and RAS Mutations in a Phase 3 Trial of Cabozantinib in Patients With Progressive, Metastatic Medullary Thyroid Cancer SO CANCER LA English DT Article DE cabozantinib; medullary thyroid cancer; RAS; RET; tyrosine kinase inhibitor ID GROWTH-FACTOR; FOLLOW-UP; C-MET; CARCINOMA; GUIDELINES; EXPRESSION; PROGNOSIS; TUMORS; XL184 AB BACKGROUND: Cabozantinib significantly prolonged progression-free survival (PFS) versus a placebo in patients with progressive, metastatic medullary thyroid cancer (MTC; P<.001). An exploratory analysis of phase 3 trial data evaluated the influence of rearranged during transfection (RET) and RAS (HRAS, KRAS, and NRAS) mutations on cabozantinib clinical activity. METHODS: Patients (n=330) were randomized to cabozantinib (140mg/day) or a placebo. The primary endpoint was PFS. Additional outcome measures included PFS, objective response rates (ORRs), and adverse events in RET and RAS mutation subgroups. RESULTS: Among all study patients, 51.2% were RET mutation-positive (38.2% with RET M918T), 34.8% were RET mutation-unknown, and 13.9% were RET mutation-negative. Sixteen patients were RAS mutation-positive. Cabozantinib appeared to prolong PFS versus the placebo in the RET mutation-positive subgroup (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.14-0.38; P<.0001), the RET mutation-unknown subgroup (HR, 0.30; 95% CI, 0.16-0.57; P=.0001), and the RAS mutation-positive subgroup (HR, 0.15; 95% CI, 0.02-1.10; P=.0317). The RET M918T subgroup achieved the greatest observed PFS benefit from cabozantinib versus the placebo (HR, 0.15; 95% CI, 0.08-0.28; P<.0001). The ORRs for RET mutation-positive, RET mutation-negative, and RAS mutation-positive patients were 32%, 22%, and 31%, respectively. No PFS benefit was observed in patients lacking both RET and RAS mutations, although the ORR was 21%. The safety profile for all subgroups was similar to that for the overall cabozantinib arm. CONCLUSIONS: These data suggest that cabozantinib provides the greatest clinical benefit to patients with MTC who have RET M918T or RAS mutations. However, a prospective trial is needed to confirm the relation between genetic variation and the response to cabozantinib. (C) 2016 American Cancer Society. C1 [Sherman, Steven I.] Univ Texas MD Anderson Canc Ctr, Unit 1461,POB 301402, Houston, TX 77230 USA. [Clary, Douglas O.; Mangeshkar, Milan; Aftab, Dana T.] Exelixis Inc, San Francisco, CA USA. [Elisei, Rossella] Univ Pisa, Pisa, Italy. [Schlumberger, Martin J.] Univ Paris Sud, Inst Gustave Roussy, Villejuif, France. [Cohen, Ezra E. W.] Univ San Diego, Moores Canc Ctr, San Diego, CA 92110 USA. [Schoffski, Patrick] Univ Hosp Leuven, Leuven, Belgium. [Wirth, Lori J.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Brose, Marcia S.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. RP Sherman, SI (reprint author), Univ Texas MD Anderson Canc Ctr, Unit 1461,POB 301402, Houston, TX 77230 USA. EM sisherma@mdanderson.org FU Exelixis, Inc. FX Funding for this clinical trial was provided by Exelixis, Inc. Financial support for medical editorial assistance was also provided by Exelixis, Inc. NR 32 TC 2 Z9 2 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD DEC 15 PY 2016 VL 122 IS 24 BP 3856 EP 3864 DI 10.1002/cncr.30252 PG 9 WC Oncology SC Oncology GA EI9KH UT WOS:000392826300018 PM 27525386 ER PT J AU Shields, RK Potoski, BA Haidar, G Hao, BH Doi, Y Chen, L Press, EG Kreiswirth, BN Clancy, CJ Nguyen, MH AF Shields, Ryan K. Potoski, Brian A. Haidar, Ghady Hao, Binghua Doi, Yohei Chen, Liang Press, Ellen G. Kreiswirth, Barry N. Clancy, Cornelius J. Hong Nguyen, M. TI Clinical Outcomes, Drug Toxicity, and Emergence of Ceftazidime-Avibactam Resistance Among Patients Treated for Carbapenem-Resistant Enterobacteriaceae Infections SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE ceftazidime-avibactam resistance; carbapenem-resistant Enterobacteriaceae; Klebsiella pneumoniae carbapenemase ID KLEBSIELLA-PNEUMONIAE; BETA-LACTAMASES; BACTEREMIA AB Thirty-seven carbapenem-resistant Enterobacteriaceae (CRE)-infected patients were treated with ceftazidime-avibactam. Clinical success and survival rates at 30 days were 59% (22/37) and 76% (28/37), respectively. In 23% (5/22) of clinical successes, CRE infections recurred within 90 days. Microbiologic failure rate was 27% (10/37). Ceftazidime-avibactam resistance was detected in 30% (3/10) of microbiologic failures. C1 [Shields, Ryan K.; Potoski, Brian A.; Haidar, Ghady; Doi, Yohei; Press, Ellen G.; Clancy, Cornelius J.; Hong Nguyen, M.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Potoski, Brian A.] Univ Pittsburgh, Dept Pharm & Therapeut, Pittsburgh, PA USA. [Shields, Ryan K.; Potoski, Brian A.; Hong Nguyen, M.] Univ Pittsburgh, Antibiot Management Program, Med Ctr, Pittsburgh, PA 15260 USA. [Shields, Ryan K.; Hao, Binghua; Clancy, Cornelius J.; Hong Nguyen, M.] Univ Pittsburgh, XDR Pathogen Lab, Med Ctr, Pittsburgh, PA 15260 USA. [Clancy, Cornelius J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Chen, Liang; Kreiswirth, Barry N.] Rutgers State Univ, New Jersey Med Sch, TB Ctr, Publ Hlth Res Inst, Newark, NJ USA. RP Clancy, CJ (reprint author), Univ Pittsburgh, Med, 3550 Terrace St,S867 Scaife Hall, Pittsburgh, PA 15261 USA. EM cjc76@pitt.edu FU University of Pittsburgh Medical Center; NIH [K08AI114883, R21AI117338, R01AI090155, R21AI111037] FX This work was supported by funding provided to the XDR Pathogen Laboratory by the University of Pittsburgh Medical Center and the NIH (awards K08AI114883. R. K. S.; R21AI117338, L. C.; R01AI090155, B. N. K.; and R21AI111037, C. J. C.). NR 12 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 15 PY 2016 VL 63 IS 12 BP 1615 EP 1618 DI 10.1093/cid/ciw636 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EI7WW UT WOS:000392716100013 PM 27624958 ER PT J AU Bernstein, KD Liebsch, N Chen, YL Niemierko, A Schwab, JH Raskin, K Lozano-Calderon, SA Cote, G Harmon, DC Choy, E Haynes, A Mullen, J Hornicek, FJ Delaney, TF AF Bernstein, Karen De Amorim Liebsch, Norbert Chen, Yen-Lin Niemierko, Andrzej Schwab, Joseph H. Raskin, Kevin Lozano-Calderon, Santiago A. Cote, Gregory Harmon, David C. Choy, Edwin Haynes, Alex Mullen, John Hornicek, Francis J. Delaney, Thomas F. TI Clinical Outcomes for Patients After Surgery and Radiation Therapy for Mesenchymal Chondrosarcomas SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Article DE mesenchymal chondrosarcomas; radiation therapy; surgery; chemotherapy; management ID SOFT-TISSUES; BONE AB Introduction: We report the outcome of 23 patients with mesenchymal chondrosarcomas treated with surgery and radiation therapy +/- chemotherapy. The intent of the project was to review the impact of patient and treatment variables on treatment outcome, in particular with regard to extent of surgery and radiation dose. Patients and Methods: Twenty-three patients with mesenchymal chondrosarcomas were treated with surgery and radiation therapy (min. dose 44 Gy; max. dose 78 Gy; median dose 60 Gy; mean dose 61 Gy). Results: The median survival for the entire cohort of patients was 21.65 years (95% confidence interval +/- 4.25). The 5- and 10-year OS was 78.6%. Median disease-free survival for the 23 patients was 7.2 years. Disease-free survival (DFS) at 3 and 5 years was 70.7% and 57.8%, respectively. The local control rate at 5 and 10 years was 89.5% (95% CI 64.1-97.3%). Only three patients experienced local failure, three patients had regional failure, and eight developed distant metastases. Conclusions: In this cohort of patients local tumor control was high when using a combination of surgery and radiation. There was not a clear relationship between radiation dose and local tumor control. (C) 2016 Wiley Periodicals, Inc. C1 [Bernstein, Karen De Amorim; Liebsch, Norbert; Chen, Yen-Lin; Niemierko, Andrzej; Delaney, Thomas F.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA. [Schwab, Joseph H.; Raskin, Kevin; Lozano-Calderon, Santiago A.; Hornicek, Francis J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthoped Surg, Boston, MA USA. [Cote, Gregory; Harmon, David C.; Choy, Edwin] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Haynes, Alex; Mullen, John] Harvard Med Sch, Massachusetts Gen Hosp, Dept Gen Surg, Boston, MA USA. RP Bernstein, KD (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA. EM kbernstein@mgh.harvard.edu NR 21 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4790 EI 1096-9098 J9 J SURG ONCOL JI J. Surg. Oncol. PD DEC 15 PY 2016 VL 114 IS 8 BP 982 EP 986 DI 10.1002/jso.24435 PG 5 WC Oncology; Surgery SC Oncology; Surgery GA EJ0ZL UT WOS:000392939700014 ER PT J AU Pereira, NRP Langerhuizen, DWG Janssen, SJ Hornicek, FJ Ferrone, ML Harris, MB Schwab, JH AF Pereira, Nuno Rui Paulino Langerhuizen, David W. G. Janssen, Stein J. Hornicek, Francis J. Ferrone, Marco L. Harris, Mitchel B. Schwab, Joseph H. TI Are Perioperative Allogeneic Blood Transfusions Associated With 90-Days Infection After Operative Treatment for Bone Metastases? SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Article DE neoplasm metastasis; spine; extremities; blood transfusion; surgery; infection ID SURGICAL SITE INFECTION; POSTOPERATIVE BACTERIAL-INFECTION; CHARLSON COMORBIDITY INDEX; GASTROINTESTINAL CANCER; SPINAL METASTASES; KNEE ARTHROPLASTY; BREAST-CANCER; RISK-FACTORS; SURGERY; SURVIVAL AB Background and Objectives: We assessed whether allogeneic blood transfusions were associated with infection-within 90 days-after surgery for bone metastatic disease. Furthermore, we assessed other risk factors associated with infection. Methods: We included 1,266 patients surgically treated for a bone metastasis at two hospitals between 2002 and 2013. Blood transfusions within 7 days before and after surgery were considered perioperative. Results: We found no independent association between exposure to blood transfusion and infection (odds ratio [OR] 1.02, 95% confidence interval [CI]: 0.76-1.37, P = 0.889), nor a dose-response relationship (OR 1.02, 95% CI: 0.98-1.07, P = 0.245). Older age (OR 1.01, 95% CI: 1.00-1.02, P = 0.035), a higher modified Charlson comorbidity index (OR 1.13, 95% CI: 1.05-1.22, P = 0.002), surgery to the axial skeleton (OR 1.89, 95% CI: 1.42-2.51, P < 0.001), and previous radiotherapy (OR 1.45, 95% CI 1.07-1.96, P = 0.015) were independently associated with infection. Conclusions: There was no association between allogeneic blood transfusion and infection. We found other risk factors that should be taken into consideration when deciding to operate. (C) 2016 Wiley Periodicals, Inc. C1 [Pereira, Nuno Rui Paulino; Langerhuizen, David W. G.; Janssen, Stein J.; Hornicek, Francis J.; Schwab, Joseph H.] Harvard Med Sch, Dept Orthopaed Surg, Orthopaed Oncol Serv, Massachusetts Gen Hosp, Boston, MA USA. [Ferrone, Marco L.; Harris, Mitchel B.] Harvard Med Sch, Dept Orthopaed Surg, Orthopaed Oncol Serv, Brigham & Womens Hosp, Boston, MA USA. RP Pereira, NRP (reprint author), Massachusetts Gen Hosp, Room 3-946,Yawkey Bldg,55 Fruit St, Boston, MA 02114 USA. EM nunorui.pp@gmail.com FU Stichting Anna Fonds; Stichting Michael van Vloten Fonds; Stichting de Drie Lichten; KWF Kankerfonds FX Dr. Janssen has received funding from: Stichting Anna Fonds, Stichting Michael van Vloten Fonds, Stichting de Drie Lichten, and the KWF Kankerfonds during the conduct of the study. The other authors have nothing to disclose. NR 40 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4790 EI 1096-9098 J9 J SURG ONCOL JI J. Surg. Oncol. PD DEC 15 PY 2016 VL 114 IS 8 BP 997 EP 1003 DI 10.1002/jso.24440 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA EJ0ZL UT WOS:000392939700017 ER PT J AU Chiang, S Weigelt, B Wen, HC Pareja, F Raghavendra, A Martelotto, LG Burke, KA Basili, T Li, AQ Geyer, FC Piscuoglio, S Ng, CKY Jungbluth, AA Balss, J Pusch, S Baker, GM Cole, KS von Deimling, A Batten, JM Marotti, JD Soh, HC McCalip, BL Serrano, J Lim, RS Siziopikou, KP Lu, S Liu, XL Hammour, T Brogi, E Snuderl, M Iafrate, AJ Reis, JS Schnitt, SJ AF Chiang, Sarah Weigelt, Britta Wen, Huei-Chi Pareja, Fresia Raghavendra, Ashwini Martelotto, Luciano G. Burke, Kathleen A. Basili, Thais Li, Anqi Geyer, Felipe C. Piscuoglio, Salvatore Ng, Charlotte K. Y. Jungbluth, Achim A. Balss, Joerg Pusch, Stefan Baker, Gabrielle M. Cole, Kimberly S. von Deimling, Andreas Batten, Julie M. Marotti, Jonathan D. Soh, Hwei-Choo McCalip, Benjamin L. Serrano, Jonathan Lim, Raymond S. Siziopikou, Kalliopi P. Lu, Song Liu, Xiaolong Hammour, Tarek Brogi, Edi Snuderl, Matija Iafrate, A. John Reis-Filho, Jorge S. Schnitt, Stuart J. TI IDH2 Mutations Define a Unique Subtype of Breast Cancer with Altered Nuclear Polarity SO CANCER RESEARCH LA English DT Article ID PAPILLARY THYROID-CARCINOMA; HER2 GENE AMPLIFICATION; TALL CELL VARIANT; 2-HYDROXYGLUTARATE; HYPERMETHYLATION; DIFFERENTIATION; ADENOCARCINOMA; PROGRESSION; PHENOTYPE; CULTURES AB Solid papillary carcinoma with reverse polarity (SPCRP) is a rare breast cancer subtype with an obscure etiology. In this study, we sought to describe its unique histopathologic features and to identify the genetic alterations that underpin SPCRP using massively parallel whole-exome and targeted sequencing. The morphologic and immunohistochemical features of SPCRP support the invasive nature of this subtype. Ten of 13 (77%) SPCRPs harbored hotspot mutations at R172 of the isocitrate dehydrogenase IDH2, of which 8 of 10 displayed concurrent pathogenic mutations affecting PIK3CA or PIK3R1. One of the IDH2 wildtype SPCRPs harbored a TET2 Q548* truncating mutation coupled with a PIK3CA H1047R hotspot mutation. Functional studies demonstrated that IDH2 and PIK3CA hotspot mutations are likely drivers of SPCRP, resulting in its reversed nuclear polarization phenotype. Our results offer a molecular definition of SPCRP as a distinct breast cancer subtype. Concurrent IDH2 and PIK3CA mutations may help diagnose SPCRP and possibly direct effective treatment. (C)2016 AACR. C1 [Chiang, Sarah; Weigelt, Britta; Wen, Huei-Chi; Pareja, Fresia; Raghavendra, Ashwini; Martelotto, Luciano G.; Burke, Kathleen A.; Basili, Thais; Li, Anqi; Geyer, Felipe C.; Piscuoglio, Salvatore; Ng, Charlotte K. Y.; Jungbluth, Achim A.; Lim, Raymond S.; Brogi, Edi; Reis-Filho, Jorge S.] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. [Balss, Joerg; Pusch, Stefan; von Deimling, Andreas] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, German Consortium Translat Canc Res DKTK, Heidelberg, Germany. [Baker, Gabrielle M.] Univ Chicago, Dept Pathol, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Cole, Kimberly S.] Univ Iowa Hosp & Clin, Dept Pathol, Iowa City, IA 52242 USA. [von Deimling, Andreas] Heidelberg Univ, Inst Pathol, Dept Neuropathol, Heidelberg, Germany. [Batten, Julie M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Marotti, Jonathan D.] Dartmouth Hitchcock Med Ctr, Dept Pathol, Lebanon, NH 03766 USA. [Soh, Hwei-Choo] North Shore Private Hosp, Pathol North, St Leonards, NSW, Australia. [McCalip, Benjamin L.] Miami Valley Hosp, Dayton, OH USA. [Serrano, Jonathan; Snuderl, Matija] NYU, Dept Pathol, Langone Med Ctr, 550 1St Ave, New York, NY 10016 USA. [Serrano, Jonathan; Snuderl, Matija] Sch Med, New York, NY USA. [Siziopikou, Kalliopi P.] Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL 60611 USA. [Lu, Song] Mon Gen Hosp, Dept Pathol, Morgantown, WV USA. [Liu, Xiaolong] ABQ Hlth Partners, Albuquerque, NM USA. [Hammour, Tarek] Maine Med Ctr, Portland, ME 04102 USA. [Iafrate, A. John; Schnitt, Stuart J.] Harvard Med Sch, Dept Pathol, Boston, MA USA. [Schnitt, Stuart J.] Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. [Wen, Huei-Chi] Icahn Sch Med Mt Sinai, Dept Dermatol, New York, NY 10029 USA. RP Schnitt, SJ (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA.; Chiang, S (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA. EM chiangs@mskcc.org; sschnitt@bidmc.harvard.edu RI von Deimling, Andreas/F-7774-2013; OI von Deimling, Andreas/0000-0002-5863-540X; Snuderl, Matija/0000-0003-0752-0917; Martelotto, Luciano/0000-0002-9625-1183; Basili de Oliveira, Thais/0000-0003-3216-3544 FU Susan G. Komen Postdoctoral Fellowship [PDF14298348]; BCRF; Friedberg Charitable Foundation; NIH/NCI Cancer Center Support Grant [P30 CA008748] FX S. Piscuoglio was funded in part by a Susan G. Komen Postdoctoral Fellowship Grant (PDF14298348). J.S. Reis-Filho is funded in part by BCRF, and M. Snuderl is supported by the Friedberg Charitable Foundation. S. Chiang, B. Weigelt, H.-C. Wen, F. Pareja, A. Raghavendra, L.G. Martelotto, K.A. Burke, T. Basili, A. Li, F.C. Geyer, S. Piscuoglio, C.K.Y. Ng, A.A. Jungbluth, R.S. Lim, E. Brogi, and J.S. Reis-Filho were funded in part by a NIH/NCI Cancer Center Support Grant (P30 CA008748). NR 48 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2016 VL 76 IS 24 BP 7118 EP 7129 DI 10.1158/0008-5472.CAN-16-0298 PG 12 WC Oncology SC Oncology GA EH0RE UT WOS:000391470600006 PM 27913435 ER PT J AU Babic, A Bao, Y Qian, ZR Yuan, C Giovannucci, EL Aschard, H Kraft, P Amundadottir, LT Stolzenberg-Solo-mon, R Morales-Oyarvide, V Ng, K Stampfer, MJ Ogino, S Buring, JE Sesso, HD Gaziano, JM Rifai, N Pollak, MN Anderson, ML Cochrane, BB Luo, JH Manson, JE Fuchs, CS Wolpin, BM AF Babic, Ana Bao, Ying Qian, Zhi Rong Yuan, Chen Giovannucci, Edward L. Aschard, Hugues Kraft, Peter Amundadottir, Laufey T. Stolzenberg-Solo-mon, Rachael Morales-Oyarvide, Vicente Ng, Kimmie Stampfer, Meir J. Ogino, Shuji Buring, Julie E. Sesso, Howard D. Gaziano, John Michael Rifai, Nader Pollak, Michael N. Anderson, Matthew L. Cochrane, Barbara B. Luo, Juhua Manson, JoAnn E. Fuchs, Charles S. Wolpin, Brian M. TI Pancreatic Cancer Risk Associated with Prediagnostic Plasma Levels of Leptin and Leptin Receptor Genetic Polymorphisms SO CANCER RESEARCH LA English DT Article ID GENOME-WIDE ASSOCIATION; C-REACTIVE PROTEIN; BODY-MASS INDEX; INSULIN-RESISTANCE; CIRCULATING LEPTIN; PHYSICAL-ACTIVITY; BREAST-CANCER; WOMENS HEALTH; OBESITY; ADIPONECTIN AB Leptin is an adipokine involved in regulating energy balance, which has been identified as a potential biologic link in the development of obesity-associated cancers, such as pancreatic cancer. In this prospective, nested case-control study of 470 cases and 1,094 controls from five U.S. cohorts, we used conditional logistic regression to evaluate pancreatic cancer risk by prediagnostic plasma leptin, adjusting for race/ethnicity, diabetes, body mass index, physical activity, plasma C-peptide, adiponectin, and 25-hydroxyvitamin D. Because of known differences in leptin levels by gender, analyses were conducted separately for men and women. We also evaluated associations between 32 tagging SNPs in the leptin receptor (LEPR) gene and pancreatic cancer risk. Leptin levels were higher in female versus male control participants (median, 20.8 vs. 6.7 ng/mL; P < 0.0001). Among men, plasma leptin was positively associated with pancreatic cancer risk and those in the top quintile had a multivariable-adjusted OR of 3.02 [ 95% confidence interval (CI), 1.27-7.16; P-trend = 0.02] compared with men in the bottom quintile. Among women, circulating leptin was not associated with pancreatic cancer risk (P-trend = 0.21). Results were similar across cohorts (P-heterogeneity = 0.88 for two male cohorts and 0.35 for three female cohorts). In genetic analyses, rs10493380 in LEPR was associated with increased pancreatic cancer risk among women, with an OR per minor allele of 1.54 (95% CI, 1.18-2.02; multiple hypothesis-corrected P = 0.03). NoSNPs were significantly associated with risk in men. In conclusion, higher prediagnostic levels of plasmaleptin were associated with an elevated risk of pancreatic cancer among men, but not among women. (C)2016 AACR. C1 [Babic, Ana; Qian, Zhi Rong; Yuan, Chen; Morales-Oyarvide, Vicente; Ng, Kimmie; Ogino, Shuji; Fuchs, Charles S.; Wolpin, Brian M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bao, Ying; Giovannucci, Edward L.; Stampfer, Meir J.; Manson, JoAnn E.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Bao, Ying; Giovannucci, Edward L.; Stampfer, Meir J.; Buring, Julie E.; Sesso, Howard D.; Gaziano, John Michael; Manson, JoAnn E.; Fuchs, Charles S.] Harvard Med Sch, Boston, MA USA. [Giovannucci, Edward L.; Aschard, Hugues; Kraft, Peter; Stampfer, Meir J.; Sesso, Howard D.; Manson, JoAnn E.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Giovannucci, Edward L.; Stampfer, Meir J.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Kraft, Peter] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Amundadottir, Laufey T.] NCI, Lab Translat Gen, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Stolzenberg-Solo-mon, Rachael] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Div MPE Mol Pathol Epidemiol, 75 Francis St, Boston, MA 02115 USA. [Buring, Julie E.; Sesso, Howard D.; Gaziano, John Michael] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Buring, Julie E.] Harvard Med Sch, Dept Ambulatory Care & Prevent, Boston, MA USA. [Gaziano, John Michael] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA USA. [Rifai, Nader] Childrens Hosp Boston, Dept Lab Med, Boston, MA USA. [Pollak, Michael N.; Manson, JoAnn E.] McGill Univ, Fac Med, Dept Oncol, Canc Prevent Res Unit, Montreal, PQ, Canada. [Anderson, Matthew L.] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Cochrane, Barbara B.] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [Luo, Juhua] West Virginia Univ, Dept Community Med, Morgantown, WV USA. RP Wolpin, BM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM bwolpin@partners.org FU NIH [UM1 CA167552, UM1 CA186107, P01 CA87969, R01 CA49449, CA97193, CA34944, CA40360, HL26490, HL34595, KL2 TR001100, U54 CA155626, P30 DK046200, K07 CA148894, R01 CA124908, P50 CA127003]; National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services [HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, HHSN268201600004C]; NIH (Bethesda, MD) [CA047988, HL043851, HL080467, HL099355, UM1 CA182913]; NCI [R35 CA197735]; Robert T. and Judith B. Hale Fund for Pancreatic Cancer; Perry S. Levy Fund for Gastrointestinal Cancer Research; Pappas Family Research Fund for Pancreatic Cancer; NIH/NCI [U01 CA210171]; Department of Defense [CA130288]; Lustgarten Foundation; Pancreatic Cancer Action Network; Noble Effort Fund; Peter R. Leavitt Family Fund; Wexler Family Fund; Promises for Purple FX HPFS is supported by NIH grant UM1 CA167552. NHS is supported by NIH grants UM1 CA186107, P01 CA87969, and R01 CA49449. PHS is supported by NIH grants CA97193, CA34944, CA40360, HL26490, and HL34595. The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. The WHS is supported by grants CA047988, HL043851, HL080467, HL099355, and UM1 CA182913 from the NIH (Bethesda, MD).; Additional support from NIH KL2 TR001100, NIH U54 CA155626, and NIH P30 DK046200 was provided to Y. Bao; NIH K07 CA148894 to K. Ng; from NCI R35 CA197735 to S. Ogino; from the Robert T. and Judith B. Hale Fund for Pancreatic Cancer, Perry S. Levy Fund for Gastrointestinal Cancer Research, Pappas Family Research Fund for Pancreatic Cancer, NIH R01 CA124908, and NIH P50 CA127003 to C.S. Fuchs; and from NIH/NCI U01 CA210171, Department of Defense CA130288, Lustgarten Foundation, Pancreatic Cancer Action Network, Noble Effort Fund, Peter R. Leavitt Family Fund, Wexler Family Fund, and Promises for Purple to B. M. Wolpin. NR 50 TC 1 Z9 1 U1 6 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2016 VL 76 IS 24 BP 7160 EP 7167 DI 10.1158/0008-5472.CAN-16-1699 PG 8 WC Oncology SC Oncology GA EH0RE UT WOS:000391470600010 PM 27780823 ER PT J AU Miles, WO Lembo, A Volorio, A Brachtel, E Tian, B Sgroi, D Provero, P Dyson, N AF Miles, Wayne O. Lembo, Antonio Volorio, Angela Brachtel, Elena Tian, Bin Sgroi, Dennis Provero, Paolo Dyson, Nicholas TI Alternative Polyadenylation in Triple-Negative Breast Tumors Allows NRAS and c-JUN to Bypass PUMILIO Posttranscriptional Regulation SO CANCER RESEARCH LA English DT Article ID 3' UNTRANSLATED REGIONS; RNA-BINDING PROTEINS; MESSENGER-RNAS; CANCER; EXPRESSION; CELLS; CLEAVAGE; GENE; DROSOPHILA; GENOME AB Alternative polyadenylation (APA) is a process that changes the posttranscriptional regulation and translation potential of mRNAs via addition or deletion of 30 untranslated region (30 UTR) sequences. To identify posttranscriptional-regulatory events affected by APA in breast tumors, tumor datasets were analyzed for recurrent APA events. Motif mapping of the changed 30 UTR regions found that APA-mediated removal of Pumilio regulatory elements (PRE) was unusually common. Breast tumor subtypespecific APA profiling identified triple-negative breast tumors as having the highest levels of APA. To determine the frequency of these events, an independent cohort of triple-negative breast tumors and normal breast tissue was analyzed for APA. APA-mediated shortening of NRAS and c-JUN was seen frequently, and this correlated with changes in the expression of downstream targets. mRNA stability and luciferase assays demonstrated APA-dependent alterations in RNA and protein levels of affected candidate genes. Examination of clinical parameters of these tumors found those with APA of NRAS and c-JUN to be smaller and less proliferative, but more invasive than non-APA tumors. RT-PCR profiling identified elevated levels of polyadenylation factor CSTF3 in tumors with APA. Overexpression of CSTF3 was common in triple-negative breast cancer cell lines, and elevated CSTF3 levels were sufficient to induce APA of NRAS and c-JUN. Our results support the hypothesis that PRE-containing mRNAs are disproportionately affected by APA, primarily due to high sequence similarity in the motifs utilized by polyadenylation machinery and the PUM complex. (C) 2016 AACR. C1 [Miles, Wayne O.; Dyson, Nicholas] Massachusetts Gen Hosp, Ctr Canc, Dept Mol Oncol, Charlestown, MA USA. [Miles, Wayne O.; Volorio, Angela; Brachtel, Elena; Sgroi, Dennis; Dyson, Nicholas] Harvard Med Sch, Charlestown, MA USA. [Miles, Wayne O.] Ohio State Univ, Dept Mol Genet, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Lembo, Antonio; Provero, Paolo] Univ Turin, Dept Mol Biotechnol & Hlth Sci, Turin, Italy. [Lembo, Antonio; Provero, Paolo] Ist Sci San Raffaele, Ctr Translat Genom & Bioinformat, Milan, Italy. [Volorio, Angela; Brachtel, Elena; Sgroi, Dennis] Massachusetts Gen Hosp, Ctr Canc, Dept Pathol, Charlestown, MA USA. [Tian, Bin] Rutgers New Jersey Med Sch, Dept Microbiol Biochem & Mol Genet, Newark, NJ USA. RP Dyson, N (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Bldg 149,13th St, Charlestown, MA 02129 USA.; Miles, WO (reprint author), Ohio State Univ, 820 Biomed Res Tower,460 West 12th St, Columbus, OH 43219 USA. EM wayne.miles@osumc.edu; dyson@helix.mgh.harvard.edu FU NIH [R01 CA112021, R01 CA163698, R01 CA64402]; Avon Foundation; DOD Breast Cancer Research Program; Susan G. Komen for the Cure FX D. Sgroi is supported by NIH grant R01 CA112021, the Avon Foundation, DOD Breast Cancer Research Program, and the Susan G. Komen for the Cure. N.J. Dyson is supported by NIH grants R01 CA163698 and R01 CA64402. N. Dyson is the James and Shirley Curvey MGH Research Scholar. NR 49 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2016 VL 76 IS 24 BP 7231 EP 7241 DI 10.1158/0008-5472.CAN-16-0844 PG 11 WC Oncology SC Oncology GA EH0RE UT WOS:000391470600016 PM 27758885 ER PT J AU Yanagita, M Redig, AJ Paweletz, CP Dahlberg, SE O'Connell, A Feeney, N Taibi, M Boucher, D Oxnard, GR Johnson, BE Costa, DB Jackman, DM Janne, PA AF Yanagita, Masahiko Redig, Amanda J. Paweletz, Cloud P. Dahlberg, Suzanne E. O'Connell, Allison Feeney, Nora Taibi, Myriam Boucher, David Oxnard, Geoffrey R. Johnson, Bruce E. Costa, Daniel B. Jackman, David M. Janne, Pasi A. TI A Prospective Evaluation of Circulating Tumor Cells and Cell-Free DNA in EGFR-Mutant Non-Small Cell Lung Cancer Patients Treated with Erlotinib on a Phase II Trial SO CLINICAL CANCER RESEARCH LA English DT Article ID TYROSINE KINASE INHIBITORS; INTERNATIONAL-ASSOCIATION; ACQUIRED-RESISTANCE; MUTATION; ADENOCARCINOMA; BLOOD; GEFITINIB; THERAPY; SAMPLES; CHEMOTHERAPY AB Purpose: Genotype-directed therapy is the standard of care for advanced non-small cell lung cancer (NSCLC), but obtaining tumor tissue for genotyping remains a challenge. Circulating tumor cell (CTC) or cell-free DNA (cfDNA) analysis may allow for noninvasive evaluation. This prospective trial evaluated CTCs and cfDNA in EGFR-mutant NSCLC patients treated with erlotinib until progression. Experimental Design: EGFR-mutant NSCLC patients were enrolled in a phase II trial of erlotinib. Blood was collected at baseline, every 2 months on study, and at disease progression. Plasma genotyping was performed by droplet digital PCR for EGFR19del, L858R, and T790M. CTCs were isolated by CellSave, enumerated, and analyzed by immunofluorescence for CD45 and pan-cytokeratin and EGFR and MET FISH were also performed. Rebiopsy was performed at disease progression. Results: Sixty patients were enrolled; 44 patients discontinued therapy for disease progression. Rebiopsy occurred in 35 of 44 patients (80%), with paired CTC/cfDNA analysis in 41 of 44 samples at baseline and 36 of 44 samples at progression. T790M was identified in 23 of 35 (66%) tissue biopsies and 9 of 39 (23%) cfDNA samples. CTC analysis at progression identified MET amplification in 3 samples in which tissue analysis could not be performed. cfDNA analysis identified T790M in 2 samples in which rebiopsy was not possible. At diagnosis, high levels of cfDNA but not high levels of CTCs correlated with progression-free survival. Conclusions: cfDNA and CTCs are complementary, noninvasive assays for evaluation of acquired resistance to first-line EGFR TKIs and may expand the number of patients in whom actionable genetic information can be obtained at acquired resistance. Serial cfDNA monitoring may offer greater clinical utility than serial monitoring of CTCs. (C)2016 AACR. C1 [Yanagita, Masahiko; Redig, Amanda J.; Paweletz, Cloud P.; Taibi, Myriam; Oxnard, Geoffrey R.; Johnson, Bruce E.; Jackman, David M.; Janne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Yanagita, Masahiko; Redig, Amanda J.; Oxnard, Geoffrey R.; Johnson, Bruce E.; Costa, Daniel B.; Jackman, David M.; Janne, Pasi A.] Harvard Med Sch, Boston, MA USA. [Redig, Amanda J.; Oxnard, Geoffrey R.; Johnson, Bruce E.; Jackman, David M.; Janne, Pasi A.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Paweletz, Cloud P.] Dana Farber Canc Inst, Belfer Ctr Appl Canc Sci, Boston, MA 02115 USA. [Dahlberg, Suzanne E.; O'Connell, Allison; Feeney, Nora] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Dahlberg, Suzanne E.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Boucher, David; Costa, Daniel B.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. RP Janne, PA (reprint author), Dana Farber Canc Inst, 450 Brook Line Ave, Boston, MA 02215 USA. EM Pasi_Janne@dfci.harvard.edu FU NCI [T32CA009172, 5R01CA114465, 5R01CA135257]; Kaplan Research Fund for Thoracic Oncology; Expect Miracles Foundation; Genentech FX This study was supported by NCI grants T32CA009172 (supporting A.J. Redig), 5R01CA114465 (to B.E. Johnson, P.A. Janne, and G.R. Oxnard), and 5R01CA135257 (to G.R. Oxnard and P.A. Johnson); Kaplan Research Fund for Thoracic Oncology (to S.E. Dahlberg); and Expect Miracles Foundation (to C.P. Paweletz). Funding for this study was also provided by Genentech. NR 41 TC 2 Z9 2 U1 5 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 DEC 15 PY 2016 VL 22 IS 24 BP 6010 EP 6020 DI 10.1158/1078-0432.CCR-16-0909 PG 11 WC Oncology SC Oncology GA EH0RW UT WOS:000391472400009 PM 27281561 ER PT J AU Jonas, O Oudin, MJ Kosciuk, T Whitman, M Gertler, FB Cima, MJ Flaherty, KT Langer, R AF Jonas, Oliver Oudin, Madeleine J. Kosciuk, Tatsiana Whitman, Matthew Gertler, Frank B. Cima, Michael J. Flaherty, Keith T. Langer, Robert TI Parallel In Vivo Assessment of Drug Phenotypes at Various Time Points during Systemic BRAF Inhibition Reveals Tumor Adaptation and Altered Treatment Vulnerabilities SO CLINICAL CANCER RESEARCH LA English DT Article ID MUTANT MELANOMA; RAF INHIBITORS; RESISTANCE; MICROENVIRONMENT; SENSITIVITY; VEMURAFENIB; PATHWAY; GROWTH; MEK AB Purpose: Treatment of BRAF-mutated melanoma tumors with BRAF inhibitor-based therapy produces high response rates, but of limited duration in the vast majority of patients. Published investigations of resistance mechanisms suggest numerous examples of tumor adaptation and signal transduction bypass mechanisms, but without insight into biomarkers that would predict which mechanism will predominate. Monitoring phenotypic response of multiple adaptive mechanisms simultaneously within the same tumor as it adapts during treatment has been elusive. Experimental Design: This study reports on a method to provide a more complete understanding of adaptive tumor responses. We simultaneously measured in vivo antitumor activity of 12 classes of inhibitors, which are suspected of enabling adaptive escape mechanisms, at various time points during systemic BRAF inhibition. We used implantable microdevices to release multiple compounds into distinct regions of a tumor to measure the efficacy of each compound independently and repeated these measurements as tumors progressed on systemic BRAF treatment. Results: We observed varying phenotypic responses to specific inhibitors before, during, and after prolonged systemic treatment with BRAF inhibitors. Our results specifically identify PI3K, PDGFR, EGFR, and HDAC inhibitors as becoming significantly more efficacious during systemic BRAF inhibition. The sensitivity to other targeted inhibitors remained mostly unchanged, whereas local incremental sensitivity to PLX4720 declined sharply. Conclusions: These findings suggest redundancy of several resistance mechanisms and may help identify optimal constituents of more effective combination therapy in BRAF-mutant melanoma. They also represent a new paradigm for dynamic measurement of adaptive signaling mechanisms within the same tumor during therapy. (C)2016 AACR. C1 [Jonas, Oliver; Oudin, Madeleine J.; Kosciuk, Tatsiana; Whitman, Matthew; Gertler, Frank B.; Cima, Michael J.; Langer, Robert] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Flaherty, Keith T.] Massachusetts Gen Hosp, Div Surg Oncol Med Oncol & Dermatol, Boston, MA 02114 USA. RP Langer, R (reprint author), MIT, 77 Massachusettes Ave, Cambridge, MA 02139 USA. EM rlanger@mit.edu FU Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund; Koch Insitute Frontier Research Fund; Ludwig Center for Molecular Oncology; Prostate Cancer Foundation; Koch Institute NCI core grant [P30-CA14051]; NCI [R21-CA177391] FX This work was supported by the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund and the Koch Insitute Frontier Research Fund, Ludwig Center for Molecular Oncology, Prostate Cancer Foundation, Koch Institute NCI core grant P30-CA14051 and by NCI grant R21-CA177391. NR 20 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2016 VL 22 IS 24 BP 6031 EP 6038 DI 10.1158/1078-0432.CCR-15-2722 PG 8 WC Oncology SC Oncology GA EH0RW UT WOS:000391472400011 PM 27091406 ER PT J AU Stover, DG Coloff, JL Barry, WT Brugge, JS Winer, EP Selfors, LM AF Stover, Daniel G. Coloff, Jonathan L. Barry, William T. Brugge, Joan S. Winer, Eric P. Selfors, Laura M. TI The Role of Proliferation in Determining Response to Neoadjuvant Chemotherapy in Breast Cancer: A Gene Expression-Based Meta-Analysis SO CLINICAL CANCER RESEARCH LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; MOLECULAR SUBTYPES; SURVIVAL; PROGNOSIS; PREDICTOR; PACLITAXEL; SIGNATURES; PROFILES; PATTERNS; BENEFIT AB Purpose: To provide further insight into the role of proliferation and other cellular processes in chemosensitivity and resistance, we evaluated the association of a diverse set of gene expression signatures with response to neoadjuvant chemotherapy (NAC) in breast cancer. Experimental Design: Expression data from primary breast cancer biopsies for 1,419 patients in 17 studies prior to NAC were identified and aggregated using common normalization procedures. Clinicopathologic characteristics, including response to NAC, were collected. Scores for 125 previously published breast cancer-related gene expression signatures were calculated for each tumor. Results: Within each receptor-based subgroup or PAM50 subtype, breast tumors with high proliferation signature scores were significantly more likely to achieve pathologic complete response to NAC. To distinguish "proliferation-associated" from "proliferation-independent" signatures, we used correlation and linear modeling approaches. Most signatures associated with response to NAC were proliferation associated: 90.5% (38/42) in ER+/HER2(-) and 63.3% (38/60) in triple-negative breast cancer (TNBC). Proliferation-independent signatures predictive of response to NAC in ER+/HER2(-) breast cancer were related to immune activity, while those in TNBC comprised a diverse set of signatures, including immune, DNA damage, signaling pathways (PI3K, AKT, Ras, and EGFR), and "stemness" phenotypes. Conclusions: Proliferation differences account for the vast majority of predictive capacity of gene expression signatures in neoadjuvant chemosensitivity for ER+/HER2(-) breast cancers and, to a lesser extent, TNBCs. Immune activation signatures are proliferation-independent predictors of pathologic complete response in ER+/HER2(-) breast cancers. In TNBCs, significant proliferation-independent signatures include gene sets that represent a diverse set of cellular processes. (C)2016 AACR. C1 [Stover, Daniel G.; Winer, Eric P.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Yawkey 12, Boston, MA 02115 USA. [Stover, Daniel G.; Coloff, Jonathan L.; Brugge, Joan S.; Selfors, Laura M.] Harvard Med Sch, Dept Cell Biol, 240 Longwood Ave,C501, Boston, MA 02115 USA. [Barry, William T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Winer, EP (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Yawkey 12, Boston, MA 02115 USA.; Selfors, LM (reprint author), Harvard Med Sch, Dept Cell Biol, 240 Longwood Ave,C501, Boston, MA 02115 USA. EM eric_winer@dfci.harvard.edu; laura_selfors@hms.harvard.edu FU Susan G. Komen for the Cure [PDF14299961]; Breast Cancer Alliance [FS45312]; Breast Cancer Research Foundation FX Financial support was provided by Susan G. Komen for the Cure PDF14299961 (D.G. Stover), Breast Cancer Alliance FS45312 (J.S. Brugge), and Breast Cancer Research Foundation (J.S. Brugge). NR 56 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2016 VL 22 IS 24 BP 6039 EP 6050 DI 10.1158/1078-0432.CCR-16-0471 PG 12 WC Oncology SC Oncology GA EH0RW UT WOS:000391472400012 PM 27330058 ER PT J AU Nishino, M Ramaiya, NH Awad, MM Sholl, LM Maattala, JA Taibi, M Hatabu, H Ott, PA Armand, PF Hodi, FS AF Nishino, Mizuki Ramaiya, Nikhil H. Awad, Mark M. Sholl, Lynette M. Maattala, Jennifer A. Taibi, Myriam Hatabu, Hiroto Ott, Patrick A. Armand, Philippe F. Hodi, F. Stephen TI PD-1 Inhibitor-Related Pneumonitis in Advanced Cancer Patients: Radiographic Patterns and Clinical Course SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; DRUG-RELATED PNEUMONITIS; LONG-TERM SAFETY; ADVANCED MELANOMA; RECEIVING NIVOLUMAB; UNTREATED MELANOMA; MAMMALIAN TARGET; ADVERSE EVENTS; IPILIMUMAB; PEMBROLIZUMAB AB Purpose: Investigate the clinical characteristics, radiographic patterns, and treatment course of PD-1 inhibitor-related pneumonitis in advanced cancer patients. Experimental Design: Among patients with advanced melanoma, lung cancer, or lymphoma treated in trials of nivolumab, we identified those who developed pneumonitis. Chest CT scans were reviewed to assess extent, distribution, and radiographic patterns of pneumonitis. Results: Among 170 patients treated in 10 different trials of nivolumab, 20 patients (10 melanoma, 6 lymphoma, and 4 lung cancer) developed pneumonitis. Five patients received nivolumab monotherapy, and 15 received combination therapy. The median time from therapy initiation to pneumonitis was 2.6 months. Radiographic pattern was cryptogenic organizing pneumonia (COP) in 13, nonspecific interstitial pneumonia (NSIP) in 3, hypersensitivity pneumonitis (HP) in 2, and acute interstitial pneumonia (AIP)/acute respiratory distress syndrome (ARDS) in 2 patients. The AIP/ARDS pattern had the highest grade, followed by COP, whereas NSIP and HP had lower grade (median grade: 3, 2, 1, 1, respectively; P = 0.006). The COP pattern was most common in all tumors and treatment regimens. Most patients (17/20; 85%) received corticosteroids, and 3 (15%) also required infliximab. Seven patients restarted nivolumab therapy; 2 of them developed recurrent pneumonitis and were successfully retreated with corticosteroids. One of the patients experienced a pneumonitis flare after completion of corticosteroid taper without nivolumab retreatment. Conclusions: PD-1 inhibitor-related pneumonitis showed a spectrum of radiographic patterns, reflecting pneumonitis grades. COP was the most common pattern across tumor types and therapeutic regimens. Most patients were successfully treated with corticosteroids. Recurrent pneumonitis and pneumonitis flare were noted in a few patients. (C)2016 AACR. C1 [Nishino, Mizuki; Ramaiya, Nikhil H.; Hatabu, Hiroto] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Nishino, Mizuki; Ramaiya, Nikhil H.; Hatabu, Hiroto] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. [Awad, Mark M.; Maattala, Jennifer A.; Taibi, Myriam; Ott, Patrick A.; Armand, Philippe F.; Hodi, F. Stephen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Sholl, Lynette M.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. RP Nishino, M (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM Mizuki_Nishino@dfci.harvard.edu FU NCI [5K23CA157631] FX M. Nishino was supported by 5K23CA157631 (NCI). NR 30 TC 3 Z9 3 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2016 VL 22 IS 24 BP 6051 EP 6060 DI 10.1158/1078-0432.CCR-16-1320 PG 10 WC Oncology SC Oncology GA EH0RW UT WOS:000391472400013 PM 27535979 ER PT J AU Rose, AAN Annis, MG Frederick, DT Biondini, M Dong, ZF Kwong, L Chin, L Keler, T Hawthorne, T Watson, IR Flaherty, KT Siegel, PM AF Rose, April A. N. Annis, Matthew G. Frederick, Dennie T. Biondini, Marco Dong, Zhifeng Kwong, Lawrence Chin, Lynda Keler, Tibor Hawthorne, Thomas Watson, Ian R. Flaherty, Keith T. Siegel, Peter M. TI MAPK Pathway Inhibitors Sensitize BRAF-Mutant Melanoma to an Antibody-Drug Conjugate Targeting GPNMB SO CLINICAL CANCER RESEARCH LA English DT Article ID GLYCOPROTEIN NONMETASTATIC B; BREAST-CANCER METASTASIS; OXIDATIVE STRESS; RESISTANCE; EXPRESSION; MITF; PIGMENTATION; MELANOGENESIS; ULTRAVIOLET; BIOGENESIS AB Purpose: To determine if BRAF and/or MEK inhibitor-induced GPNMB expression renders melanomas sensitive to CDX-011, an antibody-drug conjugate targeting GPNMB. Experimental Design: The Cancer Genome Atlas melanoma dataset was interrogated for a panel of MITF-regulated melanosomal differentiation antigens, including GPNMB. BRAF-mutant melanoma cell lines treated with BRAF or MEK inhibitors were assessed for GPNMB expression by RT-qPCR, immunoblot, and FACS analyses. Transient siRNA-mediated knockdown approaches were used to determine if MITF is requirement for treatment-induced GPNMB upregulation. GPNMB expression was analyzed in serial biopsies and serum samples from patients with melanoma taken before, during, and after disease progression on MAPK inhibitor treatment. Subcutaneous injections were performed to test the efficacy of MAPK inhibitors alone, CDX-011 alone, or their combination in suppressing melanoma growth. Results: A MITF-dependent melanosomal differentiation signature is associated with poor prognosis in patients with this disease. MITF is increased following BRAF and MEK inhibitor treatment and induces the expression of melanosomal differentiation genes, including GPNMB. GPNMB is expressed at the cell surface in MAPK inhibitor-treated melanoma cells and is also elevated in on-treatment versus pretreatment biopsies from melanoma patients receiving MAPK pathway inhibitors. Combining BRAF and/or MEK inhibitors with CDX-011, an antibody-drug conjugate targeting GPNMB, is effective in causing melanoma regression in preclinical animal models and delays the recurrent melanoma growth observed with MEK or BRAF/MEK inhibitor treatment alone. Conclusions: The combination of MAPK pathway inhibitors with an antibody-drug conjugate targeting GPNMB is an effective therapeutic option for patients with melanoma. (C)2016 AACR. C1 [Rose, April A. N.; Annis, Matthew G.; Biondini, Marco; Dong, Zhifeng; Watson, Ian R.; Siegel, Peter M.] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ, Canada. [Rose, April A. N.; Annis, Matthew G.; Biondini, Marco; Dong, Zhifeng; Siegel, Peter M.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Frederick, Dennie T.] UT Southwestern, Dept Biophys, Dallas, TX USA. [Kwong, Lawrence; Chin, Lynda] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. [Chin, Lynda] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 USA. [Keler, Tibor; Hawthorne, Thomas] Celldex Therapeut, Hampton, NJ USA. [Watson, Ian R.; Siegel, Peter M.] McGill Univ, Dept Biochem, Montreal, PQ, Canada. [Flaherty, Keith T.] Massachusetts Gen Hosp, Dept Surg Oncol, Boston, MA 02114 USA. RP Siegel, PM (reprint author), McGill Univ, 1160 Pine Ave West,Room 513, Montreal, PQ H3A 1A3, Canada. EM peter.siegel@mcgill.ca FU CIHR [MOP-119401]; DOD [CA-140389]; Adelson Medical Research Foundation; Sir Edward W. Beatty Memorial Research Award from the McGill University Faculty of Medicine FX This research has been supported by grants from the CIHR (MOP-119401 to P.M. Siegel) and the DOD (CA-140389 to P.M. Siegel and K.T. Flaherty). Banking of serial biopsies and serum samples was supported by grants from Adelson Medical Research Foundation to K.T. Flaherty. A.A.N. Rose was the recipient of a Sir Edward W. Beatty Memorial Research Award from the McGill University Faculty of Medicine. P.M. Siegel is a McGill University William Dawson Scholar. NR 48 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2016 VL 22 IS 24 BP 6088 EP 6098 DI 10.1158/1078-0432.CCR-16-1192 PG 11 WC Oncology SC Oncology GA EH0RW UT WOS:000391472400017 PM 27515299 ER PT J AU Cea, M Cagnetta, A Acharya, C Acharya, P Tai, YT Yang, C Lovera, D Soncini, D Miglino, M Fraternali-Orcioni, G Mastracci, L Nencioni, A Montecucco, F Monacelli, F Ballestrero, A Hideshima, T Chauhan, D Gobbi, M Lemoli, RM Munshi, N Treon, SP Anderson, KC AF Cea, Michele Cagnetta, Antonia Acharya, Chirag Acharya, Prakrati Tai, Yu-Tzu Yang, Cao Lovera, Davide Soncini, Debora Miglino, Maurizio Fraternali-Orcioni, Giulio Mastracci, Luca Nencioni, Alessio Montecucco, Fabrizio Monacelli, Fiammetta Ballestrero, Alberto Hideshima, Teru Chauhan, Dharminder Gobbi, Marco Lemoli, Roberto M. Munshi, Nikhil Treon, Steven P. Anderson, Kenneth C. TI Dual NAMPT and BTK Targeting Leads to Synergistic Killing of Waldenstrom Macroglobulinemia Cells Regardless of MYD88 and CXCR4 Somatic Mutation Status SO CLINICAL CANCER RESEARCH LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NAD BIOSYNTHESIS INHIBITOR; MULTIPLE-MYELOMA CELLS; BRUTON TYROSINE KINASE; NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; ANTITUMOR-ACTIVITY; DRUG-RESISTANCE; FK866; APOPTOSIS; CANCER AB Purpose: Nicotinamide phosphoribosyltransferase (Nampt) regulates intracellular NAD(+) pool and is highly expressed in a number of malignancies. FK866, a selective inhibitor of Nampt, depletes intracellular NAD(+) levels, thereby blocking cellular metabolism and triggering sensitization to other drugs and cell death. Here we characterized the antitumor effects of Nampt inhibition in Waldenstrom macroglobulinemia. Experimental Design: We investigated Nampt role in MW cells using both mRNA and protein expression analyses. We have also used loss-of-function approaches to investigate the growth and survival effects of Nampt on MW cells and further tested the anti-MW activity of dual Nampt and BTK inhibition in vitro and in vivo. Results: We found that Waldenstrom macroglobulinemia cells exhibit high levels of Nampt compared with normal B cells. Loss of function studies suggested a potential oncogenic role of Nampt in Waldenstrom macroglobulinemia cells, and BTK-inhibitor ibrutinib and FK866 resulted in a significant and synergistic anti-Waldenstrom macroglobulinemia cell death, regardless of MYD88 and CXCR4 mutational status. Cell death was associated with: (i) activation of caspase-3, PARP and downregulation of Mcl-1, (ii) enhanced intracellular ATP and NAD(+) depletion, (iii) inhibition of NF-kappa B signaling, and (iv) inhibition of multiple prosurvival signaling pathways. In a murine xenograft Waldenstrom macroglobulinemia model, low-dose combination FK866 and ibrutinib is well tolerated, significantly inhibits tumor growth, and prolongs host survival. Conclusions: Our results show intracellular NAD(+) level as crucial for proliferation and survival of Waldenstrom macroglobulinemia cells, and provides the mechanistic preclinical rationale for targeting Nampt, either alone or with Ibrutinib, to overcome drug resistance and improve patient outcome in Waldenstrom macroglobulinemia. (C)2016 AACR. C1 [Cea, Michele; Cagnetta, Antonia; Acharya, Chirag; Tai, Yu-Tzu; Hideshima, Teru; Chauhan, Dharminder; Munshi, Nikhil; Anderson, Kenneth C.] Harvard Med Sch, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Boston, MA USA. [Cea, Michele; Cagnetta, Antonia; Acharya, Chirag; Tai, Yu-Tzu; Hideshima, Teru; Chauhan, Dharminder; Munshi, Nikhil; Anderson, Kenneth C.] Harvard Med Sch, Dana Farber Canc Inst, Jerome Lipper Ctr Multiple Myeloma Res, Boston, MA USA. [Cea, Michele; Cagnetta, Antonia; Lovera, Davide; Soncini, Debora; Miglino, Maurizio; Nencioni, Alessio; Montecucco, Fabrizio; Monacelli, Fiammetta; Ballestrero, Alberto; Gobbi, Marco; Lemoli, Roberto M.] Univ Genoa, Dept Med DiMI, AOU, IRCCS San Martino IST, Genoa, Italy. [Acharya, Prakrati] Harvard Med Sch, Mt Auburn Hosp, Cambridge, MA USA. [Yang, Cao; Treon, Steven P.] Harvard Med Sch, Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA USA. [Fraternali-Orcioni, Giulio] IRCCS AUO S Martino IST, Labs Dept, Pathol Unit, Genoa, Italy. [Mastracci, Luca] Univ Genoa, Dept Surg & Diagnost Sci DISC, Pathol Unit, Genoa, Italy. [Mastracci, Luca] IRCCS AUO S Martino IST, Genoa, Italy. RP Cea, M (reprint author), Univ Genoa, I-16132 Genoa, Italy. EM michele.cea@unige.it FU IH [RO-1 50947, RO-1 73878]; DF/HCC SPORE in Multiple Myeloma [P-50100707]; International Multiple Myeloma Foundation; American Italian Cancer Foundation FX This work was supported by the IH (grants RO-1 50947 and RO-1 73878), DF/HCC SPORE in Multiple Myeloma (P-50100707); International Multiple Myeloma Foundation (to A. Cagnetta); American Italian Cancer Foundation (to M. Cea). K.C. Anderson is an American Cancer Society Clinical Research Professor. NR 45 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2016 VL 22 IS 24 BP 6099 EP 6109 DI 10.1158/1078-0432.CCR-16-0630 PG 11 WC Oncology SC Oncology GA EH0RW UT WOS:000391472400018 PM 27287071 ER PT J AU Davoli, T Mengwasser, KE Duan, JJ Chen, T Christensen, C Wooten, EC Anselmo, AN Li, MZ Wong, KK Kahle, KT Elledge, SJ AF Davoli, Teresa Mengwasser, Kristen E. Duan, Jingjing Chen, Ting Christensen, Camilla Wooten, Eric C. Anselmo, Anthony N. Li, Mamie Z. Wong, Kwok-Kin Kahle, Kristopher T. Elledge, Stephen J. TI Functional genomics reveals that tumors with activating phosphoinositide 3-kinase mutations are dependent on accelerated protein turnover SO GENES & DEVELOPMENT LA English DT Article DE PI3K; genetics screen; synthetic lethality ID NON-ONCOGENE ADDICTION; CANCER-CELL LINES; ESSENTIAL GENES; EGFR MUTATIONS; OVARIAN-CANCER; PIK3CA; PATHWAY; INHIBITOR; GROWTH; PI3K AB Activating mutations in the phosphoinositide 3-kinase (PI3K) signaling pathway are frequently identified in cancer. To identify pathways that support PI3K oncogenesis, we performed a genome-wide RNAi screen in isogenic cell lines harboring wild-type or mutant PIK3CA to search for PI3K synthetic-lethal (SL) genes. A combined analysis of these results with a meta-analysis of two other large-scale RNAi screening data sets in PI3K mutant cancer cell lines converged on ribosomal protein translation and proteasomal protein degradation as critical nononcogene dependencies for PI3K-driven tumors. Genetic or pharmacologic inhibition of either pathway alone, but not together, selectively killed PI3K mutant tumor cells in an mTOR-dependent manner. The expression of ribosomal and proteasomal components was significantly up-regulated in primary human colorectal tumors harboring PI3K pathway activation. Importantly, a PI3K SL gene signature containing the top hits of the SL genes identified in our meta-analysis robustly predicted overall patient survival in colorectal cancer, especially among patients with tumors with an activated PI3K pathway. These results suggest that disruption of protein turnover homeostasis via ribosome or proteasome inhibition may be a novel treatment strategy for PI3K mutant human tumors. C1 [Davoli, Teresa; Mengwasser, Kristen E.; Wooten, Eric C.; Anselmo, Anthony N.; Li, Mamie Z.; Elledge, Stephen J.] Harvard Med Sch, Brigham & Womens Hosp, Howard Hughes Med Inst, Dept Genet,Div Genet, Boston, MA 02115 USA. [Duan, Jingjing; Kahle, Kristopher T.] Boston Childrens Hosp, Howard Hughes Med Inst, Dept Neurobiol, Boston, MA USA. [Duan, Jingjing; Kahle, Kristopher T.] Yale Sch Med, Ctr Mendelian Gen, Dept Cellular & Mol Physiol, New Haven, CT 06511 USA. [Chen, Ting; Christensen, Camilla; Wong, Kwok-Kin] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. RP Elledge, SJ (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Howard Hughes Med Inst, Dept Genet,Div Genet, Boston, MA 02115 USA. EM selledge@genetics.med.harvard.edu FU National Institutes of Health [1U01CA199252-01, K99/R00]; Department of Defense FX We are grateful to the members of the Elledge laboratory for helpful comments and ideas on the project. We apologize to our colleagues whose work we could not cite due to space limitations. This work was funded by National Institutes of Health grant 1U01CA199252-01, a Department of Defense grant to S.J.E., and a National Institutes of Health Pathway to Independence Award (K99/R00) to T.D. S.J.E. is an Investigator with the Howard Hughes Medical Institute. NR 49 TC 0 Z9 0 U1 4 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD DEC 15 PY 2016 VL 30 IS 24 BP 2684 EP 2695 DI 10.1101/gad.290122.116 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA EH6CQ UT WOS:000391860600006 PM 28087713 ER PT J AU Frohlich, J Senturk, D Saravanapandian, V Golshani, P Reiter, LT Sankar, R Thibert, RL DiStefano, C Huberty, S Cook, EH Jeste, SS AF Frohlich, Joel Senturk, Damla Saravanapandian, Vidya Golshani, Peyman Reiter, Lawrence T. Sankar, Raman Thibert, Ronald L. DiStefano, Charlotte Huberty, Scott Cook, Edwin H. Jeste, Shafali S. TI A Quantitative Electrophysiological Biomarker of Duplication 15q11.2-q13.1 Syndrome SO PLOS ONE LA English DT Article ID INDEPENDENT COMPONENT ANALYSIS; ANGELMAN-SYNDROME; EEG; OSCILLATIONS; MIDAZOLAM; DYNAMICS; AUTISM; ABNORMALITIES; NETWORKS; DISORDER AB Background Duplications of 15q11.2-q13.1 (Dup15q syndrome) are highly penetrant for autism spectrum disorder (ASD). A distinct electrophysiological (EEG) pattern characterized by excessive activity in the beta band has been noted in clinical reports. We asked whether EEG power in the beta band, as well as in other frequency bands, distinguished children with Dup15q syndrome from those with non-syndromic ASD and then examined the clinical correlates of this electrophysiological biomarker in Dup15q syndrome. Methods In the first study, we recorded spontaneous EEG from children with Dup15q syndrome (n = 11), age-and-IQ-matched children with ASD (n = 10) and age-matched typically developing (TD) children (n = 9) and computed relative power in 6 frequency bands for 9 regions of interest (ROIs). Group comparisons were made using a repeated measures analysis of variance. In the second study, we recorded spontaneous EEG from a larger cohort of individuals with Dup15q syndrome (n = 27) across two sites and examined age, epilepsy, and duplication type as predictors of beta power using simple linear regressions. Results In the first study, spontaneous beta1 (12-20 Hz) and beta2 (20-30 Hz) power were significantly higher in Dup15q syndrome compared with both comparison groups, while delta (1-4 Hz) was significantly lower than both comparison groups. Effect sizes in all three frequency bands were large (vertical bar d vertical bar > 1). In the second study, we found that beta2 power was significantly related to epilepsy diagnosis in Dup15q syndrome. Conclusions Here, we have identified an electrophysiological biomarker of Dup15q syndrome that may facilitate clinical stratification, treatment monitoring, and measurement of target engagement for future clinical trials. Future work will investigate the genetic and neural underpinnings of this electrophysiological signature as well as the functional consequences of excessive beta oscillations in Dup15q syndrome. C1 [Frohlich, Joel; Saravanapandian, Vidya; DiStefano, Charlotte; Huberty, Scott; Jeste, Shafali S.] Univ Calif Los Angeles, Semel Inst Neurosci, Ctr Autism Res & Treatment, 760 Westwood Plaza,Suite A7-452, Los Angeles, CA 90095 USA. [Senturk, Damla] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Room 21-254C CHS, Los Angeles, CA 90024 USA. [Golshani, Peyman] David Geffen Sch Med, Dept Neurol & Psychiat, 710 Westwood Plaza, Los Angeles, CA USA. [Reiter, Lawrence T.] Univ Tennessee, Ctr Hlth Sci, Dept Neurol, 855 Monroe Ave,Link 415, Memphis, TN 38163 USA. [Reiter, Lawrence T.] Univ Tennessee, Ctr Hlth Sci, Dept Pediat, 855 Monroe Ave,Link 415, Memphis, TN 38163 USA. [Sankar, Raman] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Sankar, Raman] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA. [Thibert, Ronald L.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Cook, Edwin H.] Univ Illinois, Dept Psychiat, MC 747, Chicago, IL 60612 USA. RP Frohlich, J (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci, Ctr Autism Res & Treatment, 760 Westwood Plaza,Suite A7-452, Los Angeles, CA 90095 USA. EM joelfrohlich@gmail.com FU National Institute of Mental Health of the National Institutes of Health [T32MH073526]; Dup15q Alliance [20144605]; National Institute of General Medical Sciences [R01 GM111378-01A1]; National Institute of Mental Health [K23MH094517-01]; National Institute of Child Health and Human Development [U54HD087101]; NIMH [K23M H094517-01]; IDDRC [U54HD087101] FX JF was supported by the National Institute of Mental Health of the National Institutes of Health under Award Number T32MH073526. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also funded by grant 20144605 from the Dup15q Alliance (SSJ received funding) (http://www.dup15q.org), R01 GM111378-01A1 from the National Institute of General Medical Sciences (DS received funding) (https://www.nigms.nih.gov), National Institute of Mental Health K23MH094517-01 (SSJ received funding) (https://www.nimh.nih.gov), and National Institute of Child Health and Human Development U54HD087101 (SSJ and PG received funding) (https://www.nichd.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We warmly thank the children and families who participated in this research for making this work possible. We especially thank Andrei Irimia and Iman Mohammad-Rezazadeh for their assistance with EEG signal processing and Amaya Miquelajauregui for giving her thoughts and insights on this manuscript. Joel Frohlich was supported by the National Institute of Mental Health of the National Institutes of Health under Award Number T32MH073526. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health This work was also funded by grant 20144605 from the Dup15q Alliance, to whom we extend our sincere gratitude, as well as R01 GM11137801A1 from the National Institute of General Medical Sciences NIGMS (NIH), NIMH K23M H094517-01, and IDDRC U54HD087101. NR 50 TC 0 Z9 0 U1 3 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 DEC 15 PY 2016 VL 11 IS 12 AR e0167179 DI 10.1371/journal.pone.0167179 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG7HN UT WOS:000391217400015 PM 27977700 ER PT J AU Bajaj, NS Kalra, R Arora, P Ather, S Guichard, JL Lancaster, WJ Patel, N Raman, F Arora, G Al Solaiman, F Clark, DT Dell'Italia, LJ Leesar, MA Davies, JE McGiffin, DC Ahmed, MI AF Bajaj, Navkaranbir S. Kalra, Rajat Arora, Pankaj Ather, Sameer Guichard, Jason L. Lancaster, W. Jake Patel, Nirav Raman, Fabio Arora, Garima Al Solaiman, Firas Clark, D. Trey, III Dell'Italia, Louis J. Leesar, Massoud A. Davies, James E. McGiffin, David C. Ahmed, Mustafa I. TI Catheter-directed treatment for acute pulmonary embolism: Systematic review and single-arm meta-analyses SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Pulmonary embolism; Thrombolysis; Catheter-directed treatment ID ULTRASOUND-ACCELERATED THROMBOLYSIS; PERCUTANEOUS MECHANICAL THROMBECTOMY; ANGIOJET RHEOLYTIC THROMBECTOMY; PIGTAIL ROTATION CATHETER; DEEP-VEIN THROMBOSIS; ASSISTED THROMBOLYSIS; PLASMINOGEN-ACTIVATOR; MULTICENTER REGISTRY; HYBRID TREATMENT; FRAGMENTATION AB Background: We sought to estimate the efficacy and safety outcomes of catheter-directed treatment (CDT) for patients with acute pulmonary embolism (PE). Methods: We searched SCOPUS for studies reporting outcomes after CDT for acute PE. Studies were categorized in three groups for analyses due to heterogeneity in the classification of acute PE: 1) patients with PE causing right ventricular dysfunction and haemodynamic instability: unstable haemodynamic status, 2) patients with PE causing right ventricular dysfunction where study outcomes were not stratified by haemodynamic status: stable and unstable haemodynamic status, and 3) patients with PE causing right ventricular dysfunction who remained haemodynamically stable: stable haemodynamic status. Efficacy and safety outcomes were estimated and presented as point estimates with 95% confidence intervals. Results: In 35 studies with 1253 patients, 1277 CDTs were performed. The in-hospital mortality rates for the unstable haemodynamic status, stable and unstable haemodynamic status, and stable haemodynamic status groups were 18.1% (7.3-38.2%), 7.1% (5.0-10.1%), and 2.6% (0.8-7.3%), respectively. The major bleeding rates across the groups were estimated to be 4.5, 8.5 and 3.9 per 100 CDTs, respectively. Minor bleeding occurred in 6.2, 11.9 and 9.1 per 100 CDTs, respectively. After CDT, all groups had improvements in mean pulmonary artery pressure and right ventricular function. Conclusions: We provide descriptive measures of efficacy and safety for patients who underwent CDT for acute PE. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Bajaj, Navkaranbir S.; Arora, Pankaj; Ather, Sameer; Guichard, Jason L.; Patel, Nirav; Arora, Garima; Al Solaiman, Firas; Dell'Italia, Louis J.; Leesar, Massoud A.; Ahmed, Mustafa I.] Univ Alabama Birmingham, Div Cardiovasc Dis, Birmingham, AL USA. [Bajaj, Navkaranbir S.] Univ Alabama Birmingham, Ryals Sch Publ Hlth, Dept Epidemiol, Birmingham, AL USA. [Kalra, Rajat; Lancaster, W. Jake] Univ Alabama Birmingham, Dept Med, Birmingham, AL USA. [Raman, Fabio] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [Clark, D. Trey, III] Cleveland Clin, Dept Cardiol, Cleveland, OH 44106 USA. [Dell'Italia, Louis J.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Davies, James E.] Univ Alabama Birmingham, Dept Surg, Div Cardiothorac Surg, Birmingham, AL USA. [McGiffin, David C.] Alfred Hosp, Dept Surg, Div Cardiothorac Surg, Melbourne, Vic, Australia. [McGiffin, David C.] Monash Univ, Melbourne, Vic, Australia. [Ahmed, Mustafa I.] Baptist Princeton, Div Cardiol, 701 Princeton Ave SW, Birmingham, AL 35211 USA. [Bajaj, Navkaranbir S.] Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Bajaj, Navkaranbir S.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Bajaj, Navkaranbir S.] Harvard Med Sch, Boston, MA USA. [Kalra, Rajat] Univ Minnesota, Div Cardiovasc, Minneapolis, MN 55455 USA. RP Ahmed, MI (reprint author), Baptist Princeton, Struct Heart Program, 701 Princeton Ave SW, Birmingham, AL 35211 USA. EM musiahm@gmail.com NR 85 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD DEC 15 PY 2016 VL 225 BP 128 EP 139 DI 10.1016/j.ijcard.2016.09.036 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EF6WN UT WOS:000390472000031 PM 27718446 ER PT J AU Barik, A Shah, RV Spahillari, A Murthy, VL Ambale-Venkatesh, B Rai, RK Das, K Santra, A Hembram, JR Bhattacharya, D Freedman, JE Lima, J Das, R Bhattacharyya, P Das, S Chowdhury, A AF Barik, Anamitra Shah, Ravi V. Spahillari, Aferdita Murthy, Venkatesh L. Ambale-Venkatesh, Bharath Rai, Rajesh Kumar Das, Kaushik Santra, Amal Hembram, Jaba Ranjan Bhattacharya, Dilip Freedman, Jane E. Lima, Joao Das, Ranendra Bhattacharyya, Pinakpani Das, Saumya Chowdhury, Abhijit TI Hepatic steatosis is associated with cardiometabolic risk in a rural Indian population: A prospective cohort study SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Liver fat; India; Carotid intimal-medial thickness; Metabolic disease; Adiposity ID NONALCOHOLIC FATTY LIVER; INTIMA-MEDIA THICKNESS; CARDIOVASCULAR-DISEASE; ATHEROSCLEROSIS MESA; METABOLIC SYNDROME; CAROTID-ARTERY; SOUTH ASIANS; PREVALENCE; URBAN; ADIPOSITY AB Background/Objectives: While adiposity and hepatic steatosis are linked to cardiovascular risk in developed countries, their prevalence and impact in low-income countries are poorly understood. We investigated the association of anthropomorphic variables and hepatic steatosis with cardiometabolic risk profiles and subclinical cardiovascular disease (CVD) in a large rural Indian cohort. Methods: In 4691 individuals in the Birbhum Population Project in West Bengal, India, we performed liver ultrasonography, carotid ultrasound and biochemical and clinical profiling. We assessed the association of hepatic steatosis and anthropomorphic indices (BMI, waist circumference) with CVD risk factors (dysglycemia, dyslipidemia, hypertension) and subclinical CVD (by carotid intimal-medial thickness). Results: Rural Indians exhibited a higher visceral adiposity index and pro-atherogenic dyslipidemia at a lower BMI than Americans. Individuals with any degree of hepatic steatosis by ultrasound had a greater probability of dysglycemia (adjusted odds ratio, OR=1.67, 95% CI 1.31-2.12, P < 0.0001) and pro-atherogenic dyslipidemia (OR=1.33, 95% CI 1.07-1.63, P=0.009). Weobserved a positive association between liver fat, adiposity and carotid intimal-medial thickness (CIMT) in an unadjusted model (beta = 0.02, P = 0.0001); the former was extinguished after adjustment for cardiometabolic risk factors. Conclusions: In a large population of rural Indians, hepatic steatosis and waist circumference were associated with prevalent cardiometabolic risk and subclinical CVD at lower BMI relative to multi-ethnic Americans, though the association of the former with subclinical CVD was extinguished after adjustment. These results underscore the emerging relevance of hepatic steatosis and adiposity in the developing world, and suggest efforts to target these accessible phenotypes for cardiometabolic risk prevention. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Barik, Anamitra; Rai, Rajesh Kumar; Chowdhury, Abhijit] Soc Hlth & Demog Surveillance, Birbhum Populat Project, Suri, W Bengal, India. [Shah, Ravi V.; Das, Saumya] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Simches 3-404,185 Cambridge St, Boston, MA 02114 USA. [Spahillari, Aferdita] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA USA. [Murthy, Venkatesh L.] Univ Michigan, Dept Med, Cardiovasc Med Div, Ann Arbor, MI 48109 USA. [Ambale-Venkatesh, Bharath] Johns Hopkins Univ, Dept Med & Cardiol, Inst Heart & Vasc, Johns Hopkins Med Inst, Baltimore, MD USA. [Das, Kaushik; Santra, Amal; Hembram, Jaba Ranjan; Bhattacharya, Dilip; Chowdhury, Abhijit] Inst Post Grad Med Educ & Res, Dept Hepatol, Sch Digest & Liver Dis, Kolkata 700020, India. [Freedman, Jane E.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Lima, Joao] Johns Hopkins Univ, Dept Cardiol, Baltimore, MD USA. [Das, Ranendra] Inst Socioecon Res & Dev, Delhi, India. [Bhattacharyya, Pinakpani] Quadra Med Serv, Kolkata, India. RP Chowdhury, A (reprint author), Inst Post Grad Med Educ & Res, Dept Hepatol, Sch Digest & Liver Dis, Kolkata 700020, India.; Das, S (reprint author), Massachusetts Gen Hosp, Simches 3-404,185 Cambridge St, Boston, MA 02114 USA. EM anomitro2010@gmail.com; rvshah@partners.org; aspahill@bidmc.harvard.edu; vlmurthy@med.umich.edu; bambale1@jhmi.edu; rajesh.iips28@gmail.com; kausikdasmail@gmail.com; asantra2000@yahoo.co.in; jhembram3@gmail.com; SHDS@rediffmail.com; jane.freedman@umassmed.edu; jlima@jhmi.edu; das.ranen@gmail.com; pinakpanidr@hotmail.com; sdas@partners.org; achowdhury2002@yahoo.co.in OI Murthy, Venkatesh/0000-0002-7901-1321 NR 32 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD DEC 15 PY 2016 VL 225 BP 161 EP 166 DI 10.1016/j.ijcard.2016.09.120 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EF6WN UT WOS:000390472000038 PM 27723535 ER PT J AU Grandin, EW Wand, A Zamani, P Rame, JE Verdino, RJ AF Grandin, E. Wilson Wand, Alison Zamani, Payman Rame, J. Eduardo Verdino, Ralph J. TI Relation of Body Mass Index to Long-Term Survival After Cardiac Resynchronization Therapy SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CHRONIC HEART-FAILURE; INDEPENDENT RISK-FACTOR; MYOCARDIAL FATTY-ACID; LEFT-VENTRICULAR MASS; BUNDLE-BRANCH BLOCK; DILATED CARDIOMYOPATHY; WEIGHT-LOSS; DEFIBRILLATOR IMPLANTATION; GLUCOSE-METABOLISM; DIABETES-MELLITUS AB Obesity confers a paradoxical survival benefit in patients with heart failure, but this obesity paradox has not been well established in those who have undergone cardiac resynchronization therapy with a defibrillator (CRT-D). We sought to determine the impact of body mass index (BMI) on long-term survival in patients with heart failure after CRT-D. We identified 113 patients implanted with CRT-D at our institution from May 2002 to November 2003. Patients were divided into 3 categories by pre-implant BMI (kg/m(2)): normal weight (BMI <25), overweight (BMI 25-29), and obese (BMI >= 30). Ten-year survival free from orthotopic heart transplant or ventricular assist device implantation was analyzed with Kaplan-Meier plots, the log-rank test, and Cox proportional hazards modeling. Thirty-three patients (29%) were normal weight, 47 (42%) were overweight, and 33 were obese (29%). Median follow-up time' was 4.5 years (interquartile range 1.9 to 8.7 years). Obese patients were younger and had a higher proportion of women (both p <0.05). Ten-year survival free of orthotopic heart transplant or ventricular assist device was highest in obese patients (36.3%) followed by overweight (19.2%) and then normal-weight patients (12.1%), log-rank p trend = 0.004. After adjustment for clinical risk factors, every 1 kg/m(2) increase in BMI was associated with a 8% reduction in the risk of the primary end point (adjusted hazard ratio 0.92, 95% confidence interval 0.88 to 0.97, p = 0.002). In conclusion, higher BMI is associated with improved long-term survival after CRT-D. (C) 2016 Elsevier Inc. All rights reserved. C1 [Grandin, E. Wilson] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, Boston, MA 02115 USA. [Wand, Alison; Zamani, Payman; Rame, J. Eduardo; Verdino, Ralph J.] Univ Penn, Div Cardiovasc Med, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Grandin, EW (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, Boston, MA 02115 USA. EM wgrandin@bidmc.harvard.edu NR 31 TC 0 Z9 0 U1 0 U2 0 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 DEC 15 PY 2016 VL 118 IS 12 BP 1861 EP 1867 DI 10.1016/j.amjcard.2016.08.079 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EE8IH UT WOS:000389868400014 PM 27823599 ER PT J AU Rajabi, H Tagde, A Alam, M Bouillez, A Pitroda, S Suzuki, Y Kufe, D AF Rajabi, H. Tagde, A. Alam, M. Bouillez, A. Pitroda, S. Suzuki, Y. Kufe, D. TI DNA methylation by DNMT1 and DNMT3b methyltransferases is driven by the MUC1-C oncoprotein in human carcinoma cells SO ONCOGENE LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; ZINC-FINGER PROTEINS; BREAST-CANCER CELLS; TRANSCRIPTIONAL REGULATION; MAINTENANCE METHYLATION; LUNG-CANCER; DE-NOVO; EXPRESSION; GENE; 3B AB Aberrant expression of the DNA methyltransferases (DNMTs) and disruption of DNA methylation patterns are associated with carcinogenesis and cancer cell survival. The oncogenic MUC1-C protein is aberrantly overexpressed in diverse carcinomas; however, there is no known link between MUC1-C and DNA methylation. Our results demonstrate that MUC1-C induces the expression of DNMT1 and DNMT3b, but not DNMT3a, in breast and other carcinoma cell types. We show that MUC1-C occupies the DNMT1 and DNMT3b promoters in complexes with NF-kappa B p65 and drives DNMT1 and DNMT3b transcription. In this way, MUC1-C controls global DNA methylation as determined by analysis of LINE-1 repeat elements. The results further demonstrate that targeting MUC1-C downregulates DNA methylation of the CDH1 tumor suppressor gene in association with induction of E-cadherin expression. These findings provide compelling evidence that MUC1-C is of functional importance to induction of DNMT1 and DNMT3b and, in turn, changes in DNA methylation patterns in cancer cells. C1 [Rajabi, H.; Tagde, A.; Alam, M.; Bouillez, A.; Suzuki, Y.; Kufe, D.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Pitroda, S.] Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA. [Suzuki, Y.] Osaka Police Hosp, Dept Surg Gastroenterol, Osaka, Osaka 5430035, Japan. RP Kufe, D (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM donald_kufe@dfci.harvard.edu FU National Cancer Institute of the National Institutes of Health [CA97098, CA166480]; Lung Cancer Research Foundation FX Research reported in this paper was supported by the National Cancer Institute of the National Institutes of Health under award numbers CA97098 and CA166480, and by the Lung Cancer Research Foundation. NR 41 TC 3 Z9 3 U1 5 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 DEC 15 PY 2016 VL 35 IS 50 BP 6439 EP 6445 DI 10.1038/onc.2016.180 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA EF3TP UT WOS:000390247600008 PM 27212035 ER PT J AU Hines, MC Reed, BN Ivaturi, V Bontempo, LJ Bond, MC Hayes, BD AF Hines, Michelle C. Reed, Brent N. Ivaturi, Vijay Bontempo, Laura J. Bond, Michael C. Hayes, Bryan D. TI Diltiazem versus metoprolol for rate control in atrial fibrillation with rapid ventricular response in the emergency department SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article DE atrial fibrillation; beta-blocker; calcium channel blocker; emergency department; rate control ID MANAGEMENT; FLUTTER AB Purpose. The impact of patient-specific factors on the choice of beta-blocker versus calcium channel blocker therapy for rate control in emergency department (ED) patients treated for atrial fibrillation (AF) was investigated. Methods. A retrospective cohort study was conducted to evaluate the influence of demographics, prior medication use, hemodynamic and clinical characteristics, and other variables on selection of first-line therapy for AF among patients admitted to the ED of an academic medical center over a 22-month period (October 2012-July 2014) who received i.v. treatment with either the beta-blocker metoprolol (n = 45) or the calcium channel blocker diltiazem (n = 55) for rate control. Results. Significant predictors of the selection of metoprolol versus diltiazem included a past history of AF (odds ratio [OR], 8.3; 95% confidence interval [CI], 1.396-72.713; p = 0.032) or diabetes mellitus (OR, 7.2; 95% CI, 1.208-58.490; p = 0.042) and being prescribed a beta-blocker prior to presentation (OR, 27.8; 95% CI, 4.704-272.894; p = 0.001); a history of calcium channel blocker use prior to ED presentation was a negative predictor of beta-blocker use for initial rate control (OR, 0.1; 95% CI, 0.005-0.265; p = 0.002). No differences in the effectiveness or safety of diltiazem and metoprolol were identified. Indicators of hemodynamic and clinical response to ED management were not predictive of discharge medication selection. Conclusion. The drug class used for rate control prior to ED admission was the most significant predictor of medication selection for rate control in the ED setting. C1 [Hines, Michelle C.] Univ Maryland, Med Ctr, Dept Pharm Serv, Baltimore, MD 21201 USA. [Reed, Brent N.] Univ Maryland, Sch Pharm, Dept Pharm Practice & Sci, Baltimore, MD 21201 USA. [Ivaturi, Vijay] Univ Maryland, Sch Pharm, Translat Med, Baltimore, MD 21201 USA. [Bontempo, Laura J.; Bond, Michael C.] Univ Maryland, Sch Med, Dept Emergency Med, Baltimore, MD 21201 USA. [Hayes, Bryan D.] Massachusetts Gen Hosp, Dept Pharm, Boston, MA 02114 USA. [Hayes, Bryan D.] Harvard Med Sch, Dept Emergency Med, Boston, MA USA. RP Hines, MC (reprint author), Univ Maryland, Med Ctr, Dept Pharm Serv, Baltimore, MD 21201 USA. EM hinesmc@gmail.com OI Ivaturi, Vijay/0000-0002-6433-1154 NR 12 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 EI 1535-2900 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD DEC 15 PY 2016 VL 73 IS 24 BP 2068 EP 2076 DI 10.2146/ajhp160126 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EE8JF UT WOS:000389870800009 PM 27919874 ER PT J AU Krishnan, A Fei, F Jones, A Busto, P Marshak-Rothstein, A Ksander, BR Gregory-Ksander, M AF Krishnan, Anitha Fei, Fei Jones, Alexander Busto, Patricia Marshak-Rothstein, Ann Ksander, Bruce R. Gregory-Ksander, Meredith TI Overexpression of Soluble Fas Ligand following Adeno-Associated Virus Gene Therapy Prevents Retinal Ganglion Cell Death in Chronic and Acute Murine Models of Glaucoma SO JOURNAL OF IMMUNOLOGY LA English DT Article ID OPEN-ANGLE GLAUCOMA; OPTIC-NERVE HEAD; OCULAR IMMUNE PRIVILEGE; NORMAL-TENSION GLAUCOMA; NECROSIS-FACTOR-ALPHA; MOUSE MODEL; INTRAOCULAR-PRESSURE; DBA/2J MICE; PIGMENT EPITHELIUM; INDUCED APOPTOSIS AB Glaucoma is a multifactorial disease resulting in the death of retinal ganglion cells (RGCs) and irreversible blindness. Glaucoma-associated RGC death depends on the proapoptotic and proinflammatory activity of membrane-bound Fas ligand (mFasL). In contrast to mFasL, the natural cleavage product, soluble Fas ligand (sFasL) inhibits mFasL-mediated apoptosis and inflammation and, therefore, is an mFasL antagonist. DBA/2J mice spontaneously develop glaucoma and, predictably, RGC destruction is exacerbated by expression of a mutated membrane-only FasL gene that lacks the extracellular cleavage site. Remarkably, one-time intraocular adeno-associated virus-mediated gene delivery of sFasL provides complete and sustained neuroprotection in the chronic DBA/2J and acute microbead-induced models of glaucoma, even in the presence of elevated intraocular pressure. This protection correlated with inhibition of glial activation, reduced production of TNF-alpha, and decreased apoptosis of RGCs and loss of axons. These data indicate that cleavage of FasL under homeostatic conditions, and the ensuing release of sFasL, normally limits the neurodestructive activity of FasL. The data further support the notion that sFasL, and not mFasL, contributes to the immune-privileged status of the eye. C1 [Krishnan, Anitha; Fei, Fei; Jones, Alexander; Ksander, Bruce R.; Gregory-Ksander, Meredith] Harvard Med Sch, Schepens Eye Res Inst, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Fei, Fei] Fourth Mil Med Univ, Xijing Hosp, Dept Ophthalmol, Xian 710032, Shaanxi Provinc, Peoples R China. [Busto, Patricia; Marshak-Rothstein, Ann] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA. RP Gregory-Ksander, M (reprint author), Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM meredith_gregory@meei.harvard.edu FU National Institutes of Health [P30EY003790, AR055634, EY021543] FX This work was supported by the National Institutes of Health Core Grant P30EY003790 (to Schepens Eye Research Institute) and National Institutes of Health Grants AR055634 (to A.M.-R.) and EY021543 (to M.G.-K.). NR 83 TC 0 Z9 0 U1 4 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2016 VL 197 IS 12 BP 4626 EP 4638 DI 10.4049/jimmunol.1601488 PG 13 WC Immunology SC Immunology GA EE5HG UT WOS:000389635900014 PM 27849168 ER PT J AU Sentman, ML Murad, JM Cook, WJ Wu, MR Reder, J Baumeister, SH Dranoff, G Fanger, MW Sentman, CL AF Sentman, Marie-Louise Murad, Joana M. Cook, W. James Wu, Ming-Ru Reder, Jake Baumeister, Susanne H. Dranoff, Glenn Fanger, Michael W. Sentman, Charles L. TI Mechanisms of Acute Toxicity in NKG2D Chimeric Antigen Receptor T Cell-Treated Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CYTOKINE RELEASE SYNDROME; POTENT ANTITUMOR-ACTIVITY; NATURAL-KILLER-CELLS; IN-VIVO; TUMOR MICROENVIRONMENT; MULTIPLE-MYELOMA; SOLID TUMORS; PVR CD155; NK CELLS; GM-CSF AB Targeting cancer through the use of effector T cells bearing chimeric Ag receptors (CARs) leads to elimination of tumors in animals and patients, but recognition of normal cells or excessive activation can result in significant toxicity and even death. CAR T cells based on modified NKG2D receptors are effective against many types of tumors, and their efficacy is mediated through direct cytotoxicity and cytokine production. Under certain conditions, their ligands can be expressed on nontumor cells, so a better understanding of the potential off-tumor activity of these NKG2D CAR T cells is needed. Injection of very high numbers of activated T cells expressing CARs based on murine NKG2D or DNAM1 resulted in increased serum cytokines (IFN-gamma, IL-6, and MCP-1) and acute toxicity similar to cytokine release syndrome. Acute toxicity required two key effector molecules in CAR T cells-perforin and GM-CSF. Host immune cells also contributed to this toxicity, and mice with severe immune cell defects remained healthy at the highest CAR T cell dose. These data demonstrate that specific CAR T cell effector mechanisms and the host immune system are required for this cytokine release-like syndrome in murine models. C1 [Sentman, Marie-Louise; Cook, W. James; Wu, Ming-Ru; Sentman, Charles L.] Geisel Sch Med Dartmouth, Ctr Synthet Immun, Lebanon, NH 03756 USA. [Sentman, Marie-Louise; Cook, W. James; Wu, Ming-Ru; Sentman, Charles L.] Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, 6W Borwell Bldg,One Med Ctr Dr, Lebanon, NH 03756 USA. [Murad, Joana M.; Reder, Jake; Fanger, Michael W.] Celdara Med LLC, Lebanon, NH 03766 USA. [Baumeister, Susanne H.; Dranoff, Glenn] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Baumeister, Susanne H.] Dana Farber Canc Inst, XDepartment Pediat Oncol, Boston, MA 02215 USA. [Baumeister, Susanne H.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Baumeister, Susanne H.] Harvard Med Sch, Boston, MA 02115 USA. [Dranoff, Glenn] Novartis Inst BioMed Res, Exploratory Immunooncol, Cambridge, MA 02139 USA. RP Sentman, CL (reprint author), Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, 6W Borwell Bldg,One Med Ctr Dr, Lebanon, NH 03756 USA. EM charles.sentman@dartmouth.edu FU National Institutes of Health [R44 HL099217]; Dartmouth Center for Synthetic Immunity; National Cancer Institute [5 P30 CA023108-36]; National Institute of General Medical Sciences Grant [8 P30 GM103415-14] FX This work was supported by National Institutes of Health Grant R44 HL099217 and by funds from the Dartmouth Center for Synthetic Immunity. DartLab is a shared resource and is supported by National Cancer Institute Grant 5 P30 CA023108-36 and by National Institute of General Medical Sciences Grant 8 P30 GM103415-14. NR 49 TC 0 Z9 0 U1 8 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2016 VL 197 IS 12 BP 4674 EP 4685 DI 10.4049/jimmunol.1600769 PG 12 WC Immunology SC Immunology GA EE5HG UT WOS:000389635900018 PM 27849169 ER PT J AU Khera, AV Emdin, CA Drake, I Natarajan, P Bick, AG Cook, NR Chasman, DI Baber, U Mehran, R Rader, DJ Fuster, V Boerwinkle, E Melander, O Orho-Melander, M Ridker, PM Kathiresan, S AF Khera, Amit V. Emdin, Connor A. Drake, Isabel Natarajan, Pradeep Bick, Alexander G. Cook, Nancy R. Chasman, Daniel I. Baber, Usman Mehran, Roxana Rader, Daniel J. Fuster, Valentin Boerwinkle, Eric Melander, Olle Orho-Melander, Marju Ridker, Paul M. Kathiresan, Sekar TI Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GENOME-WIDE ASSOCIATION; IDEAL CARDIOVASCULAR HEALTH; HEART-DISEASE; ARTERY-DISEASE; PRIMARY PREVENTION; PROSPECTIVE COHORT; WOMEN; SCORE; PREDICTION; EVENTS AB BACKGROUND Both genetic and lifestyle factors contribute to individual-level risk of coronary artery disease. The extent to which increased genetic risk can be offset by a healthy lifestyle is unknown. METHODS Using a polygenic score of DNA sequence polymorphisms, we quantified genetic risk for coronary artery disease in three prospective cohorts - 7814 participants in the Atherosclerosis Risk in Communities (ARIC) study, 21,222 in the Women's Genome Health Study (WGHS), and 22,389 in the Malmo Diet and Cancer Study (MDCS) - and in 4260 participants in the cross-sectional BioImage Study for whom genotype and covariate data were available. We also determined adherence to a healthy lifestyle among the participants using a scoring system consisting of four factors: no current smoking, no obesity, regular physical activity, and a healthy diet. RESULTS The relative risk of incident coronary events was 91% higher among participants at high genetic risk (top quintile of polygenic scores) than among those at low genetic risk (bottom quintile of polygenic scores) (hazard ratio, 1.91; 95% confidence interval [CI], 1.75 to 2.09). A favorable lifestyle (defined as at least three of the four healthy lifestyle factors) was associated with a substantially lower risk of coronary events than an unfavorable lifestyle (defined as no or only one healthy lifestyle factor), regardless of the genetic risk category. Among participants at high genetic risk, a favorable lifestyle was associated with a 46% lower relative risk of coronary events than an unfavorable lifestyle (hazard ratio, 0.54; 95% CI, 0.47 to 0.63). This finding corresponded to a reduction in the standardized 10-year incidence of coronary events from 10.7% for an unfavorable lifestyle to 5.1% for a favorable lifestyle in ARIC, from 4.6% to 2.0% in WGHS, and from 8.2% to 5.3% in MDCS. In the BioImage Study, a favorable lifestyle was associated with significantly less coronary-artery calcification within each genetic risk category. CONCLUSIONS Across four studies involving 55,685 participants, genetic and lifestyle factors were independently associated with susceptibility to coronary artery disease. Among participants at high genetic risk, a favorable lifestyle was associated with a nearly 50% lower relative risk of coronary artery disease than was an unfavorable lifestyle. C1 [Khera, Amit V.; Natarajan, Pradeep; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St,CPZN 5-252, Boston, MA 02114 USA. [Khera, Amit V.; Natarajan, Pradeep; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Cook, Nancy R.; Chasman, Daniel I.; Ridker, Paul M.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Khera, Amit V.; Emdin, Connor A.; Bick, Alexander G.; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Drake, Isabel; Melander, Olle; Orho-Melander, Marju] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Baber, Usman; Mehran, Roxana; Fuster, Valentin] Icahn Sch Med Mt Sinai, Cardiovasc Inst, Mt Sinai Med Ctr, New York, NY 10029 USA. [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Boerwinkle, Eric] Univ Texas Houston, Hlth Sci Ctr, Sch Publ Hlth, Houston, TX USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St,CPZN 5-252, Boston, MA 02114 USA. EM skathiresan1@mgh.harvard.edu RI Fuster, Valentin/H-4319-2015 OI Fuster, Valentin/0000-0002-9043-9986 FU National Institutes of Health FX Funded by the National Institutes of Health and others. NR 38 TC 15 Z9 15 U1 28 U2 28 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 DEC 15 PY 2016 VL 375 IS 24 BP 2349 EP 2358 DI 10.1056/NEJMoa1605086 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EF0SO UT WOS:000390036500006 PM 27959714 ER PT J AU Chi, AS Cahill, DP Larvie, M Louis, DN AF Chi, Andrew S. Cahill, Daniel P. Larvie, Mykol Louis, David N. TI Case 38-2016: A 52-Year-Old Woman with Recurrent Oligodendroglioma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LOW-GRADE GLIOMA; TERM-FOLLOW-UP; ANAPLASTIC OLIGODENDROGLIOMA; VINCRISTINE CHEMOTHERAPY; RANDOMIZED-TRIAL; CLASSIFICATION; RADIOTHERAPY; PROCARBAZINE; ASTROCYTOMA; MUTATIONS C1 [Chi, Andrew S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Cahill, Daniel P.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Larvie, Mykol] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Louis, David N.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Chi, Andrew S.] Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. [Cahill, Daniel P.] Harvard Med Sch, Dept Neurosurg, Boston, MA USA. [Larvie, Mykol] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Louis, David N.] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Chi, AS (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.; Chi, AS (reprint author), Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. NR 27 TC 0 Z9 0 U1 2 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 DEC 15 PY 2016 VL 375 IS 24 BP 2381 EP 2389 DI 10.1056/NEJMcpc1610101 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EF0SO UT WOS:000390036500011 PM 27974037 ER PT J AU Guo, JJ Liu, XY Jiang, N Yetisen, AK Yuk, H Yang, CX Khademhosseini, A Zhao, XH Yun, SH AF Guo, Jingjing Liu, Xinyue Jiang, Nan Yetisen, Ali K. Yuk, Hyunwoo Yang, Changxi Khademhosseini, Ali Zhao, Xuanhe Yun, Seok-Hyun TI Highly Stretchable, Strain Sensing Hydrogel Optical Fibers SO ADVANCED MATERIALS LA English DT Article ID HUMAN-MOTION DETECTION; ALGINATE/POLYACRYLAMIDE HYDROGELS; TOUGH HYDROGELS; IN-SITU; SENSOR; PERFORMANCE; COMPOSITE; DESIGN; GELS AB A core-clad fiber made of elastic, tough hydrogels is highly stretchable while guiding light. Fluorescent dyes are easily doped into the hydrogel fiber by diffusion. When stretched, the transmission spectrum of the fiber is altered, enabling the strain to be measured and also its location. C1 [Guo, Jingjing; Yetisen, Ali K.; Yun, Seok-Hyun] Harvard Med Sch, 65 Landsdowne St, Cambridge, MA 02139 USA. [Guo, Jingjing; Yetisen, Ali K.; Yun, Seok-Hyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, 65 Landsdowne St, Cambridge, MA 02139 USA. [Guo, Jingjing; Yang, Changxi] Tsinghua Univ, Dept Precis Instruments, State Key Lab Precis Measurement Technol & Instru, Beijing 100084, Peoples R China. [Liu, Xinyue; Yuk, Hyunwoo; Zhao, Xuanhe] MIT, Dept Mech Engn, Soft Act Mat Lab, Cambridge, MA 02139 USA. [Jiang, Nan; Khademhosseini, Ali] Harvard Med Sch, Brigham & Womens Hosp, Engn Med Div, Biomat Innovat Res Ctr, Cambridge, MA 02139 USA. [Jiang, Nan] Wuhan Univ Technol, State Key Lab Adv Technol Mat Synth & Proc, 122 Luoshi Rd, Wuhan 430070, Peoples R China. RP Yun, SH (reprint author), Harvard Med Sch, 65 Landsdowne St, Cambridge, MA 02139 USA.; Yun, SH (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 65 Landsdowne St, Cambridge, MA 02139 USA. EM syun@hms.harvard.edu FU National Institutes of Health [R01-AI123312, P41-EB015903, R01-CA192878]; Department of Defense [FA9550-11-1-0331]; MGH Research Scholar award program; China Scholarship Council FX The authors thank Sheldon Kwok, Seonghoon Kim, and Moonseok Kim for discussions. This work was in part supported by the National Institutes of Health (R01-AI123312, P41-EB015903, R01-CA192878), Department of Defense (FA9550-11-1-0331), MGH Research Scholar award program, and J.G. acknowledges a fellowship from China Scholarship Council. NR 37 TC 0 Z9 0 U1 40 U2 40 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0935-9648 EI 1521-4095 J9 ADV MATER JI Adv. Mater. PD DEC 14 PY 2016 VL 28 IS 46 BP 10244 EP 10249 DI 10.1002/adma.201603160 PG 6 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EI8AL UT WOS:000392726400017 PM 27714887 ER PT J AU Oosting, M Kerstholt, M ter Horst, R Li, Y Deelen, P Smeekens, S Jaeger, M Lachmandas, E Vrijmoeth, H Lupse, M Flonta, M Cramer, RA Kullberg, BJ Kumar, V Xavier, R Wijmenga, C Netea, MG Joosten, LAB AF Oosting, Marije Kerstholt, Mariska ter Horst, Rob Li, Yang Deelen, Patrick Smeekens, Sanne Jaeger, Martin Lachmandas, Ekta Vrijmoeth, Hedwig Lupse, Mihaela Flonta, Mirela Cramer, Robert A. Kullberg, Bart Jan Kumar, Vinod Xavier, Ramnik Wijmenga, Cisca Netea, Mihai G. Joosten, Leo A. B. TI Functional and Genomic Architecture of Borrelia burgdorferi-Induced Cytokine Responses in Humans SO Cell Host & Microbe LA English DT Article ID IFN-GAMMA PRODUCTION; LYME ARTHRITIS; IMMUNE-RESPONSES; HOST-DEFENSE; RECOGNITION; DISEASE; INFLAMMATION; MICE; MANIFESTATIONS; INTERLEUKIN-23 AB Despite the importance of immune variation for the symptoms and outcome of Lyme disease, the factors influencing cytokine production during infection with the causal pathogen Borrelia burgdorferi remain poorly understood. Borrelia infection-induced monocyte- and T cell-derived cytokines were profiled in peripheral blood from two healthy human cohorts of Western Europeans from the Human Functional Genomics Project. Both non-genetic and genetic host factors were found to influence Borrelia-induced cytokine responses. Age strongly impaired IL-22 responses, and genetic studies identified several independent QTLs that impact Borrelia-induced cytokine production. Genetic, transcriptomic, and functional validation studies revealed an important role for HIF-1 alpha-mediated glycolysis in the cytokine response toBorrelia. HIF-1 alpha pathway activation and increase in glycolysis-derived lactate was confirmed in Lyme disease patients. In conclusion, functional genomics approaches reveal the architecture of cytokine production induced by Borrelia infection of human primary leukocytes and suggest a connection between cellular glucose metabolism and Borrelia-induced cytokine production. C1 [Oosting, Marije; Kerstholt, Mariska; Smeekens, Sanne; Jaeger, Martin; Lachmandas, Ekta; Vrijmoeth, Hedwig; Kullberg, Bart Jan; Netea, Mihai G.; Joosten, Leo A. B.] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 GA Nijmegen, Netherlands. [Oosting, Marije; Kerstholt, Mariska; ter Horst, Rob; Smeekens, Sanne; Jaeger, Martin; Lachmandas, Ekta; Vrijmoeth, Hedwig; Kullberg, Bart Jan; Netea, Mihai G.; Joosten, Leo A. B.] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis RCI, NL-6525 GA Nijmegen, Netherlands. [Li, Yang; Deelen, Patrick; Kumar, Vinod; Wijmenga, Cisca] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 GZ Groningen, Netherlands. [Deelen, Patrick] Univ Groningen, Univ Med Ctr Groningen, Genom Coordinat Ctr, NL-9713 GZ Groningen, Netherlands. [Lupse, Mihaela; Flonta, Mirela] Univ Med & Pharm Iuliu Hatieganu, Dept Infect Dis, Cluj Napoca 400012, Romania. [Cramer, Robert A.] Dartmouth Coll, Geisel Sch Med, Dept Microbiol & Immunol, Hanover, NH 03755 USA. [Xavier, Ramnik] Harvard Sch Med, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik] Harvard Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Xavier, Ramnik] Broad Inst MIT & Harvard Univ, Cambridge, MA 02142 USA. RP Joosten, LAB (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 GA Nijmegen, Netherlands.; Joosten, LAB (reprint author), Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis RCI, NL-6525 GA Nijmegen, Netherlands. EM leo.joosten@radboudumc.nl RI Oosting, Marije/H-7437-2015 FU VENI grant from the Netherlands Organization for Scientific Research (NWO) [016.176.006, 863.13.011]; ERC Consolidator Grant [310372]; ERC advanced grant [2012-322698]; Spinoza Prize [NWO SPI 92-266]; STW [13546] FX M.O. was supported by a VENI grant (016.176.006) from the Netherlands Organization for Scientific Research (NWO). M.G.N. was supported by an ERC Consolidator Grant (#310372). C.W. is supported by an ERC advanced grant (FP/2007-2013/ERC grant 2012-322698) and a Spinoza Prize (NWO SPI 92-266). Y.L. was supported by a VENI grant (863.13.011) from the Netherlands Organization for Scientific Research (NWO). S.S. was supported by STW (13546). NR 56 TC 0 Z9 0 U1 3 U2 3 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 DEC 14 PY 2016 VL 20 IS 6 BP 822 EP 833 DI 10.1016/j.chom.2016.10.006 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EI9QK UT WOS:000392843500017 PM 27818078 ER PT J AU Kastanenka, KV Bussiere, T Shakerdge, N Qian, F Weinreb, PH Rhodes, K Bacskai, BJ AF Kastanenka, Ksenia V. Bussiere, Thierry Shakerdge, Naomi Qian, Fang Weinreb, Paul H. Rhodes, Ken Bacskai, Brian J. TI Immunotherapy with Aducanumab Restores Calcium Homeostasis in Tg2576 Mice SO JOURNAL OF NEUROSCIENCE LA English DT Article DE aducanumab; Alzheimer's disease; amyloid; BIIB037; calcium ID A-BETA-PLAQUES; MODERATE ALZHEIMERS-DISEASE; AMYLOID-BETA; TRANSGENIC MICE; ANTIBODY; MEMORY; PEPTIDE; BINDING; TRIALS; RANGE AB Calcium homeostasis plays a major role in maintaining neuronal function under physiological conditions. Amyloid-beta (A beta) initiates pathological processes that include disruption in intracellular calcium levels, so amelioration of the calcium alteration could serve as an indirect functional indicator of treatment efficacy. Therefore, calcium dynamics were used as a measure of functional outcome. We evaluated the effects of the anti-A beta antibody aducanumab on calcium homeostasis and plaque clearance in aged Tg2576 mice with in vivo multiphoton imaging. Acute topical application of aducanumab to the brain resulted in clearance of amyloid plaques. Although chronic systemic administration of aducanumab in 22-month-old mice did not clear existing plaques, calcium overload was ameliorated over time. Therefore, this antibody likely restores neuronal network function that possibly underlies cognitive deficits, indicating promise as a clinical treatment. In addition, functional readouts such as calcium overload may be a more useful outcome measure to monitor treatment efficacy in models of Alzheimer's disease compared with amyloid burden alone. C1 [Kastanenka, Ksenia V.; Shakerdge, Naomi; Bacskai, Brian J.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Neurol, 114 Sixteenth St, Charlestown, MA 02129 USA. [Kastanenka, Ksenia V.; Shakerdge, Naomi; Bacskai, Brian J.] Harvard Med Sch, 114 Sixteenth St, Charlestown, MA 02129 USA. [Bussiere, Thierry; Qian, Fang; Weinreb, Paul H.; Rhodes, Ken] Biogen, Cambridge, MA 02142 USA. RP Kastanenka, KV; Bacskai, BJ (reprint author), Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Neurol, 114 Sixteenth St, Charlestown, MA 02129 USA.; Kastanenka, KV; Bacskai, BJ (reprint author), Harvard Med Sch, 114 Sixteenth St, Charlestown, MA 02129 USA. EM kkastanenka@mgh.harvard.edu; bbacskai@mgh.harvard.edu OI Weinreb, Paul/0000-0002-0802-0052 FU Biogen; Alzheimer's Association; National Institutes of Health [R01EB000768, R01AG044263, P30NS045776, S10RR025645] FX This work was supported by Biogen, the Alzheimer's Association, and the National Institutes of Health (Grants R01EB000768, R01AG044263, P30NS045776, and S10RR025645).; This research was funded by Biogen. The authors declare no competing financial interests. NR 27 TC 1 Z9 1 U1 2 U2 2 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 DEC 14 PY 2016 VL 36 IS 50 BP 12549 EP 12558 DI 10.1523/JNEUROSCI.2080-16.2016 PG 10 WC Neurosciences SC Neurosciences & Neurology GA EG6GN UT WOS:000391142700004 PM 27810931 ER PT J AU Konig, MF Abusleme, L Reinholdt, J Palmer, RJ Teles, RP Sampson, K Rosen, A Nigrovic, PA Sokolove, J Giles, JT Moutsopoulos, NM Andrade, F AF Konig, Maximilian F. Abusleme, Loreto Reinholdt, Jesper Palmer, Robert J. Teles, Ricardo P. Sampson, Kevon Rosen, Antony Nigrovic, Peter A. Sokolove, Jeremy Giles, Jon T. Moutsopoulos, Niki M. Andrade, Felipe TI Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID NEUTROPHIL EXTRACELLULAR TRAPS; LEUKOTOXIC JP2 CLONE; EPSTEIN-BARR-VIRUS; ACTINOBACILLUS-ACTINOMYCETEMCOMITANS; CITRULLINATED PROTEIN; SUBGINGIVAL PLAQUE; PEPTIDYLARGININE DEIMINASE; SYNOVIAL-FLUID; ANTIBODIES; PORPHYROMONAS AB A bacterial etiology of rheumatoid arthritis (RA) has been suspected since the beginnings of modern germ theory. Recent studies implicate mucosal surfaces as sites of disease initiation. The common occurrence of periodontal dysbiosis in RA suggests that oral pathogens may trigger the production of disease-specific autoantibodies and arthritis in susceptible individuals. We used mass spectrometry to define the microbial composition and antigenic repertoire of gingival crevicular fluid in patients with periodontal disease and healthy controls. Periodontitis was characterized by the presence of citrullinated autoantigens that are primary immune targets in RA. The citrullinome in periodontitis mirrored patterns of hypercitrullination observed in the rheumatoid joint, implicating this mucosal site in RA pathogenesis. Proteomic signatures of several microbial species were detected in hypercitrullinated periodontitis samples. Among these, Aggregatibacter actinomycetemcomitans (Aa), but not other candidate pathogens, induced hypercitrullination in host neutrophils. We identified the pore-forming toxin leukotoxin A (LtxA) as the molecular mechanism by which Aa triggers dysregulated activation of citrullinating enzymes in neutrophils, mimicking mem-branolytic pathways that sustain autoantigen citrullination in the RA joint. Moreover, LtxA induced changes in neutrophil morphology mimicking extracellular trap formation, thereby releasing the hypercitrullinated cargo. Exposure to leukotoxic Aa strains was confirmed in patients with RA and was associated with both anticitrullinated protein antibodies and rheumatoid factor. The effect of human lymphocyte antigen-DRB1 shared epitope alleles on autoantibody positivity was limited to RA patients who were exposed to Aa. These studies identify the periodontal pathogen Aa as a candidate bacterial trigger of autoimmunity in RA. C1 [Konig, Maximilian F.; Sampson, Kevon; Rosen, Antony; Andrade, Felipe] Johns Hopkins Univ, Div Rheumatol, Sch Med, Baltimore, MD 21224 USA. [Abusleme, Loreto; Palmer, Robert J.; Moutsopoulos, Niki M.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Reinholdt, Jesper] Aarhus Univ, Dept Biomed, DK-8000 Aarhus C, Denmark. [Teles, Ricardo P.] Univ North Carolina Chapel Hill, Sch Dent, Dept Periodontol, Chapel Hill, NC 27599 USA. [Teles, Ricardo P.] Forsyth Inst, Dept Appl Oral Sci, Cambridge, MA 02142 USA. [Nigrovic, Peter A.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, 75 Francis St, Boston, MA 02115 USA. [Nigrovic, Peter A.] Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Sokolove, Jeremy] Stanford Univ, Div Rheumatol & Immunol, Sch Med, Stanford, CA 94305 USA. [Giles, Jon T.] Columbia Univ, Coll Phys & Surg, Div Rheumatol, New York, NY 10032 USA. [Konig, Maximilian F.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Andrade, F (reprint author), Johns Hopkins Univ, Div Rheumatol, Sch Med, Baltimore, MD 21224 USA. EM andrade@jhmi.edu FU Jerome L. Greene Foundation; Donald B. and Dorothy L. Stabler Foundation; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/NIH grant [R01AR069569]; Intramural Research Program of the NIDCR/NIH; NIH/NIDCR grant [R37 DE12354]; NIDCR/NIH grant [DE021127-01]; Fundacion Bechara; Rheumatology Research Foundation; NIAMS/NIH [AR050026-01] FX F.A. was supported by the Jerome L. Greene Foundation, the Donald B. and Dorothy L. Stabler Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/NIH grant R01AR069569. N.M.M. and R.J.P. were supported by the Intramural Research Program of the NIDCR/NIH. A.R. was supported by NIH/NIDCR grant R37 DE12354. R.P.T. was supported by NIDCR/NIH grant DE021127-01. P.A.N. was supported by the Fundacion Bechara. J.S. was supported by the Rheumatology Research Foundation. ESCAPE RA was supported by NIAMS/NIH AR050026-01. NR 64 TC 1 Z9 1 U1 3 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD DEC 14 PY 2016 VL 8 IS 369 AR 369ra176 DI 10.1126/scitranslmed.aaj1921 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EG5UL UT WOS:000391110000002 PM 27974664 ER PT J AU Gale, EM Jones, CM Ramsay, I Farrar, CT Caravan, P AF Gale, Eric M. Jones, Chloe M. Ramsay, Ian Farrar, Christian T. Caravan, Peter TI A Janus Chelator Enables Biochemically Responsive MRI Contrast with Exceptional Dynamic Range SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID IN-VIVO; ENZYME MYELOPEROXIDASE; IMAGING PROBES; AGENTS; REDOX; COMPLEXES; GLUTATHIONE; GADOLINIUM; DESIGN; RELAXIVITY AB We introduce a new biochemically responsive Mn-based MRI contrast agent that provides a 9-fold change in relaxivity via switching between the Mn3+ and Mn2+ oxidation states. Interchange between oxidation states is promoted by a "Janus" ligand that isomerizes between binding modes that favor Mn3+ or Mn2+. It is the only ligand that supports stable complexes of Mn3+ and Mn2+ in biological milieu. Rapid interconversion between oxidation states is mediated by peroxidase activity (oxidation) and L-cysteine (reduction). This Janus system provides a new paradigm for the design of biochemically responsive MRI contrast agents. C1 [Gale, Eric M.; Jones, Chloe M.; Ramsay, Ian; Farrar, Christian T.; Caravan, Peter] Harvard Med Sch, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Inst Innovat Imaging,Dept Radiol, 149 Thirteenth St,Suite 2301, Charlestown, MA 02129 USA. RP Gale, EM (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Inst Innovat Imaging,Dept Radiol, 149 Thirteenth St,Suite 2301, Charlestown, MA 02129 USA. EM egale@nmr.mgh.harvard.edu FU National Heart, Lung, and Blood Institute [K25HL128899]; National Institute of Biomedical Imaging and Bioengineering [R01EB009062, R21EB022804]; National Center for Research Resources; Office of the Director [P41RR014075, S10RR023385, S10OD010650] FX This work was supported by grants from the National Heart, Lung, and Blood Institute (K25HL128899) and the National Institute of Biomedical Imaging and Bioengineering (R01EB009062 and R21EB022804) and instrumentation funded by the National Center for Research Resources and the Office of the Director (P41RR014075, S10RR023385, and S10OD010650). NR 41 TC 1 Z9 1 U1 7 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD DEC 14 PY 2016 VL 138 IS 49 BP 15861 EP 15864 DI 10.1021/jacs.6b10898 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA EE9RB UT WOS:000389962800017 PM 27960350 ER PT J AU Zhou, J Jin, JO Kawai, T Yu, Q AF Zhou, Jing Jin, Jun-O. Kawai, Toshihisa Yu, Qing TI Endogenous programmed death ligand-1 restrains the development and onset of Sjogren's syndrome in non-obese diabetic mice SO SCIENTIFIC REPORTS LA English DT Article ID MESSENGER-RNA EXPRESSION; NECROSIS-FACTOR-ALPHA; B-CELL ACTIVATION; T-CELL; SALIVARY-GLAND; INTERFERON-GAMMA; AUTOIMMUNE-DISEASES; PD-1 PATHWAY; MOUSE MODEL; REGULATING AUTOIMMUNITY AB Programmed death-ligand 1 (PD-L1) down-modulates various immune responses by engaging the co-inhibitory receptor programmed death-1. Expression of PD-L1 and programmed death-1 is elevated in the salivary glands of patients with Sjogren's syndrome (SS). The objective of this study is to define the role of endogenous PD-L1 in SS pathogenesis in non-obese diabetic (NOD) mouse model of this disease. We inhibited endogenous PD-L1 function by intraperitoneal administration of a blocking antibody to 6 week-old female NOD/ShiLtJ mice repeatedly during a 9-day period. PD-L1 blockade accelerated leukocyte infiltration and caspase-3 activation in the submandibular gland (SMG), production of antinuclear and anti-M3 muscarinic acetylcholine receptor (M3R) autoantibodies and impairment of saliva secretion, indicative of accelerated development and onset of SS. The effect of PD-L1 blockade was associated with increased T-and B cells and T helper 1 cytokine IFN-gamma in the SMG. Local administration of exogenous IFN-gamma to the SMG led to impaired salivary secretion accompanied by down-regulation of aquaporin 5 and an increase in anti-M3R autoantibodies. Conversely, neutralization of IFN-gamma markedly improved salivary secretion and aquaporin 5 expression in anti-PD-L1-treated NOD/ShiLtJ mice. Hence, endogenous PD-L1 hinders the development and onset of SS in NOD mice, in part by suppressing IFN-gamma production. C1 [Zhou, Jing; Jin, Jun-O.; Kawai, Toshihisa; Yu, Qing] Forsyth Inst, Dept Immunol & Infect Dis, 245 First St, Cambridge, MA 02142 USA. [Zhou, Jing; Kawai, Toshihisa; Yu, Qing] Harvard Sch Dent Med, Dept Oral Med Infect & Immun, 188 Longwood Ave, Boston, MA 02115 USA. [Jin, Jun-O.] Fudan Univ, Shanghai Med Coll, Shanghai Publ Hlth Clin Ctr, Shanghai 201508, Peoples R China. RP Yu, Q (reprint author), Forsyth Inst, Dept Immunol & Infect Dis, 245 First St, Cambridge, MA 02142 USA.; Yu, Q (reprint author), Harvard Sch Dent Med, Dept Oral Med Infect & Immun, 188 Longwood Ave, Boston, MA 02115 USA. EM qyu@forsyth.org FU National Institutes of Health [R01 DE023838, P30 DE020751] FX We thank Juan Du, Dr. Ekta S Patel and Dr. Atsushi Ikeda for technical assistance in this study. This study was supported by grants from the National Institutes of Health to QY (R01 DE023838, P30 DE020751). NR 69 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 14 PY 2016 VL 6 AR 39105 DI 10.1038/srep39105 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF3RL UT WOS:000390242000001 PM 27966604 ER PT J AU Desai, S Jena, AB AF Desai, Sunita Jena, Anupam B. TI Do celebrity endorsements matter? Observational study of BRCA gene testing and mastectomy rates after Angelina Jolie's New York Times editorial SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID RISK-REDUCING MASTECTOMY; BREAST RECONSTRUCTION; CANCER; SERVICES; WOMEN AB OBJECTIVE To examine the effect on BRCA testing and mastectomy rates of a widely viewed 2013 New York Times editorial by public figure Angelina Jolie that endorsed BRCA testing and announced Jolie's decision to undergo preventive mastectomy. DESIGN Observational study with difference-in-difference analysis. SETTING Commercially insured US population. PARTICIPANTS Women aged 18-64 years with claims in the Truven MarketScan commercial claims database (n= 9 532 836). MAIN OUTCOME MEASURES Changes in BRCA testing rates in the 15 business days before versus after 14 May 2013 (editorial date) compared with the change in the same period in 2012; mastectomy rates in the months before and after publication, both overall and within 60 days of BRCA testing among women who were tested; national estimates of incremental tests and expenditures associated with Jolie's article in the 15 days after publication. RESULTS Daily BRCA test rates increased immediately after the 2013 editorial, from 0.71 tests/100 000 women in the 15 business days before to 1.13 tests/100 000 women in the 15 business days after publication. In comparison, daily test rates were similar in the same period in 2012 (0.58/100 000 women in the 15 business days before 14 May versus 0.55/100 000 women in the 15 business days after), implying a difference-in-difference absolute daily increase of 0.45 tests/100 000 women or a 64% relative increase (P<0.001). The editorial was associated with an estimated increase of 4500 BRCA tests and $13.5m (10.8m; pound (sic)12.8) expenditure nationally among commercially insured adult women in those 15 days. Increased BRCA testing rates were sustained throughout 2013. Overall mastectomy rates remained unchanged in the months after publication, but 60 day mastectomy rates among women who had a BRCA test fell from 10% in the months before publication to 7% in the months after publication, suggesting that women who underwent tests as a result of to the editorial had a lower pre-test probability of having the BRCA mutation than women tested before the editorial. CONCLUSIONS Celebrity endorsements can have a large and immediate effect on use of health services. Such announcements can be a low cost means of reaching a broad audience quickly, but they may not effectively target the subpopulations that are most at risk for the relevant underlying condition. C1 [Desai, Sunita; Jena, Anupam B.] Harvard Med Sch, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. [Jena, Anupam B.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Jena, Anupam B.] Natl Bur Econ Res, Cambridge, MA 02138 USA. RP Jena, AB (reprint author), Harvard Med Sch, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA.; Jena, AB (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Jena, AB (reprint author), Natl Bur Econ Res, Cambridge, MA 02138 USA. EM jena@hcp.med.harvard.edu FU Office of the Director, National Institutes of Health [1DP5OD017897-01]; Marshall J Seidman fellowship at Harvard Medical School FX This research was supported by a grant from the Office of the Director, National Institutes of Health (ABJ: NIH early independence award; grant 1DP5OD017897-01) and the Marshall J Seidman fellowship at Harvard Medical School (SD). Study sponsors were not involved in study design, data interpretation, writing, or the decision to submit the article for publication. NR 10 TC 0 Z9 0 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD DEC 14 PY 2016 VL 355 AR i6357 DI 10.1136/bmj.i6357 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA EF2JS UT WOS:000390151300005 PM 27974323 ER PT J AU Marino, J Paster, J Benichou, G AF Marino, Jose Paster, Joshua Benichou, Gilles TI Allorecognition by T Lymphocytes and Allograft Rejection SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE allorecognition; T cells; regulatory T cells; allograft rejection; T cell tolerance; major histocompatibility complex; exosomes ID BONE-MARROW-TRANSPLANTATION; INNATE IMMUNE-SYSTEM; SKIN-GRAFT REJECTION; CLASS-II MOLECULES; CELLS IN-VIVO; DENDRITIC CELLS; ORGAN-TRANSPLANTATION; HETEROLOGOUS IMMUNITY; INDIRECT RECOGNITION; TOLERANCE INDUCTION AB Recognition of donor antigens by recipient T cells in secondary lymphoid organs initiates the adaptive inflammatory immune response leading to the rejection of allogeneic transplants. Allospecific T cells become activated through interaction of their T cell receptors with intact allogeneic major histocompatibility complex (MHC) molecules on donor cells (direct pathway) and/or donor peptides presented by self-MHC molecules on recipient antigen-presenting cells (APCs) (indirect pathway). In addition, recent studies show that alloreactive T cells can also be stimulated through recognition of allogeneic MHC molecules displayed on recipient APCs (MHC cross-dressing) after their transfer via cell-cell contact or through extracellular vesicles (semi-direct pathway). The specific allorecognition pathway used by T cells is dictated by intrinsic and extrinsic factors to the allograft and can influence the nature and magnitude of the alloresponse and rejection process. Consequently, various organs and tissues such as skin, cornea, and solid organ transplants are recognized differently by pro-inflammatory T cells through these distinct pathways, which may explain why these grafts are rejected in a different fashion. On the other hand, the mechanisms by which anti-inflammatory regulatory T cells (Tregs) recognize alloantigen and promote transplantation tolerance are still unclear. It is likely that thymic Tregs are activated through indirect allorecognition, while peripheral Tregs recognize alloantigens in a direct fashion. As we gain insights into the mechanisms underlying allorecognition by pro-inflammatory and Treg cells, novel strategies are being designed to prevent allograft rejection in the absence of ongoing immunosuppressive drug treatment in patients. C1 [Marino, Jose; Paster, Joshua; Benichou, Gilles] Massachusetts Gen Hosp, Harvard Med Sch, Dept Surg, Ctr Transplantat Sci, Boston, MA 02114 USA. RP Benichou, G (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Dept Surg, Ctr Transplantat Sci, Boston, MA 02114 USA. EM gbenichou@partners.org FU NIH [R21AI111191, R21AI117466] FX This study was supported by NIH grants R21AI111191 and R21AI117466 to Dr. GB. NR 117 TC 0 Z9 0 U1 11 U2 11 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD DEC 14 PY 2016 VL 7 AR 582 DI 10.3389/fimmu.2016.00582 PG 9 WC Immunology SC Immunology GA EE8EC UT WOS:000389857100001 PM 28018349 ER PT J AU Xu, YF Wu, JY Yin, CC Mao, YD AF Xu, Yaofang Wu, Jiayi Yin, Chang-Cheng Mao, Youdong TI Unsupervised Cryo-EM Data Clustering through Adaptively Constrained K-Means Algorithm SO PLOS ONE LA English DT Article ID ELECTRON-MICROSCOPY IMAGES; SINGLE-PARTICLES; BIOLOGICAL MACROMOLECULES; ANGSTROM RESOLUTION; RECONSTRUCTION; PROJECTIONS; CLASSIFICATION; HETEROGENEITY; COMPLEXES; SOFTWARE AB In single-particle cryo-electron microscopy (cryo-EM), K-means clustering algorithm is widely used in unsupervised 2D classification of projection images of biological macromolecules. 3D ab initio reconstruction requires accurate unsupervised classification in order to separate molecular projections of distinct orientations. Due to background noise in single-particle images and uncertainty of molecular orientations, traditional K-means clustering algorithm may classify images into wrong classes and produce classes with a large variation in membership. Overcoming these limitations requires further development on clustering algorithms for cryo-EM data analysis. We propose a novel unsupervised data clustering method building upon the traditional K-means algorithm. By introducing an adaptive constraint term in the objective function, our algorithm not only avoids a large variation in class sizes but also produces more accurate data clustering. Applications of this approach to both simulated and experimental cryo-EM data demonstrate that our algorithm is a significantly improved alterative to the traditional K-means algorithm in single-particle cryo-EM analysis. C1 [Xu, Yaofang; Yin, Chang-Cheng] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Biophys, Beijing, Peoples R China. [Wu, Jiayi; Mao, Youdong] Peking Univ, Ctr Quantitat Biol, Sch Phys, Inst Condensed Matter Phys,State Key Lab Artifici, Beijing, Peoples R China. [Mao, Youdong] Harvard Med Sch, Dept Microbiol & Immunobiol, Dana Farber Canc Inst, Intel Parallel Comp Ctr Struct Biol, Boston, MA USA. RP Yin, CC (reprint author), Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Biophys, Beijing, Peoples R China.; Mao, YD (reprint author), Peking Univ, Ctr Quantitat Biol, Sch Phys, Inst Condensed Matter Phys,State Key Lab Artifici, Beijing, Peoples R China.; Mao, YD (reprint author), Harvard Med Sch, Dept Microbiol & Immunobiol, Dana Farber Canc Inst, Intel Parallel Comp Ctr Struct Biol, Boston, MA USA. EM ccyin@hsc.pku.edu.cn; youdong_mao@dfci.harvard.edu FU grant of the Thousand Talents Plan of China; National Natural Science Foundation of China [91530321]; Intel Parallel Computing Center program; National Science Foundation under NSF [1541959]; NIH, Center for HIV/AIDS Vaccine Immunology and Immunogen Design (CHAVI-ID) [AI100645] FX This work was funded by a grant of the Thousand Talents Plan of China (YM), by a grant from National Natural Science Foundation of China 91530321 (YM), by the Intel Parallel Computing Center program (YM). The cryo-EM experiments were performed in part at the Center for Nanoscale Systems at Harvard University, a member of the National Nanotechnology Coordinated Infrastructure Network (NNCI), which is supported by the National Science Foundation under NSF award no. 1541959. The cryo-EM facility was funded through the NIH grant AI100645, Center for HIV/AIDS Vaccine Immunology and Immunogen Design (CHAVI-ID). The data processing was performed in part in the Sullivan supercomputer, which is funded in part by a gift from Mr. and Mrs. Daniel J. Sullivan, Jr. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 13 PY 2016 VL 11 IS 12 AR e0167765 DI 10.1371/journal.pone.0167765 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI8JY UT WOS:000392753900015 PM 27959895 ER PT J AU Pacheco-Leyva, I Matias, AC Oliveira, DV Santos, JMA Nascimento, R Guerreiro, E Michell, AC van De Vrugt, AM Machado-Oliveira, G Ferreira, G Domian, I Braganca, J AF Pacheco-Leyva, Ivette Matias, Ana Catarina Oliveira, Daniel V. Santos, Joao M. A. Nascimento, Rita Guerreiro, Eduarda Michell, Anna C. van De Vrugt, Annebel M. Machado-Oliveira, Gisela Ferreira, Guilherme Domian, Ibrahim Braganca, Jose TI CITED2 Cooperates with ISL1 and Promotes Cardiac Differentiation of Mouse Embryonic Stem Cells SO STEM CELL REPORTS LA English DT Article ID CARDIOVASCULAR PROGENITOR SPECIFICATION; HEART DEVELOPMENT; GENE-EXPRESSION; PRECURSOR CELLS; MESP1; MULTIPOTENT; MESODERM; COACTIVATOR; POPULATION; IDENTIFICATION AB The transcriptional regulator CITED2 is essential for heart development. Here, we investigated the role of CITED2 in the specification of cardiac cell fate from mouse embryonic stem cells (ESC). The overexpression of CITED2 in undifferentiated ESC was sufficient to promote cardiac cell emergence upon differentiation. Conversely, the depletion of Cited2 at the onset of differentiation resulted in a decline of ESC ability to generate cardiac cells. Moreover, loss of Cited2 expression impairs the expression of early mesoderm markers and cardiogenic transcription factors (Isl1, Gata4, Tbx5). The cardiogenic defects in Cited2-depleted cells were rescued by treatment with recombinant CITED2 protein. We showed that Cited2 expression is enriched in cardiac progenitors either derived from ESC or mouse embryonic hearts. Finally, we demonstrated that CITED2 and ISL1 proteins interact physically and cooperate to promote ESC differentiation toward cardiomyocytes. Collectively, our results show that Cited2 plays a pivotal role in cardiac commitment of ESC. C1 [Pacheco-Leyva, Ivette; Matias, Ana Catarina; Oliveira, Daniel V.; Santos, Joao M. A.; Nascimento, Rita; Guerreiro, Eduarda; Machado-Oliveira, Gisela; Braganca, Jose] Univ Algarve, Dept Biomed Sci & Med, Regenerat Med Program, P-8005139 Faro, Portugal. [Pacheco-Leyva, Ivette; Matias, Ana Catarina; Oliveira, Daniel V.; Santos, Joao M. A.; Nascimento, Rita; Guerreiro, Eduarda; Machado-Oliveira, Gisela; Braganca, Jose] Univ Algarve, CBMR, Ctr Biomed Res, Campus Gambelas,Bldg 8,Room 2-22, P-8005139 Faro, Portugal. [Braganca, Jose] Algarve Biomed Ctr, P-8005139 Faro, Portugal. [Michell, Anna C.] Univ Oxford, Wellcome Trust Ctr Human Genet, Div Cardiovasc Med, Roosevelt Dr, Oxford OX3 7BN, England. [van De Vrugt, Annebel M.; Domian, Ibrahim] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charles River Plaza,CPZN 3200,185 Cambridge St, Boston, MA 02114 USA. [van De Vrugt, Annebel M.; Domian, Ibrahim] Harvard Med Sch, 250 Longwood Ave, Boston, MA 02115 USA. [van De Vrugt, Annebel M.] Univ Med Ctr Utrecht, Dept Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands. [Ferreira, Guilherme] DSM Biotechnol Ctr, Alexander Fleminglaan 1, NL-2613 AX Delft, Netherlands. RP Braganca, J (reprint author), Univ Algarve, Dept Biomed Sci & Med, Regenerat Med Program, P-8005139 Faro, Portugal.; Braganca, J (reprint author), Univ Algarve, CBMR, Ctr Biomed Res, Campus Gambelas,Bldg 8,Room 2-22, P-8005139 Faro, Portugal.; Braganca, J (reprint author), Algarve Biomed Ctr, P-8005139 Faro, Portugal. EM jebraganca@ualg.pt OI Oliveira, Daniel/0000-0003-0622-2934; Matias, Ana Catarina/0000-0002-6385-9117 FU FCT, Fundacao para a Ciencia e a Tecnologia [UID/BIM/04773/2013 CBMR, PEst-OE/EQB/LA0023/2013, PTDC/SAU-ENB/111702/2009]; Biomedical Sciences PhD program; FCT [SFRH/BD/62054/2009]; NIH/NHLBI [U01HL100408]; [SFRH/BPD/74807/2010] FX This work is supported by national Portuguese funding through FCT, Fundacao para a Ciencia e a Tecnologia, project UID/BIM/04773/2013 CBMR, projects PEst-OE/EQB/LA0023/2013 and PTDC/SAU-ENB/111702/2009 to J.B., U01HL100408, NIH/NHLBI to I.D., and SFRH/BPD/74807/2010 to G.M.O. I.P.L. thanks the Biomedical Sciences PhD program and FCT for funding (SFRH/BD/62054/2009). J.M.A.S. is a PhD student of the ProRegeM - PhD Program in Mechanisms of Disease and Regenerative Medicine of the University of Algarve and New University of Lisbon financed by the FCT. We thank Shoumo Bhattacharya (University of Oxford) for CITED2 expressing vectors, Austin Smith (University of Cambridge) for E14/T cells and pPyCAGIP vector, Gergana Dobreva (Max Planck Institute for Heart and Lung Research) for Mef2c-luc reporter, Claudia Florindo, head of the Microscopy Facility (University of Algarve), and Jose A. Belo (New University of Lisbon) for reagents. NR 45 TC 0 Z9 0 U1 4 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD DEC 13 PY 2016 VL 7 IS 6 BP 1037 EP 1049 DI 10.1016/j.stemcr.2016.10.002 PG 13 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA EJ4LL UT WOS:000393188500003 PM 27818139 ER PT J AU Arts, RJW Novakovic, B ter Horst, R Carvalho, A Bekkering, S Lachmandas, E Rodrigues, F Silvestre, R Cheng, SC Wang, SY Habibi, E Goncalves, LG Mesquita, I Cunha, C van Laarhoven, A van de Veerdonk, FL Williams, DL van der Meer, JWM Logie, C O'Neill, LA Dinarello, CA Riksen, NP van Crevel, R Clish, C Notebaart, RA Joosten, LAB Stunnenberg, HG Xavier, RJ Netea, MG AF Arts, Rob J. W. Novakovic, Boris ter Horst, Rob Carvalho, Agostinho Bekkering, Siroon Lachmandas, Ekta Rodrigues, Fernando Silvestre, Ricardo Cheng, Shih-Chin Wang, Shuang-Yin Habibi, Ehsan Goncalves, Luis G. Mesquita, Ines Cunha, Cristina van Laarhoven, Arjan van de Veerdonk, Frank L. Williams, David L. van der Meer, Jos W. M. Logie, Colin O'Neill, Luke A. Dinarello, Charles A. Riksen, Niels P. van Crevel, Reinout Clish, Clary Notebaart, Richard A. Joosten, Leo A. B. Stunnenberg, Hendrik G. Xavier, Ramnik J. Netea, Mihai G. TI Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity SO Cell Metabolism LA English DT Article ID SYSTEMIC ACQUIRED-RESISTANCE; ENERGY-METABOLISM; AMINO-ACIDS; MONOCYTES; DEFENSE; MEMORY; DEMETHYLATION; REINFECTION; INHIBITION; PROTECTION AB Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by beta-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to beta-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by b-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues. C1 [Arts, Rob J. W.; ter Horst, Rob; Bekkering, Siroon; Lachmandas, Ekta; Cheng, Shih-Chin; van Laarhoven, Arjan; van de Veerdonk, Frank L.; van der Meer, Jos W. M.; Dinarello, Charles A.; Riksen, Niels P.; van Crevel, Reinout; Notebaart, Richard A.; Joosten, Leo A. B.; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 GA Nijmegen, Netherlands. [Novakovic, Boris; Wang, Shuang-Yin; Habibi, Ehsan; Logie, Colin; Stunnenberg, Hendrik G.] Radboud Univ Nijmegen, Fac Sci, Dept Mol Biol, NL-6525 HP Nijmegen, Netherlands. [Carvalho, Agostinho; Rodrigues, Fernando; Silvestre, Ricardo; Mesquita, Ines; Cunha, Cristina] Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst ICVS, P-4710057 Braga, Portugal. [Carvalho, Agostinho; Rodrigues, Fernando; Silvestre, Ricardo; Mesquita, Ines; Cunha, Cristina] ICVS 3Bs PT Govt Associate Lab, P-4806909 Braga, Portugal. [Cheng, Shih-Chin] Natl Tsing Hua Univ, Inst Mol Med, Hsinchu 300, Taiwan. [Goncalves, Luis G.] Univ Nova Lisboa, Inst Tecnol Quim & Biol Antonio Xavier, P-2780157 Oeiras, Portugal. [Williams, David L.] East Tennessee State Univ, Quillen Coll Med, Dept Surg, Johnson City, TN 37604 USA. [Williams, David L.] East Tennessee State Univ, Ctr Inflammat Infect Dis & Immun, Johnson City, TN 37604 USA. [O'Neill, Luke A.] Trinity Coll Dublin, Trinity Biomed Sci Inst, Dublin 2, Ireland. [Dinarello, Charles A.] Univ Colorado Denver, Dept Med, Aurora, CO 80045 USA. [Clish, Clary; Xavier, Ramnik J.] Broad Inst Harvard Univ & Massachusetts Inst Tech, Cambridge, MA 02142 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. RP Arts, RJW (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 GA Nijmegen, Netherlands. EM rob.jw.arts@radboudumc.nl RI van Crevel, reinout/A-6636-2010; Carvalho, Agostinho/D-2667-2009; Riksen, Niels/G-8260-2015; Novakovic, Boris/D-8018-2013; Logie, Colin/A-1528-2010; OI Carvalho, Agostinho/0000-0001-8935-8030; Novakovic, Boris/0000-0002-5623-9008; Logie, Colin/0000-0002-8534-6582; Silvestre, Ricardo/0000-0002-9270-2717 FU ERC [310372]; Spinoza grant of the Netherlands Organization for Scientific Research (NWO); NHMRC (Australia); Netherlands Heart Foundation [2012T051]; European Union [H2020-PHC-2015-667873-2, 667837]; Fundacao para a Ciencia e Tecnologia, FCT [IF/00735/2014, IF/00021/2014, RECI/BBB-BQB/0230/2012, SFRH/BPD/96176/2013]; Fundacao para a Ciencia e Tecnologia (FCT) - Programa Operacional Regional do Norte [ON.2-O]; Quadro de Referencia Estrategico Nacional (QREN) through the Fundo Europeu de Desenvolvimento Regional (FEDER); Projeto Estrategico [PEst-C/SAU/LA0026/2013]; NIH [DK43351, DK097485, GM53522, GM083016, GM119197, C06RR0306551]; Helmsley Trust FX M.G.N. is supported by an ERC Consolidator grant (310372) and a Spinoza grant of the Netherlands Organization for Scientific Research (NWO). B.N. is supported by an NHMRC (Australia) CJ Martin Early Career Fellowship. N.P.R. is supported by a Dr. Dekker grant (2012T051) from the Netherlands Heart Foundation (2012T051). N.P.R. and M.G.N. received a H2020 grant (H2020-PHC-2015-667873-2) from the European Union (grant agreement 667837). A.C., R.S., L.G.G., and C. Cunha were supported by the Fundacao para a Ciencia e Tecnologia, FCT (IF/00735/2014 to A.C., IF/00021/2014 to R.S., RECI/BBB-BQB/0230/2012 to L.G.G., and SFRH/BPD/96176/2013 to C. Cunha). The NMR spectrometers are part of the National NMR Facility supported by FCT (RECI/BBB-BQB/0230/2012). The research leading to these results received funding from the Fundacao para a Ciencia e Tecnologia (FCT), cofunded by Programa Operacional Regional do Norte (ON.2-O Novo Norte); from the Quadro de Referencia Estrategico Nacional (QREN) through the Fundo Europeu de Desenvolvimento Regional (FEDER) and from the Projeto Estrategico - LA 26 - 2013-2014 (PEst-C/SAU/LA0026/2013). R.J.X. was supported by NIH (DK43351 and DK097485) and Helmsley Trust. D.L.W. is supported, in part, by the NIH (GM53522, GM083016, GM119197, and C06RR0306551). NR 41 TC 1 Z9 1 U1 0 U2 0 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 DEC 13 PY 2016 VL 24 IS 6 BP 807 EP 819 DI 10.1016/j.cmet.2016.10.008 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EI9QU UT WOS:000392844600011 PM 27866838 ER PT J AU Wang, XB Zheng, Z Caviglia, JM Corey, KE Herfel, TM Cai, BS Masia, R Chung, RT Lefkowitch, JH Schwabe, RF Tabas, I AF Wang, Xiaobo Zheng, Ze Caviglia, Jorge Matias Corey, Kathleen E. Herfel, Tina M. Cai, Bishuang Masia, Ricard Chung, Raymond T. Lefkowitch, Jay H. Schwabe, Robert F. Tabas, Ira TI Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis SO Cell Metabolism LA English DT Article ID FATTY LIVER-DISEASE; HEPATIC STELLATE CELLS; ORGAN SIZE CONTROL; HIPPO PATHWAY; DIETARY-CHOLESTEROL; MICE; YAP; NASH; PROGRESSION; ACTIVATION AB Nonalcoholic steatohepatitis (NASH) is a leading cause of liver disease worldwide. However, the molecular basis of how benign steatosis progresses to NASH is incompletely understood, which has limited the identification of therapeutic targets. Here we show that the transcription regulator TAZ (WWTR1) is markedly higher in hepatocytes in human and murine NASH liver than in normal or steatotic liver. Most importantly, silencing of hepatocyte TAZ in murine models of NASH prevented or reversed hepatic inflammation, hepatocyte death, and fibrosis, but not steatosis. Moreover, hepatocyte-targeted expression of TAZ in a model of steatosis promoted NASH features, including fibrosis. In vitro and in vivo mechanistic studies revealed that a key mechanism linking hepatocyte TAZ to NASH fibrosis is TAZ/TEA domain (TEAD)-mediated induction of Indian hedgehog (Ihh), a secretory factor that activates fibrogenic genes in hepatic stellate cells. In summary, TAZ represents a previously unrecognized factor that contributes to the critical process of steatosis-to-NASH progression. C1 [Wang, Xiaobo; Zheng, Ze; Caviglia, Jorge Matias; Cai, Bishuang; Schwabe, Robert F.; Tabas, Ira] Columbia Univ, Dept Med, New York, NY 10032 USA. [Caviglia, Jorge Matias; Schwabe, Robert F.] Columbia Univ, Inst Human Nutr, New York, NY 10032 USA. [Corey, Kathleen E.; Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Corey, Kathleen E.; Masia, Ricard; Chung, Raymond T.] Harvard Med Sch, Boston, MA 02115 USA. [Herfel, Tina M.] Envigo, Teklad Diets, Madison, WI 53713 USA. [Masia, Ricard] Massachusetts Gen Hosp, Dept Pathol & Lab Med, Boston, MA 02114 USA. [Lefkowitch, Jay H.; Tabas, Ira] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Tabas, Ira] Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY 10032 USA. RP Wang, XB; Tabas, I (reprint author), Columbia Univ, Dept Med, New York, NY 10032 USA.; Tabas, I (reprint author), Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA.; Tabas, I (reprint author), Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY 10032 USA. EM xw2279@columbia.edu; iat1@columbia.edu FU NIH [HL087123, HL075662, DK078772, DK99422, R03DK101863]; AASLD Foundation; American Heart Association; NIH from the National Center for Advancing Translational Science [UL1 TR000040] FX We thank Dr. Utpal Pajvani, Columbia University, for helpful discussions; Dr. Yuri Choi, Massachusetts General Hospital, for assisting with the human liver samples; Dr. Stephen M. Lagana, Columbia University, for human NASH liver histology analysis; Dr. Rhonda Bassel-Duby and Dr. Eric Olson, UT Southwestern, for sharing Wwtr1fl/fl mice; Dr. Hongfeng Jiang, Columbia University, for conducting the liver lipid profiling experiment; and Dr. Peter Nagy, Columbia University, for assisting with the ChIP experiments. This work was supported by NIH grants HL087123 and HL075662 to I.T.; DK078772 to R.T.C.; DK99422 to K.E.C.; and R03DK101863 to J.M.C. Z.Z. is a Russell Berrie Foundation Scholar in Diabetes Research. R.M. is supported by a Pinnacle Research Award from the AASLD Foundation. B.C. is supported by an American Heart Association Post-Doctoral Fellowship. The liver lipid profiling work was supported by NIH Grant Number UL1 TR000040 from the National Center for Advancing Translational Science. NR 57 TC 0 Z9 0 U1 2 U2 2 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 DEC 13 PY 2016 VL 24 IS 6 BP 848 EP 862 DI 10.1016/j.cmet.2016.09.016 PG 15 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EI9QU UT WOS:000392844600014 PM 28068223 ER PT J AU Arroyo, JD Jourdain, AA Calvo, SE Ballarano, CA Doench, JG Root, DE Mootha, VK AF Arroyo, Jason D. Jourdain, Alexis A. Calvo, Sarah E. Ballarano, Carmine A. Doench, John G. Root, David E. Mootha, Vamsi K. TI A Genome-wide CRISPR Death Screen Identifies Genes Essential for Oxidative Phosphorylation SO Cell Metabolism LA English DT Article ID MITOCHONDRIAL RNA GRANULES; COMPLEX-I DISEASE; CELLS; TRANSLATION; DEFICIENCY; RESOLUTION; DISORDERS; MUTATIONS; PROTEINS; FASTKD2 AB Oxidative phosphorylation (OXPHOS) is the major pathway for ATP production in humans. Deficiencies in OXPHOS can arise from mutations in either mitochondrial or nuclear genomes and comprise the largest collection of inborn errors of metabolism. At present we lack a complete catalog of human genes and pathways essential for OXPHOS. Here we introduce a genome-wide CRISPR "death screen'' that actively selects dying cells to reveal human genes required for OXPHOS, inspired by the classic observation that human cells deficient in OXPHOS survive in glucose but die in galactose. We report 191 high-confidence hits essential for OXPHOS, including 72 underlying known OXPHOS diseases. Our screen reveals a functional module consisting of NGRN, WBSCR16, RPUSD3, RPUSD4, TRUB2, and FASTKD2 that regulates the mitochondrial 16S rRNA and intra-mitochondrial translation. Our work yields a rich catalog of genes required for OXPHOS and, more generally, demonstrates the power of death screening for functional genomic analysis. C1 [Arroyo, Jason D.; Jourdain, Alexis A.; Calvo, Sarah E.; Ballarano, Carmine A.; Mootha, Vamsi K.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Arroyo, Jason D.; Jourdain, Alexis A.; Calvo, Sarah E.; Ballarano, Carmine A.; Mootha, Vamsi K.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Arroyo, Jason D.; Jourdain, Alexis A.; Calvo, Sarah E.; Ballarano, Carmine A.; Mootha, Vamsi K.] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA. [Arroyo, Jason D.; Jourdain, Alexis A.; Calvo, Sarah E.; Ballarano, Carmine A.; Doench, John G.; Root, David E.; Mootha, Vamsi K.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Mootha, VK (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Mootha, VK (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA.; Mootha, VK (reprint author), Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA.; Mootha, VK (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM vamsi@hms.harvard.edu FU NIH [R01-GM077465]; EMBO long-term fellowship [ALTF 554-2015]; Broad Institute of MIT and Harvard FX We thank R. Gopal, X.R. Bao, and members of the V.K.M. laboratory for advice and feedback on the manuscript; E. Spooner for help with mass spectrometry; Y. Li for computational assistance; S. Schwartz and A. Regev for fruitful discussions; and L. Solomon for graphical design assistance. This work was supported by NIH grant R01-GM077465 (to V.K.M.), EMBO long-term fellowship ALTF 554-2015 (to A.A.J.), and the Next Generation Fund at the Broad Institute of MIT and Harvard (to J.G.D.). V.K.M. is an Investigator of the Howard Hughes Medical Institute. NR 34 TC 3 Z9 3 U1 7 U2 7 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 DEC 13 PY 2016 VL 24 IS 6 BP 875 EP 885 DI 10.1016/j.cmet.2016.08.017 PG 11 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EI9QU UT WOS:000392844600016 PM 27667664 ER PT J AU Alshikho, MJ Zurcher, NR Loggia, ML Cernasov, P Chonde, DB Garcia, DI Yasek, JE Akeju, O Catana, C Rosen, BR Cudkowicz, ME Hooker, JM Atassi, N AF Alshikho, Mohamad J. Zurcher, Nicole R. Loggia, Marco L. Cernasov, Paul Chonde, Daniel B. Garcia, David Izquierdo Yasek, Julia E. Akeju, Oluwaseun Catana, Ciprian Rosen, Bruce R. Cudkowicz, Merit E. Hooker, Jacob M. Atassi, Nazem TI Glial activation colocalizes with structural abnormalities in amyotrophic lateral sclerosis SO NEUROLOGY LA English DT Article ID VOXEL-BASED MORPHOMETRY; CORTICOSPINAL TRACT; BRAIN ATROPHY; ALS; MRI; PET; INVOLVEMENT; DISABILITY; TSPO AB Objective: In this cross-sectional study, we aimed to evaluate brain structural abnormalities in relation to glial activation in the same cohort of participants. Methods: Ten individuals with amyotrophic lateral sclerosis (ALS) and 10 matched healthy controls underwent brain imaging using integrated MR/PET and the radioligand [C-11]-PBR28. Diagnosis history and clinical assessments including Upper Motor Neuron Burden Scale (UMNB) were obtained from patients with ALS. Diffusion tensor imaging (DTI) analyses including tract-based spatial statistics and tractography were applied. DTI metrics including fractional anisotropy (FA) and diffusivities (mean, axial, and radial) were measured in regions of interest. Cortical thickness was assessed using surface-based analysis. The locations of structural changes, measured by DTI and the areas of cortical thinning, were compared to regional glial activation measured by relative [C-11]-PBR28 uptake. Results: In this cohort of individuals with ALS, reduced FA and cortical thinning colocalized with regions demonstrating higher radioligand binding. [C-11]-PBR28 binding in the left motor cortex was correlated with FA (r=-0.68, p < 0.05) and cortical thickness (r=-0.75, p < 0.05). UMNB was correlated with glial activation (r=+0.75, p < 0.05), FA (r=-20.77, p, 0.05), and cortical thickness (r = -0.75, p < 0.05) in the motor cortex. Conclusions: Increased uptake of the glial marker [C-11]-PBR28 colocalizes with changes in FA and cortical thinning. This suggests a link between disease mechanisms (gliosis and inflammation) and structural changes (cortical thinning and white and gray matter changes). In this multimodal neuroimaging work, we provide an in vivo model to investigate the pathogenesis of ALS. C1 [Alshikho, Mohamad J.; Zurcher, Nicole R.; Loggia, Marco L.; Chonde, Daniel B.; Garcia, David Izquierdo; Catana, Ciprian; Rosen, Bruce R.; Hooker, Jacob M.] Harvard Med Sch, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Alshikho, Mohamad J.; Cernasov, Paul; Yasek, Julia E.; Cudkowicz, Merit E.; Atassi, Nazem] Harvard Med Sch, Massachusetts Gen Hosp, Neurol Clin Res Inst, Dept Neurol, Charlestown, MA 02129 USA. [Akeju, Oluwaseun] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesiol, Charlestown, MA USA. RP Hooker, JM (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA.; Atassi, N (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Neurol Clin Res Inst, Dept Neurol, Charlestown, MA 02129 USA. EM hooker@nmr.mgh.harvard.edu; natassi@mgh.harvard.edu FU Harvard NeuroDiscovery Center; NINDS [1K23NS083715-01A1] FX Funded by a grant from the Harvard NeuroDiscovery Center (PI: Dr. Atassi) and 1K23NS083715-01A1 grant from NINDS (PI: Dr. Atassi). NR 39 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD DEC 13 PY 2016 VL 87 IS 24 BP 2554 EP 2561 DI 10.1212/WNL.0000000000003427 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EI1NN UT WOS:000392244200015 PM 27837005 ER PT J AU Winkelman, JW Armstrong, MJ Allen, RP Chaudhuri, KR Ondo, W Trenkwalder, C Zee, PC Gronseth, GS Gloss, D Zesiewicz, T AF Winkelman, John W. Armstrong, Melissa J. Allen, Richard P. Chaudhuri, K. Ray Ondo, William Trenkwalder, Claudia Zee, Phyllis C. Gronseth, Gary S. Gloss, David Zesiewicz, Theresa TI Practice guideline summary: Treatment of restless legs syndrome in adults Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology SO NEUROLOGY LA English DT Article ID PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; PARALLEL-GROUP; CROSSOVER TRIAL; SYNDROME RLS; L-DOPA; PRAMIPEXOLE; EFFICACY; SLEEP; ROPINIROLE AB Objective: To make evidence-based recommendations regarding restless legs syndrome (RLS) management in adults. Methods: Articles were classified per the 2004 American Academy of Neurology evidence rating scheme. Recommendations were tied to evidence strength. Results and recommendations: In moderate to severe primary RLS, clinicians should consider prescribing medication to reduce RLS symptoms. Strong evidence supports pramipexole, rotigotine, cabergoline, and gabapentin enacarbil use (Level A); moderate evidence supports ropinirole, pregabalin, and IV ferric carboxymaltose use (Level B). Clinicians may consider prescribing levodopa (Level C). Few head-to-head comparisons exist to suggest agents preferentially. Cabergoline is rarely used (cardiac valvulopathy risks). Augmentation risks with dopaminergic agents should be considered. When treating periodic limb movements of sleep, clinicians should consider prescribing ropinirole (Level A) or pramipexole, rotigotine, cabergoline, or pregabalin (Level B). For subjective sleep measures, clinicians should consider prescribing cabergoline or gabapentin enacarbil (Level A), or ropinirole, pramipexole, rotigotine, or pregabalin (Level B). For patients failing other treatments for RLS symptoms, clinicians may consider prescribing prolonged-release oxycodone/naloxone where available (Level C). In patients with RLS with ferritin <= 75 mu g/L, clinicians should consider prescribing ferrous sulfate with vitamin C (Level B). When nonpharmacologic approaches are desired, clinicians should consider prescribing pneumatic compression (Level B) and may consider prescribing near-infrared spectroscopy or transcranial magnetic stimulation (Level C). Clinicians may consider prescribing vibrating pads to improve subjective sleep (Level C). In patients on hemodialysis with secondary RLS, clinicians should consider prescribing vitamin C and E supplementation (Level B) and may consider prescribing ropinirole, levodopa, or exercise (Level C). C1 [Winkelman, John W.] Harvard Med Sch, Boston, MA 02115 USA. [Winkelman, John W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Armstrong, Melissa J.] Univ Florida, Coll Med, Dept Neurol, Gainesville, FL 32611 USA. [Allen, Richard P.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Chaudhuri, K. Ray] Kings Coll London, London, England. [Chaudhuri, K. Ray] Kings Coll Hosp London, London, England. [Ondo, William] Methodist Neurol Inst, Houston, TX USA. [Trenkwalder, Claudia] Univ Med Ctr, Dept Neurol, Gottingen, Germany. [Zee, Phyllis C.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Gronseth, Gary S.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Gloss, David] CAMC, Neurol Sect, Charleston, WV USA. [Zesiewicz, Theresa] Univ S Florida, Dept Neurol, James A Haley Vet Adm Hosp, Tampa, FL USA. RP Winkelman, JW (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Winkelman, JW (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. FU American Academy of Neurology FX This guideline was developed with financial support from the American Academy of Neurology. Authors who serve or served as AAN subcommittee members or methodologists (M.J.A., G.S.G., D.G., T.Z.) were reimbursed by the AAN for expenses related to travel to subcommittee meetings where drafts of manuscripts were reviewed. NR 40 TC 1 Z9 1 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD DEC 13 PY 2016 VL 87 IS 24 BP 2585 EP 2593 DI 10.1212/WNL.0000000000003388 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA EI1NN UT WOS:000392244200019 PM 27856776 ER PT J AU Jeffries, CD Perkins, DO Chandler, SD Stark, T Yeo, E Addington, J Bearden, CE Cadenhead, KS Cannon, TD Cornblatt, BA Mathalon, DH McGlashan, TH Seidman, LJ Walker, EF Woods, SW Glatt, SJ Tsuang, M AF Jeffries, C. D. Perkins, D. O. Chandler, S. D. Stark, T. Yeo, E. Addington, J. Bearden, C. E. Cadenhead, K. S. Cannon, T. D. Cornblatt, B. A. Mathalon, D. H. McGlashan, T. H. Seidman, L. J. Walker, E. F. Woods, S. W. Glatt, S. J. Tsuang, M. TI Insights into psychosis risk from leukocyte microRNA expression SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID SCHIZOPHRENIA-PATIENTS; TARGET RECOGNITION; GENE-EXPRESSION; IMMUNE-SYSTEM; FOLLOW-UP; BLOOD; METAANALYSIS; CELLS; BRAIN; NEUROGENESIS AB Dysregulation of immune system functions has been implicated in schizophrenia, suggesting that immune cells may be involved in the development of the disorder. With the goal of a biomarker assay for psychosis risk, we performed small RNA sequencing on RNA isolated from circulating immune cells. We compared baseline microRNA (miRNA) expression for persons who were unaffected (n = 27) or who, over a subsequent 2-year period, were at clinical high risk but did not progress to psychosis (n = 37), or were at high risk and did progress to psychosis (n = 30). A greedy algorithm process led to selection of five miRNAs that when summed with +/- 1 weights distinguished progressed from nonprogressed subjects with an area under the receiver operating characteristic curve of 0.86. Of the five, miR-941 is human-specific with incompletely understood functions, but the other four are prominent in multiple immune system pathways. Three of those four are downregulated in progressed vs. nonprogressed subjects (with weight -1 in a classifier function that increases with risk); all three have also been independently reported as downregulated in monocytes from schizophrenia patients vs. unaffected subjects. Importantly, these findings passed stringent randomization tests that minimized the risk of conclusions arising by chance. Regarding miRNA-miRNA correlations over the three groups, progressed subjects were found to have much weaker miRNA orchestration than nonprogressed or unaffected subjects. If independently verified, the leukocytic miRNA biomarker assay might improve accuracy of psychosis high-risk assessments and eventually help rationalize preventative intervention decisions. C1 [Jeffries, C. D.] Univ N Carolina, Renaissance Comp Inst, Chapel Hill, NC 27517 USA. [Perkins, D. O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Chandler, S. D.; Tsuang, M.] Univ Calif San Diego, Dept Psychiat, Ctr Behav Genom, San Diego, CA 92103 USA. [Chandler, S. D.; Tsuang, M.] Univ Calif San Diego, Inst Genom Med, San Diego, CA 92103 USA. [Stark, T.] Univ Calif San Diego, Div Biol Sci, San Diego, CA 92103 USA. [Yeo, E.] Univ Calif San Diego, Dept Cellular & Mol Med, San Diego, CA 92103 USA. [Addington, J.] Univ Calgary, Hotchkiss Brain Inst, Dept Psychiat, Calgary, AB, Canada. [Bearden, C. E.] Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Los Angeles, CA USA. [Bearden, C. E.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA. [Cadenhead, K. S.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Cannon, T. D.] Yale Univ, Dept Psychol, New Haven, CT USA. [Cannon, T. D.; McGlashan, T. H.; Woods, S. W.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Cornblatt, B. A.] Zucker Hillside Hosp, Dept Psychiat, Glen Oaks, NY USA. [Mathalon, D. H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Seidman, L. J.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Psychiat, Boston, MA USA. [Seidman, L. J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Walker, E. F.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Walker, E. F.] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Glatt, S. J.] SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, Syracuse, NY 13210 USA. RP Jeffries, CD (reprint author), Univ N Carolina, Renaissance Comp Inst, Chapel Hill, NC 27517 USA. EM clark_jeffries@med.unc.edu FU International Mental Health Research Organization (IMHRO); Gerber Foundation; Sidney R. Baer, Jr Foundation; NARSAD: The Brain and Behavioral Research Foundation [5R01MH085521-03]; NIH [P30 DK34987]; [U01MH082004]; [U01MH081984]; [P50MH066286]; [U01MH081944]; [U01MH081902]; [U01MH081857]; [R01MH076989]; [U01MH081928]; [U01MH081988]; [U01MH82022] FX This study was supported by U01MH082004 (CDJ), U01MH082004 (DOP), U01MH081984 (JA), P50MH066286 (CEB), U01MH081944 (KSC), U01MH081902 (TDC), U01MH081857 (BAC), R01MH076989 (DHM), U01MH081928 (LJS), U01MH081988 (EFW), U01MH82022 (SWW). Additional support was provided by a gift to the UCLA Foundation from the International Mental Health Research Organization (IMHRO) (MT). NAPLS authors were also supported by a gift to the UCLA Foundation from the International Mental Health Research Organization (IMHRO). Sarah McCoy provided technical assistance in miRNA library preparation. SJG was supported by the Gerber Foundation, the Sidney R. Baer, Jr Foundation, NARSAD: The Brain and Behavioral Research Foundation and 5R01MH085521-03. HT-PCR assays were conducted at UNC at CGIBD Advanced Analytics Core by Carlton Anderson, supported by NIH grant P30 DK34987. Stephanie Lane created the R programs for CALF now available at https://cran.r-project.org/web/packages/CALF/index.html. NR 58 TC 0 Z9 0 U1 2 U2 2 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 DEC 13 PY 2016 VL 6 AR e981 DI 10.1038/tp.2016.148 PG 8 WC Psychiatry SC Psychiatry GA EI0BV UT WOS:000392137600005 PM 27959328 ER PT J AU Schneider, BP Lai, DB Shen, F Jiang, GL Radovich, M Li, L Gardner, L Miller, KD O'Neill, A Sparano, JA Xue, G Foroud, T Sledge, GW AF Schneider, Bryan P. Lai, Dongbing Shen, Fei Jiang, Guanglong Radovich, Milan Li, Lang Gardner, Laura Miller, Kathy D. O'Neill, Anne Sparano, Joseph A. Xue, Gloria Foroud, Tatiana Sledge, George W., Jr. TI Charcot-Marie-Tooth gene, SBF2, associated with taxane-induced peripheral neuropathy in African Americans SO ONCOTARGET LA English DT Article DE whole exome sequencing; African American; paclitaxel; peripheral neuropathy; SBF2 ID GENOME-WIDE ASSOCIATION; BREAST-CANCER PATIENTS; SENSORY NEUROPATHY; PACLITAXEL; CHEMOTHERAPY; VARIANTS; NEUROTOXICITY; POLYMORPHISMS; ECOG-5103 AB Purpose: Taxane-induced peripheral neuropathy (TIPN) is one of the most important survivorship issues for cancer patients. African Americans (AA) have previously been shown to have an increased risk for this toxicity. Germline predictive biomarkers were evaluated to help identify a priori which patients might be at extraordinarily high risk for this toxicity. Experimental design: Whole exome sequencing was performed using germline DNA from 213 AA patients who received a standard dose and schedule of paclitaxel in the adjuvant, randomized phase III breast cancer trial, E5103. Cases were defined as those with either grade 3-4 (n=64) or grade 2-4 (n=151) TIPN and were compared to controls (n=62) that were not reported to have experienced TIPN. We retained for analysis rare variants with a minor allele frequency < 3% and which were predicted to be deleterious by protein prediction programs. A gene-based, case-control analysis using SKAT was performed to identify genes that harbored an imbalance of deleterious variants associated with increased risk of TIPN. Results: Five genes had a p-value < 10(-4) for grade 3-4 TIPN analysis and three genes had a p-value < 10-4 for the grade 2-4 TIPN analysis. For the grade 3-4 TIPN analysis, SET binding factor 2 (SBF2) was significantly associated with TIPN (p-value=4.35 x10(-6)). Five variants were predicted to be deleterious in SBF2. Inherited mutations in SBF2 have previously been associated with autosomal recessive, Type 4B2 Charcot-Marie-Tooth (CMT) disease. Conclusion: Rare variants in SBF2, a CMT gene, predict an increased risk of TIPN in AA patients receiving paclitaxel. C1 [Schneider, Bryan P.; Lai, Dongbing; Shen, Fei; Jiang, Guanglong; Radovich, Milan; Li, Lang; Gardner, Laura; Miller, Kathy D.; Xue, Gloria; Foroud, Tatiana] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [O'Neill, Anne] Dana Farber Canc Inst, ECOG ACRIN Biostat Ctr, Boston, MA 02115 USA. [Sparano, Joseph A.] Albert Einstein Univ, Montefiore Med Ctr, Bronx, NY USA. [Sledge, George W., Jr.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. RP Schneider, BP (reprint author), Indiana Univ Sch Med, Indianapolis, IN 46202 USA. EM bpschnei@iupui.edu FU ECOG-ACRIN Cancer Research Group; Public Health Service Grants [CA180820, CA180794, CA21115, CA23318, CA66636, CA180795, CA49883, CA189859, CA14958, CA180816]; Susan G. Komen for the Cure FX This study was conducted by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported in part by Public Health Service Grants CA180820, CA180794, CA21115, CA23318, CA66636, CA180795, CA49883, CA189859, CA14958, CA180816, Susan G. Komen for the Cure (BP Schneider). Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. NR 31 TC 0 Z9 0 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD DEC 13 PY 2016 VL 7 IS 50 BP 82244 EP 82253 DI 10.18632/oncotarget.12545 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EG9BQ UT WOS:000391352800025 PM 27732968 ER PT J AU Bibi, S Zhang, YY Hugonin, C Mangean, MD He, L Wedeh, G Launay, JM Van Rijn, S Wurdinger, T Louache, F Arock, M AF Bibi, Siham Zhang, Yanyan Hugonin, Caroline Mangean, Mallorie Depond He, Liang Wedeh, Ghaith Launay, Jean-Marie Van Rijn, Sjoerd Wurdinger, Thomas Louache, Fawzia Arock, Michel TI A new humanized in vivo model of KIT D816V(+) advanced systemic mastocytosis monitored using a secreted luciferase SO ONCOTARGET LA English DT Article DE KIT D816V mutant; ROSA(KIT D816V) cell line; gluc reporter; NSG mice; advanced systemic mastocytosis ID MAST-CELL LEUKEMIA; DIAGNOSTIC-CRITERIA; C-KIT; CONSENSUS PROPOSAL; PERIPHERAL-BLOOD; MYELOID-LEUKEMIA; PROGENITOR CELLS; CLASSIFICATION; MUTATION; TRYPTASE AB Systemic mastocytosis are rare neoplasms characterized by accumulation of mast cells in at least one internal organ. The majority of systemic mastocytosis patients carry KIT D816V mutation, which activates constitutively the KIT receptor. Patient with advanced forms of systemic mastocytosis, such as aggressive systemic mastocytosis or mast cell leukemia, are poorly treated to date. Unfortunately, the lack of in vivo models reflecting KIT D816V+ advanced disease hampers pathophysiological studies and preclinical development of new therapies for such patients. Here, we describe a new in vivo model of KIT D816V(+) advanced systemic mastocytosis developed by transplantation of the human ROSAKIT D816V-Gluc mast cell line in NOD-SCID IL-2R g(-/-) mice, using Gaussia princeps luciferase as a reporter. Intravenous injection of ROSA(KIT D816V-Gluc) cells led, in 4 weeks, to engraftment in all injected primary recipient mice. Engrafted cells were found at high levels in bone marrow, and at lower levels in spleen, liver and peripheral blood. Disease progression was easily monitored by repeated quantification of Gaussia princeps luciferase activity in peripheral blood. This quantification evidenced a linear relationship between the number of cells injected and the neoplastic mast cell burden in mice. Interestingly, the secondary transplantation of ROSA(KIT D816V-Gluc) cells increased their engraftment capability. To conclude, this new in vivo model mimics at the best the features of human KIT D816V(+) advanced systemic mastocytosis. In addition, it is a unique and convenient tool to study the kinetics of the disease and the potential in vivo activity of new drugs targeting neoplastic mast cells. C1 [Bibi, Siham; Hugonin, Caroline; Wedeh, Ghaith; Arock, Michel] Ecole Normale Super, CNRS, Mol & Cellular Oncol Res Grp, LBPA,UMR 8113, Cachan, France. [Zhang, Yanyan; Mangean, Mallorie Depond; He, Liang; Louache, Fawzia] Univ Paris Sud Villejuif, INSERM, Unit U1170, Hematopoiese Normale & Pathol, Gustave Roussy Campus, Orsay, France. [Launay, Jean-Marie] Univ Paris Diderot Paris VII Paris, Hop Lariboisiere, AP HP, INSERM,Lab Biochim & Biol Mol,U942, Paris, France. [Van Rijn, Sjoerd; Wurdinger, Thomas] Vrije Univ Amsterdam, Med Ctr, Canc Ctr Amsterdam, Neurooncol Res Grp,Dept Neurosurg, Amsterdam, Netherlands. [Wurdinger, Thomas] Harvard Med Sch, Massachussetts Gen Hosp, Dept Neurol, Ctr Neurosci, Boston, MA USA. [Wurdinger, Thomas] Harvard Med Sch, Neurosci Program, Boston, MA USA. [Arock, Michel] Univ Pierre & Marie Curie UPMC Paris VI, Grp Hosp Pitie Salpetriere, AP HP, Cent Hematol Lab, Paris, France. RP Bibi, S (reprint author), Ecole Normale Super, CNRS, Mol & Cellular Oncol Res Grp, LBPA,UMR 8113, Cachan, France. EM sbibi@ens-cachan.fr FU Deciphera Pharmaceuticals, LLC.; French Society of Hematology (SFH) FX This study was supported in part by Deciphera Pharmaceuticals, LLC. SB received a Ph D grant from the French Society of Hematology (SFH). NR 44 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD DEC 13 PY 2016 VL 7 IS 50 BP 82985 EP 83000 DI 10.18632/oncotarget.12824 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EG9BQ UT WOS:000391352800085 PM 27783996 ER PT J AU Liu, T Li, ZH Zhang, Q Bernstein, KD Lozano-Calderon, S Choy, E Hornicek, FJ Duan, ZF AF Liu, Tang Li, Zhihong Zhang, Qing Bernstein, Karen De Amorim Lozano-Calderon, Santiago Choy, Edwin Hornicek, Francis J. Duan, Zhenfeng TI Targeting ABCB1 (MDR1) in multi-drug resistant osteosarcoma cells using the CRISPR-Cas9 system to reverse drug resistance SO ONCOTARGET LA English DT Article DE osteosarcoma; CRISPR-Cas9; meta-analysis; ABCB1; P-glycoprotein ID HIGH-GRADE OSTEOSARCOMA; P-GLYCOPROTEIN; GENE-EXPRESSION; PRIMARY TUMOR; METAANALYSIS; CHEMOTHERAPY; CANCER; RNA; NSC23925; P53 AB Background: Multi-drug resistance (MDR) remains a significant obstacle to successful chemotherapy treatment for osteosarcoma patients. One of the central causes of MDR is the overexpression of the membrane bound drug transporter protein P-glycoprotein (P-gp), which is the protein product of the MDR gene ABCB1. Though several methods have been reported to reverse MDR in vitro and in vivo when combined with anticancer drugs, they have yet to be proven useful in the clinical setting. Results: The meta-analysis demonstrated that a high level of P-gp may predict poor survival in patients with osteosarcoma. The expression of P-gp can be efficiently blocked by the clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas9 system (CRISPR-Cas9). Inhibition of ABCB1 was associated with reversing drug resistance in osteosarcoma MDR cell lines (KHOSR2 and U-2OSR2) to doxorubicin. Materials and Methods: We performed a meta-analysis to investigate the relationship between P-gp expression and survival in patients with osteosarcoma. Then we adopted the CRISPR-Cas9, a robust and highly efficient novel genome editing tool, to determine its effect on reversing drug resistance by targeting endogenous ABCB1 gene at the DNA level in osteosarcoma MDR cell lines. Conclusion: These results suggest that the CRISPR-Cas9 system is a useful tool for the modification of ABCB1 gene, and may be useful in extending the long-term efficacy of chemotherapy by overcoming P-gp-mediated MDR in the clinical setting. C1 [Liu, Tang; Li, Zhihong; Zhang, Qing] Cent S Univ, Xiangya Hosp 2, Dept Orthopaed, Changsha 410011, Hunan, Peoples R China. [Liu, Tang; Bernstein, Karen De Amorim; Lozano-Calderon, Santiago; Choy, Edwin; Hornicek, Francis J.; Duan, Zhenfeng] Massachusetts Gen Hosp, Dept Orthopaed Surg, Sarcoma Biol Lab, Boston, MA 02114 USA. [Liu, Tang; Bernstein, Karen De Amorim; Lozano-Calderon, Santiago; Choy, Edwin; Hornicek, Francis J.; Duan, Zhenfeng] Harvard Med Sch, Boston, MA 02114 USA. RP Liu, T (reprint author), Cent S Univ, Xiangya Hosp 2, Dept Orthopaed, Changsha 410011, Hunan, Peoples R China.; Liu, T; Duan, ZF (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Sarcoma Biol Lab, Boston, MA 02114 USA.; Liu, T; Duan, ZF (reprint author), Harvard Med Sch, Boston, MA 02114 USA. EM liutang1204@csu.edu.cn; zduan@mgh.harvard.edu FU Gattegno and Wechsler funds; Kenneth Stanton Fund; Jennifer Hunter Yates Foundation; Sarcoma Foundation of America (SFA); National Cancer Institute (NCI)/National Institutes of Health (NIH) [UO1, CA 151452-01]; Sarcoma SPORE/NIH; Academic Enrichment Fund of MGH Orthopaedics; Chinese Scholarship Council FX This work was supported, in part, by the Gattegno and Wechsler funds, the Kenneth Stanton Fund, and the Jennifer Hunter Yates Foundation. Dr. Duan is supported, in part, through a grant from Sarcoma Foundation of America (SFA), a grant from National Cancer Institute (NCI)/National Institutes of Health (NIH), UO1, CA 151452-01, a pilot grant from Sarcoma SPORE/NIH, and a grant from an Academic Enrichment Fund of MGH Orthopaedics. Dr. Liu is supported by a scholarship from the Chinese Scholarship Council. NR 44 TC 0 Z9 0 U1 4 U2 4 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD DEC 13 PY 2016 VL 7 IS 50 BP 83502 EP 83513 DI 10.18632/oncotarget.13148 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EG9BQ UT WOS:000391352800124 PM 27835872 ER PT J AU Sheffrin, M Cenzer, IS Steinman, MA AF Sheffrin, Meera Cenzer, Irena Stijacic Steinman, Michael A. TI Desire for predictive testing for Alzheimer's disease and impact on advance care planning: a cross-sectional study SO ALZHEIMERS RESEARCH & THERAPY LA English DT Article DE Alzheimer's disease; Advance care planning; Attitudes and knowledge; Predictive testing ID PUBLIC-ATTITUDES; OLDER-ADULTS; RISK; PREVALENCE; DIRECTIVES; BEHAVIOR AB Background: It is unknown whether older adults in the United States would be willing to take a test predictive of future Alzheimer's disease, or whether testing would change behavior. Using a nationally representative sample, we explored who would take a free and definitive test predictive of Alzheimer's disease, and examined how using such a test may impact advance care planning. Methods: A cross-sectional study within the 2012 Health and Retirement Study of adults aged 65 years or older asked questions about a test predictive of Alzheimer's disease (N = 874). Subjects were asked whether they would want to take a hypothetical free and definitive test predictive of future Alzheimer's disease. Then, imagining they knew they would develop Alzheimer's disease, subjects rated the chance of completing advance care planning activities from 0 to 100. We classified a score > 50 as being likely to complete that activity. We evaluated characteristics associated with willingness to take a test for Alzheimer's disease, and how such a test would impact completing an advance directive and discussing health plans with loved ones. Results: Overall, 75% (N = 648) of the sample would take a free and definitive test predictive of Alzheimer's disease. Older adults willing to take the test had similar race and educational levels to those who would not, but were more likely to be <= 75 years old (odds ratio 0.71 (95% CI 0.53-0.94)). Imagining they knew they would develop Alzheimer's, 81% would be likely to complete an advance directive, although only 15% had done so already. Conclusions: In this nationally representative sample, 75% of older adults would take a free and definitive test predictive of Alzheimer's disease. Many participants expressed intent to increase activities of advance care planning with this knowledge. This confirms high public interest in predictive testing for Alzheimer's disease and suggests this may be an opportunity to engage patients in advance care planning discussions. C1 [Sheffrin, Meera] Stanford Univ, Sch Med, Div Gen Internal Med Disciplines, Geriatr Med Sect, Stanford, CA USA. [Cenzer, Irena Stijacic; Steinman, Michael A.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. [Cenzer, Irena Stijacic; Steinman, Michael A.] San Francisco VA Med Ctr, 4150 Clement St,Box 181-G, San Francisco, CA 94121 USA. RP Sheffrin, M (reprint author), Stanford Univ, Sch Med, Div Gen Internal Med Disciplines, Geriatr Med Sect, Stanford, CA USA. EM sheffrin@stanford.edu FU National Institute on Aging; American Federation on Aging Research [T32 AG000212-21, K23-AG030999, K24: K24AG049057, RC1-AG036377]; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development, VA Information Resource Center [SDR 02-237, 98-004] FX This work was supported by grant funding from the National Institute on Aging and the American Federation on Aging Research (T32 AG000212-21, K23-AG030999, K24: K24AG049057, and RC1-AG036377). Support for VA/CMS data is provided by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development, VA Information Resource Center (Project Numbers SDR 02-237 and 98-004). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. NR 17 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-9193 J9 ALZHEIMERS RES THER JI Alzheimers Res. Ther. PD DEC 13 PY 2016 VL 8 AR 55 DI 10.1186/s13195-016-0223-9 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EG9XK UT WOS:000391413500001 PM 27955707 ER PT J AU Graham, DB Lefkovith, A Deelen, P de Klein, N Varma, M Boroughs, A Desch, AN Ng, ACY Guzman, G Schenone, M Petersen, CP Bhan, AK Rivas, MA Daly, MJ Carr, SA Wijmenga, C Xavier, RJ AF Graham, Daniel B. Lefkovith, Ariel Deelen, Patrick de Klein, Niek Varma, Mukund Boroughs, Angela Desch, A. Nicole Ng, Aylwin C. Y. Guzman, Gaelen Schenone, Monica Petersen, Christine P. Bhan, Atul K. Rivas, Manuel A. Daly, Mark J. Carr, Steven A. Wijmenga, Cisca Xavier, Ramnik J. TI TMEM258 Is a Component of the Oligosaccharyltransferase Complex Controlling ER Stress and Intestinal Inflammation SO CELL REPORTS LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; POLYUNSATURATED FATTY-ACIDS; CORONARY-ARTERY-DISEASE; BOWEL-DISEASE; CROHNS-DISEASE; GENETIC RISK; ASSOCIATION; CELLS; TRANSCRIPTOME; SUSCEPTIBILITY AB Significant insights into disease pathogenesis have been gleaned from population-level genetic studies; however, many loci associated with complex genetic disease contain numerous genes, and phenotypic associations cannot be assigned unequivocally. In particular, a gene-dense locus on chromosome 11 (61.5-61.65 Mb) has been associated with inflammatory bowel disease, rheumatoid arthritis, and coronary artery disease. Here, we identify TMEM258 within this locus as a central regulator of intestinal inflammation. Strikingly, Tmem258 haploinsufficient mice exhibit severe intestinal inflammation in a model of colitis. At the mechanistic level, we demonstrate that TMEM258 is a required component of the oligosaccharyltransferase complex and is essential for N-linked protein glycosylation. Consequently, homozygous deficiency of Tmem258 in colonic organoids results in unresolved endoplasmic reticulum ( ER) stress culminating in apoptosis. Collectively, our results demonstrate that TMEM258 is a central mediator of ER quality control and intestinal homeostasis. C1 [Graham, Daniel B.; Lefkovith, Ariel; Varma, Mukund; Desch, A. Nicole; Guzman, Gaelen; Schenone, Monica; Petersen, Christine P.; Rivas, Manuel A.; Daly, Mark J.; Carr, Steven A.; Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Graham, Daniel B.; Xavier, Ramnik J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Graham, Daniel B.; Ng, Aylwin C. Y.; Xavier, Ramnik J.] Harvard Med Sch, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Graham, Daniel B.; Ng, Aylwin C. Y.; Bhan, Atul K.; Xavier, Ramnik J.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Deelen, Patrick; de Klein, Niek; Wijmenga, Cisca] Univ Groningen, Univ Med Ctr Groningen, Genom Coordinat Ctr, Dept Genet, NL-9713 EX Groningen, Netherlands. [Boroughs, Angela; Xavier, Ramnik J.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Bhan, Atul K.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Xavier, Ramnik J.] MIT, Ctr Microbiome Informat & Therapeut, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Graham, DB; Xavier, RJ (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Graham, DB; Xavier, RJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Graham, DB; Xavier, RJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA.; Graham, DB; Xavier, RJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA.; Xavier, RJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA.; Xavier, RJ (reprint author), MIT, Ctr Microbiome Informat & Therapeut, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM dgraham@broadinstitute.org; xavier@molbio.mgh.harvard.edu FU Leona M. and Harry B. Helmsley Charitable Trust [2014PG-IBD016]; Crohn's and Colitis Foundation of America; National Institutes of Health [DK043351, DK097485] FX This work was supported by funding from The Leona M. and Harry B. Helmsley Charitable Trust (2014PG-IBD016), the Crohn's and Colitis Foundation of America, and National Institutes of Health grants DK043351 and DK097485 to R.J.X. We thank Richard Cummings, Isabel Latorre, Elizabeth Creasey, Natalia Nedelsky, and Bihua Li for scientific input and technical expertise. NR 39 TC 0 Z9 0 U1 4 U2 4 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 DEC 13 PY 2016 VL 17 IS 11 BP 2955 EP 2965 DI 10.1016/j.celrep.2016.11.042 PG 11 WC Cell Biology SC Cell Biology GA EG2SP UT WOS:000390894700016 PM 27974209 ER PT J AU Shishehbor, MH Jaff, MR AF Shishehbor, Mehdi H. Jaff, Michael R. TI Percutaneous Therapies for Peripheral Artery Disease SO CIRCULATION LA English DT Article DE critical limb ischemia; endovascular therapy; limb salvage; peripheral artery disease; vascular diseases ID CRITICAL LIMB ISCHEMIA; SUPERFICIAL FEMORAL-ARTERY; AORTOILIAC OCCLUSIVE DISEASE; PACLITAXEL-COATED BALLOON; RANDOMIZED CLINICAL-TRIAL; SIROLIMUS-ELUTING STENTS; INTER-SOCIETY CONSENSUS; BARE-METAL STENTS; OF-INTERVENTIONAL-RADIOLOGY; FEMOROPOPLITEAL ARTERY C1 [Shishehbor, Mehdi H.] Cleveland Clin, Inst Heart & Vasc, Cleveland, OH 44106 USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Fireman Vasc Ctr, Boston, MA 02114 USA. RP Jaff, MR (reprint author), Harvard Med Sch, Newton Wellesley Hosp, Med, 2014 Washington St,Suite 41200, Newton, MA 02462 USA. EM mjaff@partners.org NR 132 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD DEC 13 PY 2016 VL 134 IS 24 BP 2008 EP 2027 DI 10.1161/CIRCULATIONAHA.116.022546 PG 20 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF8DI UT WOS:000390558300012 PM 27956404 ER PT J AU Lessing, D Dial, TO Wei, CY Payer, B Carrette, LLG Kesner, B Szanto, A Jadhav, A Maloney, DJ Simeonov, A Theriault, J Hasaka, T Bedalov, A Bartolomei, MS Lee, JT AF Lessing, Derek Dial, Thomas O. Wei, Chunyao Payer, Bernhard Carrette, Lieselot L. G. Kesner, Barry Szanto, Attila Jadhav, Ajit Maloney, David J. Simeonov, Anton Theriault, Jimmy Hasaka, Thomas Bedalov, Antonio Bartolomei, Marisa S. Lee, Jeannie T. TI A high-throughput small molecule screen identifies synergism between DNA methylation and Aurora kinase pathways for X reactivation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE X reactivation; high-throughput screen; small molecules; Aurora kinase; DNA methyltransferase ID EARLY MOUSE EMBRYOS; CHROMOSOME INACTIVATION; INHIBITOR SELECTIVITY; DOSAGE COMPENSATION; XIST RNA; TSIX RNA; IN-VIVO; CELLS; GENE; DIFFERENTIATION AB X-chromosome inactivation is a mechanism of dosage compensation in which one of the two X chromosomes in female mammals is transcriptionally silenced. Once established, silencing of the inactive X (Xi) is robust and difficult to reverse pharmacologically. However, the Xi is a reservoir of > 1,000 functional genes that could be potentially tapped to treat X-linked disease. To identify compounds that could reactivate the Xi, here we screened similar to 367,000 small molecules in an automated high-content screen using an Xi-linked GFP reporter in mouse fibroblasts. Given the robust nature of silencing, we sensitized the screen by "priming" cells with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5azadC). Compounds that elicited GFP activity include VX680, MLN8237, and 5azadC, which are known to target the Aurora kinase and DNA methylation pathways. We demonstrate that the combinations of VX680 and 5azadC, as well as MLN8237 and 5azadC, synergistically up-regulate genes on the Xi. Thus, our work identifies a synergism between the DNA methylation and Aurora kinase pathways as being one of interest for possible pharmacological reactivation of the Xi. C1 [Lessing, Derek; Dial, Thomas O.; Wei, Chunyao; Carrette, Lieselot L. G.; Kesner, Barry; Szanto, Attila; Lee, Jeannie T.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Lessing, Derek; Dial, Thomas O.; Wei, Chunyao; Carrette, Lieselot L. G.; Kesner, Barry; Szanto, Attila; Lee, Jeannie T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Lessing, Derek; Dial, Thomas O.; Wei, Chunyao; Carrette, Lieselot L. G.; Kesner, Barry; Szanto, Attila; Lee, Jeannie T.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Payer, Bernhard] Ctr Genom Regulat, Barcelona 08003, Spain. [Carrette, Lieselot L. G.] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium. [Jadhav, Ajit; Maloney, David J.; Simeonov, Anton] Natl Ctr Adv Translat Sci, Div Preclin Innovat, NIH, Rockville, MD 20850 USA. [Theriault, Jimmy; Hasaka, Thomas] Broad Inst, Cambridge, MA 02142 USA. [Bedalov, Antonio] Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA 98109 USA. [Bartolomei, Marisa S.] Univ Penn, Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. RP Lee, JT (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA.; Lee, JT (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Lee, JT (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. EM lee@molbio.mgh.harvard.edu OI Payer, Bernhard/0000-0002-4694-2082 FU Molecular Libraries Program [1 U54 HG005032-01]; Rett Syndrome Research Trust; NIH [R03-MH097478, R01-DA36895]; National Center for Research Resources Grant [1S10RR023440-01]; Human Frontier Science Program; Charles King Postdoctoral Fellowships; Fund for Scientific Research-Flanders; Belgian American Educational Foundation; Plateforme pour l'Education et le Talent; National Center for Advancing Translational Sciences; Molecular Libraries Initiative of the NIH Roadmap for Medical Research [U54MH084681] FX We thank D. Dombkowski for assistance with FACS (Massachusetts General Hospital Pathology Flow Cytometry Core), H. Sunwoo for Xist probes and FISH advice, Y. Jeon for control fibroblasts, P. Shinn and D. van Leer for assistance with compound management, and Stuart L. Schreiber and Nicola Tolliday for support as part of the Molecular Libraries Program (1 U54 HG005032-01). We acknowledge the following funding: the Rett Syndrome Research Trust (J.T.L., M.S.B., and A.B.), NIH Grants R03-MH097478 and R01-DA36895 (to J.T.L.), National Center for Research Resources Grant 1S10RR023440-01, the Human Frontier Science Program (B.P.), Charles King Postdoctoral Fellowships (to B.P.), the Fund for Scientific Research-Flanders, and the Belgian American Educational Foundation and Plateforme pour l'Education et le Talent (L.L.G.C.). A.J., D.J.M., and A. Simeonov were supported by the National Center for Advancing Translational Sciences and the Molecular Libraries Initiative of the NIH Roadmap for Medical Research (U54MH084681). J.T.L. is an Investigator of the Howard Hughes Medical Institute. NR 47 TC 1 Z9 1 U1 8 U2 8 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 DEC 13 PY 2016 VL 113 IS 50 BP 14366 EP 14371 DI 10.1073/pnas.1617597113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE6CQ UT WOS:000389696700063 PM 28182563 ER PT J AU Baskin-Sommers, A Stuppy-Sullivan, AM Buckholtz, JW AF Baskin-Sommers, Arielle Stuppy-Sullivan, Allison M. Buckholtz, Joshua W. TI Psychopathic individuals exhibit but do not avoid regret during counterfactual decision making SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE psychopathy; counterfactual reasoning; affect; decision making; reward ID ORBITOFRONTAL CORTEX; COGNITIVE NEUROSCIENCE; PREFRONTAL CORTEX; COMMUNITY SAMPLE; PERSONALITY; BEHAVIOR; TRAITS; CHOICE; SENSITIVITY; EXPERIENCE AB Psychopathy is associated with persistent antisocial behavior and a striking lack of regret for the consequences of that behavior. Although explanatory models for psychopathy have largely focused on deficits in affective responsiveness, recent work indicates that aberrant value-based decision making may also play a role. On that basis, some have suggested that psychopathic individuals may be unable to effectively use prospective simulations to update action value estimates during cost-benefit decision making. However, the specific mechanisms linking valuation, affective deficits, and maladaptive decision making in psychopathy remain unclear. Using a counterfactual decision-making paradigm, we found that individuals who scored high on a measure of psychopathy were as or more likely than individuals low on psychopathy to report negative affect in response to regret-inducing counterfactual outcomes. However, despite exhibiting intact affective regret sensitivity, they did not use prospective regret signals to guide choice behavior. In turn, diminished behavioral regret sensitivity predicted a higher number of prior incarcerations, and moderated the relationship between psychopathy and incarceration history. These findings raise the possibility that maladaptive decision making in psychopathic individuals is not a consequence of their inability to generate or experience negative emotions. Rather, antisocial behavior in psychopathy may be driven by a deficit in the generation of forward models that integrate information about rules, costs, and goals with stimulus value representations to promote adaptive behavior. C1 [Baskin-Sommers, Arielle; Stuppy-Sullivan, Allison M.] Yale Univ, Dept Psychol, New Haven, CT 06511 USA. [Buckholtz, Joshua W.] Harvard Univ, Dept Psychol, 33 Kirkland St, 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. RP Baskin-Sommers, A (reprint author), Yale Univ, Dept Psychol, New Haven, CT 06511 USA.; Buckholtz, JW (reprint author), Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA.; Buckholtz, JW (reprint author), Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA.; Buckholtz, JW (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM arielle.baskin-sommers@yale.edu; joshuabuckholtz@fas.harvard.edu FU American Psychological Foundation; American Psychology-Law Society; Harry Frank Guggenheim Foundation; Massachusetts General Hospital Center for Law, Brain, and Behavior; Brain and Behavior Research Fund; Alfred P. Sloan Foundation FX We thank Claire Gillan, Samuel Gershman, and Edward Patzelt for insightful discussions. This research was supported in part by grants through the American Psychological Foundation, the American Psychology-Law Society, and the Harry Frank Guggenheim Foundation (to A.B.-S.) and by the Massachusetts General Hospital Center for Law, Brain, and Behavior; the Brain and Behavior Research Fund; and the Alfred P. Sloan Foundation (J.W.B.). NR 54 TC 0 Z9 0 U1 8 U2 8 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 DEC 13 PY 2016 VL 113 IS 50 BP 14438 EP 14443 DI 10.1073/pnas.1609985113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE6CQ UT WOS:000389696700075 PM 27911790 ER PT J AU Woerman, AL Aoyagi, A Patel, S Kazmi, SA Lobach, I Grinberg, LT Mckee, AC Seeley, WW Olson, SH Prusiner, SB AF Woerman, Amanda L. Aoyagi, Atsushi Patel, Smita Kazmi, Sabeen A. Lobach, Iryna Grinberg, Lea T. McKee, Ann C. Seeley, William W. Olson, Steven H. Prusiner, Stanley B. TI Tau prions from Alzheimer's disease and chronic traumatic encephalopathy patients propagate in cultured cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE argyrophilic grain disease; corticobasal degeneration; Pick's disease; progressive supranuclear palsy; tauopathies ID MICROTUBULE-ASSOCIATED PROTEIN; PAIRED HELICAL FILAMENTS; SHARE ANTIGENIC DETERMINANTS; FRONTOTEMPORAL DEMENTIA; TRANSGENIC MICE; NEUROFIBRILLARY TANGLES; PICKS-DISEASE; ABNORMAL PHOSPHORYLATION; BRAIN-INJURY; MOUSE-BRAIN AB Tau prions are thought to aggregate in the central nervous system, resulting in neurodegeneration. Among the tauopathies, Alzheimer's disease (AD) is the most common, whereas argyrophilic grain disease (AGD), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick's disease (PiD), and progressive supranuclear palsy (PSP) are less prevalent. Brain extracts from deceased individuals with PiD, a neurodegenerative disorder characterized by three-repeat (3R) tau prions, were used to infect HEK293T cells expressing 3R tau fused to yellow fluorescent protein (YFP). Extracts from AGD, CBD, and PSP patient samples, which contain four-repeat (4R) tau prions, were transmitted to HEK293T cells expressing 4R tau fused to YFP. These studies demonstrated that prion propagation in HEK cells requires isoform pairing between the infecting prion and the recipient substrate. Interestingly, tau aggregates in AD and CTE, containing both 3R and 4R isoforms, were unable to robustly infect either 3R-or 4R-expressing cells. However, AD and CTE prions were able to replicate in HEK293T cells expressing both 3R and 4R tau. Unexpectedly, increasing the level of 4R isoform expression alone supported the propagation of both AD and CTE prions. These results allowed us to determine the levels of tau prions in AD and CTE brain extracts. C1 [Woerman, Amanda L.; Aoyagi, Atsushi; Patel, Smita; Kazmi, Sabeen A.; Olson, Steven H.; Prusiner, Stanley B.] Univ Calif San Francisco, Inst Neurodegenerat Dis, Weill Inst Neurosci, San Francisco, CA 94143 USA. [Woerman, Amanda L.; Grinberg, Lea T.; Seeley, William W.; Olson, Steven H.; Prusiner, Stanley B.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Aoyagi, Atsushi] Daiichi Sankyo Co Ltd, Tokyo 1408710, Japan. [Lobach, Iryna] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Grinberg, Lea T.; Seeley, William W.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [McKee, Ann C.] Boston Univ, Sch Med, Chron Traumat Encephalopathy Program, Alzheimers Dis Ctr, Boston, MA 02118 USA. [McKee, Ann C.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [McKee, Ann C.] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. [McKee, Ann C.] US Dept Vet Affairs, Vet Affairs Boston Healthcare Syst, Jamaica Plain, MA 02130 USA. [McKee, Ann C.] US Dept Vet Affairs, Med Ctr, Bedford, MA 01730 USA. [Prusiner, Stanley B.] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA. RP Prusiner, SB (reprint author), Univ Calif San Francisco, Inst Neurodegenerat Dis, Weill Inst Neurosci, San Francisco, CA 94143 USA.; Prusiner, SB (reprint author), Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA.; Prusiner, SB (reprint author), Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA. EM stanley.prusiner@ucsf.edu FU NIH [AG002132, AG031220, AG023501, AG19724]; Daiichi Sankyo; Dana Foundation; Glenn Foundation; Sherman Fairchild Foundation; Tau Consortium; Consortium for Frontotemporal Dementia Research; Department of Veterans Affairs, National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering [NS086559]; National Institute on Aging, Boston University Alzheimer's Disease Center [AG13846, 0572063345-5]; Concussion Legacy Foundation; Andlinger Foundation; World Wrestling Entertainment, Inc FX We thank George A. Carlson for his thoughtful revisions and comments, and Brittany N. Dugger for microdissecting the CTE patient samples. This work was supported by NIH Grants AG002132 and AG031220, Daiichi Sankyo, Dana Foundation, Glenn Foundation, Sherman Fairchild Foundation, and a gift from the Rainwater Charitable Foundation. Control, AD, AGD, CBD, PiD, and PSP tissue samples were provided by the University of California, San Francisco, Neurodegenerative Disease Brain Bank, which is supported by NIH Grants AG023501 and AG19724 (to W.W.S.), Tau Consortium, and Consortium for Frontotemporal Dementia Research. CTE tissue samples were provided by the Boston University Alzheimer's Disease Center Chronic Traumatic Encephalopathy Center, which is supported by the Department of Veterans Affairs, National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering (NS086559), National Institute on Aging, Boston University Alzheimer's Disease Center (AG13846; Supplement 0572063345-5), Concussion Legacy Foundation, Andlinger Foundation, and World Wrestling Entertainment, Inc. Additional control samples were provided by the University of Miami Brain Endowment Bank. NR 71 TC 0 Z9 0 U1 14 U2 14 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 DEC 13 PY 2016 VL 113 IS 50 BP E8187 EP E8196 DI 10.1073/pnas.1616344113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE6CQ UT WOS:000389696700022 PM 27911827 ER PT J AU Secemsky, EA Kirtane, A Bangalore, S Jovin, IS Shah, RM Ferro, EG Wimmer, NJ Roe, M Dai, D Mauri, L Yeh, RW AF Secemsky, Eric A. Kirtane, Ajay Bangalore, Sripal Jovin, Ion S. Shah, Rachit M. Ferro, Enrico G. Wimmer, Neil J. Roe, Matthew Dai, Dadi Mauri, Laura Yeh, Robert W. TI Use and Effectiveness of Bivalirudin Versus Unfractionated Heparin for Percutaneous Coronary Intervention Among Patients With ST-Segment Elevation Myocardial Infarction in the United States SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE bivalirudin; bleeding; mortality; percutaneous coronary; intervention; ST-segment elevation; myocardial infarction ID CARDIOVASCULAR DATA REGISTRY; ASSOCIATION TASK-FORCE; PRACTICE GUIDELINES; ELDERLY-PATIENTS; RADIAL ACCESS; PRIMARY PCI; OUTCOMES; FRAILTY; RISK; PREVALENCE AB OBJECTIVES The purpose of this study was to describe temporal trends and determine the comparative effectiveness of bivalirudin versus unfractionated heparin (UFH) during percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). BACKGROUND Several clinical trials have compared the safety and effectiveness of bivalirudin versus UFH during PCI for STEMI, but results have been conflicting. METHODS Trends in anticoagulant use were examined among 513,775 PCIs for STEMI from July 2009 through December 2014 within the National Cardiovascular Data Registry CathPCI Registry. We conducted an instrumental variable analysis comparing bivalirudin with UFH, using operator preference for bivalirudin as the instrument. We used a test of mediation to determine the extent to which differences in outcomes between anticoagulants were due to differences in use of glycoprotein IIb/IIIa inhibitors (GPI). Primary outcomes were in-hospital bleeding and mortality. RESULTS Bivalirudin use increased from 2009 through 2013, followed by a new decline. GPIs were used in 74.7% of UFH PCIs versus 26.5% of bivalirudin PCIs. In unadjusted analyses, bivalirudin was associated with decreased bleeding (risk difference [ RD]: -4.2%; p < 0.001) and mortality (RD: -0.84%; p < 0.001). After instrumental variable analyses, bivalirudin remained associated with less bleeding (RD: -3.75%; p < 0.001), but not mortality (RD: -0.10%; p = 0.280). The higher rate of GPI use with UFH was responsible for more than one-half of bivalrudin's bleeding reduction (GPI-adjusted RD: -1.57%; p < 0.001). Bleeding reductions were negligible for transradial PCI (RD: -0.11%; p = 0.842). CONCLUSIONS The use of bivalirudin during STEMI has decreased. Bivalirudin was associated with reduced bleeding and no mortality difference. The bleeding reduction with bivalirudin was largely explained by the greater use of GPIs with UFH. (J Am Coll Cardiol Intv 2016; 9: 2376-86) (C) 2016 by the American College of Cardiology Foundation. C1 [Secemsky, Eric A.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Secemsky, Eric A.; Ferro, Enrico G.; Mauri, Laura; Yeh, Robert W.] Harvard Med Sch, Boston, MA USA. [Secemsky, Eric A.; Yeh, Robert W.] Beth Israel Deaconess Med Ctr, Dept Med, Smith Ctr Outcomes Res Cardiol, 375 Longwood Ave,MASCO 4, Boston, MA 02215 USA. [Kirtane, Ajay] Columbia Univ, Dept Med, Div Cardiol, New York, NY USA. [Kirtane, Ajay] Columbia Univ, Ctr Intervent Vasc Therapy, New York, NY USA. [Bangalore, Sripal] NYU, Sch Med, Dept Med, Div Cardiol, New York, NY USA. [Jovin, Ion S.; Shah, Rachit M.] Virginia Commonwealth Univ, Dept Med, Div Cardiol, Med Coll Virginia Campus, Richmond, VA 23298 USA. [Wimmer, Neil J.] Christiana Care Hlth Syst, Dept Med, Div Cardiol, Newark, DE USA. [Roe, Matthew; Dai, Dadi] Duke Univ, Duke Clin Res Inst, Durham, NC USA. [Mauri, Laura] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. EM ryeh@bidmc.harvard.edu OI Bangalore, Sripal/0000-0001-9485-0652 FU American College of Cardiology Foundation's National Cardiovascular Data Registry; Boston Scientific; Abbott Vascular; Medtronic; Abiomed; St. Jude Medical; Eli Lilly; GlaxoSmithKline; Sanofi; Daiichi-Sankyo; Janssen Pharmaceuticals; Ferring Pharmaceuticals; AstraZeneca; American College of Cardiology; American Heart Association; Familial Hypercholesterolemia Foundation; Abbott; Medtronic Vascular; Biotronik; Boehringher-Ingelheim; Bristol-Myers Squibb FX From the Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Smith Center for Outcomes Research in Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Division of Cardiology, Department of Medicine, and Center for Interventional Vascular Therapy, Columbia University, New York, New York; Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York; Division of Cardiology, Department of Medicine, Virginia Commonwealth University, Richmond, Virginia; Division of Cardiology, Department of Medicine, Christiana Care Health System, Newark, Delaware; Duke Clinical Research Institute, Duke University, Durham, North Carolina; and the Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. This research was supported by the American College of Cardiology Foundation's National Cardiovascular Data Registry. Dr. Kirtane receives grants to institution from Boston Scientific, Abbott Vascular, Medtronic, Abiomed, St. Jude Medical, Eli Lilly, and GlaxoSmithKline. Dr. Bangalore is on the advisory board of The Medicines Company. Dr. Roe has received research funding from Eli Lilly, Sanofi, Daiichi-Sankyo, Janssen Pharmaceuticals, Ferring Pharmaceuticals, AstraZeneca, American College of Cardiology, American Heart Association, and the Familial Hypercholesterolemia Foundation; and he provides consulting or has received honoraria from PriMed, AstraZeneca, Boehringer Ingelheim, Merck, Amgen, Myokardia, Eli Lilly, Daiichi-Sanyko, and Elsevier Publishers. Dr. Mauri has received grants to institution from Abbott, Boston Scientific, Medtronic Vascular, Eli Lilly, Daiichi-Sankyo, Biotronik, Boehringher-Ingelheim, Sanofi, and Bristol-Myers Squibb; and provides consulting to Medtronic Vascular, AstraZeneca, St. Jude Medical, Biotronik, Boehringher-Ingelheim, and Eli Lilly. Dr. Yeh has received research funding from Abiomed and Boston Scientific; and is a consultant and serves on advisory boards for Abbott Vascular and Boston Scientific. All other authors reported that they have no relationships relevant to the contents of this article to disclose. NR 34 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 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD DEC 12 PY 2016 VL 9 IS 23 BP 2376 EP 2386 DI 10.1016/j.jcin.2016.09.020 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI6PW UT WOS:000392618900004 PM 27838271 ER PT J AU Weinberg, I Jaff, MR AF Weinberg, Ido Jaff, Michael R. TI Can Inferior Vena Cava Filters Change Their Struts? SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material DE deep vein thrombosis; IVC filter; venous thromboembolism ID VENOUS THROMBOEMBOLISM; PULMONARY-EMBOLISM; HEPARIN C1 [Weinberg, Ido; Jaff, Michael R.] Massachusetts Gen Hosp, Fireman Vasc Ctr, Boston, MA 02114 USA. EM iweinberg@mgh.harvard.edu NR 12 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 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD DEC 12 PY 2016 VL 9 IS 23 BP 2449 EP 2451 DI 10.1016/j.jcin.2016.09.013 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI6PW UT WOS:000392618900016 PM 27838265 ER PT J AU Ikonomovic, MD Buckley, CJ Heurling, K Sherwin, P Jones, PA Zanette, M Mathis, CA Klunk, WE Chakrabarty, A Ironside, J Ismail, A Smith, C Thal, DR Beach, TG Farrar, G Smith, APL AF Ikonomovic, Milos D. Buckley, Chris J. Heurling, Kerstin Sherwin, Paul Jones, Paul A. Zanette, Michelle Mathis, Chester A. Klunk, William E. Chakrabarty, Aruna Ironside, James Ismail, Azzam Smith, Colin Thal, Dietmar R. Beach, Thomas G. Farrar, Gill Smith, Adrian P. L. TI Post-mortem histopathology underlying beta-amyloid PET imaging following flutemetamol F 18 injection SO ACTA NEUROPATHOLOGICA COMMUNICATIONS LA English DT Article DE Flutemetamol; PET; Amyloid; Alzheimer's disease; Neuropathology (4-6 allowed) ID PITTSBURGH-COMPOUND-B; POSITRON-EMISSION-TOMOGRAPHY; PROGRESSIVE SUPRANUCLEAR PALSY; NINDS NEUROPATHOLOGIC CRITERIA; ALZHEIMERS-DISEASE; LEWY BODIES; DIFFUSE PLAQUES; BINDING-SITES; HUMAN BRAIN; PATHOLOGY AB In vivo imaging of fibrillar beta-amyloid deposits may assist clinical diagnosis of Alzheimer's disease (AD), aid treatment selection for patients, assist clinical trials of therapeutic drugs through subject selection, and be used as an outcome measure. A recent phase III trial of [F-18]flutemetamol positron emission tomography (PET) imaging in 106 end-of-life subjects demonstrated the ability to identify fibrillar beta-amyloid by comparing in vivo PET to post-mortem histopathology. Post-mortem analyses demonstrated a broad and continuous spectrum of beta-amyloid pathology in AD and other dementing and non-dementing disease groups.The GE067-026 trial demonstrated 91% sensitivity and 90% specificity of [F-18] flutemetamol PET by majority read for the presence of moderate or frequent plaques. The probability of an abnormal [F-18] flutemetamol scan increased with neocortical plaque density and AD diagnosis. All dementia cases with non-AD neurodegenerative diseases and those without histopathological features of beta-amyloid deposits were [F-18] flutemetamol negative. Majority PET assessments accurately reflected the amyloid plaque burden in 90% of cases. However, ten cases demonstrated a mismatch between PET image interpretations and post-mortem findings. Although tracer retention was best associated with amyloid in neuritic plaques, amyloid in diffuse plaques and cerebral amyloid angiopathy best explain three [F-18] flutemetamol positive cases with mismatched (sparse) neuritic plaque burden. Advanced cortical atrophy was associated with the seven false negative [F-18] flutemetamol images. The interpretation of images from pathologically equivocal cases was associated with low reader confidence and inter-reader agreement. Our results support that amyloid in neuritic plaque burden is the primary form of beta-amyloid pathology detectable with [F-18] flutemetamol PET imaging. ClinicalTrials.gov NCT01165554. Registered June 21, 2010; NCT02090855. Registered March 11, 2014. C1 [Ikonomovic, Milos D.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA. [Buckley, Chris J.; Jones, Paul A.; Farrar, Gill; Smith, Adrian P. L.] GE Healthcare, Grove Ctr GC18,White Lion Rd, Amersham HP7 9LL, Bucks, England. [Heurling, Kerstin] GE Healthcare, S-75184 Uppsala, Sweden. [Heurling, Kerstin] Uppsala Univ, Dept Surg Sci, S-75185 Uppsala, Sweden. [Sherwin, Paul; Zanette, Michelle] GE Healthcare, Marlborough, MA 01752 USA. [Mathis, Chester A.] Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15213 USA. [Ikonomovic, Milos D.; Klunk, William E.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. [Chakrabarty, Aruna; Ismail, Azzam] St James Univ Hosp, Leeds Inst Mol Med, Pathol & Tumour Biol, Leeds, W Yorkshire, England. [Ironside, James] Univ Edinburgh, Western Gen Hosp, Natl CJD Res & Surveillance Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Smith, Colin] Ctr Clin Brain Sci, Acad Dept Neuropathol, Edinburgh EH16 4SB, Midlothian, Scotland. [Thal, Dietmar R.] Katholieke Univ Leuven, Neuropathol Lab, Dept Neurosci, Leuven, Belgium. [Beach, Thomas G.] Banner Sun Hlth Res Inst, Sun City, AZ 85351 USA. [Ikonomovic, Milos D.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Thal, Dietmar R.] UZ Leuven, Dept Pathol, Leuven, Belgium. RP Smith, APL (reprint author), GE Healthcare, Grove Ctr GC18,White Lion Rd, Amersham HP7 9LL, Bucks, England. EM Adrian.Smith@ge.com FU GE Healthcare FX We wish to acknowledge Stacy Simpson Logan, CMPP, of Winfield Consulting, for her editorial assistance, funded by GE Healthcare and Dr Jan Wolber for critical manuscript review. This study was funded by GE Healthcare. NR 65 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-5960 J9 ACTA NEUROPATHOL COM JI Acta Neuropathol. Commun. PD DEC 12 PY 2016 VL 4 AR 130 DI 10.1186/s40478-016-0399-z PG 24 WC Neurosciences SC Neurosciences & Neurology GA EG2XJ UT WOS:000390907100001 PM 27955679 ER PT J AU Schwarzwalder, GM Scott, DR Vanderwal, CD AF Schwarzwalder, Gregg M. Scott, David R. Vanderwal, Christopher D. TI A Synthesis of Exiguaquinol Dessulfate SO CHEMISTRY-A EUROPEAN JOURNAL LA English DT Article DE antibiotics; epimers; Heck cyclization; natural product synthesis; sulfation ID PYLORI GLUTAMATE RACEMASE; SELECTIVE ANTIBACTERIAL AGENTS; HELICOBACTER-PYLORI; PYRIDODIAZEPINE AMINES; ALKALOID JAMTINE; GASTRIC-CANCER; MARINE SPONGE; CORE; 3,6-DIMETHOXYBENZOCYCLOBUTENONE; INHIBITORS AB A concise and stereoselective synthesis of exiguaquinol dessulfate is described. Sequential application of a Diels-Alder cycloaddition, a desymmetrizing aldol addition, and a reductive Heck cyclization established most of the architecture of exiguaquinol, and a carefully choreographed introduction of the polar substituents afforded the title compound; unfortunately, naphthoquinol sulfation could not be achieved to deliver exiguaquinol. Our hypothesis regarding the configurational preference of the N-acyl hemiaminal, which was based upon an analysis of internal hydrogen-bonding interactions with polar functional groups, was proven correct. A late-stage intermediate did not demonstrate bactericidal activity against H. pylori cultures. C1 [Schwarzwalder, Gregg M.; Vanderwal, Christopher D.] Univ Calif Irvine, Dept Chem, 1102 Nat Sci 2, Irvine, CA 92697 USA. [Scott, David R.] UC Los Angeles, Dept Physiol, VA Greater Los Angeles Healthcare Syst, 11310 Wilshire Blvd,Bldg 113,Rm 324, Los Angeles, CA 90073 USA. RP Vanderwal, CD (reprint author), Univ Calif Irvine, Dept Chem, 1102 Nat Sci 2, Irvine, CA 92697 USA. EM cdv@uci.edu FU NIH [CA180568] FX We thank the NIH for an F31 predoctoral NRSA fellowship (CA180568) to G.M.S. We acknowledge the assistance of Dr. Greg Basarab (AstraZeneca) in our attempts to learn about the MurI inhibitory activity of our intermediates, and AstraZeneca for sharing a MurI plasmid and synthetic inhibitor. Professor Eduardo Garcia-Junceda (CSIC, Spain) is acknowledged for providing the plasmid encoding the aryl sulfotransferase enzyme from Haliangium ochraceum. We thank Jacob Milligan and Professor Sheryl Tsai (UCI) for helping to express MurI and the sulfotransferase enzyme and Dr. Hung Pham and Professor Ken Houk (UCLA) for the previously published but critical ground-state computations shown in Figure 2. NR 41 TC 1 Z9 1 U1 5 U2 5 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0947-6539 EI 1521-3765 J9 CHEM-EUR J JI Chem.-Eur. J. PD DEC 12 PY 2016 VL 22 IS 50 BP 17953 EP 17957 DI 10.1002/chem.201604506 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA EF8UE UT WOS:000390604600012 PM 27673578 ER PT J AU Ligthart, S Marzi, C Aslibekyan, S Mendelson, MM Conneely, KN Tanaka, T Colicino, E Waite, LL Joehanes, R Guan, WH Brody, JA Elks, C Marioni, R Jhun, MA Agha, G Bressler, J Ward-Caviness, CK Chen, BH Huan, TX Bakulski, K Salfati, EL Wahl, S Schramm, K Sha, J Hernandez, DG Just, AC Smith, JA Sotoodehnia, N Pilling, LC Pankow, JS Tsao, PS Liu, CY Zhao, W Guarrera, S Michopoulos, VJ Smith, AK Peters, MJ Melzer, D Vokonas, P Fornage, M Prokisch, H Bis, JC Chu, AY Herder, C Grallert, H Yao, C Shah, S McRae, AF Lin, HH Horvath, S Fallin, D Hofman, A Wareham, NJ Wiggins, KL Feinberg, AP Starr, JM Visscher, PM Murabito, JM Kardia, SLR Absher, DM Binder, EB Singleton, AB Bandinelli, S Peters, A Waldenberger, M Matullo, G Schwartz, JD Demerath, EW Uitterlinden, AG van Meurs, JBJ Franco, OH Chen, YDI Levy, D Turner, ST Deary, IJ Ressler, KJ Dupuis, J Ferrucci, L Ong, KK Assimes, TL Boerwinkle, E Koenig, W Arnett, DK Baccarelli, AA Benjamin, EJ Dehghan, A AF Ligthart, Symen Marzi, Carola Aslibekyan, Stella Mendelson, Michael M. Conneely, Karen N. Tanaka, Toshiko Colicino, Elena Waite, Lindsay L. Joehanes, Roby Guan, Weihua Brody, Jennifer A. Elks, Cathy Marioni, Riccardo Jhun, Min A. Agha, Golareh Bressler, Jan Ward-Caviness, Cavin K. Chen, Brian H. Huan, Tianxiao Bakulski, Kelly Salfati, Elias L. Wahl, Simon Schramm, Katharina Sha, Jin Hernandez, Dena G. Just, Allan C. Smith, Jennifer A. Sotoodehnia, Nona Pilling, Luke C. Pankow, James S. Tsao, Phil S. Liu, Chunyu Zhao, Wei Guarrera, Simonetta Michopoulos, Vasiliki J. Smith, Alicia K. Peters, Marjolein J. Melzer, David Vokonas, Pantel Fornage, Myriam Prokisch, Holger Bis, Joshua C. Chu, Audrey Y. Herder, Christian Grallert, Harald Yao, Chen Shah, Sonia McRae, Allan F. Lin, Honghuang Horvath, Steve Fallin, Daniele Hofman, Albert Wareham, Nicholas J. Wiggins, Kerri L. Feinberg, Andrew P. Starr, John M. Visscher, Peter M. Murabito, Joanne M. Kardia, Sharon L. R. Absher, Devin M. Binder, Elisabeth B. Singleton, Andrew B. Bandinelli, Stefania Peters, Annette Waldenberger, Melanie Matullo, Giuseppe Schwartz, Joel D. Demerath, Ellen W. Uitterlinden, Andre G. van Meurs, Joyce B. J. Franco, Oscar H. Chen, Yii-Der Ida Levy, Daniel Turner, Stephen T. Deary, Ian J. Ressler, Kerry J. Dupuis, Josee Ferrucci, Luigi Ong, Ken K. Assimes, Themistocles L. Boerwinkle, Eric Koenig, Wolfgang Arnett, Donna K. Baccarelli, Andrea A. Benjamin, Emelia J. Dehghan, Abbas CA WHI-EMPC Invest Giovanni Fiorito CHARGE Epigenetics Coronary Heart TI DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases SO GENOME BIOLOGY LA English DT Article DE Inflammation; DNA methylation; Epigenome-wide association study; C-reactive protein; Body mass index; Diabetes; Coronary heart disease ID WIDE ASSOCIATION; ATHEROSCLEROSIS AB Background: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. Results: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 x 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 x 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 x 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 x 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58x 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R-2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants. Conclusion: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation. C1 [Ligthart, Symen; Hofman, Albert; Franco, Oscar H.; Dehghan, Abbas] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Marzi, Carola; Wahl, Simon; Grallert, Harald; Waldenberger, Melanie] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Inst Epidemiol 2, Neuherber, Germany. [Marzi, Carola; Wahl, Simon; Grallert, Harald] German Ctr Diabet Res DZD eV, Munich, Germany. [Aslibekyan, Stella; Sha, Jin] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Mendelson, Michael M.; Murabito, Joanne M.; Levy, Daniel; Benjamin, Emelia J.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Mendelson, Michael M.] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [Mendelson, Michael M.; Huan, Tianxiao; Liu, Chunyu; Chu, Audrey Y.; Yao, Chen; Levy, Daniel; Dehghan, Abbas] NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA. [Conneely, Karen N.] Emory Univ, Dept Human Genet, Sch Med, Atlanta, GA 30322 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Colicino, Elena; Agha, Golareh; Just, Allan C.; Baccarelli, Andrea A.; Dehghan, Abbas] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Waite, Lindsay L.; Absher, Devin M.] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. [Joehanes, Roby] Harvard Med Sch, Hebrew SeniorLife, Boston, MA USA. [Guan, Weihua] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Brody, Jennifer A.; Sotoodehnia, Nona; Bis, Joshua C.; Wiggins, Kerri L.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Elks, Cathy; Wareham, Nicholas J.; Ong, Ken K.] Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England. [Marioni, Riccardo; Starr, John M.; Visscher, Peter M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Marioni, Riccardo; Starr, John M.; Deary, Ian J.; Dehghan, Abbas] Univ Edinburgh, Med Genet Sect, Ctr Genom & Expt Med, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Marioni, Riccardo; Shah, Sonia; McRae, Allan F.; Visscher, Peter M.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Jhun, Min A.; Smith, Jennifer A.; Zhao, Wei; Kardia, Sharon L. R.; Dehghan, Abbas] Univ Michigan, Dept Epidemiol, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Bressler, Jan; Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA. [Ward-Caviness, Cavin K.; Peters, Annette] Helmholtz Zentrum Munchen, Inst Epidemiol 2, German Res Ctr Environm Hlth, Neuherber, Germany. [Chen, Brian H.] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Bakulski, Kelly; Fallin, Daniele; Feinberg, Andrew P.] Johns Hopkins Univ, Ctr Epigenet, Sch Med, Baltimore, MD USA. [Salfati, Elias L.] Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA. [Guarrera, Simonetta; Matullo, Giuseppe] Human Genet Fdn, Turin, Italy. [Guarrera, Simonetta; Matullo, Giuseppe; WHI-EMPC Invest Giovanni Fiorito] Univ Turin, Dept Med Sci, Turin, Italy. [Schramm, Katharina; Prokisch, Holger] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Human Genet, Neuherberg, Germany. [Schramm, Katharina; Prokisch, Holger] Tech Univ Munich, Inst Human Genet, Munich, Germany. [Hernandez, Dena G.; Singleton, Andrew B.] NIA, Lab Neurogenet, Bethesda, MD 20892 USA. [Pilling, Luke C.; Melzer, David] Univ Exeter, Epidemiol & Publ Hlth, Sch Med, Exeter, Devon, England. [Pankow, James S.; Demerath, Ellen W.] Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, Minneapolis, MN USA. [Tsao, Phil S.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Tsao, Phil S.] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Liu, Chunyu; Lin, Honghuang; Dupuis, Josee] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02118 USA. [Michopoulos, Vasiliki J.; Smith, Alicia K.; Binder, Elisabeth B.; Ressler, Kerry J.] Emory Univ, Dept Psychiat & Behav Sci, Sch Med, Atlanta, GA 30322 USA. [Peters, Marjolein J.; Uitterlinden, Andre G.; van Meurs, Joyce B. J.] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Vokonas, Pantel] VA Boston Healthcare Syst, Boston, MA USA. [Vokonas, Pantel] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Vokonas, Pantel] Boston Univ, Sch Med, Boston, MA 02215 USA. [Herder, Christian] Univ Dusseldorf, Leibniz Ctr Diabet Res Heinrich Heine, Inst Clin Diabetol, German Diabet Ctr, Dusseldorf, Germany. [Herder, Christian] German Ctr Diabet Res DZD eV, Munich, Germany. [Shah, Sonia; McRae, Allan F.; Visscher, Peter M.] Univ Queensland, Translat Res Inst, Diamantina Inst, Brisbane, Qld, Australia. [Horvath, Steve] Univ Calif Los Angeles, Dept Human Genet, Gonda Res Ctr, David Geffen Sch Med, Los Angeles, CA USA. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Binder, Elisabeth B.] Max Planck Inst Psychiat, Munich, Germany. [Bandinelli, Stefania] ASF, Geriatr Unit, Florence, Italy. [Schwartz, Joel D.] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth & Epidemiol, Boston, MA USA. [Chen, Yii-Der Ida] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Turner, Stephen T.] Mayo Clin, Div Nephrol & Hypertens, Rochester, MN USA. [Ressler, Kerry J.] McLean Hosp, Div Depress & Anxiety Disorders, Belmont, MA 02178 USA. [Ressler, Kerry J.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Assimes, Themistocles L.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Koenig, Wolfgang] Univ Ulm, Dept Internal Med Cardiol 2, Med Ctr, Ulm, Germany. [Koenig, Wolfgang] Tech Univ Munich, Deutsches Herzzentrum Munchen, Munich, Germany. [Koenig, Wolfgang] DZHK German Ctr Cardiovasc Res, Munich Heart Alliance, Munich, Germany. [Arnett, Donna K.] Univ Kentucky, Coll Publ Hlth, Lexington, KY USA. [Benjamin, Emelia J.] Boston Univ, Dept Epidemiol, Sch Publ Hlth, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Boston, MA 02215 USA. [Benjamin, Emelia J.] NHLBIs Framingham Heart Study, Boston, MA USA. [Dehghan, Abbas] Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Biostat & Epidemiol, London, England. RP Dehghan, A (reprint author), Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. EM a.dehghan@erasmusmc.nl RI Shah, Sonia/N-7547-2013; Grallert, Harald/B-3424-2013; OI Shah, Sonia/0000-0001-5860-4526; Just, Allan/0000-0003-4312-5957; Pankow, James/0000-0001-7076-483X FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Institutes of Health (NIH) through the American Recovery and Reinvestment Act (ARRA) [5RC2HL102419]; NHLBI [R01HL105756, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL092111, R01HL103612, R01HL111089, R01HL116747, R01HL120393]; National Institute on Aging (NIA) [R01AG023629]; Laughlin Family; Alpha Phi Foundation; Locke Charitable Foundation; National Center for Advancing Translational Sciences, CTSI grant [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; Medical Research Council (MRC) [G9502233, G0401527]; Cancer Research UK [C864/A8257]; MRC Cambridge initiative in metabolomic science [MR/L00002/1]; MRC programme [MC_UU_12015/1, MC_UU_12015/2]; U.S. NIH [N01-HC-25195, HHSN268201500001I]; Division of Intramural Research, NHLBI, NIH; Director's Challenge Award, NIH; Division of Intramural Research, NHLBI; Center for Information Technology, NIH, Bethesda, MD; Tommy Kaplan Fund, Boston Children's Hospital; NHLBI of the NIH [HL054457, HL100185, HL119443]; NIH [R01HL104135]; National Institute of Mental Health [MH096764, MH071537]; Emory and Grady Memorial Hospital General Clinical Research Center; Max Planck Society; Behrens-Weise Foundation, NIH National Centers for Research Resources [M01RR00039]; National Center for Advancing Translational Sciences of the NIH [UL1TR000454]; Helmholtz Zentrum Munchen - German Research Center for Environmental Health - German Federal Ministry of Education and Research (BMBF); State of Bavaria; Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ; European Union [603288, HEALTH-F2-2013-602736]; BMBF e:Med project: e:AtheroSysMed - Systems medicine of myocardial infarction and stroke; BMBF; German National Genome Research Network (NGFNplus) [01GS0834]; University of Ulm; U.S. National Institute of Environmental Health Sciences (NIEHS) [R01ES015172, R01ES021733]; Cooperative Studies Program/ERIC, US Department of Veterans Affairs; US Department of Agriculture, Agricultural Research Service [53-K06-510]; Genetic Laboratory of the Department of Internal Medicine; Erasmus MC; Netherlands Organization for Scientific Research (NWO) [184021007]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; [1RO1 HL64753]; [R01 HL076784]; [1R01 AG028321]; [1P50HL120163] FX The Atherosclerosis Risk in Communities (ARIC) study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Funding support for "Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium" was provided by the National Institutes of Health (NIH) through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419).; CHS: Infrastructure for the CHARGE Consortium is supported in part by the NHLBI grant R01HL105756. The CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL092111, R01HL105756, R01HL103612, R01HL111089, R01HL116747, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA) as well as the Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.; EPIC-Norfolk is supported by programme grants from the Medical Research Council (MRC) (G9502233; G0401527) and Cancer Research UK (C864/A8257). The generation and management of the Illumina 450 K methylation array data in this cohort is supported through the MRC Cambridge initiative in metabolomic science (MR/L00002/1). CEE, KKO, and NJW are supported by MRC programme grants (MC_UU_12015/1 and MC_UU_12015/2). FHS is funded by the U.S. NIH contract N01-HC-25195 and HHSN268201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, NHLBI, NIH, and by a Director's Challenge Award, NIH (DL). The analytical component of this project was funded by the Division of Intramural Research, NHLBI, and the Center for Information Technology, NIH, Bethesda, MD. This study utilized the computational resources of the Biowulf system at the NIH, Bethesda, MD (https://hpc.nih.gov/docs/user_guides.html). MMM is partly supported by the Tommy Kaplan Fund, Boston Children's Hospital. EJB was supported by 1RO1 HL64753, R01 HL076784, 1R01 AG028321, and 1P50HL120163. Support for the Genetic Epidemiology Network of Arteriopathy (GENOA) was provided by the NHLBI (HL054457, HL100185, and HL119443) of the NIH. GOLDN is supported by NIH grant R01HL104135.; Methylation and expression work for GTP was primarily supported by the National Institute of Mental Health (MH096764 and MH071537 to KJR). Support was also received from Emory and Grady Memorial Hospital General Clinical Research Center, the Max Planck Society, the Behrens-Weise Foundation, NIH National Centers for Research Resources (M01RR00039), and the National Center for Advancing Translational Sciences of the NIH (UL1TR000454).; The KORA study was initiated and financed by the Helmholtz Zentrum Munchen - German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ. The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 603288 (SysVasc) and HEALTH-F2-2013-602736 (PAIN-OMICS) and BMBF e:Med project: e:AtheroSysMed - Systems medicine of myocardial infarction and stroke. Furthermore, this study was supported in part by a grant from the BMBF to the German Center for Diabetes Research (DZD). In addition, part of this work was financed by the German National Genome Research Network (NGFNplus, project no. 01GS0834) and through additional funds from the University of Ulm.; The present work on the US Department of Veterans Affairs (VA) Normative Aging Study has been supported by funding from the U.S. National Institute of Environmental Health Sciences (NIEHS) (R01ES015172, R01ES021733). The VA Normative Aging Study is supported by the Cooperative Studies Program/ERIC, US Department of Veterans Affairs, and is a research component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). Additional support to the VA Normative Aging Study was provided by the US Department of Agriculture, Agricultural Research Service (contract 53-K06-510). The views expressed in this paper are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs.; The generation and management of the Illumina 450 K methylation array data (EWAS data) for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. The EWAS data were funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by the Netherlands Organization for Scientific Research (NWO; project number 184021007). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. NR 29 TC 1 Z9 1 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD DEC 12 PY 2016 VL 17 AR 255 DI 10.1186/s13059-016-1119-5 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EF3BI UT WOS:000390199000001 PM 27955697 ER PT J AU Felicetti, P Trotta, F Bonetto, C Santuccio, C Pernus, YB Burgner, D Chandler, R Girolomoni, G Hadden, RDM Kochar, S Kucuku, M Monaco, G Ozen, S Pahud, B Phuong, L Bachtiar, NS Teeba, A Top, K Varricchio, F Wise, RP Zanoni, G Zivkovic, S Bonhoeffer, J AF Felicetti, Patrizia Trotta, Francesco Bonetto, Caterina Santuccio, Carmela Pernus, Yolanda Brauchli Burgner, David Chandler, Rebecca Girolomoni, Giampiero Hadden, Robert D. M. Kochar, Sonali Kucuku, Merita Monaco, Giuseppe Ozen, Seza Pahud, Barbara Phuong, Linny Bachtiar, Novilia Sjafri Teeba, Amina Top, Karina Varricchio, Frederick Wise, Robert P. Zanoni, Giovanna Zivkovic, Saga Bonhoeffer, Jan CA Brighton Collaboration Vasculitis TI Spontaneous reports of vasculitis as an adverse event following immunization: A descriptive analysis across three international databases SO VACCINE LA English DT Article DE Vasculitis; Vaccines; Immunization; Adverse event following immunization (AEFI); Spontaneous reporting; Eudravigilance; VigiBase (R); VAERS; Pharmacovigilance ID SYSTEMIC VASCULITIDES; INFLUENZA VACCINATION; CONSENSUS CONFERENCE; KAWASAKI-DISEASE; CLASSIFICATION; CRITERIA; GRANULOMATOSIS; NOMENCLATURE AB Background: Vasculitides have been reported as adverse events following immunization (AEFI) following various vaccines. We describe reports of vasculitis to three international spontaneous reporting systems. Methods: All spontaneous reports of vasculitis following immunization between January 2003 and June 2014 were retrieved from Eudravigilance (EV), the Vaccine Adverse Event Reporting System (VAERS), and VigiBase (R). A Standard MedDRA Query (SMQ) for vasculitis was used and vaccine types were categorized using the Anatomical Therapeutic Chemical classification system. We performed a descriptive analysis by source, sex, age, country, time to onset, vaccine, and type of vasculitis. Results: We retrieved 1797 reports of vasculitis in EV, 1171 in VAERS, and 2606 in VigiBase (R). Vasculitis was predominantly reported in children aged 1-17 years, and less frequently in the elderly (>65 years). The generic term "vasculitis" was the most frequently reported AEFI" in this category across the three databases (range 21.9% to 27.5% of all reported vasculitis for vaccines). For the more specific terms, Henoch-Schoenlein Purpura (HSP) was most frequently reported, (19.1% on average), followed by Kawasaki disease (10) (16.1% on average) and polymyalgia rheumatica (PMR) (9.2% on average). Less frequently reported subtypes were cutaneous vasculitis (CuV), vasculitis of the central nervous system (CNS-V), and Behcet's syndrome (BS). HSP, PMR and CuV were more frequently reported with influenza vaccines: on average in 29.3% for HSP reports, 61.5% for PMR reports and in 39.2% for CuV reports KD was reported with pneumococcal vaccines in 32.0% of KD reports and with rotavirus vaccines in more than 20% of KD reports. BS was most frequently reported after hepatitis and HPV vaccines and CNS-V after HPV vaccines. Conclusion: Similar reporting patterns of vasculitides were observed in different databases. Implementation of standardized case definitions for specific vasculitides could improve overall data quality and comparability of reports. Published by Elsevier Ltd. C1 [Felicetti, Patrizia; Trotta, Francesco; Bonetto, Caterina; Santuccio, Carmela] Italian Med Agcy, Rome, Italy. [Pernus, Yolanda Brauchli; Bonhoeffer, Jan] Brighton Collaborat Fdn, Basel, Switzerland. [Burgner, David] Monash Childrens Hosp Clayton, Melbourne, Vic, Australia. [Burgner, David] Univ Melbourne, Dept Paediat, MCRI, Melbourne, Vic 3010, Australia. [Chandler, Rebecca] Uppsala Monitoring Ctr, Uppsala, Sweden. [Girolomoni, Giampiero] Univ Verona, Dept Med, Sect Dermatol & Venereol, Verona, Italy. [Hadden, Robert D. M.] Kings Coll Hosp London, London, England. [Kochar, Sonali] JSIPL, Deliver Project, USAID, New Delhi, India. [Kucuku, Merita] Natl Agcy Med & Med Devices, Dept Vaccines Control, Tirana, Albania. [Monaco, Giuseppe] Ctr Pharmacovigilance, Milan, Italy. [Ozen, Seza] Hacettepe Univ, Dept Pediat Rheumatol, Ankara, Turkey. [Pahud, Barbara] Childrens Mercy Hosp, Kansas City, MO 64108 USA. [Phuong, Linny] Monash Childrens Hosp, Melbourne, Vic, Australia. [Phuong, Linny] Royal Childrens Hosp, Melbourne, Vic, Australia. [Bachtiar, Novilia Sjafri] Bio Farma Vaccine Inst, Java, Indonesia. [Teeba, Amina] Ctr Natl Anti Poison & Pharmacovigilance, Rabat, Morocco. [Top, Karina] Dalhousie Univ, Dept Pediat, Halifax, NS, Canada. [Wise, Robert P.] MedImmune AstraZeneca, Gaithersburg, MD USA. [Zanoni, Giovanna] Azienda Osped Univ Integrata Verona, Immunol Unit, Verona, Italy. [Zivkovic, Saga] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Zivkovic, Saga] VA Pittsburgh Healthcare Syst, MSL, Neurol Serv, Pittsburgh, PA USA. [Bonhoeffer, Jan] Univ Basel, Childrens Hosp, Basel, Switzerland. RP Felicetti, P (reprint author), Italian Med Agcy, Rome, Italy. EM contact@brightoncollaboration.org RI Trotta, Francesco/G-8702-2013 OI Trotta, Francesco/0000-0001-6889-8484 FU Italian Medicines Agency (AIFA) FX The Italian Medicines Agency (AIFA) financed the cost of the project "Working group for the Vasculitis case definition" performed by the Brighton Collaboration. NR 23 TC 2 Z9 2 U1 5 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD DEC 12 PY 2016 VL 34 IS 51 BP 6634 EP 6640 DI 10.1016/j.vaccine.2015.09.027 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EF7JO UT WOS:000390506100021 PM 26392009 ER PT J AU Letai, A AF Letai, Anthony TI S63845, an MCL-1 Selective BH3 Mimetic: Another Arrow in Our Quiver SO CANCER CELL LA English DT Editorial Material AB A recent study reports a novel small molecule inhibitor of MCL-1 with efficacy in killing MCL-1-dependent cancer cells in vitro and in vivo. With the advent of S63845, the targeting of BCL-2, BCL-XL, and MCL-1 is now possible in vivo, but optimal clinical use is yet to be determined. C1 [Letai, Anthony] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Letai, A (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02215 USA. EM anthony_letai@dfci.harvard.edu NR 8 TC 0 Z9 0 U1 6 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD DEC 12 PY 2016 VL 30 IS 6 BP 834 EP 835 DI 10.1016/j.ccell.2016.11.016 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE9SV UT WOS:000389967400006 PM 27960083 ER PT J AU Xu, HM Valerio, DG Eisold, ME Sinha, A Koche, RP Hu, WH Chen, CW Chu, SH Brien, GL Park, CY Hsieh, JJ Ernst, P Armstrong, SA AF Xu, Haiming Valerio, Daria G. Eisold, Meghan E. Sinha, Amit Koche, Richard P. Hu, Wenhuo Chen, Chun-Wei Chu, S. Haihua Brien, Gerard L. Park, Christopher Y. Hsieh, James J. Ernst, Patricia Armstrong, Scott A. TI NUP98 Fusion Proteins Interact with the NSL and MLL1 Complexes to Drive Leukemogenesis SO CANCER CELL LA English DT Article ID HOX GENE-EXPRESSION; ACUTE MYELOID-LEUKEMIA; HEMATOPOIETIC STEM-CELLS; NUCLEAR-PORE COMPLEXES; H3K79 METHYLATION; METHYLTRANSFERASE ACTIVITY; NUCLEOPORIN NUP98; DISTINCT; MICE; MOF AB The nucleoporin 98 gene (NUP98) is fused to a variety of partner genes in multiple hematopoietic malignancies. Here, we demonstrate that NUP98 fusion proteins, including NUP98-HOXA9 (NHA9), NUP98-HOXD13 (NHD13), NUP98-NSD1, NUP98-PHF23, and NUP98-TOP1 physically interact with mixed lineage leukemia 1 (MLL1) and the non-specific lethal (NSL) histone-modifying complexes. Chromatin immunoprecipitation sequencing illustrates that NHA9 and MLL1 co-localize on chromatin and are found associated with Hox gene promoter regions. Furthermore, MLL1 is required for the proliferation of NHA9 cells in vitro and in vivo. Inactivation of MLL1 leads to decreased expression of genes bound by NHA9 and MLL1 and reverses a gene expression signature found in NUP98-rearranged human leukemias. Our data reveal a molecular dependency on MLL1 function in NUP98-fusion-driven leukemogenesis. C1 [Xu, Haiming; Valerio, Daria G.; Eisold, Meghan E.; Sinha, Amit; Koche, Richard P.; Chen, Chun-Wei; Chu, S. Haihua; Brien, Gerard L.; Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA. [Xu, Haiming; Chen, Chun-Wei; Chu, S. Haihua; Brien, Gerard L.; Armstrong, Scott A.] Harvard Med Sch, Dept Pediat Oncol, Dana Farber Canc Inst, Boston Childrens Hosp, Boston, MA 02215 USA. [Xu, Haiming; Chen, Chun-Wei; Chu, S. Haihua; Brien, Gerard L.; Armstrong, Scott A.] Harvard Med Sch, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02215 USA. [Park, Christopher Y.; Hsieh, James J.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Ernst, Patricia] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO 80045 USA. RP Xu, HM; Armstrong, SA (reprint author), Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA.; Xu, HM; Armstrong, SA (reprint author), Harvard Med Sch, Dept Pediat Oncol, Dana Farber Canc Inst, Boston Childrens Hosp, Boston, MA 02215 USA.; Xu, HM; Armstrong, SA (reprint author), Harvard Med Sch, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02215 USA. EM haiming_xu@dfci.harvard.edu; scott_armstrong@dfci.harvard.edu FU NIH [PO1 CA66996, R01 CA140575]; Leukemia and Lymphoma Society; Gabrielle's Angel Research Foundation; DoD Bone Marrow Failure Postdoctoral Fellowship [W81XWH-12-1-0568]; Cure Childhood Cancer Foundation FX We acknowledge Alan Chramiec, Matthew Witkin, and Li Yang for assistance with the preparation of ChIP-seq libraries, and Ke Xu for assistance with the confocal microscopy. This work was supported by NIH grants PO1 CA66996, R01 CA140575, the Leukemia and Lymphoma Society, and Gabrielle's Angel Research Foundation (to S.A.A.); by a DoD Bone Marrow Failure Postdoctoral Fellowship award (W81XWH-12-1-0568) (to H.X.); and by the Cure Childhood Cancer Foundation (to D.G.V.). S.A.A. is a consultant for Epizyme, Imago Biosciences, and Vitae Pharmaceuticals. NR 44 TC 1 Z9 1 U1 0 U2 0 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 DEC 12 PY 2016 VL 30 IS 6 BP 863 EP 878 DI 10.1016/j.ccell.2016.10.019 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE9SV UT WOS:000389967400009 PM 27889185 ER PT J AU Nakagawa, S Wei, L Song, WM Higashi, T Ghoshal, S Kim, RS Bian, CB Yamada, S Sun, XC Venkatesh, A Goossens, N Bain, G Lauwers, GY Koh, AP El-Abtah, M Ahmad, NB Hoshida, H Erstad, DJ Gunasekaran, G Lee, Y Yu, ML Chuang, WL Dai, CY Kobayashi, M Kumada, H Beppu, T Baba, H Mahajan, M Nair, VD Lanuti, M Villanueva, A Sangiovanni, A Iavarone, M Colombo, M Llovet, JM Subramanian, A Tager, AM Friedman, SL Baumert, TF Schwarz, ME Chung, RT Tanabe, KK Zhang, B Fuchs, BC Hoshida, Y AF Nakagawa, Shigeki Wei, Lan Song, Won Min Higashi, Takaaki Ghoshal, Sarani Kim, Rosa S. Bian, C. Billie Yamada, Suguru Sun, Xiaochen Venkatesh, Anu Goossens, Nicolas Bain, Gretchen Lauwers, Gregory Y. Koh, Anna P. El-Abtah, Mohamed Ahmad, Noor B. Hoshida, Hiroki Erstad, Derek J. Gunasekaran, Ganesh Lee, Youngmin Yu, Ming-Lung Chuang, Wan-Long Dai, Chia-Yen Kobayashi, Masahiro Kumada, Hiromitsu Beppu, Toru Baba, Hideo Mahajan, Milind Nair, Venugopalan D. Lanuti, Michael Villanueva, Augusto Sangiovanni, Angelo Iavarone, Massimo Colombo, Massimo Llovet, Josep M. Subramanian, Aravind Tager, Andrew M. Friedman, Scott L. Baumert, Thomas F. Schwarz, Myron E. Chung, Raymond T. Tanabe, Kenneth K. Zhang, Bin Fuchs, Bryan C. Hoshida, Yujin CA Precision Liver Canc Prevention TI Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition SO CANCER CELL LA English DT Article ID CHRONIC HEPATITIS-C; EARLY-STAGE CIRRHOSIS; HEPATOCELLULAR-CARCINOMA; GENE-EXPRESSION; GROWTH-FACTOR; FIBROSIS; AUTOTAXIN; SURVEILLANCE; MORTALITY; DISEASE AB Cirrhosis is a milieu that develops hepatocellular carcinoma (HCC), the second most lethal cancer worldwide. HCC prediction and prevention in cirrhosis are key unmet medical needs. Here we have established an HCC risk gene signature applicable to all major HCC etiologies: hepatitis B/C, alcohol, and non-alcoholic steatohepatitis. A transcriptome meta-analysis of >500 human cirrhotics revealed global regulatory gene modules driving HCC risk and the lysophosphatidic acid pathway as a central chemoprevention target. Pharmacological inhibition of the pathway in vivo reduced tumors and reversed the gene signature, which was verified in organotypic ex vivo culture of patient-derived fibrotic liver tissues. These results demonstrate the utility of clinical organ transcriptome to enable a strategy, namely, reverse-engineering precision cancer prevention. C1 [Nakagawa, Shigeki; Song, Won Min; Higashi, Takaaki; Kim, Rosa S.; Bian, C. Billie; Sun, Xiaochen; Venkatesh, Anu; Goossens, Nicolas; Koh, Anna P.; El-Abtah, Mohamed; Ahmad, Noor B.; Hoshida, Hiroki; Lee, Youngmin; Villanueva, Augusto; Llovet, Josep M.; Friedman, Scott L.; Hoshida, Yujin] Icahn Sch Med Mt Sinai, Liver Canc Program, Tisch Canc Inst, Grad Sch Biomed Sci,Div Liver Dis,Dept Med, New York, NY 10029 USA. [Nakagawa, Shigeki; Higashi, Takaaki; Beppu, Toru; Baba, Hideo] Kumamoto Univ, Grad Sch Med Sci, Dept Surg Gastroenterol, Kumamoto 8608556, Japan. [Wei, Lan; Ghoshal, Sarani; Yamada, Suguru; Erstad, Derek J.; Tanabe, Kenneth K.; Fuchs, Bryan C.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, Boston, MA 02114 USA. [Song, Won Min; Mahajan, Milind; Zhang, Bin] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Goossens, Nicolas] Univ Hosp Geneva, Div Gastroenterol & Hepatol, CH-41205 Geneva, Switzerland. [Bain, Gretchen] PharmAkea Therapeut, San Diego, CA 92109 USA. [Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Lauwers, Gregory Y.] Harvard Med Sch, Boston, MA 02114 USA. [Gunasekaran, Ganesh; Schwarz, Myron E.] Icahn Sch Med Mt Sinai, Recanati Miller Transplantat Inst, New York, NY 10029 USA. [Yu, Ming-Lung; Chuang, Wan-Long; Dai, Chia-Yen] Kaohsiung Med Univ Hosp, Hepatobiliary Div, Dept Internal Med, Kaohsiung 807, Taiwan. [Yu, Ming-Lung; Chuang, Wan-Long; Dai, Chia-Yen] Kaohsiung Med Univ Hosp, Hepatitis Ctr, Kaohsiung 807, Taiwan. [Yu, Ming-Lung; Chuang, Wan-Long; Dai, Chia-Yen] Kaohsiung Med Univ, Fac Med, Coll Med, Kaohsiung 807, Taiwan. [Yu, Ming-Lung; Chuang, Wan-Long; Dai, Chia-Yen] Kaohsiung Med Univ, Ctr Infect Dis & Canc Res, Kaohsiung 807, Taiwan. [Yu, Ming-Lung] Natl Sun Yat Sen Univ, Inst Biomed Sci, Kaohsiung 804, Taiwan. [Kobayashi, Masahiro; Kumada, Hiromitsu] Toranomon Gen Hosp, Dept Hepatol, Tokyo 1050001, Japan. [Nair, Venugopalan D.] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Lanuti, Michael] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Div Thorac Surg, Boston, MA 02114 USA. [Sangiovanni, Angelo; Iavarone, Massimo; Colombo, Massimo] Univ Milan, M&A Migliavacca Ctr Liver Dis, Fdn IRCCS Ca Granda Osped Maggiore Policlin, I-20122 Milan, Italy. [Sangiovanni, Angelo; Iavarone, Massimo; Colombo, Massimo] Univ Milan, Div Gastroenterol 1, Fdn IRCCS Ca Granda Osped Maggiore Policlin, I-20122 Milan, Italy. [Llovet, Josep M.] Univ Barcelona, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Inst Catalana Recerca & Estudis Avangats,Hosp Cli, Liver Canc Translat Res Lab,Liver Unit,CIBERehd,B, E-08036 Barcelona, Spain. [Subramanian, Aravind] Broad Inst MIT & Harvard Univ, Canc Program, Cambridge, MA 02142 USA. [Tager, Andrew M.] Harvard Med Sch, Pulm & Crit Care Unit, Ctr Immunol & Inflammatory Dis, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Baumert, Thomas F.] Univ Strasbourg, INSERM, U1110, Inst Rech Malad Virales & Hepat, F-67081 Strasbourg, France. [Baumert, Thomas F.] Nouvel Hop Civil, Inst Hosp Univ, Pole Hepatodigestif, F-67000 Strasbourg, France. [Baumert, Thomas F.; Chung, Raymond T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Liver Ctr,Gastrointestinal Div, Boston, MA 02114 USA. RP Hoshida, Y (reprint author), Icahn Sch Med Mt Sinai, Liver Canc Program, Tisch Canc Inst, Grad Sch Biomed Sci,Div Liver Dis,Dept Med, New York, NY 10029 USA.; Fuchs, BC (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, Boston, MA 02114 USA. EM bfuchs@mgh.harvard.edu; yujin.hoshida@mssm.edu FU Uehara Memorial Foundation; FLAGS foundation; Nuovo-Soldati Cancer Research Foundation; Geneva University Hospital; Kaohsiung Medical University [KMU-TP103E06, KMU-TP103E07, KMU-TP103E08]; Kaohsiung Medical University Hospital [KMUH102-2T01]; ARC, Paris; Institut Hospitalo-Universitaire, Strasbourg [IHUARC IHU201301187]; Laboratory of Excellence HEPSYS [ANR-10-LABX-0028]; European Union [ERC-2014-AdG-671231-HEPCIR]; NIH/NIDDK [DK078772, DK098079, DK104956, DK099558]; NIH/NCI [CA140861]; American Institute for Cancer Research; Irma T. Hirschl Trust; Dr. Harold and Golden Lamport Research Award; U.S. Department of Defense [W81XWH-16-1-0363] FX The nCounter assay was performed at Mount Sinai qPCR Shared Resource Facility. Bioinformatics analysis was performed by using the High Power Computing facility at Mount Sinai Genomics Core and Department of Scientific Computing. De-identified clinical liver tissues for organotypic ex vivo culture were obtained via Mount Sinai Biorepository. S.N. was supported by Uehara Memorial Foundation. N.G. was supported by FLAGS foundation, Nuovo-Soldati Cancer Research Foundation, and an advanced training grant from Geneva University Hospital. M.Y., W.-L.C., and C.-Y.D. were supported partially by Kaohsiung Medical University "Aim for the Top Universities Grant, grant No. KMU-TP103E06 & No. KMU-TP103E07 & No. KMU-TP103E08," and by a grant from Kaohsiung Medical University Hospital (KMUH102-2T01). T.F.B. was supported by ARC, Paris, Institut Hospitalo-Universitaire, Strasbourg (IHUARC IHU201301187), Laboratory of Excellence HEPSYS (ANR-10-LABX-0028), and European Union (ERC-2014-AdG-671231-HEPCIR). R.T.C. was supported by NIH/NIDDK (DK078772, DK098079). B.C.F. was supported by NIH/NCI (CA140861), NIH/NIDDK (DK104956), and grant from American Institute for Cancer Research. Y.H. was supported by NIH/NIDDK (DK099558), Irma T. Hirschl Trust, Dr. Harold and Golden Lamport Research Award, European Union (ERC-2014-AdG-671231-HEPCIR), and U.S. Department of Defense (W81XWH-16-1-0363). The HCC risk gene signature Elements assay probes are available upon request to the lead contact (Y.H.) or at www.hoshida-lab.org. NR 41 TC 2 Z9 2 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD DEC 12 PY 2016 VL 30 IS 6 BP 879 EP 890 DI 10.1016/j.ccell.2016.11.004 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE9SV UT WOS:000389967400010 PM 27960085 ER PT J AU Iwaki, M Wickham, SF Ikezaki, K Yanagida, T Shih, WM AF Iwaki, M. Wickham, S. F. Ikezaki, K. Yanagida, T. Shih, W. M. TI A programmable DNA origami nanospring that reveals force-induced adjacent binding of myosin VI heads SO NATURE COMMUNICATIONS LA English DT Article ID SINGLE-MOLECULE FLUORESCENCE; HAND-OVER-HAND; ACTIN-FILAMENTS; MOTOR PROTEIN; LEVER ARM; STEPS; KINESIN; SHAPES; TRANSPORT; MECHANISM AB Mechanosensitive biological nanomachines such as motor proteins and ion channels regulate diverse cellular behaviour. Combined optical trapping with single-molecule fluorescence imaging provides a powerful methodology to clearly characterize the mechanoresponse, structural dynamics and stability of such nanomachines. However, this system requires complicated experimental geometry, preparation and optics, and is limited by low data-acquisition efficiency. Here we develop a programmable DNA origami nanospring that overcomes these issues. We apply our nanospring to human myosin VI, a mechanosensory motor protein, and demonstrate nanometre-precision single-molecule fluorescence imaging of the individual motor domains (heads) under force. We observe force-induced transitions of myosin VI heads from non-adjacent to adjacent binding, which correspond to adapted roles for low-load and high-load transport, respectively. Our technique extends single-molecule studies under force and clarifies the effect of force on biological processes. C1 [Iwaki, M.; Yanagida, T.] RIKEN, OLABB, Quantitat Biol Ctr, 6-2-3 Furuedai, Suita, Osaka 5650874, Japan. [Iwaki, M.; Yanagida, T.] Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan. [Wickham, S. F.; Shih, W. M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Wickham, S. F.; Shih, W. M.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Wickham, S. F.; Shih, W. M.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Ikezaki, K.] Univ Tokyo, Sch Frontier Sci, Kashiwa, Chiba 2778561, Japan. [Yanagida, T.] NICT, Ctr Informat & Neural Networks, Suita, Osaka 5650874, Japan. RP Iwaki, M (reprint author), RIKEN, OLABB, Quantitat Biol Ctr, 6-2-3 Furuedai, Suita, Osaka 5650874, Japan.; Iwaki, M (reprint author), Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan. EM iwaki@fbs.osaka-u.ac.jp OI Iwaki, Mitsuhiro/0000-0002-8893-1103 FU MEXT [20118009]; JSPS [24654139] FX We thank colleagues of the Riken Quantitative Biology Center and T. Komori for discussions, and P. Karagiannis for helpful comments on the manuscript. We especially thank R. Kawaguchi for technical help, and Y. Ke and N.D. Derr for technical advice. This work was supported by Grant-in-Aid for Scientific Research on Innovative Areas (20118009, MEXT) (to M.I.), Grant-in-Aid for challenging Exploratory Research (24654139, JSPS) (to M.I.). NR 49 TC 0 Z9 0 U1 27 U2 27 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD DEC 12 PY 2016 VL 7 AR 13715 DI 10.1038/ncomms13715 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4PI UT WOS:000389585600001 PM 27941751 ER PT J AU McLeod, CM Mauck, RL AF McLeod, Claire M. Mauck, Robert L. TI High fidelity visualization of cell-to-cell variation and temporal dynamics in nascent extracellular matrix formation SO SCIENTIFIC REPORTS LA English DT Article ID NEWLY SYNTHESIZED PROTEINS; NONCANONICAL AMINO-ACIDS; MESENCHYMAL STEM-CELLS; PERICELLULAR MATRIX; ARTICULAR-CARTILAGE; CLICK CHEMISTRY; IN-VIVO; ENGINEERED CARTILAGE; DEVELOPING ZEBRAFISH; AGAROSE CULTURE AB Extracellular matrix dynamics are key to tissue morphogenesis, homeostasis, injury, and repair. The spatiotemporal organization of this matrix has profound biological implications, but is challenging to monitor using standard techniques. Here, we address these challenges by using noncanonical amino acid tagging to fluorescently label extracellular matrix synthesized in the presence of bio-orthogonal methionine analogs. This strategy labels matrix proteins with high resolution, without compromising their distribution or mechanical function. We demonstrate that the organization and temporal dynamics of the proteinaceous matrix depend on the biophysical features of the microenvironment, including the biomaterial scaffold and the niche constructed by cells themselves. Pulse labeling experiments reveal that, in immature constructs, nascent matrix is highly fibrous and interdigitates with pre-existing matrix, while in more developed constructs, nascent matrix lacks fibrous organization and is retained in the immediate pericellular space. Inhibition of collagen crosslinking increases matrix synthesis, but compromises matrix organization. Finally, these data demonstrate marked cell-to-cell heterogeneity amongst both chondrocytes and mesenchymal stem cells undergoing chondrogenesis. Collectively, these results introduce fluorescent noncanonical amino acid tagging as a strategy to investigate spatiotemporal matrix organization, and demonstrate its ability to identify differences in phenotype, microenvironment, and matrix assembly at the single cell level. C1 [McLeod, Claire M.; Mauck, Robert L.] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. [McLeod, Claire M.; Mauck, Robert L.] Univ Penn, Perelman Sch Med, Dept Orthopaed Surg, McKay Orthopaed Res Lab, Philadelphia, PA 19104 USA. [McLeod, Claire M.; Mauck, Robert L.] Philadelphia VA Med Ctr, Translat Musculoskeletal Res Ctr, Philadelphia, PA 19104 USA. RP Mauck, RL (reprint author), Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA.; Mauck, RL (reprint author), Univ Penn, Perelman Sch Med, Dept Orthopaed Surg, McKay Orthopaed Res Lab, Philadelphia, PA 19104 USA.; Mauck, RL (reprint author), Philadelphia VA Med Ctr, Translat Musculoskeletal Res Ctr, Philadelphia, PA 19104 USA. EM lemauck@mail.med.upenn.edu FU National Institutes of Health [R01 EB008722, T32 HL007954]; Penn Center for Musculoskeletal Disorders [P30 AR050950] FX This work was funded by the National Institutes of Health (R01 EB008722, T32 HL007954) and the Penn Center for Musculoskeletal Disorders (P30 AR050950). We gratefully acknowledge Bhavana Mohanraj and Dr. George Dodge for their thoughtful discussion and input to this work. NR 46 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 12 PY 2016 VL 6 AR 38852 DI 10.1038/srep38852 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE7PT UT WOS:000389816000001 PM 27941914 ER PT J AU Bartenstein, DW Diven, DG AF Bartenstein, Diana W. Diven, Dayna G. TI Shelf life considerations as EpiPen price increases SO LANCET LA English DT Letter ID EPINEPHRINE; AUTOINJECTORS C1 [Bartenstein, Diana W.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bartenstein, Diana W.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Diven, Dayna G.] Univ Texas Austin, Dell Med Sch, Austin, TX 78712 USA. RP Bartenstein, DW (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02114 USA.; Bartenstein, DW (reprint author), Tufts Univ, Sch Med, Boston, MA 02111 USA. EM dbartenstein@partners.org NR 7 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD DEC 10 PY 2016 VL 388 IS 10062 BP 2871 EP 2871 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EE5FU UT WOS:000389631700029 PM 27979405 ER PT J AU Teerlink, JR Felker, GM McMurray, JJV Solomon, SD Adams, KF Cleland, JGF Ezekowitz, JA Goudev, A Macdonald, P Metra, M Mitrovic, V Ponikowski, P Serpytis, P Spinar, J Tomcsanyi, J Vandekerckhove, HJ Voors, AA Monsalvo, ML Johnston, J Malik, FI Honarpour, N AF Teerlink, John R. Felker, G. Michael McMurray, John J. V. Solomon, Scott D. Adams, Kirkwood F., Jr. Cleland, John G. F. Ezekowitz, Justin A. Goudev, Assen Macdonald, Peter Metra, Marco Mitrovic, Veselin Ponikowski, Piotr Serpytis, Pranas Spinar, Jindrich Tomcsanyi, Janos Vandekerckhove, Hans J. Voors, Adriaan A. Monsalvo, Maria Laura Johnston, James Malik, Fady I. Honarpour, Narimon CA COSMIC-HFf Investigators TI Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial SO LANCET LA English DT Article ID CARDIAC RESYNCHRONIZATION THERAPY; OMECAMTIV MECARBIL; TIME; MECHANISMS; PREDICTION; MORTALITY; EXERCISE; SAFETY AB Background Impaired contractility is a feature of heart failure with reduced ejection fraction. We assessed the pharmacokinetics and eff ects on cardiac function and structure of the cardiac myosin activator, omecamtiv mecarbil. Methods In this randomised, double-blind study, done at 87 sites in 13 countries, we recruited patients with stable, symptomatic chronic heart failure and left ventricular ejection fraction 40% or lower. Patients were randomly assigned equally, via an interactive web response system, to receive 25 mg oral omecamtiv mecarbil twice daily (fixed-dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group), or placebo for 20 weeks. We assessed the maximum concentration of omecamtiv mecarbil in plasma (primary endpoint) and changes in cardiac function and ventricular diameters. This trial is registered with ClinicalTrials. gov, number NCT01786512. Findings From March 17, 2014, to March 5, 2015, we enrolled 150 patients in the fi xed-dose omecamtiv mecarbil group and 149 in the pharmacokinetic-titration and placebo groups. Mean maximum concentration of omecamtiv mecarbil at 12 weeks was 200 (SD 71) ng/mL in the fi xed-dose group and 318 (129) ng/mL in the pharmacokinetic-titration group. For the pharmacokinetic-titration group versus placebo group at 20 weeks, least square mean diff erences were as follows: systolic ejection time 25 ms (95% CI 18-32, p< 0.0001), stroke volume 3.6 mL (0.5-6.7, p= 0.0217), left ventricular end-systolic diameter -1.8 mm (-2.9 to -0.6, p= 0.0027), left ventricular end-diastolic diameter -1.3 mm, (-2.3 to 0.3, p= 0.0128), heart rate -3.0 beats per min (-5.1 to -0.8, p= 0.0070), and N-terminal pro B-type natriuretic peptide concentration in plasma -970 pg/mL (-1672 to -268, p= 0.0069). The frequency of adverse clinical events did not diff er between groups. Interpretation Omecamtiv mecarbil dosing guided by pharmacokinetics achieved plasma concentrations associated with improved cardiac function and decreased ventricular diameter. C1 [Teerlink, John R.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Teerlink, John R.] San Francisco VA Med Ctr, Cardiol Sect, San Francisco, CA USA. [Felker, G. Michael] Duke Univ, Sch Med, Div Cardiol, Durham, NC USA. [McMurray, John J. V.] Univ Glasgow, British Heart Fdn, Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Solomon, Scott D.] Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Solomon, Scott D.] Harvard Med Sch, Boston, MA USA. [Adams, Kirkwood F., Jr.] Univ North Carolina Chapel Hill, Div Cardiol, Chapel Hill, NC USA. [Cleland, John G. F.] Imperial Coll, Royal Brompton Hosp, Natl Heart & Lung Inst, London, England. [Cleland, John G. F.] Imperial Coll, Harefield Hosp, London, England. [Cleland, John G. F.] Univ Glasgow, Robertson Ctr Biostat & Clin Trials, Glasgow, Lanark, Scotland. [Ezekowitz, Justin A.] Univ Alberta, Dept Med, Edmonton, AB, Canada. [Goudev, Assen] Queen Giovanna Univ Hosp, Dept Cardiol, Sofia, Bulgaria. [Goudev, Assen] Med Univ Sofia, Sofia, Bulgaria. [Macdonald, Peter] St Vincents Hosp, Heart Transplant Unit, Sydney, NSW, Australia. [Macdonald, Peter] Victor Chang Cardiac Res Inst, Transplantat Res Lab, Sydney, NSW, Australia. [Macdonald, Peter] Univ New South Wales, Sydney, NSW, Australia. [Metra, Marco] Univ Brescia, Div Cardiol, Brescia, Italy. [Mitrovic, Veselin] Kerckhoff Klin Forsch Gesell, Frankfurt, Germany. [Mitrovic, Veselin] Goethe Univ Frankfurt, Mainz, Germany. [Ponikowski, Piotr] Med Univ, Dept Heart Dis, Wroclaw, Poland. [Ponikowski, Piotr] Mil Hosp, Ctr Heart Dis, Wroclaw, Poland. [Serpytis, Pranas] Vilnius Univ Hosp Santariskiu Klin, Emergency Ctr, Vilnius, Lithuania. [Serpytis, Pranas] Vilnius Univ, Vilnius, Lithuania. [Spinar, Jindrich] Univ Hosp Brno, Brno, Czech Republic. [Spinar, Jindrich] Masaryk Univ, Fac Med, Brno, Czech Republic. [Tomcsanyi, Janos] St John God Hosp, Dept Cardiol, Budapest, Hungary. [Vandekerckhove, Hans J.] AZ St Lucas, Dept Cardiol, Ghent, Belgium. [Voors, Adriaan A.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Monsalvo, Maria Laura; Johnston, James; Honarpour, Narimon] Amgen Inc, Thousand Oaks, CA USA. [Malik, Fady I.] Cytokinetics, San Francisco, CA USA. RP Teerlink, JR (reprint author), San Francisco VA Med Ctr, Cardiol, 111C,4150 Clement St, San Francisco, CA 94121 USA. EM john.teerlink@ucsf.edu OI mcmurray, john/0000-0002-6317-3975 FU Amgen; Cytokinetics FX Amgen.; The COSMIC-HF study was funded and done by Amgen in collaboration with Cytokinetics. NR 23 TC 1 Z9 1 U1 10 U2 10 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 DEC 10 PY 2016 VL 388 IS 10062 BP 2895 EP 2903 DI 10.1016/S0140-6736(16)32049-9 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EE5FU UT WOS:000389631700034 PM 27914656 ER PT J AU Brown, JC Meyerhardt, JA AF Brown, Justin C. Meyerhardt, Jeffrey A. TI Obesity and Energy Balance in GI Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID BODY-MASS INDEX; METASTATIC COLORECTAL-CANCER; GASTRIC-CARCINOMA PATIENTS; TREATMENT-RELATED TOXICITY; VISCERAL FAT ACCUMULATION; LONG-TERM SURVIVAL; III COLON-CANCER; HEPATOCELLULAR-CARCINOMA; PHYSICAL-ACTIVITY; PANCREATIC-CANCER AB The prevalence of overweight (body mass index [BMI], 25 to 29.9 kg/m(2)) and obesity (BMI $ 30 kg/m(2)) have increased dramatically in the United States. Because increasing BMI is associated with the development of multiple different cancer types, including most GI cancers, providers will frequently encounter patients with GI cancer who are overweight or obese. Mounting evidence associates overweight and/or obesitywithworsened prognosis in multiple GI cancers, including esophageal, gastric, hepatocellular, pancreatic, and colorectal. However, these data are observational and may be subject to bias and/or confounding. Furthermore, in some cancer types, the associations between BMI and outcomes is not linear, where overweight and class I obese patients may have an improvement in outcome. This report provides a brief highlight of existing studies that have linked overweight and/or obesity to prognosis in GI cancer; provides recommendations on best management practices; and discusses limitations, controversies, and future directions in this rapidly evolving area. There are multiple areas of promise that warrant continued investigation: What are the comparative contributions of energy balance, including weight, dietary patterns, and physical activity on cancer prognosis? What are the specific physiologic pathways that mediate the relationship between energy balance and prognosis? What is the relationship between low muscle mass (sarcopenia) or sarcopenic obesity and cancer prognosis? Are there subsets of patients for whom purposefully altering energy balance would be deleterious to prognosis? This area is rich with opportunities to understand how states of energy (im) balance can be favorably altered to promote healthy survivorship. (C) 2016 by American Society of Clinical Oncology C1 [Brown, Justin C.] Univ Penn, Philadelphia, PA 19104 USA. [Meyerhardt, Jeffrey A.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. RP Brown, JC (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM brown@dfci.harvard.edu FU National Cancer Institute [U54CA155850, R21CA182767, F31CA192560, R25CA092203, U54CA155626, R01CA149222, R01CA169141, R01CA118553] FX Supported by National Cancer Institute Grants No. U54CA155850, R21CA182767, F31CA192560, and R25CA092203 (J.C.B.); and U54CA155626, R01CA149222, R01CA169141, and R01CA118553 (J.A.M.). NR 75 TC 2 Z9 2 U1 18 U2 18 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 DEC 10 PY 2016 VL 34 IS 35 BP 4217 EP + DI 10.1200/JCO.2016.66.8699 PG 9 WC Oncology SC Oncology GA ED5YX UT WOS:000388931200003 PM 27903148 ER PT J AU Ligibel, JA Wollins, D AF Ligibel, Jennifer A. Wollins, Dana TI American Society of Clinical Oncology Obesity Initiative: Rationale, Progress, and Future Directions SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID BODY-MASS INDEX; CANCER SURVIVORS; BREAST-CANCER; PHYSICAL-ACTIVITY; PROSTATE-CANCER; METAANALYSIS; OVERWEIGHT; HEALTH; MORTALITY; OUTCOMES AB Obesity is increasingly being linked to the risk of developing and dying from cancer. In recognition of the growing contribution of obesity to cancer risk and outcomes, ASCO made obesity and cancer one of its core initiatives in 2014. The goals of this initiative included raising awareness of the relationship between obesity and cancer, providing tools and resources to oncology providers and patients to help encourage conversations regarding weight management in cancer survivors, fostering a robust research agenda, and advocating for access to evidence-based weight management programs for cancer survivors. Efforts to date have included developing patient and provider toolkits focused on weight management and physical activity, publishing a policy statement outlining ASCO's initiatives in this area, and hosting a summit focused on obesity research in cancer populations. As ASCO has defined its priorities in the area of obesity and cancer, it has become increasingly clear that obesity is a problem that extends far beyond its impact on cancer risk and outcomes. Many groups, including those focused on heart disease, diabetes, and endocrinology, have been developing, testing, and implementing obesity prevention and treatment strategies for years. As ASCO moves forward with its obesity initiative, the next steps will focus on forging collaboration with groups working on obesity-related initiatives both within and outside of the field of cancer to learn from their efforts and to partner with them on efforts to increase the education of medical professionals; raising awareness in lay populations regarding the negative health consequences of obesity and effective strategies to foster weight loss; developing collaborative research initiatives; and working together to advocate for the societal changes that will be needed to combat the obesity epidemic in the United States and beyond. (C) 2016 by American Society of Clinical Oncology C1 [Ligibel, Jennifer A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ligibel, Jennifer A.] Harvard Med Sch, Boston, MA USA. [Wollins, Dana] Amer Soc Clin Oncol, Alexandria, VA USA. RP Ligibel, JA (reprint author), Harvard Med Sch, Dana Farber Canc Inst, 450 Brookline Ave,Yawkey 1233, Boston, MA 02215 USA. EM jligibel@partners.org NR 37 TC 1 Z9 1 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 DEC 10 PY 2016 VL 34 IS 35 BP 4256 EP + DI 10.1200/JCO.2016.67.4051 PG 7 WC Oncology SC Oncology GA ED5YX UT WOS:000388931200008 PM 27903156 ER PT J AU Kudrimoti, M Curtis, A Azawi, S Worden, F Katz, S Adkins, D Bonomi, M Elder, J Sonis, ST Straube, R Donini, O AF Kudrimoti, Mahesh Curtis, Amarintha Azawi, Samar Worden, Francis Katz, Sanford Adkins, Douglas Bonomi, Marcelo Elder, Jenna Sonis, Stephen T. Straube, Richard Donini, Oreola TI Dusquetide: A novel innate defense regulator demonstrating a significant and consistent reduction in the duration of oral mucositis in preclinical data and a randomized, placebo-controlled phase 2a clinical study SO JOURNAL OF BIOTECHNOLOGY LA English DT Article DE Innate; Immune; Oral mucositis; Head and neck cancer; Cancer supportive care; Dusquetide ID NECK-CANCER; PALIFERMIN; RADIATION; THERAPY; GENE; HEAD; CHEMOTHERAPY; MECHANISMS; PREVENTION; MANAGEMENT AB Dusquetide, a novel Innate Defense Regulator, modulates the innate immune system at a key convergence point in intracellular signaling pathways and has demonstrated activity in both reducing inflammation and increasing clearance of bacterial infection. Innate immunity has also been implicated in the pathogenesis of oral mucositis (OM), a universal toxicity of chemoradiation therapy (CRT). Testing the hypothesis that dusquetide can mitigate the development and duration of OM, preclinical studies have been completed and correlated with interim results from a Phase 2 clinical study in patients undergoing CRT for head and neck cancer. Dusquetide reduced the duration of OM in mouse and hamster models by approximately 50%, which was recapitulated by the 50% reduction of severe OM (SOM) in the Phase 2 trial. A reduction in the clinical rate of infection was also observed, consistent with previously reported pre-clinical studies. In aggregate, these results not only demonstrate the safety and efficacy of dusquetide in addressing this unmet medical need, but also provide proof of concept for the translation of dusquetide action between animal models and the human clinical setting, and further support the contention that innate immunity is an important driver for the initiation and continued impact of OM. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license. C1 [Kudrimoti, Mahesh] Univ Kentucky, Radiat Oncol, 800 Rose St, Lexington, KY 40536 USA. [Curtis, Amarintha] Spartanburg Reg Hosp, Gibbs Canc Ctr, 101 E Wood, Spartanburg, SC 29303 USA. [Azawi, Samar] Vet Affairs Long Beach Hosp, 5901 E 7th St,Mail Code 114A, Long Beach, CA 98022 USA. [Worden, Francis] Univ Michigan Hlth Syst, Dept Med, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. [Katz, Sanford] Willis Knighton Canc Ctr, Dept Radiat Oncol, 2600 Kings Highway, Shreveport, LA 71103 USA. [Adkins, Douglas] Washington Univ, Div Hematol & Oncol, 660 South Euclid Ave, St Louis, MO 63110 USA. [Bonomi, Marcelo] Wake Forest Hlth Sci Med Ctr, Dept Hematol & Oncol, 1 Med Ctr Blvd, Winston Salem, NC 27157 USA. [Elder, Jenna] PharPoint Res, 5003S Miami Blvd 100, Durham, NC 27703 USA. [Sonis, Stephen T.] Brigham & Womens Hosp, Div Oral Med, 75 Francis St, Boston, MA 02115 USA. [Sonis, Stephen T.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sonis, Stephen T.] Biomodels LLC, 313 Pleasant St, Watertown, MA 02472 USA. [Straube, Richard; Donini, Oreola] Soligenix Inc, 29 Emmons Dr,Suite C-10, Princeton, NJ 08540 USA. RP Donini, O (reprint author), Soligenix Inc, 29 Emmons Dr,Suite C-10, Princeton, NJ 08540 USA. EM odonini@shaw.ca FU National Institute of Dental and Craniofacial Research Small Business Innovation Research grant [1R43 DE024032-01] FX Some of this work was supported by the National Institute of Dental and Craniofacial Research Small Business Innovation Research grant # 1R43 DE024032-01 (Soligenix, Inc). NR 32 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1656 EI 1873-4863 J9 J BIOTECHNOL JI J. Biotechnol. PD DEC 10 PY 2016 VL 239 BP 115 EP 125 DI 10.1016/j.jbiotec.2016.10.010 PG 11 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA EC5DJ UT WOS:000388153000018 PM 27746305 ER PT J AU Chen, HCI Burke, JF Cohen, AS AF Chen, Han-Chiao I. Burke, John F. Cohen, Akiva S. TI Editorial: Traumatic Brain Injury As a Systems Neuroscience Problem SO FRONTIERS IN SYSTEMS NEUROSCIENCE LA English DT Editorial Material DE traumatic brain injury; neural circuits; neural networks; systems neuroscience; neuromodulation C1 [Chen, Han-Chiao I.] Univ Penn, Perelman Sch Med, Dept Neurosurg, Philadelphia, PA 19104 USA. [Chen, Han-Chiao I.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Burke, John F.] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA USA. [Cohen, Akiva S.] Childrens Hosp Philadelphia, Dept Anesthesiol & Crit Care Med, Philadelphia, PA 19104 USA. [Cohen, Akiva S.] Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care Med, Philadelphia, PA 19104 USA. RP Chen, HCI (reprint author), Univ Penn, Perelman Sch Med, Dept Neurosurg, Philadelphia, PA 19104 USA.; Chen, HCI (reprint author), Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. EM saac.chen@uphs.upenn.edu NR 10 TC 0 Z9 0 U1 3 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5137 J9 FRONT SYST NEUROSCI JI Front. Syst. Neurosci. PD DEC 9 PY 2016 VL 10 AR 100 DI 10.3339/fnsys.2016.00100 PG 3 WC Neurosciences SC Neurosciences & Neurology GA EE5UM UT WOS:000389673200001 PM 28018187 ER PT J AU Arffa, ML Zapf, MA Kothari, AN Chang, V Gupta, GN Ding, X Al-Gayyar, MM Syn, W Elsherbiny, NM Kuo, PC Mi, Z AF Arffa, M. L. Zapf, M. A. Kothari, A. N. Chang, V. Gupta, G. N. Ding, X. Al-Gayyar, M. M. Syn, W. Elsherbiny, N. M. Kuo, P. C. Mi, Z. TI Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis SO PLOS ONE LA English DT Article ID GREEN TEA CATECHINS; FATTY LIVER-DISEASE; HEPATOCELLULAR-CARCINOMA; NONALCOHOLIC STEATOHEPATITIS; OXIDATIVE STRESS; EXPRESSION; GALLATE; RNA; CELLS; MODEL AB Osteopontin (OPN) promotes hepatic fibrosis, and developing therapies targeting OPN expression in settings of hepatic injury holds promise. The polyphenol epigallocatechin-3-gallate (EGCG), found in high concentrations in green tea, downregulates OPN expression through OPN mRNA degradation, but the mechanism is unknown. Previous work has shown that microRNAs can decrease OPN mRNA levels, and other studies have shown that EGCG modulates the expression of multiple microRNAs. In our study, we first demonstrated that OPN induces hepatic stellate cells to transform into an activated state. We then identified three microRNAs which target OPN mRNA: miR-181a, miR-10b, and miR-221. In vitro results show that EGCG upregulates all three microRNAs, and all three microRNAs are capable of down regulating OPN mRNA when administered alone. Interestingly, only miR-221 is necessary for EGCG-mediated OPN mRNA degradation and miR-221 inhibition reduces the effects of EGCG on cell function. In vivo experiments show that thioacetamide (TAA)-induced cell cytotoxicity upregulates OPN expression; treatment with EGCG blocks the effects of TAA. Furthermore, chronic treatment of EGCG in vivo upregulates all three microRNAs equally, suggesting that in more chronic treatment all three microRNAs are involved in modulating OPN expression. We conclude that in in vitro and in vivo models of TAA-induced hepatic fibrosis, EGCG inhibits OPN-dependent injury and fibrosis. EGCG works primarily by upregulating miR-221 to accelerate OPN degradation. EGCG may therefore have utility as a protective agent in settings of liver injury. C1 [Arffa, M. L.; Zapf, M. A.; Kothari, A. N.; Chang, V.; Gupta, G. N.; Ding, X.; Kuo, P. C.; Mi, Z.] Loyola Univ, Med Ctr, Dept Surg, Maywood, IL 60153 USA. [Al-Gayyar, M. M.; Elsherbiny, N. M.] Mansoura Univ, Dept Biochem, Fac Pharm, Mansoura, Egypt. [Syn, W.] Med Univ South Carolina, Div Gastroenterol & Hepatol, Charleston, SC 29425 USA. [Syn, W.] Ralph H Johnson Vet Affairs Med Ctr, Gastroenterol Sect, Charleston, SC USA. [Al-Gayyar, M. M.] Univ Tabuk, Dept Pharmaceut Chem, Tabuk, Saudi Arabia. RP Kuo, PC (reprint author), Loyola Univ, Med Ctr, Dept Surg, Maywood, IL 60153 USA. EM pkuo@lumc.edu OI Arffa, Matthew/0000-0002-9539-9100 NR 57 TC 0 Z9 0 U1 5 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 DEC 9 PY 2016 VL 11 IS 12 AR e0167435 DI 10.1371/journal.pone.0167435 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4PU UT WOS:000389587100097 PM 27935974 ER PT J AU Desmonde, S Avit, D Petit, J Folquet, MA Eboua, FT Bosse, CA Dainguy, E Mea, V Timite-Konan, M Ngbeche, S Ciaranello, A Leroy, V AF Desmonde, Sophie Avit, Divine Petit, Junie Folquet, Madeleine Amorissani Eboua, Francois Tanoh Bosse, Clarisse Amani Dainguy, Evelyne Mea, Vearonique Timite-Konan, Marguerite Ngbeche, Sylvie Ciaranello, Andrea Leroy, Valeriane TI Costs of Care of HIV-Infected Children Initiating Lopinavir/Ritonavir-Based Antiretroviral Therapy before the Age of Two in Cote d'Ivoire SO PLOS ONE LA English DT Article ID RESOURCE-LIMITED SETTINGS; PROGRAMS; EFFICIENCY; NEVIRAPINE; MORBIDITY; MORTALITY; INFANTS; ABIDJAN AB Objectives To access the costs of care for Ivoirian children before and after initiating LPV/r-based anti-retroviral therapy (ART) before the age of two. Methods We assessed the direct costs of care for all HIV-infected children over the first 12 months on LPV/r-based ART initiated <2 years of age in Abidjan. We recorded all drug prescriptions, ART and cotrimoxazole prophylaxis delivery, medical analyses/examinations and hospital admissions. We compared these costs to those accrued in the month prior to ART initiation. Costs and 95% confidence intervals (95% CI) were estimated per child-month, according to severe morbidity. Results Of the 114 children screened, 99 initiated LPV/r-based ART at a median age of 13.5 months (IQR: 6.8 - 18.6); 45% had reached World Health Organization stage 3 or 4. During the first 12 months on ART, 5% died and 3% were lost to follow-up. In the month before ART initiation, the mean cost of care per child-month reached $123.39 (95% CI:$121.02-$ 125.74). After ART initiation, it was $42.53 (95% CI:$42.15-$42.91); 50% were ART costs. The remaining costs were non-antiretroviral drugs (18%) and medical analyses/examinations (14%). Mean costs were significantly higher within the first three months on ART ($48.76, 95% CI:$47.95-$49.56) and in children experiencing severe morbidity ($49.76, 95% CI: $48.61-50.90). Conclusion ART reduces the overall monthly cost of care of HIV-infected children < 2 years. Because children were treated at an advanced HIV disease stage, the additional costs of treating severe morbidity on ART remain substantial. Strategies for treating HIV-infected children as early as possible must remain a priority in Cote d'Ivoire. C1 [Desmonde, Sophie] Bordeaux Univ, INSERM, U1219, Bordeaux, France. [Desmonde, Sophie; Petit, Junie] Bordeaux Univ, Inst Sante Publ Epidemiol & Dev, Bordeaux, France. [Desmonde, Sophie; Ciaranello, Andrea] Massachusetts Gen Hosp, Dept Med, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Avit, Divine; Folquet, Madeleine Amorissani; Eboua, Francois Tanoh; Bosse, Clarisse Amani; Mea, Vearonique; Timite-Konan, Marguerite] Programme PACCI, Site ANRS, Abidjan, Cote Ivoire. [Folquet, Madeleine Amorissani; Dainguy, Evelyne] Ctr Hosp Univ CHU Cocody, Serv Pediat, Abidjan, Cote Ivoire. [Timite-Konan, Marguerite] Ctr Hosp Univ CHU Yopougon, Serv Pediat, Abidjan, Cote Ivoire. [Ngbeche, Sylvie] Ctr Prise Charge Rech & Format CePReF, Serv Enfant, Abidjan, Cote Ivoire. [Ciaranello, Andrea] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Leroy, Valeriane] Univ Toulouse 3, INSERM, Unit 1027, Toulouse, France. RP Desmonde, S (reprint author), Bordeaux Univ, INSERM, U1219, Bordeaux, France.; Desmonde, S (reprint author), Bordeaux Univ, Inst Sante Publ Epidemiol & Dev, Bordeaux, France.; Desmonde, S (reprint author), Massachusetts Gen Hosp, Dept Med, Med Practice Evaluat Ctr, Boston, MA 02114 USA. EM Sophie.Desmonde@isped.u-bordeaux2.fr RI Leroy, Valeriane/F-8129-2013 OI Leroy, Valeriane/0000-0003-3542-8616 FU INSERM-ANRS; European and Developing Countries Clinical Trials Partnership (EDCTP); Centre pour la Recherche en Sante (CRP-Sante), Luxembourg; National Institute of Health through the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [R01HD079214]; Sidaction Young Investigator Award FX Overall support for the MONOD project was provided by the French INSERM-ANRS, the European and Developing Countries Clinical Trials Partnership (EDCTP) and the Centre pour la Recherche en Sante (CRP-Sante), Luxembourg. This study was supported in part by the National Institute of Health through the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) under award number R01HD079214. Sophie Desmonde is supported by the Sidaction Young Investigator Award. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of any of the institutions above. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 9 PY 2016 VL 11 IS 12 AR e0166466 DI 10.1371/journal.pone.0166466 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4PU UT WOS:000389587100027 PM 27935971 ER PT J AU Kareva, I Abou-Slaybi, A Dodd, O Dashevsky, O Klement, GL AF Kareva, Irina Abou-Slaybi, Abdo Dodd, Oliver Dashevsky, Olga Klement, Giannoula Lakka TI Normal Wound Healing and Tumor Angiogenesis as a Game of Competitive Inhibition SO PLOS ONE LA English DT Article ID PLATELET HEMOSTATIC FUNCTIONS; ENDOTHELIAL GROWTH-FACTOR; ALPHA-GRANULE PROTEINS; HEPARIN AFFINITY; RELEASE; ENDOSTATIN; CANCER; STROMA; CELLS AB Both normal wound healing and tumor angiogenesis are mitigated by the sequential, carefully orchestrated release of growth stimulators and inhibitors. These regulators are released from platelet clots formed at the sites of activated endothelium in a temporally and spatially controlled manner, and the order of their release depends on their affinity to glycosaminoglycans (GAG) such as heparan sulfate (HS) within the extracellular matrix, and platelet open canallicular system. The formation of vessel sprouts, triggered by angiogenesis regulating factors with lowest affinities for heparan sulfate (e.g. VEGF), is followed by vessel-stabilizing PDGF-B or bFGF with medium affinity for HS, and by inhibitors such as PF-4 and TSP-1 with the highest affinities for HS. The invasive wound-like edge of growing tumors has an overabundance of angiogenesis stimulators, and we propose that their abundance out-competes angiogenesis inhibitors, effectively preventing inhibition of angiogenesis and vessel maturation. We evaluate this hypothesis using an experimentally motivated agent-based model, and propose a general theoretical framework for understanding mechanistic similarities and differences between the processes of normal wound healing and pathological angiogenesis from the point of view of competitive inhibition. C1 [Kareva, Irina; Abou-Slaybi, Abdo; Dodd, Oliver; Dashevsky, Olga; Klement, Giannoula Lakka] Tufts Med Ctr, Floating Hosp Children, Boston, MA 02111 USA. [Kareva, Irina] Arizona State Univ, Math Computat & Modeling Sci Ctr, Tempe, AZ USA. [Dodd, Oliver] MIT, Boston, MA USA. [Dashevsky, Olga] Harvard Med Sch, Dana Farber Canc Inst, Dept Med, Dept Med Oncol, Boston, MA USA. [Klement, Giannoula Lakka] Tufts Med Ctr, Floating Hosp Children, Pediat Hematol Oncol, Boston, MA 02111 USA. [Klement, Giannoula Lakka] Tufts Univ, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA. RP Klement, GL (reprint author), Tufts Med Ctr, Floating Hosp Children, Boston, MA 02111 USA.; Klement, GL (reprint author), Tufts Med Ctr, Floating Hosp Children, Pediat Hematol Oncol, Boston, MA 02111 USA.; Klement, GL (reprint author), Tufts Univ, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA. EM Giannoula.Klement@tufts.edu FU NIH [R01GM093050]; [R01GM093050-01A1] FX This work was supported by R01GM093050-01A1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We would like to acknowledge the editorial help of Allison Jenks in preparation of this manuscript. GLK would like to acknowledge funding from NIH R01GM093050 grant. NR 37 TC 0 Z9 0 U1 5 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 DEC 9 PY 2016 VL 11 IS 12 AR e0166655 DI 10.1371/journal.pone.0166655 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4PU UT WOS:000389587100039 PM 27935954 ER PT J AU Ramratnam, M Salama, G Sharma, RK Wang, DWR Smith, SH Banerjee, SK Huang, XN Gifford, LM Pruce, ML Gabris, BE Saba, S Shroff, SG Ahmad, F AF Ramratnam, Mohun Salama, Guy Sharma, Ravi K. Wang, David Wen Rui Smith, Stephen H. Banerjee, Sanjay K. Huang, Xueyin N. Gifford, Lindsey M. Pruce, Michele L. Gabris, Bethann E. Saba, Samir Shroff, Sanjeev G. Ahmad, Ferhaan TI Gene-Targeted Mice with the Human Troponin T R141W Mutation Develop Dilated Cardiomyopathy with Calcium Desensitization SO PLOS ONE LA English DT Article ID HEART-FAILURE; MOUSE HEARTS; MODEL; TRANSIENTS; PROTEINS AB Most studies of the mechanisms leading to hereditary dilated cardiomyopathy (DCM) have been performed in reconstituted in vitro systems. Genetically engineered murine models offer the opportunity to dissect these mechanisms in vivo. We generated a gene-targeted knock-in murine model of the autosomal dominant Arg141Trp (R141W) mutation in Tnnt2, which was first described in a human family with DCM. Mice heterozygous for the mutation (Tnnt2(R141W/+)) recapitulated the human phenotype, developing left ventricular dilation and reduced contractility. There was a gene dosage effect, so that the phenotype in Tnnt2(R141W/+) mice was attenuated by transgenic overexpression of wildtype Tnnt2 mRNA transcript. Male mice exhibited poorer survival than females. Biomechanical studies on skinned fibers from Tnnt2(R141W/+) hearts showed a significant decrease in pCa(50) (-log[Ca2+] required for generation of 50% of maximal force) relative to wildtype hearts, indicating Ca2+ desensitization. Optical mapping studies of Langendorff-perfused Tnnt2(R141W/+) hearts showed marked increases in diastolic and peak systolic intracellular Ca2+ ([Ca2+] i), and prolonged systolic rise and diastolic fall of [Ca2+] i. Perfused Tnnt2(R141W/+) hearts had slower intrinsic rates in sinus rhythm and reduced peak heart rates in response to isoproterenol. Tnnt2(R141W/+) hearts exhibited a reduction in phosphorylated phospholamban relative to wildtype mice. However, crossing Tnnt2(R141W/+) mice with phospholamban knockout (Pln(-/-)) mice, which exhibit increased Ca2+ transients and contractility, had no effect on the DCM phenotype. We conclude that the Tnnt2(R141W) mutation causes a Ca2+ desensitization and mice adapt by increasing Ca2+-transient amplitudes, which impairs Ca2+ handling dynamics, metabolism and responses to beta-adrenergic activation. C1 [Ramratnam, Mohun] Univ Wisconsin, Dept Med, Div Cardiovasc Med, Madison, WI USA. [Ramratnam, Mohun] William S Middleton Mem Vet Adm Med Ctr, Med Serv, Cardiol Sect, Madison, WI USA. [Ramratnam, Mohun; Salama, Guy; Sharma, Ravi K.; Wang, David Wen Rui; Banerjee, Sanjay K.; Huang, Xueyin N.; Pruce, Michele L.; Gabris, Bethann E.; Saba, Samir; Ahmad, Ferhaan] Univ Pittsburgh, UPMC Heart & Vasc Inst, Pittsburgh, PA 15260 USA. [Ramratnam, Mohun; Salama, Guy; Sharma, Ravi K.; Wang, David Wen Rui; Banerjee, Sanjay K.; Huang, Xueyin N.; Pruce, Michele L.; Gabris, Bethann E.; Saba, Samir; Ahmad, Ferhaan] Univ Pittsburgh, Dept Med, Div Cardiol, Pittsburgh, PA 15260 USA. [Smith, Stephen H.; Shroff, Sanjeev G.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. [Gifford, Lindsey M.; Ahmad, Ferhaan] Univ Iowa, Dept Internal Med, Carver Coll Med, Div Cardiovasc Med, Iowa City, IA 52242 USA. [Gifford, Lindsey M.; Ahmad, Ferhaan] Univ Iowa, Abboud Cardiovasc Res Ctr, Iowa City, IA 52242 USA. [Banerjee, Sanjay K.] Translat Hlth Sci & Technol Inst, Gurgaon, India. RP Ahmad, F (reprint author), Univ Pittsburgh, UPMC Heart & Vasc Inst, Pittsburgh, PA 15260 USA.; Ahmad, F (reprint author), Univ Pittsburgh, Dept Med, Div Cardiol, Pittsburgh, PA 15260 USA.; Ahmad, F (reprint author), Univ Iowa, Dept Internal Med, Carver Coll Med, Div Cardiovasc Med, Iowa City, IA 52242 USA.; Ahmad, F (reprint author), Univ Iowa, Abboud Cardiovasc Res Ctr, Iowa City, IA 52242 USA. EM ferhaan-ahmad@uiowa.edu FU National Heart, Lung, and Blood Institute (US) [U01 HL108642]; Ferhaan Ahmad National Heart, Lung, and Blood Institute (US) [R21 HL1098121]; Ferhaan Ahmad American Heart Association (US) [053531N, 0725359U] FX National Heart, Lung, and Blood Institute (US) Award Number: U01 HL108642 vertical bar Recipient: Ferhaan Ahmad National Heart, Lung, and Blood Institute (US) Award Number: R21 HL1098121 vertical bar Recipient: Ferhaan Ahmad American Heart Association (US) Award Number: Scientist Development Grant 053531N vertical bar Recipient: Ferhaan Ahmad American Heart Association (US) Award Number: 0725359U vertical bar Recipient: Sanjay Banerjee NR 42 TC 1 Z9 1 U1 1 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 DEC 9 PY 2016 VL 11 IS 12 AR e0167681 DI 10.1371/journal.pone.0167681 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4PU UT WOS:000389587100148 PM 27936050 ER PT J AU Liu, PK Liu, CH AF Liu, Philip K. Liu, Christina H. TI Epigenetics of amphetamine-induced sensitization: HDAC5 expression and microRNA in neural remodeling SO JOURNAL OF BIOMEDICAL SCIENCE LA English DT Article DE Amphetamine; Brain repair; Compartmentalization of iron oxide; MCE MRI; Drugs of abuse; Microglia; miRNA; Molecular imaging; Nanoparticles; Endogenous progenitors; Precision delivery; Signal sensitivity; Target specificity ID HISTONE DEACETYLASE INHIBITION; VENTRAL TEGMENTAL AREA; MRI CONTRAST AGENT; IN-VIVO; BEHAVIORAL SENSITIZATION; MAJOR DEPRESSION; GENE TRANSCRIPTS; PROGENITOR CELLS; LATERAL SEPTUM; HIV-INFECTION AB Background: Histone deacetylase (HDAC) activities modify chromatin structure and play a role in learning and memory during developmental processes. Studies of adult mice suggest HDACs are involved in neural network remodeling in brain repair, but its function in drug addiction is less understood. We aimed to examine in vivo HDAC5 expression in a preclinical model of amphetamine-induced sensitization (AIS) of behavior. We generated specific contrast agents to measure HDAC5 levels by in vivo molecular contrast-enhanced (MCE) magnetic resonance imaging (MRI) in amphetamine-naive mice as well as in mice with AIS. To validate the MRI results we used ex vivo methods including in situ hybridization, RT-PCR, immunohistochemistry, and transmision electron microscopy. Methods: We compared the expression of HDAC5 mRNA in an acute exposure paradigm (in which animals experienced a single drug exposure [A1]) and in a chronic-abstinence-challenge paradigm (in which animals were exposed to the drug once every other day for seven doses, then underwent 2 weeks of abstinence followed by a challenge dose [A7WA]). Control groups for each of these exposure paradigms were given saline. To delineate how HDAC5 expression was related to AIS, we compared the expression of HDAC5 mRNA at sequences where no known microRNA (miR) binds (hdac5AS2) and at sequences where miR-2861 is known to bind (miD2861). We synthesized and labeled phosphorothioated oligonucleic acids (sODN) of hdac5AS2 or miD2861 linked to superparamagentic iron oxide nanoparticles (SPION), and generated HDAC5-specific contrast agents (30 +/- 20 nm, diameter) for MCE MRI; the same sequences were used for primers for TaqMan (R) analysis (RT-qPCR) in ex vivo validation. In addition, we used subtraction R2* maps to identify regional HDAC5 expression. Results: Naive C57black6 mice that experience acute exposure to amphetamine (4 mg/kg, by injection intraperitoneally) show expression of both total and phosphorylated (S259) HDAC5 antigens in GFAP(+) and GFAP-cells, but the appearance of these cells was attenuated in the chronic paradigm. We found that MCE MRI reports HDAC5 mRNA with precision in physiological conditions because the HDAC5 mRNA copy number reported by TaqMan analysis was positively correlated (with a linear coefficient of 1.0) to the Delta R2* values (the frequency of signal reduction above background, 1/s) measured by MRI. We observed SPION-mid2861 as electron dense nanoparticles (EDNs) of less than 30 nm in the nucleus of the neurons, macrophages, and microglia, but not in glia and endothelia. We found no preferential distribution in any particular type of neural cells, but observed scattered EDNs of 60-150 nm (dia) in lysosomes. In the acute paradigm, mice pretreated with miD2861 (1.2 mmol/kg, i.p./icv) exhibited AIS similar to that exibited by mice in the chronic exposure group, which exhibited null response to mid2861 pretreatment. Moreover, SPION-miD2861 identified enhanced HDAC5 expression in the lateral septum and the striatum after amphetamine, where we found neurprogenitor cells coexpressing NeuN and GFAP. Conclusions: We conclude that miD2681 targets HDAC5 mRNA with precision similar to that of RT-PCR. Our MCE MRI detects RNA-bound nanoparticles (NPs) in vivo, and ex vivo validation methods confirm that EDNs do not accumulate in any particular cell type. As HDAC5 expression may help nullify AIS and identify progenitor cells, the precise delivery of miD2861 may serve as a vehicle for monitoring network remodeling with target specificity and signal sensitivity after drug exposure that identifies brain repair processes in adult animals. C1 [Liu, Philip K.] Massachusetts Gen Hosp, Dept Radiol, Mol Contrast Enhanced MRI Lab, Athinoula A Martinos Ctr Biomed Imaging, CNY149 2301 Thirteenth St, Charlestown, MA 02129 USA. Harvard Med Sch, CNY149 2301 Thirteenth St, Charlestown, MA 02129 USA. RP Liu, PK (reprint author), Massachusetts Gen Hosp, Dept Radiol, Mol Contrast Enhanced MRI Lab, Athinoula A Martinos Ctr Biomed Imaging, CNY149 2301 Thirteenth St, Charlestown, MA 02129 USA. EM philipl@nmr.mgh.harvard.edu FU NIH [R01EB013768, P30DK057521-14]; Boston Area Diabetes Endocrinology Research Center; [S10RR023009] FX This project was supported by NIH grants R01EB013768 (PK Liu), P30DK057521-14, the Boston Area Diabetes Endocrinology Research Center (J Avruch), and S10RR023009 (J Ackerman). NR 71 TC 0 Z9 0 U1 7 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1021-7770 EI 1423-0127 J9 J BIOMED SCI JI J. Biomed. Sci. PD DEC 8 PY 2016 VL 23 AR 90 DI 10.1186/s12929-016-0294-8 PG 20 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EF4HE UT WOS:000390285000001 PM 27931227 ER PT J AU Iaccarino, HF Singer, AC Martorell, AJ Rudenko, A Gao, F Gillingham, TZ Mathys, H Seo, J Kritskiy, O Abdurrob, F Adaikkan, C Canter, RG Rueda, R Brown, EN Boyden, ES Tsai, LH AF Iaccarino, Hannah F. Singer, Annabelle C. Martorell, Anthony J. Rudenko, Andrii Gao, Fan Gillingham, Tyler Z. Mathys, Hansruedi Seo, Jinsoo Kritskiy, Oleg Abdurrob, Fatema Adaikkan, Chinnakkaruppan Canter, Rebecca G. Rueda, Richard Brown, Emery N. Boyden, Edward S. Tsai, Li-Huei TI Gamma frequency entrainment attenuates amyloid load and modifies microglia SO NATURE LA English DT Article ID HIPPOCAMPAL PLACE CELLS; ALZHEIMERS-DISEASE; NEURONAL-ACTIVITY; BETA DEPOSITION; NEURAL CIRCUITS; VISUAL-CORTEX; AWAKE STATE; MOUSE MODEL; OSCILLATIONS; ACTIVATION AB Changes in gamma oscillations (20-50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer's disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40 Hz), but not other frequencies, reduces levels of amyloid-beta (A beta)(1-40) and A beta(1-42) isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with A beta. Subsequently, we designed a non-invasive 40 Hz light-flickering regime that reduced A beta(1-40) and A beta(1-42) levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer's-disease-associated pathology. C1 [Iaccarino, Hannah F.; Martorell, Anthony J.; Rudenko, Andrii; Gao, Fan; Gillingham, Tyler Z.; Mathys, Hansruedi; Seo, Jinsoo; Kritskiy, Oleg; Abdurrob, Fatema; Adaikkan, Chinnakkaruppan; Canter, Rebecca G.; Rueda, Richard; Brown, Emery N.; Tsai, Li-Huei] MIT, Picower Inst Learning & Memory, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Singer, Annabelle C.; Boyden, Edward S.] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Iaccarino, Hannah F.; Singer, Annabelle C.; Martorell, Anthony J.; Rudenko, Andrii; Gao, Fan; Gillingham, Tyler Z.; Mathys, Hansruedi; Seo, Jinsoo; Kritskiy, Oleg; Abdurrob, Fatema; Adaikkan, Chinnakkaruppan; Canter, Rebecca G.; Rueda, Richard; Brown, Emery N.; Boyden, Edward S.; Tsai, Li-Huei] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Singer, Annabelle C.; Boyden, Edward S.] MIT, Dept Biol Engn, MIT Media Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Singer, Annabelle C.; Boyden, Edward S.] MIT, Dept Brain & Cognit Sci, MIT Media Lab, E25-618, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Brown, Emery N.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tsai, Li-Huei] Broad Inst Harvard & MIT, Cambridge, MA 02139 USA. [Singer, Annabelle C.] Emory Univ, Georgia Inst Technol, Coulter Dept Biomed Engn, Atlanta, GA 30332 USA. [Rudenko, Andrii] CUNY, Dept Biol, New York, NY 10031 USA. RP Tsai, LH (reprint author), MIT, Picower Inst Learning & Memory, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Tsai, LH (reprint author), MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA.; Tsai, LH (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02139 USA. EM lhtsai@mit.edu FU Barbara J. Weedon Fellowship; National Institutes of Health (NIH) [1R01EY023173, 1DP1NS087724] FX We are grateful to S. Tonegawa and D. Roy for APP/PS1 mice, and E. Demmons, W. Raja, E. Wu, and B. Arkhurst and the Boyden laboratory for technical assistance. We thank members of the Tsai and Boyden laboratories, C. Moore, C. Deister, D. Rei, J. Penney, R. Madabhushi, A. Mungenast, A. Bero, and J. Young for discussions and comments on the paper. H.F.I. acknowledges the Cameron Hayden Lord Foundation and Barbara J. Weedon Fellowship; E.S.B. acknowledges the New York Stem Cell Foundation-Robertson Award, National Institutes of Health (NIH) 1R01EY023173, and NIH 1DP1NS087724; L.H.T. acknowledges the JPB Foundation, Belfer Neurodegeneration Consortium, Halls Family Foundation. and NIH RF1 AG047661. E.S.B. and E.N.B. acknowledge NIH ROI GM104948. NR 41 TC 3 Z9 3 U1 35 U2 35 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 DEC 8 PY 2016 VL 540 IS 7632 BP 230 EP + DI 10.1038/nature20587 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4CF UT WOS:000389548700049 PM 27929004 ER PT J AU Ferres, MA Bianchi, DW Siegel, AE Bronson, RT Huggins, GS Guedj, F AF Ferres, Millie A. Bianchi, Diana W. Siegel, Ashley E. Bronson, Roderick T. Huggins, Gordon S. Guedj, Faycal TI Perinatal Natural History of the Ts1Cje Mouse Model of Down Syndrome: Growth Restriction, Early Mortality, Heart Defects, and Delayed Development SO PLOS ONE LA English DT Article ID MIDTRIMESTER AMNIOCENTESIS; BEHAVIORAL ABNORMALITIES; CARDIAC ANOMALIES; SYNDROME FETUSES; SYNDROME MICE; MATERNAL AGE; SURVIVAL; PHENOTYPE; REGIONS; TRENDS AB Background The Ts1Cje model of Down syndrome is of particular interest for perinatal studies because affected males are fertile. This permits affected pups to be carried in wild-type females, which is similar to human pregnancies. Here we describe the early natural history and growth profiles of Ts1Cje embryos and neonates and determine if heart defects are present in this strain. Methods Pups were studied either on embryonic (E) day 15.5, or from postnatal (P) day 3 through weaning on P21. PCR amplification targeting the neomycin cassette (present in Ts1Cje) and Sry (present in males) was used to analyze pup genotypes and sex ratios. Body weights and lengths, as well as developmental milestones, were recorded in Ts1Cje mice and compared to their wild-type (WT) littermates. Histological evaluations were performed at E15.5 to investigate the presence or absence of heart defects. Pups were divided into two groups: Ts1Cje-I pups survived past weaning and Ts1Cje-II pups died at some point before P21. Results Ts1Cje mouse embryos showed expected Mendelian ratios (45.8%, n = 66 for Ts1Cje embryos; 54.2%, n = 78 for WT embryos). Histological analysis revealed the presence of ventricular septal defects (VSDs) in 21% of Ts1Cje E15.5 embryos. After weaning, only 28.2% of pups were Ts1Cje (185 Ts1Cje out of 656 total pups generated), with males predominating (male: female ratio of 1.4:1). Among the recovered dead pups (n = 207), Ts1Cje (63.3%, n = 131, p<0.01) genotype was found significantly more often than WT (36.7%, n = 76). Retrospective analysis of Ts1Cje-II (pre-weaning deceased) pups showed that they were growth restricted compared to Ts1Cje-I pups (post-weaning survivors). Growth restriction correlated with statistically significant delays in achieving several neonatal milestones between P3 and P21 compared to Ts1Cje-I (post-weaning survivors) neonates and WT littermates. Conclusions Ts1Cje genotype is not associated with increased early in utero mortality. Cardiac defects, specifically VSDs, are part of the phenotype in this strain. There is increased neonatal mortality in Ts1Cje pups, with sex differences observed. Ts1Cje mice that died in the neonatal period were more likely to be growth restricted and delayed in achieving neonatal developmental milestones. C1 [Ferres, Millie A.; Bianchi, Diana W.; Siegel, Ashley E.; Guedj, Faycal] Tufts Med Ctr, MIRI, Boston, MA 02111 USA. [Ferres, Millie A.; Bianchi, Diana W.; Siegel, Ashley E.; Guedj, Faycal] Floating Hosp Children, Boston, MA 02116 USA. [Ferres, Millie A.] Beth Israel Deaconess Med Ctr, Div Maternal Fetal Med, Dept Obstet & Gynecol, Boston, MA 02215 USA. [Bronson, Roderick T.] Dana Farber Harvard Canc Ctr, Rodent Histopathol Core, Boston, MA USA. [Huggins, Gordon S.] Tufts Med Ctr, Mol Cardiol Res Inst, Boston, MA USA. RP Ferres, MA; Guedj, F (reprint author), Tufts Med Ctr, MIRI, Boston, MA 02111 USA.; Ferres, MA; Guedj, F (reprint author), Floating Hosp Children, Boston, MA 02116 USA.; Ferres, MA (reprint author), Beth Israel Deaconess Med Ctr, Div Maternal Fetal Med, Dept Obstet & Gynecol, Boston, MA 02215 USA. EM mferres@bidmc.harvard.edu; faycal.guedj@tufts.edu FU Verinata Health, Inc., an Illumina company [250-10396-12547000001]; Tufts Clinical and Translational Science Institute (CTSI, NIH) [UL1TR001064] FX This work was sponsored by a research grant from Verinata Health, Inc., an Illumina company, Grant Number: 250-10396-12547000001. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We would like to acknowledge the Department of Laboratory Animal Medicine (DLAM) for providing helpful advice concerning breeding strategies; Tufts University Histology Core for their help in sectioning and staining the embryo hearts; and Dr. Lauren Richey (DLAM); and Tufts Clinical and Translational Science Institute (CTSI, NIH award UL1TR001064) for assistance with the statistical analysis. After submission of this paper for consideration of publication, another study was published demonstrating the presence of heart defects in the Ts1Cje mouse model of DS (Li et al, 2016, PMID 27029737) [35]. NR 35 TC 0 Z9 0 U1 1 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 DEC 8 PY 2016 VL 11 IS 12 AR e0168009 DI 10.1371/journal.pone.0168009 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4OA UT WOS:000389580900070 PM 27930746 ER PT J AU Morieri, ML Shah, H Doria, A AF Morieri, Mario L. Shah, Hetal Doria, Alessandro CA Action Control Cardiovasc Risk Dia TI Variants in ANGPTL4 and the Risk of Coronary Artery Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Morieri, Mario L.; Shah, Hetal; Doria, Alessandro] Joslin Diabet Ctr, Boston, MA 02215 USA. RP Doria, A (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA. EM alessandro.doria@joslin.harvard.edu NR 3 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 DEC 8 PY 2016 VL 375 IS 23 BP 2304 EP 2305 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EE0ZQ UT WOS:000389310000023 PM 28112899 ER PT J AU Fathi, AT Graubert, TA Kulkarni, NM Kuo, FC Hasserjian, RP AF Fathi, Amir T. Graubert, Timothy A. Kulkarni, Naveen M. Kuo, Frank C. Hasserjian, Robert P. TI Case 37-2016: An 86-Year-Old Woman with Leukocytosis and Splenomegaly SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CHRONIC NEUTROPHILIC LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; CLONAL HEMATOPOIESIS; ATYPICAL CML; MYELOPROLIFERATIVE NEOPLASMS; MYELODYSPLASTIC SYNDROMES; CSF3R MUTATIONS; DIAGNOSIS; GENETICS; REVISION C1 [Fathi, Amir T.; Graubert, Timothy A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Kulkarni, Naveen M.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kuo, Frank C.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Fathi, Amir T.; Graubert, Timothy A.] Harvard Med Sch, Dept Med, Boston, MA USA. [Kulkarni, Naveen M.] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Kuo, Frank C.; Hasserjian, Robert P.] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Fathi, AT (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Fathi, AT (reprint author), Harvard Med Sch, Dept Med, Boston, MA USA. FU Merck; Juno Therapeutics; Tolero Pharmaceuticals; Baxalta; Celgene; Seattle Genetics; Amgen; Incyte; Sanofi; Promedior FX Dr. Fathi reports receiving fees for serving on advisory boards from Merck, Juno Therapeutics, Tolero Pharmaceuticals, and Baxalta, consulting fees from Celgene and Seattle Genetics, and clinical trial support from Celgene, Seattle Genetics, Takeda Pharmaceuticals, and Exelixis; and Dr. Hasserjian, receiving fees for serving on advisory boards from Amgen and Incyte and consulting fees from Sanofi and Promedior. No other potential conflict of interest relevant to this article was reported. NR 33 TC 0 Z9 0 U1 3 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 8 PY 2016 VL 375 IS 23 BP 2273 EP 2283 DI 10.1056/NEJMcpc1509539 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EE0ZQ UT WOS:000389310000012 PM 27959687 ER PT J AU Braunwald, E AF Braunwald, Eugene TI Treatment of Left Main Coronary Artery Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID ANGIOPLASTY; STENOSIS; SURGERY C1 [Braunwald, Eugene] Brigham & Womens Hosp, Cardiovasc Div, Thrombolysis Myocardial Infarct TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. [Braunwald, Eugene] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. RP Braunwald, E (reprint author), Brigham & Womens Hosp, Cardiovasc Div, Thrombolysis Myocardial Infarct TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA.; Braunwald, E (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA. NR 10 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 DEC 8 PY 2016 VL 375 IS 23 BP 2284 EP 2285 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EE0ZQ UT WOS:000389310000013 PM 27797298 ER PT J AU Krause, F Younger, ASE Baumhauer, JF Daniels, TR Glazebrook, M Evangelista, PT Pinzur, MS Thevendran, G Donahue, RMJ DiGiovanni, CW AF Krause, Fabian Younger, Alastair S. E. Baumhauer, Judith F. Daniels, Timothy R. Glazebrook, Mark Evangelista, Peter T. Pinzur, Michael S. Thevendran, Gowreeson Donahue, Rafe M. J. DiGiovanni, Christopher W. TI Clinical Outcomes of Nonunions of Hindfoot and Ankle Fusions SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID RETROGRADE INTRAMEDULLARY NAIL; FOOT FUNCTION INDEX; END-STAGE ANKLE; TIBIOTALOCALCANEAL ARTHRODESIS; SUBTALAR ARTHRODESIS; CONSECUTIVE PATIENTS; CIGARETTE-SMOKING; RISK-FACTORS; BONE-GRAFT; FIXATION AB Background: While nonunion after foot and ankle fusion surgery has been associated with poor outcomes, we are not aware of any longitudinal study on this subject. Thus, we prospectively evaluated the impact of nonunion on clinical outcomes of foot and ankle fusions and identified potential risk factors for nonunion after these procedures. Methods: Using data from a randomized clinical trial on recombinant human platelet-derived growth factor-BB (rhPDGF-BB; Augment Bone Graft, BioMimetic Therapeutics), union was defined either by assessment of computed tomography (CT) scans at 24 weeks by a reviewer blinded to the type of treatment or by the surgeon's composite assessment of clinical and radiographic findings at 52 weeks and CT findings at 24 or 36 weeks. The nonunion and union groups (defined with each assessment) were then compared in terms of clinical outcome scores on the American Orthopaedic Foot & Ankle Society Ankle-Hindfoot Scale (AOFAS-AHS), Foot Function Index (FFI), and Short Form-12 (SF-12) as well as age, sex, body mass index (BMI), smoking status, diabetes status, work status, and arthrodesis site. Results: Blinded CT assessment identified nonunion in 67 (18%) of 370 patients, and surgeon assessment found nonunion in 21 (5%) of 389 patients. Postoperatively, the nonunion group scored worse than the union group, regardless of the method used to define the nonunion, on the AOFAS-AHS and FFI, with mean differences of 10 and 12 points, respectively, when nonunion was determined by blinded CT assessment and 19 and 20 points when it was assessed by the surgeon. The nonunion group also had worse SF-12 Physical Component Summary scores. Differences between the union and nonunion groups were clinically meaningful for all outcome measures, regardless of the nonunion assessment method. The concept of an asymptomatic nonunion (i.e., imaging indicating nonunion but the patient doing well) was not supported. Patients with nonunion were more likely to be overweight, smokers, and not working. Conclusions: This prospective longitudinal study demonstrated poorer functional outcomes in patients with a nonunion after foot and ankle fusion, regardless of whether the diagnosis of nonunion was based on CT only or on combined clinical, radiographic, and CT assessment. C1 [Krause, Fabian; Younger, Alastair S. E.; Baumhauer, Judith F.; Daniels, Timothy R.; Glazebrook, Mark; Evangelista, Peter T.; Pinzur, Michael S.; Thevendran, Gowreeson; Donahue, Rafe M. J.; DiGiovanni, Christopher W.] Univ British Columbia, Collaborat North Amer Orthoped Foot & Ankle Study, Vancouver, BC V5Z 1M9, Canada. [Krause, Fabian] Univ Bern, Inselspital, Dept Orthopaed Surg, Bern, Switzerland. [Younger, Alastair S. E.] Univ British Columbia, Dept Orthopaed, Vancouver, BC, Canada. [Younger, Alastair S. E.] St Pauls Hosp, BCs Foot & Ankle Clin, Vancouver, BC, Canada. [Baumhauer, Judith F.] Univ Rochester, Sch Med, Dept Orthopaed, Rochester, NY USA. [Daniels, Timothy R.] St Michaels Hosp, Div Orthopaed Surg, Toronto, ON, Canada. [Daniels, Timothy R.] Univ Toronto, Toronto, ON, Canada. [Glazebrook, Mark] Dalhousie Univ, Halifax, NS, Canada. [Glazebrook, Mark] Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. [Evangelista, Peter T.; DiGiovanni, Christopher W.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Div Foot & Ankle Surg, Waltham, MA USA. [Evangelista, Peter T.; DiGiovanni, Christopher W.] Newton Wellesley Hosp, Waltham, MA USA. [Pinzur, Michael S.] Loyola Univ Hlth Syst, Dept Orthopaed Surg & Rehabil, Maywood, IL USA. [Thevendran, Gowreeson] Tock Seng Hosp, Dept Trauma & Orthopaed, Foot & Ankle Serv, Singapore, Singapore. [Donahue, Rafe M. J.] Wright Med NV, Franklin, TN USA. RP Younger, ASE (reprint author), Univ British Columbia, Collaborat North Amer Orthoped Foot & Ankle Study, Vancouver, BC V5Z 1M9, Canada.; Younger, ASE (reprint author), Univ British Columbia, Dept Orthopaed, Vancouver, BC, Canada.; Younger, ASE (reprint author), St Pauls Hosp, BCs Foot & Ankle Clin, Vancouver, BC, Canada. EM asyounger@shaw.ca FU BioMimetic Therapeutics, Inc. FX One author was an employee of BioMimetic Therapeutics, Inc. (Wright Medical, Inc.) at the time that this study was conducted. The remaining authors received funding to cover research costs through an unrestricted grant and/or were working as consultants for BioMimetic Therapeutics, Inc. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked "yes" to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work and "yes" to indicate that the author had a patent and/or copyright, planned, pending, or issued, broadly relevant to this work. NR 42 TC 0 Z9 0 U1 0 U2 0 PU JOURNAL BONE JOINT SURGERY PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02492 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD DEC 7 PY 2016 VL 98 IS 23 BP 2006 EP 2016 DI 10.2106/JBJS.14.00872 PG 11 WC Orthopedics; Surgery SC Orthopedics; Surgery GA EN4AF UT WOS:000395948700014 PM 27926682 ER PT J AU Schaefer, EAK Meixiong, J Mark, C Deik, A Motola, DL Fusco, D Yang, A Brisac, C Salloum, S Lin, WY Clish, CB Peng, LF Chung, RT AF Schaefer, Esperance A. K. Meixiong, James Mark, Christina Deik, Amy Motola, Daniel L. Fusco, Dahlene Yang, Andrew Brisac, Cynthia Salloum, Shadi Lin, Wenyu Clish, Clary B. Peng, Lee F. Chung, Raymond T. TI Apolipoprotein B100 is required for hepatitis C infectivity and Mipomersen inhibits hepatitis C SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Apolipoprotein; Lipid; Hepatitis C virus; Gene silencing; Viral replication ID HIGH-DENSITY-LIPOPROTEIN; VIRUS-PARTICLES; CELL-CULTURE; SCAVENGER RECEPTOR; VIRAL ENVELOPE; HEPG2 CELLS; LIFE-CYCLE; IN-VIVO; SR-BI; CHOLESTEROL AB AIM To characterize the role of apolipoprotein B100 (apoB100) in hepatitis C viral (HCV) infection. METHODS In this study, we utilize a gene editing tool, transcription activator-like effector nucleases (TALENs), to generate human hepatoma cells with a stable genetic deletion of APOB to assess of apoB in HCV. Using infectious cell culture-competent HCV, viral pseudoparticles, replicon models, and lipidomic analysis we determined the contribution of apoB to each step of the viral lifecycle. We further studied the effect of mipomersen, an FDA-approved antisense inhibitor of apoB100, on HCV using in vitro cell-culture competent HCV and determined its impact on viral infectivity with the TCID50 method. RESULTS We found that apoB100 is indispensable for HCV infection. Using the JFH-1 fully infectious cell-culture competent virus in Huh 7 hepatoma cells with TALEN-mediated gene deletion of apoB ( APOB KO), we found a significant reduction in HCV RNA and protein levels following infection. Pseudoparticle and replicon models demonstrated that apoB did not play a role in HCV entry or replication. However, the virus produced by APOB KO cells had significantly diminished infectivity as measured by the TCID-50 method compared to wildtype virus. Lipidomic analysis demonstrated that these virions have a fundamentally altered lipidome, with complete depletion of cholesterol esters. We further demonstrate that inhibition of apoB using mipomersen, an FDA-approved anti-sense oligonucleotide, results in a potent anti-HCV effect and significantly reduces the infectivity of the virus. CONCLUSION ApoB is required for the generation of fully infectious HCV virions, and inhibition of apoB with mipomersen blocks HCV. Targeting lipid metabolic pathways to impair viral infectivity represents a novel host targeted strategy to inhibit HCV. C1 [Schaefer, Esperance A. K.; Meixiong, James; Mark, Christina; Motola, Daniel L.; Fusco, Dahlene; Yang, Andrew; Brisac, Cynthia; Salloum, Shadi; Lin, Wenyu; Peng, Lee F.; Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Schaefer, Esperance A. K.; Motola, Daniel L.; Peng, Lee F.; Chung, Raymond T.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Deik, Amy; Clish, Clary B.] MIT, Broad Inst Harvard, Cambridge, MA 02142 USA. RP Peng, LF (reprint author), Temple Univ Hlth Syst, 3509 N Broad St,9th Floor, Philadelphia, PA 19140 USA. EM lee.peng@tuhs.temple.edu FU States National Institutes of Health (NIH) [F32-DK097855, T32-DK008191, K08-DK088951, K24-DK078772] FX Supported by the United States National Institutes of Health (NIH), No. F32-DK097855 (to Schaefer EAK), No. T32-DK008191 (to Motola DL), No. K08-DK088951 (to Peng LF), and No. K24-DK078772 (to Chung RT). NR 45 TC 0 Z9 0 U1 2 U2 2 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD DEC 7 PY 2016 VL 22 IS 45 BP 9954 EP 9965 DI 10.3748/wjg.v22.i45.9954 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EE8BC UT WOS:000389848200008 PM 28018102 ER PT J AU McEwan, DL Feinbaum, RL Stroustrup, N Haas, W Conery, AL Anselmo, A Sadreyev, R Ausubel, FM AF McEwan, Deborah L. Feinbaum, Rhonda L. Stroustrup, Nicholas Haas, Wilhelm Conery, Annie L. Anselmo, Anthony Sadreyev, Ruslan Ausubel, Frederick M. TI Tribbles ortholog NIPI-3 and bZIP transcription factor CEBP-1 regulate a Caenorhabditis elegans intestinal immune surveillance pathway SO BMC BIOLOGY LA English DT Article DE Surveillance immunity; Tribbles-like kinase; C/EBP; Pseudomonas aeruginosa; Exotoxin A; Translational inhibition; Caenorhabditis elegans; Innate epithelial immunity; Lifespan machine ID TRANSLATIONAL INHIBITION; DIFFERENTIAL EXPRESSION; SIGNALING PATHWAY; AXON REGENERATION; MAPK PHOSPHATASE; GENE-EXPRESSION; INNATE IMMUNITY; PROTEIN; PATHOGEN; INFECTION AB Background: Many pathogens secrete toxins that target key host processes resulting in the activation of immune pathways. The secreted Pseudomonas aeruginosa toxin Exotoxin A (ToxA) disrupts intestinal protein synthesis, which triggers the induction of a subset of P. aeruginosa-response genes in the nematode Caenorhabditis elegans. Results: We show here that one ToxA-induced C. elegans gene, the Tribbles pseudokinase ortholog nipi-3, is essential for host survival following exposure to P. aeruginosa or ToxA. We find that NIPI-3 mediates the post-developmental expression of intestinal immune genes and proteins and primarily functions in parallel to known immune pathways, including p38 MAPK signaling. Through mutagenesis screening, we identify mutants of the bZIP C/EBP transcription factor cebp-1 that suppress the hypersusceptibility defects of nipi-3 mutants. Conclusions: NIPI-3 is a negative regulator of CEBP-1, which in turn negatively regulates protective immune mechanisms. This pathway represents a previously unknown innate immune signaling pathway in intestinal epithelial cells that is involved in the surveillance of cellular homeostasis. Because NIPI-3 and CEBP-1 are also essential for C. elegans development, NIPI-3 is analogous to other key innate immune signaling molecules such as the Toll receptors in Drosophila that have an independent role during development. C1 [McEwan, Deborah L.; Feinbaum, Rhonda L.; Conery, Annie L.; Anselmo, Anthony; Sadreyev, Ruslan; Ausubel, Frederick M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [McEwan, Deborah L.; Feinbaum, Rhonda L.; Conery, Annie L.; Anselmo, Anthony; Sadreyev, Ruslan; Ausubel, Frederick M.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Stroustrup, Nicholas] Harvard Med Sch, Dept Syst Biol, Boston, MA USA. [Haas, Wilhelm] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Sadreyev, Ruslan] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Conery, Annie L.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Ausubel, FM (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Ausubel, FM (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. EM ausubel@molbio.mgh.harvard.edu FU National Institutes of Health [F32 AI098307, R01 AI085581, P30 DK040561]; Glenn Award from the Glenn Foundation for Medical Research FX This work was supported by National Institutes of Health grants F32 AI098307 awarded to DM, R01 AI085581 and P30 DK040561 awarded to FMA, and Glenn Award from the Glenn Foundation for Medical Research to NS. NR 56 TC 0 Z9 0 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD DEC 7 PY 2016 VL 14 AR 105 DI 10.1186/s12915-016-0334-6 PG 16 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EE4CV UT WOS:000389550600001 PM 27927200 ER PT J AU Flores, R Dohrmann, S Schaal, C Hakkim, A Nizet, V Corriden, R AF Flores, Roxana Dohrmann, Simon Schaal, Christina Hakkim, Abdul Nizet, Victor Corriden, Ross TI The Selective Estrogen Receptor Modulator Raloxifene Inhibits Neutrophil Extracellular Trap Formation SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE neutrophils; raloxifene; MRSA; host-pathogen interactions; extracellular traps ID INNATE IMMUNITY AB Raloxifene is a selective estrogen receptor modulator typically prescribed for the prevention/treatment of osteoporosis in postmenopausal women. Although raloxifene is known to have anti-inflammatory properties, its effects on human neutrophils, the primary phagocytic leukocytes of the immune system, remain poorly understood. Here, through a screen of pharmacologically active small molecules, we find that raloxifene prevents neutrophil cell death in response to the classical activator phorbol 12-myristate 13-acetate (PMA), a compound known to induce formation of DNA-based neutrophil extracellular traps (NETs). Inhibition of PMA-induced NET production by raloxifene was confirmed using quantitative and imaging-based assays. Human neutrophils from both male and female donors express the nuclear estrogen receptors ER alpha and ER beta, known targets of raloxifene. Similar to raloxifene, selective antagonists of these receptors inhibit PMA-induced NET production. Furthermore, raloxifene inhibited PMA- induced ERK phosphorylation, but not reactive oxygen species production, pathways known to be key modulators of NET production. Finally, we found that raloxifene inhibited PMA-induced, NET-based killing of the leading human bacterial pathogen, methicillin-resistant Staphylococcus aureus. Our results reveal that raloxifene is a potent modulator of neutrophil function and NET production. C1 [Flores, Roxana; Dohrmann, Simon; Nizet, Victor] Univ Calif San Diego, Dept Pediat, Div Host Microbe Syst & Therapeut, La Jolla, CA 92093 USA. [Schaal, Christina] Univ Vet Med Hannover, Dept Physiol Chem, Hannover, Germany. [Hakkim, Abdul] Harvard Med Sch, Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA USA. [Corriden, Ross] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. RP Corriden, R (reprint author), Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. EM rcorriden@ucsd.edu FU NIH [U54 HD071600, HD071600, AI057153, AI052453] FX This research was supported by NIH grants U54 HD071600, HD071600, AI057153, and AI052453 (to VN). NR 14 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD DEC 7 PY 2016 VL 7 AR 566 DI 10.3389/fimmu.2016.00566 PG 7 WC Immunology SC Immunology GA EE3GW UT WOS:000389476800001 PM 28003814 ER PT J AU Khalili, H Malik, S Ananthakrishnan, AN Garber, JJ Higuchi, LM Joshi, A Peloquin, J Richter, JM Stewart, KO Curhan, GC Awasthi, A Yajnik, V Chan, AT AF Khalili, Hamed Malik, Sakshi Ananthakrishnan, Ashwin N. Garber, John J. Higuchi, Leslie M. Joshi, Amit Peloquin, Joanna Richter, James M. Stewart, Kathleen O. Curhan, Gary C. Awasthi, Amit Yajnik, Vijay Chan, Andrew T. TI Identification and Characterization of a Novel Association between Dietary Potassium and Risk of Crohn's Disease and Ulcerative Colitis SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE inflammatory bowel disease; Crohn's disease; ulcerative colitis; dietary potassium; immune tolerance; T(H)17 pathway; Nurses' Health Study ID INFLAMMATORY-BOWEL-DISEASE; REGULATORY T-CELLS; FOOD FREQUENCY QUESTIONNAIRE; PATHOGENIC T(H)17 CELLS; PREMENOPAUSAL WOMEN; PHYSICAL-ACTIVITY; BREAST-CANCER; SUPPRESSIVE FUNCTION; OLMSTED COUNTY; TH17 CELLS AB Background: Recent animal studies have identified that dietary salt intake may modify the risk and progression of autoimmune disorders through modulation of the IL-23/T(H)17 pathway, which is critical in the pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD). Methods: We conducted a prospective study of U.S. women enrolled in the Nurses' Health Study (NHS) and NHSII who provided detailed and validated information on diet and lifestyle beginning in 1984 in NHS and 1991 in NHSII. We confirmed incident cases of UC and CD reported through 2010 in NHS and 2011 in NHSII. We used Cox proportional hazards models to calculate hazard ratios and 95% confidence intervals. In a case-control study nested within these cohorts, we evaluated the interaction between single nucleotide polymorphisms (SNPs) in genes involved in T(H)17 pathway and dietary potassium on risk of CD and UC. In a cohort of healthy volunteers, we also assessed the effect of supplemental potassium on development of naive and memory T cells, differentiated with TGF beta 1 or T(H)17 conditions. Results: Among a total of 194,711 women over a follow-up of 3,220,247 person-years, we documented 273 cases of CD and 335 cases of UC. Dietary intake of potassium (P-trend = 0.005) but not sodium (P-trend = 0.44) was inversely associated with risk of CD. Although, both dietary potassium and sodium were not significantly associated with risk of UC, there was a suggestion of an inverse association with dietary potassium (P-trend = 0.08). The association of potassium with risk of CD and UC appeared to be modified by loci involved in the T(H)17 pathway that have previously been associated with susceptibility to CD, particularly SNP rs7657746 (IL21) (P-interaction, = 0.004 and 0.01, respectively). In vitro, potassium enhanced the expression of Foxp3 in both naive and memory CD4(+) T cells via activating Smad2/3 and inhibiting Smad7 in T(H)17 cells. Conclusion: Dietary potassium is inversely associated with risk of CD with both in vitro and gene-environment interaction data suggesting a potential role for potassium in regulating immune tolerance through its effect on Tregs and T(H)17 pathway. C1 [Khalili, Hamed; Ananthakrishnan, Ashwin N.; Garber, John J.; Joshi, Amit; Richter, James M.; Stewart, Kathleen O.; Yajnik, Vijay; Chan, Andrew T.] Harvard Med Sch, Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Khalili, Hamed; Ananthakrishnan, Ashwin N.; Joshi, Amit; Chan, Andrew T.] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA. [Malik, Sakshi; Awasthi, Amit] NCR Biotech Sci Cluster, Translat Hlth Sci & Technol Inst, Faridabad, India. [Higuchi, Leslie M.] Harvard Med Sch, Boston Childrens Hosp, Div Gastroenterol & Nutr, Boston, MA USA. [Peloquin, Joanna] Johns Hopkins Sch Med, Div Gastroenterol & Hepatol, Baltimore, MD USA. [Curhan, Gary C.; Chan, Andrew T.] Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. RP Khalili, H; Yajnik, V; Chan, AT (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02115 USA.; Khalili, H; Chan, AT (reprint author), Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA.; Awasthi, A (reprint author), NCR Biotech Sci Cluster, Translat Hlth Sci & Technol Inst, Faridabad, India.; Chan, AT (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. EM hkhalili@mgh.harvard.edu; aawasthi@thsti.res.in; vyajnik@mgh.harvard.edu; achan@mgh.harvard.edu FU India Alliance DBT-Wellcome Trust fellowship [IA/I/12/1/500524]; Crohn's and Colitis Foundation of America (CCFA); American Gastroenterological Association (AGA); National Institute of Diabetes and Digestive and Kidney Diseases [K23 DK099681, K08 DK064256]; DBT-Wellcome Trust Intermediate fellowship; Council of Scientific and Industrial Research (CSIR), Govt. of India; [R01 CA050385]; [P01 CA87969]; [CA49449]; [CA67262]; [P30 DK043351]; [K24 DK098311]; [K24 DK91417]; [K23 DK091742]; [UM1 CA176726]; [UM1 CA186107] FX This study was funded by R01 CA050385, P01 CA87969, CA49449, CA67262, P30 DK043351, K23 DK099681, K08 DK064256, K24 DK098311, K24 DK91417, K23 DK091742, UM1 CA176726, UM1 CA186107, and India Alliance DBT-Wellcome Trust fellowship (IA/I/12/1/500524). Dr. AC is supported by a senior investigator grant from the Crohns and Colitis Foundation of America (CCFA). Dr. HK is supported by a career development award from the American Gastroenterological Association (AGA) and by National Institute of Diabetes and Digestive and Kidney Diseases (K23 DK099681). Dr. LH is supported by National Institute of Diabetes and Digestive and Kidney Diseases (K08 DK064256). Dr. AA is supported by DBT-Wellcome Trust Intermediate fellowship and Sakshi Malik is supported by a fellowship from Council of Scientific and Industrial Research (CSIR), Govt. of India. NR 48 TC 0 Z9 0 U1 2 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD DEC 7 PY 2016 VL 7 AR 554 DI 10.3389/fimmu.2016.00554 PG 12 WC Immunology SC Immunology GA EE3GF UT WOS:000389475100001 PM 28003811 ER PT J AU Rosenblatt, J Stone, RM Uhl, L Neuberg, D Joyce, R Levine, JD Arnason, J McMasters, M Luptakova, K Jain, S Zwicker, JI Hamdan, A Boussiotis, V Steensma, DP DeAngelo, DJ Galinsky, I Dutt, PS Logan, E Bryant, MP Stroopinsky, D Werner, L Palmer, K Coll, M Washington, A Cole, L Kufe, D Avigan, D AF Rosenblatt, Jacalyn Stone, Richard M. Uhl, Lynne Neuberg, Donna Joyce, Robin Levine, James D. Arnason, Jon McMasters, Malgorzata Luptakova, Katarina Jain, Salvia Zwicker, Jeffrey I. Hamdan, Ayad Boussiotis, Vassiliki Steensma, David P. DeAngelo, Daniel J. Galinsky, Ilene Dutt, Poorvi Somaiya Logan, Emma Bryant, Mary Paty Stroopinsky, Dina Werner, Lillian Palmer, Kristen Coll, Max Washington, Abigail Cole, Leandra Kufe, Donald Avigan, David TI Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions SO Science Translational Medicine LA English DT Article ID ACUTE MYELOID-LEUKEMIA; CYTOTOXIC T-LYMPHOCYTES; WT1 PEPTIDE VACCINATION; MULTIPLE-MYELOMA; CARCINOMA-CELLS; DENDRITIC CELLS; CLINICAL-RESPONSES; OLDER PATIENTS; FUSIONS; ANTIGEN AB We developed a personalized cancer vaccine in which patient-derived acute myeloid leukemia (AML) cells are fused with autologous dendritic cells, generating a hybridoma that potently stimulates broad antitumor responses. We report results obtained from the first 17 AML patients, who achieved remission after chemotherapy and were then serially vaccinated to target minimal residual disease and prevent relapse. Vaccination was well tolerated and induced inflammatory responses at the site of administration, characterized by the dense infiltration of T cells. Vaccination was also associated with a marked rise in circulating T cells recognizing whole AML cells and leukemia-specific antigens that persisted for more than 6 months. Twelve of 17 vaccinated patients (71%; 90% confidence interval, 52 to 89%) remain alive without recurrence at a median follow-up of 57 months. The results demonstrate that personalized vaccination of AML patients in remission induces the expansion of leukemia-specific T cells and may be protective against disease relapse. C1 [Rosenblatt, Jacalyn; Uhl, Lynne; Joyce, Robin; Levine, James D.; Arnason, Jon; McMasters, Malgorzata; Luptakova, Katarina; Jain, Salvia; Zwicker, Jeffrey I.; Hamdan, Ayad; Boussiotis, Vassiliki; Dutt, Poorvi Somaiya; Logan, Emma; Bryant, Mary Paty; Stroopinsky, Dina; Palmer, Kristen; Coll, Max; Washington, Abigail; Cole, Leandra; Avigan, David] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Stone, Richard M.; Neuberg, Donna; Steensma, David P.; DeAngelo, Daniel J.; Galinsky, Ilene; Werner, Lillian; Kufe, Donald] Dana Farber Canc Inst, Boston, MA 02215 USA. RP Rosenblatt, J (reprint author), Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. EM jrosenb1@bidmc.harvard.edu FU NIH/NCI [R21CA149987-02]; Leukemia and Lymphoma Society Translational Research Program FX This work was supported by NIH/NCI R21CA149987-02 (J.R.) and the Leukemia and Lymphoma Society Translational Research Program (D.A.). NR 27 TC 0 Z9 0 U1 2 U2 2 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 DEC 7 PY 2016 VL 8 IS 368 AR 368ra171 DI 10.1126/scitranslmed.aag1298 PG 7 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EE2XY UT WOS:000389450500001 PM 27928025 ER PT J AU Comper, WD Russo, LM Vuchkova, J AF Comper, W. D. Russo, L. M. Vuchkova, J. TI Are filtered plasma proteins processed in the same way by the kidney? SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE Proteinuria; Albuminuria; Glomerular filter; Proximal tubular uptake; Retrieval pathway; Renal degradation pathway ID GLOMERULAR-FILTRATION BARRIER; DEPENDENT DIABETES-MELLITUS; NEGATIVELY CHARGED FICOLL; MOLECULAR-WEIGHT PROTEINS; PROXIMAL TUBULE CELLS; FRACTIONAL CLEARANCE; NEPHROTIC SYNDROME; SIZE-SELECTIVITY; RENAL PASSAGE; AMINONUCLEOSIDE NEPHROSIS AB In order to understand the mechanism of albuminuria we have explored how other plasma proteins are processed by the kidney as compared to inert molecules like Ficolls. When fractional clearances are plotted versus protein radius there is a remarkable parallelism between protein (molecular weight range 30150 kDa) clearance in healthy controls, in Dent's disease, in nephrotic states and the clearance of Ficolls. Although there are significant differences in the levels of fractional clearances in these states. Dent's disease results in a 2-fold increase in the fractional clearance of proteins as compared to healthy controls whereas in nephrotic states there is a further 3-fold increase in fractional clearance. Previous thinking that albumin uptake was controlled primarily by the megalin/cubilin receptor does not explain the albumin urinary excretion data and is therefore an incorrect concept. Protein clearance in nephrotic states approach the fractional clearance of inert Ficolls for a given radius. It therefore appears that there are two pathways processing these proteins. A low capacity pathway associated with megalin/cubilin that degrades filtered protein (that is inhibited in Dent's disease) and a high capacity pathway that retrieves the filtered protein and returns it to the blood supply (without retrieval nephrotic protein excretion will occur and this will account for hypoproteinemia). On the other hand low molecular weight proteins (< 20 kDa) are processed entirely differently by the kidney. They are not retrieved but are comprehensively degraded in the kidney with the degradation products predominantly returned to the blood supply. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Comper, W. D.] SalAqua Diagnost, New York, NY 10019 USA. [Comper, W. D.] Kantum Diagnost, Concord, NH 03301 USA. [Russo, L. M.] Massachusetts Gen Hosp, Syst Biol, Boston, MA 02114 USA. [Vuchkova, J.] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic, Australia. RP Comper, WD (reprint author), SalAqua Diagnost, New York, NY 10019 USA.; Comper, WD (reprint author), Kantum Diagnost, Concord, NH 03301 USA. EM wcomper@hotmail.com NR 83 TC 0 Z9 0 U1 4 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 EI 1095-8541 J9 J THEOR BIOL JI J. Theor. Biol. PD DEC 7 PY 2016 VL 410 BP 18 EP 24 DI 10.1016/j.jtbi.2016.09.013 PG 7 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA ED5SO UT WOS:000388912800003 PM 27647256 ER PT J AU Fischer, DB Boes, AD Demertzi, A Evrard, HC Laureys, S Edlow, BL Liu, HS Saper, CB Pascual-Leone, A Fox, MD Geerling, JC AF Fischer, David B. Boes, Aaron D. Demertzi, Athena Evrard, Henry C. Laureys, Steven Edlow, Brian L. Liu, Hesheng Saper, Clifford B. Pascual-Leone, Alvaro Fox, Michael D. Geerling, Joel C. TI A human brain network derived from coma-causing brainstem lesions SO NEUROLOGY LA English DT Article ID INTRINSIC FUNCTIONAL CONNECTIVITY; LOCKED-IN SYNDROME; ANTERIOR CINGULATE; CONSCIOUSNESS; CORTEX; NEURONS; FLUCTUATIONS; REFLECTS; SLEEP; APES AB Objective: To characterize a brainstem location specific to coma-causing lesions, and its functional connectivity network. Methods: We compared 12 coma-causing brainstem lesions to 24 control brainstem lesions using voxel-based lesion-symptom mapping in a case-control design to identify a site significantly associated with coma. We next used resting-state functional connectivity from a healthy cohort to identify a network of regions functionally connected to this brainstem site. We further investigated the cortical regions of this network by comparing their spatial topography to that of known networks and by evaluating their functional connectivity in patients with disorders of consciousness. Results: A small region in the rostral dorsolateral pontine tegmentum was significantly associated with coma-causing lesions. In healthy adults, this brainstem site was functionally connected to the ventral anterior insula (AI) and pregenual anterior cingulate cortex (pACC). These cortical areas aligned poorly with previously defined resting-state networks, better matching the distribution of von Economo neurons. Finally, connectivity between the AI and pACC was disrupted in patients with disorders of consciousness, and to a greater degree than other brain networks. Conclusions: Injury to a small region in the pontine tegmentum is significantly associated with coma. This brainstem site is functionally connected to 2 cortical regions, the AI and pACC, which become disconnected in disorders of consciousness. This network of brain regions may have a role in the maintenance of human consciousness. C1 [Fischer, David B.; Boes, Aaron D.; Pascual-Leone, Alvaro; Fox, Michael D.] Harvard Med Sch, Dept Neurol, Div Cognit Neurol, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA 02115 USA. [Edlow, Brian L.; Saper, Clifford B.; Pascual-Leone, Alvaro; Fox, Michael D.; Geerling, Joel C.] Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Fischer, David B.] Harvard Med Sch, Boston, MA 02115 USA. [Boes, Aaron D.] Harvard Med Sch, Dept Pediat Neurol, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. [Demertzi, Athena] Hop La Pitie Salpetriere, Inst Cerveau & Moelle Epiniere ICM, Brain & Spine Inst, Paris, France. [Demertzi, Athena; Laureys, Steven] Univ Liege, GIGA Res, Coma Sci Grp, Liege, Belgium. [Demertzi, Athena; Laureys, Steven] Univ Liege, Cyclotron Res Ctr, Liege, Belgium. [Demertzi, Athena; Laureys, Steven] Univ Hosp Liege, GIGA Res, Coma Sci Grp, Liege, Belgium. [Demertzi, Athena; Laureys, Steven] Univ Hosp Liege, Cyclotron Res Ctr, Liege, Belgium. [Evrard, Henry C.] Ctr Integrat Neurosci, Funct & Comparat Neuroanat Lab, Tubingen, Germany. [Evrard, Henry C.] Max Planck Inst Biol Cybernet, Tubingen, Germany. [Edlow, Brian L.; Liu, Hesheng; Fox, Michael D.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM d.b.fisch@gmail.com; foxmdphd@gmail.com OI Demertzi, Athena/0000-0001-8021-3759 FU Howard Hughes Medical Institute; Parkinson's Disease Foundation; NIH [S10RR023043, K23NS083741, R01HD069776, R01NS073601, R01NS085477, R21MH099196, R21NS082870, R21NS085491, R21HD07616, R25NS065743, R25NS070682, T32 HL007901, P01HL095491]; Academy of Neurology/American Brain Foundation; Sidney R. Baer, Jr. Foundation; Harvard Catalyst; Belgian National Funds for Scientific Research; European Commission; James McDonnell Foundation; European Space Agency; Mind Science Foundation; French Speaking Community Concerted Research Action [ARC-06/11-340]; Public Utility Foundation "Universite Europeenne du Travail"; Fondazione Europea di Ricerca Biomedica; University and University Hospital of Liege; Center for Integrative Neuroscience; Max Planck Society FX This work was supported by the Howard Hughes Medical Institute, the Parkinson's Disease Foundation, the NIH (Shared Instrument Grant S10RR023043, K23NS083741, R01HD069776, R01NS073601, R01NS085477, R21MH099196, R21NS082870, R21NS085491, R21HD07616, R25NS065743, R25NS070682, T32 HL007901, P01HL095491), American Academy of Neurology/American Brain Foundation, Sidney R. Baer, Jr. Foundation, Harvard Catalyst, the Belgian National Funds for Scientific Research, the European Commission, the James McDonnell Foundation, the European Space Agency, Mind Science Foundation, the French Speaking Community Concerted Research Action (ARC-06/11-340), the Public Utility Foundation "Universite Europeenne du Travail," "Fondazione Europea di Ricerca Biomedica," the University and University Hospital of Liege, the Center for Integrative Neuroscience, and the Max Planck Society. NR 40 TC 3 Z9 3 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD DEC 6 PY 2016 VL 87 IS 23 BP 2427 EP 2434 DI 10.1212/WNL.0000000000003404 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EI1MQ UT WOS:000392241900011 PM 27815400 ER PT J AU Moura, LMVR Schwamm, E Junior, VM Seitz, MP Hsu, J Cole, AJ Schwamm, LH AF Moura, Lidia M. V. R. Schwamm, Eli Junior, Valdery Moura Seitz, Michael P. Hsu, John Cole, Andrew J. Schwamm, Lee H. TI Feasibility of the collection of patient-reported outcomes in an ambulatory neurology clinic SO NEUROLOGY LA English DT Article ID QUALITY-OF-LIFE; PAPER QUESTIONNAIRES; CANCER PATIENTS; PHONE SURVEY; TABLET; EPILEPSY; CARE; DISPARITIES; COMPUTERS; COVERAGE AB Objective: To determine whether patients could self-report physical and mental health assessments in the waiting room and whether these assessments would be associated with modified Rankin Scale (mRS) and Quality of Life in Epilepsy (QOLIE-10) scores. Methods: We offered iPad-based surveys to consecutive adult neurology patients at check-in to collect patient-reported outcome measures (PROMs). We collected demographic and clinical data on 6,075 patients through survey or administrative claims and PROMs from participating patients. We compared demographic characteristics of participants and nonparticipants and tested associations between physical and mental health scores and mRS and QOLIE-10. Results: Of 6,075 patients seen by neurologists during the study period, 2,992 (49.3%) participated in the survey. Compared to nonparticipating patients, participating patients more often were privately insured (53.5% vs 42.7%, p < 0.01), married (51.5% vs 47.9%, p < 0.01), and seen in general neurology (nonsubspecialty) clinics (53.1% vs 46.6%, p < 0.01) and more likely to report English as their preferred language (50.1% vs 38.4%, p < 0.01). Participating patients had a mean physical health T score of 28.7 (SD 15) and mental health T score of 33 (SD 15), which were 3 and 2 SD worse than the average for the US general population, respectively. Mean T scores in every category of the mRS were different from every other category (n = 232, p < 0.01). Patient Reported Outcomes Measurement Information System-10 T scores were linearly associated with QOLIE-10 scores (n = 202, p < 0.01) Conclusions: Systematic digital collection of PROMs is feasible. Differences among survey participants and nonparticipants highlight the need to develop multilingual measurement tools that may improve collection from vulnerable populations. C1 [Moura, Lidia M. V. R.; Schwamm, Eli; Junior, Valdery Moura; Seitz, Michael P.; Cole, Andrew J.; Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Hsu, John] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. EM lidia.moura@mgh.harvard.edu FU Massachusetts General Hospital Department of Neurology FX Study funded by Massachusetts General Hospital Department of Neurology. NR 37 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD DEC 6 PY 2016 VL 87 IS 23 BP 2435 EP 2442 DI 10.1212/WNL.0000000000003409 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EI1MQ UT WOS:000392241900013 PM 27815405 ER PT J AU Hohman, TJ McLaren, DG Mormino, EC Gifford, KA Libon, DJ Jefferson, AL AF Hohman, Timothy J. McLaren, Donald G. Mormino, Elizabeth C. Gifford, Katherine A. Libon, David J. Jefferson, Angela L. CA Alzheimer's Dis Neuroimaging TI Asymptomatic Alzheimer disease Defining resilience SO NEUROLOGY LA English DT Article ID NEUROIMAGING INITIATIVE ADNI; SURFACE-BASED ANALYSIS; COGNITIVE RESERVE; CORTICAL SURFACE; OLDER-ADULTS; AMYLOID DEPOSITION; COORDINATE SYSTEM; COMPOSITE SCORE; HIPPOCAMPAL; MEMORY AB Objective: To define robust resilience metrics by leveraging CSF biomarkers of Alzheimer disease (AD) pathology within a latent variable framework and to demonstrate the ability of such metrics to predict slower rates of cognitive decline and protection against diagnostic conversion. Methods: Participants with normal cognition (n = 297) and mild cognitive impairment (n = 432) were drawn from the Alzheimer's Disease Neuroimaging Initiative. Resilience metrics were defined at baseline by examining the residuals when regressing brain aging outcomes (hippocampal volume and cognition) on CSF biomarkers. A positive residual reflected better outcomes than expected for a given level of pathology (high resilience). Residuals were integrated into a latent variable model of resilience and validated by testing their ability to independently predict diagnostic conversion, cognitive decline, and the rate of ventricular dilation. Results: Latent variables of resilience predicted a decreased risk of conversion (hazard ratio < 0.54, p < 0.0001), slower cognitive decline (beta > 0.02, p < 0.001), and slower rates of ventricular dilation (beta < -4.7, p < 2 x 10(-15)). These results were significant even when analyses were restricted to clinically normal individuals. Furthermore, resilience metrics interacted with biomarker status such that biomarker-positive individuals with low resilience showed the greatest risk of subsequent decline. Conclusions: Robust phenotypes of resilience calculated by leveraging AD biomarkers and baseline brain aging outcomes provide insight into which individuals are at greatest risk of short-term decline. Such comprehensive definitions of resilience are needed to further our understanding of the mechanisms that protect individuals from the clinical manifestation of AD dementia, especially among biomarker-positive individuals. C1 [Hohman, Timothy J.; Gifford, Katherine A.; Jefferson, Angela L.] Vanderbilt Univ, Med Ctr, Vanderbilt Memory & Alzheimers Ctr, Nashville, TN 37232 USA. [McLaren, Donald G.] Biospective Inc, Montreal, PQ, Canada. [Mormino, Elizabeth C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Libon, David J.] Rowan Univ, Sch Osteopath Med, New Jersey Inst Successful Aging, Dept Geriatr & Gerontol, Stratford, NJ USA. Rowan Univ, Sch Osteopath Med, Dept Psychol, Stratford, NJ USA. EM Timothy.J.Hohman@Vanderbilt.edu FU Vanderbilt Memory & Alzheimer's Center; ADNI (NIH) [U01 AG024904]; Department of Defense ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; Northern California Institute for Research and Education; [K01-AG049164]; [K24-AG046373]; [K23-AG045966]; [R01-AG034962]; [R01-HL111516]; [K12-HD043483] FX This research was supported in part by K01-AG049164 (T.J.H.), K24-AG046373 (A.L.J.), K23-AG045966 (K.A.G.), R01-AG034962 (A.L.J.), R01-HL111516 (A.L.J.), K12-HD043483 (TJ.H.), and the Vanderbilt Memory & Alzheimer's Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data collection and sharing for this project were funded by the ADNI (NIH grant U01 AG024904) and Department of Defense ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, by the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc; Biogen Idec Inc; Bristol-Myers Squibb Co; Eisai Inc; Elan Pharmaceuticals, Inc; Eli Lilly and Co; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc; Fujirebio; GE Healthcare; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Medpace, Inc; Merck & Co, Inc; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corp; Pfizer Inc; Piramal Imaging; Servier; Synarc Inc; and Takeda Pharmaceutical Co. 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, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. NR 25 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD DEC 6 PY 2016 VL 87 IS 23 BP 2443 EP 2450 DI 10.1212/WNL.0000000000003397 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EI1MQ UT WOS:000392241900014 PM 27815399 ER PT J AU Ogunbiyi, JO Stefan, DC Rebbeck, TR AF Ogunbiyi, J. Olufemi Stefan, D. Cristina Rebbeck, Timothy R. TI African Organization for Research and Training in Cancer: position and vision for cancer research on the African Continent SO INFECTIOUS AGENTS AND CANCER LA English DT Article DE African Cancer Burden; Infections and cancer in Africa; Diagnosis of cancer; Access to healthcare; Cancer research ID SUB-SAHARAN AFRICA AB The African Organization for Research and training in Cancer (AORTIC) bases the following position statements on a critical appraisal of the state on cancer research and cancer care in Africa including information on the availability of data on cancer burden, screening and prevention for cancer in Africa, cancer care personnel, treatment modalities, and access to cancer care. C1 [Ogunbiyi, J. Olufemi] Univ Ibadan, AORTIC Res Comm, Ibadan, Nigeria. [Stefan, D. Cristina] Walter Sisulu, AORTIC Res Comm, Umtata, South Africa. [Stefan, D. Cristina] Int Prevent Res Inst, Lyon, France. [Rebbeck, Timothy R.] Dana Farber Canc Inst, AORTIC Res Comm, Boston, MA 02115 USA. [Rebbeck, Timothy R.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Ogunbiyi, J. Olufemi] Univ Ibadan, Dept Pathol, Coll Med, Ibadan, Nigeria. RP Ogunbiyi, JO (reprint author), Univ Ibadan, AORTIC Res Comm, Ibadan, Nigeria.; Ogunbiyi, JO (reprint author), Univ Ibadan, Dept Pathol, Coll Med, Ibadan, Nigeria. EM f_ogunbiyi@yahoo.com NR 11 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-9378 J9 INFECT AGENTS CANCER JI Infect. Agents Cancer PD DEC 6 PY 2016 VL 11 AR 63 DI 10.1186/s13027-016-0110-9 PG 6 WC Oncology; Immunology SC Oncology; Immunology GA EH2WJ UT WOS:000391629000001 PM 27980610 ER PT J AU Tzeng, A Kauke, MJ Zhu, EF Moynihan, KD Opel, CF Yang, NJ Mehta, N Kelly, RL Szeto, GL Overwijk, WW Irvine, DJ Wittrup, KD AF Tzeng, Alice Kauke, Monique J. Zhu, Eric F. Moynihan, Kelly D. Opel, Cary F. Yang, Nicole J. Mehta, Naveen Kelly, Ryan L. Szeto, Gregory L. Overwijk, Willem W. Irvine, Darrell J. Wittrup, K. Dane TI Temporally Programmed CD8 alpha(+) DC Activation Enhances Combination Cancer Immunotherapy SO CELL REPORTS LA English DT Article ID CELLS IN-VIVO; DENDRITIC CELLS; CROSS-PRESENTATION; T-CELLS; IMMUNITY; INTERFERON; INNATE; ANTIBODY; THERAPY; VACCINE AB Numerous synergistic cancer immunotherapy combinations have been identified, but the effects of relative dose timing are rarely considered. In established syngeneic mouse tumor models, we found that staggering interferon-alpha (IFN alpha) administration after, rather than before or simultaneously with, serum-persistent interleukin-2 (IL-2) and tumor-specific antibody significantly increased long-term survival. Successful combination therapy required IFN alpha-induced activation of cross-presenting CD8 alpha(+) dendritic cells (DCs) following the release of antigenic tumor debris by the IL-2-and antibody-mediated immune response. Due to decreased phagocytic ability post-maturation, DCs activated too early captured less antigen and could not effectively prime CD8(+) T cells. Temporally programmingDCactivation to occur after tumoricidal activity enhanced tumor control by multiple distinct combination immunotherapies, highlighting dose schedule as an underappreciated factor that can profoundly affect the success of multi-component immunotherapies. C1 [Tzeng, Alice; Moynihan, Kelly D.; Mehta, Naveen; Kelly, Ryan L.; Irvine, Darrell J.; Wittrup, K. Dane] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Kauke, Monique J.; Zhu, Eric F.; Opel, Cary F.; Yang, Nicole J.; Wittrup, K. Dane] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Irvine, Darrell J.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. [Tzeng, Alice; Kauke, Monique J.; Zhu, Eric F.; Moynihan, Kelly D.; Opel, Cary F.; Yang, Nicole J.; Mehta, Naveen; Kelly, Ryan L.; Irvine, Darrell J.; Wittrup, K. Dane] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Irvine, Darrell J.] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02214 USA. [Irvine, Darrell J.] Harvard Univ, Boston, MA 02214 USA. [Irvine, Darrell J.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Szeto, Gregory L.] Univ Maryland Baltimore Cty, Dept Chem Biochem & Environm Engn, Baltimore, MD 21250 USA. [Overwijk, Willem W.] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA. RP Wittrup, KD (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Wittrup, KD (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA.; Wittrup, KD (reprint author), MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. EM wittrup@mit.edu FU Ludwig Center for Molecular Oncology; NSF Graduate Research Fellowships; Hertz Foundation Fellowship; [CA174795]; [CA101830] FX We thank the staff of the Swanson Biotechnology Center at the Koch Institute for technical assistance. This work was funded by CA174795 and CA101830. A.T. was supported by a Ludwig Center for Molecular Oncology Graduate Fellowship and Siebel Scholarship. E.F.Z. and C.F.O. were supported by NSF Graduate Research Fellowships. K.D.M. was supported by a Hertz Foundation Fellowship. NR 28 TC 0 Z9 0 U1 6 U2 6 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 DEC 6 PY 2016 VL 17 IS 10 BP 2503 EP 2511 DI 10.1016/j.celrep.2016.11.020 PG 9 WC Cell Biology SC Cell Biology GA EG2SK UT WOS:000390894200001 PM 27926855 ER PT J AU Liu, X Grogan, TR Hieronymus, H Hashimoto, T Mottahedeh, J Cheng, DH Zhang, LJ Huang, K Stoyanova, T Park, JW Shkhyan, RO Nowroozizadeh, B Rettig, MB Sawyers, CL Elashoff, D Horvath, S Huang, JT Witte, ON Goldstein, AS AF Liu, Xian Grogan, Tristan R. Hieronymus, Haley Hashimoto, Takao Mottahedeh, Jack Cheng, Donghui Zhang, Lijun Huang, Kevin Stoyanova, Tanya Park, Jung Wook Shkhyan, Ruzanna O. Nowroozizadeh, Behdokht Rettig, Matthew B. Sawyers, Charles L. Elashoff, David Horvath, Steve Huang, Jiaoti Witte, Owen N. Goldstein, Andrew S. TI Low CD38 Identifies Progenitor-like Inflammation-Associated Luminal Cells that Can Initiate Human Prostate Cancer and Predict Poor Outcome SO CELL REPORTS LA English DT Article ID BASAL-CELLS; STEM-CELL; MURINE PROSTATE; ACCELERATES INITIATION; RADICAL PROSTATECTOMY; IN-VITRO; ORIGIN; DIFFERENTIATION; METASTASIS; EPITHELIUM AB Inflammation is a risk factor for prostate cancer, but the mechanisms by which inflammation increases that risk are poorly understood. Here, we demonstrate that low expression of CD38 identifies a progenitor-like subset of luminal cells in the human prostate. CD38(lo) luminal cells are enriched in glands adjacent to inflammatory cells and exhibit epithelial nuclear factor kappa B (NF-kappa B) signaling. In response to oncogenic transformation, CD38(lo) luminal cells can initiate human prostate cancer in an in vivo tissue-regeneration assay. Finally, the CD38(lo) luminal phenotype and gene signature are associated with disease progression and poor outcome in prostate cancer. Our results suggest that prostate inflammation expands the pool of progenitor-like target cells susceptible to tumorigenesis. C1 [Liu, Xian; Hashimoto, Takao; Mottahedeh, Jack; Shkhyan, Ruzanna O.; Goldstein, Andrew S.] Univ Calif Los Angeles, Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. [Zhang, Lijun; Huang, Kevin; Witte, Owen N.] Univ Calif Los Angeles, David Geffen Sch Med, Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Grogan, Tristan R.; Elashoff, David] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med Stat Core, Los Angeles, CA 90095 USA. [Hieronymus, Haley; Sawyers, Charles L.] Mem Sloan Kettering Canc Ctr, Program Human Oncol, New York, NY 10065 USA. [Hieronymus, Haley; Sawyers, Charles L.] Mem Sloan Kettering Canc Ctr, Program Pathogenesis, New York, NY 10065 USA. [Cheng, Donghui; Huang, Jiaoti; Witte, Owen N.; Goldstein, Andrew S.] Univ Calif Los Angeles, Ctr Regenerat Med & Stem Cell Res, Eli & Edythe Broad, Los Angeles, CA 90095 USA. [Stoyanova, Tanya; Park, Jung Wook; Witte, Owen N.] Univ Calif Los Angeles, Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. [Nowroozizadeh, Behdokht; Huang, Jiaoti] Univ Calif Los Angeles, David Geffen Sch Med, Pathol & Lab Med, Los Angeles, CA 90095 USA. [Rettig, Matthew B.] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol Oncol, Los Angeles, CA 90095 USA. [Rettig, Matthew B.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90024 USA. [Rettig, Matthew B.; Goldstein, Andrew S.] Univ Calif Los Angeles, David Geffen Sch Med, Urol, Los Angeles, CA 90095 USA. [Rettig, Matthew B.; Elashoff, David; Huang, Jiaoti; Witte, Owen N.; Goldstein, Andrew S.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Horvath, Steve] Univ Calif Los Angeles, David Geffen Sch Med, Human Genet, Los Angeles, CA 90095 USA. [Horvath, Steve] Univ Calif Los Angeles, UCLA Fielding Sch Publ Hlth, Biostat, Los Angeles, CA 90095 USA. [Witte, Owen N.] Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90095 USA. [Stoyanova, Tanya] Stanford Univ, Sch Med, Dept Radiol, Canary Ctr Stanford Canc Early Detect, Palo Alto, CA 94304 USA. [Huang, Jiaoti] Duke Univ, Sch Med, Dept Pathol, Durham, NC 27710 USA. RP Goldstein, AS (reprint author), Univ Calif Los Angeles, Mol Cell & Dev Biol, Los Angeles, CA 90095 USA.; Goldstein, AS (reprint author), Univ Calif Los Angeles, Ctr Regenerat Med & Stem Cell Res, Eli & Edythe Broad, Los Angeles, CA 90095 USA.; Goldstein, AS (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Urol, Los Angeles, CA 90095 USA.; Goldstein, AS (reprint author), Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. EM agoldstein@mednet.ucla.edu FU Department of Defense Idea Development Award [W81XWH-13-1-0470]; Prostate Cancer Foundation Young Investigator Award; Broad Stem Cell Research Center; AACR/PCF/Stand Up 2 Cancer West Coast Dream Team Award; National Institute of Health/National Cancer Institute grant [P50CA092131]; NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI grant [UL1TR000124]; National Institute of Health/National Cancer Institute K99 Pathway to Independence Award [4R00CA184397]; Howard Hughes Medical Institute; Department of Defense [PC030686] FX This work was supported by Department of Defense Idea Development Award W81XWH-13-1-0470 (A.S.G. and S.H.), a Prostate Cancer Foundation Young Investigator Award (A.S.G. and T.S.), the Broad Stem Cell Research Center (A.S.G. and J.H.), an AACR/PCF/Stand Up 2 Cancer West Coast Dream Team Award (O.N.W., J.H., M.R., and A.S.G.), a National Institute of Health/National Cancer Institute grant (P50CA092131/UCLA SPORE in Prostate Cancer; D.E., S.H., O.N.W., J.H., M.R., and A.S.G), a NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI grant (UL1TR000124; T.R.G. and D.E.), a National Institute of Health/National Cancer Institute K99 Pathway to Independence Award (4R00CA184397; T.S.), and the Howard Hughes Medical Institute (O.N.W.). M.R. and funding for TMA creation were supported by the Department of Defense (PC030686). NR 54 TC 0 Z9 0 U1 2 U2 2 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 DEC 6 PY 2016 VL 17 IS 10 BP 2596 EP 2606 DI 10.1016/j.celrep.2016.11.010 PG 11 WC Cell Biology SC Cell Biology GA EG2SK UT WOS:000390894200010 PM 27926864 ER PT J AU Comaills, V Kabeche, L Morris, R Buisson, R Yu, M Madden, MW LiCausi, JA Boukhali, M Tajima, K Pan, SW Aceto, N Sil, S Zheng, Y Sundaresan, T Yae, T Jordan, NV Miyamoto, DT Ting, DT Ramaswamy, S Haas, W Zou, L Haber, DA Maheswaran, S AF Comaills, Valentine Kabeche, Lilian Morris, Robert Buisson, Remi Yu, Min Madden, Marissa Wells LiCausi, Joseph A. Boukhali, Myriam Tajima, Ken Pan, Shiwei Aceto, Nicola Sil, Srinjoy Zheng, Yu Sundaresan, Tilak Yae, Toshifumi Jordan, Nicole Vincent Miyamoto, David T. Ting, David T. Ramaswamy, Sridhar Haas, Wilhelm Zou, Lee Haber, Daniel A. Maheswaran, Shyamala TI Genomic Instability Is Induced by Persistent Proliferation of Cells Undergoing Epithelial-to-Mesenchymal Transition SO CELL REPORTS LA English DT Article ID DNA-DAMAGE; TGF-BETA; CHROMOSOMAL INSTABILITY; CANCER-CELLS; MORPHOGENESIS; METASTASIS; MITOSIS; DROSOPHILA; CHEMORESISTANCE; GASTRULATION AB TGF-beta secreted by tumor stroma induces epithelialto- mesenchymal transition (EMT) in cancer cells, a reversible phenotype linked to cancer progression and drug resistance. However, exposure to stromal signals may also lead to heritable changes in cancer cells, which are poorly understood. We show that epithelial cells failing to undergo proliferation arrest during TGF-beta-induced EMT sustain mitotic abnormalities due to failed cytokinesis, resulting in aneuploidy. This genomic instability is associated with the suppression of multiple nuclear envelope proteins implicated in mitotic regulation and is phenocopied by modulating the expression of LaminB1. While TGF-beta-induced mitotic defects in proliferating cells are reversible upon its withdrawal, the acquired genomic abnormalities persist, leading to increased tumorigenic phenotypes. In metastatic breast cancer patients, increased mesenchymal marker expression within single circulating tumor cells is correlated with genomic instability. These observations identify a mechanism whereby microenvironment-derived signals trigger heritable genetic changes within cancer cells, contributing to tumor evolution. C1 [Comaills, Valentine; Kabeche, Lilian; Morris, Robert; Buisson, Remi; Yu, Min; Madden, Marissa Wells; LiCausi, Joseph A.; Boukhali, Myriam; Tajima, Ken; Pan, Shiwei; Aceto, Nicola; Sil, Srinjoy; Zheng, Yu; Sundaresan, Tilak; Yae, Toshifumi; Jordan, Nicole Vincent; Miyamoto, David T.; Ting, David T.; Ramaswamy, Sridhar; Haas, Wilhelm; Zou, Lee; Haber, Daniel A.; Maheswaran, Shyamala] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Zheng, Yu; Jordan, Nicole Vincent; Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Comaills, Valentine; Tajima, Ken; Yae, Toshifumi; Maheswaran, Shyamala] Harvard Med Sch, Dept Surg, Charlestown, MA 02129 USA. [Sundaresan, Tilak; Miyamoto, David T.; Ting, David T.; Ramaswamy, Sridhar; Haber, Daniel A.] Harvard Med Sch, Dept Med, Charlestown, MA 02129 USA. [Zou, Lee] Harvard Med Sch, Dept Pathol, Charlestown, MA 02129 USA. [Yu, Min] Univ Southern Calif, Dept Stem Cell Biol & Regenerat Med, Los Angeles, CA 90033 USA. [Aceto, Nicola] Univ Basel, Dept Biomed, CH-4058 Basel, Switzerland. RP Maheswaran, S (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA.; Maheswaran, S (reprint author), Harvard Med Sch, Dept Surg, Charlestown, MA 02129 USA. EM maheswaran@helix.mgh.harvard.edu OI Ting, David/0000-0002-3261-2322 FU Susan G. Komen for the Cure [KG09042]; ESSCO-MGH Breast Cancer Research Fund; NCI Federal Share Program and Income; Philippe Foundation Grant; Stand Up to Cancer; Breast Cancer Research Foundation; National Foundation for Cancer Research; Howard Hughes Medical Institute; NIH [CA129933, GM076388]; Tosteson Postdoctoral Fellowship Award; Marsha Rivkin Scientific Scholar Award FX This work was supported by grants from the Susan G. Komen for the Cure KG09042 (S.M.), ESSCO-MGH Breast Cancer Research Fund (S.M.), NCI Federal Share Program and Income (S.M.), Philippe Foundation Grant (V.C. and R.B.), Stand Up to Cancer (D.A.H. and S.M.), Breast Cancer Research Foundation (D.A.H.), National Foundation for Cancer Research (D.A.H.), Howard Hughes Medical Institute (D.A.H.), NIH CA129933 (D.A.H.), and NIH GM076388 (L.Z.). L.Z. is a Jim & Ann Orr MGH Research Scholar. S.R. is a Samana Cay MGH Research Scholar. N.A. is a fellow of the Human Frontiers Science Program, the Swiss National Science Foundation, and the Swiss Foundation for Grants in Biology and Medicine. R.B. is supported by the Tosteson Postdoctoral Fellowship Award and the Marsha Rivkin Scientific Scholar Award. We would like to thank Drs. Joseph Jerry and Karen Dunphy (University of Massachusetts, Amherst) for the CD beta geo cells, Dr. Linda Nieman and Tiffany N. Lewis (MGH Cancer Center) for helping with time-lapse imaging of cells, Drs. Cristina Montagna and Jidong Shan (Albert Einstein College of Medicine, NY) for interphase DNA-FISH analysis, Dr. Nick Dyson for critical reading of the manuscript, and Ms. Laura Libby and Mr. Daniel Garcia for technical support. NR 49 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD DEC 6 PY 2016 VL 17 IS 10 BP 2632 EP 2647 DI 10.1016/j.celrep.2016.11.022 PG 16 WC Cell Biology SC Cell Biology GA EG2SK UT WOS:000390894200013 PM 27926867 ER PT J AU Davidson, D Zhong, MC Pandolfi, PP Bolland, S Xavier, RJ Seed, B Li, X Gu, H Veillette, A AF Davidson, Dominique Zhong, Ming-Chao Pandolfi, Pier Paolo Bolland, Silvia Xavier, Ramnik J. Seed, Brian Li, Xin Gu, Hua Veillette, Andre TI The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors SO CELL REPORTS LA English DT Article ID PROTEIN-KINASE P50(CSK); TRANSMEMBRANE ADAPTER; NEGATIVE REGULATION; LYMPHOCYTE DEVELOPMENT; ANTIGEN RECEPTOR; LIPID RAFTS; CBL; FAMILY; AUTOIMMUNITY; REGULATOR AB The transmembrane adaptor PAG (Cbp) has been proposed to mediate membrane recruitment of Csk, a cytoplasmic protein tyrosine kinase playing a critical inhibitory role during T cell activation, by inactivating membrane-associated Src kinases. However, this model has not been validated by genetic evidence. Here, we demonstrate that PAG-deficient mice display enhanced T cell activation responses in effector, but not in naive, T cells. PAG-deficient mice also have augmented T cell-dependent autoimmunity and greater resistance to T cell anergy. Interestingly, in the absence of PAG, Csk becomes more associated with alternative partners; i.e., phosphatase PTPN22 and Dok adaptors. Combining PAG deficiency with PTPN22 or Dok adaptor deficiency further enhances effector T cell responses. Unlike PAG, Cbl ubiquitin ligases inhibit the activation of naive, but not of effector, T cells. Thus, Csk-associating PAG is a critical component of the inhibitory machinery controlling effector T cell activation in cooperation with PTPN22 and Dok adaptors. C1 [Davidson, Dominique; Zhong, Ming-Chao; Veillette, Andre] Inst Rech Clin Montreal, Lab Mol Oncol, Montreal, PQ H2W 1R7, Canada. [Pandolfi, Pier Paolo] Beth Israel Deaconess Med Ctr, Canc Res Inst, Boston, MA 02215 USA. [Bolland, Silvia] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Seed, Brian] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Li, Xin; Gu, Hua] Inst Rech Clin Montreal, Lab Mol Immunol, Montreal, PQ H2W 1R7, Canada. [Gu, Hua; Veillette, Andre] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. [Gu, Hua; Veillette, Andre] McGill Univ, Dept Med, Montreal, PQ H3G 1Y6, Canada. RP Davidson, D; Veillette, A (reprint author), Inst Rech Clin Montreal, Lab Mol Oncol, Montreal, PQ H2W 1R7, Canada.; Veillette, A (reprint author), Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada.; Veillette, A (reprint author), McGill Univ, Dept Med, Montreal, PQ H3G 1Y6, Canada. EM dominique.davidson@ircm.qc.ca; veillea@ircm.qc.ca FU Canadian Institutes of Health Research (FRN) [143338] FX We thank the members of the A.V. lab for discussions. This work was supported by a grant from the Canadian Institutes of Health Research (FRN #143338) (to A.V.). A.V. holds the Canada Research Chair in Signaling in the Immune System. NR 32 TC 0 Z9 0 U1 1 U2 1 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 DEC 6 PY 2016 VL 17 IS 10 BP 2776 EP 2788 DI 10.1016/j.celrep.2016.11.035 PG 13 WC Cell Biology SC Cell Biology GA EG2SK UT WOS:000390894200024 PM 27926878 ER PT J AU Koblan, LW Buckley, DL Ott, CJ Fitzgerald, ME Ember, SWJ Zhu, JY Liu, S Roberts, JM Remillard, D Vittori, S Zhang, W Schonbrunn, E Bradner, JE AF Koblan, Luke W. Buckley, Dennis L. Ott, Christopher J. Fitzgerald, Mark E. Ember, Stuart W. J. Zhu, Jin-Yi Liu, Shuai Roberts, Justin M. Remillard, David Vittori, Sarah Zhang, Wei Schonbrunn, Ernst Bradner, James E. TI Assessment of Bromodomain Target Engagement by a Series of BI2536 Analogues with Miniaturized BET-BRET SO CHEMMEDCHEM LA English DT Article DE bromodomain inhibition; drug design; epigenetics; fluorescence; in-cell target engagement assays; luminescence ID INHIBITORS; BRD4; SELECTIVITY; LEUKEMIA; PLK1 AB Evaluating the engagement of a small molecule ligand with a protein target in cells provides useful information for chemical probe optimization and pharmaceutical development. While several techniques exist that can be performed in a low-throughput manner, systematic evaluation of large compound libraries remains a challenge. In-cell engagement measurements are especially useful when evaluating compound classes suspected to target multiple cellular factors. In this study we used a bioluminescent resonant energy transfer assay to assess bromodomain engagement by a compound series containing bromodomain-and kinase-biasing polypharmacophores based on the known dual BRD4 bromodomain/PLK1 kinase inhibitor BI2536. With this assay, we discovered several novel agents with bromodomain-selective specificity profiles and cellular activity. Thus, this platform aids in distinguishing molecules whose cellular activity is difficult to assess due to polypharmacologic effects. C1 [Buckley, Dennis L.; Ott, Christopher J.; Roberts, Justin M.; Remillard, David; Vittori, Sarah; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Buckley, Dennis L.; Ott, Christopher J.; Bradner, James E.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Koblan, Luke W.; Ott, Christopher J.; Fitzgerald, Mark E.; Vittori, Sarah; Bradner, James E.] Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA. [Ember, Stuart W. J.; Zhu, Jin-Yi; Schonbrunn, Ernst] H Lee Moffitt Canc Ctr & Res Inst, Drug Discovery Dept, Tampa, FL 33612 USA. [Liu, Shuai; Zhang, Wei] Univ Massachusetts, Dept Chem, Boston, MA 02125 USA. [Bradner, James E.] Novartis Inst Biomed Res, Cambridge, MA 02139 USA. [Ember, Stuart W. J.] React Biol Corp, Malvern, PA 19355 USA. [Fitzgerald, Mark E.] C4 Therapeut, Cambridge, MA 02142 USA. RP Bradner, JE (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Bradner, JE (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA.; Bradner, JE (reprint author), Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.; Bradner, JE (reprint author), Novartis Inst Biomed Res, Cambridge, MA 02139 USA. EM james_bradner@dfci.harvard.edu FU US National Science Foundation (NSF) [DGE1144152]; US NIH National Institute of General Medical Sciences (NIH/NIGMS) [5T32M095450-04]; Leukemia and Lymphoma Society [5667-13]; NCI [K99A190861]; US National Cancer Institute (NCI) [P30-CA076292]; NIH/NICHD [HHSN275201300017C, U01-HD076508]; US NIH National Cancer Institute (NIH/NCI) [1U54CA156732-05]; William Lawrence & Blanche Hughes Foundation; Dana-Farber Cancer Institute FX We thank Dr. Ralph Mazitschek for assistance with spectral characterizations, and Dr. Dannette Daniels for helpful advice on BRET assay development. We also thank Dr. Jennifer Perry for critical reading of the manuscript. L.W.K. is supported by a US National Science Foundation (NSF) GRFP fellowship (DGE1144152) as well as the US NIH National Institute of General Medical Sciences (NIH/NIGMS) (5T32M095450-04). C.J.O. acknowledges support from a Fellow Award from the Leukemia and Lymphoma Society (5667-13) and by an NCI Pathway to Independence Award (K99A190861). D.L.B. is a Merck Fellow of the Damon Runyon Cancer Research Foundation (DRG-2196-14). S.W.J.E., E.S., and J.-Y.Z. thank the Moffitt Chemical Biology Core for use of the protein crystallography facility (US National Cancer Institute (NCI) grant P30-CA076292). E.S. acknowledges support from the NIH/NICHD contract HHSN275201300017C. W.Z. and J.E.B. acknowledge US NIH National Cancer Institute (NIH/NCI) grant (1U54CA156732-05). J.E.B. acknowledges support from the William Lawrence & Blanche Hughes Foundation, the Dana-Farber Cancer Institute Accelerator Fund, and NIH/NICHD grant U01-HD076508. NR 22 TC 0 Z9 0 U1 5 U2 5 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1860-7179 EI 1860-7187 J9 CHEMMEDCHEM JI ChemMedChem PD DEC 6 PY 2016 VL 11 IS 23 BP 2575 EP 2581 DI 10.1002/cmdc.201600502 PG 7 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EG8FY UT WOS:000391292600003 PM 27862999 ER PT J AU Maumet, C Auer, T Bowring, A Chen, G Das, S Flandin, G Ghosh, S Glatard, T Gorgolewski, KJ Helmer, KG Jenkinson, M Keator, DB Nichols, BN Poline, JB Reynolds, R Sochat, V Turner, J Nichols, TE AF Maumet, Camille Auer, Tibor Bowring, Alexander Chen, Gang Das, Samir Flandin, Guillaume Ghosh, Satrajit Glatard, Tristan Gorgolewski, Krzysztof J. Helmer, Karl G. Jenkinson, Mark Keator, David B. Nichols, B. Nolan Poline, Jean-Baptiste Reynolds, Richard Sochat, Vanessa Turner, Jessica Nichols, Thomas E. TI Sharing brain mapping statistical results with the neuroimaging data model SO SCIENTIFIC DATA LA English DT Article ID FMRI; REPRODUCIBILITY; METAANALYSIS; TRANSPARENCY; NEUROSCIENCE; EVOLUTION; ONTOLOGY AB Only a tiny fraction of the data and metadata produced by an fMRI study is finally conveyed to the community. This lack of transparency not only hinders the reproducibility of neuroimaging results but also impairs future meta-analyses. In this work we introduce NIDM-Results, a format specification providing a machine-readable description of neuroimaging statistical results along with key image data summarising the experiment. NIDM-Results provides a unified representation of mass univariate analyses including a level of detail consistent with available best practices. This standardized representation allows authors to relay methods and results in a platform-independent regularized format that is not tied to a particular neuroimaging software package. Tools are available to export NIDM-Result graphs and associated files from the widely used SPM and FSL software packages, and the NeuroVault repository can import NIDM-Results archives. The specification is publically available at: http://nidm.nidash.org/specs/nidm-results.html. C1 [Maumet, Camille; Bowring, Alexander; Nichols, Thomas E.] Univ Warwick, WMG, Coventry CV4 7AL, W Midlands, England. [Auer, Tibor] MRC Cognit & Brain Sci Unit, Cambridge CB2 7EF, England. [Chen, Gang; Reynolds, Richard] NIMH, Sci & Stat Comp Core, NIH, Bethesda, MD 20892 USA. [Das, Samir; Glatard, Tristan] Montreal Neurol Inst, Ludmer Ctr, McGill Ctr Integrat Neurosci, Montreal, PQ H3A 2B4, Canada. [Flandin, Guillaume] UCL, Inst Neurol, Wellcome Trust Ctr Neuroimaging, London WC1N 3BG, England. [Ghosh, Satrajit] MIT, McGovern Inst Brain, Cambridge, MA 02139 USA. [Glatard, Tristan] Univ Claude Bernard Lyon 1, INSA Lyon, Inserm U1044, Univ Lyon,CREATIS,CNRS UMR5220, F-69100 Villeurbanne, France. [Gorgolewski, Krzysztof J.; Sochat, Vanessa] Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. [Helmer, Karl G.] Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Jenkinson, Mark] Univ Oxford, Oxford OX3 9DU, England. [Keator, David B.] Univ Calif Irvine, Dept Neurol, Dept Comp Sci, Dept Psychiat & Human Behav, Irvine, CA 92697 USA. [Nichols, B. Nolan] SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. [Poline, Jean-Baptiste] Univ Calif Berkeley, H Wheeler Jr Brain Imaging Ctr, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [Turner, Jessica] Georgia State Univ, Psychol & Neurosci, Atlanta, GA 30302 USA. [Nichols, Thomas E.] Univ Warwick, Dept Stat, Coventry CV4 7AL, W Midlands, England. RP Maumet, C (reprint author), Univ Warwick, WMG, Coventry CV4 7AL, W Midlands, England. EM c.m.j.maumet@warwick.ac.uk OI Gorgolewski, Krzysztof/0000-0003-3321-7583; Ghosh, Satrajit/0000-0002-5312-6729; Nichols, Nolan/0000-0003-1099-3328 FU Wellcome Trust [100309/Z/12/Z]; Medical Research Council (United Kingdom) [MC-A060-53114]; NIH [AA012388, AA021697, AA021697-04S1, 1R01EB020740-01A1, 1P41EB019936-01A1]; NIH-NIBIB grant [P41-EB019936]; Laura and John Arnold Foundation; NIH-NIDA grant [U24-038653]; Function Biomedical Informatics Re-search Network [NIH 1 [U24 U24 RR021992]]; BIRN Coordinating Center [NIH 1 [U24 RR025736-01], NIH U24 RR025736-01]; Conte Center on Brain Programming in Adolescent Vulnerabilities [1P50MH096889-01A1]; NIMH; NINDS Intramural Research Programs of the NIH/HHS, USA [ZICMH002888]; Morphometry Biomedical Informatics Research Network (MBIRN) [NIH U24 RR021382]; Irving Ludmer Family Foundation; Ludmer Centre for Neuroinformatics and Mental Health FX We gratefully acknowledge Matthew Webster, Paul McCarthy, Eugene Duff and Steve Smith, from the FMRIB and Robert Cox and Ziad Saad from the NIH, for their inputs on the integration of NIDM-Results within FSL and AFNI; as well as the NIDASH task force members for their inputs during the development of the model. We also gratefully acknowledge the Tracey group at FMRIB for sharing their pain datasets used in the meta-analysis. The INCF supported and organised the task force meetings in which the model was discussed. A.B., C.M. and T.E.N. were supported by the Wellcome Trust [100309/Z/12/Z]. T.A. was supported by the Medical Research Council (United Kingdom) [MC-A060-53114]. BNN was supported by NIH grants [AA012388, AA021697, AA021697-04S1]. S.G. was partially supported by NIH grants [1R01EB020740-01A1, 1P41EB019936-01A1]. J.B.P. was partially supported by a NIH-NIBIB grant [P41-EB019936], the Laura and John Arnold Foundation and by a NIH-NIDA grant [U24-038653]. D.B.K. was supported by the Function Biomedical Informatics Re-search Network (NIH 1 [U24 U24 RR021992]), the BIRN Coordinating Center (https://www.nitrc.org/projects/birn/; NIH 1 [U24 RR025736-01]) and the Conte Center on Brain Programming in Adolescent Vulnerabilities [1P50MH096889-01A1]. G.C. and R.R. were supported by the NIMH and NINDS Intramural Research Programs (ZICMH002888) of the NIH/HHS, USA. K.J.G. was sponsored by the Laura and John Arnold Foundation. K.G.H. was supported by the Morphometry Biomedical Informatics Research Network (MBIRN, NIH U24 RR021382), the BIRN Coordinating Center (NIH U24 RR025736-01). S.D. and T.G. were supported by the Irving Ludmer Family Foundation and the Ludmer Centre for Neuroinformatics and Mental Health. NR 54 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2052-4463 J9 SCI DATA JI Sci. Data PD DEC 6 PY 2016 VL 3 AR UNSP 160102 DI 10.1038/sdata.2016.102 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF3QC UT WOS:000390238300001 PM 27922621 ER PT J AU Troncone, L Luciani, M Coggins, M Wilker, EH Ho, CY Codispoti, KE Frosch, MP Kayed, R del Monte, F AF Troncone, Luca Luciani, Marco Coggins, Matthew Wilker, Elissa H. Ho, Cheng-Ying Codispoti, Kari Elise Frosch, Matthew P. Kayed, Rakez del Monte, Federica TI A beta Amyloid Pathology Affects the Hearts of Patients With Alzheimer's Disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE amyloidosis; cardiomyopathy; dementia; heart failure; protein aggregates ID IDIOPATHIC DILATED CARDIOMYOPATHY; PLAQUE CORE PROTEIN; CARDIAC DYSFUNCTION; NEUROPATHOLOGIC ASSESSMENT; ASSOCIATION GUIDELINES; NATIONAL INSTITUTE; VASCULAR DEMENTIA; FAILURE; RISK; MYOCYTES AB BACKGROUND Individually, heart failure (HF) and Alzheimer's disease (AD) are severe threats to population health, and their potential coexistence is an alarming prospect. In addition to sharing analogous epidemiological and genetic profiles, biochemical characteristics, and common triggers, the authors recently recognized common molecular and pathological features between the 2 conditions. Whereas cognitive impairment has been linked to HF through perfusion defects, angiopathy, and inflammation, whether patients with AD present with myocardial dysfunction, and if the 2 conditions bear a common pathogenesis as neglected siblings are unknown. OBJECTIVES Here, the authors investigated whether amyloid beta (A beta) protein aggregates are present in the hearts of patients with a primary diagnosis of AD, affecting myocardial function. METHODS The authors examined myocardial function in a retrospective cross-sectional study from a cohort of AD patients and age-matched controls. Imaging and proteomics approaches were used to identify and quantify A beta deposits in AD heart and brain specimens compared with controls. Cell shortening and calcium transients were measured on isolated adult cardiomyocytes. RESULTS Echocardiographic measurements of myocardial function suggest that patients with AD present with an anticipated diastolic dysfunction. As in the brain, A beta(40) and A beta(42) are present in the heart, and their expression is increased in AD. CONCLUSIONS Here, the authors provide the first report of the presence of compromised myocardial function and intramyocardial deposits of A beta in AD patients. The findings depict a novel biological framework in which AD may be viewed either as a systemic disease or as a metastatic disorder leading to heart, and possibly multiorgan failure. AD and HF are both debilitating and life-threatening conditions, affecting enormous patient populations. Our findings underline a previously dismissed problem of a magnitude that will require new diagnostic approaches and treatments for brain and heart disease, and their combination. (C) 2016 by the American College of Cardiology Foundation. C1 [Troncone, Luca; Luciani, Marco; Coggins, Matthew; Wilker, Elissa H.; del Monte, Federica] Beth Israel Deaconess Med Ctr, Cardiovasc Inst, 3 Blackfan Circle E CLS9-911, Boston, MA 02215 USA. [Wilker, Elissa H.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Ho, Cheng-Ying; Codispoti, Kari Elise] Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 21287 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kayed, Rakez] Univ Texas Med Branch Hlth, Dept Neurol, Galveston, TX USA. [del Monte, Federica] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP del Monte, F (reprint author), Beth Israel Deaconess Med Ctr, Cardiovasc Inst, 3 Blackfan Circle E CLS9-911, Boston, MA 02215 USA. EM fdelmont@bidmc.harvard.edu FU National Institutes of Health; NHLBI [R01HL098468]; AHA [14IRG18980028] FX This work was supported by grants from the National Institutes of Health, NHLBI R01HL098468, and the AHA 14IRG18980028 to Dr. del Monte, and by an Italian Society of Cardiology fellowship to Dr. Luciani. Dr. Luciani's fellowship from the Italian Society of Cardiology is with the contribution of Merck Sharp & Dohme Italia. Dr. Coggins has edited educational content for DynaMed. Dr. Wilker received reimbursement to attend a conference from Servier Laboratories. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Troncone and Luciani contributed equally to this work. NR 52 TC 2 Z9 2 U1 5 U2 5 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 DEC 6 PY 2016 VL 68 IS 22 BP 2395 EP 2407 DI 10.1016/j.jacc.2016.08.073 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EE4RF UT WOS:000389592000001 PM 27908343 ER PT J AU Zile, MR Claggett, BL Prescott, MF McMurray, JJV Packer, M Rouleau, JL Swedberg, K Desai, AS Gong, JJ Shi, VC Solomon, SD AF Zile, Michael R. Claggett, Brian L. Prescott, Margaret F. McMurray, John J. V. Packer, Milton Rouleau, Jean L. Swedberg, Karl Desai, Akshay S. Gong, Jianjian Shi, Victor C. Solomon, Scott D. TI Prognostic Implications of Changes in N-Terminal Pro-B-Type Natriuretic Peptide in Patients With Heart Failure SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE biomarker; chronic heart failure; natriuretic peptide; reduced ejection fraction ID GUIDED THERAPY; CARDIAC RESYNCHRONIZATION; NEPRILYSIN INHIBITION; RANDOMIZED-TRIAL; RELAX-AHF; VAL-HEFT; MORTALITY; MANAGEMENT; ENALAPRIL; BNP AB BACKGROUND Natriuretic peptides (NP) have prognostic value in heart failure (HF), although the clinical importance of changes in NP from baseline is unclear. OBJECTIVES The authors assessed whether a reduction in N-terminal pro-B-type NP (NT-proBNP) was associated with a decrease in HF hospitalization and cardiovascular mortality (primary endpoint) in patients with HF and reduced ejection fraction, whether treatment with sacubitril/valsartan reduced NT-proBNP below specific partition values more than enalapril, and whether the relationship between changes in NT-proBNP and changes in the primary endpoint were dependent on assigned treatment. METHODS In PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial), baseline NT-proBNP was measured in 2,080 patients; 1,292 had baseline values >1,000 pg/ml and were reassessed at 1 and 8 months. We related change in NT-proBNP to outcomes. RESULTS One month after randomization, 24% of the baseline NT-proBNP levels >1,000 pg/ml had fallen to <= 1,000 pg/ml. Risk of the primary endpoint was 59% lower in patients with a fall in NT-proBNP to <= 1,000 pg/ml than in those without such a fall. In sacubitril/valsartan-treated patients, median NT-proBNP was significantly lower 1 month after randomization than in enalapril-treated patients, and it fell to <= 1,000 pg/ml in 31% versus 17% of patients treated with sacubitril/valsartan and enalapril, respectively. There was no significant interaction between treatment and the relationship between change in NT-proBNP and the subsequent risk of the primary endpoint. CONCLUSIONS Patients who attained a significant reduction in NT-proBNP had a lower subsequent rate of cardiovascular death or HF hospitalization independent of the treatment group. Treatment with sacubitril/valsartan was nearly twice as likely as enalapril to reduce NT-proBNP to values <= 1,000 pg/ml. (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) [PARADIGM-HF]; NCT01035255.) (C) 2016 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. C1 [Zile, Michael R.] Med Univ South Carolina, Charleston, SC USA. [Zile, Michael R.] Ralph H Johnson Vet Adm Med Ctr, Charleston, SC USA. [Claggett, Brian L.; Desai, Akshay S.; Solomon, Scott D.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Prescott, Margaret F.; Gong, Jianjian; Shi, Victor C.] Novartis Pharmaceut, E Hanover, NJ USA. [McMurray, John J. V.] Univ Glasgow, Glasgow, Lanark, Scotland. [Packer, Milton] Baylor Univ, Med Ctr, Dallas, TX USA. [Rouleau, Jean L.] Montreal Heart Inst, Montreal, PQ, Canada. [Rouleau, Jean L.] Univ Montreal, Montreal, PQ, Canada. [Swedberg, Karl] Univ Gothenburg, Gothenburg, Sweden. RP Zile, MR (reprint author), Med Univ South Carolina, Charleston, SC USA.; Zile, MR (reprint author), Ralph H Johnson Vet Adm Med Ctr, Charleston, SC USA.; Zile, MR (reprint author), Med Univ South Carolina, Div Cardiol, Dept Med, 114 Doughty St,Room 323, Charleston, SC 29425 USA. EM zilem@musc.edu OI mcmurray, john/0000-0002-6317-3975 FU Novartis; Servier FX This study was funded by Novartis. All authors have consulted for and received research support from Novartis, sponsor of the PARADIGM-HF trial. Drs. Prescott, Gong, and Shi are employees of Novartis. Professor McMurray's employer, University of Glasgow, was paid by Novartis for Professor McMurray's time spent as co-chairman of the PARADIGM-HF trial. Dr. Packer has served as a consultant for Admittance Technologies, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BioControl, CardioKinetix, CardioMEMS, Cardiorentis, Celyad, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Janssen, Pfizer, Sanofi, Takeda, and ZS Pharma. Dr. Swedberg has received honoraria from Novartis for sponsored lectures; has served as a consultant for AstraZeneca and Amgen and he has also received research support from Servier. Dr. Desai has served as a consultant for St. Jude Medical, Relypsa, Sanofi, and Merck. NR 46 TC 1 Z9 1 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 DEC 6 PY 2016 VL 68 IS 22 BP 2425 EP 2436 DI 10.1016/j.jacc.2016.09.931 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EE4RF UT WOS:000389592000005 PM 27908347 ER PT J AU Pitts, R Gunzburger, E Ballantyne, CM Barter, PJ Kallend, D Leiter, LA Leitersdorf, E McMurray, JJV Nicholls, SJ Niesor, EJ Olsson, AG Shah, PK Tardif, JC Kittelson, J Schwartz, GG AF Pitts, Reynaria Gunzburger, Elise Ballantyne, Christie M. Barter, Philip J. Kallend, David Leiter, Lawrence A. Leitersdorf, Eran McMurray, John J. V. Nicholls, Stephen J. Niesor, Eric J. Olsson, Anders G. Shah, Prediman K. Tardif, Jean-Claude Kittelson, John Schwartz, Gregory G. TI Treatment With Dalcetrapib Modifies the Relationship Between High-Density Lipoprotein Cholesterol and C-Reactive Protein SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter ID HDL C1 [Schwartz, Gregory G.] Denver VA Med Ctr, Cardiol Sect, 111B,1055 Clermont St, Denver, CO 80220 USA. RP Schwartz, GG (reprint author), Denver VA Med Ctr, Cardiol Sect, 111B,1055 Clermont St, Denver, CO 80220 USA. EM gregory.schwartz@va.gov OI mcmurray, john/0000-0002-6317-3975 NR 3 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD DEC 6 PY 2016 VL 68 IS 22 BP 2488 EP 2490 DI 10.1016/j.jacc.2016.09.932 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EE4RF UT WOS:000389592000014 PM 27908356 ER PT J AU Grande, D Armstrong, K AF Grande, David Armstrong, Katrina TI Will Physicians Vote? SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Grande, D (reprint author), Univ Penn, Perelman Sch Med, Div Gen Internal Med, 3641 Locust Walk,Colonial Penn Ctr 407, Philadelphia, PA 19104 USA. EM dgrande@wharton.upenn.edu NR 8 TC 0 Z9 0 U1 1 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD DEC 6 PY 2016 VL 165 IS 11 BP 814 EP + DI 10.7326/M16-2470 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EE0KO UT WOS:000389263900012 PM 27802503 ER PT J AU Kalra, A Suri, K AF Kalra, Ankur Suri, Kunal TI Alienated SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID J-1 C1 [Kalra, Ankur] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Kalra, Ankur] Houston Methodist Hosp, Houston Methodist DeBakey Heart & Vasc Ctr, Houston, TX USA. [Kalra, Ankur] Weill Cornell Med Coll, New York, NY USA. [Kalra, Ankur] Harvard Med Sch, Safety Qual Informat & Leadership, Boston, MA USA. [Suri, Kunal] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA USA. RP Kalra, A (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA.; Kalra, A (reprint author), Houston Methodist Hosp, Houston Methodist DeBakey Heart & Vasc Ctr, Houston, TX USA.; Kalra, A (reprint author), Weill Cornell Med Coll, New York, NY USA.; Kalra, A (reprint author), Harvard Med Sch, Safety Qual Informat & Leadership, Boston, MA USA. EM kalramd.ankur@gmail.com NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 6 PY 2016 VL 316 IS 21 BP 2191 EP 2192 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EE0YV UT WOS:000389307400003 PM 27923094 ER PT J AU Wray, CM Chaudhry, S Pincavage, A Miller, R DeCherrie, L Ouchida, K Arora, VM AF Wray, Charlie M. Chaudhry, Saima Pincavage, Amber Miller, Rachel DeCherrie, Linda Ouchida, Karin Arora, Vineet M. TI Resident Shift Handoff Strategies in US Internal Medicine Residency Programs SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Wray, Charlie M.] San Francisco VA Med Ctr, Div Hosp Med, San Francisco, CA USA. [Chaudhry, Saima] Mem Healthcare Syst, Off Acad Affairs, Ft Lauderdale, FL USA. [Arora, Vineet M.] Univ Chicago, Med Ctr, Gen Internal Med Sect, Chicago, IL 60637 USA. [Miller, Rachel] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [DeCherrie, Linda] Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, New York, NY 10029 USA. [Ouchida, Karin] Weill Cornell Med Coll, Div Geriatr & Palliat Med, New York, NY USA. RP Wray, CM (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM charlie.wray@ucsf.edu NR 6 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 6 PY 2016 VL 316 IS 21 BP 2273 EP 2275 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EE0YV UT WOS:000389307400014 PM 27923083 ER PT J AU Jiang, GQ Liu, J Ren, BY Tang, YW Owusu, L Li, M Zhang, J Liu, LK Li, WL AF Jiang, Guoqiang Liu, Jia Ren, Baoyin Tang, Yawei Owusu, Lawrence Li, Man Zhang, Jing Liu, Likun Li, Weiling TI Anti-tumor effects of osthole on ovarian cancer cells in vitro SO JOURNAL OF ETHNOPHARMACOLOGY LA English DT Article DE Osthole; Anti-tumor effect; Ovarian cancer; Apoptosis; Migration ID CYCLE ARREST; INHIBITS PROLIFERATION; SIGNALING PATHWAY; G2/M PHASE; APOPTOSIS; EXTRACT; EXPRESSION; MIGRATION; LINE; PHOSPHORYLATION AB Ethnopharmacological relevance: Cnidium monnieri (L.) Cusson is a commonly used traditional Chinese medicine to treat gynecological disease in some countries. Osthole, an active O-methylated coumadin isolated from Cnidium monnieri (L) Cusson, has been shown to induce various beneficial biochemical effects such as anti-seizure and anti-inflammatory effects. However, the anti-tumor mechanism of osthole is not well known. Aim of study: Here, we show that osthole inhibited the proliferation and migration of two widely used ovarian cancer cell lines, A2780 and OV2008 cells, in a dose-dependent manner. The study investigated the molecular mechanisms underlying ovarian cancer cells proliferation, apoptosis, cell cycle arrest and migration triggered by osthole. Materials and methods: Ovarian cancer cell lines A2780, OV2008 and normal ovarian cell line IOSE80 were used as experimental model. MTT assay was employed to evaluate cell viability. Flow cytometry assays were performed to confirm apoptosis and cell cycle. We employed wound healing and transwell assays to delineate invasive and migratory potential triggered by osthole. Results: MTT assays indicated that cell viability significantly decreased in ovarian cancer cells treated with osthole without effect on normal ovarian cells. Flow cytometric analysis revealed that osthole suppressed cells proliferation by promoting G2/M arrest and inducing apoptosis. The underlying mechanisms involved were regulation of the relative apoptotic protein Bcl-2, Bax and Caspase 3/9. In addition, wound healing and transwell assays revealed that the migratory potential and activity of matrix metalloproteinase MMP-2 and MMP-9 were markedly inhibited when cells were exposed to osthole. Conclusion: Our findings suggested that osthole has the potential to be used in novel anti-cancer therapeutic formulations for ovarian cancer treatment. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Jiang, Guoqiang; Liu, Jia; Ren, Baoyin; Zhang, Jing; Liu, Likun; Li, Weiling] Dalian Med Univ, Dept Biotechnol, Dalian 116044, Liaoning, Peoples R China. [Tang, Yawei] Dalian Med Univ, Coll Basic Med Sci, Dept Immunol, Lvshun South Rd, Dalian 116044, Liaoning, Peoples R China. [Owusu, Lawrence] Dalian Med Univ, Dept Integrat Med, Dalian 116044, Liaoning, Peoples R China. [Owusu, Lawrence] Kwame Nkrumah Univ Sci & Technol, Dept Biochem & Biotechnol, Kumasi, Ghana. [Li, Man] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Li, Man] Harvard Med Sch, Charlestown, MA 02129 USA. RP Li, WL (reprint author), Dalian Med Univ, Dept Biotechnol, Dalian 116044, Liaoning, Peoples R China. EM liweiling2015@163.com NR 41 TC 0 Z9 0 U1 17 U2 17 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-8741 J9 J ETHNOPHARMACOL JI J. Ethnopharmacol. PD DEC 4 PY 2016 VL 193 BP 368 EP 376 DI 10.1016/j.jep.2016.08.045 PG 9 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA ED7ZF UT WOS:000389090600040 PM 27566206 ER PT J AU Rauch, SD AF Rauch, Steven D. TI Meniere's disease: damaged hearing but reduced vertigo SO LANCET LA English DT Editorial Material C1 [Rauch, Steven D.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. RP Rauch, SD (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. EM steven_rauch@meei.harvard.edu NR 3 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD DEC 3 PY 2016 VL 388 IS 10061 BP 2716 EP 2717 DI 10.1016/S0140-6736(16)32166-3 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EE5FB UT WOS:000389629800005 PM 27865534 ER PT J AU Kamat, AM Hahn, NM Efstathiou, JA Lerner, SP Malmstrom, PU Choi, W Guo, CC Lotan, Y Kassouf, W AF Kamat, Ashish M. Hahn, Noah M. Efstathiou, Jason A. Lerner, Seth P. Malmstrom, Per-Uno Choi, Woonyoung Guo, Charles C. Lotan, Yair Kassouf, Wassim TI Bladder cancer SO LANCET LA English DT Review ID BACILLUS-CALMETTE-GUERIN; TRANSITIONAL-CELL-CARCINOMA; INVASIVE UROTHELIAL CARCINOMA; LONG-TERM OUTCOMES; COMBINED-MODALITY THERAPY; PHASE-III TRIAL; PERIOPERATIVE BLOOD-TRANSFUSION; EAU INTERNATIONAL CONSULTATION; CISPLATIN-BASED CHEMOTHERAPY; GEMCITABINE PLUS CISPLATIN AB Bladder cancer is a complex disease associated with high morbidity and mortality rates if not treated optimally. Awareness of haematuria as the major presenting symptom is paramount, and early diagnosis with individualised treatment and follow-up is the key to a successful outcome. For non-muscle-invasive bladder cancer, the mainstay of treatment is complete resection of the tumour followed by induction and maintenance immunotherapy with intravesical BCG vaccine or intravesical chemotherapy. For muscle-invasive bladder cancer, multimodal treatment involving radical cystectomy with neoadjuvant chemotherapy offers the best chance for cure. Selected patients with muscle-invasive tumours can be offered bladder-sparing trimodality treatment consisting of transurethral resection with chemoradiation. Advanced disease is best treated with systemic cisplatin-based chemotherapy; immunotherapy is emerging as a viable salvage treatment for patients in whom first-line chemotherapy cannot control the disease. Developments in the past 2 years have shed light on genetic subtypes of bladder cancer that might differ from one another in response to various treatments. C1 [Kamat, Ashish M.; Choi, Woonyoung] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Guo, Charles C.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Hahn, Noah M.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Hahn, Noah M.] Johns Hopkins Univ, Sch Med, Dept Urol, Baltimore, MD 21205 USA. [Efstathiou, Jason A.] Harvard Med Sch, Dept Radiat Oncol, Massachusetts Gen Hosp, Boston, MA USA. [Lerner, Seth P.] Baylor Coll Med, Scott Dept Urol, Houston, TX 77030 USA. [Malmstrom, Per-Uno] Uppsala Univ, Urol, Dept Urol Surg, Uppsala, Sweden. [Lotan, Yair] Univ Texas Southwestern, Dept Urol, Dallas, TX USA. [Kassouf, Wassim] McGill Univ, Dept Surg, Ctr Hlth, Montreal, PQ, Canada. RP Kamat, AM (reprint author), Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. EM akamat@mdanderson.org FU Theralase; Sanofi; Taris; Spectrum Pharmaceuticals; MDxHealth; Heat Biologics; Photocure; Telesta Therapeutics; Merck; Abbott Molecular; FKD; Pacific Edge; BioCancell; Vaxxion; UroGen; Telesta; Sitka; Neucleixx; Bladder Cancer Journal; Ferring; ENDO Pharmaceuticals; Viventia; Roche/Genentech; Genome DX; Abbott; Cepheid FX AMK reports consulting fees from Theralase, Sanofi, Taris, Spectrum Pharmaceuticals, and MDxHealth; reports research support from Heat Biologics, Photocure, Telesta Therapeutics, Merck, Abbott Molecular, FKD, and Pacific Edge; and has a patent pending for cytokine assay for response to intravesical therapy (CYPRIT) for the University of Texas. NMH reports consulting for Merck, Oncogenex, and Bristol-Myers Squibb, and research funding to institution from Novartis, Genentech, Merck, Oncogenex, Mirati Therapeutics, and Acerta Pharma, outside the submitted work. JAE reports consulting for Medivation and Astellas. SPL reports consulting fees from BioCancell, Vaxxion, UroGen, Telesta, Sitka, Neucleixx, Taris, Bladder Cancer Journal, and Ferring and grants from ENDO Pharmaceuticals, FKD, Viventia, Roche/Genentech, and Genome DX, during the conduct of the study. P-UM reports speaker fees from Medac GmbH and scientific advisory from Photocure ASA, and APIM Therapeutics AS, outside the submitted work. WC has a patent pending for methods of characterising and treating molecular subset of muscle-invasive bladder cancer. YL reports grants from Abbott, Cepheid, and MDxHealth and grants and personal fees from Pacific Edge, during the conduct of the study; and grants from genomedx and grants and personal fees from photocure, outside the submitted work. CCG and WK declare no competing interests. NR 179 TC 3 Z9 3 U1 12 U2 12 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 DEC 3 PY 2016 VL 388 IS 10061 BP 2796 EP 2810 DI 10.1016/S0140-6736(16)30512-8 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA EE5FB UT WOS:000389629800031 PM 27345655 ER PT J AU Lewis, RC Hauser, R Maynard, AD Neitzel, RL Wang, L Kavet, R Morey, P Ford, JB Meeker, JD AF Lewis, Ryan C. Hauser, Russ Maynard, Andrew D. Neitzel, Richard L. Wang, Lu Kavet, Robert Morey, Patricia Ford, Jennifer B. Meeker, John D. CA Earth Study Team TI PERSONAL MEASURES OF POWER-FREQUENCY MAGNETIC FIELD EXPOSURE AMONG MEN FROM AN INFERTILITY CLINIC: DISTRIBUTION, TEMPORAL VARIABILITY AND CORRELATION WITH THEIR FEMALE PARTNERS' EXPOSURE SO RADIATION PROTECTION DOSIMETRY LA English DT Article ID RESIDENTIAL PROXIMITY; PREGNANCY; RISK; MISCARRIAGE; WOMEN AB Power-frequency magnetic field exposure science as it relates to men and couples have not been explored despite the advantage of this information in the design and interpretation of reproductive health epidemiology studies. This analysis examined the distribution and temporal variability of exposures in men, and the correlation of exposures within couples using data from a longitudinal study of 25 men and their female partners recruited from an infertility clinic. The average and 90th percentile demonstrated fair to good reproducibility, whereas the maximum showed poor reproducibility over repeated sampling days, each separated by a median of 4.6 weeks. Average magnetic field exposures were also strongly correlated within couples, suggesting that one partner's data could be used as a surrogate in the absence of data from the other for this metric. Environment was also an important effect modifier in these explored matters. These issues should be considered in future relevant epidemiology studies. C1 [Lewis, Ryan C.; Maynard, Andrew D.; Neitzel, Richard L.; Meeker, John D.] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, 1415 Washington Hts, Ann Arbor, MI 48109 USA. [Lewis, Ryan C.] Exponent Inc, Ctr Occupat & Environm Hlth Risk Assessment, 475 14th St,Suite 400, Oakland, CA 94612 USA. [Hauser, Russ; Morey, Patricia; Ford, Jennifer B.] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Bldg 1,14th Floor,665 Huntington Ave, Boston, MA 02115 USA. [Hauser, Russ; Morey, Patricia; Ford, Jennifer B.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Bldg 1,14th Floor,665 Huntington Ave, Boston, MA 02115 USA. [Hauser, Russ; Earth Study Team] Massachusetts Gen Hosp, Vincent Mem Obstet & Gynecol Serv, 55 Fruit St, Boston, MA 02114 USA. [Wang, Lu] Univ Michigan, Sch Publ Hlth, Dept Biostat, 1415 Washington Hts, Ann Arbor, MI 48109 USA. [Kavet, Robert] Elect Power Res Inst, 3420 Hillview Ave, Palo Alto, CA 94304 USA. RP Meeker, JD (reprint author), Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, 1415 Washington Hts, Ann Arbor, MI 48109 USA. EM meekerj@umich.edu FU Electric Power Research Institute [1-SP0239]; National Institute of Environmental Health Sciences, National Institutes of Health [R01 ES009718, R01 ES016099]; University of Michigan FX This work was supported by project 1-SP0239 from the Electric Power Research Institute and grants R01 ES009718 and R01 ES016099 from the National Institute of Environmental Health Sciences, National Institutes of Health. R.C.L. was also supported by the Rackham Predoctoral Fellowship Award from the University of Michigan. NR 25 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0144-8420 EI 1742-3406 J9 RADIAT PROT DOSIM JI Radiat. Prot. Dosim. PD DEC 2 PY 2016 VL 172 IS 4 BP 401 EP 408 DI 10.1093/rpd/ncv515 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA EJ4IH UT WOS:000393179700010 PM 26705359 ER PT J AU Das, DK Mallis, RJ Duke-Cohan, JS Hussey, RE Tetteh, PW Hilton, M Wagner, G Lang, MJ Reinherz, EL AF Das, Dibyendu Kumar Mallis, Robert J. Duke-Cohan, Jonathan S. Hussey, Rebecca E. Tetteh, Paul W. Hilton, Mark Wagner, Gerhard Lang, Matthew J. Reinherz, Ellis L. TI Pre-T Cell Receptors (Pre-TCRs) Leverage V Complementarity Determining Regions (CDRs) and Hydrophobic Patch in Mechanosensing Thymic Self-ligands SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE allosteric regulation; cell differentiation; cell surface receptor; crystallography; major histocompatibility complex (MHC); nuclear magnetic resonance (NMR); optical tweezers; mechanobiology; pre-T cell receptor; structural transition ID BETA FG LOOP; THYMOCYTE DEVELOPMENT; MECHANICAL FORCE; STRUCTURAL BASIS; ANTIGEN RECEPTOR; FAB FRAGMENT; PEPTIDE-MHC; IN-VITRO; COMPLEX; SELECTION AB The pre-T cell receptor (pre-TCR) is a pT- heterodimer functioning in early T cell development. Although once thought to be ligand-autonomous, recent studies show that pre-TCRs participate in thymic repertoire formation through recognition of peptides bound to major histocompatibility molecules (pMHC). Using optical tweezers, we probe pre-TCR bonding with pMHC at the single molecule level. Like the TCR, the pre-TCR is a mechanosensor undergoing force-based structural transitions that dynamically enhance bond lifetimes and exploiting allosteric control regulated via the C FG loop region. The pre-TCR structural transitions exhibit greater reversibility than TCR and ordered force-bond lifetime curves. Higher piconewton force requires binding through both complementarity determining region loops and hydrophobic V patch apposition. This patch functions in the pre-TCR as a surrogate V domain, fostering ligand promiscuity to favor development of chains with self-reactivity but is occluded by subunit replacement of pT upon TCR formation. At the double negative 3 thymocyte stage where the pre-TCR is first expressed, pre-TCR interaction with self-pMHC ligands imparts growth and survival advantages as revealed in thymic stromal cultures, imprinting fundamental self-reactivity in the T cell repertoire. Collectively, our data imply the existence of sequential mechanosensor TCR repertoire tuning via the pre-TCR. C1 [Das, Dibyendu Kumar; Hilton, Mark; Lang, Matthew J.] Vanderbilt Univ, Dept Chem & Biomol Engn, 221 Kirkland Hall, Nashville, TN 37235 USA. [Mallis, Robert J.; Wagner, Gerhard] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Duke-Cohan, Jonathan S.; Tetteh, Paul W.; Reinherz, Ellis L.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Duke-Cohan, Jonathan S.; Hussey, Rebecca E.; Tetteh, Paul W.; Reinherz, Ellis L.] Dana Farber Canc Inst, Immunobiol Lab, Dept Med Oncol, Boston, MA 02115 USA. [Lang, Matthew J.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37235 USA. RP Lang, MJ (reprint author), Vanderbilt Univ, Dept Chem & Biomol Engn, 221 Kirkland Hall, Nashville, TN 37235 USA.; Reinherz, EL (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA.; Reinherz, EL (reprint author), Dana Farber Canc Inst, Immunobiol Lab, Dept Med Oncol, Boston, MA 02115 USA.; Lang, MJ (reprint author), Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37235 USA. EM matt.lang@vanderbilt.edu; ellis_reinherz@dfci.harvard.edu FU National Institutes of Health [R01AI100643, R01AI37581, P01GM047467]; National Science Foundation [MCB-1330792]; Singapore-Massachusetts Institute of Technology Alliance for Research and Technology (SMART) Program; American Association for Cancer Research [SU2C-AACR-DT-13-14] FX This work was supported by National Institutes of Health Grants R01AI100643, R01AI37581, and P01GM047467; National Science Foundation Grant MCB-1330792; the Singapore-Massachusetts Institute of Technology Alliance for Research and Technology (SMART) Program; and American Association for Cancer Research Grant SU2C-AACR-DT-13-14. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 57 TC 0 Z9 0 U1 0 U2 0 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 DEC 2 PY 2016 VL 291 IS 49 BP 25292 EP 25305 DI 10.1074/jbc.M116.752865 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EF1OV UT WOS:000390095300002 PM 27707880 ER PT J AU Kwon, SH Oh, S Nacke, M Mostov, KE Lipschutz, JH AF Kwon, Sang-Ho Oh, Sekyung Nacke, Marisa Mostov, Keith E. Lipschutz, Joshua H. TI Adaptor Protein CD2AP and L-type Lectin LMAN2 Regulate Exosome Cargo Protein Trafficking through the Golgi Complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE endosome; extracellular vesicles; G protein-coupled receptor (GPCR); Golgi; membrane trafficking; CD2AP; exosomes; LMAN2; urinary proteins; multivesicular ID WNT-PRODUCING CELLS; MULTIVESICULAR ENDOSOMES; EXTRACELLULAR VESICLES; SECRETION; RETROMER; BIOGENESIS; WNTLESS; GPRC5B; VIP36; SITE AB Exosomes, 40-150-nm extracellular vesicles, transport biological macromolecules that mediate intercellular communications. Although exosomes are known to originate from maturation of endosomes into multivesicular endosomes (also known as multivesicular bodies) with subsequent fusion of the multivesicular endosomes with the plasma membrane, it remains unclear how cargos are selected for exosomal release. Using an inducible expression system for the exosome cargo protein GPRC5B and following its trafficking trajectory, we show here that newly synthesized GPRC5B protein accumulates in the Golgi complex prior to its release into exosomes. The L-type lectin LMAN2 (also known as VIP36) appears to be specifically required for the accumulation of GPRC5B in the Golgi complex and restriction of GPRC5B transport along the exosomal pathway. This may occur due to interference with the adaptor protein GGA1-mediated trans Golgi network-to-endosome transport of GPRC5B. The adaptor protein CD2AP-mediated internalization following cell surface delivery appears to contribute to the Golgi accumulation of GPRC5B, possibly in parallel with biosynthetic/secretory trafficking from the endoplasmic reticulum. Our data thus reveal a Golgi-traversing pathway for exosomal release of the cargo protein GPRC5B in which CD2AP facilitates the entry and LMAN2 impedes the exit of the flux, respectively. C1 [Kwon, Sang-Ho; Lipschutz, Joshua H.] Med Univ South Carolina, Div Nephrol, Dept Med, Charleston, SC 29425 USA. [Oh, Sekyung] Stanford Univ, Sch Med, Dept Radiol, Stanford Cardiovasc Inst, Stanford, CA 94305 USA. [Oh, Sekyung] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Nacke, Marisa; Mostov, Keith E.] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. [Nacke, Marisa; Mostov, Keith E.] Univ Calif San Francisco, Dept Biochem Biophys, San Francisco, CA 94143 USA. [Lipschutz, Joshua H.] Ralph H Johnson Vet Affairs Med Ctr, Dept Med, Charleston, SC 29401 USA. RP Kwon, SH (reprint author), Med Univ South Carolina, Dept Med, 70 President St,Drug Discovery Bldg Rm 509, Charleston, SC 29425 USA. EM kwonk@musc.edu OI Oh, Sekyung/0000-0002-6880-5281 FU Medical University of South Carolina; American Society of Nephrology Gottschalk Research Scholar grant; National Institutes of Health [DK074398, DK091530, DK074038]; Veterans Affairs Merit Award [2I01BX000820] FX This work was supported by a start-up package from the Medical University of South Carolina and an American Society of Nephrology Gottschalk Research Scholar grant (to S.-H. K.), National Institutes of Health Grants DK074398 and DK091530 (to K. E. M.) and DK074038 (to J. H. L.), and Veterans Affairs Merit Award 2I01BX000820 (to J. H. L.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 62 TC 0 Z9 0 U1 5 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 DEC 2 PY 2016 VL 291 IS 49 BP 25462 EP 25475 DI 10.1074/jbc.M116.729202 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EF1OV UT WOS:000390095300016 PM 27765817 ER PT J AU Huang, SC Zhou, AY Nguyen, DT Zhang, HS Benz, EJ AF Huang, Shu-Ching Zhou, Anyu Nguyen, Dan T. Zhang, Henry S. Benz, Edward J., Jr. TI Protein 4.1R Influences Myogenin Protein Stability and Skeletal Muscle Differentiation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE E3 ubiquitin ligase; myogenesis; protein degradation; protein stability; ubiquitylation (ubiquitination); myogenin; protein 4; 1R; von Hippel Lindau ID TUMOR-SUPPRESSOR PROTEIN; MYOD MESSENGER-RNA; UBIQUITIN LIGASE; PROTEASOMAL DEGRADATION; NONERYTHROID ISOFORM; IN-VITRO; EXPRESSION; GENE; IDENTIFICATION; PATHOGENESIS AB Protein 4.1R (4.1R) isoforms are expressed in both cardiac and skeletal muscle. 4.1R is a component of the contractile apparatus. It is also associated with dystrophin at the sarcolemma in skeletal myofibers. However, the expression and function of 4.1R during myogenesis have not been characterized. We now report that 4.1R expression increases during C2C12 myoblast differentiation into myotubes. Depletion of 4.1R impairs skeletal muscle differentiation and is accompanied by a decrease in the levels of myosin heavy and light chains and caveolin-3. Furthermore, the expression of myogenin at the protein, but not mRNA, level is drastically decreased in 4.1R knockdown myocytes. Similar results were obtained using MyoD-induced differentiation of 4.1R(-/-) mouse embryonic fibroblast cells. von Hippel-Lindau (VHL) protein is known to destabilize myogenin via the ubiquitin-proteasome pathway. We show that 4.1R associates with VHL and, when overexpressed, reverses myogenin ubiquitination and stability. This suggests that 4.1R may influence myogenesis by preventing VHL-mediated myogenin degradation. Together, our results define a novel biological function for 4.1R in muscle differentiation and provide a molecular mechanism by which 4.1R promotes myogenic differentiation. C1 [Huang, Shu-Ching; Zhou, Anyu; Nguyen, Dan T.; Zhang, Henry S.; Benz, Edward J., Jr.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. [Huang, Shu-Ching; Benz, Edward J., Jr.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Huang, Shu-Ching; Benz, Edward J., Jr.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Benz, Edward J., Jr.] Dana Farber Harvard Canc Ctr, Boston, MA 02115 USA. RP Huang, SC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM shu-ching_huang@dfci.harvard.edu FU National Institutes of Health [HL24385, HL44985, HL61295]; Claudia Barr Award FX This work was supported by National Institutes of Health Grants HL24385 and HL44985 (to E.J.B.) and National Institutes of Health Grant HL61295 and the Claudia Barr Award (to S.C.H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare that they have no conflicts of interest with the contents of this article. NR 68 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 2 PY 2016 VL 291 IS 49 BP 25591 EP 25607 DI 10.1074/jbc.M116.761296 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EF1OV UT WOS:000390095300026 PM 27780863 ER PT J AU Hu, KJ Chen, C Meng, QY Williams, Z Xu, WD AF Hu, Kejia Chen, Chao Meng, Qingyao Williams, Ziv Xu, Wendong TI Scientific profile of brain-computer interfaces: Bibliometric analysis in a 10-year period SO NEUROSCIENCE LETTERS LA English DT Article DE Bibliometrics; Brain-machine interface; Brain-computer interface; Citation analysis; Neural prosthetic; Neurorehabilitation ID JOURNAL IMPACT FACTORS; CITATION ANALYSIS; CITED ARTICLES; MACHINE INTERFACES; TETRAPLEGIA; PROSTHETICS; SURGERY; WORKS; ARM AB Background: With the tremendous advances in the field of brain computer interfaces (BCI), the literature in this field has grown exponentially; examination of highly cited articles is a tool that can help identify outstanding scientific studies and landmark papers. This study examined the characteristics of 100 highly cited BCI papers over the past 10 years. Methods: The Web of Science was searched for highly cited papers related to BCI research published from 2006 to 2015. The top 100 highly cited articles were identified. The number of citations and countries, and the corresponding institutions, year of publication, study design, and research area were noted and analyzed. Results: The 100 highly cited articles had a mean of 137.1(SE: 15.38) citations. These articles were published in 45 high-impact journals, and mostly in TRANSACTIONS ON BIOMEDICAL ENGINEERING (n=14). Of the 100 articles, 72 were original articles and the rest were review articles. These articles came from 15 countries, with the USA contributing most of the highly cited articles (n =52). Fifty-seven institutions produced these 100 highly cited articles, led by Duke University (n = 7). Conclusions: This study provides a historical perspective on the progress in the field of BCI, allows recognition of the most influential reports, and provides useful information that can indicate areas requiring further investigation. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Hu, Kejia; Xu, Wendong] Fudan Univ, Huashan Hosp, Dept Hand Surg, 12 Wulumuqi Middle Rd, Shanghai 200040, Peoples R China. [Hu, Kejia; Williams, Ziv] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St, Boston, MA 02114 USA. [Hu, Kejia; Williams, Ziv] Harvard Med Sch, MGH HMS Ctr Nervous Syst Repair, Boston, MA 02114 USA. [Hu, Kejia; Xu, Wendong] Fudan Univ, Shanghai Key Lab Peripheral Nerve & Microsurg, Shanghai 200040, Peoples R China. [Chen, Chao] Western Univ, Dept Chem & Biochem Engn, London, ON N6A 3K7, Canada. [Meng, Qingyao] Donghua Univ, Art Design Inst, Fash, Shanghai 200051, Peoples R China. [Hu, Kejia; Xu, Wendong] Jingan Dist Cent Hosp, Dept Hand & Upper Extrem Surg, Shanghai 200040, Peoples R China. [Xu, Wendong] Fudan Univ, Collaborat Innovat Ctr Brain Sci, State Key Lab Med Neurobiol, Shanghai 200031, Peoples R China. RP Xu, WD (reprint author), Fudan Univ, Huashan Hosp, Dept Hand Surg, 12 Wulumuqi Middle Rd, Shanghai 200040, Peoples R China.; Williams, Z (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St, Boston, MA 02114 USA. EM zwilliams@mgh.harvard.edu; wendongxu@fudan.edu.cn FU China Scholarship Council (CSC) FX We greatly thank Mohsen Jamali, Raymundo Baez -Mendoza, Ziev Moses, Firas Bounni, Gabriel Friedman, William Li, Jonas St Fleur and Emma Mastrobattista in MGH HMS Center for Nervous System Repair, for their insightful discussions and supports. Kejia Hu also specially thank The China Scholarship Council (CSC) for support and encouragement. NR 34 TC 0 Z9 0 U1 25 U2 25 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD DEC 2 PY 2016 VL 635 BP 61 EP 66 DI 10.1016/j.neulet.2016.10.022 PG 6 WC Neurosciences SC Neurosciences & Neurology GA ED8CX UT WOS:000389100700010 PM 27751787 ER PT J AU Ito, K Turcotte, R Cui, JH Zimmerman, SE Pinho, S Mizoguchi, T Arai, F Runnels, JM Alt, C Teruya-Feldstein, J Mar, JC Singh, R Suda, T Lin, CP Frenette, PS Ito, K AF Ito, Kyoko Turcotte, Raphael Cui, Jinhua Zimmerman, Samuel E. Pinho, Sandra Mizoguchi, Toshihide Arai, Fumio Runnels, Judith M. Alt, Clemens Teruya-Feldstein, Julie Mar, Jessica C. Singh, Rajat Suda, Toshio Lin, Charles P. Frenette, Paul S. Ito, Keisuke TI Self-renewal of a purified Tie2(+) hematopoietic stem cell population relies on mitochondrial clearance SO SCIENCE LA English DT Article ID AUTOPHAGY; MAINTENANCE; QUIESCENCE; OXIDATION AB A single hematopoietic stem cell (HSC) is capable of reconstituting hematopoiesis and maintaining homeostasis by balancing self-renewal and cell differentiation. The mechanisms ofHSCdivision balance, however, are not yet defined. Herewe demonstrate, by characterizing at the single-cell level a purified and minimally heterogeneous murine Tie2(+) HSC population, that these top hierarchical HSCs preferentially undergo symmetric divisions. The induction ofmitophagy, a quality control process in mitochondria, plays an essential role in self-renewing expansion of Tie2(+) HSCs. Activation of the PPAR (peroxisome proliferator-activated receptor)-fatty acid oxidation pathway promotes expansion of Tie2(+) HSCs through enhanced Parkin recruitment in mitochondria. These metabolic pathways are conserved in human TIE2(+) HSCs. Our data thus identify mitophagy as a key mechanism of HSC expansion and suggest potential methods of cell-fate manipulation through metabolic pathways. C1 [Ito, Kyoko; Cui, Jinhua; Zimmerman, Samuel E.; Pinho, Sandra; Mizoguchi, Toshihide; Mar, Jessica C.; Frenette, Paul S.; Ito, Keisuke] Albert Einstein Coll Med, Ruth L & David S Gottesman Inst Stem Cell & Regen, Bronx, NY 10461 USA. [Ito, Kyoko; Frenette, Paul S.; Ito, Keisuke] Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. [Ito, Kyoko; Frenette, Paul S.; Ito, Keisuke] Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10461 USA. [Turcotte, Raphael; Runnels, Judith M.; Alt, Clemens; Lin, Charles P.] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Ctr Syst Biol,Adv Microscopy Program, Boston, MA 02114 USA. [Cui, Jinhua; Pinho, Sandra; Mizoguchi, Toshihide; Frenette, Paul S.; Ito, Keisuke] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. [Cui, Jinhua; Pinho, Sandra; Mizoguchi, Toshihide; Frenette, Paul S.; Ito, Keisuke] Albert Einstein Coll Med, Stem Cell Inst, Bronx, NY 10461 USA. [Zimmerman, Samuel E.; Mar, Jessica C.] Albert Einstein Coll Med, Dept Syst & Computat Biol, Bronx, NY 10461 USA. [Arai, Fumio; Suda, Toshio] Keio Univ, Sch Med, Sakaguchi Lab Dev Biol, Dept Cell Differentiat, Tokyo 108, Japan. [Teruya-Feldstein, Julie] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Dept Pathol, New York, NY 10021 USA. [Mar, Jessica C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Singh, Rajat] Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA. [Singh, Rajat; Ito, Keisuke] Albert Einstein Coll Med, Diabet Res Ctr, Bronx, NY 10461 USA. [Suda, Toshio] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore, Singapore. RP Ito, K (reprint author), Albert Einstein Coll Med, Ruth L & David S Gottesman Inst Stem Cell & Regen, Bronx, NY 10461 USA.; Ito, K (reprint author), Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA.; Ito, K (reprint author), Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10461 USA.; Ito, K (reprint author), Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA.; Ito, K (reprint author), Albert Einstein Coll Med, Stem Cell Inst, Bronx, NY 10461 USA.; Ito, K (reprint author), Albert Einstein Coll Med, Diabet Res Ctr, Bronx, NY 10461 USA. EM keisuke.ito@einstein.yu.edu RI Arai, Fumio/J-5241-2013 OI Arai, Fumio/0000-0003-1936-4907 FU NIH [R01DK98263, R01DK100689]; NYSTEM (New York State Stem Cell Science single-cell-core) [C029154]; Harvard Stem Cell Institute; NIH; Ellison Medical Foundation; Leukemia Lymphoma Society; Japan Society for the Promotion of Science; [P30CA013330] FX We thank all members of the Ito lab and Einstein Stem Cell Institute for their comments on HSC self-renewal and M. Wolfgang, A. Carracedo, H. You, and the Einstein Flow Cytometry and Analytical Imaging core facilities (grant P30CA013330) for help and materials. This work was supported by NIH (grants R01DK98263 and R01DK100689 to Ke.I.) and NYSTEM (New York State Stem Cell Science single-cell-core, grant C029154 to Ke.I.), Harvard Stem Cell Institute (to C.P.L.), NIH and Ellison Medical Foundation (to R.S.), NIH and Leukemia Lymphoma Society (to P.S.F.), and Japan Society for the Promotion of Science (to T.S.). We declare no competing financial interests. NR 13 TC 5 Z9 5 U1 16 U2 16 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 DEC 2 PY 2016 VL 354 IS 6316 BP 1156 EP 1160 DI 10.1126/science.aaf5530 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED5TY UT WOS:000388916400044 PM 27738012 ER PT J AU Pauken, KE Sammons, MA Odorizzi, PM Manne, S Godec, J Khan, O Drake, AM Chen, ZY Sen, DR Kurachi, M Barnitz, RA Bartman, C Bengsch, B Huang, AC Schenkel, JM Vahedi, G Haining, WN Berger, SL Wherry, EJ AF Pauken, Kristen E. Sammons, Morgan A. Odorizzi, Pamela M. Manne, Sasikanth Godec, Jernej Khan, Omar Drake, Adam M. Chen, Zeyu Sen, Debattama R. Kurachi, Makoto Barnitz, R. Anthony Bartman, Caroline Bengsch, Bertram Huang, Alexander C. Schenkel, Jason M. Vahedi, Golnaz Haining, W. Nicholas Berger, Shelley L. Wherry, E. John TI Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade SO SCIENCE LA English DT Article ID CHRONIC VIRAL-INFECTION; INHIBITORY RECEPTOR PD-1; CHECKPOINT BLOCKADE; ANTIGEN; MEMORY; EXPRESSION; THERAPY; CANCER; RESPONSES; CHROMATIN AB Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 Tcells (TEX) andimprove control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable memory Tcells (TMEM) is unclear. We found that reinvigoration of TEX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated TEX became reexhausted if antigen concentration remained high and failed to become TMEM upon antigen clearance. TEX acquired an epigenetic profile distinct from that of effector Tcells (TEFF) and TMEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that TEX are a distinct lineage of CD8 Tcells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the TEX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies. C1 [Pauken, Kristen E.; Odorizzi, Pamela M.; Manne, Sasikanth; Khan, Omar; Chen, Zeyu; Kurachi, Makoto; Bartman, Caroline; Bengsch, Bertram; Wherry, E. John] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Pauken, Kristen E.; Odorizzi, Pamela M.; Manne, Sasikanth; Khan, Omar; Chen, Zeyu; Kurachi, Makoto; Bartman, Caroline; Bengsch, Bertram; Wherry, E. John] Univ Penn, Inst Immunol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Sammons, Morgan A.; Drake, Adam M.; Berger, Shelley L.] Univ Penn, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. [Sammons, Morgan A.; Drake, Adam M.; Vahedi, Golnaz; Berger, Shelley L.] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Sammons, Morgan A.; Drake, Adam M.; Berger, Shelley L.] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. [Sammons, Morgan A.; Drake, Adam M.; Berger, Shelley L.] Univ Penn, Penn Epigenet Program, Philadelphia, PA 19104 USA. [Godec, Jernej; Barnitz, R. Anthony; Haining, W. Nicholas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Godec, Jernej] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA USA. [Huang, Alexander C.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Huang, Alexander C.] Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA. [Schenkel, Jason M.] Univ Minnesota, Dept Microbiol & Immunol, Minneapolis, MN USA. [Vahedi, Golnaz] Univ Penn, Inst Immunol, Philadelphia, PA 19104 USA. [Haining, W. Nicholas] Broad Inst MIT & Harvard, Cambridge, MA USA. [Haining, W. Nicholas] Harvard Med Sch, Childrens Hosp, Div Hematol Oncol, Boston, MA USA. RP Wherry, EJ (reprint author), Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA.; Wherry, EJ (reprint author), Univ Penn, Inst Immunol, Perelman Sch Med, Philadelphia, PA 19104 USA. EM wherry@mail.med.upenn.edu FU Robertson Foundation-Cancer Research Institute Irvington Fellowship; American Cancer Society; National Institutes of Health [F30DK100159, T32 2T32CA009615-26, CA78831, AI105343, AI112521, AI082630, AI115712, AI117950, AI108545]; German Research Foundation [BE5496/1-1]; Parker Institute for Cancer Immunotherapy FX We thank the Wherry lab for discussions and critically reading the manuscript. We thank C. Surh for providing the antibody against IL-7 (anti-IL-7). The anti-IL-7 antibody is available from La Jolla Institute of Allergy and Immunology, and the IL-7 used is available from the National Cancer Institute, both under material transfer agreements with the University of Pennsylvania. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. Sequencing data are available at Gene Expression Omnibus [accession numbers GSE86796 (microarray), GSE86881 (RNA seq), and GSE86797 (ATAC seq)]. This study was supported by a Robertson Foundation-Cancer Research Institute Irvington Fellowship (K.E.P.), an American Cancer Society Postdoctoral Fellowship (M.A.S.), National Institutes of Health grant F30DK100159 (J.M.S.), German Research Foundation Fellowship BE5496/1-1 (B.B.), and National Institutes of Health grant T32 2T32CA009615-26 (A.C.H.). This work was funded by the National Institutes of Health (grant CA78831 to S.L.B. and grants AI105343, AI112521, AI082630, AI115712, AI117950, and AI108545 to E.J.W.). This research was also supported by the Parker Institute for Cancer Immunotherapy. E.J.W. has a patent licensing agreement on the PD-1 pathway. The authors declare no additional conflicts of interest. NR 30 TC 9 Z9 9 U1 18 U2 18 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 DEC 2 PY 2016 VL 354 IS 6316 BP 1160 EP 1165 DI 10.1126/science.aaf2807 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED5TY UT WOS:000388916400045 PM 27789795 ER PT J AU Sen, DR Kaminski, J Barnitz, RA Kurachi, M Gerdemann, U Yates, KB Tsao, HW Godec, J LaFleur, MW Brown, FD Tonnerre, P Chung, RT Tully, DC Allen, TM Frahm, N Lauer, GM Wherry, EJ Yosef, N Haining, WN AF Sen, Debattama R. Kaminski, James Barnitz, R. Anthony Kurachi, Makoto Gerdemann, Ulrike Yates, Kathleen B. Tsao, Hsiao-Wei Godec, Jernej LaFleur, Martin W. Brown, Flavian D. Tonnerre, Pierre Chung, Raymond T. Tully, Damien C. Allen, Todd M. Frahm, Nicole Lauer, Georg M. Wherry, E. John Yosef, Nir Haining, W. Nicholas TI The epigenetic landscape of T cell exhaustion SO SCIENCE LA English DT Article ID CHRONIC VIRAL-INFECTION; REGULATORY DNA; CHROMATIN AB Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1). However, the regulation of gene expression in exhausted T cells is poorly understood. Here, we define the accessible chromatin landscape in exhausted CD8(+) T cells and show that it is distinct from functional memory CD8(+) T cells. Exhausted CD8(+) T cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers. Genome editing shows that PD-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential RAR, T-bet, and Sox3 motifs. Functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted CD8(+) T cells. C1 [Sen, Debattama R.; Barnitz, R. Anthony; Gerdemann, Ulrike; Yates, Kathleen B.; Tsao, Hsiao-Wei; Godec, Jernej; LaFleur, Martin W.; Brown, Flavian D.; Haining, W. Nicholas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Sen, Debattama R.; Godec, Jernej; LaFleur, Martin W.; Brown, Flavian D.] Harvard Med Sch, Div Med Sci, Boston, MA 02115 USA. [Kaminski, James; Yosef, Nir] Univ Calif Berkeley, Ctr Computat Biol, Berkeley, CA 94720 USA. [Kurachi, Makoto; Wherry, E. John] Univ Penn, Inst Immunol, Philadelphia, PA 19104 USA. [Kurachi, Makoto; Wherry, E. John] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. [Tonnerre, Pierre; Chung, Raymond T.; Lauer, Georg M.] Harvard Med Sch, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02115 USA. [Tonnerre, Pierre; Chung, Raymond T.; Lauer, Georg M.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Liver, Boston, MA 02115 USA. [Tully, Damien C.; Allen, Todd M.; Yosef, Nir] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02139 USA. [Tully, Damien C.; Allen, Todd M.; Yosef, Nir] Harvard Univ, Boston, MA 02139 USA. [Frahm, Nicole] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA. [Yosef, Nir] Univ Calif Berkeley, Dept Elect Engn & Comp Sci, Berkeley, CA 94720 USA. [Haining, W. Nicholas] Childrens Hosp, Div Pediat Hematol & Oncol, Boston, MA 02115 USA. [Haining, W. Nicholas] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA. RP Haining, WN (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA.; Yosef, N (reprint author), Univ Calif Berkeley, Ctr Computat Biol, Berkeley, CA 94720 USA.; Yosef, N (reprint author), MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02139 USA.; Yosef, N (reprint author), Harvard Univ, Boston, MA 02139 USA.; Yosef, N (reprint author), Univ Calif Berkeley, Dept Elect Engn & Comp Sci, Berkeley, CA 94720 USA.; Haining, WN (reprint author), Childrens Hosp, Div Pediat Hematol & Oncol, Boston, MA 02115 USA.; Haining, WN (reprint author), Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA. EM niryosef@berkeley.edu; nicholas_haining@dfci.harvard.edu FU NIH [AI115712, AI091493, AI082630, 1R21AI078809-01, UM1 AI068618]; BRAIN Initiative from the NIH [MH105979, HG007910] FX The authors thank members of the Yosef and Haining laboratories for their input, the research subjects for their participation, and J. Doench and the entire Genetic Perturbation Platform at the Broad Institute for their advice on Cas9-mediated screening technology. The authors are grateful for input from the Cancer Center for Genome Discovery. The data reported in this manuscript are tabulated in the main paper and in the supplementary materials. Genome-wide data generated in this study can be accessed via GEO accession no. GSE87646. This research was supported by AI115712, AI091493, and AI082630 to W.N.H. from the NIH; by the BRAIN Initiative grants MH105979 and HG007910 from the NIH to N.Y.; and by 1R21AI078809-01 and UM1 AI068618 from the NIH to N.F. The authors declare no potential conflicts of interest. D.R.S., J.K., N.Y., E.J.W., and W.N.H. are inventors on a patent application (U.S. Patent Application no. 62/310,903) held and submitted by Dana-Farber Cancer Institute. NR 22 TC 10 Z9 10 U1 21 U2 21 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 DEC 2 PY 2016 VL 354 IS 6316 BP 1165 EP 1169 DI 10.1126/science.aae0491 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED5TY UT WOS:000388916400046 PM 27789799 ER PT J AU Esson, D Mather, AE Scanlan, E Gupta, S de Vries, SPW Bailey, D Harris, SR McKinley, TJ Meric, G Berry, SK Mastroeni, P Sheppard, SK Christie, G Thomson, NR Parkhill, J Maskell, DJ Grant, AJ AF Esson, Diane Mather, Alison E. Scanlan, Eoin Gupta, Srishti de Vries, Stefan P. W. Bailey, David Harris, Simon R. McKinley, Trevelyan J. Meric, Guillaume Berry, Sophia K. Mastroeni, Pietro Sheppard, Samuel K. Christie, Graham Thomson, Nicholas R. Parkhill, Julian Maskell, Duncan J. Grant, Andrew J. TI Genomic variations leading to alterations in cell morphology of Campylobacter spp SO SCIENTIFIC REPORTS LA English DT Article ID PERFORMANCE LIQUID-CHROMATOGRAPHY; FIELD GEL-ELECTROPHORESIS; PHASE-VARIABLE GENES; ESCHERICHIA-COLI; PEPTIDOGLYCAN HYDROLASES; NEISSERIA-MENINGITIDIS; PATHOGENIC BACTERIA; HELICOBACTER-PYLORI; MEMBRANE-PROTEIN; MISMATCH REPAIR AB Campylobacter jejuni, the most common cause of bacterial diarrhoeal disease, is normally helical. However, it can also adopt straight rod, elongated helical and coccoid forms. Studying how helical morphology is generated, and how it switches between its different forms, is an important objective for understanding this pathogen. Here, we aimed to determine the genetic factors involved in generating the helical shape of Campylobacter. A C. jejuni transposon (Tn) mutant library was screened for nonhelical mutants with inconsistent results. Whole genome sequence variation and morphological trends within this Tn library, and in various C. jejuni wild type strains, were compared and correlated to detect genomic elements associated with helical and rod morphologies. All rod-shaped C. jejuni Tn mutants and all rod-shaped laboratory, clinical and environmental C. jejuni and Campylobacter coli contained genetic changes within the pgp1 or pgp2 genes, which encode peptidoglycan modifying enzymes. We therefore confirm the importance of Pgp1 and Pgp2 in the maintenance of helical shape and extended this to a wide range of C. jejuni and C. coli isolates. Genome sequence analysis revealed variation in the sequence and length of homopolymeric tracts found within these genes, providing a potential mechanism of phase variation of cell shape. C1 [Esson, Diane; Mather, Alison E.; Scanlan, Eoin; Gupta, Srishti; de Vries, Stefan P. W.; McKinley, Trevelyan J.; Berry, Sophia K.; Mastroeni, Pietro; Maskell, Duncan J.; Grant, Andrew J.] Univ Cambridge, Dept Vet Med, Madingley Rd, Cambridge, England. [Mather, Alison E.; Harris, Simon R.; Thomson, Nicholas R.; Parkhill, Julian] Wellcome Trust Genome Campus, Wellcome Trust Sanger Inst, Cambridge, England. [Bailey, David; Christie, Graham] Univ Cambridge, Dept Chem Engn & Biotechnol, New Museums Site,Pembroke St, Cambridge, England. [Meric, Guillaume; Sheppard, Samuel K.] Univ Bath, Dept Biol & Biotechnol, Milner Ctr Evolut, Claverton Down, Bath, Avon, England. [Thomson, Nicholas R.] London Sch Hyg & Trop Med, London, England. [Scanlan, Eoin] San Francisco VA Med Ctr, San Francisco, CA USA. [Scanlan, Eoin] Univ Calif San Francisco, San Francisco, CA 94143 USA. [McKinley, Trevelyan J.] Univ Exeter, Coll Engn Math & Phys Sci, Treliever Rd, Penryn, Cornwall, England. RP Grant, AJ (reprint author), Univ Cambridge, Dept Vet Med, Madingley Rd, Cambridge, England. EM ajg60@cam.ac.uk FU Wellcome Trust; Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge; BBSRC [BB/K004514/1, BB/ M014088/1]; Wellcome Trust [098051, 088786/C/09/Z]; Biotechnology and Biological Sciences Research Council [BB/I02464X/1]; Medical Research Council [MR/L015080/1]; National Institute for Social Care and Health Research Fellowship [HF-14-13] FX Scanning Electron Microscopy was kindly performed by Dr Jeremy Skepper (Cambridge Advanced Imaging Centre). This work was funded by The Wellcome Trust through a PhD training studentship awarded to DE, and was supported by an Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge joint research grant awarded to AJG. SG and SPWDV were funded by BBSRC grant BB/K004514/1. AEM, SH, NRT and JP were supported by the Wellcome Trust grant number 098051. AEM was also supported by BBSRC grant BB/ M014088/1. SKS was funded by Biotechnology and Biological Sciences Research Council grant BB/I02464X/1, Medical Research Council grant MR/L015080/1 and Wellcome Trust grant 088786/C/09/Z. GM was supported by a National Institute for Social Care and Health Research Fellowship (HF-14-13). NR 71 TC 1 Z9 1 U1 10 U2 10 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 DEC 2 PY 2016 VL 6 AR 38303 DI 10.1038/srep38303 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED8LQ UT WOS:000389123400001 PM 27910897 ER PT J AU Liu, CA Sui, J Cote, CJ Anderson, TA AF Liu, C. A. Sui, J. Cote, C. J. Anderson, T. A. TI Use of epinephrine in caudal anaesthesia increases stroke volume and cardiac output in children SO BRITISH JOURNAL OF ANAESTHESIA LA English DT Meeting Abstract CT PostGraduate Assembly Resident Research Contest CY DEC 10, 2016 CL New York, NY C1 [Liu, C. A.; Sui, J.; Cote, C. J.; Anderson, T. A.] Massachusetts Gen Hosp, Dept Anesthesiol Crit Care & Pain Med, Boston, MA 02114 USA. EM amber.chang.liu@gmail.com 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 0007-0912 EI 1471-6771 J9 BRIT J ANAESTH JI Br. J. Anaesth. PD DEC PY 2016 VL 117 SU 3 SI SI BP 74 EP 74 PG 1 WC Anesthesiology SC Anesthesiology GA EM4PC UT WOS:000395294100011 ER PT J AU Ahmed, F Michelen, S Massoud, R Kaafarani, H AF Ahmed, Faheem Michelen, Sophia Massoud, Rashad Kaafarani, Haytham TI Are the SDGs leaving safer surgical systems behind? SO INTERNATIONAL JOURNAL OF SURGERY LA English DT Editorial Material DE Health policy; Public health; Development goals; Surgery; Health systems; Surgical health systems; Sustainable development goals (SDGs) AB The World Health Organisation (WHO) has set out its new aims for the post-2015 global agenda in the form of the Sustainable Development Goals (SDGs). Discussions around the historically neglected role of emergency and essential surgical interventions in global health has attracted widespread attention with the help of well-timed, high-profile reports including the Lancet Commission for Global Surgery [1]. The case for promoting safe surgery is clear with evidence suggesting that at least two-thirds of the years of life lost globally will be attributed to surgical conditions by 2025 [1]. In 2010 alone, almost 17 million lives, and more than 70 million disability-adjusted life years (DALYs) were lost due to surgically treatable conditions [1]. A central component of the SDGs is its renewed focus on health as a human right in the form of Universal Health Coverage (UHC). However, there are doubts as to how nations will be able to keep the 'promise of leaving no-one behind' without explicit reference to global surgery within the SDG framework [2]. (C) 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved. C1 [Ahmed, Faheem] Kings Coll London, Guys Kings & St Thomas Sch Med, London, England. [Ahmed, Faheem; Michelen, Sophia] London Sch Hyg & Trop Med, London, England. [Massoud, Rashad] Univ Res Co LLC Ctr Human Serv, USAID Applying Sci Strengthen & Improve Syst Proj, Chevy Chase, MD USA. [Kaafarani, Haytham] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Kaafarani, Haytham] Harvard Med Sch, Boston, MA USA. RP Ahmed, F (reprint author), Kings Coll London, Guys Kings & St Thomas Sch Med, London, England.; Ahmed, F (reprint author), London Sch Hyg & Trop Med, London, England. EM faheem.ahmed@kcl.ac.uk; sophia.michelen1@student.lshtm.ac.uk; rmassoud@urc-chs.com; hkaafarani@mgh.harvard.edu NR 7 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1743-9191 EI 1743-9159 J9 INT J SURG JI Int. J. Surg. PD DEC PY 2016 VL 36 BP 74 EP 75 DI 10.1016/j.ijsu.2016.09.095 PN A PG 2 WC Surgery SC Surgery GA EO1KZ UT WOS:000396458700015 PM 27702551 ER PT J AU Eisner, BH AF Eisner, Brian H. TI Renal stones editorial SO INTERNATIONAL JOURNAL OF SURGERY LA English DT Editorial Material C1 [Eisner, Brian H.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Urol, Boston, MA 02115 USA. RP Eisner, BH (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Urol, Boston, MA 02115 USA. EM BEISNER@mgh.harvard.edu 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 1743-9191 EI 1743-9159 J9 INT J SURG JI Int. J. Surg. PD DEC PY 2016 VL 36 BP 589 EP 589 DI 10.1016/j.ijsu.2016.11.029 PN D PG 1 WC Surgery SC Surgery GA EO1LM UT WOS:000396460000001 PM 27871807 ER PT J AU McCarthy, CJ Baliyan, V Kordbacheh, H Sajjad, Z Sahani, D Kambadakone, A AF McCarthy, Colin J. Baliyan, Vinit Kordbacheh, Hamed Sajjad, Zafar Sahani, Dushyant Kambadakone, Avinash TI Radiology of renal stone disease SO INTERNATIONAL JOURNAL OF SURGERY LA English DT Review DE Nephrolithiasis; Radiology; Computed Tomography; Low dose; Ultrasound ID DUAL-ENERGY CT; SHOCK-WAVE LITHOTRIPSY; SPIRAL COMPUTED-TOMOGRAPHY; UNENHANCED HELICAL CT; MULTIDETECTOR CT; EMERGENCY-DEPARTMENT; URETERAL CALCULI; URINARY CALCULI; DOSE REDUCTION; KIDNEY-STONES AB Nephrolithiasis is a common cause of abdominal pain and will affect approximately 1 in 10 people in their lifetime. In the past two decades, there have been several technological advances that have changed the imaging approach to stone diagnosis and follow-up. We present a review of the current imaging evaluation for renal stone disease, and outline how new technology has helped with diagnosis and management. (C) 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved. C1 [McCarthy, Colin J.; Baliyan, Vinit; Kordbacheh, Hamed; Sahani, Dushyant; Kambadakone, Avinash] Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,White 270, Boston, MA 02114 USA. [Sajjad, Zafar] Aga Khan Univ Hosp, Dept Radiol, Stadium Rd, Karachi 74800, Pakistan. RP Kambadakone, A (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,White 270, Boston, MA 02114 USA. EM colin.mccarthy@mgh.harvard.edu; vbaliyan@mgh.harvard.edu; hkordbacheh@mgh.harvard.edu; zafar.sajjad@aku.edu; DSAHANI@mgh.harvard.edu; AKAMBADAKONE@mgh.harvard.edu NR 67 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1743-9191 EI 1743-9159 J9 INT J SURG JI Int. J. Surg. PD DEC PY 2016 VL 36 BP 638 EP 646 DI 10.1016/j.ijsu.2016.10.045 PN D PG 9 WC Surgery SC Surgery GA EO1LM UT WOS:000396460000009 PM 27816704 ER PT J AU Svehlova, K Lawrence, MS Bednarova, L Curtis, EA AF Svehlova, Katerina Lawrence, Michael S. Bednarova, Lucie Curtis, Edward A. TI Altered biochemical specificity of G-quadruplexes with mutated tetrads SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA G-QUADRUPLEX; RNA G-QUADRUPLEX; HIGHER-ORDER STRUCTURE; IN-VITRO SELECTION; PEROXIDASE-ACTIVITY; HUMAN GENOME; CIRCULAR-DICHROISM; GENE-EXPRESSION; NMR OBSERVATION; NUCLEIC-ACIDS AB A fundamental motif in canonical nucleic acid structure is the base pair. Mutations that disrupt base pairs are typically destabilizing, but stability can often be restored by a second mutation that replaces the original base pair with an isosteric variant. Such concerted changes are a way to identify helical regions in secondary structures and to identify new functional motifs in sequenced genomes. In principle, such analysis can be extended to non-canonical nucleic acid structures, but this approach has not been utilized because the sequence requirements of such structures are not well understood. Here we investigate the sequence requirements of a G-quadruplex that can both bind GTP and promote peroxidase reactions. Characterization of all 256 variants of the central tetrad in this structure indicates that certain mutations can compensate for canonical G-G-G-G tetrads in the context of both GTPbinding and peroxidase activity. Furthermore, the sequence requirements of these two motifs are significantly different, indicating that tetrad sequence plays a role in determining the biochemical specificity of Gquadruplex activity. Our results provide insight into the sequence requirements of G- quadruplexes, and should facilitate the analysis of such motifs in sequenced genomes. C1 [Svehlova, Katerina; Bednarova, Lucie; Curtis, Edward A.] ASCR, Inst Organ Chem & Biochem, Prague 16610, Czech Republic. [Svehlova, Katerina] Charles Univ Prague, Fac Sci, CR-12844 Prague, Czech Republic. [Lawrence, Michael S.] Harvard Med Sch, Massachusetts Gen Hosp, Canc Ctr, Boston, MA 02114 USA. [Lawrence, Michael S.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Curtis, EA (reprint author), ASCR, Inst Organ Chem & Biochem, Prague 16610, Czech Republic. EM curtis@uochb.cas.cz FU Institute of Organic Chemistry and Biochemistry ASCR FX Institute of Organic Chemistry and Biochemistry ASCR start-up grant (to E.A.C.). Funding for open access charge: Institute of Organic Chemistry and Biochemistry ASCR. NR 65 TC 0 Z9 0 U1 2 U2 2 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 DEC PY 2016 VL 44 IS 22 BP 10789 EP 10803 DI 10.1093/nar/gkw987 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN1AP UT WOS:000395742900023 PM 27789695 ER PT J AU Cossio-Aranda, J Del Valle Zamora, K Nanda, NC Uzendu, A Keirns, C Verdejo-Paris, J Martinez-Rios, MA Espinola-Zavaleta, N AF Cossio-Aranda, Jorge Del Valle Zamora, Karina Nanda, Navin C. Uzendu, Anezi Keirns, Candace Verdejo-Paris, Juan Antonio Martinez-Rios, Marco Espinola-Zavaleta, Nilda TI Echocardiographic correlates of severe pulmonary hypertension in adult patients with ostium secundum atrial septal defect SO ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES LA English DT Article DE atrial septal defect; echocardiography; pulmonary hypertension; right ventricular function ID CONGENITAL HEART-DISEASE; RIGHT-VENTRICULAR-FUNCTION; SURGICAL-TREATMENT; AMERICAN SOCIETY; PRESSURE; CLASSIFICATION; ASSOCIATION; PERFORMANCE; GUIDELINES; CARDIOLOGY AB Objective: To identify echocardiographic factors that correlate with pulmonary hypertension (PH) in adults with ostium secundum atrial septal defect (ASD). Methods: Between November 2009 and November 2013, 92 adults with ASD were studied. All had clinical history and transthoracic echocardiogram. Results: Thirty-nine percent of patients had severe PH defined as systolic pulmonary artery pressure (sPAP) of 70 mm Hg or more. The size of ASD (31.84+/-8.21 mm) and a right-sided tricuspid inflow E-wave to tissue Doppler e'-wave ratio > 6.2 correlated with severe PH with AUC of 0.704 (CI 95%=0.59 to 0.818, P<.001) and 0.65 (CI 95%=0.531 to 0.773, P<.014), respectively. Multivariate logistic regression showed that sPAP > 70 mm Hg was the variable that most precisely correlated with right ventricular (RV) dysfunction as evidenced by TAPSE < 17 mm and RV fractional shortening area (RVFSA) < 35%. Left ventricular (LV) diastolic function was also significantly reduced in the group with severe PH with mitral inflow E/A ratio of 0.73+/-0.23 vs 1.13+/-0.42 in the group without severe PH (sPAP < 70 mm Hg, (P=.001). The pulmonary (Qp) to systemic (Qs) cardiac output ratio (3.09+/-1.12) and right-sided tissue Doppler S < 9.5 cm/s most accurately predicted a Tei index >0.55. Conclusions: Larger size of ASD using the QP/QS ratio and increased right-sided tricuspid E/e' ratio correlated with severe PH with a sPAP of 70 mm Hg or more. Patients with severe PH had more severe RV dysfunction as evaluated by TAPSE and RVFSA in comparison to those with PH < 70 mm Hg. LV diastolic function was also reduced in the severe PH group. C1 [Cossio-Aranda, Jorge; Del Valle Zamora, Karina; Espinola-Zavaleta, Nilda] Natl Inst Cardiol Ignacio Chavez, Outpatient Dept, Mexico City, DF, Mexico. [Nanda, Navin C.; Uzendu, Anezi] Univ Alabama, Dept Med, Tuscaloosa, AL USA. [Keirns, Candace] Massachusetts Gen Hosp, Interpreters Serv, Boston, MA USA. [Verdejo-Paris, Juan] Natl Inst Cardiol Ignacio Chavez, Mexico City, DF, Mexico. RP Espinola-Zavaleta, N (reprint author), Natl Inst Cardiol Ignacio Chavez, Outpatient Dept, Mexico City, DF, Mexico. EM niesza2001@hotmail.com NR 43 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0742-2822 EI 1540-8175 J9 ECHOCARDIOGR-J CARD JI Echocardiography-J. Cardiovasc. Ultrasound Allied Tech. PD DEC PY 2016 VL 33 IS 12 BP 1891 EP 1896 DI 10.1111/echo.13358 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EM6EM UT WOS:000395405600015 PM 27596111 ER PT J AU Hu, QH Wang, M Cho, MS Wang, CY Nick, AM Thiagarajan, P Aung, FM Han, XL Sood, AK Afshar-Kharghan, V AF Hu, Qianghua Wang, Miao Cho, Min Soon Wang, Chunyan Nick, Alpa M. Thiagarajan, Perumal Aung, Fleur M. Han, Xianlin Sood, Anil K. Afshar-Kharghan, Vahid TI Lipid profile of platelets and platelet-derived microparticles in ovarian cancer SO BBA CLINICAL LA English DT Article DE Platelet; Lipidomics; Venous thrombosis; Hypercoagulability; Ovarian cancer; Lipid phosphate phosphatase 1 ID VENOUS THROMBOSIS; BLOOD-COAGULATION; MICROVESICLES; PHOSPHATIDYLETHANOLAMINE; LYSOPHOSPHATIDYLCHOLINE; INVASION; ACID AB Background: Ovarian cancer patients have a high risk of developing venous thrombosis. The membrane lipid bilayer of platelets and platelet-derived microparticles (PMP) provides a platform for assembly of coagulation proteins and generation of blood clots. Methods: We compared the lipid composition of platelets and PMPs in patients with ovarian cancer to those in healthy subjects. We used shotgun lipidomics to quantify 12 classes and 177 species of lipids. Results: We found a significant change in 2 classes of lipids in platelets and PMPs isolated from ovarian cancer patients: higher phosphatidylinositol and lower lyso-phosphatidylcholine. The level of 28 species of lipids was also significantly altered in the direction of an increase in the pro-coagulant and a reduction in the anticoagulant lipids. We found that cancer platelets expressed less lipid phosphate phosphatase 1 (LPP1), a key enzyme in phospholipid biosynthesis pathways, than normal platelets. The reduction in LPP1 might contribute to the changes in the lipid profile of cancer platelets. Conclusion: Our results support a procoagulant lipid profile of platelets in ovarian cancer patients that can play a role in the increased risk of venous thrombosis in these patients. General significance: As far as we are aware, our study is the first study on platelet lipidomics in ovarian cancer. The importance of our findings for the future studies are: 1) a similar change in lipid profile of platelets and PMP may be responsible for hypercoagulability in other cancers, and 2) plasma level of high-risk lipids for venous thrombosis may be useful biomarkers. (C) 2016 The Authors. Published by Elsevier B.V. C1 [Hu, Qianghua; Cho, Min Soon; Afshar-Kharghan, Vahid] Univ Texas MD Anderson Canc Ctr, Dept Benign Hematol, Houston, TX 77030 USA. [Wang, Miao; Wang, Chunyan; Han, Xianlin] Sanford Burnham Med Res Inst, Diabet & Obes Res Ctr, 6400 Sanger Rd, Orlando, FL 32827 USA. [Nick, Alpa M.; Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX 77030 USA. [Thiagarajan, Perumal] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Ctr Translat Res Inflammatory Dis, Houston, TX 77030 USA. [Aung, Fleur M.] Univ Texas MD Anderson Canc Ctr, Dept Lab Med, Houston, TX 77030 USA. RP Afshar-Kharghan, V (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Benign Hematol, Houston, TX 77030 USA. EM vakharghan@mdanderson.org OI Thiagarajan, Perumal/0000-0003-2186-7036 FU Ovarian Cancer Research Fund [258813]; [R01CA177909] FX This work was supported in part by R01CA177909 (to V.A-K. and A.K.S.), Ovarian Cancer Research Fund (Grant number 258813 to V.A-K. and A.K.S). NR 29 TC 0 Z9 0 U1 2 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2214-6474 J9 BBA CLIN JI BBA Clin. PD DEC PY 2016 VL 6 BP 76 EP 81 DI 10.1016/j.bbacli.2016.06.003 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA EM4JW UT WOS:000395280300011 PM 27453821 ER PT J AU Hamblin, MR AF Hamblin, Michael R. TI Shining light on the head: Photobiomodulation for brain disorders SO BBA CLINICAL LA English DT Review DE Photobiomodulation; Low level laser (light) therapy; Ischemic stroke; Traumatic brain injury; Alzheimer's disease; Parkinson's disease; Major depression; Cognitive enhancement ID NEAR-INFRARED LIGHT; LEVEL LASER THERAPY; DOPAMINERGIC CELL-SURVIVAL; ACUTE ISCHEMIC-STROKE; TERM NEUROLOGICAL DEFICITS; BIPHASIC DOSE-RESPONSE; CHRONIC MILD STRESS; MPTP-TREATED MICE; MOUSE MODEL; NITRIC-OXIDE AB Photobiomodulation (PBM) describes the use of red or near-infrared light to stimulate, heal, regenerate, and protect tissue that has either been injured, is degenerating, or else is at risk of dying. One of the organ systems of the human body that is most necessary to life, and whose optimum functioning is most worried about by humankind in general, is the brain. The brain suffers from many different disorders that can be classified into three broad groupings: traumatic events (stroke, traumatic brain injury, and global ischemia), degenerative diseases (dementia, Alzheimer's and Parkinson's), and psychiatric disorders (depression, anxiety, post traumatic stress disorder). There is some evidence that all these seemingly diverse conditions can be beneficially affected by applying light to the head. There is even the possibility that PBM could be used for cognitive enhancement in normal healthy people. In this transcranial PBM (tPBM) application, near-infrared (NIR) light is often applied to the forehead because of the better penetration (no hair, longer wavelength). Some workers have used lasers, but recently the introduction of inexpensive light emitting diode (LED) arrays has allowed the development of light emitting helmets or "brain caps". This review will cover the mechanisms of action of photobiomodulation to the brain, and summarize some of the key pre-clinical studies and clinical trials that have been undertaken for diverse brain disorders. (C) 2016 The Authors. Published by Elsevier B.V. C1 [Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hamblin, Michael R.] Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM Hamblin@helix.mgh.harvard.edu FU US NIH [R01AI050875, R21AI121700]; Air Force Office of Scientific Research grant [FA9550-13-1-0068]; US Army Medical Research Acquisition Activity grant [W81XWH-09-1-0514]; US Army Medical Research and Materiel Command grant [W81XWH-13-2-0067] FX MRH was supported by the US NIH grants R01AI050875 and R21AI121700, the Air Force Office of Scientific Research grant FA9550-13-1-0068, the US Army Medical Research Acquisition Activity grant W81XWH-09-1-0514, and by the US Army Medical Research and Materiel Command grant W81XWH-13-2-0067. NR 120 TC 1 Z9 1 U1 4 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2214-6474 J9 BBA CLIN JI BBA Clin. PD DEC PY 2016 VL 6 BP 113 EP 124 DI 10.1016/j.bbacli.2016.09.002 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EM4JW UT WOS:000395280300016 PM 27752476 ER PT J AU Goyal, A Linskey, KR Kay, J Duncan, LM Nazarian, RM AF Goyal, Amrita Linskey, Katy R. Kay, Jonathan Duncan, Lyn M. Nazarian, Rosalynn M. TI Differential Expression of Hedgehog and Snail in Cutaneous Fibrosing Disorders Implications for Targeted Inhibition SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Dermatopathology; Hedgehog; Snail; Fibrosis; Scleroderma ID EPITHELIAL-MESENCHYMAL TRANSITION; NEPHROGENIC SYSTEMIC FIBROSIS; INDIAN HEDGEHOG; SONIC HEDGEHOG; SKIN; ACTIVATION; RAPAMYCIN; PATHWAY; CELLS; PROLIFERATION AB Objectives: To examine Hedgehog signaling in cutaneous fibrosing disorders for which effective approved therapies are lacking, expand our knowledge of pathophysiology, and explore the rationale for targeted inhibition. Methods: Stain intensity and percentage of cells staining for Sonic hedgehog (Shh), Indian hedgehog (Ihh), Patched (etch), glycogen synthase kinase 3 beta (GSK3-beta), beta-catenin, and Snail were evaluated in human skin biopsy specimens of keloid, hypertrophic scar (Hscar), scleroderma, nephrogenic systemic fibrosis (NSF), scar, and normal skin using a tissue microarray. Results: Ihh, but not Shh, was detected in a significantly larger proportion of cells for all case types. Ptch, GSK3-beta, and beta-catenin showed a gradient of expression: highest in NSF and keloid; moderate in normal skin, scar, and Hscar; and lowest in scleroderma. Snail expression was binary: low in normal skin but high in all fibrosing conditions studied. Conclusions: Differential overexpression of Hedgehog and Snail in cutaneous fibrosing disorders demonstrates a role for targeted inhibition. Ptch, GSK3-beta, and beta-catenin can help differentiate scleroderma from NSF in histologically subtle cases. Differences in expression between keloid and hypertrophic scar support the concept that they are pathophysiologically distinct disorders. Our findings implicate Snail as a target for the prevention of fibrogenesis or fibrosis progression and may offer a means to assess response to therapy. C1 [Goyal, Amrita; Linskey, Katy R.; Duncan, Lyn M.; Nazarian, Rosalynn M.] Massachusetts Gen Hosp, Pathol Serv, Dermatopathol Unit, Boston, MA 02114 USA. [Goyal, Amrita; Linskey, Katy R.; Duncan, Lyn M.; Nazarian, Rosalynn M.] Harvard Med Sch, Boston, MA 02114 USA. [Kay, Jonathan] UMass Mem Med Ctr, Dept Med, Div Rheumatol, Worcester, MA USA. [Kay, Jonathan] Univ Massachusetts, Sch Med, Worcester, MA USA. RP Nazarian, RM (reprint author), Massachusetts Gen Hosp, Pathol Serv, Dermatopathol Unit, 55 Fruit St,WRN829A, Boston, MA 02114 USA. EM rmnazarian@partners.org NR 31 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD DEC PY 2016 VL 146 IS 6 BP 709 EP 717 DI 10.1093/AJCP/AQW192 PG 9 WC Pathology SC Pathology GA EJ9FX UT WOS:000393533100007 PM 28077400 ER PT J AU Aisagbonhi, OA Tulecke, MA Wilbur, DC Goldar-Najafi, A Iqbal, S Sadow, PM Faquin, WC AF Aisagbonhi, Omonigho A. Tulecke, Mark A. Wilbur, David C. Goldar-Najafi, Atoussa Iqbal, Shams Sadow, Peter M. Faquin, William C. TI Fine-Needle Aspiration of Epithelial-Myoepithelial Carcinoma of the Parotid Gland With Prominent Adenoid Cystic Carcinoma-Like Cribriform Features Avoiding a Diagnostic Pitfall SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Fine-needle aspiration; Epithelial-myoepithelial carcinoma; Adenoid cystic carcinoma; Salivary gland ID SALIVARY-GLANDS; EXPRESSION; CELL AB Objectives: Epithelial-myoepithelial carcinoma (EMC) is a rare salivary gland malignancy associated with an overall good prognosis. Fine-needle aspiration (FNA) typically shows a dual population of myoepithelial and ductal cells. Rarely, acellular matrix globules are present, raising a differential diagnosis of adenoid cystic carcinoma (AdCC), a more aggressive salivary gland malignancy associated with a poor long-term prognosis. We report an FNA case of EMC containing a predominant pattern of AdCC-like spherical globules. Methods: We compare features of an unusual case of EMC with those of cribriform AdCC to arrive at morphologic clues to the correct diagnosis. Results: Distinguishing features of EMC on FNA include (1) a prominent population of myoepithelial cells vs the predominance of basaloid cells in AdCC and (2) cohesive matrix globules with a peripheral rim of pale-staining basement membrane material compared with the dyscohesive matrix globules of AdCC. Immunochemical markers (S100, CD117, and MyB) are also useful. Conclusions: Although EMC and AdCC can both contain spherical matrix globules, close evaluation of the cytomorphology of the globules and their relationship to surrounding cells provides a clue to distinguish the two neoplasms. C1 [Aisagbonhi, Omonigho A.; Wilbur, David C.; Sadow, Peter M.; Faquin, William C.] Massachusetts Gen Hosp, Dept Pathol, WRN 2-219,55 Fruit St, Boston, MA 02114 USA. [Aisagbonhi, Omonigho A.; Wilbur, David C.; Sadow, Peter M.; Faquin, William C.] Harvard Med Sch, WRN 2-219,55 Fruit St, Boston, MA 02114 USA. [Tulecke, Mark A.] North Shore Med Ctr, Dept Pathol, Salem, MA USA. [Goldar-Najafi, Atoussa; Iqbal, Shams] Lahey Hosp & Med Ctr, Dept Pathol, Burlington, MA USA. RP Aisagbonhi, OA (reprint author), Massachusetts Gen Hosp, Dept Pathol, WRN 2-219,55 Fruit St, Boston, MA 02114 USA.; Aisagbonhi, OA (reprint author), Harvard Med Sch, WRN 2-219,55 Fruit St, Boston, MA 02114 USA. EM oaisagbonhi@partners.org NR 14 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD DEC PY 2016 VL 146 IS 6 BP 741 EP 746 DI 10.1093/AJCP/AQW128 PG 6 WC Pathology SC Pathology GA EJ9FX UT WOS:000393533100011 PM 27614667 ER PT J AU Barber, GE Yajnik, V Khalili, H Giallourakis, C Garber, J Xavier, R Ananthakrishnan, AN AF Barber, Grant E. Yajnik, Vijay Khalili, Hamed Giallourakis, Cosmas Garber, John Xavier, Ramnik Ananthakrishnan, Ashwin N. TI Genetic Markers Predict Primary Non-Response and Durable Response To Anti-TNF Biologic Therapies in Crohn's Disease SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; INFLIXIMAB TREATMENT; ULCERATIVE-COLITIS; ASSOCIATION; POLYMORPHISMS; EXPRESSION; COHORT; ADALIMUMAB; ANCA AB OBJECTIVES : One-fifth of patients with Crohn's disease (CD) are primary non-responders to anti-tumor necrosis factor (anti-TNF) therapy, and an estimated 10-15% will fail therapy annually. Little is known about the genetics of response to anti-TNF therapy. The aim of our study was to identify genetic factors associated with primary non-response (PNR) and loss of response to anti-TNFs in CD. METHODS: From a prospective registry, we characterized the response of 427 CD patients to their first anti-TNF therapy. Patients were designated as achieving primary response, durable response, and non-durable response based on clinical, endoscopic, and radiologic criteria. Genotyping was performed on the Illumina Immunochip. Separate genetic scores based on presence of predictive genetic alleles were calculated for PNR and durable response and performance of clinical and genetics models were compared. RESULTS: From 359 patients, 36 were adjudged to have PNR (10%), 200 had durable response, and 74 had non-durable response. PNRs had longer disease duration and were more likely to be smokers. Fifteen risk alleles were associated with PNR. Patients with PNR had a significantly higher genetic risk score (GRS) (P=8x10(-12)). A combined clinical-genetic model more accurately predicted PNR when compared with a clinical only model (0.93 vs. 0.70, P<0.001). Sixteen distinct single nucleotide polymorphisms predicted durable response with a higher GRS (P=7x10(-13)).The GRSs for PNR and durable response were not mutually correlated, suggesting distinct mechanisms. CONCLUSIONS: Genetic risk alleles can predict primary non-response and durable response to anti-TNF therapy in CD. C1 [Barber, Grant E.; Yajnik, Vijay; Khalili, Hamed; Giallourakis, Cosmas; Garber, John; Xavier, Ramnik; Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA USA. [Barber, Grant E.; Yajnik, Vijay; Khalili, Hamed; Giallourakis, Cosmas; Garber, John; Xavier, Ramnik; Ananthakrishnan, Ashwin N.] Harvard Med Sch, Boston, MA USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@mgh.harvard.edu FU National Institutes of Health [K23 DK097142]; National Institutes of Health (NIH) [P30 DK043351] FX Ananthakrishnan is supported in part by a grant from the National Institutes of Health (K23 DK097142). This work is also supported by the National Institutes of Health (NIH; P30 DK043351) to the Center for Study of Inflammatory Bowel Diseases. NR 32 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD DEC PY 2016 VL 111 IS 12 BP 1816 EP 1822 DI 10.1038/ajg.2016.408 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK6TP UT WOS:000394057300028 PM 27596696 ER PT J AU Emens, L Adams, S Loi, S Schneeweiss, A Rugo, H Winer, E Barrios, C Dieras, V de la Haba-Rodriguez, J Gianni, L Kusuma, N Chui, SY Schmid, P AF Emens, L. Adams, S. Loi, S. Schneeweiss, A. Rugo, H. Winer, E. Barrios, C. Dieras, V. de la Haba-Rodriguez, J. Gianni, L. Kusuma, N. Chui, S. Y. Schmid, P. TI IMpassion130: Phase III trial comparing 1L atezolizumab with nab-paclitaxel versus placebo with nab-paclitaxel in treatment-naive patients with mTNBC SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 [Emens, L.] Johns Hopkins Univ, Sch Med, Oncol, Baltimore, MD USA. [Adams, S.] NYU, Sch Med, New York, NY USA. [Loi, S.] Peter MacCallum Canc Ctr, Div Canc Med, Melbourne, Vic, Australia. [Schneeweiss, A.] Univ Heidelberg Hosp, Womens Hosp, Heidelberg, Germany. [Rugo, H.] Univ Calif San Francisco, Ctr Comprehens Canc, San Francisco, CA 94143 USA. [Winer, E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Barrios, C.] PUCRS Sch Med, Dept Med, Porto Alegre, RS, Brazil. [Dieras, V.] Inst Curie, Med Oncol, Paris, France. [de la Haba-Rodriguez, J.] Hosp Univ Reina Sofia, Cordoba, Spain. [Gianni, L.] Ist Sci San Raffaele, Milan, Italy. [Kusuma, N.] Roche Singapore Pte Ltd, Singapore, Singapore. [Chui, S. Y.] Genentech Inc, San Francisco, CA 94080 USA. [Schmid, P.] Queen Mary Univ London, Barts Canc Inst, London, England. FU F. Hoffmann-La Roche Ltd FX F. Hoffmann-La Roche Ltd 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 DEC PY 2016 VL 27 SU 9 MA 136TiP PG 1 WC Oncology SC Oncology GA EK5QJ UT WOS:000393980600135 ER PT J AU Hong, DS Dowlati, A Burris, HA Lee, JJ Brose, MS Farago, AF Bauer, TM Taylor, M Shaw, AT Smith, S Nanda, N Cruickshank, S Cox, MC Doebele, R AF Hong, D. S. Dowlati, A. Burris, H. A., III Lee, J. J. Brose, M. S. Farago, A. F. Bauer, T. M. Taylor, M. Shaw, A. T. Smith, S. Nanda, N. Cruickshank, S. Cox, M. C. Doebele, R. TI Clinical safety and activity from a phase 1 study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 [Hong, D. S.] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX 77030 USA. [Dowlati, A.] Univ Hosp Case Med Ctr, Hematol Oncol, Cleveland, OH USA. [Burris, H. A., III; Bauer, T. M.] Tennessee Oncol PLLC, Sarah Cannon Res Inst, Drug Dev, Nashville, TN USA. [Lee, J. J.] Univ Pittsburgh, Inst Canc, Med Oncol & Hematol, Pittsburgh, PA USA. [Brose, M. S.] Univ Penn, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Farago, A. F.; Shaw, A. T.] Massachusetts Gen Hosp, Hematol Oncol, Boston, MA 02114 USA. [Taylor, M.] Oregon Hlth & Sci Univ, Hematol Oncol, Portland, OR USA. [Smith, S.; Nanda, N.; Cruickshank, S.; Cox, M. C.] Loxo Oncol Inc, Clin Dev, San Francisco, CA USA. [Doebele, R.] Univ Colorado, Med Oncol, Denver, CO 80202 USA. FU Loxo Oncology, Inc. FX Loxo Oncology, Inc. 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 DEC PY 2016 VL 27 SU 9 MA 150O PG 1 WC Oncology SC Oncology GA EK5QJ UT WOS:000393980600150 ER PT J AU Iwata, H Rubovszky, G Loibl, S Ciruelos, E Campone, M Juric, D Rugo, H Mayer, I Conte, PF Kaufman, B Inoue, K Tesch, H Li, YS Mingorance, ID Ryvo, L Iwase, H Longin, AS Mills, D Wilke, C Andre, F AF Iwata, H. Rubovszky, G. Loibl, S. Ciruelos, E. Campone, M. Juric, D. Rugo, H. Mayer, I. Conte, P. F. Kaufman, B. Inoue, K. Tesch, H. Li, Y-S. Mingorance, I. D. Ryvo, L. Iwase, H. Longin, A-S. Mills, D. Wilke, C. Andre, F. TI A phase III study of alpelisib and fulvestrant for hormone receptor-positive (HR1), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) progressing on or after aromatase inhibitor (AI) therapy (SOLAR-1) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 [Iwata, H.] Aichi Canc Ctr Hosp, Dept Breast Oncol, Nagoya, Aichi, Japan. [Rubovszky, G.] Orszagos Onkol Intezet, Internal Med Oncol Div B, Budapest, Hungary. [Rubovszky, G.] Orszagos Onkol Intezet, Clin Pharmacol, Budapest, Hungary. [Loibl, S.] German Breast Grp GBG Forsch GmbH, Med & Res, Neu Isenburg, Germany. [Ciruelos, E.] Univ Hosp 12 Octubre, Breast Canc Unit, Madrid, Spain. [Campone, M.] ICO Inst Cancerol Ouest Rene Gauducheau, Med Oncol, St Herblain, France. [Juric, D.] Massachusetts Gen Hosp, Hematol Oncol, Boston, MA 02114 USA. [Rugo, H.] Univ Calif San Francisco, Ctr Comprehens Canc, Dept Med Hematol Oncol, San Francisco, CA 94143 USA. [Mayer, I.] Vanderbilt Ingram Canc Ctr, 1301 Med Ctr Dr Suite 1710, Nashville, TN USA. [Conte, P. F.] IRCCS, Ist Oncol Veneto, Div Surg Oncol & Gastroenterol, Padua, Italy. [Kaufman, B.] Chaim Sheba Med Ctr, Div Oncol, Ramat Gan, Israel. [Inoue, K.] Saitama Canc Ctr, Div Breast Oncol, Saitama, Japan. [Tesch, H.] Ctr Hamatol & Onkol Bethanien, Onkol Bethanien, Frankfurt, Germany. [Li, Y-S.] Natl Taiwan Univ Hosp, Dept Oncol, Taipei, Taiwan. [Mingorance, I. D.] Hosp Infanta Cristina, Opt Med Oncol Clin Trials Unit, Badajoz, Spain. [Ryvo, L.] Tel Aviv Sourasky Med Ctr Ichilov, Dept Oncol, Tel Aviv, Israel. [Iwase, H.] Kumamoto Univ, Breast & Endocrine Surg, Kumamoto, Japan. [Longin, A-S.] Novartis Pharma SAS, Oncol Global Dev, Paris, France. [Mills, D.; Wilke, C.] Novartis Pharma AG, Oncol Global Dev, Basel, Switzerland. [Andre, F.] Inst Gustave Roussy, Med Oncol, Villejuif, France. FU Novartis Pharmaceutical Corporation FX Novartis Pharmaceutical Corporation NR 0 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD DEC PY 2016 VL 27 SU 9 MA 137TiP PG 2 WC Oncology SC Oncology GA EK5QJ UT WOS:000393980600136 ER PT J AU Ly, SH Krall, EB Hahn, WC AF Ly, S. H. Krall, E. B. Hahn, W. C. TI Identification of novel bypasses of KRAS addiction SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 [Ly, S. H.] Harvard Univ, Div Med Sci, Boston, MA 02115 USA. [Krall, E. B.; Hahn, W. C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. FU USA National Institutes of Health FX USA National Institutes of Health 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 DEC PY 2016 VL 27 SU 9 MA 205P PG 2 WC Oncology SC Oncology GA EK5QJ UT WOS:000393980600205 ER PT J AU Ma, BBY Rudin, CM Cervantes, A Dowlati, A Costa, D Schmid, P Heist, R Villaflor, VM Sarkar, I Huseni, MA Foster, P O'Hear, C Gettinger, S Besse, B AF Ma, B. B. Y. Rudin, C. M. Cervantes, A. Dowlati, A. Costa, D. Schmid, P. Heist, R. Villaflor, V. M. Sarkar, I. Huseni, M. A. Foster, P. O'Hear, C. Gettinger, S. Besse, B. TI Preliminary safety and clinical activity of erlotinib plus atezolizumab from a Phase Ib study in advanced NSCLC SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 [Ma, B. B. Y.] Chinese Univ Hong Kong, Prince Wales Hosp, Phase Clin Trial Ctr 1, Hong Kong, Hong Kong, Peoples R China. [Rudin, C. M.] Mem Sloan Kettering Canc Ctr, Thorac Oncol Serv, 1275 York Ave, New York, NY 10021 USA. [Cervantes, A.] Hosp Clin Univ Valencia, Dept Med Oncol, Valencia, Spain. [Dowlati, A.] Univ Hosp Case Med Ctr, Hematol Oncol, Cleveland, OH USA. [Costa, D.] Beth Israel Deaconess Med Ctr, Hematol Oncol, Boston, MA 02215 USA. [Schmid, P.] Barts Canc Inst, Ctr Expt Canc Med, London, England. [Heist, R.] Massachusetts Gen Hosp, Med Oncoloy, Boston, MA 02114 USA. [Villaflor, V. M.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Sarkar, I.] Genentech Inc, Biostat, San Francisco, CA USA. [Huseni, M. A.] Genentech Inc, Oncol Biomarkers Dev, San Francisco, CA USA. [Foster, P.; O'Hear, C.] Genentech Inc, Prod Dev Oncol, San Francisco, CA USA. [Gettinger, S.] Yale Canc Ctr, Thorac Oncol Program, New Haven, CT USA. [Besse, B.] Inst Cancerol Gustave Roussy, Canc Med, Villejuif, France. FU F. Hoffmann-La Roche Ltd FX F. Hoffmann-La Roche Ltd 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 DEC PY 2016 VL 27 SU 9 MA 441O PG 1 WC Oncology SC Oncology GA EK5QJ UT WOS:000393980600440 ER PT J AU Mima, K Nishihara, R Qian, ZR Baba, H Ogino, S AF Mima, K. Nishihara, R. Qian, Z. R. Baba, H. Ogino, S. TI MicroRNA MIR21, T cells, and PTGS2 expression in Colorectal Cancer SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 [Mima, K.; Baba, H.] Kumamoto Univ, Deapartment Gastroenterol Surg, Kumamoto, Japan. [Nishihara, R.; Qian, Z. R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ogino, S.] Brigham & Womens Hosp, Div MPE Mol Pathol Epidemiol, 75 Francis St, Boston, MA 02115 USA. FU USA National Institutes of Health (NIH) FX USA National Institutes of Health (NIH) 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 DEC PY 2016 VL 27 SU 9 MA 173PD PG 1 WC Oncology SC Oncology GA EK5QJ UT WOS:000393980600173 ER PT J AU Mok, TSK Scagliotti, G Kim, TM Crino, L Liu, G Gridelli, C Novello, S Kiura, K Bearz, A Gautschi, O Felip, E Nishio, M Spigel, DR Urban, P Deudon, S Zheng, C Shaw, AT AF Mok, T. S. K. Scagliotti, G. Kim, T. M. Crino, L. Liu, G. Gridelli, C. Novello, S. Kiura, K. Bearz, A. Gautschi, O. Felip, E. Nishio, M. Spigel, D. R. Urban, P. Deudon, S. Zheng, C. Shaw, A. T. TI Patient-reported outcomes (PROs) in ASCEND-5: A randomized, phase 3 study of ceritinib vs chemotherapy (CT) in patients (pts) with advanced anaplastic lymphoma kinase rearranged (ALK plus ) NSCLC previously treated with CT and crizotinib (CRZ) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 [Mok, T. S. K.] Chinese Univ Hong Kong, Clin Oncol, Hong Kong, Hong Kong, Peoples R China. [Scagliotti, G.] Univ Turin, Oncol, Orbassano, Italy. [Kim, T. M.] Seoul Natl Univ Hosp, Internal Med, Seoul, South Korea. [Crino, L.] Univ Med Sch Perugia, Med Oncol, Perugia, Italy. [Liu, G.] Princess Margaret Canc Ctr, Med, Toronto, ON, Canada. [Gridelli, C.] SG Moscati Hosp, Med Oncol, Avellino, Italy. [Novello, S.] Univ Turin, Dept Oncol, Turin, Italy. [Kiura, K.] Okayama Univ Hosp, Dept Allergy & Resp Med Thorac Oncol, Okayama, Japan. [Bearz, A.] IRCCS CRO, Div Med Oncol, Aviano, Italy. [Gautschi, O.] Cantonal Hosp Lucerne, Dept Med, Med Oncol, Luzern, Switzerland. [Felip, E.] Vall dHebron Univ Hosp, Med Oncol, Barcelona, Spain. [Nishio, M.] Japanese Fdn Canc Res, Thorac Med Oncol, Canc Inst Hosp, Tokyo, Japan. [Spigel, D. R.] Sarah Cannon Res Inst, Med Oncol, Nashville, TN USA. [Urban, P.; Deudon, S.] Novartis Pharma AG, Clin Res, Basel, Switzerland. [Zheng, C.] Novartis Pharmaceut, Biostat, E Hanover, NJ USA. [Shaw, A. T.] Massachusetts Gen Hosp, Med Oncol, Boston, MA 02114 USA. FU Novartis Pharmaceutical Corporation FX Novartis Pharmaceutical Corporation 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 DEC PY 2016 VL 27 SU 9 MA 444PD PG 2 WC Oncology SC Oncology GA EK5QJ UT WOS:000393980600443 ER PT J AU Nakagawa, K Yang, JCH Park, K Ohe, Y Wu, YL Gainor, J Blackwood-Chirchir, A Yang, R Chang, IF Mok, T AF Nakagawa, K. Yang, J. C-H. Park, K. Ohe, Y. Wu, Y-L. Gainor, J. Blackwood-Chirchir, A. Yang, R. Chang, I-F. Mok, T. TI Checkmate 722: A phase 3 trial of nivolumab with chemotherapy or ipilimumab vs chemotherapy in epidermal growth factor receptor (EGFR)-mutation, T790M-negative stage IV or recurrent non-small cell lung cancer (NSCLC) after EGFR tyrosine kinase inhibitor (TKI) therapy SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 [Nakagawa, K.] Kindai Univ Hosp, Dept Clin Oncol, Osaka, Japan. [Yang, J. C-H.] Natl Taiwan Univ Hosp, Dept Oncol, Taipei, Taiwan. [Park, K.] Samsung Comprehens Canc Ctr, Dept Med, Seoul, South Korea. [Ohe, Y.] Natl Canc Ctr, Dept Thorac Oncol, Tokyo, Japan. [Wu, Y-L.] Guangdong Gen Hosp, Dept Oncol, Guangzhou, Guangdong, Peoples R China. [Gainor, J.] Massachusetts Gen Hosp, Dept Thorac Oncol, Boston, MA 02114 USA. [Blackwood-Chirchir, A.; Chang, I-F.] Bristol Myers Squibb, Global Clin Res, Princeton, NJ USA. [Yang, R.] Bristol Myers Squibb, Global Biostat, Princeton, NJ USA. [Mok, T.] Chinese Univ Hong Kong, Dept Clin Oncol, Shatin, Hong Kong, Peoples R China. FU Bristol-Myers Squibb FX Bristol-Myers Squibb 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 DEC PY 2016 VL 27 SU 9 MA 481TiP PG 1 WC Oncology SC Oncology GA EK5QJ UT WOS:000393980600480 ER PT J AU Park, SH Castellano, D Petrylak, DP Galsky, MD van der Heijden, MS Loriot, Y Ogawa, O Su, WP Huang, W Levin, W Ferro, S Ben, Y Bellmunt, J Powles, T AF Park, S. H. Castellano, D. Petrylak, D. P. Galsky, M. D. van der Heijden, M. S. Loriot, Y. Ogawa, O. Su, W-P. Huang, W. Levin, W. Ferro, S. Ben, Y. Bellmunt, J. Powles, T. TI DANUBE: A Phase 3 randomised study of first-line durvalumab (MEDI4736) +/- tremelimumab vs standard of care (SoC) chemotherapy (CT) in patients (pts) with Stage IV urothelial carcinoma (UC) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 [Park, S. H.] Samsung Med Ctr, Dept Med, Seoul, South Korea. [Castellano, D.] Hosp Univ 12 Octubre, Dept Med Oncol, Madrid, Spain. [Petrylak, D. P.] Yale Univ, Dept Med, New Haven, CT 06520 USA. [Galsky, M. D.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [van der Heijden, M. S.] Netherlands Canc Inst, Dept Med Oncol, Amsterdam, Netherlands. [Loriot, Y.] Inst Gustave Roussy, Dept Canc Med, Villejuif, France. [Ogawa, O.] Kyoto Univ, Dept Urol, Kyoto, Japan. [Su, W-P.] Natl Cheng Kung Univ Hosp, Dept Internal Med, Tainan, Taiwan. [Huang, W.; Levin, W.; Ferro, S.; Ben, Y.] AstraZeneca, Global Med Dev, Gaithersburg, MD USA. [Bellmunt, J.] Harvard Med Sch, Dana Farber Canc Inst, Bladder Canc Ctr, Boston, MA USA. [Powles, T.] Queen Mary Univ London, Barts Canc Inst, Expt Canc Med Ctr, London, England. FU AstraZeneca FX AstraZeneca 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 DEC PY 2016 VL 27 SU 9 MA 285TiP PG 2 WC Oncology SC Oncology GA EK5QJ UT WOS:000393980600284 ER PT J AU van den Bent, M Lassman, AB Gan, HK Reardon, DA Kumthekar, P Butowski, N Lwin, Z Mikkelsen, T Nabors, LB Papadopoulos, KP Penas-Prado, M Simes, J Wheeler, H Gomez, E Lee, HJ Roberts-Rapp, L Xiong, H Bain, E Holen, K Merrell, R AF van den Bent, M. Lassman, A. B. Gan, H. K. Reardon, D. A. Kumthekar, P. Butowski, N. Lwin, Z. Mikkelsen, T. Nabors, L. B. Papadopoulos, K. P. Penas-Prado, M. Simes, J. Wheeler, H. Gomez, E. Lee, H-J. Roberts-Rapp, L. Xiong, H. Bain, E. Holen, K. Merrell, R. TI Efficacy of a novel antibody-drug conjugate (ADC), ABT-414, with temozolomide (TMZ) in recurrent glioblastoma (rGBM) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 [van den Bent, M.] Erasmus MC Canc Inst, Neurooncol, Rotterdam, Netherlands. [Lassman, A. B.] Columbia Univ, Dept Neurol, New York, IL USA. [Lassman, A. B.] Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, IL USA. [Gan, H. K.] Austin Hlth, Med Oncol, Melbourne, Vic, Australia. [Gan, H. K.] Olivia Newton John Canc Res Inst, Melbourne, Vic, Australia. [Gan, H. K.] Univ Melbourne, Dept Med, Melbourne, Vic, Australia. [Gan, H. K.] La Trobe Univ, Sch Canc Med, Melbourne, Vic, Australia. [Reardon, D. A.] Dana Farber Canc Inst, Neurooncol, Boston, MA 02115 USA. [Kumthekar, P.] Northwestern Univ, Dept Neurol, Chicago, IL 60611 USA. [Butowski, N.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [Lwin, Z.] Univ Queensland, Royal Brisbane & Womens Hosp, Sch Med, Dept Med Oncol, Brisbane, Qld, Australia. [Mikkelsen, T.] Henry Ford Hlth Syst, Neurosurg & Neurosci Res, Detroit, MI USA. [Nabors, L. B.] Univ Alabama Birmingham, Dept Neurobiol, Birmingham, AL USA. [Papadopoulos, K. P.] START, Dept Clin Res, Houston, TX USA. [Penas-Prado, M.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Simes, J.] Univ Sydney, NHMRC Clin Trials Ctr, Sydney, NSW, Australia. [Wheeler, H.] Royal North Shore Hosp, Med Oncol, Sydney, NSW, Australia. [Gomez, E.; Lee, H-J.; Roberts-Rapp, L.; Xiong, H.; Bain, E.; Holen, K.] AbbVie Inc, Global Pharmaceut R&D, N Chicago, IL USA. [Merrell, R.] NorthShore Univ Hlth Syst, Dept Neurol, Evanston, IL USA. FU AbbVie Inc. FX AbbVie Inc. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD DEC PY 2016 VL 27 SU 9 MA 138O PG 1 WC Oncology SC Oncology GA EK5QJ UT WOS:000393980600138 ER PT J AU Dominici, LS Morrow, M Mittendorf, E Bellon, J King, TA AF Dominici, Laura S. Morrow, Monica Mittendorf, Elizabeth Bellon, Jennifer King, Tari A. TI Trends and controversies in multidisciplinary care of the patient with breast cancer SO CURRENT PROBLEMS IN SURGERY LA English DT Editorial Material C1 [Dominici, Laura S.; King, Tari A.] Harvard Med Sch, Dana Farber Canc Inst, Brigham & Womens Hosp, Surg Oncol, Boston, MA USA. [Morrow, Monica] Mem Sloan Kettering Canc Ctr, Dept Surg, Weill Cornell Med Coll, 1275 York Ave, New York, NY 10021 USA. [Mittendorf, Elizabeth] Univ Texas MD Anderson Canc Ctr, Dept Breast Surg Oncol, Houston, TX 77030 USA. [Bellon, Jennifer] Harvard Med Sch, Dana Farber Canc Inst, Brigham & Womens Hosp, Radiat Oncol, Boston, MA USA. RP King, TA (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Brigham & Womens Hosp, 450 Brookline Ave, Boston, MA 02215 USA. EM Tking7@partners.org NR 0 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 0011-3840 EI 1535-6337 J9 CURR PROB SURG JI Curr. Probl. Surg. PD DEC PY 2016 VL 53 IS 12 BP 556 EP 557 DI 10.1067/j.cpsurg.2016.11.004 PG 2 WC Surgery SC Surgery GA EK4XX UT WOS:000393932300002 PM 28160789 ER PT J AU Dominici, LS Morrow, M Mittendorf, E Bellon, J King, TA AF Dominici, Laura S. Morrow, Monica Mittendorf, Elizabeth Bellon, Jennifer King, Tari A. TI Trends and controversies in multidisciplinary care of the patient with breast cancer SO CURRENT PROBLEMS IN SURGERY LA English DT Review ID NIPPLE-SPARING MASTECTOMY; SENTINEL-NODE BIOPSY; SURGICAL ADJUVANT BREAST; CARCINOMA IN-SITU; ONCOLOGY CONSENSUS GUIDELINE; PATHOLOGICAL COMPLETE RESPONSE; RANDOMIZED CONTROLLED-TRIAL; TERM-FOLLOW-UP; NEOADJUVANT SYSTEMIC TREATMENT; ROUTINE AXILLARY DISSECTION C1 [Dominici, Laura S.; King, Tari A.] Harvard Med Sch, Dana Farber Canc Inst, Brigham & Womens Hosp, Surg Oncol, Boston, MA USA. [Morrow, Monica] Mem Sloan Kettering Canc Ctr, Dept Surg, Weill Cornell Med Coll, 1275 York Ave, New York, NY 10021 USA. [Mittendorf, Elizabeth] Univ Texas MD Anderson Canc Ctr, Dept Breast Surg Oncol, Houston, TX 77030 USA. [Bellon, Jennifer] Harvard Med Sch, Dana Farber Canc Inst, Brigham & Womens Hosp, Radiat Oncol, Boston, MA USA. RP King, TA (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Brigham & Womens Hosp, 450 Brookline Ave, Boston, MA 02115 USA. EM Tking7@partners.org FU NIH/NCI, United States, Cancer Center Support Grant [P30 CA008748] FX This article was funded in part by NIH/NCI, United States, Cancer Center Support Grant no. P30 CA008748. The authors have no conflicts of interest to declare, and the findings presented here have not been published elsewhere. NR 211 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 0011-3840 EI 1535-6337 J9 CURR PROB SURG JI Curr. Probl. Surg. PD DEC PY 2016 VL 53 IS 12 BP 559 EP 595 DI 10.1067/j.cpsurg.2016.11.003 PG 37 WC Surgery SC Surgery GA EK4XX UT WOS:000393932300003 PM 28160790 ER PT J AU McLean, WJ McLean, DT Eatock, RA Edge, ASB AF McLean, Will J. McLean, Dalton T. Eatock, Ruth Anne Edge, Albert S. B. TI Distinct capacity for differentiation to inner ear cell types by progenitor cells of the cochlea and vestibular organs SO DEVELOPMENT LA English DT Article DE Hair cell; Neuron; Neural stem cell; Cochlea; Vestibular; Spiral ganglion; Mouse ID OUTER HAIR-CELLS; DORSAL-ROOT GANGLIA; NEURAL STEM-CELLS; SUPPORTING CELLS; NERVOUS-SYSTEM; MOUSE COCHLEA; RAT COCHLEA; POSTNATAL-DEVELOPMENT; DEVELOPMENTAL-CHANGES; ACTION-POTENTIALS AB Disorders of hearing and balance are most commonly associated with damage to cochlear and vestibular hair cells or neurons. Although these cells are not capable of spontaneous regeneration, progenitor cells in the hearing and balance organs of the neonatal mammalian inner ear have the capacity to generate new hair cells after damage. To investigate whether these cells are restricted in their differentiation capacity, we assessed the phenotypes of differentiated progenitor cells isolated from three compartments of the mouse inner ear - the vestibular and cochlear sensory epithelia and the spiral ganglion - by measuring electrophysiological properties and gene expression. Lgr5(+) progenitor cells from the sensory epithelia gave rise to hair cell-like cells, but not neurons or glial cells. Newly created hair cell- like cells had hair bundle proteins, synaptic proteins and membrane proteins characteristic of the compartment of origin. PLP1(+) glial cells from the spiral ganglion were identified as neural progenitors, which gave rise to neurons, astrocytes and oligodendrocytes, but not hair cells. Thus, distinct progenitor populations from the neonatal inner ear differentiate to cell types associated with their organ of origin. C1 [McLean, Will J.; McLean, Dalton T.; Edge, Albert S. B.] Harvard Med Sch, Dept Otol & Laryngol, Boston, MA 02114 USA. [McLean, Will J.; McLean, Dalton T.; Edge, Albert S. B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs Auditory Physiol, Boston, MA 02114 USA. [McLean, Will J.; Edge, Albert S. B.] Harvard & MIT, Div Hlth Sci & Technol, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA. [Eatock, Ruth Anne] Univ Chicago, Dept Neurobiol, Chicago, IL 60637 USA. [Edge, Albert S. B.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Edge, ASB (reprint author), Harvard Med Sch, Dept Otol & Laryngol, Boston, MA 02114 USA.; Edge, ASB (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Labs Auditory Physiol, Boston, MA 02114 USA.; Edge, ASB (reprint author), Harvard & MIT, Div Hlth Sci & Technol, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA.; Eatock, RA (reprint author), Univ Chicago, Dept Neurobiol, Chicago, IL 60637 USA.; Edge, ASB (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM eatock@uchicago.edu; albert_edge@meei.harvard.edu OI Edge, Albert/0000-0001-8641-755X FU National Institute on Deafness and Other Communication Disorders [DC002290, DC012347, DC007174]; European Commission FX This work was supported by the National Institute on Deafness and Other Communication Disorders [DC002290 and DC012347 to R.A.E., DC007174 to A.S.B.E.]; and by a cooperative grant from the European Commission (FP7 Health 2013 Innovation). Deposited in PMC for release after 12 months. NR 106 TC 0 Z9 0 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD DEC 1 PY 2016 VL 143 IS 23 BP 4381 EP 4393 DI 10.1242/dev.139840 PG 13 WC Developmental Biology SC Developmental Biology GA EJ8DE UT WOS:000393454100009 PM 27789624 ER PT J AU Kadayifci, A Atar, M Forcione, DG Casey, BW Kelsey, PB Brugge, WR AF Kadayifci, Abdurrahman Atar, Mustafa Forcione, David G. Casey, Brenna W. Kelsey, Peter B. Brugge, William R. TI Radiofrequency ablation for the management of occluded biliary metal stents SO ENDOSCOPY LA English DT Article ID OBSTRUCTION; STRICTURES AB Background and study aim: Obstruction of biliary self-expandable metal stents (SEMSs) is seen frequently. Radiofrequency ablation (RFA) causes tissue necrosis. This study aimed to assess the efficacy of RFA for management of occluded SEMS. Patients and methods: Patients with biliary malignancy and treated for an occluded SEMS were retrospectively reviewed. The study group comprised patients treated with RFA using an Habib endoprobe inside the SEMS. The control group comprised patients treated only with insertion of a plastic stent into an occluded SEMS. The end points were; 90-day stent patency rate, time to stent reocclusion, 30-day mortality, and 3-and 6-month survival rates. Results: During the 5-year study period 25 patients with an occluded SEMS underwent RFA and 25 patients underwent a plastic stent placement only. Both groups were matched for age and diagnosis. Immediate biliary drainage was restored in all patients. In the RFA group, the stenosis was ablated successfully in 14 patients (56 %); ablation failed in 11 and a plastic stent was then inserted into the SEMS for these. The control group had only placement of a plastic stent across the stenosis. Stent patency rate at 90 days was 56% and 24% in the RFA and control groups, respectively (P=0.04). The mean stent patency time was significantly longer in the RFA group compared to the control group (119.5 vs. 65.3 days, P=0.03). Conclusion: The application of RFA for occluded SEMS improves stent patency. RFA is an alternative treatment of tissue ingrowth in malignant biliary obstruction. C1 [Kadayifci, Abdurrahman; Atar, Mustafa; Forcione, David G.; Casey, Brenna W.; Kelsey, Peter B.; Brugge, William R.] Harvard Med Sch, Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA USA. [Kadayifci, Abdurrahman] Gaziantep Univ, Sch Med, Div Gastroenterol, Gaziantep, Turkey. RP Kadayifci, A (reprint author), Massachusetts Gen Hosp, H GI Associates 3, Zero Emerson Pl,Blossom St, Boston, MA USA. EM kadayifci@hotmail.com NR 21 TC 0 Z9 0 U1 1 U2 1 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0013-726X EI 1438-8812 J9 ENDOSCOPY JI Endoscopy PD DEC PY 2016 VL 48 IS 12 BP 1096 EP 1101 DI 10.1055/s-0042-115938 PG 6 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA EJ9QC UT WOS:000393560300007 PM 27716861 ER PT J AU Rodan, LH Cohen, J Fatemi, A Gillis, T Lucente, D Gusella, J Picker, JD AF Rodan, Lance H. Cohen, Julie Fatemi, Ali Gillis, Tammy Lucente, Diane Gusella, James Picker, Jonathan D. TI A novel neurodevelopmental disorder associated with compound heterozygous variants in the huntingtin gene SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID DISEASE GENE; CAG REPEAT; INACTIVATION; EXPANSION AB We report compound heterozygous variants in HTT, the gene encoding huntingtin, in association with an autosomal recessive neurodevelopmental disorder. Three siblings presented with severe global developmental delay since birth, central hypotonia progressing to spastic quadraparesis, feeding difficulties, dystonia (2/3 sibs), prominent midline stereotypies (2/3), bruxism (1/3), high myopia (2/3), and epilepsy (1/3). Whole exome sequencing identified compound heterozygous variants in HTT that co-segregated in the three affected sibs and were absent in an unaffected sib. There were no additional variants in other genes that could account for the reported phenotype. Molecular analysis of HTT should be considered, not just for Huntington's disease, but also in children with a Rett-like syndrome who test negative for known Rett and Rett-like syndrome genes. C1 [Rodan, Lance H.; Picker, Jonathan D.] Boston Childrens Hosp, Div Genet & Genom, 300 Longwood Ave, Boston, MA 02115 USA. [Cohen, Julie; Fatemi, Ali] Johns Hopkins Med Inst, Kennedy Krieger Inst, Div Neurogenet, Baltimore, MD 21205 USA. [Gillis, Tammy; Lucente, Diane; Gusella, James] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Gusella, James] Harvard Med Sch, Dept Genet, Boston, MA USA. RP Rodan, LH (reprint author), Boston Childrens Hosp, Div Genet & Genom, 300 Longwood Ave, Boston, MA 02115 USA. EM Lancerodan@gmail.com NR 8 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD DEC PY 2016 VL 24 IS 12 BP 1826 EP 1827 DI 10.1038/ejhg.2016.74 PG 2 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EK7OG UT WOS:000394114500027 PM 27329733 ER PT J AU Gane, EJ Lawitz, E Pugatch, D Papatheodoridis, GV Brau, N Brown, AS Pol, S Leroy, V Persico, M Moreno, C Colombo, M Yoshida, EM Nelson, DR Lei, Y Kosloski, MP Mensa, FJ AF Gane, Edward J. Lawitz, Eric Pugatch, David Papatheodoridis, George V. Braeu, Norbert Brown, Ashley S. Pol, Stanislas Leroy, Vincent Persico, Marcello Moreno, Christophe Colombo, Massimo Yoshida, Eric M. Nelson, David R. Lei, Yang Kosloski, Matthew P. Mensa, Federico J. TI EXPEDITION-IV: Safety and Efficacy of GLE/PIB in Adults with renal impairment and Chronic Hepatitis C Virus Genotype 1-6 Infection SO HEPATOLOGY LA English DT Meeting Abstract CT 67th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 11-15, 2016 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Pugatch, David; Lei, Yang; Kosloski, Matthew P.; Mensa, Federico J.] AbbVie, N Chicago, IL USA. [Lawitz, Eric] Univ Texas San Antonio, Hlth Sci Ctr, Texas Liver Inst, San Antonio, TX USA. [Gane, Edward J.] Auckland City Hosp, Liver Unit, Auckland, New Zealand. [Papatheodoridis, George V.] Univ Athens, Med Sch Natl & Kapodistrian, Athens, Greece. [Braeu, Norbert] James J Peters VA Med Ctr, Bronx, NY USA. [Brown, Ashley S.] Imperial Coll Health care, London, England. [Pol, Stanislas] Groiupe Hosp Cochin St Vincent De Paul, Paris, France. [Leroy, Vincent] Ctr Hosp Univ Grenoble, Grenoble, France. [Persico, Marcello] Univ Salerno, Internal Med & Hepatol Unit, Salerno, Italy. [Moreno, Christophe] Univ Libre Bruxelles, CUB Hop Erasme, Brussels, Belgium. [Colombo, Massimo] Univ Milan, Osped Maggiore Policlin, Milan, Italy. [Yoshida, Eric M.] Univ British Columbia, Vancouver, BC, Canada. [Nelson, David R.] Univ Florida, Dept Med, Gainesville, FL 32611 USA. [Papatheodoridis, George V.] Laiko Gen Hosp Athens, Athens, Greece. [Braeu, Norbert] Icahn Sch Med Mt Sinai, New York, NY USA. FU AbbVie; Achillion Pharmaceuticals; Boehringer Ingelheim; Bristol-Myers Squibb; Gilead Sciences; GlaxoSmith-Kline; Idenix Pharmaceuticals; Intercept Pharmaceuticals; Janssen; Merck Co; Novartis; Nitto Denko; Theravance; Salix; Enanta; Roche; Gilead; Bristol-Meyer Squibb; MSD; Astellas; Merck Inc; Springbank; Jannsen Inc; Gilead Sciences Inc; Intercept; BMS; Merck FX Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharmaceuticals, Regulus, Theravance, Enanta, Idenix Pharmaceuticals, Janssen, Merck & Co, Novartis, Gilead; Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmith-Kline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Nitto Denko, Theravance, Salix, Enanta; Speaking and Teaching: Gilead, Janssen, AbbVie, Bristol Meyers Squibb, Merck, intercept; George V. Papatheodoridis - Advisory Committees or Review Panels: Merck Sharp & Dohme, Novartis, Abbvie, Boerhinger Ingelheim, Bristol-Meyer Squibb, Gilead, Roche, Janssen, GlaxoSmith Kleine; Grant/Research Support: Roche, Gilead, Bristol-Meyer Squibb, Abbvie, Janssen; Speaking and Teaching: Merck Sharp & Dohme, Bristol-Meyer Squibb, Gilead, Roche, Janssen, Abbvie; Stanislas Pol - Board Membership: Bristol- Myers-Squibb, Boehringer Ingelheim, Tibotec Janssen Cilag, Gilead, Glaxo Smith Kline, Roche, MSD, Novartis; Grant/Research Support: Gilead, Roche, MSD; Speaking and Teaching: Bristol- Myers-Squibb, Boehringer Ingelheim, Tibotec Janssen Cilag, Gilead, Roche, MSD, Novartis; Marcello Persico - Advisory Committees or Review Panels: abbvie; Grant/Research Support: gilead; Speaking and Teaching: Jansen, Bristol Myers Squibb, MSD; Christophe Moreno - Consulting: Abbvie, Janssen, Gilead, BMS, MSD; Grant/Research Support: Janssen, Gilead, Roche, Astellas, Abbvie; Eric M. Yoshida - Advisory Committees or Review Panels: Gilead Sciences Inc; Grant/Research Support: Abbvie, Merck Inc, Springbank, Jannsen Inc, Gilead Sciences Inc, Intercept; Speaking and Teaching: Gilead Sciences Inc, Merck Canada, Celgene Canada, Merck Inc; David R. Nelson - Grant/Research Support: Abbvie, BMS, Gilead, Merck, Janssen 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 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD DEC PY 2016 VL 64 IS 6 MA LB-11 BP 1125A EP 1125A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4MF UT WOS:000393900200012 ER PT J AU Bhan, I Kalinich, M Kwan, TT Miyamoto, DT Javaid, S Licausi, JA Milner, JD Hong, X Goyal, L Sil, S Choz, M Kapur, R Muzikansky, A Zhang, HD Weitz, DA Sequist, LV Ryan, DP Chung, RT Zhu, AX Ting, DT Toner, M Maheswaran, S Daniel, HA AF Bhan, Irun Kalinich, Mark Kwan, Tanya T. Miyamoto, David T. Javaid, Sarah Licausi, Joseph A. Milner, John D. Hong, Xin Goyal, Lipika Sil, Srinjoy Choz, Melissa Kapur, Ravi Muzikansky, Alona Zhang, Huidan Weitz, David A. Sequist, Lecia V. Ryan, David P. Chung, Raymond T. Zhu, Andrew X. Ting, David T. Toner, Mehmet Maheswaran, Shyamala Daniel, Haber A. TI An RNA-based signature enables high specificity detection of circulating tumor cells in hepatocellular carcinoma SO HEPATOLOGY LA English DT Meeting Abstract CT 67th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 11-15, 2016 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Bhan, Irun; Kalinich, Mark; Kwan, Tanya T.; Miyamoto, David T.; Javaid, Sarah; Licausi, Joseph A.; Milner, John D.; Hong, Xin; Goyal, Lipika; Sil, Srinjoy; Choz, Melissa; Muzikansky, Alona; Sequist, Lecia V.; Ryan, David P.; Zhu, Andrew X.; Ting, David T.; Toner, Mehmet; Maheswaran, Shyamala; Daniel, Haber A.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. [Bhan, Irun; Chung, Raymond T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Miyamoto, David T.] Massachusetts Gen Hosp, Div Radiat Oncol, Boston, MA 02114 USA. [Goyal, Lipika; Sequist, Lecia V.; Ryan, David P.; Zhu, Andrew X.; Ting, David T.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Kapur, Ravi; Toner, Mehmet] Massachusetts Gen Hosp, Ctr Bioengn Med, Boston, MA 02114 USA. [Muzikansky, Alona] Harvard Med Sch, Div Biostat, Boston, MA USA. [Zhang, Huidan; Weitz, David A.] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA. [Daniel, Haber A.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Maheswaran, Shyamala] Massachusetts Gen Hosp, Div Surg, Boston, MA 02114 USA. FU Gilead; Abbvie; Merck; BMS FX Raymond T. Chung - Grant/Research Support: Gilead, Abbvie, Merck, BMS 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 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD DEC PY 2016 VL 64 IS 6 MA LB-20 BP 1131A EP 1132A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4MF UT WOS:000393900200021 ER PT J AU Salloum, S Holmes, JA Jindal, R Bale, SS Brisac, C Alatrakchi, N Lidofsky, A Kruger, AJ Fusco, DN Luther, J Schaefer, EA Lin, WY Yarmush, ML Chung, RT AF Salloum, Shadi Holmes, Jacinta A. Jindal, Rohit Bale, Shyam S. Brisac, Cynthia Alatrakchi, Nadia Lidofsky, Anna Kruger, Annie J. Fusco, Dahlene N. Luther, Jay Schaefer, Esperance A. Lin, Wenyu Yarmush, Martin L. Chung, Raymond T. TI Exposure to Human Immunodeficiency Virus/Hepatitis C Virus in Hepatic and Stellate Cell Lines Reveals Cooperative Profibrotic Transcriptional Activation Between Viruses and Cell Types SO HEPATOLOGY LA English DT Article ID INDUCED LIVER FIBROSIS; CORE PROTEIN; APOPTOTIC BODIES; REPORTER CELLS; ROS PRODUCTION; IN-VITRO; EXPRESSION; INFECTION; HIV; COINFECTION AB Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection accelerates progressive liver fibrosis; however, the mechanisms remain poorly understood. HCV and HIV independently induce profibrogenic markers transforming growth factor beta-1 (TGF beta 1) (mediated by reactive oxygen species [ROS]) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappa B) in hepatocytes and hepatic stellate cells in monoculture; however, they do not account for cellular crosstalk that naturally occurs. We created an in vitro coculture model and investigated the contributions of HIV and HCV to hepatic fibrogenesis. Green fluorescent protein reporter cell lines driven by functional ROS (antioxidant response elements), NF kappa B, and mothers against decapentaplegic homolog 3 (SMAD3) promoters were created in Huh7.5.1 and LX2 cells, using a transwell to generate cocultures. Reporter cell lines were exposed to HIV, HCV, or HIV/HCV. Activation of the 3 pathways was measured and compared according to infection status. Extracellular matrix products (collagen type 1 alpha 1 (CoL1A1) and tissue inhibitor of metalloproteinase 1 (TIMP1)) were also measured. Both HCV and HIV independently activated TGFb1 signaling through ROS (antioxidant response elements), NF kappa B, and SMAD3 in both cell lines in coculture. Activation of these profibrotic pathways was additive following HIV/HCV coexposure. This was confirmed when examining CoL1A1 and TIMP1, where messenger RNA and protein levels were significantly higher in LX2 cells in coculture following HIV/HCV coexposure compared with either virus alone. In addition, expression of these profibrotic genes was significantly higher in the coculture model compared to either cell type in monoculture, suggesting an interaction and feedback mechanism between Huh7.5.1 and LX2 cells. Conclusion: HIV accentuates an HCV-driven profibrogenic program in hepatocyte and hepatic stellate cell lines through ROS, NF kappa B, and TGFb1 up-regulation; coculture of hepatocyte and hepatic stellate cell lines significantly increased expression of CoL1A1 and TIMP1; and our novel coculture reporter cell model represents an efficient and more authentic system for studying transcriptional fibrosis responses and may provide important insights into hepatic fibrosis. C1 [Salloum, Shadi; Holmes, Jacinta A.; Brisac, Cynthia; Alatrakchi, Nadia; Lidofsky, Anna; Kruger, Annie J.; Fusco, Dahlene N.; Luther, Jay; Schaefer, Esperance A.; Lin, Wenyu; Chung, Raymond T.] Harvard Med Sch, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA USA. [Jindal, Rohit; Bale, Shyam S.; Yarmush, Martin L.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA USA. RP Chung, RT (reprint author), Massachusetts Gen Hosp, Ctr Liver, 55 Fruit St, Boston, MA 02114 USA.; Chung, RT (reprint author), Massachusetts Gen Hosp, Gastrointestinal Div, 55 Fruit St, Boston, MA 02114 USA. EM rtchung@partners.org FU National Institutes of Health [DK098079, DK108370] FX Supported by the National Institutes of Health (DK098079 and DK108370, both to R.T.C.). NR 32 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD DEC PY 2016 VL 64 IS 6 BP 1951 EP 1968 DI 10.1002/hep.28766 PG 18 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4MF UT WOS:000393900200053 PM 27531241 ER PT J AU Motai, Y Ma, D Yoshida, H AF Motai, Yuichi Ma, Dingkun Yoshida, Hiroyuki TI Smart Anomaly Prediction in Nonstationary CT Colonography Screening SO IEEE TRANSACTIONS ON INDUSTRIAL INFORMATICS LA English DT Article DE Anomaly detection; computed tomographic colonography; healthcare systems; kernel feature analysis; longitudinal prediction; nonstationary datasets ID SUPPORT VECTOR MACHINES; COLORECTAL-CANCER; KERNEL; ONLINE; POLYPS; CAD AB To enhance the quality of economically efficient healthcare, we propose a preventive planning service for next-generation screening based on a longitudinal prediction. This newly proposed framework may bring important advancements in prevention by identifying the early stages of cancer, which will help in further diagnoses and initial treatment planning. The preventive service may also solve the obstacles of cost and availability of scanners in screening. For nonstationary medical data, anomaly detection is the key problem in the prediction of cancer staging. To address anomaly detection in a huge stream of databases, we applied a composite kernel to the prediction of cancer staging for the first time. The proposed longitudinal analysis of composite kernels (LACK) is designed for the prediction of anomaly status and cancer stage for further diagnosis and the future likelihood of cancer stage progression. The prediction error of LACK is relatively small even if the prediction is made far ahead of time. The computation time for nonstationary learning is reduced by 33% compared with stationary learning. C1 [Motai, Yuichi; Ma, Dingkun] Virginia Commonwealth Univ, Dept Elect & Comp Engn, Richmond, VA 23284 USA. [Yoshida, Hiroyuki] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Yoshida, Hiroyuki] Harvard Med Sch, Boston, MA 02114 USA. RP Motai, Y (reprint author), Virginia Commonwealth Univ, Dept Elect & Comp Engn, Richmond, VA 23284 USA. EM ymotai@vcu.edu; madingkun@gmail.com; yoshida.hiro@mgh.harvard.edu FU CTSA from the National Center for Advancing Translational Sciences; Center for Clinical and Translational Research Endowment Fund of Virginia Commonwealth University; CAREER Award from the National Science Foundation [1054333]; National Institutes of Health [R01CA166816] FX This work was supported in part by CTSA UL1TR000058 from the National Center for Advancing Translational Sciences, Center for Clinical and Translational Research Endowment Fund of Virginia Commonwealth University, CAREER Award 1054333 from the National Science Foundation, and R01CA166816 from the National Institutes of Health. Paper no. TII-15-0165.R4 NR 25 TC 0 Z9 0 U1 2 U2 2 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1551-3203 EI 1941-0050 J9 IEEE T IND INFORM JI IEEE Trans. Ind. Inform. PD DEC PY 2016 VL 12 IS 6 BP 2292 EP 2301 DI 10.1109/TII.2016.2595399 PG 10 WC Automation & Control Systems; Computer Science, Interdisciplinary Applications; Engineering, Industrial SC Automation & Control Systems; Computer Science; Engineering GA EG8II UT WOS:000391299700032 ER PT J AU Khan, N Patel, D Shah, Y Yang, YX AF Khan, Nabeel Patel, Dhruvan Shah, Yash Yang, Yu-Xiao TI Factors Predicting Testing and Treatment of Iron Deficiency in a Nationwide Cohort of Anemic UC Patients SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE iron deficiency; ulcerative colitis; testing and treatment ID INFLAMMATORY-BOWEL-DISEASE; QUALITY-OF-LIFE; ULCERATIVE-COLITIS; EUROPEAN COUNTRIES; OLDER-ADULTS; MANAGEMENT; DIAGNOSIS; HEMOGLOBIN; HEALTH; IBD AB Background: Iron deficiency anemia (IDA) is an often unrecognized and undertreated complication of ulcerative colitis (UC). We conducted the first nationwide study in the United States to evaluate the prevalence of testing for iron deficiency (ID) in anemic UC patients and determine the frequency of treatment with iron supplementation in patients with IDA. Methods: Nationwide cohort of patients with newly diagnosed UC in the Veterans Affairs health care system was identified. Primary outcome was to evaluate if anemic UC patients were tested for ID and subsequently treated with iron replacement therapy if IDA is confirmed. Candidate parameters included factors that can impact testing and treatment of anemia including patients' demographics, severity of anemia, and endoscopic findings. Results: Of 836 newly diagnosed patients with UC, 585 patients (70%) developed anemia over the course of median 8 years of follow-up. Of 585 patients, 401 patients (68.6%) had iron study evaluation. Two hundred fifty-one patients (62.6%) were diagnosed with IDA, and among them, 191 patients (76.1%) were treated with oral iron therapy. None of the patient received intravenous iron therapy. In multivariate analysis, patients with mild/moderate anemia and patients from Midwest and South region were independent predictors of iron study evaluation in patients with anemia. Conclusions: More than a third of anemic UC patients were not tested for ID. Once tested, almost a quarter of the patients with IDA were not treated with iron replacement therapy. Testing for ID and subsequent treatment with iron replacement therapy should be considered among the quality process indicators in UC. C1 [Khan, Nabeel; Yang, Yu-Xiao] Univ Penn, Gastroenterol Sect, Philadelphia, PA 19104 USA. [Khan, Nabeel; Shah, Yash; Yang, Yu-Xiao] VA Med Ctr, Gastroenterol Sect, Philadelphia, PA USA. [Patel, Dhruvan] Mercy Catholic Med Ctr, Dept Internal Med, Darby, PA USA. RP Khan, N (reprint author), Univ Penn, Gastroenterol Sect, Perelman Sch Med, Philadelphia VA Med Ctr, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM nabeelk@mail.med.upenn.edu FU Luitpold pharmaceuticals FX The authors acknowledge Luitpold pharmaceuticals for providing an unrestricted research grant. NR 41 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD DEC PY 2016 VL 22 IS 12 BP 2894 EP 2901 DI 10.1097/MIB.0000000000000947 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4JR UT WOS:000393893400014 PM 27763952 ER PT J AU Jazic, I Schrag, D Sargent, DJ Haneuse, S AF Jazic, Ina Schrag, Deborah Sargent, Daniel J. Haneuse, Sebastien TI Beyond Composite Endpoints Analysis: Semicompeting Risks as an Underutilized Framework for Cancer Research SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID PROGRESSION-FREE SURVIVAL; METASTATIC COLORECTAL-CANCER; SEMI-COMPETING RISKS; INDIVIDUAL PATIENT DATA; ADJUVANT COLON-CANCER; DISEASE-FREE SURVIVAL; CLINICAL-TRIALS; RANDOMIZED-TRIALS; FRAILTY MODELS; OPEN-LABEL AB Background: Composite endpoints (CEP), such as progression-free survival, are commonly used in cancer research. Notwithstanding their popularity, however, CEP analyses suffer from a number of drawbacks, especially when death is combined with a nonterminal event (ie, progression or recurrence), exemplifying the semicompeting risks setting. We investigated the semicompeting risks framework as a complementary analysis strategy that avoids certain drawbacks of CEPs. Methods: The illness-death model under the semicompeting risks framework was compared with standard analysis approaches: CEP analyses and (separate) univariate analyses for each component endpoint. Data from a previously published phase III randomized clinical trial in metastatic colon cancer including 1419 participants in the N9741 trial (conducted between 1997 and 2003) were used to determine the impact of the loss of information associated with combining multiple endpoints, as well as of ignoring the potentially informative role of death. A simulation study was conducted to further explore these issues. Results: Failure to account for critical features of semicompeting risks data can lead to potentially severely misleading conclusions. Advantages of semicompeting risks analyses include a clear delineation of treatment effects on both events, the ability to draw conclusions about a patient's joint risk of the two events, and an assessment of the dependence between the two event types. Conclusions: Embedding and analyzing component outcomes in the semicompeting risks framework, either as a supplement or alternative to CEP analyses, represents an important, underutilized, and feasible opportunity for cancer research. C1 [Jazic, Ina; Haneuse, Sebastien] Harvard TH Chan Sch Publ Hlth, Dept Biostat, 677 Huntington Ave, Boston, MA 02115 USA. [Schrag, Deborah] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Sargent, Daniel J.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. RP Jazic, I (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Biostat, 677 Huntington Ave, Boston, MA 02115 USA. EM ijazic@fas.harvard.edu FU National Cancer Institute (NCI) at the National Institutes of Health [R01 CA181360-01, T32 CA009337-33, K05 CA16938, U10 CA180882] FX This work was supported, in part, by the National Cancer Institute (NCI) at the National Institutes of Health (R01 CA181360-01 to SH, T32 CA009337-33 to IJ, K05 CA16938 to DS, and U10 CA180882 to DJS). NR 52 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD DEC PY 2016 VL 108 IS 12 AR djw154 DI 10.1093/jnci/djw154 PG 6 WC Oncology SC Oncology GA EK4LP UT WOS:000393898500003 ER PT J AU Marshall, DC Moy, B Jackson, ME Mackey, TK Hattangadi-Gluth, JA AF Marshall, Deborah C. Moy, Beverly Jackson, Madeleine E. Mackey, Tim K. Hattangadi-Gluth, Jona A. TI Distribution and Patterns of Industry-Related Payments to Oncologists in 2014 SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CONFLICTS-OF-INTEREST; CANCER-RESEARCH; PHYSICIANS; DISCLOSURE; TRIALS; DRUGS; EXPENDITURES; FREQUENCY; COMPANIES; GIFTS AB Background: Industry-physician collaboration is critical for anticancer therapeutic development, but financial relationships introduce conflicts of interest. We examined the specialty variation and context of physician payments and ownership interest among oncologists. Methods: We performed a population-based multivariable analysis of 2014 Open Payments reports of industry payments to US physicians matched to physician and practice data, including sex, specialty, practice location, and sole proprietor status. Payment data were aggregated per physician and compared by specialty (medical, radiation, surgical, and nononcology), and practice location linked with spending level (low, average, and high). Primary outcomes included likelihood, mean annual amount, and number of general payments. Secondary outcomes included likelihood of holding ownership interests and receipt of royalty/license payments. Estimates for each outcome were determined using multivariable models, including logistic regression for likelihood and linear regression with gamma distribution and log-link for value, adjusted for physician specialty, sex, sole proprietor status, and practice spending. All statistical tests were two-sided. Results: In 2014, there were 883 438 physicians, including 22 712 oncologists, licensed to practice in the United States. Among oncology specialties, 52.4% to 63.0% of physicians received a general payment in 2014, totaling $76 million, $4 million, and $5 million to medical, radiation, and surgical oncology, respectively. The median annual per-physician payment to medical oncologists was $632 (IQR = 136-2500), compared with $124 (IQR = 39-323) in radiation oncology and $250 (IQR = 84-1369) in surgical oncology. After controlling for physician and practice characteristics, oncologists were 1.09 to 1.75 times as likely to receive a general payment compared with nononcologists (overall P<. 001). There was a 67.6% difference (95% confidence interval [CI] = 63.6 to 71.5, P <.001) in the mean annual value of payments between medical oncology and nononcology specialties (vs -92.7%, 95% CI = -100.2 to -85.0, P <.001] for radiation oncology). Medical and radiation oncologists were more likely to hold ownership interest (adjusted OR = 3.72, 95% CI = 3.22 to 4.27, and 2.27, 95% CI = 1.65 to 3.03, respectively, P <.001 both comparisons). Conclusions: In 2014, industry-oncologist financial relationships were common, and their impact on oncology practice should be further explored. C1 [Marshall, Deborah C.; Hattangadi-Gluth, Jona A.] Univ Calif San Diego, Dept Radiat Med & Appl Sci, La Jolla, CA 92093 USA. [Mackey, Tim K.] Univ Calif San Diego, Dept Anesthesiol, La Jolla, CA 92093 USA. [Marshall, Deborah C.; Jackson, Madeleine E.] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Moy, Beverly] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Hattangadi-Gluth, JA (reprint author), Univ Calif San Diego, Moores Canc Ctr, Dept Radiat Med & Appl Sci, 3960 Hlth Sci Dr 0865, La Jolla, CA 92093 USA. EM jhattangadi@ucsd.edu OI Mackey, Tim/0000-0002-2191-7833 FU National Institutes of Health [1TL1TR001443, 5T35HL007491, UL1TR000100, 1KL2TR001444] FX This work was supported by the National Institutes of Health (grants 1TL1TR001443 to DCM, 5T35HL007491 to MEJ, UL1TR000100 to JAH, and 1KL2TR001444 to JAH). NR 48 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD DEC PY 2016 VL 108 IS 12 AR djw163 DI 10.1093/jnci/djw163 PG 10 WC Oncology SC Oncology GA EK4LP UT WOS:000393898500004 ER PT J AU Zuber, V Marconett, CN Shi, JX Hua, X Wheeler, W Yang, CC Song, L Dale, AM Laplana, M Risch, A Witoelar, A Thompson, WK Schork, AJ Bettella, F Wang, YP Djurovic, S Zhou, BY Borok, Z van der Heijden, HFM de Graaf, J Swinkels, D Aben, KK McKay, J Hung, RJ Bikeboller, H Stevens, VL Albanes, D Caporaso, NE Han, YH Wei, YY Panadero, MA Mayordomo, JI Christiani, DC Kiemeney, L Andreassen, OA Houlston, R Amos, CI Chatterjee, N Laird-Offringa, IA Mills, IG Landi, MT AF Zuber, Verena Marconett, Crystal N. Shi, Jianxin Hua, Xing Wheeler, William Yang, Chenchen Song, Lei Dale, Anders M. Laplana, Marina Risch, Angela Witoelar, Aree Thompson, Wesley K. Schork, Andrew J. Bettella, Francesco Wang, Yunpeng Djurovic, Srdjan Zhou, Beiyun Borok, Zea van der Heijden, Henricus F. M. de Graaf, Jacqueline Swinkels, Dorine Aben, Katja K. McKay, James Hung, Rayjean J. Bikeboller, Heike Stevens, Victoria L. Albanes, Demetrius Caporaso, Neil E. Han, Younghun Wei, Yongyue Panadero, Maria Angeles Mayordomo, Jose I. Christiani, David C. Kiemeney, Lambertus Andreassen, Ole A. Houlston, Richard Amos, Christopher I. Chatterjee, Nilanjan Laird-Offringa, Ite A. Mills, Ian G. Landi, Maria Teresa TI Pleiotropic Analysis of Lung Cancer and Blood Triglycerides SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID RISK; INFLAMMATION; VARIANTS; IMMUNITY; DISEASE AB Epidemiologically related traits may share genetic risk factors, and pleiotropic analysis could identify individual loci associated with these traits. Because of their shared epidemiological associations, we conducted pleiotropic analysis of genome-wide association studies of lung cancer (12 160 lung cancer case patients and 16 838 control subjects) and cardiovascular disease risk factors (blood lipids from 188 577 subjects, type 2 diabetes from 148 821 subjects, body mass index from 123 865 subjects, and smoking phenotypes from 74 053 subjects). We found that 6p22.1 (rs6904596, ZNF184) was associated with both lung cancer (P = 5.50x10(-6)) and blood triglycerides (P = 1.39x10(-5)). We replicated the association in 6097 lung cancer case patients and 204 657 control subjects (P = 2.40x10(-4)) and in 71 113 subjects with triglycerides data (P =.01). rs6904596 reached genome-wide significance in lung cancer meta-analysis (odds ratio = 1.15, 95% confidence interval = 1.10 to 1.21, P-combined = 5.20x10(-9)). The large sample size provided by the lipid GWAS data and the shared genetic risk factors between the two traits contributed to the uncovering of a hitherto unidentified genetic locus for lung cancer. C1 [Zuber, Verena; Witoelar, Aree; Bettella, Francesco; Wang, Yunpeng; Andreassen, Ole A.] Univ Oslo, Inst Clin Med, KG Jebsen Ctr Psychosis Res, NORMENT, Oslo, Norway. [Zuber, Verena; Mills, Ian G.] Univ Oslo, Nord EMBL Partnership, Ctr Mol Med Norway, Prostate Canc Res Grp, Oslo, Norway. [Zuber, Verena; Witoelar, Aree; Bettella, Francesco; Wang, Yunpeng; Andreassen, Ole A.] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway. [Zuber, Verena] European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge, England. [Marconett, Crystal N.; Yang, Chenchen; Laird-Offringa, Ite A.] Univ So Calif, Keck Sch Med, Dept Surg, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Marconett, Crystal N.; Yang, Chenchen; Laird-Offringa, Ite A.] Univ So Calif, Keck Sch Med, Dept Biochem & Mol Biol, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Zhou, Beiyun; Borok, Zea] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Will Rogers Inst,Pulm Res Ctr, Los Angeles, CA 90033 USA. [Zhou, Beiyun; Borok, Zea] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Div Pulm Crit Care & Sleep Med,Dept Med, Los Angeles, CA 90033 USA. [Shi, Jianxin; Hua, Xing; Song, Lei; Caporaso, Neil E.; Chatterjee, Nilanjan; Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, NIH, US Publ Hlth Serv, Bethesda, MD 20892 USA. [Wheeler, William] Information Management Serv Inc, Rockville, MD USA. [Dale, Anders M.; Schork, Andrew J.] Univ Calif San Diego, Multimodal Imaging Lab, La Jolla, CA 92093 USA. [Dale, Anders M.; Schork, Andrew J.] Univ Calif San Diego, Ctr Human Dev, La Jolla, CA 92093 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Thompson, Wesley K.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Schork, Andrew J.] Univ Calif San Diego, Cognit Sci Grad Program, La Jolla, CA 92093 USA. [Laplana, Marina; Risch, Angela] German Canc Res Ctr, Div Epigen & Canc Risk Factors, Heidelberg, Germany. [Risch, Angela] Salzburg Univ, Dept Mol Biol, Salzburg, Austria. [Risch, Angela] TLRC H, Heidelberg, Germany. [Risch, Angela] German Ctr Lung Res DZL, Heidelberg, Germany. [Djurovic, Srdjan] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway. [Mills, Ian G.] Oslo Univ Hosp, Dept Mol Oncol, Inst Canc Res, Oslo, Norway. [Mills, Ian G.] Oslo Univ Hosp, Dept Urol, Oslo, Norway. [Djurovic, Srdjan] Univ Bergen, NORMENT, KG Jebsen Ctr Psychosis Res, Dept Clin Sci, Bergen, Norway. [van der Heijden, Henricus F. M.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands. [Swinkels, Dorine] Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Med Ctr, Nijmegen, Netherlands. [Aben, Katja K.] Netherlands Comprehens Canc Org, Utrecht, Netherlands. [McKay, James] WHO, IARC, Lyon, France. [Hung, Rayjean J.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Bikeboller, Heike] Univ Med Gottingen, Zentrum Informat Stat & Epidemiol, Gottingen, Germany. [Stevens, Victoria L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Han, Younghun; Amos, Christopher I.] Dartmouth Coll, Ctr Genom Med, Dept Community & Family Med, Geisel Sch Med, 1 Med Ctr Dr, Lebanon, NH 03756 USA. [Wei, Yongyue; Panadero, Maria Angeles; Christiani, David C.] Harvard Sch Publ Hlth, Dept Epidemiol & Environm Hlth, Boston, MA USA. [Mayordomo, Jose I.] Ciudad Coria Hosp, Div Med Oncol, Coria, Spain. [Kiemeney, Lambertus] Univ Hosp, Div Med Oncol, Zaragoza, Spain. [Christiani, David C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Pulm Crit Care, Boston, MA USA. [Houlston, Richard] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Mills, Ian G.] Queens Univ, Ctr Canc Res & Cell Biol, Prostate Canc UK Movember Ctr Excellence Prostate, Belfast, Antrim, North Ireland. RP Mills, IG (reprint author), Queens Univ, Ctr Canc Res & Cell Biol, Prostate Canc UK Movember Ctr Excellence Prostate, Belfast, Antrim, North Ireland.; Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Room 6E446,MSC 9769, Bethesda, MD 20892 USA.; Mills, IG (reprint author), Queens Univ Belfast, CCRCB, 97 Lisburn Rd, Belfast BT9 7BL, Antrim, North Ireland. EM I.Mills@qub.ac.uk; landim@mail.nih.gov OI Zuber, Verena/0000-0001-9827-1877; Laplana, Marina/0000-0002-2548-0704; van der Heijden, Erik/0000-0003-3596-518X; Houlston, Richard/0000-0002-5268-0242 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD.; Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics; US Public Health Service from the NCI [N01-CN-45165, N01-RC45035, N01-RC-37004]; NCI to the University of Colorado Denver [NO1-CN-25514]; Georgetown University [NO1-CN-25522]; Pacific Health Research Institute [NO1-CN-25515]; Henry Ford Health System [NO1-CN-25512]; University of Minnesota [NO1-CN-25513]; Washington University [NO1-CN-25516]; University of Pittsburgh [NO1-CN-25511]; University of Utah [NO1-CN-25524]; Westat, Inc. [NO1-CN-25476]; University of California, Los Angeles [NO1-CN25404]; American Cancer Society; National Institutes of Health (NIH); Genes, Environment and Health Initiative (GEI) [Z01 CP 010200]; NIH [U01 HG004446, 1 R01 HL114094, 1 P30 H101258, R37HL062569-13]; NIH GEI [U01HG 004438]; National Institutes of Health [R01 CA092824, P50 CA090578, R01 CA074386]; Chaire de pneumologie de la Fondation JD Begin de l'Universite Laval; Fondation de l'Institut universitaire de cardiologie et de pneumologie de Quebec; Respiratory Health Network of the FRQS; Canadian Institutes of Health Research [MOP - 123369]; Cancer Research Society and Read for the Cure; Fonds de recherche Quebec-Sante (FRQS); Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services; Ralph Edgington Chair in Medicine; department of Surgery, University of Southern California; Norris Comprehensive Cancer Center core grant from the National Cancer Institute [P30CA014089] FX This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD.; Transdisciplinary Research for Cancer of Lung (TRICL): National Institute of Health U19 CA148127-01 (PI: Amos), Canadian Cancer Society Research Institute (No. 020214, PI: Hung). The Environment and Genetics in Lung Cancer Etiology (EAGLE), Prostate, Lung, Colon, Ovary Screening Trial (PLCO), and Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) studies were supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics. ATBC was also supported by US Public Health Service contracts (N01-CN-45165, N01-RC45035, and N01-RC-37004) from the NCI.; PLCO was also supported by individual contracts from the NCI to the University of Colorado Denver (NO1-CN-25514), Georgetown University (NO1-CN-25522), the Pacific Health Research Institute (NO1-CN-25515), the Henry Ford Health System (NO1-CN-25512), the University of Minnesota (NO1-CN-25513), Washington University (NO1-CN-25516), the University of Pittsburgh (NO1-CN-25511), the University of Utah (NO1-CN-25524), the Marshfield Clinic Research Foundation (NO1-CN-25518), the University of Alabama at Birmingham (NO1-CN-75022), Westat, Inc. (NO1-CN-25476), and the University of California, Los Angeles (NO1-CN25404). The Cancer Prevention Study-II (CPS-II) Nutrition Cohort was supported by the American Cancer Society. Funding for the Lung Cancer and Smoking study was provided by the National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. Harvard Lung Study: The Harvard Lung Cancer Study is supported by the National Institutes of Health (R01 CA092824, P50 CA090578, and R01 CA074386).; Lung eQTL study: The lung eQTL study at Laval University was supported by the Chaire de pneumologie de la Fondation JD Begin de l'Universite Laval, the Fondation de l'Institut universitaire de cardiologie et de pneumologie de Quebec, the Respiratory Health Network of the FRQS, the Canadian Institutes of Health Research (MOP - 123369), and the Cancer Research Society and Read for the Cure. Y. Bosse is the recipient of a Junior 2 Research Scholar award from the Fonds de recherche Quebec-Sante (FRQS).; Lung meQTL study: The meQTL study based on the environment and Genetics in Lung Cancer Etiology (EAGLE) study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services.; Epigenetics: This study was supported by NIH grant 1 R01 HL114094 to IAL-O and ZB, NIH grants 1 P30 H101258 and R37HL062569-13 to ZB. ZB is supported by the Ralph Edgington Chair in Medicine. CNM was supported in part by the department of Surgery, University of Southern California. Generation of epigenetic data was supported in part by a Norris Comprehensive Cancer Center core grant, award number P30CA014089, from the National Cancer Institute. NR 15 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD DEC PY 2016 VL 108 IS 12 AR djw167 DI 10.1093/jnci/djw167 PG 4 WC Oncology SC Oncology GA EK4LP UT WOS:000393898500007 ER PT J AU Morrison, RS Dickman, E Hwang, U Akhtar, S Ferguson, T Huang, J Jeng, CL Nelson, BP Rosenblatt, MA Silverstein, JH Strayer, RJ Torrillo, TM Todd, KH AF Morrison, R. Sean Dickman, Eitan Hwang, Ula Akhtar, Saadia Ferguson, Taja Huang, Jennifer Jeng, Christina L. Nelson, Bret P. Rosenblatt, Meg A. Silverstein, Jeffrey H. Strayer, Reuben J. Torrillo, Toni M. Todd, Knox H. TI Regional Nerve Blocks Improve Pain and Functional Outcomes in Hip Fracture: A Randomized Controlled Trial SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE pain; hip fracture; functional recovery ID OLDER-ADULTS; EMERGENCY-DEPARTMENT; MANAGEMENT; ANALGESIA; NECK; IMPACT AB OBJECTIVES: To compared outcomes of regional nerve blocks with those of standard analgesics after hip fracture. DESIGN: Multisite randomized controlled trial from April 2009 to March 2013. SETTING: Three New York hospitals. PARTICIPANTS: Individuals with hip fracture (N = 161). INTERVENTION: Participants were randomized to receive an ultrasound-guided, single-injection, femoral nerve block administered by emergency physicians at emergency department (ED) admission followed by placement of a continuous fascia iliaca block by anesthesiologists within 24 hours (n = 79) or conventional analgesics (n = 82). MEASUREMENTS: Pain (0-10 scale), distance walked on Postoperative Day (POD) 3, walking ability 6 weeks after discharge, opioid side effects. RESULTS: Pain scores 2 hours after ED presentation favored the intervention group over controls (3.5 vs 5.3, P =.002). Pain scores on POD 3 were significantly better for the intervention than the control group for pain at rest (2.9 vs 3.8, P =.005), with transfers out of bed (4.7 vs 5.9, P =.005), and with walking (4.1 vs 4.8, P =.002). Intervention participants walked significantly further than controls in 2 minutes on POD 3 (170.6 feet, 95% confidence interval (CI) = 109.3-232 vs 100.0 feet, 95% CI = 65.1-134.9; P =.04). At 6 weeks, intervention participants reported better walking and stair climbing ability (mean Functional Independence Measure locomotion score of 10.3 (95% CI = 9.6-11.0) vs 9.1 (95% CI = 8.2-10.0), P =.04). Intervention participants were significantly less likely to report opioid side effects (3% vs 12.4%, P =.03) and required 33% to 40% fewer parenteral morphine sulfate equivalents. CONCLUSION: Femoral nerve blocks performed by emergency physicians followed by continuous fascia iliaca blocks placed by anesthesiologists are feasible and result in superior outcomes. C1 [Morrison, R. Sean; Rosenblatt, Meg A.; Silverstein, Jeffrey H.; Torrillo, Toni M.] Icahn Sch Med Mt Sinai, Dept Anesthesia, New York, NY 10029 USA. [Morrison, R. Sean; Hwang, Ula; Ferguson, Taja] Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, New York, NY 10029 USA. [Morrison, R. Sean; Hwang, Ula] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. [Dickman, Eitan] Maimonides Hosp, Brooklyn, NY 11219 USA. [Hwang, Ula; Huang, Jennifer; Nelson, Bret P.; Strayer, Reuben J.] Icahn Sch Med Mt Sinai, Dept Emergency Med, New York, NY 10029 USA. [Akhtar, Saadia; Todd, Knox H.] Mt Sinai Beth Israel, New York, NY USA. Icahn Sch Med Mt Sinai, Dept Orthoped, New York, NY 10029 USA. [Todd, Knox H.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Morrison, RS (reprint author), Icahn Sch Med Mt Sinai, Brookdale Dept Geriatr & Palliat Med, Box 1070,One Gustave Levy Pl, New York, NY 10029 USA. EM sean.morrison@mssm.edu FU National Institute on Aging [R01AG030141]; Mid-Career Investigator Award in Patient-Oriented Research from the National Institute on Aging [AGK24AG022345]; Older Adult Independence Center Grant from the National Institute on Aging [5P30AG028741]; Mentored Patient-Oriented Research Career Development Award from the National Institute on Aging [K23AG031218] FX This project was supported by Grant R01AG030141 from the National Institute on Aging. Dr. Morrison was supported by Mid-Career Investigator Award in Patient-Oriented Research AGK24AG022345 and Older Adult Independence Center Grant 5P30AG028741 from the National Institute on Aging. Dr. Hwang was supported by Mentored Patient-Oriented Research Career Development Award K23AG031218 from the National Institute on Aging. NR 31 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD DEC PY 2016 VL 64 IS 12 BP 2433 EP 2439 DI 10.1111/jgs.14386 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EK0AR UT WOS:000393589200020 PM 27787895 ER PT J AU Maust, DT Kales, HC Wiechers, IR Blow, FC Olfson, M AF Maust, Donovan T. Kales, Helen C. Wiechers, Ilse R. Blow, Frederic C. Olfson, Mark TI No End in Sight: Benzodiazepine Use in Older Adults in the United States SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE benzodiazepine; psychotropic; insomnia; anxiety ID COGNITIVE-BEHAVIORAL THERAPY; HEALTH MAINTENANCE ORGANIZATION; RANDOMIZED CONTROLLED-TRIALS; ANXIETY DISORDERS; METAANALYSIS; DISCONTINUATION; PREVALENCE; MEDICATION; RISK; PRESCRIPTIONS AB OBJECTIVES: To establish the rate of new and continuation of benzodiazepine use in older adults seen by nonpsychiatrist physicians and to identify subpopulations at risk of new and continuation benzodiazepine use. DESIGN: Cross-sectional analysis. SETTING: National Ambulatory Medical Care Survey (2007-10). PARTICIPANTS: Adults visiting office-based nonpsychiatrist physicians (n = 98,818) who were prescribed a benzodiazepine (new or continuation). MEASUREMENTS: Percentage of benzodiazepine visits of all outpatient encounters according to patient age and corresponding annual visit rate per 1,000 population. Analysis was then limited to adults aged 65 and older, demographic, clinical, and visits characteristics were used to compare visits of benzodiazepine users with those of nonusers and visits of continuation users with those of new users. RESULTS: The overall proportion of benzodiazepine visits ranged from 3.2% (95% confidence interval (CI) = 2.73.7) of those aged 18 to 34 to 6.6% (95% CI = 5.8-7.6) of those aged 80 and older, and the proportion of continuation visits increased with age, rising to 90.2% (95% CI = 86.2-93.1) of those aged 80 and older. The population-based visit rate ranged from 61.7 (95% CI = 50.7-72.7) per 1,000 persons in the youngest adults to 463.7 (95% CI = 385.4-542.0) in those aged 80 and older. Only 16.0% (95% CI = 13.5-18.8) of continuation users had any mental health diagnosis. Of all benzodiazepine users, fewer than 1% (95% CI =.4-1.8) were provided or referred to psychotherapy, and 10.0% (95% CI = 7. 2-13.3) were also prescribed an opioid. CONCLUSION: In the United States, few older adult benzodiazepine users receive a clinical mental health diagnosis, and almost none are provided or referred to psychotherapy. Prescribing to older adults continues despite decades of evidence documenting safety concerns, effective alternative treatments, and effective methods for tapering even chronic users. C1 [Maust, Donovan T.; Kales, Helen C.; Blow, Frederic C.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Maust, Donovan T.; Kales, Helen C.; Blow, Frederic C.] Univ Michigan, Inst Healthcare Policy & Innovat, Ann Arbor, MI 48109 USA. [Maust, Donovan T.; Kales, Helen C.; Blow, Frederic C.] Vet Affairs Ann Arbor Healthcare Syst, Ctr Clin Management Res, Ann Arbor, MI USA. [Wiechers, Ilse R.] US Dept Vet Affairs, Northeast Program Evaluat Ctr, Off Mental Hlth Operat, West Haven, CT USA. [Wiechers, Ilse R.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Olfson, Mark] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Olfson, Mark] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. RP Maust, DT (reprint author), Dept Psychiat, 2800 Plymouth Rd,NCRC Bldg 16,Room 222W, Ann Arbor, MI 48109 USA. EM maustd@umich.edu FU Beeson Career Development Award Program (National Institute on Aging) [K08AG048321]; Beeson Career Development Award Program (AFAR); Beeson Career Development Award Program (John A. Hartford Foundation); Beeson Career Development Award Program (Atlantic Philanthropies) FX This work was supported by the 'Beeson Career Development Award Program (National Institute on Aging K08AG048321, AFAR, The John A. Hartford Foundation, and The Atlantic Philanthropies). NR 42 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD DEC PY 2016 VL 64 IS 12 BP 2546 EP 2553 DI 10.1111/jgs.14379 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EK0AR UT WOS:000393589200036 PM 27879984 ER PT J AU Sheehan, OC Ritchie, CS Fathi, R Garrigues, SK Saliba, D Leff, B AF Sheehan, Orla C. Ritchie, Christine S. Fathi, Roya Garrigues, Sarah K. Saliba, Debra Leff, Bruce TI Development of Quality Indicators to Address Abuse and Neglect in Home-Based Primary Care and Palliative Care SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE abuse; neglect; quality indicators; home-based primary care; home-based palliative care ID ELDER ABUSE; REPORTING MISTREATMENT; PHYSICIANS; SET; STANDARDS AB OBJECTIVES: To develop candidate quality indicators (QIs) for the quality standard of "addressing abuse and neglect" in the setting of home-based medical care. DESIGN: Systematic literature review of both the peer-reviewed and gray literature. SETTING: Home-based primary and palliative care practices. PARTICIPANTS: Homebound community-dwelling older adults. MEASUREMENTS: Articles were identified to inform the development of candidate indicators of the quality by which home-based primary and palliative care practices addressed abuse and neglect. The literature guided the development of patient-level QIs and practice-level quality standards. A technical expert panel (TEP) representing exemplary home-based primary care and palliative care providers then participated in a modified Delphi process to assess the validity and feasibility of each measure and identify candidate QIs suitable for testing in the field. RESULTS: The literature review yielded 4,371 titles and abstracts that were reviewed; 25 publications met final inclusion criteria and informed development of nine candidate QIs. The TEP rated all but one of the nine candidate indicators as having high validity and feasibility. CONCLUSION: Translating the complex problem of addressing abuse and neglect into QIs may ultimately serve to improve care delivered to vulnerable home-limited adults who receive home-based medical care. C1 [Sheehan, Orla C.] Johns Hopkins Univ, Sch Med, Ctr Aging & Hlth, Div Geriatr Med & Gerontol, Baltimore, MD USA. [Ritchie, Christine S.; Fathi, Roya; Garrigues, Sarah K.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. [Fathi, Roya] San Francisco VA Med Ctr, Vet Affairs Qual Scholars Fellowship Program, San Francisco, CA USA. [Saliba, Debra] Univ Calif Los Angeles, Los Angeles, CA USA. [Saliba, Debra] Jewish Home Borun Ctr, Los Angeles, CA USA. [Saliba, Debra] Vet Affairs Geriatr Res, Los Angeles, CA USA. [Leff, Bruce] Johns Hopkins Univ, Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD USA. [Leff, Bruce] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. [Leff, Bruce] Johns Hopkins Univ, Sch Nursing, Dept Community & Publ Hlth, Baltimore, MD USA. RP Sheehan, OC (reprint author), Johns Hopkins Univ, Dept Med, Div Geriatr Med & Gerontol, Ctr Aging & Hlth, Baltimore, MD 21205 USA. EM osheeha1@jhmi.edu FU Commonwealth Fund FX This work was supported by the Commonwealth Fund. NR 45 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD DEC PY 2016 VL 64 IS 12 BP 2577 EP 2584 DI 10.1111/jgs.14365 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EK0AR UT WOS:000393589200041 PM 27787878 ER PT J AU Levy, C Whitfield, EA AF Levy, Cari Whitfield, Emily A. TI Medical Foster Homes: Can the Adult Foster Care Model Substitute for Nursing Home Care? SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE adult foster care; veteran; nursing home ID LONG-TERM-CARE; OF-LIFE ISSUES; DECISION-MAKING; RESIDENTS; DEMENTIA; VETERANS; PROGRAM; HEALTH; IMPACT; END AB OBJECTIVE: To compare characteristics, healthcare use, and costs of care of veterans in the rapidly expanding Veterans Health Administration (VHA) medical foster home (MFH) with those of three other VHA long-term care (LTC) programs. DESIGN: Descriptive, unmatched study. SETTING: VHA MFHs, home-based primary care (HBPC), community living centers (CLCs), and community nursing homes (CNHs). PARTICIPANTS: Veterans newly enrolled in one of the four LTC settings in calendar years 2010 or 2011. MEASUREMENTS: Using VA and Medicare data from fiscal years 2010 and 2011, demographic characteristics, healthcare use, and costs of 388 veterans in MFHs were compared with 26,037 of those in HBPC, 5,355 in CLCs, and 5,517 in CNHs in the year before and the year after enrollment. RESULTS: Veterans enrolled in the MFH program were more likely to be unmarried than those in other LTC programs and had higher levels of comorbidity and frailty than veterans receiving HBPC but had similar levels of comorbidity, frailty, and healthcare use as those in CLCs and CNHs. MFH veterans incurred lower costs than those in CNHs and CLCs. CONCLUSION: MFHs served a distinct subset of veterans with levels of comorbidity and frailty similar to those of veterans cared for in CLCs and CNHs at costs that were comparable to or lower than those of the VHA. Propensity-matched comparisons will be necessary to confirm these findings. C1 [Levy, Cari; Whitfield, Emily A.] Denver Vet Affairs Med Ctr, Denver Seattle Ctr Innovat, Denver, CO USA. [Levy, Cari] Univ Colorado, Sch Med, Div Hlth Care Policy & Res, Aurora, CO USA. RP Levy, C (reprint author), Denver VA Med Ctr, 1055 Clermont St, Denver, CO 80220 USA. EM cari.levy@va.gov FU VHA HSRD FX VHA HSR&D provided funding for this study only. NR 43 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD DEC PY 2016 VL 64 IS 12 BP 2585 EP 2592 DI 10.1111/jgs.14517 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EK0AR UT WOS:000393589200042 PM 27739060 ER PT J AU Fung, CH Vitiello, MV Alessi, CA Kuchel, GA AF Fung, Constance H. Vitiello, Michael V. Alessi, Cathy A. Kuchel, George A. CA AGS NIA Sleep Conference Planning TI Report and Research Agenda of the American Geriatrics Society and National Institute on Aging Bedside-to-Bench Conference on Sleep, Circadian Rhythms, and Aging: New Avenues for Improving Brain Health, Physical Health, and Functioning SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE aging; circadian; disorders; interventions; sleep ID EXCESSIVE DAYTIME SLEEPINESS; NURSING-HOME RESIDENTS; CONTROLLED COMPARATIVE EFFICACY; COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; POSITIVE AIRWAY PRESSURE; ALL-CAUSE MORTALITY; OLDER-ADULTS; RISK-FACTORS; FOLLOW-UP AB The American Geriatrics Society, with support from the National Institute on Aging and other funders, held its eighth Bedside-to-Bench research conference, entitled "Sleep, Circadian Rhythms, and Aging: New Avenues for Improving Brain Health, Physical Health and Functioning," October 4 to 6, 2015, in Bethesda, Maryland. Part of a conference series addressing three common geriatric syndromes-delirium, sleep and circadian rhythm (SCR) disturbance, and voiding dysfunction-the series highlighted relationships and pertinent clinical and pathophysiological commonalities between these three geriatric syndromes. The conference provided a forum for discussing current sleep, circadian rhythm, and aging research; identifying gaps in knowledge; and developing a research agenda to inform future investigative efforts. The conference also promoted networking among developing researchers, leaders in the field of SCR and aging, and National Institutes of Health program personnel. C1 [Fung, Constance H.; Alessi, Cathy A.] Vet Affairs Greater Los Angeles Healthcare Syst, Geriatr Res Educ & Clin Ctr, Los Angeles, CA USA. [Fung, Constance H.; Alessi, Cathy A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Vitiello, Michael V.] Univ Washington, Psychiat & Behav Sci, Seattle, WA 98195 USA. [Kuchel, George A.] Univ Connecticut, Ctr Hlth, Ctr Aging, Farmington, CT USA. RP Fung, CH (reprint author), Care of Mikhailovich A, Amer Geriatr Soc, Special Projects, 40 Fulton St,18th Floor, New York, NY 10038 USA. RI Irwin, Michael/H-4870-2013; OI Irwin, Michael/0000-0002-1502-8431; Irwin, Michael/0000-0001-5801-274X FU NIA, NIH [K23AG045937]; Beeson Career Development in Aging Research Award Program - NIA; Beeson Career Development in Aging Research Award Program - AFAR; Beeson Career Development in Aging Research Award Program - John A. Hartford Foundation; Beeson Career Development in Aging Research Award Program - Atlantic Philanthropies; NIA [NIA 5U13AG0-39151-02]; American Academy of Sleep Medicine; Pfizer; Philips Respironics FX Constance H. Fung has grant funding supported by the NIA, NIH (K23AG045937) and The Beeson Career Development in Aging Research Award Program (supported by NIA, AFAR, John A. Hartford Foundation, Atlantic Philanthropies). The grant focuses on one of the research aims proposed in the paper, "What are the optimal methods of developing and implementing an individualized approach to sleep/CR treatment, accounting for personal preferences and physiological differences in risk factor profiles among individuals?" She has received an honorarium to serve as a National Sleep Foundation expert panel on sleep quality, including sleep quality in older adults.; The NIA funded this conference (NIA 5U13AG0-39151-02). Additional funding for the conference was provided by the American Academy of Sleep Medicine, Pfizer, and Philips Respironics. We thank Marie A. Bernard, PhD, Basil Eldadah, MD, PhD, Nancy Lundebjerg, MPA, Miroslaw Mackiewicz, PhD, and all conference participants. We appreciate the excellent administrative support provided by Anna Mikhailovich and Alanna Goldstein, MPH, and the detailed program evaluation provided by Julie Robison, PhD. NR 142 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD DEC PY 2016 VL 64 IS 12 BP E238 EP E247 DI 10.1111/jgs.14493 PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EK0AR UT WOS:000393589200001 PM 27858974 ER PT J AU Odden, MC Wu, CK Shlipak, MG Psaty, BM Katz, R Applegate, WB Harris, T Newman, AB Peralta, CA AF Odden, Michelle C. Wu, Chenkai Shlipak, Michael G. Psaty, Bruce M. Katz, Ronit Applegate, William B. Harris, Tamara Newman, Anne B. Peralta, Carmen A. CA Hlth ABC Study TI Blood Pressure Trajectory, Gait Speed, and Outcomes: The Health, Aging, and Body Composition Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Blood pressure; Epidemiology; Function; Gait speed; Hypertension ID OLDER-ADULTS; LEIDEN 85-PLUS; ASSOCIATION; MORTALITY; FRAILTY AB Background: The present study aimed to (i) evaluate previous observations that the association of blood pressure (BP) with outcomes varies by gait speed and (ii) evaluate the association of subsequent changes in BP and cardiovascular risk. Methods: Participants included 2,669 adults aged 70-79 years in the Health, Aging, and Body Composition (Health ABC) study. Gait speed was dichotomized at >= 1.0 m/s over a 20-m test at baseline. BP was measured at baseline, and changes in BP over 5 years were evaluated using (i) population-based trajectory models and (ii) intraindividual mean and slope. Results: Over a mean of 10 years, there were 1,366 deaths, 336 first myocardial infarctions, and 295 first strokes. There was a differential pattern of association between baseline systolic BP and diastolic BP and outcomes among brisk and moderate speed walkers. For example, the association between higher diastolic BP and mortality was in the protective direction for moderate speed walkers (hazard ratio = 0.75; 95% confidence interval: 0.63, 0.91) per 10 mmHg higher, whereas it was null in brisk walkers (hazard ratio = 1.05; 95% confidence interval: 0.98, 1.11), p value for interaction.01. The 5-year population-based trajectories did not add important information beyond baseline BP. Individual slopes in both systolic BP and diastolic BP did not appear to have important associations with the outcomes. Conclusions: In this study, we found that the overall level of BP was associated with myocardial infarction, stroke, and death, and this association differed by baseline gait speed, whereas changes in BP were not associated with these outcomes. C1 [Odden, Michelle C.; Wu, Chenkai] Oregon State Univ, Sch Biol & Populat Hlth Sci, 141B Milam Hall, Corvallis, OR 97331 USA. [Shlipak, Michael G.; Peralta, Carmen A.] Univ Calif San Francisco, Dept Med, Kidney Hlth Res Collaborat, San Francisco, CA USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Shlipak, Michael G.; Peralta, Carmen A.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Sci, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Katz, Ronit] Univ Washington, Dept Med, Kidney Res Inst, Seattle, WA USA. [Applegate, William B.] Wake Forest Univ, Baptist Med Ctr, Internal Med & Geriatr Med, Winston Salem, NC 27109 USA. [Harris, Tamara] NIA, Geriatr Epidemiol Sect, Bethesda, MD 20892 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. RP Odden, MC (reprint author), Oregon State Univ, Sch Biol & Populat Hlth Sci, 141B Milam Hall, Corvallis, OR 97331 USA. EM Michelle.Odden@oregonstate.edu FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, K01AG039387, R01AG46206]; NINR [R01-NR012459]; Intramural Research Program of the NIH, NIA FX The Health ABC study was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050; and NINR grant R01-NR012459, and in part by the Intramural Research Program of the NIH, NIA. Additional support for this research was provided by NIA (K01AG039387, R01AG46206). NR 15 TC 2 Z9 2 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD DEC PY 2016 VL 71 IS 12 BP 1688 EP 1694 DI 10.1093/gerona/glw076 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EL2JW UT WOS:000394446900023 PM 27142696 ER PT J AU Odden, MC Wu, CK Shlipak, MG Psaty, BM Katz, R Applegate, WB Harris, T Newman, AB Peralta, CA AF Odden, Michelle C. Wu, Chenkai Shlipak, Michael G. Psaty, Bruce M. Katz, Ronit Applegate, William B. Harris, Tamara Newman, Anne B. Peralta, Carmen A. CA Hlth ABC Study TI Blood Pressure Trajectory, Gait Speed, and Outcomes: The Health, Aging, and Body Composition Study (vol 71, pg 1688, 2016) SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Correction C1 [Odden, Michelle C.; Wu, Chenkai] Oregon State Univ, Sch Biol & Populat Hlth Sci, 141B Milam Hall, Corvallis, OR 97331 USA. [Shlipak, Michael G.; Peralta, Carmen A.] Univ Calif San Francisco, Dept Med, Kidney Hlth Res Collaborat, San Francisco, CA USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Shlipak, Michael G.; Peralta, Carmen A.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Katz, Ronit] Univ Washington, Dept Med, Kidney Res Inst, Seattle, WA USA. [Applegate, William B.] Wake Forest Univ, Baptist Med Ctr, Internal Med & Geriatr Med, Winston Salem, NC 27109 USA. [Harris, Tamara] NIA, Geriatr Epidemiol Sect, Bethesda, MD 20892 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. RP Odden, MC (reprint author), Oregon State Univ, Sch Biol & Populat Hlth Sci, 141B Milam Hall, Corvallis, OR 97331 USA. EM Michelle.Odden@oregonstate.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD DEC PY 2016 VL 71 IS 12 BP E1 EP E1 DI 10.1093/gerona/glw230 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EL2JW UT WOS:000394446900001 PM 27838648 ER PT J AU Pacor, JM Younus, A Malik, R Osondu, CU Aziz, M Ogunmoroti, O Younus, MA Aneni, EC Spatz, ES Humayun, C Virani, S Blaha, M Nasir, K AF Pacor, Justin M. Younus, Adnan Malik, Rehan Osondu, Chukwuemeka U. Aziz, Muhammad Ogunmoroti, Oluseye Younus, Muhammad Amir Aneni, Ehimen C. Spatz, Erica S. Humayun, Choudhry Virani, Salim Blaha, Michael Nasir, Khurram TI Prevalence of ideal cardiovascular health metrics in children & adolescents: A systematic review SO PROGRESS IN PEDIATRIC CARDIOLOGY LA English DT Review ID AMERICAN-HEART-ASSOCIATION; NATIONAL-HEALTH; YOUNG FINNS; DISEASE; RISK; CHILDHOOD; AGE AB Background: Although the prevalence of ideal cardiovascular health (CVH) has been extensively studied, its distribution in younger populations is not well established. In this systematic review we aggregated available evidence to examine prevalence of ideal CVH metrics in the adolescent and children population. Methods: A MEDLINE database search was conducted for studies published between January 2010 and July 2015. To be included in the study, studies had to report prevalence data on at least four of the seven metrics. Each study was meticulously reviewed by two independent reviewers, and studies with prevalence percentages across different percentiles were included. Results: Overall 6 studies met the inclusion and exclusion criteria. BMI and diet were the only metrics for which all 6 studies reported prevalence of ideal. Prevalence of ideal for fasting plasma glucose was reported least frequently, with 2 of the studies failing to assess it. A prevalence of >50% for ideal blood pressure or BMI was seen uniformly across all studies included in the review. By contrast, the healthy diet has the lowest prevalence among ideal CVH metrics ranging from 0 to 10%. Physical activity was the most variable with a range of 6.2-85.4%. Conclusion: Ideal diet and physical activity had the lowest prevalence among CVH metrics. Focused efforts on standardizing assessment of these metrics as well delineating strategies to achieve ideal CVH among children and adolescents are required. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Pacor, Justin M.; Younus, Adnan; Malik, Rehan; Osondu, Chukwuemeka U.; Aziz, Muhammad; Ogunmoroti, Oluseye; Younus, Muhammad Amir; Aneni, Ehimen C.; Humayun, Choudhry; Nasir, Khurram] Baptist Hlth South Florida, Ctr Healthcare Adv & Outcomes, Miami, FL USA. [Pacor, Justin M.] Marshall Univ, Joan C Edwards Sch Med, Huntington, WV USA. [Aneni, Ehimen C.] Mt Sinai Med Ctr, Dept Internal Med, Miami, FL USA. [Spatz, Erica S.] Yale New Haven Med Ctr, Ctr Outcomes Res & Evaluat, 20 York St, New Haven, CT 06504 USA. [Virani, Salim] Baylor Coll Med, Dept Med, Sect Cardiovasc Res, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Blaha, Michael; Nasir, Khurram] Johns Hopkins Univ Hosp, Ciccarone Prevent Cardiol Ctr, Baltimore, MD 21287 USA. [Nasir, Khurram] Florida Int Univ, Robert Stempel Coll Publ Hlth, Dept Epidemiol, Miami, FL 33199 USA. [Nasir, Khurram] Florida Int Univ, Herbert Wertheim Coll Med, Dept Med, Miami, FL 33199 USA. RP Nasir, K (reprint author), Baptist Hlth South Florida, Ctr Healthcare Adv & Outcomes, 1691 Michigan Ave Suite 500, Miami Beach, FL 33139 USA. EM KhurramN@baptisthealth.net OI Younus, Adnan/0000-0002-4915-1139 NR 14 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1058-9813 EI 1558-1519 J9 PROG PEDIATR CARDIOL JI Prog. Pediatr. Cardiol. PD DEC PY 2016 VL 43 BP 141 EP 146 DI 10.1016/j.ppedcard.2016.09.002 PG 6 WC Cardiac & Cardiovascular Systems; Pediatrics SC Cardiovascular System & Cardiology; Pediatrics GA EL5QU UT WOS:000394676700023 ER PT J AU Raposeiras-Roubin, S Triant, V AF Raposeiras-Roubin, Sergio Triant, Virginia TI Ischemic Heart Disease in HIV: An In-depth Look at Cardiovascular Risk SO REVISTA ESPANOLA DE CARDIOLOGIA LA English DT Review DE HIV; Cardiovascular disease; Myocardial infarction ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACUTE MYOCARDIAL-INFARCTION; INFECTED PATIENTS; ANTIRETROVIRAL THERAPY; DAD; COLLABORATION; INDIVIDUALS; ASSOCIATION; MORTALITY; TRENDS AB Although the incidence of cardiovascular diseases classically associated with human immunodeficiency virus (HIV) has decreased considerably with antiretroviral therapy, cardiovascular risk, and especially ischemic heart disease, are higher in HIV-infected patients than in uninfected individuals. This is due to the interaction of patient-dependent factors with virus-dependent factors, as well as factors associated with antiretroviral therapy. With increasing of life expectancy and the chronicity of HIV infection, cardiovascular disease has emerged as an important cause of morbidity and mortality in HIV patients. In developed countries, the most common cardiovascular manifestation of HIV is ischemic heart disease. Currently, it is not uncommon to find HIV patients with acute coronary syndrome and, given the important pharmacokinetic interactions of antiretroviral drugs, it is important to know which cardiovascular treatments are safe in this group of patients. The ideal approach would be to mitigate the cardiovascular risk in HIV patients with specific primary prevention measures. All these issues are discussed in this review, which aims to aid clinical cardiologists faced with HIV patients with ischemic heart disease or with high cardiovascular risk in daily clinical practice. (C) 2016 Sociedad Espanola de Cardiologia. Published by Elsevier Espana, S.L.U. All rights reserved. C1 [Raposeiras-Roubin, Sergio] Hosp Univ Alvaro Cunqueiro, Serv Cardiol, Estr Clara Campoamor 341, Vigo 36312, Pontevedra, Spain. [Triant, Virginia] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Triant, Virginia] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Triant, Virginia] Harvard Med Sch, Boston, MA USA. RP Raposeiras-Roubin, S (reprint author), Hosp Univ Alvaro Cunqueiro, Serv Cardiol, Estr Clara Campoamor 341, Vigo 36312, Pontevedra, Spain. EM raposeiras26@hotmail.com NR 40 TC 0 Z9 0 U1 0 U2 0 PU EDICIONES DOYMA S A PI BARCELONA PA TRAV DE GRACIA 17-21, 08021 BARCELONA, SPAIN SN 0300-8932 EI 1579-2242 J9 REV ESP CARDIOL JI Rev. Esp. Cardiol. PD DEC PY 2016 VL 69 IS 12 BP 1204 EP 1213 DI 10.1016/j.rec.2016.10.005 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ4SY UT WOS:000393208400012 PM 27840147 ER PT J AU Coghlan, G Gaine, S Channick, R Di Scala, L Galie, N Ghofrani, HA Hoeper, MM Lang, I McLaughlin, V Preiss, R Rubin, LJ Simonneau, G Sitbon, O Tapson, VF Chin, K AF Coghlan, G. Gaine, S. Channick, R. Di Scala, L. Galie, N. Ghofrani, H. A. Hoeper, M. M. Lang, I. McLaughlin, V. Preiss, R. Rubin, L. J. Simonneau, G. Sitbon, O. Tapson, V. F. Chin, K. TI TARGETING THE PROSTACYCLIN PATHWAY IN THE TREATMENT OF CONNECTIVE TISSUE DISEASE ASSOCIATED PULMONARY ARTERIAL HYPERTENSION (PAH): INSIGHTS FROM THE RANDOMISED CONTROLLED GRIPHON TRIAL WITH SELEXIPAG SO THORAX LA English DT Meeting Abstract C1 [Coghlan, G.] Natl Hlth Serv Fdn Trust, Royal Free Hosp, Natl Pulm Hypertens Serv, London, England. [Gaine, S.] Mater Misericordiae Univ Hosp, Natl Pulm Hypertens Unit, Dublin, Ireland. [Channick, R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Di Scala, L.; Preiss, R.] Actel Pharmaceut Ltd, Allschwil, Switzerland. [Galie, N.] Univ Bologna, Ist Malattie Apparato Cardiovasc, Bologna, Italy. [Ghofrani, H. A.] German Ctr Lung Res DZL, UGMLC, Giessen, Germany. [Ghofrani, H. A.] Imperial Coll London, Dept Med, London, England. [Hoeper, M. M.] Hannover Med Sch, Dept Resp Med, Hannover, Germany. [Hoeper, M. M.] German Ctr Lung Res, Hannover, Germany. [Lang, I.] Med Univ Vienna, Div Cardiol, Dept Internal Med 2, Allgemeines Krankenhaus, Vienna, Austria. [McLaughlin, V.] Univ Michigan Hlth Syst, Div Cardiovasc Med, Ann Arbor, MI USA. [Rubin, L. J.] Univ Calif San Diego, Div Pulm & Crit Care Med, San Diego, CA 92103 USA. [Simonneau, G.; Sitbon, O.] Univ Paris Sud, Hop Univ Bicetre, Le Kremlin Bicetre, France. [Tapson, V. F.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Chin, K.] UT Southwestern Med Ctr, Dallas, TX USA. NR 0 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 0040-6376 EI 1468-3296 J9 THORAX JI Thorax PD DEC PY 2016 VL 71 SU 3 MA S109 BP A65 EP A65 DI 10.1136/thoraxjnl-2016-209333.115 PG 1 WC Respiratory System SC Respiratory System GA EJ3SF UT WOS:000393131200112 ER PT J AU Farahani, K Kalpathy-Cramer, J Chenevert, TL Rubin, DL Sunderland, JJ Nordstrom, RJ Buatti, J Hylton, N AF Farahani, Keyvan Kalpathy-Cramer, Jayashree Chenevert, Thomas L. Rubin, Daniel L. Sunderland, John J. Nordstrom, Robert J. Buatti, John Hylton, Nola TI Computational Challenges and Collaborative Projects in the NCI Quantitative Imaging Network SO TOMOGRAPHY LA English DT Article DE quantitative imaging; cancer therapy; crowdsourcing; challenge; collaborative project AB The Quantitative Imaging Network (QIN) of the National Cancer Institute (NCI) conducts research in development and validation of imaging tools and methods for predicting and evaluating clinical response to cancer therapy. Members of the network are involved in examining various imaging and image assessment parameters through network-wide cooperative projects. To more effectively use the cooperative power of the network in conducting computational challenges in benchmarking of tools and methods and collaborative projects in analytical assessment of imaging technologies, the QIN Challenge Task Force has developed policies and procedures to enhance the value of these activities by developing guidelines and leveraging NCI resources to help their administration and manage dissemination of results. Challenges and Collaborative Projects (CCPs) are further divided into technical and clinical CCPs. As the first NCI network to engage in CCPs, we anticipate a variety of CCPs to be conducted by QIN teams in the coming years. These will be aimed to benchmark advanced software tools for clinical decision support, explore new imaging biomarkers for therapeutic assessment, and establish consensus on a range of methods and protocols in support of the use of quantitative imaging to predict and assess response to cancer therapy. C1 [Farahani, Keyvan; Nordstrom, Robert J.] NCI, Canc Imaging Program, 9609 Med Ctr Dr,4W-312, Bethesda, MD 20892 USA. [Kalpathy-Cramer, Jayashree] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Chenevert, Thomas L.] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Rubin, Daniel L.] Stanford Univ, Dept Radiol Biomed Data Sci & Med Biomed Informat, Palo Alto, CA 94304 USA. [Sunderland, John J.] Univ Iowa, Dept Radiol, Iowa City, IA 52242 USA. [Buatti, John] Univ Iowa, Dept Radiat Oncol, Iowa City, IA USA. [Hylton, Nola] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. RP Farahani, K (reprint author), NCI, Canc Imaging Program, 9609 Med Ctr Dr,4W-312, Bethesda, MD 20892 USA. EM farahani@nih.gov FU National Cancer Institute, National Institutes of Health [U01CA142555, U01CA190214, U01CA187947, U01CA166104, U01CA140206, U01CA151235, U01CA154601] FX This work was supported, in part, by grants from the National Cancer Institute, National Institutes of Health, U01CA142555, U01CA190214, U01CA187947, U01CA166104, U01CA140206, U01CA151235, and U01CA154601. NR 17 TC 0 Z9 0 U1 0 U2 0 PU GRAPHO PUBLICATIONS PI ANN ARBOR PA PO BOX 131281, ANN ARBOR, MI 48112-1281 USA SN 2379-1381 J9 TOMOGRAPHY JI Tomography PD DEC PY 2016 VL 2 IS 4 BP 242 EP 249 DI 10.18383/j.tom.2016.00265 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EK4BG UT WOS:000393871500002 ER PT J AU Kurland, BF Aggarwal, S Yankeelov, TE Gerstner, ER Mountz, JM Linden, HM Jones, EF Bodeker, KL Buatti, JM AF Kurland, Brenda F. Aggarwal, Sameer Yankeelov, Thomas E. Gerstner, Elizabeth R. Mountz, James M. Linden, Hannah M. Jones, Ella F. Bodeker, Kellie L. Buatti, John M. TI Accrual Patterns for Clinical Studies Involving Quantitative Imaging: Results of an NCI Quantitative Imaging Network (QIN) Survey SO TOMOGRAPHY LA English DT Article DE clinical trial; MRI; PET; patient enrollment; accrual ID CANCER; TRIALS; PARTICIPATION; BARRIERS; PET/CT; TIME AB Patient accrual is essential for the success of oncology clinical trials. Recruitment for trials involving the development of quantitative imaging biomarkers may face different challenges than treatment trials. This study surveyed investigators and study personnel for evaluating accrual performance and perceived barriers to accrual and for soliciting solutions to these accrual challenges that are specific to quantitative imaging-based trials. Responses for 25 prospective studies were received from 12 sites. The median percent annual accrual attained was 94.5% (range, 3%-350%). The most commonly selected barrier to recruitment (n = 11/ 25, 44%) was that "patients decline participation, "followed by "too few eligible patients" (n = 10/ 25, 40%). In a forced choice for the single greatest recruitment challenge, "too few eligible patients" was the most common response (n = 8/ 25, 32%). Quantitative analysis and qualitative responses suggested that interactions among institutional, physician, and patient factors contributed to accrual success and challenges. Multidisciplinary collaboration in trial design and execution is essential to accrual success, with attention paid to ensuring and communicating potential trial benefits to enrolled and future patients. C1 [Kurland, Brenda F.] Univ Pittsburgh, Dept Biostat, Suite 325,Sterling Plaza,201 N Craig St, Pittsburgh, PA 15213 USA. [Mountz, James M.] Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15260 USA. [Aggarwal, Sameer] George Washington Univ, Dept Med, Washington, DC USA. [Yankeelov, Thomas E.] Univ Texas Austin, Inst Computat & Engn Sci, Austin, TX 78712 USA. [Yankeelov, Thomas E.] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. [Yankeelov, Thomas E.] Univ Texas Austin, Dept Internal Med, Austin, TX 78712 USA. [Yankeelov, Thomas E.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Gerstner, Elizabeth R.] Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15260 USA. [Linden, Hannah M.] Univ Washington, Div Med Oncol, Seattle, WA 98195 USA. [Jones, Ella F.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Bodeker, Kellie L.; Buatti, John M.] Univ Iowa, Dept Radiat Oncol, Iowa City, IA USA. RP Kurland, BF (reprint author), Univ Pittsburgh, Dept Biostat, Suite 325,Sterling Plaza,201 N Craig St, Pittsburgh, PA 15213 USA. EM bfk10@pitt.edu FU National Institutes of Health Quantitative Imaging Network [U01-CA148131, CA140230, CA140206, CA142565, CA15460, CA151235]; [P30-CA047904]; [UL1TR000005] FX This work is supported by the National Institutes of Health Quantitative Imaging Network (U01-CA148131, CA140230, CA140206, CA142565, CA15460, and CA151235). It used the UPCI Biostatistics Shared Resource Facility that is supported in part by award P30-CA047904, and the REDCap installation that is supported by UL1TR000005. The authors are grateful to both study and survey participants, and to Robert Nordstrom, Pushpa Tandon, Lori Henderson, and Bhadrasain Vikram for helpful discussions. NR 20 TC 0 Z9 0 U1 0 U2 0 PU GRAPHO PUBLICATIONS PI ANN ARBOR PA PO BOX 131281, ANN ARBOR, MI 48112-1281 USA SN 2379-1381 J9 TOMOGRAPHY JI Tomography PD DEC PY 2016 VL 2 IS 4 BP 276 EP 282 DI 10.18383/j.tom.2016.00169 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EK4BG UT WOS:000393871500006 PM 28127586 ER PT J AU Malyarenko, DI Wilmes, LJ Arlinghaus, LR Jacobs, MA Huang, W Helmer, KG Taouli, B Yankeelov, TE Newitt, D Chenevert, TL AF Malyarenko, Dariya I. Wilmes, Lisa J. Arlinghaus, Lori R. Jacobs, Michael A. Huang, Wei Helmer, Karl G. Taouli, Bachir Yankeelov, Thomas E. Newitt, David Chenevert, Thomas L. TI QIN DAWG Validation of Gradient Nonlinearity Bias Correction Workflow for Quantitative Diffusion-Weighted Imaging in Multicenter Trials SO TOMOGRAPHY LA English DT Article DE nonuniform diffusion weighting; gradient nonlinearity bias; correction validation ID ICE-WATER PHANTOM; PROSTATE-CANCER; COEFFICIENT; MRI; REPEATABILITY; CELLULARITY; DISTORTIONS; ONCOLOGY; VALUES; ECHO AB Previous research has shown that system-dependent gradient nonlinearity (GNL) introduces a significant spatial bias (nonuniformity) in apparent diffusion coefficient (ADC) maps. Here, the feasibility of centralized retrospective system-specific correction of GNL bias for quantitative diffusion-weighted imaging (DWI) in multisite clinical trials is demonstrated across diverse scanners independent of the scanned object. Using corrector maps generated from system characterization by ice-water phantom measurement completed in the previous project phase, GNL bias correction was performed for test ADC measurements from an independent DWI phantom (room temperature agar) at two offset locations in the bore. The precomputed three-dimensional GNL correctors were retrospectively applied to test DWI scans by the central analysis site. The correction was blinded to reference DWI of the agar phantom at magnet isocenter where the GNL bias is negligible. The performance was evaluated from changes in ADC region of interest histogram statistics before and after correction with respect to the unbiased reference ADC values provided by sites. Both absolute error and nonuniformity of the ADC map induced by GNL (median, 12%; range, - 35% to + 10%) were substantially reduced by correction (7-fold in median and 3-fold in range). The residual ADC nonuniformity errors were attributed to measurement noise and other non-GNL sources. Correction of systematic GNL bias resulted in a 2-fold decrease in technical variability across scanners (down to site temperature range). The described validation of GNL bias correction marks progress toward implementation of this technology in multicenter trials that utilize quantitative DWI. C1 [Malyarenko, Dariya I.; Chenevert, Thomas L.] Univ Michigan, Dept Radiol, 1500 E Med Ctr, Ann Arbor, MI 48109 USA. [Wilmes, Lisa J.; Newitt, David] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Arlinghaus, Lori R.] Vanderbilt Univ, Med Ctr, Inst Imaging Sci, Nashville, TN USA. [Jacobs, Michael A.] Johns Hopkins Univ, Sch Med, Russel H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. [Huang, Wei] Oregon Hlth & Sci Univ, Adv Imaging Res Ctr, Portland, OR 97201 USA. [Helmer, Karl G.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Taouli, Bachir] Icahn Sch Med Mt Sinai, Translat & Mol Imaging Inst, New York, NY 10029 USA. [Yankeelov, Thomas E.] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. RP Malyarenko, DI (reprint author), Univ Michigan, Dept Radiol, 1500 E Med Ctr, Ann Arbor, MI 48109 USA. EM dariya@umich.edu FU National Institutes of Health [U01CA166104, U01CA151235, U01CA154602, U01CA154601, U01CA140204, U01CA142565, U01CA172320, R01CA190299] FX This research was supported by National Institutes of Health Grants: U01CA166104, U01CA151235, U01CA154602, U01CA154601, U01CA140204, U01CA142565, U01CA172320, and R01CA190299. NR 24 TC 0 Z9 0 U1 0 U2 0 PU GRAPHO PUBLICATIONS PI ANN ARBOR PA PO BOX 131281, ANN ARBOR, MI 48112-1281 USA SN 2379-1381 J9 TOMOGRAPHY JI Tomography PD DEC PY 2016 VL 2 IS 4 BP 396 EP 405 DI 10.18383/j.tom.2016.00214 PG 10 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EK4BG UT WOS:000393871500020 PM 28105469 ER PT J AU Kalpathy-Cramer, J Mamomov, A Zhao, BS Lu, L Cherezov, D Napel, S Echegaray, S Rubin, D McNitt-Gray, M Lo, P Sieren, JC Uthoff, J Dilger, SKN Driscoll, B Yeung, I Hadjiiski, L Cha, K Balagurunathan, Y Gillies, R Goldgof, D AF Kalpathy-Cramer, Jayashree Mamomov, Artem Zhao, Binsheng Lu, Lin Cherezov, Dmitry Napel, Sandy Echegaray, Sebastian Rubin, Daniel McNitt-Gray, Michael Lo, Pechin Sieren, Jessica C. Uthoff, Johanna Dilger, Samantha K. N. Driscoll, Brandan Yeung, Ivan Hadjiiski, Lubomir Cha, Kenny Balagurunathan, Yoganand Gillies, Robert Goldgof, Dmitry TI Radiomics of Lung Nodules: A Multi-Institutional Study of Robustness and Agreement of Quantitative Imaging Features SO TOMOGRAPHY LA English DT Article DE radiomics; reproducibility; imaging features; lung cancer ID COMPUTER-AIDED DIAGNOSIS; CT SCANS; PULMONARY NODULES; REPRODUCIBILITY; SEGMENTATION; RESOURCE; DATABASE; IMAGES AB Radiomics is to provide quantitative descriptors of normal and abnormal tissues during classification and prediction tasks in radiology and oncology. Quantitative Imaging Network members are developing radiomic "feature" sets to characterize tumors, in general, the size, shape, texture, intensity, margin, and other aspects of the imaging features of nodules and lesions. Efforts are ongoing for developing an ontology to describe radiomic features for lung nodules, with the main classes consisting of size, local and global shape descriptors, margin, intensity, and texture-based features, which are based on wavelets, Laplacian of Gaussians, Law's features, gray-level cooccurrence matrices, and run-length features. The purpose of this study is to investigate the sensitivity of quantitative descriptors of pulmonary nodules to segmentations and to illustrate comparisons across different feature types and features computed by different implementations of feature extraction algorithms. We calculated the concordance correlation coefficients of the features as a measure of their stability with the underlying segmentation; 68% of the 830 features in this study had a concordance CC of >= 0.75. Pairwise correlation coefficients between pairs of features were used to uncover associations between features, particularly as measured by different participants. A graphical model approach was used to enumerate the number of uncorrelated feature groups at given thresholds of correlation. At a threshold of 0.75 and 0.95, there were 75 and 246 subgroups, respectively, providing a measure for the features' redundancy. C1 [Kalpathy-Cramer, Jayashree; Mamomov, Artem] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Zhao, Binsheng; Lu, Lin] Columbia Univ, Med Ctr, New York, NY USA. [Cherezov, Dmitry; Goldgof, Dmitry] Univ S Florida, Tampa, FL USA. [Napel, Sandy; Echegaray, Sebastian; Rubin, Daniel] Stanford Univ, Stanford, CA 94305 USA. [McNitt-Gray, Michael; Lo, Pechin] Univ Calif Los Angeles, Los Angeles, CA USA. [Sieren, Jessica C.; Uthoff, Johanna; Dilger, Samantha K. N.] Univ Iowa, Iowa City, IA USA. [Driscoll, Brandan; Yeung, Ivan] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Hadjiiski, Lubomir; Cha, Kenny] Univ Michigan, Ann Arbor, MI 48109 USA. [Balagurunathan, Yoganand; Gillies, Robert] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. RP Kalpathy-Cramer, J (reprint author), Massachusetts Gen Hosp, 149 13th St, Charlestown, MA 02129 USA. EM kalpathy@nmr.mgh.harvard.edu FU NIH/NCI [U24CA180927, U24CA180918, U01CA154601, R01 CA149490, U01 CA140207, U01 CA181156, R01 CA160251, U01 CA187947, U01CA179106, 1U01 CA 143062-01, U24180927]; NIH/NHLBI [R01HL112986]; NIH [R01 CA93517]; Canadian Institute of Health Research; State of Florida James & Esther King Biomedical Research Program [2KT01] FX J.K.C. and A.M. were supported, in part, through funding from NIH/NCI (U24CA180927, U24CA180918, and U01CA154601); B.Z. and L.L. were supported, in part, through funding from NIH/NCI (U24CA180927, R01 CA149490, and U01 CA140207); M.M.G and P.L. were supported, in part, through funding from NIH/NCI (U01 CA181156); S.N. and S.E. were supported, in part, through funding from NIH/NCI (R01 CA160251 and U01 CA187947); J.C.S. and S.K.N.D. were supported, in part, through funding from NIH/NHLBI (R01HL112986); L.H. and K.C. were supported, in part, by NIH/NCI (U01CA179106). A large part of the general Michigan feature extraction pipeline was developed under the support of NIH award number R01 CA93517 (PI: Heang-Ping Chan). The authors would also like to acknowledge Dr. Heang-Ping Chan for her substantial contribution to the Michigan team in the QIN Feature challenge. The work of PMCC was partially supported by the Canadian Institute of Health Research. D.C., D.G., Y.B., and RG were supported, in part, through funding from NIH/NCI (1U01 CA 143062-01 and U24180927) and State of Florida James & Esther King Biomedical Research Program (2KT01). NR 21 TC 0 Z9 0 U1 2 U2 2 PU GRAPHO PUBLICATIONS PI ANN ARBOR PA PO BOX 131281, ANN ARBOR, MI 48112-1281 USA SN 2379-1381 J9 TOMOGRAPHY JI Tomography PD DEC PY 2016 VL 2 IS 4 BP 430 EP 437 DI 10.18383/j.tom.2016.00235 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EK4BG UT WOS:000393871500024 PM 28149958 ER PT J AU Gokbuget, N Dombret, H Ribera, JM Fielding, AK Advani, A Bassan, R Chia, V Doubek, M Giebel, S Hoelzer, D Ifrah, N Katz, A Kelsh, M Martinelli, G Morgades, M O'Brien, S Rowe, JM Stieglmaier, J Wadleigh, M Kantarjian, H AF Goekbuget, Nicola Dombret, Herve Ribera, Jose-Maria Fielding, Adele K. Advani, Anjali Bassan, Renato Chia, Victoria Doubek, Michael Giebel, Sebastian Hoelzer, Dieter Ifrah, Norbert Katz, Aaron Kelsh, Michael Martinelli, Giovanni Morgades, Mireia O'Brien, Susan Rowe, Jacob M. Stieglmaier, Julia Wadleigh, Martha Kantarjian, Hagop TI International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia SO HAEMATOLOGICA LA English DT Article ID ACUTE LYMPHOCYTIC-LEUKEMIA; SALVAGE THERAPY; PHASE-II; RELAPSE; REMISSIONS; BLINATUMOMAB; PROGNOSIS; TRIAL AB Adults with relapsed/refractory acute lymphoblastic leukemia have an unfavourable prognosis, which is influenced by disease and patient characteristics. To further evaluate these characteristics, a retrospective analysis of 1,706 adult patients with Ph-negative relapsed/refractory B-precursor acute lymphoblastic leukemia diagnosed between 1990-2013 was conducted using data reflecting the standard of care from 11 study groups and large centers in Europe and the United States. Outcomes included complete remission, overall survival, and realization of stem cell transplantation after salvage treatment. The overall complete remission rate after first salvage was 40%, ranging from 35%-41% across disease status categories (primary refractory, relapsed with or without prior transplant), and was lower after second (21%) and third or greater (11%) salvage. The overall complete remission rate was higher for patients diagnosed from 2005 onward (45%, 95% CI: 39%-50%). One-and three-year survival rates after first, second, and third or greater salvage were 26% and 11%, 18% and 6%, and 15% and 4%, respectively, and rates were 2%-5% higher among patients diagnosed from 2005. Prognostic factors included younger age, longer duration of first remission, and lower white blood cell counts at primary diagnosis. This large dataset can provide detailed reference outcomes for patients with relapsed/refractory Ph-negative B-precursor acute lymphoblastic leukemia. clinicaltrials.gov identifier: 02003612 C1 [Goekbuget, Nicola; Hoelzer, Dieter] Goethe Univ, Univ Hosp, Frankfurt, Germany. [Dombret, Herve] Hop St Louis, Paris, France. [Ribera, Jose-Maria; Morgades, Mireia] Hosp Badalona Germans Trias & Pujol, ICO, Jose Carreras Res Inst, Barcelona, Spain. [Fielding, Adele K.] UCL, Inst Canc, London, England. [Advani, Anjali] Cleveland Clin, Cleveland, OH 44106 USA. [Bassan, Renato] Osped Angelo, UOC Ematol, Mestre Venezia, Italy. [Chia, Victoria; Katz, Aaron; Kelsh, Michael] Amgen Inc, Ctr Observat Res, Thousand Oaks, CA USA. [Doubek, Michael] Univ Hosp, Brno, Czech Republic. [Giebel, Sebastian] Maria Sklodowska Curie Mem Canc Ctr, Gliwice, Poland. [Giebel, Sebastian] Inst Oncol, Gliwice, Poland. [Ifrah, Norbert] Ctr Hosp Univ, Angers, France. [Martinelli, Giovanni] Ist Seragnoli, Policlin St Orsola, Bologna, Italy. [O'Brien, Susan; Kantarjian, Hagop] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Rowe, Jacob M.] Rambam Med Ctr, Haifa, Israel. [Stieglmaier, Julia] Amgen Inc, Clin Dev, Munich, Germany. [Wadleigh, Martha] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Gokbuget, N (reprint author), Goethe Univ, Univ Hosp, Frankfurt, Germany. EM goekbuget@em.uni-frankfurt.de FU Amgen FX The authors would like to thank James O'Kelly, an employee of Amgen, for providing medical writing assistance; and Sharon Dunn and Richard Bo, consultants paid by Amgen, who provided statistical programming support. NR 23 TC 3 Z9 3 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD DEC PY 2016 VL 101 IS 12 BP 1524 EP 1533 DI 10.3324/haematol.2016.144311 PG 10 WC Hematology SC Hematology GA EI6DE UT WOS:000392584400012 PM 27587380 ER PT J AU Long, GV Grob, JJ Nathan, P Ribas, A Robert, C Schadendorf, D Lane, SR Mak, C Legenne, P Flaherty, KT Davies, MA AF Long, Georgina V. Grob, Jean-Jacques Nathan, Paul Ribas, Antoni Robert, Caroline Schadendorf, Dirk Lane, Stephen R. Mak, Carmen Legenne, Philippe Flaherty, Keith T. Davies, Michael A. TI Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials SO LANCET ONCOLOGY LA English DT Article ID ADVANCED MELANOMA; METASTATIC MELANOMA; UNTREATED MELANOMA; BRAF INHIBITION; NRAS MUTATIONS; MEK INHIBITION; NIVOLUMAB; IPILIMUMAB; MUTANT AB Background Dabrafenib plus trametinib treatment provides significant benefits over BRAF-inhibitor monotherapy in patients with BRAF(V600E)-mutant or BRAF(V600K)-mutant advanced melanoma; however, in many patients the disease progresses, leading to death. With many treatment options available, understanding clinical factors that predict long-term response and survival for treatments is important for optimisation of patient management. We aimed to identify clinical factors associated with long-term response and survival using pooled data from randomised trials of dabrafenib plus trametinib in patients with metastatic BRAF-mutant melanoma. Methods We did a retrospective individual data analysis based on all published randomised trials that included treatment-naive patients with BRAF(V600E)-mutant or BRAF(V600K)-mutant metastatic melanoma who received the approved dose of dabrafenib 150 mg twice daily plus trametinib 2 mg once daily. Data were pooled from patients in the BRF113220 (part C; March 26, 2010, to Jan 15, 2015), COMBI-d (May 4, 2012, to Jan 12, 2015), and COMBI-v (June 4, 2012, to March 13, 2015) randomised trials. Patients with untreated brain metastases were not permitted to enrol in these trials. Baseline factors, identified a priori based on known melanoma clinical or prognostic characteristics, were analysed for association with progression-free survival and overall survival using univariate and multivariateanalyses and assessed for hierarchical effect on outcomes using regression tree analyses. We also analysed factors identifiedafter baseline, on treatment, and at progression, for associations with survival after progression. The trials included in this analysis are registered with ClinicalTrials.gov: BRF113220, number NCT01072175; COMBI-d, number NCT01584648; COMBI-v, number NCT01597908. Findings 617 patients were included in this analysis with a median follow-up of 20.0 months (range 0-48.0, IQR 10.1-24.8); 396 patients had progression events (ie, disease progression or death) and 290 patients had died. Median progression-free survival (11.1 months [95% CI 9.7-12.9]), median overall survival (25.6 months [23.1-34.3]), 1-year progression-free survival (48% [44-52]) and overall survival (74% [71-78]), and 2-year progression-free survival (30% [26-34]) and overall survival (53% [49-57]) were consistent with those in the individual trials. Patients with normal lactate dehydrogenase (LDH) concentration and fewer than three organ sites containing metastases (n=237) had the longest 1-year progression-free survival (68% [95% CI 62-74]) and overall survival (90% [87-94]) and 2-year progression-free survival (46% [40-54]) and overall survival (75% [70-81]), whereas patients with LDH concentration at least two times the upper limit of normal (n=70) had the shortest 1-year progression-free survival (8% [3-19]) and overall survival (40% [29-55]) and 2-year progression-free survival (2% [0-13]) and overall survival (7% [3-19]). Of patients with disease progression (n=379), survival after progression was longest in those with progression in baseline or new non-CNS lesions (n=205; median 10.0 months [95% CI 7.9-12.0]) and shortest in those with new CNS lesions or concurrent progression in baseline and new lesions (n=171; median 4.0 months [3.5-4.9]). Interpretation Several patient and clinical characteristics at and after baseline are associated with outcomes with dabrafenib plus trametinib, and durable benefit is possible with targeted treatment in defined patient subsets. C1 [Long, Georgina V.] Univ Sydney, Melanoma Inst Australia, Sydney, NSW, Australia. [Long, Georgina V.] Royal North Shore & Mater Hosp, Sydney, NSW, Australia. [Grob, Jean-Jacques] Aix Marseille Univ, Ctr Hosp Univ Timone, Serv Dermatol, Marseille 05, France. [Nathan, Paul] Mt Vernon Canc Ctr, Northwood, Middx, England. [Ribas, Antoni] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Dept Med, Hematol Oncol, Los Angeles, CA 90024 USA. [Robert, Caroline] Gustave Roussy, Dept Med Oncol, Serv Dermatol, Villejuif, France. [Robert, Caroline] Univ Paris Sud, Fac Med, Villejuif, France. [Schadendorf, Dirk] Univ Hosp Essen, Dept Dermatol, Essen, Germany. [Schadendorf, Dirk] German Canc Consortium, Heidelberg, Germany. [Lane, Stephen R.; Mak, Carmen] Novartis Pharmaceut, Biostat, E Hanover, NJ USA. [Legenne, Philippe] Novartis Pharma AG, Global Oncol, Basel, Switzerland. [Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Dev Therapeut Program, Boston, MA 02114 USA. [Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Melanoma Program, Boston, MA 02114 USA. [Davies, Michael A.] Univ Texas MD Anderson Canc Ctr, Melanoma Med Oncol & Syst Biol, Houston, TX 77030 USA. RP Long, GV (reprint author), Univ Sydney, Melanoma Inst Australia, Sydney, NSW 2060, Australia. EM georgina.long@sydney.edu.au FU Novartis FX Novartis. NR 34 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD DEC PY 2016 VL 17 IS 12 BP 1743 EP 1754 DI 10.1016/S1470-2045(16)30578-2 PG 12 WC Oncology SC Oncology GA EE3YG UT WOS:000389537700042 PM 27864013 ER PT J AU Qu, HY Shewchuk, RM Alarcon, G Fraenkel, L Leong, A Dall'era, M Yazdany, J Singh, JA AF Qu, Haiyan Shewchuk, Richard M. Alarcon, Graciela Fraenkel, Liana Leong, Amye Dall'era, Maria Yazdany, Jinoos Singh, Jasvinder A. TI Mapping Perceptions of Lupus Medication Decision-Making Facilitators: The Importance of Patient Context SO ARTHRITIS CARE & RESEARCH LA English DT Article ID HEALTH-PROFESSIONALS PERCEPTIONS; CLINICAL-PRACTICE; SOCIOECONOMIC-STATUS; ERYTHEMATOSUS; NEPHRITIS; BARRIERS; CARE; COHORT; MORTALITY; ADHERENCE AB Objective. Numerous factors can impede or facilitate patients' medication decision-making and adherence to physicians' recommendations. Little is known about how patients and physicians jointly view issues that affect the decision-making process. Our objective was to derive an empirical framework of patient-identified facilitators to lupus medication decision-making from key stakeholders (including 15 physicians, 5 patients/patient advocates, and 8 medical professionals) using a patient-centered cognitive mapping approach. Methods. We used nominal group patient panels to identify facilitators to lupus treatment decision-making. Stakeholders independently sorted the identified facilitators (n=98) based on their similarities and rated the importance of each facilitator in patient decision-making. Data were analyzed using multidimensional scaling and hierarchical cluster analysis. Results. A cognitive map was derived that represents an empirical framework of facilitators for lupus treatment decisions from multiple stakeholders' perspectives. The facilitator clusters were 1) hope for a normal/healthy life, 2) understand benefits and effectiveness of taking medications, 3) desire to minimize side effects, 4) medication-related data, 5) medication effectiveness for "me," 6) family focus, 7) confidence in physician, 8) medication research, 9) reassurance about medication, and 10) medication economics. Conclusion. Consideration of how different stakeholders perceive the relative importance of lupus medication decision-making clusters is an important step toward improving patient-physician communication and effective shared decision-making. The empirically derived framework of medication decision-making facilitators can be used as a guide to develop a lupus decision aid that focuses on improving physician-patient communication. C1 [Qu, Haiyan; Shewchuk, Richard M.; Alarcon, Graciela; Singh, Jasvinder A.] Univ Alabama Birmingham, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA. [Fraenkel, Liana] Yale Univ, Sch Med, New Haven, CT USA. [Leong, Amye] Hlth Motivat, Santa Barbara, CA USA. [Dall'era, Maria; Yazdany, Jinoos] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Singh, Jasvinder A.] Birmingham VA Med Ctr, Birmingham, AL USA. [Singh, Jasvinder A.] Mayo Clin, Coll Med, Rochester, MN USA. RP Singh, JA (reprint author), Univ Alabama Birmingham, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA. EM Jasvinder.md@gmail.com FU Patient-Centered Outcomes Research Institute [CE-1304-6631] FX Supported by a research contract (CE-1304-6631) from the Patient-Centered Outcomes Research Institute. NR 43 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD DEC PY 2016 VL 68 IS 12 BP 1787 EP 1794 DI 10.1002/acr.22904 PG 8 WC Rheumatology SC Rheumatology GA EJ2GF UT WOS:000393027400007 PM 27059939 ER PT J AU Resnick, CM Vakilian, PM Breen, M Zurakowski, D Caruso, P Henderson, L Nigrovic, PA Kaban, LB Peacock, ZS AF Resnick, Cory M. Vakilian, Pouya M. Breen, Micheal Zurakowski, David Caruso, Paul Henderson, Lauren Nigrovic, Peter A. Kaban, Leonard B. Peacock, Zachary S. TI Quantifying Temporomandibular Joint Synovitis in Children With Juvenile Idiopathic Arthritis SO ARTHRITIS CARE & RESEARCH LA English DT Article ID EARLY RHEUMATOID-ARTHRITIS; CONTRAST-ENHANCED MRI; DISEASE-ACTIVITY; FINGER JOINTS; INVOLVEMENT; EROSIONS; WRIST; METHOTREXATE; ULTRASOUND; AGREEMENT AB Objective. Juvenile idiopathic arthritis (JIA) frequently affects the temporomandibular joints (TMJs) and is often undetected by history, examination, and plain imaging. Qualitative assessment of gadolinium-enhanced magnetic resonance images (MRIs) is currently the standard for diagnosis of TMJ synovitis associated with JIA. The purpose of this study is to apply a quantitative analysis of synovial enhancement to MRIs of patients with and without JIA to establish a disease threshold and sensitivity and specificity for the technique. Methods. This is a retrospective case-control study of children (age <= 16 years) who had MRIs with gadolinium including the TMJs. Subjects were divided into a JIA group and a control group. From a coronal T1-weighted image, a ratio (enhancement ratio [ER]) of the average pixel intensity within three 0.2-mm(2) regions of interest (ROIs) in the TMJ synovium to that of a 50-mm(2) ROI of the longus capitis muscle was calculated. Receiver operating characteristic curves were used to determine the sensitivity and specificity. The inter-and intraexaminer reliability was evaluated with Bland-Altman plots and 2-way mixed, absolute agreement intraclass correlation coefficients. Results. There were 187 and 142 TMJs included in the JIA and control groups, respectively. An ER threshold of 1.55 had a sensitivity and specificity for detecting synovitis of 91% and 96%, respectively. The inter-and intraexaminer reliability was excellent. Conclusion. Calculating a ratio of pixel intensity between the TMJ synovium and the longus capitis muscle is a reliable way to quantify synovial enhancement. An ER of 1.55 differentiates normal TMJs from those affected by inflammatory arthritis. C1 [Resnick, Cory M.; Breen, Micheal; Zurakowski, David; Henderson, Lauren] Boston Childrens Hosp, Boston, MA USA. [Resnick, Cory M.; Vakilian, Pouya M.; Kaban, Leonard B.; Peacock, Zachary S.] Harvard Sch Dent Med, Boston, MA USA. [Breen, Micheal; Zurakowski, David; Caruso, Paul; Henderson, Lauren] Harvard Med Sch, Boston, MA USA. [Caruso, Paul; Kaban, Leonard B.; Peacock, Zachary S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nigrovic, Peter A.] Harvard Med Sch, Boston Childrens Hosp, Boston, MA USA. [Nigrovic, Peter A.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Resnick, CM (reprint author), Boston Childrens Hosp, Dept Plast & Oral Surg, 300 Longwood Ave, Boston, MA 02115 USA. EM cory.resnick@childrens.harvard.edu NR 34 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD DEC PY 2016 VL 68 IS 12 BP 1795 EP 1802 DI 10.1002/acr.22911 PG 8 WC Rheumatology SC Rheumatology GA EJ2GF UT WOS:000393027400008 PM 27110936 ER PT J AU Yazdany, J Bansback, N Clowse, M Collier, D Law, K Liao, KP Michaud, K Morgan, EM Oates, JC Orozco, C Reimold, A Simard, JF Myslinski, R Kazi, S AF Yazdany, Jinoos Bansback, Nick Clowse, Megan Collier, Deborah Law, Karen Liao, Katherine P. Michaud, Kaleb Morgan, Esi M. Oates, James C. Orozco, Catalina Reimold, Andreas Simard, Julia F. Myslinski, Rachel Kazi, Salahuddin TI Rheumatology Informatics System for Effectiveness: A National Informatics-Enabled Registry for Quality Improvement SO ARTHRITIS CARE & RESEARCH LA English DT Article AB Objective. The Rheumatology Informatics System for Effectiveness (RISE) is a national electronic health record (EHR)enabled registry. RISE passively collects data from EHRs of participating practices, provides advanced quality measurement and data analytic capacities, and fulfills national quality reporting requirements. Here we report the registry's architecture and initial data, and we demonstrate how RISE is being used to improve the quality of care. Methods. RISE is a certified Centers for Medicare and Medicaid Services Qualified Clinical Data Registry, allowing collection of data without individual patient informed consent. We analyzed data between October 1, 2014 and September 30, 2015 to characterize initial practices and patients captured in RISE. We also analyzed medication use among rheumatoid arthritis (RA) patients and performance on several quality measures. Results. Across 55 sites, 312 clinicians contributed data to RISE; 72% were in group practice, 21% in solo practice, and 7% were part of a larger health system. Sites contributed data on 239,302 individuals. Among the subset with RA, 34.4% of patients were taking a biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) at their last encounter, and 66.7% were receiving a nonbiologic DMARD. Examples of quality measures include that 55.2% had a disease activity score recorded, 53.6% a functional status score, and 91.0% were taking a DMARD in the last year. Conclusion. RISE provides critical infrastructure for improving the quality of care in rheumatology and is a unique data source to generate new knowledge. Data validation and mapping are ongoing and RISE is available to the research and clinical communities to advance rheumatology. C1 [Yazdany, Jinoos] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Bansback, Nick] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC, Canada. [Clowse, Megan] Duke Univ, Durham, NC USA. [Collier, Deborah] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Law, Karen] Emory Univ, Atlanta, GA 30322 USA. [Liao, Katherine P.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Michaud, Kaleb] Univ Nebraska Med Ctr, Omaha, NE USA. [Michaud, Kaleb] Natl Data Bank Rheumat Dis, Wichita, KS USA. [Morgan, Esi M.] Cincinnati Childrens Hosp Med Ctr, James M Anderson Ctr Hlth Syst Excellence, Cincinnati, OH 45229 USA. [Oates, James C.] Med Univ South Carolina, Charleston, SC 29425 USA. [Orozco, Catalina] Rheumatol Associates, Dallas, TX USA. [Reimold, Andreas] Dallas Vet Affairs Med Ctr, Dallas, TX USA. [Reimold, Andreas; Kazi, Salahuddin] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Simard, Julia F.] Stanford Sch Med, Stanford, CA USA. [Myslinski, Rachel] Amer Coll Rheumatol, 60 Execut Pk S,Suite 150, Atlanta, GA 30329 USA. RP Yazdany, J (reprint author), Univ Calif San Francisco, Div Rheumatol, Box 0920, San Francisco, CA 94143 USA. EM jinoos.yazdany@ucsf.edu FU American College of Rheumatology; Robert L. Kroc Chair in Rheumatic and Connective Tissue Diseases (I) [AHRQ-R01-HS024412]; Russell/Engleman Medical Research Center for Arthritis; Pfizer FX Supported by the American College of Rheumatology. Dr. Yazdany's work was supported by the Robert L. Kroc Chair in Rheumatic and Connective Tissue Diseases (I), AHRQ-R01-HS024412, and the Russell/Engleman Medical Research Center for Arthritis.; Dr. Yazdany has received an independent research award from Pfizer. NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD DEC PY 2016 VL 68 IS 12 BP 1866 EP 1873 DI 10.1002/acr.23089 PG 8 WC Rheumatology SC Rheumatology GA EJ2GF UT WOS:000393027400016 PM 27696755 ER PT J AU Varga, TV Winters, AH Jablonski, KA Horton, ES Khare-Ranade, P Knowler, WC Marcovina, SM Renstrom, F Watson, KE Goldberg, R Florez, JC Pollin, TI Franks, PW AF Varga, Tibor V. Winters, Alexandra H. Jablonski, Kathleen A. Horton, Edward S. Khare-Ranade, Prajakta Knowler, William C. Marcovina, Santica M. Renstrom, Frida Watson, Karol E. Goldberg, Ronald Florez, Jose C. Pollin, Toni I. Franks, Paul W. CA Diabetes Prevention Program Res Gr TI Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE clinical trial; genetics; lifestyle; lipids; lipoproteins; molecular epidemiology; polymorphism, genetic ID LOW-DENSITY-LIPOPROTEIN; REACTOME PATHWAY KNOWLEDGEBASE; CARDIOVASCULAR-DISEASE RISK; CORONARY-ARTERY-DISEASE; BODY-MASS INDEX; GENETIC-VARIANTS; SATURATED-FAT; LIFE-STYLE; CHOLESTEROL; POPULATION AB Background-We assessed whether 234 established dyslipidemia-associated loci modify the effects of metformin treatment and lifestyle intervention (versus placebo control) on lipid and lipid subfraction levels in the Diabetes Prevention Program randomized controlled trial. Methods and Results-We tested gene treatment interactions in relation to baseline-adjusted follow-up blood lipid concentrations (high-density lipoprotein [HDL] and low-density lipoprotein-cholesterol, total cholesterol, and triglycerides) and lipoprotein subfraction particle concentrations and size in 2993 participants with pre-diabetes. Of the previously reported single-nucleotide polymorphism associations, 32.5% replicated at P<0.05 with baseline lipid traits. Trait-specific genetic risk scores were robustly associated (3x10(-4)>P>1.1x10(-16)) with their respective baseline traits for all but 2 traits. Lifestyle modified the effect of the genetic risk score for large HDL particle numbers, such that each risk allele of the genetic risk scores was associated with lower concentrations of large HDL particles at follow-up in the lifestyle arm (beta=-0.11 mu mol/L per genetic risk scores risk allele; 95% confidence interval, -0.188 to -0.033; P=5x10(-3); P-interaction=1x10(-3) for lifestyle versus placebo), but not in the metformin or placebo arms (P>0.05). In the lifestyle arm, participants with high genetic risk had more favorable or similar trait levels at 1-year compared with participants at lower genetic risk at baseline for 17 of the 20 traits. Conclusions-Improvements in large HDL particle concentrations conferred by lifestyle may be diminished by genetic factors. Lifestyle intervention, however, was successful in offsetting unfavorable genetic loading for most lipid traits. C1 [Varga, Tibor V.; Renstrom, Frida; Franks, Paul W.] Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden. [Winters, Alexandra H.; Pollin, Toni I.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Winters, Alexandra H.; Pollin, Toni I.] Univ Maryland, Sch Med, Program Genet & Genom Med, Baltimore, MD 21201 USA. [Jablonski, Kathleen A.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Horton, Edward S.; Florez, Jose C.] Harvard Med Sch, Dept Med, Boston, MA USA. [Horton, Edward S.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Khare-Ranade, Prajakta] Washington Univ, St Louis, MO USA. [Knowler, William C.] NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Marcovina, Santica M.] Univ Washington, Northwest Lipid Metab & Diabet Res Labs, Seattle, WA 98195 USA. [Renstrom, Frida] Umea Univ, Dept Biobank Res, Umea, Sweden. [Franks, Paul W.] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Watson, Karol E.] Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. [Goldberg, Ronald] Univ Miami, Leonard M Miller Sch Med, Div Endocrinol Diabet & Metab, Lipid Disorders Clin,Diabet Res Inst, Coral Gables, FL 33124 USA. [Florez, Jose C.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. [Franks, Paul W.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. RP Franks, PW (reprint author), Skane Univ Hosp Malmo, Dept Clin Sci, Genet & Mol Epidemiol Unit, CRC, Bldg 91,Level 10,Jan Waldenstroms Gata 35, SE-20502 Malmo, Sweden. EM Paul.Franks@med.lu.se FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; NIDDK; Indian Health Service; Office of Research on Minority Health; National Institute of Child Health and Human Development; National Institute on Aging; Centers for Disease Control and Prevention; Office of Research on Women's Health; American Diabetes Association; National Institutes of Health/NIDDK [R01DK072041]; Swedish Heart-Lung Foundation; Faculty of Medicine at Umea University; EPiHealth (Lund University) FX The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the Coordinating Center for the design and conduct of the study, and collection, management, analysis, and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, supported data collection at many of the clinical centers. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the National Institute of Child Health and Human Development, the National Institute on Aging, the Centers for Disease Control and Prevention, the Office of Research on Women's Health, and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided medication. This research was also supported, in part, by the intramural research program of the NIDDK. LifeScan, Health O Meter, Hoechst Marion Roussel, Merck-Medco Managed Care, Merck, Nike Sports Marketing, Slim Fast Foods, and Quaker Oats donated materials, equipment, or medicines for concomitant conditions. McKesson BioServices, Matthews Media Group, and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. A complete list of centers, investigators, and staff is shown in the Acknowledgments. The Diabetes Prevention Program Genetics Project was supported by National Institutes of Health/NIDDK grant R01DK072041; additional funding from the Swedish Heart-Lung Foundation supported the costs of data analysis (for Dr Varga). Part of the work described in this article was undertaken as part of the 2013 to 2014 BLUE ScY educational exchange program, which was supported by the Faculty of Medicine at Umea University and EPiHealth (Lund University; for Dr Varga). NR 40 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1942-325X EI 1942-3268 J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD DEC PY 2016 VL 9 IS 6 BP 495 EP + DI 10.1161/CIRCGENETICS.116.001457 PG 169 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA EH5OZ UT WOS:000391823900005 PM 27784733 ER PT J AU Natarajan, P Bis, JC Bielak, LF Cox, AJ Dorr, M Feitosa, MF Franceschini, N Guo, X Hwang, SJ Isaacs, A Jhun, MA Kavousi, M Li-Gao, R Lyytikainen, LP Marioni, RE Schminke, U Stitziel, NO Tada, H van Setten, J Smith, AV Vojinovic, D Yanek, LR Yao, J Yerges-Armstrong, LM Amin, N Baber, U Borecki, IB Carr, JJ Chen, YDI Cupples, LA de Jong, PA de Koning, H de Vos, BD Demirkan, A Fuster, V Franco, OH Goodarzi, MO Harris, TB Heckbert, SR Heiss, G Hoffmann, U Hofman, A Isgum, I Jukema, JW Kahonen, M Kardia, SLR Kral, BG Launer, LJ Massaro, J Mehran, R Mitchell, BD Jr, THM de Mutsert, R Newman, AB Nguyen, KD North, KE O'Connell, JR Oudkerk, M Pankow, JS Peloso, GM Post, W Province, MA Raffield, LM Raitakari, OT Reilly, DF Rivadeneira, F Rosendaal, F Sartori, S Taylor, KD Teumer, A Trompet, S Turner, ST Uitterlinden, AG Vaidya, D van der Lugt, A Volker, U Wardlaw, JM Wassel, CL Weiss, S Wojczynski, MK Becker, DM Becker, LC Boerwinkle, E Bowden, DW Deary, IJ Dehghan, A Felix, SB Gudnason, V Lehtimaki, T Mathias, R Mook-Kanamori, DO Psaty, BM Rader, DJ Rotter, JI Wilson, JG van Duijn, CM Volzke, H Kathiresan, S Peyser, PA O'Donnell, CJ AF Natarajan, Pradeep Bis, Joshua C. Bielak, Lawrence F. Cox, Amanda J. Dorr, Marcus Feitosa, Mary F. Franceschini, Nora Guo, Xiuqing Hwang, Shih-Jen Isaacs, Aaron Jhun, Min A. Kavousi, Maryam Li-Gao, Ruifang Lyytikainen, Leo-Pekka Marioni, Riccardo E. Schminke, Ulf Stitziel, Nathan O. Tada, Hayato van Setten, Jessica Smith, Albert V. Vojinovic, Dina Yanek, Lisa R. Yao, Jie Yerges-Armstrong, Laura M. Amin, Najaf Baber, Usman Borecki, Ingrid B. Carr, J. Jeffrey Chen, Yii-Der Ida Cupples, L. Adrienne de Jong, Pim A. de Koning, Harry de Vos, Bob D. Demirkan, Ayse Fuster, Valentin Franco, Oscar H. Goodarzi, Mark O. Harris, Tamara B. Heckbert, Susan R. Heiss, Gerardo Hoffmann, Udo Hofman, Albert Isgum, Ivana Jukema, J. Wouter Kahonen, Mika Kardia, Sharon L. R. Kral, Brian G. Launer, Lenore J. Massaro, Joe Mehran, Roxana Mitchell, Braxton D. Jr, Thomas H. Mosley de Mutsert, Renee Newman, Anne B. Nguyen, Khanh-dung North, Kari E. O'Connell, Jeffrey R. Oudkerk, Matthijs Pankow, James S. Peloso, Gina M. Post, Wendy Province, Michael A. Raffield, Laura M. Raitakari, Olli T. Reilly, Dermot F. Rivadeneira, Fernando Rosendaal, Frits Sartori, Samantha Taylor, Kent D. Teumer, Alexander Trompet, Stella Turner, Stephen T. Uitterlinden, Andre G. Vaidya, Dhananjay van der Lugt, Aad Volker, Uwe Wardlaw, Joanna M. Wassel, Christina L. Weiss, Stefan Wojczynski, Mary K. Becker, Diane M. Becker, Lewis C. Boerwinkle, Eric Bowden, Donald W. Deary, Ian J. Dehghan, Abbas Felix, Stephan B. Gudnason, Vilmundur Lehtimaki, Terho Mathias, Rasika Mook-Kanamori, Dennis O. Psaty, Bruce M. Rader, Daniel J. Rotter, Jerome I. Wilson, James G. van Duijn, Cornelia M. Volzke, Henry Kathiresan, Sekar Peyser, Patricia A. O'Donnell, Christopher J. CA CHARGE Consortium TI Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE carotid intima-media thickness; coronary artery calcification; exome; genome-wide association study; genomics ID CORONARY-ARTERY CALCIFICATION; INTIMA-MEDIA THICKNESS; HEART-DISEASE RISK; DEFECTIVE APOLIPOPROTEIN B-100; BEAM COMPUTED-TOMOGRAPHY; OLD ORDER AMISH; CARDIOVASCULAR RISK; III HYPERLIPOPROTEINEMIA; MYOCARDIAL-INFARCTION; AORTIC CALCIFICATION AB Background-The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. Methods and Results-We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima-media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima-media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3x10(-10)). The APOE epsilon 2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1x10(-12)) and 1.4% reduced carotid intima-media thickness (P=4x10(-14)) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the epsilon 2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of epsilon 2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1x10(-11)). Conclusions-Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE epsilon 2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease. C1 [Natarajan, Pradeep; Peloso, Gina M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Natarajan, Pradeep; Peloso, Gina M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Natarajan, Pradeep; Peloso, Gina M.; Kathiresan, Sekar] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Heckbert, Susan R.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth, Grp Hlth Res Inst, Seattle, WA USA. [Bielak, Lawrence F.; Jhun, Min A.; Kardia, Sharon L. R.; Peyser, Patricia A.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Cox, Amanda J.; Raffield, Laura M.; Bowden, Donald W.] Wake Forest Hlth Sci, Diabet Heart Study, Winston Salem, NC USA. [Dorr, Marcus; Felix, Stephan B.] Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany. [Schminke, Ulf] Univ Med Greifswald, Dept Neurol, Greifswald, Germany. [Teumer, Alexander; Volzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Volker, Uwe; Weiss, Stefan] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Dorr, Marcus; Teumer, Alexander; Volker, Uwe; Weiss, Stefan; Felix, Stephan B.; Volzke, Henry] DZHK German Ctr Cardiovasc Res, Greifswald, Germany. [Feitosa, Mary F.; Stitziel, Nathan O.; Province, Michael A.; Wojczynski, Mary K.] Washington Univ, Sch Med, Dept Genet, Div Stat Genet, St Louis, MO 63110 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Genet, Div Cardiovasc, St Louis, MO 63110 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO USA. [Franceschini, Nora; Heiss, Gerardo; North, Kari E.] Univ N Carolina, Gilling Sch Global Publ Hlth, Epidemiol, Chapel Hill, NC USA. [Guo, Xiuqing; Yao, Jie; Chen, Yii-Der Ida; Taylor, Kent D.; Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Guo, Xiuqing; Yao, Jie; Chen, Yii-Der Ida; Taylor, Kent D.; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Hwang, Shih-Jen] NHLBI, Framingham Heart Study, NIH, Framingham, MA USA. [Kavousi, Maryam; Vojinovic, Dina; Amin, Najaf; Demirkan, Ayse; Franco, Oscar H.; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; Dehghan, Abbas; van Duijn, Cornelia M.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [van der Lugt, Aad] Univ Med Ctr Rotterdam, Erasmus MC, Dept Radiol, Rotterdam, Netherlands. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Dehghan, Abbas] Imperial Coll London, MRC PHE Ctr Environm & Hlth, London, England. [Isaacs, Aaron] Maastricht Univ, Maastricht Ctr Syst Biol MaCSBio, Maastricht, Netherlands. [Li-Gao, Ruifang; de Mutsert, Renee; Rosendaal, Frits; Mook-Kanamori, Dennis O.] Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands. [Jukema, J. Wouter; Trompet, Stella] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Mook-Kanamori, Dennis O.] Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, Leiden, Netherlands. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, Tampere, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Dept Clin Physiol, Tampere, Finland. [Marioni, Riccardo E.; Wardlaw, Joanna M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Marioni, Riccardo E.] Univ Edinburgh, Ctr Genom & Expt Med, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Wardlaw, Joanna M.] Univ Edinburgh, Div Neuroimaging Sci, Edinburgh, Midlothian, Scotland. [Wardlaw, Joanna M.] Univ Edinburgh, Brain Res Imaging Ctr, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland. [Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [Marioni, Riccardo E.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Tada, Hayato] Kanazawa Univ, Grad Sch Med, Div Cardiovasc Med, Kanazawa, Ishikawa, Japan. [van Setten, Jessica] Univ Med Ctr Utrecht, Cardiol, Utrecht, Netherlands. [de Jong, Pim A.] Univ Med Ctr Utrecht, Dept Radiol, Utrecht, Netherlands. [de Vos, Bob D.; Isgum, Ivana] Univ Med Ctr Utrecht, Image Sci Inst, Utrecht, Netherlands. [Smith, Albert V.; Gudnason, Vilmundur] Icelandic Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Yanek, Lisa R.; Kral, Brian G.; Post, Wendy; Vaidya, Dhananjay; Becker, Diane M.; Becker, Lewis C.; Mathias, Rasika] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Yerges-Armstrong, Laura M.; Mitchell, Braxton D.; O'Connell, Jeffrey R.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Baber, Usman; Fuster, Valentin; Mehran, Roxana; Sartori, Samantha] Icahn Sch Med Mt Sinai, Cardiovasc Inst, New York, NY 10029 USA. [Borecki, Ingrid B.] Regeneron Pharmaceut Inc, Analyt Genet, Tirrytown, NY USA. [Carr, J. Jeffrey] Vanderbilt, Radiol, Cardiovasc Med & Biomed Informat, Nashville, TN USA. [Cupples, L. Adrienne; Massaro, Joe; Peloso, Gina M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Cupples, L. Adrienne] NHLBI, Framingham Heart Study, NIH, Framingham, MA USA. [de Koning, Harry] Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Goodarzi, Mark O.] Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Intramural Res, NIH, Baltimore, MD 21224 USA. [Jukema, J. Wouter] Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Jukema, J. Wouter] Netherlands Heart Inst, InterUniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland. [Mitchell, Braxton D.] Baltimore Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA. [Jr, Thomas H. Mosley] Univ Mississippi, Med Ctr, Dept Med, Div Geriatr Med, Jackson, MS 39216 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Nguyen, Khanh-dung] Merck & Co Inc, MRL, Genet & Pharmacogen Dept, Boston, MA USA. [Reilly, Dermot F.] Merck Sharpe & Dohme Corp, Genet & Pharmacogen Dept, Boston, MA USA. [Oudkerk, Matthijs] Univ Groningen, Univ Med Ctr Groningen, Ctr Med Imaging North East Netherlands, Groningen, Netherlands. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Rivadeneira, Fernando; Uitterlinden, Andre G.; van Duijn, Cornelia M.] Netherlands Consortium Hlth Aging, Rotterdam, Netherlands. [Turner, Stephen T.] Mayo Clin, Dept Internal Med, Div Nephrol & Hypertens, Rochester, MN USA. [Wassel, Christina L.] Univ Vermont, Dept Pathol & Lab Med, Colchester, Essex, England. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Dept Epidemiol, Sch Publ Hlth, Houston, TX 77030 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Rader, Daniel J.] Univ Penn, Dept Med, Perelman Sch Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA. [Volzke, Henry] German Ctr Diabet Res DZD, Greifswald, Germany. [O'Donnell, Christopher J.] Boston Vet Affairs Healthcare Syst, Div Cardiol, Boston, MA USA. RP O'Donnell, CJ (reprint author), Harvard Med Sch, Boston Vet Affairs Healthcare Syst, 1400 Vet Foreign Wars Pkwy,Bldg 1 5B-113, Boston, MA 02132 USA.; Natarajan, P (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.; Natarajan, P (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. EM pnatarajan@partners.org; odonnellc@nhlbi.nih.gov RI Fuster, Valentin/H-4319-2015; Feitosa, Mary/K-8044-2012; OI Fuster, Valentin/0000-0002-9043-9986; Feitosa, Mary/0000-0002-0933-2410; Carr, John/0000-0002-4398-8237; Mitchell, Braxton/0000-0003-4920-4744; Vaidya, Dhananjay/0000-0002-7164-1601; Pankow, James/0000-0001-7076-483X FU John S. LaDue Memorial Fellowship in Cardiology, Harvard Medical School; NWO VENI grant (VENI) [91616079]; National Heart, Lung, and Blood Institute [R01HL105756, R01HL120393]; Data Supplement FX Dr Natarajan is supported by the John S. LaDue Memorial Fellowship in Cardiology, Harvard Medical School. Dr Kavousi is supported by the NWO VENI grant (VENI, 91616079). Infrastructure for the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology) is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. Funding support for the CHARGE Consortium Exome Chip analyses is provided in part by the National Heart, Lung, and Blood Institute grant R01HL120393. Please refer to the Data Supplement regarding additional sources of funding. NR 88 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1942-325X EI 1942-3268 J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD DEC PY 2016 VL 9 IS 6 BP 511 EP + DI 10.1161/CIRCGENETICS.116.001572 PG 57 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA EH5OZ UT WOS:000391823900007 PM 27872105 ER PT J AU Rosenthal, PA Lundy, KC Massoglia, DP Payne, EH Gilbert, G Gebregziabher, M AF Rosenthal, Peter A. Lundy, Katherine C. Massoglia, Dino P. Payne, Elizabeth H. Gilbert, Gregory Gebregziabher, Mulugeta TI Incidental paranasal sinusitis on routine brain magnetic resonance scans: association with atherosclerosis SO INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY LA English DT Article DE atherosclerosis; magnetic resonance; computed tomography; stroke; paranasal sinusitis; chronic rhinosinusitis ID AMERICAN-HEART-ASSOCIATION; COMPUTED-TOMOGRAPHY CBCT; MAXILLARY SINUS; CHRONIC RHINOSINUSITIS; PERIODONTAL-DISEASE; RADIOLOGICAL FINDINGS; RISK-FACTORS; STROKE; ABNORMALITIES; MORTALITY AB Background: Incidental paranasal sinusitis (IPS) is common on imaging for non-sinusitis disorders, usually without symptoms or obstructive features, and possibly arising from periodontitis (PD). PD associations with atherosclerosis have been widely reported. We test if IPS may also be associated with atherosclerosis. Methods: IPS was scored retrospectively in a random sample of 180 magnetic resonance (MR) brain scans and compared with chart review for atherosclerosis (all subtypes), rhinosinusitis, and related factors (smoking, asthma, and relevant surgery). IPS was scored out of 30, from all sinuses, with maxillary sinuses weighted double volumetrically. Significant IPS (Sig IPS) was designated as 6 or more out of 30. Bivariate logistic regression was used to test for associations of Sig IPS to the clinical data, with multivariate analysis then testing for potential confounders. Results: A total of 173 subjects were analyzed (7 exclusions). MR indications included suspected acute/prior stroke (22.0%). Sig IPS found in 20 (11.6%). Positive histories for atherosclerosis were cerebral, 57 (32.9%); coronary, 48 (27.7%); and peripheral arterial disease, 14 (8.1%). IPS >= 6 was strongly associated with cerebrovascular disease (odds ratio [OR] 6.0, p < 0.001), and less robustly to smoking (OR 2.9, p = 0.07) and rhinosinusitis (OR 2.4, p = 0.09). No associations with coronary or peripheral artery diseases were found. After controlling for smoking and rhinosinusitis, yielding significant subclinical sinusitis, the link of Sig IPS to cerebrovascular disease persisted (modified OR 5.2, p = 0.002). Conclusion: Significant incidental sinusitis, which is mostly subclinical sinusitis, is associated with cerebrovascular disease but not other atheroscleroses. This suggests possible common causation of both by PD. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. C1 [Rosenthal, Peter A.; Lundy, Katherine C.; Massoglia, Dino P.; Payne, Elizabeth H.; Gilbert, Gregory; Gebregziabher, Mulugeta] Ralph H Johnson VA Med Ctr, Bee St, Charleston, SC 29401 USA. [Payne, Elizabeth H.; Gebregziabher, Mulugeta] Med Univ South Carolina, Charleston, SC 29425 USA. [Payne, Elizabeth H.] Emmes Corp, Rockville, MD USA. RP Rosenthal, PA (reprint author), Ralph H Johnson VA Med Ctr, Bee St, Charleston, SC 29401 USA. EM Peter.Rosenthal@va.gov OI Gebregziabher, Mulugeta/0000-0002-4826-481X FU Veterans Health Administration; Ralph H. Johnson VA Medical Center FX We acknowledge with gratitude the support of the Veterans Health Administration and the Ralph H. Johnson VA Medical Center for the conduct of this research. The study was unfunded. Thanks also for kind assistance from Michael E. Ullian, MD, Professor in Nephrology, and Jonathan Halford, MD, Associate Professor in Neurology, both at Medical University of South Carolina and Ralph H. Johnson VA Medical Center. NR 47 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2042-6976 EI 2042-6984 J9 INT FORUM ALLERGY RH JI Int. Forum Allergy Rhinol. PD DEC PY 2016 VL 6 IS 12 BP 1253 EP 1263 DI 10.1002/alr.21824 PG 11 WC Otorhinolaryngology SC Otorhinolaryngology GA EJ2MN UT WOS:000393044400006 PM 27509266 ER PT J AU Brown, PD Ballman, KV Cerhan, J Anderson, SK Carrero, XW Whitton, AC Greenspoon, J Parney, IF Laack, NN Ashman, JB Bahary, JP Hadjipanayis, CG Urbanic, JJ Barker, FG Farace, E Khuntia, D Giannini, C Buckner, JC Galanis, E Roberge, D AF Brown, P. D. Ballman, K. V. Cerhan, J. Anderson, S. K. Carrero, X. W. Whitton, A. C. Greenspoon, J. Parney, I. F. Laack, N. N. Ashman, J. B. Bahary, J. P. Hadjipanayis, C. G. Urbanic, J. J. Barker, F. G., II Farace, E. Khuntia, D. Giannini, C. Buckner, J. C. Galanis, E. Roberge, D. TI N107C/CEC.3: A Phase III Trial of Post-Operative Stereotactic Radiosurgery (SRS) Compared with Whole Brain Radiotherapy (WBRT) for Resected Metastatic Brain Disease SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY SEP 25-28, 2016 CL Boston, MA SP Amer Soc Radiat Oncol C1 [Brown, P. D.; Cerhan, J.; Anderson, S. K.; Carrero, X. W.; Parney, I. F.; Laack, N. N.; Giannini, C.; Buckner, J. C.; Galanis, E.] Mayo Clin, Rochester, MN USA. [Brown, P. D.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Ballman, K. V.] Weill Cornell Med, New York, NY USA. [Whitton, A. C.; Greenspoon, J.] Juravinski Canc Ctr, Hamilton, ON, Canada. [Ashman, J. B.] Mayo Clin, Phoenix, AZ USA. [Bahary, J. P.; Roberge, D.] CHUM, Hop Notre Dame, Montreal, PQ, Canada. [Hadjipanayis, C. G.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Urbanic, J. J.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Barker, F. G., II] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Farace, E.] Penn State Univ, Coll Med, Hershey, PA USA. [Khuntia, D.] Western Radiat Oncol, Mountain View, CA USA. NR 0 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD DEC 1 PY 2016 VL 96 IS 5 MA LBA-1 BP 937 EP 937 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EJ5XM UT WOS:000393292200005 ER PT J AU Michalski, JM Janss, A Vezina, G Gajjar, A Pollack, I Merchant, TE FitzGerald, TJ Booth, T Tarbell, NJ Li, Y Billups, CA Perkins, SM Timmerman, RD Cherlow, JM Packer, R AF Michalski, J. M. Janss, A. Vezina, G. Gajjar, A. Pollack, I. Merchant, T. E. FitzGerald, T. J. Booth, T. Tarbell, N. J. Li, Y. Billups, C. A. Perkins, S. M. Timmerman, R. D. Cherlow, J. M. Packer, R. TI Results of COG ACNS0331: A Phase III Trial of Involved-Field Radiotherapy (IFRT) and Low Dose Craniospinal Irradiation (LD-CSI) with Chemotherapy in Average-Risk Medulloblastoma: A Report from the Children's Oncology Group SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY SEP 25-28, 2016 CL Boston, MA SP Amer Soc Radiat Oncol C1 [Michalski, J. M.; Li, Y.; Perkins, S. M.] Washington Univ, Sch Med, St Louis, MO USA. [Janss, A.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Vezina, G.; Packer, R.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Gajjar, A.; Merchant, T. E.; Billups, C. A.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Pollack, I.] UPMC, Childrens Hosp Pittsburgh, Pittsburgh, PA USA. [FitzGerald, T. J.] UMass Mem Med Ctr, Worcester, MA USA. [Booth, T.] UT Southwestern Simmons Canc Ctr, Lincoln, RI USA. [Tarbell, N. J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Timmerman, R. D.] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Cherlow, J. M.] Long Beach Mem Med Ctr, Long Beach, CA USA. 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 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD DEC 1 PY 2016 VL 96 IS 5 MA LBA-2 BP 937 EP 938 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EJ5XM UT WOS:000393292200006 ER PT J AU Arthur, DW Moughan, J Kuerer, HM Haffty, BG Cuttino, LW Todor, DA Simone, NL Hayes, SB Woodward, WA McCormick, B Cohen, RJ Sahijdak, WM Canaday, DJ Brown, DR Currey, AD Fisher, CM Jagsi, R White, JR AF Arthur, D. W. Moughan, J. Kuerer, H. M. Haffty, B. G. Cuttino, L. W. Todor, D. A. Simone, N. L. Hayes, S. B. Woodward, W. A. McCormick, B. Cohen, R. J. Sahijdak, W. M. Canaday, D. J. Brown, D. R. Currey, A. D. Fisher, C. M. Jagsi, R. White, J. R. TI NRG Oncology/RTOG 1014: 3 Year Efficacy Report From a Phase II Study of Repeat Breast Preserving Surgery and 3D Conformal Partial Breast Re-Irradiation (PBrI) for In-Breast Recurrence SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY SEP 25-28, 2016 CL Boston, MA SP Amer Soc Radiat Oncol C1 [Arthur, D. W.; Cuttino, L. W.; Todor, D. A.] Virginia Commonwealth Univ, Richmond, VA USA. [Moughan, J.] NRG Oncol Stat & Data Management Ctr, Philadelphia, PA USA. [Kuerer, H. M.; Woodward, W. A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Haffty, B. G.] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. [Simone, N. L.] Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. [Hayes, S. B.] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [McCormick, B.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Cohen, R. J.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Sahijdak, W. M.] Michigan Canc Res Consortium CCOP, Ann Arbor, MI USA. [Canaday, D. J.] Massachusetts Gen Hosp, Cape Cod Hosp Accrail, Hyannis, MA USA. [Brown, D. R.] Wake Forest Baptist Hlth Accruals Arizona Oncol S, Winston Salem, NC USA. [Currey, A. D.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Fisher, C. M.] Univ Colorado Denver, Aurora, CO USA. [Jagsi, R.] Univ Michigan, Med Ctr, Ann Arbor, MI USA. [White, J. R.] Ohio State Univ, Columbus, OH 43210 USA. FU NCI [U10s CA180868, CA180822, U24CA180803] FX NCI Grants U10s CA180868, CA180822, U24CA180803 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD DEC 1 PY 2016 VL 96 IS 5 MA LBA-10 BP 941 EP 941 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EJ5XM UT WOS:000393292200014 ER PT J AU Mak, KS Smith, AB Eidelman, A Clayman, R Niemierko, A Cheng, JS Matthews, J Drumm, MR Nielsen, ME Feldman, AS Lee, RJ Zietman, AL Chen, RC Shipley, WU Milowsky, MI Efstathiou, JA AF Mak, Kimberley S. Smith, Angela B. Eidelman, Alec Clayman, Rebecca Niemierko, Andrzej Cheng, Jed-Sian Matthews, Jonathan Drumm, Michael R. Nielsen, Matthew E. Feldman, Adam S. Lee, Richard J. Zietman, Anthony L. Chen, Ronald C. Shipley, William U. Milowsky, Matthew I. Efstathiou, Jason A. TI Quality of Life in Long-term Survivors of Muscle-Invasive Bladder Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID COMBINED-MODALITY THERAPY; EXPANDED PROSTATE-CANCER; TRANSURETHRAL RESECTION; RADICAL CYSTECTOMY; OUTCOMES; ONCOLOGY; PRESERVATION; DIVERSION; RADIATION AB Purpose: Health-related quality of life (QOL) has not been well-studied in survivors of muscle-invasive bladder cancer (MIBC). The present study compared long-term QOL in MIBC patients treated with radical cystectomy (RC) versus bladder-sparing trimodality therapy (TMT). Methods and Materials: This cross-sectional bi-institutional study identified 226 patients with nonmetastatic cT2-cT4 MIBC, diagnosed in 1990 to 2011, who were eligible for RC and were disease free for >= 2 years. Six validated QOL instruments were administered: EuroQOL EQ-5D, European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire and EORTC MIBC module, Expanded Prostate Cancer Index Composite bowel scale, Cancer Treatment and Perception Scale, and Impact of Cancer, version 2. Multivariable analyses of the mean QOL scores were conducted using propensity score matching. Results: The response rate was 77% (n=173). The median follow-up period was 5.6 years. Of the 173 patients, 64 received TMT and 109, RC. The median interval from diagnosis to questionnaire completion was 9 years after TMT and 7 years after RC (P=.009). No significant differences were found in age, gender, comorbidities, tobacco history, performance status, or tumor stage. On multivariable analysis, patients who received TMT had better general QOL by 9.7 points of 100 compared with those who had received RC (P=.001) and higher physical, role, social, emotional, and cognitive functioning by 6.6 to 9.9 points (P <=.04). TMT was associated with better bowel function by 4.5 points (P=.02) and fewer bowel symptoms by 2.7 to 7.1 points (P <=.05). The urinary symptom scores were similar. TMT was associated with better sexual function by 8.7 to 32.1 points (P <=.02) and body image by 14.8 points (P<.001). The patients who underwent TMT reported greater informed decision-making scores by 13.6 points (P=.01) and less concern about the negative effect of cancer by 6.8 points (P=.006). The study limitations included missing baseline QOL data and different follow-up times. Conclusions: Both TMT and RC result in good long-term QOL outcomes in MIBC survivors, supporting TMT as a good alternative to RC for selected patients. Whether TMT leads to superior QOL requires prospective validation. (C) 2016 Elsevier Inc. All rights reserved. C1 [Mak, Kimberley S.] Harvard Radiat Oncol Program, Boston, MA USA. [Mak, Kimberley S.] Boston Univ, Sch Med, Boston Med Ctr, Boston, MA 02118 USA. [Smith, Angela B.; Matthews, Jonathan; Nielsen, Matthew E.; Chen, Ronald C.; Milowsky, Matthew I.] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Eidelman, Alec; Clayman, Rebecca; Niemierko, Andrzej; Cheng, Jed-Sian; Drumm, Michael R.; Feldman, Adam S.; Lee, Richard J.; Zietman, Anthony L.; Shipley, William U.; Efstathiou, Jason A.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. RP Efstathiou, JA (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St, Boston, MA 02114 USA. EM jefstathiou@partners.org OI Matthews, Jonathan/0000-0003-1497-7843 FU National Institutes of Health; American Cancer Society; Urology Care Foundation/Astellas; Myriad Genetics; Janssen Biotech; Accuray FX A. B. Smith has been a consultant for Photocure. M. E. Nielsen has been a consultant for Grand Rounds and American College of Physicians and has received grant support from the National Institutes of Health, American Cancer Society, and Urology Care Foundation/Astellas. A. Feldman has been a consultant for Myriad Genetics and Olympus and has received grant support from Myriad Genetics. R. Lee has been a consultant and received grant support from Janssen Biotech. R. Chen has received grant support from Accuray. W. U. Shipley has stock ownership in Pfizer. NR 29 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD DEC 1 PY 2016 VL 96 IS 5 BP 1028 EP 1036 DI 10.1016/j.ijrobp.2016.08.023 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EJ5XM UT WOS:000393292200027 PM 27727064 ER PT J AU Pisansky, TM Agrawal, S Hamstra, DA Koontz, BF Liauw, SL Efstathiou, JA Michalski, JM Feng, FY Abramowitz, MC Pollack, A Anscher, MS Moghanaki, D Den, RB Stephans, KL Zietman, AL Lee, WR Kattan, MW Stephenson, AJ Tendulkar, RD AF Pisansky, Thomas M. Agrawal, Shree Hamstra, Daniel A. Koontz, Bridget F. Liauw, Stanley L. Efstathiou, Jason A. Michalski, Jeff M. Feng, Felix Y. Abramowitz, Matthew C. Pollack, Alan Anscher, Mitchell S. Moghanaki, Drew Den, Robert B. Stephans, Kevin L. Zietman, Anthony L. Lee, W. Robert Kattan, Michael W. Stephenson, Andrew J. Tendulkar, Rahul D. TI Salvage Radiation Therapy Dose Response for Biochemical Failure of Prostate Cancer After Prostatectomy-A Multi-Institutional Observational Study SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID INTENSITY-MODULATED RADIOTHERAPY; RADICAL PROSTATECTOMY; COMPETING RISK; TOXICITY; ADJUVANT; GUIDELINES; SURVIVAL; RELAPSE; MODEL; TRIAL AB Purpose: To determine whether a dose-response relationship exists for salvage radiation therapy (RT) of biochemical failure after prostatectomy for prostate cancer. Methods and Materials: Individual data from 1108 patients who underwent salvage RT at 10 academic centers were pooled. The cohort was enriched for selection criteria more likely associated with tumor recurrence in the prostate bed (margin positive and pre-RT prostate-specific antigen [PSA] level of <= 2.0 ng/mL) and without the confounding of planned androgen suppression. The cumulative incidence of biochemical failure and distant metastasis over time was computed, and competing risks hazard regression models were used to investigate the association between potential predictors and these outcomes. The association of radiation dose with outcomes was the primary focus. Results: With a 65.2-month follow-up duration, the 5- and 10-year estimates of freedom from post-RT biochemical failure (PSA level >0.2 ng/mL and rising) was 63.5% and 49.8%, respectively, and the cumulative incidence of distant metastasis was 12.4% by 10 years. A Gleason score of >= 7, higher pre-RT PSA level, extraprostatic tumor extension, and seminal vesicle invasion were associated with worse biochemical failure and distant metastasis outcomes. A salvage radiation dose of >= 66.0 Gy was associated with a reduced cumulative incidence of biochemical failure, but not of distant metastasis. Conclusions: The use of salvage radiation doses of >= 66.0 Gy are supported by evidence presented in the present multicenter pooled analysis of individual patient data. The observational reporting method, limited sample size, few distant metastasis events, modest follow-up duration, and elective use of salvage therapy might have diminished the opportunity to identify an association between the radiation dose and this endpoint. (C) 2016 Elsevier Inc. All rights reserved. C1 [Pisansky, Thomas M.] Mayo Clin, Dept Radiat Oncol, 200 First St SW, Rochester, MN 55905 USA. [Agrawal, Shree] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Hamstra, Daniel A.; Feng, Felix Y.] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. [Koontz, Bridget F.; Lee, W. Robert] Duke Canc Inst, Dept Radiat Oncol, Durham, NC USA. [Liauw, Stanley L.] Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA. [Efstathiou, Jason A.; Zietman, Anthony L.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Michalski, Jeff M.] Washington Univ, Dept Radiat Oncol, St Louis, MO USA. [Abramowitz, Matthew C.; Pollack, Alan] Univ Miami, Dept Radiat Oncol, Miami, FL USA. [Anscher, Mitchell S.; Moghanaki, Drew] Virginia Commonwealth Univ, Dept Radiat Oncol, Richmond, VA USA. [Moghanaki, Drew] Hunter Holmes McGuire Vet Adm Med Ctr, Richmond, VA USA. [Den, Robert B.] Thomas Jefferson Univ, Dept Radiat Oncol, Philadelphia, PA 19107 USA. [Stephans, Kevin L.; Tendulkar, Rahul D.] Cleveland Clin, Dept Radiat Oncol, Cleveland, OH 44106 USA. [Kattan, Michael W.] Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA. [Stephenson, Andrew J.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. RP Pisansky, TM (reprint author), Mayo Clin, Dept Radiat Oncol, 200 First St SW, Rochester, MN 55905 USA. EM pisansky.thomas@mayo.edu FU Novartis; Janssen Pharmaceuticals; Prostate Cancer Foundation; Varian Medical Systems; Elekta; Elsevier Publishing; Practical Radiation Oncology FX Dr Pisansky is a member of the NRG Oncology Genitourinary Core Committee. Dr Hamstra received a research grant from Novartis; is a consultant to Augmenix, Johnson & Johnson, Medivation, and Myriad; and is a member of the Speaker's Bureau for Varian. Dr Koontz received a research grant from Janssen Pharmaceuticals; is on the advisory board of Blue Earth Diagnostics, GenomeDx Biosciences, and ChanRX; and is a member of the NRG Oncology Genitourinary Core Committee, Cancer Prevention Control Committee, IHE-RO Planning Committee, and Clinical Advisory Committee. Dr Efstathiou received funding from the Prostate Cancer Foundation; is a member of the NRG Oncology Genitourinary Core Committee and the Massachusetts Prostate Cancer Coalition Board of Directors; is Co-Chair of the National Cancer Institute Bladder Task Force and NRG Comparative Effectiveness Committee; is Chair of the American Society for Radiation Oncology Genitourinary Track; is on the advisory board of Medivation/Astellas and Genetech; and is a member of the Joint Safety Review Committee for Bayer Healthcare. Dr Feng received funding from Varian Medical Systems; is a consultant to Astellas/Medivation, Celgene, and GenomeDx Biosciences; is President and Founder of PFS Genomics; and is a liaison to the NRG Oncology Genitourinary Translational Research Program. Dr Abramowitz is a consultant to General Electric Corporation and received grant funding from Elekta. Dr Pollack is a consultant to Astellas/Medivation. Dr Den is a member of the Advisory Board of GenomeDx Biosciences and Bayer Healthcare. Dr Zietman receives an editorial stipend from Elsevier Publishing. Dr Lee receives royalties from UpToDate and a stipend from Practical Radiation Oncology as editor-in-chief. The remaining authors report no conflicts of interest. 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 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD DEC 1 PY 2016 VL 96 IS 5 BP 1046 EP 1053 DI 10.1016/j.ijrobp.2016.08.043 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EJ5XM UT WOS:000393292200029 PM 27745980 ER PT J AU Unkelbach, J Botas, P Giantsoudi, D Gorissen, BL Paganetti, H AF Unkelbach, Jan Botas, Pablo Giantsoudi, Drosoula Gorissen, Bram L. Paganetti, Harald TI Reoptimization of Intensity Modulated Proton Therapy Plans Based on Linear Energy Transfer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID RELATIVE BIOLOGICAL EFFECTIVENESS; PARTICLE THERAPY; OPTIMIZATION; MODEL; BEAMS; IMRT AB Purpose: We describe a treatment plan optimization method for intensity modulated proton therapy (IMPT) that avoids high values of linear energy transfer (LET) in critical structures located within or near the target volume while limiting degradation of the best possible physical dose distribution. Methods and Materials: To allow fast optimization based on dose and LET, a GPU-based Monte Carlo code was extended to provide dose-averaged LET in addition to dose for all pencil beams. After optimizing an initial IMPT plan based on physical dose, a prioritized optimization scheme is used to modify the LET distribution while constraining the physical dose objectives to values close to the initial plan. The LET optimization step is performed based on objective functions evaluated for the product of LET and physical dose (LET x D). To first approximation, LET x D represents a measure of the additional biological dose that is caused by high LET. Results: The method is effective for treatments where serial critical structures with maximum dose constraints are located within or near the target. We report on 5 patients with intracranial tumors (high-grade meningiomas, base-of-skull chordomas, ependymomas) in whom the target volume overlaps with the brainstem and optic structures. In all cases, high LET x D in critical structures could be avoided while minimally compromising physical dose planning objectives. Conclusion: LET-based reoptimization of IMPT plans represents a pragmatic approach to bridge the gap between purely physical dose-based and relative biological effectiveness (RBE)-based planning. The method makes IMPT treatments safer by mitigating a potentially increased risk of side effects resulting from elevated RBE of proton beams near the end of range. (C) 2016 Elsevier Inc. All rights reserved. C1 [Unkelbach, Jan; Botas, Pablo; Giantsoudi, Drosoula; Gorissen, Bram L.; Paganetti, Harald] Massachusetts Gen Hosp, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA. [Botas, Pablo] Heidelberg Univ, Fac Phys, Heidelberg, Germany. RP Unkelbach, J (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA. EM junkelbach@mgh.harvard.edu FU National Cancer Institute [U19 CA021239-35]; Federal Share of program income earned by Massachusetts General Hospital, Proton Therapy Research and Treatment Center [C06 CA059267] FX Supported in part by the National Cancer Institute (grant U19 CA021239-35) and the Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267, Proton Therapy Research and Treatment Center. NR 17 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 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD DEC 1 PY 2016 VL 96 IS 5 BP 1097 EP 1106 DI 10.1016/j.ijrobp.2016.08.038 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EJ5XM UT WOS:000393292200035 PM 27869082 ER PT J AU Zietman, A Smith, J Klein, E Droller, M Dasgupta, P Catto, J AF Zietman, Anthony Smith, Joseph Klein, Eric Droller, Michael Dasgupta, Prokar Catto, James TI Editorial Statement on Gleason Scoring for Prostate Cancer Reply SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Letter C1 [Zietman, Anthony] Massachusetts Gen Hosp, Phys, Int Journal Radiat Oncol Biol, Boston, MA 02114 USA. RP Zietman, A (reprint author), Massachusetts Gen Hosp, Phys, Int Journal Radiat Oncol Biol, Boston, MA 02114 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD DEC 1 PY 2016 VL 96 IS 5 BP 1127 EP 1128 DI 10.1016/j.ijrobp.2016.02.055 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EJ5XM UT WOS:000393292200041 PM 27869088 ER PT J AU Fava, M Menard, F Davidsen, CK Baker, RA AF Fava, Maurizio Menard, Francois Davidsen, Charlotte Kampp Baker, Ross A. TI Adjunctive Brexpiprazole in Patients With Major Depressive Disorder and Irritability: An Exploratory Study SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID PHYSICAL FUNCTIONING QUESTIONNAIRE; ANGER ATTACKS; INADEQUATE RESPONSE; VALIDITY; SCALE; MICE; ANTIDEPRESSANTS; RELIABILITY; VALIDATION; SEVERITY AB Objective: To evaluate the effects of adjunctive brexpiprazole on symptoms of irritability in patients with major depressive disorder (MDD). Methods: Patients diagnosed with MDD according to DSM-IV-TR criteria who had inadequate response to antidepressant treatment continued treatment with their current antidepressant for 2 weeks. Patients still having inadequate response, and with irritability, received 6 weeks of open-label treatment with their current antidepressant at the same dose and adjunctive brexpiprazole (target dose: 3 mg/d). Brexpiprazole was discontinued at week 6, and the patients continued with their antidepressant until week 10. Changes from baseline to week 6 and week 6 to week 10 were analyzed. Results: This study was conducted between October 7, 2013, and July 30, 2014. Fifty-four patients were treated with adjunctive brexpiprazole. At week 6, clinically relevant improvements were observed in Sheehan Irritability Scale total (-21.1) and item 1 (irritable mood) (-3.5) scores, Kellner Symptom Questionnaire total (-24.4) and anger-hostility subscale (-7.7) scores, and 30-item Inventory of Depressive Symptomatology, clinician version (IDS-C30), item 6 (irritable mood) score (-1.2). More (15 patients) stopped than developed (5 patients) anger attacks during treatment, as measured by the Anger Attacks Questionnaire. The Clinical Global Impressions-Severity of Illness score improved (-1.4), as did the depressive symptoms (IDS-C30 total score, -17.8; Kellner Symptom Questionnaire depression subscale score, -7.7; and Montgomery-Asberg Depression Rating Scale total score, -14.2). Irritability symptoms worsened after brexpiprazole discontinuation, assessed at week 10. Adjunctive brexpiprazole was well tolerated. Conclusions: Adjunctive treatment with brexpiprazole may represent a strategy for patients with MDD and inadequate response to antidepressant treatment who have symptoms of irritability. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Fava, Maurizio] Massachusetts Gen Hosp, 55 Fruit St,Bulfinch 351, Boston, MA 02114 USA. [Menard, Francois; Davidsen, Charlotte Kampp] H Lundbeck & Co AS, Valby, Denmark. [Baker, Ross A.] Otsuka Pharmaceut Dev & Commercializat Inc, Princeton, NJ USA. RP Fava, M (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Bulfinch 351, Boston, MA 02114 USA. EM mfava@mgh.harvard.edu FU H. Lundbeck A/S (Valby, Denmark); Otsuka Pharmaceutical Development & Commercialization, Inc (Princeton, New Jersey) FX This work was supported by H. Lundbeck A/S (Valby, Denmark) and Otsuka Pharmaceutical Development & Commercialization, Inc (Princeton, New Jersey). NR 30 TC 2 Z9 2 U1 1 U2 1 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD DEC PY 2016 VL 77 IS 12 BP 1695 EP + DI 10.4088/JCP.15m10470 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EJ2EL UT WOS:000393022700025 PM 27379823 ER PT J AU Egede, LE Acierno, R Knapp, RG Walker, RJ Payne, EH Frueh, BC AF Egede, Leonard E. Acierno, Ron Knapp, Rebecca G. Walker, Rebekah J. Payne, Elizabeth H. Frueh, B. Christopher TI Psychotherapy for Depression in Older Veterans Via Telemedicine: Effect on Quality of Life, Satisfaction, Treatment Credibility, and Service Delivery Perception SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID BEHAVIORAL ACTIVATION TREATMENT; HEALTH SURVEY QUESTIONNAIRE; COLLABORATIVE CARE; TELEMENTAL HEALTH; RANDOMIZED-TRIAL; ADULTS; SF-36; TELEPSYCHIATRY; EPIDEMIOLOGY; POPULATION AB Objective: To analyze the impact of telepsychology and same-room care on functioning, satisfaction, and perception of care based on a noninferiority trial of psychotherapy delivered via telemedicine or same-room care to elderly patients with depression. Methods: 241 elderly patients with depression (meeting DSM-IV diagnostic criteria) were randomly assigned to either telemedicine (n = 120) or same-room treatment (n = 121) between April 1, 2007, and July 31, 2011. The primary outcomes included quality of life (36-item Short Form Survey [SF-36]), satisfaction (Charleston Psychiatric Outpatient Satisfaction Scale), treatment credibility, and service delivery perception scores obtained at 4 weeks, 8 weeks, 3 months, and 12 months. Comparisons of intervention means were carried out at each time point using independent sample t tests and SAS Procedure MIANALYZE to combine results across the multiply imputed complete data sets. If significant differences were detected for a given outcome within a domain, a Bonferroni correction was applied to determine if significance was maintained. Results: None of the SF-36 scores showed a significant difference between the 2 treatment groups by the end of the study period, with little significance shown throughout the intermediate time points. Similarly, over all time points, there was no statistically significant difference in patient satisfaction or treatment credibility. Conclusions: This study found that telemedicine is a viable alternative modality for providing evidence-based psychotherapy for elderly patients with depression. Results provide evidence that quality of life and satisfaction with care are not adversely influenced by the decision to use a telehealth modality instead of in-person treatment, and, as a result, resources can be devoted to offering services in patients' homes through telemedicine. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Egede, Leonard E.; Acierno, Ron; Knapp, Rebecca G.; Walker, Rebekah J.; Payne, Elizabeth H.] Ralph H Johnson Vet Affairs Med Ctr, HEROIC, Charleston, SC USA. [Egede, Leonard E.; Walker, Rebekah J.] Med Univ South Carolina, Ctr Hlth Dispar Res, 135 Rutledge Ave,Room 280G, Charleston, SC 29425 USA. [Egede, Leonard E.; Walker, Rebekah J.] Med Univ South Carolina, Dept Med, Div Gen Internal Med & Geriatr, Charleston, SC USA. [Acierno, Ron] Med Univ South Carolina, Coll Nursing, Charleston, SC USA. [Knapp, Rebecca G.; Payne, Elizabeth H.] Med Univ South Carolina, Dept Publ Hlth Sci, Charleston, SC USA. [Frueh, B. Christopher] Univ Hawaii, Dept Psychol, Hilo, HI 96720 USA. [Frueh, B. Christopher] Menninger Clin, Dept Psychol, Houston, TX USA. RP Egede, LE (reprint author), Med Univ South Carolina, Ctr Hlth Dispar Res, 135 Rutledge Ave,Room 280G, Charleston, SC 29425 USA. EM egedel@musc.edu FU US Veterans Affairs Health Services Research and Development program [IIR 04-421] FX This study was supported by grant IIR 04-421 funded by the US Veterans Affairs Health Services Research and Development program. NR 44 TC 0 Z9 0 U1 0 U2 0 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD DEC PY 2016 VL 77 IS 12 BP 1704 EP 1711 DI 10.4088/JCP.16m10951 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EJ2EL UT WOS:000393022700027 PM 27835713 ER PT J AU Goodman, M Banthin, D Blair, NJ Mascitelli, KA Wilsnack, J Chen, J Messenger, JW Perez-Rodriguez, MM Triebwasser, J Koenigsberg, HW Goetz, RR Hazlett, EA New, AS AF Goodman, Marianne Banthin, David Blair, Nicholas J. Mascitelli, Kathryn A. Wilsnack, Jaime Chen, Jennifer Messenger, Julie W. Perez-Rodriguez, M. Mercedes Triebwasser, Joseph Koenigsberg, Harold W. Goetz, Raymond R. Hazlett, Erin A. New, Antonia S. TI A Randomized Trial of Dialectical Behavior Therapy in High-Risk Suicidal Veterans SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID BORDERLINE PERSONALITY-DISORDER; BINGE-EATING DISORDER; ADOLESCENTS; WOMEN; DEPRESSION; CARE; INTERVENTION; PREVENTION; INVENTORY; EFFICACY AB Objective: Despite advances in suicide prevention implemented throughout the US Department of Veterans Affairs (VA) including the hiring of Suicide Prevention Coordinators (SPCs) at every VA hospital, enhanced monitoring, and the availability of 24-hour crisis hotline services, suicide by veterans remains a critical problem affecting 20 veterans daily. Few empirically based treatment strategies for suicide prevention for postdeployment military personnel exist. This study aimed to test whether dialectical behavior therapy (DBT), one of the few psychosocial treatments with proven efficacy in diminishing suicidal behavior in individuals with personality disorder, can be applied to veterans irrespective of personality diagnosis. Methods: From January 2010 to December 2014, 91 nonpsychotic veterans at high risk for suicide (61 men, 30 women) were randomly assigned to a 6-month treatment trial at a veterans' medical center comparing standard DBT to treatment as usual (TAU) and followed for 6 months after trial completion. Primary outcome was suicide attempts, measured with the Columbia-Suicide Severity Rating Scale, and secondary outcomes were suicide ideation, depression, hopelessness, and anxiety. There were no exclusions pertaining to substance abuse, homelessness, or medical comorbidity. Results: Both DBT and TAU resulted in improvements in suicidal ideation, depression, and anxiety during the course of the 6-month treatment trial that did not differ between treatment arms. Survival analyses for suicide attempts and hospitalizations did not differ between treatment arms. However, DBT subjects utilized significantly more individual mental health services than TAU subjects (28.5 +/- 19.6 vs 14.7 +/- 10.9, F-1,F-77 = 11.60, P = .001). Conclusions: This study is the first to examine 6-month DBT in a mostly male, veteran population. Increased mental health treatment service delivery, which included enhanced monitoring, outreach, and availability of a designated SPC, did not yield statistically significant differences in outcome for veterans at risk for suicide in TAU as compared to the DBT treatment arm. However, both treatments had difficulty with initial engagement post-hospitalization. Future studies examining possible sex differences and strategies to boost retention in difficult-to-engage, homeless, and substance-abusing populations are indicated. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Goodman, Marianne; Perez-Rodriguez, M. Mercedes; Triebwasser, Joseph; Koenigsberg, Harold W.; Hazlett, Erin A.; New, Antonia S.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Goodman, Marianne; Blair, Nicholas J.; Mascitelli, Kathryn A.; Wilsnack, Jaime; Chen, Jennifer; Messenger, Julie W.; Hazlett, Erin A.] James J Peters VA Med Ctr, VISN Mental Illness Res Educ & Clin Ctr MIRECC 3, Bronx, NY USA. [Goodman, Marianne; Triebwasser, Joseph; Koenigsberg, Harold W.] James J Peters VA Med Ctr, Outpatient Psychiat, Bronx, NY USA. [Banthin, David] Mt Sinai St Lukes Roosevelt, Ctr Intens Treatment Personal Disorders, New York, NY USA. [Goetz, Raymond R.] New York State Psychiat Inst & Hosp, Div Clin Phenomenol, New York, NY 10032 USA. [Goetz, Raymond R.] Columbia Univ, Coll Phys & Surg, New York, NY 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 US Department of Defense Grant [WX81XWH-09-1-0722] FX This study was supported by US Department of Defense Grant WX81XWH-09-1-0722 (to Dr Goodman, principal investigator). NR 54 TC 2 Z9 2 U1 6 U2 6 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 DEC PY 2016 VL 77 IS 12 BP E1591 EP E1600 DI 10.4088/JCP.15m10235 PG 10 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EJ2EL UT WOS:000393022700007 PM 27780335 ER PT J AU Weamer, EA DeMichele-Sweet, MAA Cloonan, YK Lopez, OL Sweet, RA AF Weamer, Elise A. DeMichele-Sweet, Mary Ann A. Cloonan, Yona K. Lopez, Oscar L. Sweet, Robert A. TI Incident Psychosis in Subjects With Mild Cognitive Impairment or Alzheimer's Disease SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; LAST 2 DECADES; NEUROPSYCHIATRIC SYMPTOMS; NATIONAL INSTITUTE; RISK-FACTORS; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; FOLLOW-UP; DEMENTIA; HALLUCINATIONS AB Objective: To estimate the incidence of psychotic symptoms in Alzheimer's disease. Methods: The study consists of 776 elderly subjects presenting to the Alzheimer Disease Research Center at the University of Pittsburgh (Pittsburgh, Pennsylvania) between May 9, 2000, and August 19, 2014. All participants were diagnosed with mild cognitive impairment (National Institute on Aging-Alzheimer's Association workgroup criteria) or possible or probable Alzheimer's disease (National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria) and were without psychosis at entry. Psychotic symptoms were evaluated using the Consortium to Establish a Registry for Alzheimer's Disease Behavioral Rating Scale every 6 months. One-, 3- and 5-year cumulative incidences of psychosis were calculated. Results: The 1-year psychosis incidence was 10% (95% CI, 8%-12%), and this annual rate remained remarkably consistent at 3 and 5 years. Psychosis incidence was related to cognitive status at all time points. However, the incidence rate reached a plateau during the disease course. Cumulative psychosis incidence at 5 years was 61% (95% CI, 52%-69%) in individuals with moderate to severe Alzheimer's disease, not statistically significantly different from the cumulative incidence at 3 years in this group, which was 48% (95% CI, 40%-55%) or from the 5-year incidence in individuals who entered the study with mild Alzheimer's disease, which was 48% (95% CI, 41%-56%). Conclusions: Psychosis in Alzheimer's disease has been associated with a number of adverse clinical outcomes. We provide estimates of the risk of psychosis onset within clinically defined subgroups of individuals, a tool clinicians can use in treatment planning. Anticipating which subjects are at high risk for psychosis and the poor outcomes associated with it can help with family education and support decisions to implement nonpharmacologic strategies that may reduce or prevent symptoms. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Weamer, Elise A.; Lopez, Oscar L.; Sweet, Robert A.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15260 USA. [DeMichele-Sweet, Mary Ann A.; Lopez, Oscar L.; Sweet, Robert A.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA. [Cloonan, Yona K.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Sweet, Robert A.] VA Pittsburgh Healthcare Syst, VISN Mental Illness Res Educ & Clin Ctr 4, Pittsburgh, PA USA. RP Sweet, RA (reprint author), Biomed Sci Tower,Rm W-1645,3811 OHara St, Pittsburgh, PA 15213 USA. EM sweetra@upmc.edu FU Veterans Health Administration Grant [BX000452]; National Institutes of Health Grants [AG027224, AG005133] FX This work was supported by Veterans Health Administration Grant BX000452 and National Institutes of Health Grants AG027224 and AG005133. NR 46 TC 0 Z9 0 U1 0 U2 0 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD DEC PY 2016 VL 77 IS 12 BP E1564 EP + DI 10.4088/JCP.15m10617 PG 10 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EJ2EL UT WOS:000393022700003 PM 28086011 ER PT J AU Shaffer, KM Riklin, E Jacobs, JM Rosand, J Vranceanu, AM AF Shaffer, Kelly M. Riklin, Eric Jacobs, Jamie M. Rosand, Jonathan Vranceanu, Ana-Maria TI Psychosocial resiliency is associated with lower emotional distress among dyads of patients and their informal caregivers in the neuroscience intensive care unit SO JOURNAL OF CRITICAL CARE LA English DT Article DE Neuroscience ICU; Anxiety; Depression; Anger; Resilience; Informal caregiver ID QUALITY-OF-LIFE; CORONARY-HEART-DISEASE; STRESS-MANAGEMENT; CANCER-PATIENTS; INITIAL VALIDATION; INTIMATE BONDS; SELF-EFFICACY; RISK-FACTORS; STROKE; DEPRESSION AB Purpose: The purpose of the study is to examine the associations of patients' and their informal caregivers' psychosocial resiliency factors with their own and their partners' emotion domains (distress, anxiety, depression, and anger) after admission to the neuroscience intensive care unit (Neuro-ICU). Materials and methods: Eighty-three dyads of patients (total n= 87) and their informal caregivers (total n= 99) participated in this observational, cross-sectional study by self-reporting demographics and measures of resiliency factors (mindfulness [Cognitive and Affective Mindfulness Scale Revised], coping [Measure of Coping Status-A], intimate bond [Intimate Bond Measure], self-efficacy [patients: General Self-Efficacy Scale; caregivers: Revised Caregiver Self-Efficacy Scale]) and emotion domains (Emotion Thermometers) within 2 weeks of Neuro-ICU admission. Results: There were no differences between patients' and caregivers' levels of psychosocial resiliency, distress, or anxiety. Patients reported greater depression and anger relative to their caregivers. Overall, roughly half of patients (50.6%) and caregivers (42.4%) reported clinically significant emotional distress. Patients' and caregivers' own psychosocial resiliency factors were associated with their own, but not their partner's, emotion domains. Conclusions: Findings of high distress among both patients and caregivers at admission emphasize the importance of attending to the mental health of both patients and caregivers in the Neuro-ICU. As modifiable psychosocial resiliency factors were associated with emotion domains for both patients and caregivers, interventions to enhance these factors may ameliorate emotional distress among these vulnerable populations. (C) 2016 Elsevier Inc. All rights reserved. C1 [Shaffer, Kelly M.; Riklin, Eric; Jacobs, Jamie M.; Vranceanu, Ana-Maria] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Shaffer, Kelly M.] Univ Miami, Dept Psychol, POB 248185, Coral Gables, FL 33124 USA. [Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Div Neurocrit & Emergency Neurol, Boston, MA 02114 USA. RP Vranceanu, AM (reprint author), Massachusetts Gen Hosp, Behav Med Serv, Dept Psychiat, One Bowdoin Sq,7th Floor,Suite 758, Boston, MA 02114 USA. EM avranceanu@partners.org OI Shaffer, Kelly/0000-0002-9749-8006 FU National Institute of Neurological Disorders and Stroke Clinical Trials Methodology Course [5R25NS088248-02] FX This work was supported by the National Institute of Neurological Disorders and Stroke Clinical Trials Methodology Course (grant no. 5R25NS088248-02 to Dr Vranceanu). NR 46 TC 0 Z9 0 U1 6 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 0883-9441 EI 1557-8615 J9 J CRIT CARE JI J. Crit. Care PD DEC PY 2016 VL 36 BP 154 EP 159 DI 10.1016/j.jcrc.2016.07.010 PG 6 WC Critical Care Medicine SC General & Internal Medicine GA EJ2YS UT WOS:000393078100028 PM 27546765 ER PT J AU Sin, JH Berger, K Lesch, CA AF Sin, Jonathan H. Berger, Karen Lesch, Christine A. TI Four-factor prothrombin complex concentrate for life-threatening bleeds or emergent surgery: A retrospective evaluation SO JOURNAL OF CRITICAL CARE LA English DT Article DE prothrombin complex concentrates; blood coagulation factors; anticoagulants; vitamin K; thrombosis; anticoagulant reversal ID K ANTAGONIST REVERSAL; FRESH-FROZEN PLASMA; REQUIRING URGENT REVERSAL; VITAMIN-K; WARFARIN REVERSAL; ORAL ANTICOAGULANTS; INTRACRANIAL HEMORRHAGE; HEALTHY-VOLUNTEERS; CARDIAC-SURGERY; BERIPLEX P/N AB Purpose: Previous trials investigating usage of four-factor prothrombin complex concentrate (4F-PCC) excluded patients with various thrombotic risk factors. The objective of this study was to evaluate the safety and effectiveness of 4F-PCC in a real-world setting based on an institutional protocol that does not have strict exclusion criteria. Methods: This was a retrospective study of adult patients who received 4F-PCC. The primary outcome was a confirmed thromboembolism within 14 days after 4F-PCC administration. Secondary outcomes included international normalized ratio (INR) correction to <1.5 at first draw and incidence of INR rebound for patients undergoing reversal of warfarin and hemostatic effectiveness for patients experiencing a bleed. Results: Ninety-three patients received 4F-PCC. Sixty-three (67.7%) were reversed for bleeding and 30 (32.3%) for surgery. Eleven patients (11.8%) developed a thromboembolism within 14 days. The median (interquartile range) time to event was 5 (2-7) days. Significant risk factors were heparin-induced thrombocytopenia (P=.01) and major surgery within 14 days (P=.02), as well as the presence of >6 thrombotic risk factors (P=.01). For patients post-warfarin reversal, 45/63 (71.4%) achieved INR correction at first draw, 55/63 (87.3%) achieved INR correction within 24 hours, and 14/55 (25.5%) experienced INR rebound. Of these 14 patients, 8 (57.1%) did not receive concomitant vitamin K. Conclusions: 4F-PCC was associated with a notable thromboembolic risk. All patient-specific risk factors should be considered prior to administration. 4F-PCC remains a useful agent for warfarin reversal. Lack of concomitant vitamin K may contribute to INR rebound. (C) 2016 Elsevier Inc. All rights reserved. C1 [Sin, Jonathan H.; Berger, Karen] NewYork Presbyterian Hosp, Weill Cornell Med Ctr, Dept Pharm, 525 East 68th St, New York, NY 10065 USA. [Lesch, Christine A.] Columbia Univ, Med Ctr, NewYork Presbyterian Hosp, Dept Pharm, 630 West 168th St, New York, NY 10032 USA. RP Sin, JH (reprint author), Massachusetts Gen Hosp, Dept Pharm, 55 Fruit St,GRB 005, Boston, MA 02114 USA. EM rxjsin@gmail.com; cal9005@nyp.org NR 61 TC 1 Z9 1 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 0883-9441 EI 1557-8615 J9 J CRIT CARE JI J. Crit. Care PD DEC PY 2016 VL 36 BP 166 EP 172 DI 10.1016/j.jcrc.2016.06.024 PG 7 WC Critical Care Medicine SC General & Internal Medicine GA EJ2YS UT WOS:000393078100030 PM 27546767 ER PT J AU Attridge, RT Frei, CR Pugh, MJV Lawson, KA Ryan, L Anzueto, A Metersky, ML Restrepo, MI Mortensen, EM AF Attridge, Russell T. Frei, Christopher R. Pugh, Mary Jo V. Lawson, Kenneth A. Ryan, Laurajo Anzueto, Antonio Metersky, Mark L. Restrepo, Marcos I. Mortensen, Eric M. TI Health care-associated pneumonia in the intensive care unit: Guideline-concordant antibiotics and outcomes SO JOURNAL OF CRITICAL CARE LA English DT Article DE Pneumonia; Critical care; Guideline-concordant therapy; Health outcomes; Antibiotic therapy ID COMMUNITY-ACQUIRED PNEUMONIA; MULTIDRUG-RESISTANT PATHOGENS; CLINICAL-OUTCOMES; RISK-FACTORS; HOSPITALIZED-PATIENTS; THERAPY; EPIDEMIOLOGY; MULTICENTER; MORTALITY; METAANALYSIS AB Purpose: Recent data have not demonstrated improved outcomes when guideline-concordant (GC) antibiotics are given to patients with health care-associated pneumonia (HCAP). This study was designed to evaluate the relationship between health outcomes and GC therapy in patients admitted to an intensive care unit (ICU) with HCAP. Materials and methods: We performed a population-based cohort study of patients admitted to greater than 150 hospitals in the US Veterans Health Administration system to compare baseline characteristics, bacterial pathogens, and health outcomes in ICU patients with HCAP receiving GC-HCAP therapy, GC community acquired pneumonia (GC-CAP) therapy, or non-GC therapy. The primary outcome was 30-day patient mortality. Risk factors for the primary outcome were assessed in a multivariable logistic regression model. Results: A total of 3593 patients met inclusion criteria and received GC-HCAP therapy (26%), GC-CAP therapy (23%), or non-GC therapy (51%). Patients receiving GC-HCAP had higher 30-day patient mortality compared to GC-CAP patients (34% vs 22%; P<.0001). After controlling for confounders, risk factors for 30-day patient mortality were vasopressor use (odds ratio, 1.67; 95% confidence interval, 1.30-2.13), recent hospital admission (1.53; 1.15-2.02), and receipt of GC-HCAP therapy (1.51; 1.20-1.90). Conclusions: Our data do not demonstrate improved outcomes among ICU patients with HCAP who received GC-HCAP therapy. Published by Elsevier Inc. C1 [Attridge, Russell T.] Univ Incarnate Word, Feik Sch Pharm, 4301 Broadway,CPO 99, San Antonio, TX 78209 USA. [Attridge, Russell T.; Pugh, Mary Jo V.; Anzueto, Antonio; Restrepo, Marcos I.] South Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX 78229 USA. [Frei, Christopher R.; Lawson, Kenneth A.; Ryan, Laurajo] Univ Texas Austin, Coll Pharm, Austin, TX 78712 USA. [Frei, Christopher R.; Ryan, Laurajo] Univ Texas Hlth Sci Ctr San Antonio, Sch Med, Pharmacotherapy Educ & Res Ctr, San Antonio, TX 78229 USA. [Pugh, Mary Jo V.; Ryan, Laurajo; Anzueto, Antonio; Restrepo, Marcos I.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Metersky, Mark L.] Univ Connecticut, Sch Med, Farmington, CT 06030 USA. [Mortensen, Eric M.] VA North Texas Hlth Care Syst, Gen Internal Med Sect, Dallas, TX 75216 USA. [Mortensen, Eric M.] Univ Texas Southwestern Med Ctr Dallas, Div Gen Internal Med, Dallas, TX 75390 USA. RP Attridge, RT (reprint author), Univ Incarnate Word, Feik Sch Pharm, 4301 Broadway,CPO 99, San Antonio, TX 78209 USA. EM attridge@uiwtx.edu; freic@uthscsa.edu; pughm@uthscsa.edu; ken.lawson@austin.utexas.edu; ryanl@uthscsa.edu; anzueto@uthscsa.edu; Metersky@nso.uchc.edu; restrepom@uthscsa.edu; eric.mortensen@utsouthwestern.edu OI Mortensen, Eric/0000-0002-3880-5563 FU National Institute of Nursing Research [R01NR010828]; Agency for Health Care Research and Quality [1R24HS022418-01]; National Heart, Lung, and Blood Institute [K23HL096054] FX This project was supported by grant number R01NR010828 from the National Institute of Nursing Research. Dr. Mortensenwas supported by Project Number 1R24HS022418-01 from the Agency for Health Care Research and Quality. Dr. Restrepo's time is partially protected by Award Number K23HL096054 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health; the Department of Veterans Affairs; or the National Heart, Lung, and Blood Institute. This material is the result of work supported with resources and the use of facilities at the South Texas Veterans Health Care System and VA North Texas Health Care System. The funding agencies had no role in conducting the study or role in the preparation, review, or approval of the manuscript. NR 40 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 0883-9441 EI 1557-8615 J9 J CRIT CARE JI J. Crit. Care PD DEC PY 2016 VL 36 BP 265 EP 271 DI 10.1016/j.jcrc.2016.08.004 PG 7 WC Critical Care Medicine SC General & Internal Medicine GA EJ2YS UT WOS:000393078100046 PM 27595461 ER PT J AU Soni, NJ Reyes, LF Keyt, H Arango, A Gelfond, JA Peters, JI Levine, SM Adams, SG Restrepo, MI AF Soni, Nilam J. Reyes, Luis F. Keyt, Holly Arango, Alejandro Gelfond, Jonathan A. Peters, Jay I. Levine, Stephanie M. Adams, Sandra G. Restrepo, Marcos I. TI Use of ultrasound guidance for central venous catheterization: a national survey of intensivists and hospitalists SO JOURNAL OF CRITICAL CARE LA English DT Article DE Central venous catheters; Central venous catheterization; Ultrasound; Jugular vein; Subclavian vein; Femoral vein ID CRITICAL-CARE MEDICINE; EMERGENCY-DEPARTMENT; TIME ULTRASOUND; SELF-REPORT; GUIDELINES; PLACEMENT; CANNULATION; INFECTIONS; PHYSICIANS; METAANALYSIS AB Purpose: The purpose of the study is to evaluate the frequency and barriers to use of ultrasound guidance for central venous catheter (CVC) insertion by physicians specializing in critical care and hospital medicine. Materials and methods: A national cross-sectional electronic survey of intensivists and hospitalists was administered from November 2014 to January 2015. Results: The survey response rate was 5.9% (1013/17 233). Moderate to very frequent use of ultrasound guidance varied by site: internal jugular vein (80%), subclavian vein (31%), and femoral vein (45%). Nearly all physicians (99%) who insert internal jugular CVCs daily use ultrasound guidance, whereas only 46% of physicians who insert subclavian CVCs daily use ultrasound guidance. Use of real-time ultrasound guidance varied by insertion site: internal jugular vein (73%), subclavian vein (28%), and femoral vein (42%). Most physicians (59%) reported not being comfortable with real-time needle tracking at the subclavian site. The most frequently reported barriers to use of ultrasound guidance were (1) limited availability of ultrasound equipment (28%), (2) perception of increased total procedure time (22%), and (3) concern for loss of landmark skills (13%). Conclusions: Most intensivists routinely use ultrasound guidance to insert internal jugular CVCs but not subclavian CVCs. The most commonly reported barrier to ultrasound use was limited access to an ultrasound machine. Published by Elsevier Inc. C1 [Soni, Nilam J.] Univ Texas Sch Med San Antonio, Div Hosp Med, San Antonio, TX 78229 USA. [Soni, Nilam J.; Reyes, Luis F.; Keyt, Holly; Peters, Jay I.; Levine, Stephanie M.; Adams, Sandra G.; Restrepo, Marcos I.] Univ Texas Sch Med San Antonio, Div Pulm & Crit Care Med, San Antonio, TX 78229 USA. [Soni, Nilam J.; Keyt, Holly; Peters, Jay I.; Levine, Stephanie M.; Adams, Sandra G.; Restrepo, Marcos I.] South Texas Vet Hlth Care Syst, Sect Pulm & Crit Care Med, San Antonio, TX 78229 USA. [Arango, Alejandro] Harvard Sch Dent Med, Dept Oral & Maxillofacial Surg, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gelfond, Jonathan A.] Univ Texas Hlth Sci Ctr, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. RP Soni, NJ (reprint author), 7703 Floyd Curl Dr,MC 7982, San Antonio, TX 78229 USA. EM sonin@uthscsa.edu FU Division of Pulmonary and Critical Care Medicine at the University of Texas Health Science Center San Antonio FX Institutional funds from the Division of Pulmonary and Critical Care Medicine at the University of Texas Health Science Center San Antonio. NR 50 TC 4 Z9 4 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 0883-9441 EI 1557-8615 J9 J CRIT CARE JI J. Crit. Care PD DEC PY 2016 VL 36 BP 277 EP 283 DI 10.1016/j.jcrc.2016.07.014 PG 7 WC Critical Care Medicine SC General & Internal Medicine GA EJ2YS UT WOS:000393078100048 PM 27491563 ER PT J AU Morioka, C Meng, F Taira, R Sayre, J Zimmerman, P Ishimitsu, D Huang, J Shen, LY El-Saden, S AF Morioka, Craig Meng, Frank Taira, Ricky Sayre, James Zimmerman, Peter Ishimitsu, David Huang, Jimmy Shen, Luyao El-Saden, Suzie TI Automatic Classification of Ultrasound Screening Examinations of the Abdominal Aorta SO JOURNAL OF DIGITAL IMAGING LA English DT Article DE Classification; Coding; Natural language processing; Abdominal aortic aneurysm ID ANEURYSM; PROGRAM AB Our work facilitates the identification of veterans who may be at risk for abdominal aortic aneurysms (AAA) based on the 2007 mandate to screen all veteran patients that meet the screening criteria. The main research objective is to automatically index three clinical conditions: pertinent negative AAA, pertinent positive AAA, and visually unacceptable image exams. We developed and evaluated a ConText-based algorithm with the GATE (General Architecture for Text Engineering) development system to automatically classify 1402 ultrasound radiology reports for AAA screening. Using the results from JAPE (Java Annotation Pattern Engine) transducer rules, we developed a feature vector to classify the radiology reports with a decision table classifier. We found that ConText performed optimally on precision and recall for pertinent negative (0.99 (0.98-0.99), 0.99 (0.99-1.00)) and pertinent positive AAA detection (0.98 (0.95-1.00), 0.97 (0.92-1.00)), and respectably for determination of non-diagnostic image studies (0.85 (0.77-0.91), 0.96 (0.91-0.99)). In addition, our algorithm can determine the AAA size measurements for further characterization of abnormality. We developed and evaluated a regular expression based algorithm using GATE for determining the three contextual conditions: pertinent negative, pertinent positive, and non-diagnostic from radiology reports obtained for evaluating the presence or absence of abdominal aortic aneurysm. ConText performed very well at identifying the contextual features. Our study also discovered contextual trigger terms to detect sub-standard ultrasound image quality. Limitations of performance included unknown dictionary terms, complex sentences, and vague findings that were difficult to classify and properly code. C1 [Morioka, Craig; Zimmerman, Peter; Ishimitsu, David; Huang, Jimmy; El-Saden, Suzie] VA Greater Los Angeles Healthcare Syst, Dept Radiol, Los Angeles, CA USA. [Morioka, Craig; Meng, Frank; Taira, Ricky; Sayre, James; El-Saden, Suzie] Univ Calif Los Angeles, Med Imaging Informat, Los Angeles, CA USA. [Morioka, Craig; Meng, Frank; Taira, Ricky; Sayre, James; Zimmerman, Peter; Ishimitsu, David; Huang, Jimmy; Shen, Luyao; El-Saden, Suzie] Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA USA. RP Morioka, C (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Radiol, Los Angeles, CA USA.; Morioka, C (reprint author), Univ Calif Los Angeles, Med Imaging Informat, Los Angeles, CA USA.; Morioka, C (reprint author), Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA USA. EM Craig.Morioka@va.gov NR 23 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0897-1889 EI 1618-727X J9 J DIGIT IMAGING JI J. Digit. Imaging PD DEC PY 2016 VL 29 IS 6 BP 742 EP 748 DI 10.1007/s10278-016-9889-6 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EJ3KY UT WOS:000393112300015 PM 27400914 ER PT J AU Herr, K Arnstein, P AF Herr, Keela Arnstein, Paul TI The Opioid Epidemic and Persistent Pain Management in Older Adults SO JOURNAL OF GERONTOLOGICAL NURSING LA English DT Editorial Material C1 [Herr, Keela] Univ Iowa, Coll Nursing, Iowa City, IA 52242 USA. [Arnstein, Paul] Massachusetts Gen Hosp, Clin Nurse Specialist Pain Relief, Boston, MA USA. RP Herr, K (reprint author), Univ Iowa, Coll Nursing, Iowa City, IA 52242 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0098-9134 EI 1938-243X J9 J GERONTOL NURS JI J. Gerontol. Nurs. PD DEC PY 2016 VL 42 IS 12 BP 3 EP 4 DI 10.3928/00989134-20161110-01 PG 2 WC Geriatrics & Gerontology; Gerontology; Nursing SC Geriatrics & Gerontology; Nursing GA EJ4MS UT WOS:000393192000001 PM 27898127 ER PT J AU Marie, BS Arnstein, P AF Marie, Barbara St. Arnstein, Paul TI Quality Pain Care for Older Adults in an Era of Suspicion and Scrutiny SO JOURNAL OF GERONTOLOGICAL NURSING LA English DT Article ID OPIOID-TREATED PATIENTS; SUBSTANCE USE DISORDER; SELF-MANAGEMENT; DRUG-USE; COMMUNITY; PEOPLE; EXPERIENCES; VALIDATION; STRATEGIES; GUIDELINE AB In two decades, the pendulum has swung from focusing on the undertreatment of pain by prescribers who fail to use medically necessary opioid agents to an intense focus on overprescribing opioid medications and the harms they cause. Within these two extremes rests the older adult with pain and in need of safe and effective care. Today, health care providers are practicing in an era of scrutiny, with new guidelines and regulations superseding their compassion and clinical judgment about the best treatment options when older adults have pain across the care continuum. Media depicting opioid medications as lethal, unnecessary, and highly addictive that do not distinguish non-medical from therapeutic use or legitimately versus illegally obtained drugs are widely reported. These reports and legislative focus on treating addiction have silenced and further stigmatized older adults with persistent pain. Patients and professionals treating pain need to provide balance of multimodal pain management strategies to safely manage persistent pain based on a comprehensive assessment and personalized approach. C1 [Marie, Barbara St.] Univ Iowa, Coll Nursing, 50 Newton Rd, Iowa City, IA 52242 USA. [Arnstein, Paul] Massachusetts Gen Hosp, Boston, MA USA. RP Marie, BS (reprint author), Univ Iowa, Coll Nursing, 50 Newton Rd, Iowa City, IA 52242 USA. EM Barbara-stmarie@uiowa.edu NR 58 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0098-9134 EI 1938-243X J9 J GERONTOL NURS JI J. Gerontol. Nurs. PD DEC PY 2016 VL 42 IS 12 BP 31 EP 39 DI 10.3928/00989134-20161110-07 PG 9 WC Geriatrics & Gerontology; Gerontology; Nursing SC Geriatrics & Gerontology; Nursing GA EJ4MS UT WOS:000393192000005 PM 27898134 ER PT J AU Yu, KOA Randolph, AG Agan, AA Yip, WK Truemper, EJ Weiss, SL Ackerman, KG Schwarz, AJ Giuliano, JS Hall, MW Wardenburg, JB AF Yu, Karl O. A. Randolph, Adrienne G. Agan, Anna A. Yip, Wai-Ki Truemper, Edward J. Weiss, Scott L. Ackerman, Kate G. Schwarz, Adam J. Giuliano, John S., Jr. Hall, Mark W. Wardenburg, Juliane Bubeck CA PALISI PICFlu Study Grp TI Staphylococcus aureus alpha-Toxin Response Distinguishes Respiratory Virus-Methicillin-Resistant S. aureus Coinfection in Children SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE influenza; pneumonia; bacteria; intensive care unit; pediatric; respiratory failure ID INFLUENZA-VIRUS; UNITED-STATES; PNEUMONIA; INFECTION; EPIDEMIC; ANTIBODY; EXOTOXINS; SEPSIS; MICE AB Background. Development of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia after a respiratory viral infection is frequently fatal in children. In mice, S. aureus alpha-toxin directly injures pneumocytes and increases mortality, whereas alpha-toxin blockade mitigates disease. The role of alpha-toxin in pediatric staphylococcal-viral coinfection is unclear. Methods. We enrolled children across 34 North American pediatric intensive care units with acute respiratory failure and suspected influenza virus infection. Serial serum anti-alpha-toxin antibody titers and functional alpha-toxin neutralization capacity were compared across children coinfected with MRSA or methicillin-susceptible S. aureus (MSSA) and control children infected with influenza virus only. MRSA isolates were tested for a-toxin production and lethality in a murine pneumonia model. Results. Influenza virus was identified in 22 of 25 children with MRSA coinfection (9 died) and 22 patients with MSSA coinfection (all survived). Initial alpha-toxin-specific antibody titers were similar, compared with those in the 13 controls. In patients with serial samples, only MRSA-coinfected patients showed time-dependent increases in anti-a-toxin titer and functional neutralization capacity. MRSA alpha-toxin production from patient isolates correlated with initial serologic titers and with mortality in murine pneumonia. Conclusions. These data implicate a-toxin as a relevant antigen in severe pediatric MRSA pneumonia associated with respiratory viral infection, supporting a potential role for toxin-neutralizing therapy. C1 [Yu, Karl O. A.; Wardenburg, Juliane Bubeck] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. [Wardenburg, Juliane Bubeck] Univ Chicago, Dept Microbiol, Chicago, IL 60637 USA. [Randolph, Adrienne G.; Agan, Anna A.] Boston Childrens Hosp, Dept Anesthesia Perioperat & Pain Med, 300 Longwood Ave,Bader 634, Boston, MA 02115 USA. [Randolph, Adrienne G.; Agan, Anna A.] Harvard Med Sch, Dept Anaesthesia, Boston, MA USA. [Randolph, Adrienne G.; Agan, Anna A.] Harvard Med Sch, Dept Pediat, Boston, MA USA. [Yip, Wai-Ki] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Yip, Wai-Ki] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Truemper, Edward J.] Childrens Hosp Nebraska, Dept Pediat, Omaha, NE USA. [Weiss, Scott L.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Ackerman, Kate G.] Golisano Childrens Hosp, Dept Pediat, Rochester, NY USA. [Schwarz, Adam J.] Childrens Hosp Orange Cty, Dept Pediat, Orange, CA 92668 USA. [Giuliano, John S., Jr.] Yale New Haven Childrens Hosp, Dept Pediat, New Haven, CT USA. [Hall, Mark W.] Nationwide Childrens Hosp, Dept Pediat, Columbus, OH USA. RP Randolph, AG (reprint author), Boston Childrens Hosp, Dept Anesthesia Perioperat & Pain Med, 300 Longwood Ave,Bader 634, Boston, MA 02115 USA. EM adrienne.randolph@childrens.harvard.edu FU National Institutes of Health [AI084011, AI097434]; Centers for Disease Control and Prevention FX This work was supported by the National Institutes of Health (grants AI084011 [to A. G. R.] and AI097434 [to J. B. W.]) and the Centers for Disease Control and Prevention. NR 31 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 1 PY 2016 VL 214 IS 11 BP 1638 EP 1646 DI 10.1093/infdis/jiw441 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EJ3RH UT WOS:000393128800005 PM 27651418 ER PT J AU Reddy, KP Parker, RA Losina, E Baggett, TP Paltiel, AD Rigotti, NA Weinstein, MC Freedberg, KA Walensky, RP AF Reddy, Krishna P. Parker, Robert A. Losina, Elena Baggett, Travis P. Paltiel, A. David Rigotti, Nancy A. Weinstein, Milton C. Freedberg, Kenneth A. Walensky, Rochelle P. TI Impact of Cigarette Smoking and Smoking Cessation on Life Expectancy Among People With HIV: A US-Based Modeling Study SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE smoking; tobacco; smoking cessation; life expectancy; HIV; United States; mathematical model ID HUMAN-IMMUNODEFICIENCY-VIRUS; COMBINATION ANTIRETROVIRAL THERAPY; ONCE-DAILY DOLUTEGRAVIR; CORONARY-HEART-DISEASE; COST-EFFECTIVENESS; UNITED-STATES; INFECTED INDIVIDUALS; UNINFECTED INDIVIDUALS; NAIVE ADULTS; DOUBLE-BLIND AB Background. In the United States, > 40% of people infected with human immunodeficiency virus (HIV) smoke cigarettes. Methods. We used a computer simulation of HIV disease and treatment to project the life expectancy of HIV-infected persons, based on smoking status. We used age-and sex-specific data on mortality, stratified by smoking status. The ratio of the non-AIDS-related mortality risk for current smokers versus that for never smokers was 2.8, and the ratio for former smokers versus never smokers was 1.0-1.8, depending on cessation age. Projected survival was based on smoking status, sex, and initial age. We also estimated the total potential life-years gained if a proportion of the approximately 248 000 HIV-infected US smokers quit smoking. Results. Men and women entering HIV care at age 40 years (mean CD4(+) T-cell count, 360 cells/mu L) who continued to smoke lost 6.7 years and 6.3 years of life expectancy, respectively, compared with never smokers; those who quit smoking upon entering care regained 5.7 years and 4.6 years, respectively. Factors associated with greater benefits from smoking cessation included younger age, higher initial CD4(+) T-cell count, and complete adherence to antiretroviral therapy. Smoking cessation by 10%-25% of HIV-infected smokers could save approximately 106 000-265 000 years of life. Conclusions. HIV-infected US smokers aged 40 years lose > 6 years of life expectancy from smoking, possibly outweighing the loss from HIV infection itself. Smoking cessation should become a priority in HIV treatment programs. C1 [Reddy, Krishna P.; Parker, Robert A.; Losina, Elena; Freedberg, Kenneth A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, 50 Staniford St,9th Fl, Boston, MA 02114 USA. [Reddy, Krishna P.] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Parker, Robert A.; Baggett, Travis P.; Rigotti, Nancy A.; Freedberg, Kenneth A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Parker, Robert A.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Rigotti, Nancy A.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Rigotti, Nancy A.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Freedberg, Kenneth A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Reddy, Krishna P.; Parker, Robert A.; Losina, Elena; Baggett, Travis P.; Rigotti, Nancy A.; Freedberg, Kenneth A.; Walensky, Rochelle P.] Harvard Med Sch, Boston, MA USA. [Losina, Elena] Brigham & Womens Hosp, Dept Orthoped Surg, 75 Francis St, Boston, MA 02115 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. [Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Freedberg, Kenneth A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Baggett, Travis P.] Harvard TH Chan Sch Publ Hlth, Boston Hlth Care Homeless Program, Boston, MA USA. [Weinstein, Milton C.; Freedberg, Kenneth A.] Harvard TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Paltiel, A. David] Yale Sch Publ Hlth, New Haven, CT USA. RP Reddy, KP (reprint author), Massachusetts Gen Hosp, Med Practice Evaluat Ctr, 50 Staniford St,9th Fl, Boston, MA 02114 USA. EM kpreddy@mgh.harvard.edu FU National Institute of Allergy and Infectious Diseases, NIH [T32 AI007433, R01 AI420006, R37 AI093269]; Massachusetts General Hospital (Research Scholars Award) FX This work was supported by the National Institute of Allergy and Infectious Diseases, NIH (grants T32 AI007433, R01 AI420006, and R37 AI093269); and Massachusetts General Hospital (Research Scholars Award to R. P. W.). NR 50 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 1 PY 2016 VL 214 IS 11 BP 1672 EP 1681 DI 10.1093/infdis/jiw430 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EJ3RH UT WOS:000393128800009 PM 27815384 ER PT J AU Wegmann, S Nicholls, S Takeda, S Fan, ZY Hyman, BT AF Wegmann, Susanne Nicholls, Samantha Takeda, Shuko Fan, Zhanyun Hyman, Bradley T. TI Formation, release, and internalization of stable tau oligomers in cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE dimerization; Gaussia luciferase assay; oligomers; tau protein ID PAIRED HELICAL FILAMENTS; PROTEIN-TAU; ALZHEIMERS-DISEASE; CEREBROSPINAL-FLUID; ENDOGENOUS TAU; REPEAT DOMAIN; MOUSE MODEL; IN-VITRO; PROPAGATION; AGGREGATION AB Tau is a neuronal microtubule-binding protein that, in Alzheimer's disease and other neurodegenerative diseases, can form oligomeric and large fibrillar aggregates, which deposit in neurofibrillary tangles. Tau's physiological state of multimerization appears to vary across conditions, and a stable dimeric form of soluble tau has been suggested from experiments using recombinant tau in vitro. We tested if tau dimerization or oligomerization, also occurs in cells, and if soluble tau oligomers are relevant for the release and internalization of tau. We developed a sensitive tau splitluciferase assay to show the rapid intracellular formation of stable tau dimers that are released and taken up by cells. Our data further suggest that tau dimerization can be accelerated slightly by aggregation catalysts. We conclude that tau oligomers are a stable physiological form of tau, and that tau oligomerization does not necessarily lead to tau aggregation. C1 [Wegmann, Susanne; Nicholls, Samantha; Takeda, Shuko; Fan, Zhanyun; Hyman, Bradley T.] Massachusetts Gen Hosp, MIND, Dept Neurol, Charlestown, MA USA. [Wegmann, Susanne; Nicholls, Samantha; Takeda, Shuko; Fan, Zhanyun; Hyman, Bradley T.] Harvard Med Sch, Dept Neurol, Boston, MA USA. RP Hyman, BT (reprint author), Massachusetts Gen Hosp, Dept Neurol, 114 16th St, Charlestown, MA 02129 USA. EM swegmann@mgh.harvard.edu; bhyman@mgh.harvard.edu FU Massachusetts General Hospital; German Research Foundation (DFG) [WE 5324/1-1]; NIH FX We thank Daniel Mueller for discussion and providing access to his AFM instruments. There are no conflicts of interest from any of the authors. The work has been funded by Massachusetts General Hospital, the German Research Foundation (DFG, WE 5324/1-1), and the NIH. NR 52 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2016 VL 139 IS 6 BP 1163 EP 1174 DI 10.1111/jnc.13866 PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA EJ2KK UT WOS:000393038700017 PM 27731899 ER PT J AU Gemmell, LA Terhorst, L Jhamb, M Unruh, M Myaskovsky, L Kester, L Steel, JL AF Gemmell, Leigh A. Terhorst, Lauren Jhamb, Manisha Unruh, Mark Myaskovsky, Larissa Kester, Lauren Steel, Jennifer L. TI Gender and Racial Differences in Stress, Coping, and Health-Related Quality of Life in Chronic Kidney Disease SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Health-related quality of life; gender; chronic kidney disease; stress; coping ID DIALYSIS OUTCOMES; PRACTICE PATTERNS; MISSING DATA; SURVEY SF-36; HEMODIALYSIS; DEPRESSION; STRATEGIES; DOPPS AB Context. Living with chronic kidney disease can be stressful and influence an individual's health-related quality of life. Effective coping strategies may reduce stress and improve quality of life in individuals with chronic medical conditions. Objectives. Health-related quality of life (HRQOL) is an important outcome for patients living with chronic kidney disease (CKD), and it is necessary to better understand potential gender and racial differences and predictors associated with reduced HRQOL, so that effective interventions can be developed. Methods. Participants included 182 patients with CKD who were administered a battery of questions that included the Medical Outcomes Study Short-Form 36, Perceived Stress Scale, and the Brief COPE. Demographic and disease-specific information was abstracted from the patients' medical record. Results. No differences by race were observed with regard to stress, quality of life, or coping with the exception that minority patients reported use of religious coping more often (P = 0.001) and had higher levels of energy compared with nonminority patients with CKD (P = 0.27). Women with CKD tended to use self-distraction (P = 0.002), positive reframing (P = 0.035), venting (P = 0.024), and religious coping (P = 0 < 0.001) more often than men. No significant differences in perceived stress or domains of quality of life were observed between men and women with CKD. A link between coping strategies and HRQOL was observed in women (P = 0.001-0.02) but not men. Perceived stress was associated with poorer quality of life for men (P = 0.017 to < 0.001) and women (P = 0.001 to < 0.001), but more domains of men's quality of life were affected by perceived stress compared with women. Conclusions. The findings of the study suggest that the wider range of coping strategies used by women may be associated with buffering the link between perceived stress and quality of life. Men with CKD may benefit from interventions that not only reduce stress but also facilitate the use of a broader range of coping strategies to reduce stress and improve quality of life. (C) 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. C1 [Gemmell, Leigh A.; Steel, Jennifer L.] Univ Pittsburgh, Sch Med, Dept Surg, 3459 Fifth Ave,Montefiore 7S, Pittsburgh, PA 15213 USA. [Terhorst, Lauren] Univ Pittsburgh, Sch Hlth & Rehabil Sci, Dept Occupat Therapy, Pittsburgh, PA 15260 USA. [Jhamb, Manisha; Unruh, Mark; Kester, Lauren] Univ Pittsburgh, Sch Med, Dept Renal Electrolyte Div, Pittsburgh, PA 15260 USA. [Myaskovsky, Larissa] Univ Pittsburgh, Sch Med, Dept Med & Psychiat, Pittsburgh, PA 15260 USA. [Myaskovsky, Larissa] VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. [Steel, Jennifer L.] Univ Pittsburgh, Sch Med, Dept Surg, Psychiat & Psychol, Pittsburgh, PA 15260 USA. RP Steel, JL (reprint author), Univ Pittsburgh, Sch Med, Dept Surg, 3459 Fifth Ave,Montefiore 7S, Pittsburgh, PA 15213 USA. EM steeljl@upmc.edu FU NIDDK NIH HHS [R01 DK077785] NR 22 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD DEC PY 2016 VL 52 IS 6 BP 806 EP 812 DI 10.1016/j.jpainsymman.2016.05.029 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA EJ4KE UT WOS:000393184800317 PM 27697565 ER PT J AU Wang, SY Aldridge, MD Canavan, M Cherlin, E Bradley, E AF Wang, Shi-Yi Aldridge, Melissa D. Canavan, Maureen Cherlin, Emily Bradley, Elizabeth TI Continuous Home Care Reduces Hospice Disenrollment and Hospitalization After Hospice Enrollment SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Hospice; continuous home care; hospice disenrollment; end-of-life care ID MARKET-STRUCTURE; LIFE; PATTERNS; END AB Context. Among the four levels of hospice care, continuous home care (CHC) is the most expensive care, and infrequently provided in practice. Objectives. To identify hospice and patient characteristics associated with the use of CHC and to examine the associations between CHC utilization and hospice disenrollment or hospitalization after hospice enrollment. Methods. Using 100% fee-for-service Medicare claims data for beneficiaries aged 66 years or older who died between July and December 2011, we identified the percentage of hospice agencies in which patients used CHC in 2011 and determined hospice and patient characteristics associated with the use of CHC. Using multivariable analyses, we examined the associations between CHC utilization and hospice disenrollment and hospitalization after hospice enrollment, adjusted for hospice and patient characteristics. Results. Only 42.7% of hospices (1533 of 3592 hospices studied) provided CHC to at least one patient during the study period. Patients enrolled with for-profit, larger, and urban located hospices were more likely to use CHC (P < 0.001). Within these 1533 hospices, only 11.4% of patients used CHC. Patients who were white, had cancer, and had more comorbidities were more likely to use CHC. In multivariable models, compared with patients who did not use CHC, patients who used CHC were less likely to have hospice disenrollment (adjusted odds ratio 0.21; 95% CI 0.19, 0.23) and less likely to be hospitalized after hospice enrollment (adjusted odds ratio 0.37; 95% CI 0.34, 0.40). Conclusion. Although a minority of patients uses CHC, such services may be protective against hospice disenrollment and hospitalization after hospice enrollment. (C) 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. C1 [Wang, Shi-Yi] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Wang, Shi-Yi] Yale Canc Ctr, Canc Outcomes Publ Policy & Effectiveness Res COP, New Haven, CT USA. [Wang, Shi-Yi] Yale Univ, Sch Med, New Haven, CT USA. [Aldridge, Melissa D.] Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, New York, NY 10029 USA. [Aldridge, Melissa D.] James J Peters VA Med Ctr, Bronx, NY USA. [Canavan, Maureen; Cherlin, Emily; Bradley, Elizabeth] Yale Univ, Sch Publ Hlth, Dept Hlth Policy & Management, New Haven, CT USA. RP Wang, SY (reprint author), Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, 60 Coll St, New Haven, CT 06520 USA. EM shiyi.wang@yale.edu OI Wang, Shi-Yi/0000-0002-3294-5784 FU National Cancer Institute [1R01CA116398-01A2]; John D. Thompson Foundation; National Institute of Nursing Research [1R01NR013499-01A1]; Agency for Healthcare Research and Quality [1K01HS023900-01] FX This study was supported by grant 1R01CA116398-01A2 from the National Cancer Institute (Drs. Aldridge and Bradley); the John D. Thompson Foundation (Dr. Bradley); grant 1R01NR013499-01A1 from the National Institute of Nursing Research (Dr. Aldridge); and grant 1K01HS023900-01 from the Agency for Healthcare Research and Quality (Dr. Wang). NR 22 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD DEC PY 2016 VL 52 IS 6 BP 813 EP 821 DI 10.1016/j.jpainsymman.2016.05.031 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA EJ4KE UT WOS:000393184800318 PM 27697564 ER PT J AU Duc, J Widger, K Johnston, K Rapoport, A Siden, H Feudtner, C Wolfe, J AF Duc, Jacqueline Widger, Kimberley Johnston, Kelly Rapoport, Adam Siden, Harold Feudtner, Chris Wolfe, Joanne TI Identifying Indicators of Quality Pediatric Palliative Care: A Systematic Review SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Meeting Abstract C1 [Duc, Jacqueline] Lady Cilento Childrens Hosp, Brisbane, Qld, Australia. [Widger, Kimberley; Johnston, Kelly] Univ Toronto, Toronto, ON, Canada. [Rapoport, Adam] Hosp Sick Children, Toronto, ON, Canada. [Siden, Harold] Univ British Columbia, Vancouver, BC, Canada. [Feudtner, Chris] Childrens Hosp Philadelphia, Philadelphia, PA USA. [Wolfe, Joanne] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD DEC PY 2016 VL 52 IS 6 MA P253 BP E133 EP E134 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA EJ4KE UT WOS:000393184800265 ER PT J AU Gupta, S Sutradhar, R Rapoport, A Pole, J Kassam, A Earle, C Wolfe, J Widger, K AF Gupta, Sumit Sutradhar, Rinku Rapoport, Adam Pole, Jason Kassam, Alisha Earle, Craig Wolfe, Joanne Widger, Kimberley TI Predictors of and Trends in High-Intensity End-of-Life Care Among Children with Cancer: A Population-Based Study Using Health Services Data SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Meeting Abstract C1 [Gupta, Sumit; Rapoport, Adam; Widger, Kimberley] Hosp Sick Children, Toronto, ON, Canada. [Gupta, Sumit; Sutradhar, Rinku; Earle, Craig] Inst Clin & Evaluat Sci, Toronto, ON, Canada. [Gupta, Sumit; Widger, Kimberley] Univ Toronto, Toronto, ON, Canada. [Pole, Jason] Pediat Oncol Grp Ontario, Toronto, ON, Canada. [Kassam, Alisha] Southlake Reg Hlth Ctr, Newmarket, Suffolk, England. [Wolfe, Joanne] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD DEC PY 2016 VL 52 IS 6 MA RF2-B BP E29 EP E29 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA EJ4KE UT WOS:000393184800052 ER PT J AU Widger, K Friedrichsdorf, S Wolfe, J Liben, S Pole, JD Bouffet, E Greenberg, M Husain, A Siden, H Whitlock, JA Rapoport, A AF Widger, Kimberley Friedrichsdorf, Stefan Wolfe, Joanne Liben, Stephen Pole, Jason D. Bouffet, Eric Greenberg, Mark Husain, Amna Siden, Harold Whitlock, James A. Rapoport, Adam TI Quality of Palliative Care for Children with Cancer SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Meeting Abstract C1 [Widger, Kimberley; Pole, Jason D.; Bouffet, Eric; Greenberg, Mark; Husain, Amna; Whitlock, James A.; Rapoport, Adam] Univ Toronto, Toronto, ON, Canada. [Widger, Kimberley; Bouffet, Eric; Whitlock, James A.; Rapoport, Adam] Hosp Sick Children, Toronto, ON, Canada. [Friedrichsdorf, Stefan] Childrens Hosp & Clin Minnesota, Minneapolis, MN USA. [Wolfe, Joanne] Dana Farber Canc Inst, Boston, MA 02115 USA. [Liben, Stephen] Montreal Childrens Hosp, Montreal, PQ, Canada. [Pole, Jason D.; Greenberg, Mark] Pediat Oncol Grp Ontario, Toronto, ON, Canada. [Husain, Amna] Mt Sinai Hosp, Toronto, ON, Canada. [Siden, Harold] Canuck Pl Childrens Hosp, Vancouver, BC, Canada. 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 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD DEC PY 2016 VL 52 IS 6 MA D03-D BP E32 EP E32 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA EJ4KE UT WOS:000393184800057 ER PT J AU You, J Simon, J Jayaraman, D Sharma, N Smrke, A Sudore, R Allatt, P Block, S Swinton, M Heyland, D AF You, John Simon, Jessica Jayaraman, Dev Sharma, Nishan Smrke, Alannah Sudore, Rebecca Allatt, Peter Block, Susan Swinton, Marilyn Heyland, Daren TI Improving Communication about Goals of Care with Hospitalized Patients Who Have Serious Illness: A Canadian, MultiCentre Program of Research SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Meeting Abstract C1 [You, John; Smrke, Alannah; Swinton, Marilyn] McMaster Univ, Hamilton, ON, Canada. [Simon, Jessica; Sharma, Nishan] Univ Calgary, Calgary, AB, Canada. [Jayaraman, Dev] McGill Univ, Montreal, PQ, Canada. [Sudore, Rebecca] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Allatt, Peter] Bridgepoint Hlth, Toronto, ON, Canada. [Block, Susan] Dana Farber Canc Inst, Boston, MA USA. [Heyland, Daren] Queens Univ, Kingston, ON, Canada. 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 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD DEC PY 2016 VL 52 IS 6 MA F05-A BP E49 EP E50 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA EJ4KE UT WOS:000393184800093 ER PT J AU El-Sharkawy, HM Anees, MM Van Dyke, TE AF El-Sharkawy, Hesham M. Anees, Mohamed M. Van Dyke, Thomas E. TI Propolis Improves Periodontal Status and Glycemic Control in Patients With Type 2 Diabetes Mellitus and Chronic Periodontitis: A Randomized Clinical Trial SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE Diabetes mellitus; periodontitis; therapeutics ID ACID PHENETHYL ESTER; COMPLICATIONS; INFLAMMATION; DISEASE; CHROMATOGRAPHY; METAANALYSIS; MOUTHRINSE; THERAPY AB Background: Propolis is a natural resin made by bees from various plant sources and exerts antimicrobial, anti-inflammatory, immunomodulatory, antioxidant, and antidiabetic properties. The purpose of this study is to assess adjunctive benefit of propolis supplementation in individuals with chronic periodontitis (CP) and type 2 diabetes mellitus (DMt2) receiving scaling and root planing (SRP). Methods: A 6-month masked, randomized clinical trial comparing SRP with placebo (placebo + SRP group, n = 26) or SRP combined with a 6-month regimen of 400 mg oral propolis once daily (propolis + SRP group, n = 24) was performed in patients with long-standing DMt2 and CP. Treatment outcomes included changes in hemoglobin (Hb) A1c (primary outcome), fasting plasma glucose (FPG), serum N-(sic)-(carboxymethyl) lysine (CML), and periodontal parameters (secondary outcomes). Results: After 3 and 6 months, average HbA1c levels in the propolis group decreased significantly by 0.82% and 0.96% units, respectively (P < 0.01); however, there were no significant differences in the placebo group. Likewise, FPG and CML levels were significantly reduced in the propolis group, but not in the placebo group. After therapy, periodontal parameters of CP were significantly improved in both groups. The propolis group showed significantly greater probing depth reduction and clinical attachment level gain than the control group after 3 and 6 months. Conclusion: A 6-month regimen of 400 mg propolis once daily is a potentially viable adjunct to SRP that significantly reduces levels of HbA1c, FPG, and CML, and improves periodontal therapy outcome in people with DMt2 and CP. C1 [El-Sharkawy, Hesham M.; Anees, Mohamed M.] Mansoura Univ, Dept Periodontol & Oral Med, Fac Dent, Mansoura, Egypt. [Van Dyke, Thomas E.] Forsyth Inst, Dept Appl Oral Sci, Cambridge, MA USA. RP El-Sharkawy, HM (reprint author), Mansoura Univ, Fac Dent, Elgomhoria St, Mansoura, Egypt. EM elsharkawyh@tudent.org NR 44 TC 0 Z9 0 U1 3 U2 3 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 EI 1943-3670 J9 J PERIODONTOL JI J. Periodont. PD DEC PY 2016 VL 87 IS 12 BP 1418 EP 1426 DI 10.1902/jop.2016.150694 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA EJ2UB UT WOS:000393065800006 PM 27468795 ER PT J AU Hussain, AJ AF Hussain, Ali J. TI Alternative Scheduling Models: Improving Continuity of Care, Medical Outcomes, and Graduate Medical Education in Resident Ambulatory Training SO JOURNAL OF THE AMERICAN OSTEOPATHIC ASSOCIATION LA English DT Article DE clinic scheduling models; continuity of care; graduate medical education; residency ID INTERNAL-MEDICINE; CLINIC HANDOFFS; REDESIGN; ASSOCIATION; BLOCK AB An association has been consistently made about continuity of care with improved quality of care and improved medical outcomes. However, resident ambulatory block scheduling prevents the optimization of continuity of care in ambulatory clinical education. The author performed a PubMed search for studies examining continuity of care and curriculum scheduling in US primary care residency clinics. These studies indicate the success of an X + Y scheduling model in resident ambulatory training. Additional benefits have also been noted, including improved clinical teaching and learning, increased sense of teamwork, increased resident satisfaction, improved recruitment and retention, improved patient satisfaction, and elimination of year-end patient care issues after graduation. Many allopathic institutions have begun to implement such curricular changes with demonstrated success. The author argues that osteopathic graduate medical education should embrace the X + Y scheduling model. C1 [Hussain, Ali J.] US Dept Vet Affairs, Washington, DC USA. RP Hussain, AJ (reprint author), 2361 S State St,L15, Chicago, IL 60616 USA. EM drajhussain@gmail.com NR 38 TC 0 Z9 0 U1 0 U2 0 PU AMER OSTEOPATHIC ASSN PI CHICAGO PA 142 EAST ONTARIO STREET, CHICAGO, IL 60611-2864 USA SN 0098-6151 EI 1945-1997 J9 J AM OSTEOPATH ASSOC JI J. Am. Osteopath. Assoc. PD DEC PY 2016 VL 116 IS 12 BP 794 EP 800 DI 10.7556/jaoa.2016.155 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA EJ2OR UT WOS:000393050400006 PM 27893146 ER PT J AU McDonnell, MJ Aliberti, S Goeminne, PC Restrepo, MI Finch, S Pesci, A Dupont, LJ Fardon, TC Wilson, R Loebinger, MR Skrbic, D Obradovic, D De Soyza, A Ward, C Laffey, JG Rutherford, RM Chalmers, JD AF McDonnell, Melissa J. Aliberti, Stefano Goeminne, Pieter C. Restrepo, Marcos I. Finch, Simon Pesci, Alberto Dupont, Lieven J. Fardon, Thomas C. Wilson, Robert Loebinger, Michael R. Skrbic, Dusan Obradovic, Dusanka De Soyza, Anthony Ward, Chris Laffey, John G. Rutherford, Robert M. Chalmers, James D. TI Comorbidities and the risk of mortality in patients with bronchiectasis: an international multicentre cohort study SO LANCET RESPIRATORY MEDICINE LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; CYSTIC FIBROSIS BRONCHIECTASIS; VALIDATION; STATEMENT; DIAGNOSIS; SEVERITY; REFLUX; CANCER; COPD AB Background Patients with bronchiectasis often have concurrent comorbidities, but the nature, prevalence, and impact of these comorbidities on disease severity and outcome are poorly understood. We aimed to investigate comorbidities in patients with bronchiectasis and establish their prognostic value on disease severity and mortality rate. Methods An international multicentre cohort analysis of outpatients with bronchiectasis from four European centres followed up for 5 years was done for score derivation. Eligible patients were those with bronchiectasis confirmed by high-resolution CT and a compatible clinical history. Comorbidity diagnoses were based on standardised definitions and were obtained from full review of paper and electronic medical records, prescriptions, and investigator definitions. Weibull parametric survival analysis was used to model the prediction of the 5 year mortality rate to construct the Bronchiectasis Aetiology Comorbidity Index (BACI). We tested the BACI as a predictor of outcomes and explored whether the BACI added further prognostic information when used alongside the Bronchiectasis Severity Index (BSI). The BACI was validated in two independent international cohorts from the UK and Serbia. Findings Between June 1, 2006, and Nov 22, 2013, 1340 patients with bronchiectasis were screened and 986 patients were analysed. Patients had a median of four comorbidities (IQR 2-6; range 0-20). 13 comorbidities independently predicting mortality rate were integrated into the BACI. The overall hazard ratio for death conferred by a one-point increase in the BACI was 1.18 (95% CI 1.14-1.23; p<0.0001). The BACI predicted 5 year mortality rate, hospital admissions, exacerbations, and health-related quality of life across all BSI risk strata (p<0.0001 for mortality and hospital admissions, p=0.03 for exacerbations, p=0.0008 for quality of life). When used in conjunction with the BSI, the combined model was superior to either model alone (p=0.01 for combined vs BACI; p=0.008 for combined vs BSI). Interpretation Multimorbidity is frequent in bronchiectasis and can negatively affect survival. The BACI complements the BSI in the assessment and prediction of mortality and disease outcomes in patients with bronchiectasis. C1 [McDonnell, Melissa J.; Rutherford, Robert M.] Galway Univ Hosp, Dept Resp Med, Galway H91 YR71, Ireland. [McDonnell, Melissa J.; De Soyza, Anthony; Ward, Chris] Newcastle Univ, Inst Cell & Mol Biosci, Newcastle Upon Tyne, Tyne & Wear, England. [McDonnell, Melissa J.; De Soyza, Anthony; Ward, Chris] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England. [McDonnell, Melissa J.; Laffey, John G.] Natl Univ Ireland, Lung Biol Grp, Galway, Ireland. [Aliberti, Stefano] Univ Milan, Dept Pathophysiol & Transplantat, Cardiothorac Unit, Milan, Italy. [Aliberti, Stefano] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Cyst Fibrosis Adult Ctr, Milan, Italy. [Goeminne, Pieter C.; Dupont, Lieven J.] Univ Hosp Gasthuisberg, Dept Resp Med, Leuven, Belgium. [Goeminne, Pieter C.] AZ Nikolaas, Dept Resp Med, St Niklaas, Belgium. [Restrepo, Marcos I.] South Texas Vet Hlth Care Syst, Div Pulm Dis & Crit Care, San Antonio, TX USA. [Restrepo, Marcos I.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Pesci, Alberto] Univ Milano Bicocca, Sch Med & Surg, Resp Unit, AO San Gerardo, Monza, Italy. [Finch, Simon; Fardon, Thomas C.; Chalmers, James D.] Univ Dundee, Scottish Ctr Resp Res, Dundee, Scotland. [Wilson, Robert; Loebinger, Michael R.] Royal Brompton Hosp, Host Def Unit, London, England. [Skrbic, Dusan; Obradovic, Dusanka] Inst Pulm Dis Vojvodina Sremska Kamenica, Sremska Kamenica, Serbia. [Skrbic, Dusan; Obradovic, Dusanka] Univ Novi Sad, Fac Med, Novi Sad, Serbia. [Laffey, John G.] Univ Toronto, St Michaels Hosp, Keenan Res Ctr Biomed Sci, Dept Anesthesia, Toronto, ON, Canada. RP McDonnell, MJ (reprint author), Galway Univ Hosp, Dept Resp Med, Galway H91 YR71, Ireland. EM melissajanefriel@gmail.com FU European Bronchiectasis Network (EMBARC) FX European Bronchiectasis Network (EMBARC). NR 30 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-2600 J9 LANCET RESP MED JI Lancet Resp. Med. PD DEC PY 2016 VL 4 IS 12 BP 969 EP 979 DI 10.1016/S2213-2600(16)30320-4 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EJ2GC UT WOS:000393027100017 PM 27864036 ER PT J AU Wu, XM Yao, ZP Zhao, L Zhang, Y Cao, MH Li, T Ding, WB Liu, Y Deng, RJ Dong, ZX Chen, H Novakovic, VA Bi, YY Kou, JJ Tian, Y Zhou, J Shi, JL AF Wu, Xiaoming Yao, Zhipeng Zhao, Lu Zhang, Yan Cao, Muhua Li, Tao Ding, Wenbo Liu, Yan Deng, Ruijuan Dong, Zengxiang Chen, He Novakovic, Valerie A. Bi, Yayan Kou, Junjie Tian, Ye Zhou, Jin Shi, Jialan TI Phosphatidylserine on blood cells and endothelial cells contributes to the hypercoagulable state in cirrhosis SO LIVER INTERNATIONAL LA English DT Article DE blood cells; endothelial cells; hypercoagulable state; cirrhosis; phosphatidylserine ID PORTAL-VEIN THROMBOSIS; ACUTE PROMYELOCYTIC LEUKEMIA; VON-WILLEBRAND-FACTOR; PROCOAGULANT ACTIVITY; LIVER-DISEASE; EXPOSURE; HEMOSTASIS; PLATELETS; ANTICOAGULATION; TRANSPLANTATION AB Background & Aims: The mechanism of thrombogenicity in cirrhosis is largely unknown. Our objective was to study the relationship between phosphatidylserine on blood cells and endothelial cells and the hypercoagulable state in cirrhotic patients. Methods: Patients with cirrhosis and healthy controls were studied. Lactadherin was used to quantify phosphatidylserine exposure on blood cells and endothelial cells. Procoagulant activity of cells was evaluated using clotting time and purified coagulation complex assays. Fibrin production was determined by turbidity. Phosphatidylserine exposure, fibrin strands and FVa/Xa binding on cells were observed using confocal microscopy. Results: Our study showed that phosphatidylserine exposure on erythrocytes, platelets and leucocytes in cirrhotic patients increased progressively with Child-Pugh categories. In addition, we found that endothelial cells treated with cirrhotic serum in vitro exposed more phosphatidylserine than those exposed to healthy serum. The exposed phosphatidylserine supported a shorter coagulation time and increased FXa, thrombin and fibrin formation. Notably, phosphatidylserine(+) erythrocytes also promoted shorter coagulation times and more fibrin generation in cirrhotic microparticle-depleted plasma, regardless of Child-Pugh categories. Confocal microscopy data showed that the FVa/FXa complex and fibrin fibrils colocalized with phosphatidylserine on endothelial cells. Lactadherin significantly inhibited FXa and thrombin generation and consequently decreased fibrin production in normal or cirrhotic plasma. Conclusions: These results lead us to believe that exposed phosphatidylserine on activated or injured erythrocytes, platelets, leucocytes and endothelial cells plays an important role in the hypercoagulable state in cirrhotic patients. Thus, blocking phosphatidylserine binding sites might be a new therapeutic target for preventing thrombosis. C1 [Wu, Xiaoming; Yao, Zhipeng; Zhao, Lu; Zhang, Yan; Cao, Muhua; Li, Tao; Liu, Yan; Deng, Ruijuan; Zhou, Jin; Shi, Jialan] Harbin Med Univ, Hosp 1, Dept Hematol, 23 Youzheng St, Harbin 150001, Peoples R China. [Ding, Wenbo; Kou, Junjie] Harbin Med Univ, Hosp 2, Dept Cardiol, Harbin, Peoples R China. [Dong, Zengxiang; Bi, Yayan; Tian, Ye] Harbin Med Univ, Hosp 1, Dept Cardiol, Harbin, Peoples R China. [Chen, He] Harbin Med Univ, Dept Pathol, Harbin, Peoples R China. [Novakovic, Valerie A.] Harvard Med Sch, VA Boston Healthcare Syst, Brigham & Womens Hosp, Dept Res, Boston, MA USA. [Shi, Jialan] Harvard Med Sch, VA Boston Healthcare Syst, Brigham & Womens Hosp, Dept Surg, Boston, MA USA. RP Zhou, J; Shi, JL (reprint author), Harbin Med Univ, Hosp 1, Dept Hematol, 23 Youzheng St, Harbin 150001, Peoples R China.; Shi, JL (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Surg, VA Boston Healthcare Syst, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM jinzhouyx09@163.com; jialan_shi@hms.harvard.edu FU National Science Foundation of China [81270588, 81470301] FX This study was in part supported by grants (81270588, 81470301) from the National Science Foundation of China. NR 41 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1478-3223 EI 1478-3231 J9 LIVER INT JI Liver Int. PD DEC PY 2016 VL 36 IS 12 BP 1800 EP 1810 DI 10.1111/liv.13167 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EJ3HS UT WOS:000393103800012 PM 27206310 ER PT J AU Kitahara, S Desaki, J Yoshii, A Matsui, A Morikawa, S Ezaki, T AF Kitahara, Shuji Desaki, Junzo Yoshii, Asuka Matsui, Aya Morikawa, Shunichi Ezaki, Taichi TI Electron microscopic study of capillary network remodeling in the extensor digitorum longus muscle of normal adult rat SO MICROSCOPY LA English DT Article DE capillary; remodeling; fenestration; pore; extensor digitorum longus muscle ID EXPERIMENTAL LIMB IMMOBILIZATION; SOLEUS MUSCLE; AGED RAT; MORPHOLOGICAL-CHANGES; STRUCTURAL-CHANGES; BLOOD-VESSELS; BRAIN-TUMORS; MICROVESSELS; CONTRACTION; PERICYTES AB Capillary networks demonstrate structural changes during maturation, aging, vascular disease, and cancer. Their morphological structure and function have an important influence on each other. Understanding the process of morphological vascular changes in the capillary network with advancing age may help overcome fatal vascular diseases. Aging-related structural changes of the capillary segments may accompany degeneration and regeneration of muscle fibers and serve to remodel the capillary network as a means of adapting to the changing environment. However, difficulty in obtaining human samples has hampered clarification of these microstructural changes. Herein, we examined serial ultrathin sections of capillary segments in the extensor digitorum longus muscle of normal mature (12 months old) rats in an attempt to analyze their structural changes. After bifurcation, a minimum of one capillary segment was filled with erythrocytes and was found to have fenestrations and plural endothelial disruptions, or pores, at the fenestrated portions. Some of the stagnated erythrocytes demonstrated extended protrusions, and their processes appeared to penetrate the basal lamina through the pores. These findings can also show that capillary segments are involved in partial remodeling of the capillary network. A better understanding of age-related structural changes of the capillary networks will help in fine-tuning novel vascular therapy for not only several fatal vascular diseases but also malignant tumors. C1 [Kitahara, Shuji; Yoshii, Asuka; Matsui, Aya; Morikawa, Shunichi; Ezaki, Taichi] Tokyo Womens Med Univ, Sch Med, Dept Anat & Dev Biol, Tokyo 1628666, Japan. [Kitahara, Shuji] Massachusetts Gen Hosp, Harvard Med Sch, Dept Radiat Oncol, Boston, MA 02114 USA. [Desaki, Junzo] Ehime Univ, Sch Med, Dept Integrated Basic Med Res, Ehime 02114, Japan. [Yoshii, Asuka] Boston Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02118 USA. [Yoshii, Asuka] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. RP Ezaki, T (reprint author), Tokyo Womens Med Univ, Sch Med, Dept Anat & Dev Biol, Tokyo 1628666, Japan. EM ezakit@research.twmu.ac.jp FU Japan Society for the Promotion of Science (JSPS) KAKENHI [JP25861218]; JSPS Fujita Memorial Fund for Medical Research; JSPS Research Fellowship for Young Scientists DC1 [26-12011] FX Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant Number JP25861218), JSPS Fujita Memorial Fund for Medical Research and JSPS Research Fellowship for Young Scientists DC1 (26-12011). NR 25 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2050-5698 EI 2050-5701 J9 MICROSCOPY-JPN JI Microscopy PD DEC PY 2016 VL 65 IS 6 BP 508 EP 516 DI 10.1093/jmicro/dfw040 PG 9 WC Microscopy SC Microscopy GA EJ4IG UT WOS:000393179600006 PM 27655937 ER PT J AU Willis, AW Thibault, DP Schmidt, PN Dorsey, ER Weintraub, D AF Willis, Allison. W. Thibault, Dylan P. Schmidt, Peter N. Dorsey, E. Ray Weintraub, Daniel TI Hospital Care for Mental Health and Substance Abuse Conditions in Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; suicide; psychiatry; addiction; epidemiology ID DEEP BRAIN-STIMULATION; GENDER-DIFFERENCES; ANXIETY DISORDERS; DEPRESSION; SUICIDE; FREQUENCY; DOPAMINE; DISPARITIES; DEMENTIA; VETERANS AB Objective: The objective of this study was to examine mental health conditions among hospitalized individuals with Parkinson's disease in the United States. Methods: This was a serial cross-sectional study of hospitalizations of individuals aged >= 60 identified in the Nationwide Inpatient Sample dataset from 2000 to 2010. We identified all hospitalizations with a diagnosis of PD, alcohol abuse, anxiety, bipolar disorder, depression, impulse control disorders, mania, psychosis, substance abuse, and attempted suicide/suicidal ideation. National estimates of each mental health condition were compared between hospitalized individuals with and without PD. Hierarchical logistic regression models determined which inpatient mental health diagnoses were associated with PD, adjusting for demographic, payer, geographic, and hospital characteristics. Results: We identified 3,918,703 mental health and substance abuse hospitalizations. Of these, 2.8% (n=104, 437) involved a person also diagnosed with PD. The majority of mental health and substance abuse patients were white (86.9% of PD vs 83.3% of non-PD). Women were more common than men in both groups (male: female prevalence ratio, PD: 0.78, 0.78-0.79, non-PD: 0.58, 0.57-0.58). Depression (adjusted odds ratio 1.32, 1.31-1.34), psychosis (adjusted odds ratio 1.25, 1.15-1.33), bipolar disorder (adjusted odds ratio 2.74, 2.69-2.79), impulse control disorders (adjusted odds ratio 1.51, 1.31-1.75), and mania (adjusted odds ratio 1.43, 1.18-1.74) were more likely among PD patients, alcohol abuse was less likely (adjusted odds ratio 0.26, 0.25-0.27). We found no PD-associated difference in suicide-related care. Conclusions: PD patients have unique patterns of acute care for mental health and substance abuse. Research is needed to guide PD treatment in individuals with pre-existing psychiatric illnesses, determine cross provider reliability of psychiatric diagnoses in PD patients, and inform efforts to improve psychiatric outcomes. (C) 2016 International Parkinson and Movement Disorder Society. C1 [Willis, Allison. W.; Thibault, Dylan P.; Weintraub, Daniel] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Willis, Allison. W.] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Willis, Allison. W.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Willis, Allison. W.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Schmidt, Peter N.] Natl Parkinsons Fdn, Miami, FL USA. [Dorsey, E. Ray] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA. [Weintraub, Daniel] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, Philadelphia, PA USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA USA. RP Willis, AW (reprint author), Blockley Hall 723,423 Guardian Dr, Philadelphia, PA 19104 USA. EM allison.willis@uphs.upenn.edu FU National Institutes of Health (NIH); National Institute of Neurological Disease and Stroke (NINDS) via a Mentored Career Development Award [K23NS081087]; University of Pennsylvania Perelman School of Medicine Department of Neurology Movement Disorders Division FX This study was funded primarily by the National Institutes of Health (NIH) and the National Institute of Neurological Disease and Stroke (NINDS) via a Mentored Career Development Award K23NS081087(PI-Willis) and the University of Pennsylvania Perelman School of Medicine Department of Neurology Movement Disorders Division. NR 39 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD DEC PY 2016 VL 31 IS 12 BP 1810 EP 1819 DI 10.1002/mds.26832 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA EJ3PD UT WOS:000393123200011 PM 27943472 ER PT J AU Hughes, KC Gao, X Kim, IY Rimm, EB Wang, ML Weisskopf, MG Schwarzschild, MA Ascherio, A AF Hughes, Katherine C. Gao, Xiang Kim, Iris Y. Rimm, Eric B. Wang, Molin Weisskopf, Marc G. Schwarzschild, Michael A. Ascherio, Alberto TI Intake of Antioxidant Vitamins and Risk of Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; vitamin C; vitamin E; carotenoids; oxidative stress ID FOOD-FREQUENCY QUESTIONNAIRE; URIC-ACID LEVELS; DIETARY ANTIOXIDANTS; PLASMA URATE; CAROTENOIDS; COHORT; MEN; REPRODUCIBILITY; PREDICTOR; VALIDITY AB Introduction: Oxidative stress is proposed to be one of the potential mechanisms leading to neurodegeneration in Parkinson's disease. However, previous epidemiologic studies investigating associations between antioxidant vitamins, such as vitamins E and C and carotenoids, and PD risk have produced inconsistent results. Objective: The objective of this work was to prospectively examine associations between intakes of antioxidant vitamins, including vitamins E and C and carotenoids, and PD risk. Methods: Cases were identified in two large cohorts: the Nurses' Health Study and the Health Professionals Follow-up Study. Cohort members completed semi-quantitative food frequency questionnaires every 4 years. Results: A total of 1036 PD cases were identified. Dietary intakes of vitamin E and carotenoids were not associated with PD risk; the multivariable-adjusted relative risk comparing extreme intake quintiles were 0.93 (95% confidence interval: 0.75-1.14) and 0.97 (95% confidence interval: 0.69-1.37), respectively. Dietary vitamin C intake was significantly associated with reduced PD risk (relative risk: 0.81; 95% confidence interval: 0.65-1.01; p(trend), 0.01); however, this result was not significant in a 4-year lag analysis. For vitamins E and C, intake from foods and supplements combined were also unrelated to PD risk. Conclusions: Our results do not support the hypothesis that intake of antioxidant vitamins reduces the risk of PD. (C) 2016 International Parkinson and Movement Disorder Society C1 [Hughes, Katherine C.; Kim, Iris Y.; Rimm, Eric B.; Wang, Molin; Weisskopf, Marc G.; Ascherio, Alberto] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. [Gao, Xiang] Penn State Univ, Dept Nutr Hlth, University Pk, PA 16802 USA. [Rimm, Eric B.; Ascherio, Alberto] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Rimm, Eric B.; Wang, Molin; Ascherio, Alberto] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Rimm, Eric B.; Wang, Molin; Ascherio, Alberto] Harvard Med Sch, Boston, MA USA. [Wang, Molin] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Weisskopf, Marc G.] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Schwarzschild, Michael A.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Boston, MA 02114 USA. RP Hughes, KC (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM kch460@mail.harvard.edu FU NIH [UM1 CA186107, UM1 CA167552, R01 NS061858]; Department of Defense [W81XWH-14-0131] FX This study was supported by NIH grants UM1 CA186107, UM1 CA167552, and R01 NS061858 and by Department of Defense grant W81XWH-14-0131. NR 37 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD DEC PY 2016 VL 31 IS 12 BP 1909 EP 1914 DI 10.1002/mds.26819 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA EJ3PD UT WOS:000393123200023 PM 27787934 ER PT J AU Tamez, H AF Tamez, Hector TI African Americans with left ventricular hypertrophy and chronic kidney disease: what should we do? SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article ID THERAPY; MASS; RISK; MEN C1 [Tamez, Hector] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc Med, 185 Pilgrim Rd,Baker 4, Boston, MA 02215 USA. RP Tamez, H (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc Med, 185 Pilgrim Rd,Baker 4, Boston, MA 02215 USA. EM htamez@post.harvard.edu NR 9 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 EI 1460-2385 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD DEC PY 2016 VL 31 IS 12 BP 1969 EP 1970 DI 10.1093/ndt/gfw229 PG 2 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA EJ2RV UT WOS:000393059700001 PM 27282167 ER PT J AU Bansal, N Katz, R Himmelfarb, J Afkarian, M Kestenbaum, B de Boer, IH Young, B AF Bansal, Nisha Katz, Ronit Himmelfarb, Jonathan Afkarian, Maryam Kestenbaum, Bryan de Boer, Ian H. Young, Bessie TI Markers of kidney disease and risk of subclinical and clinical heart failure in African Americans: the Jackson Heart Study SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE African Americans; chronic kidney disease; echocardiogram; heart failure; left ventricular hypertrophy ID LEFT-VENTRICULAR HYPERTROPHY; PRESERVED EJECTION FRACTION; GLOMERULAR-FILTRATION-RATE; RENAL-FUNCTION; RACIAL-DIFFERENCES; YOUNG-ADULTS; CYSTATIN C; MASS INDEX; OUTCOMES; CKD AB Background. African Americans and patients with chronic kidney disease (CKD) are at high risk for clinical heart failure (HF). In this study, we aimed to determine the association of markers of kidney disease with subclinical HF (by echocardiogram) and risk of clinical HF among a large, well-characterized community-based cohort of African American patients. We also examined whether the association of markers of kidney disease with HF was attenuated with adjustment for echocardiographic measures. Methods. We studied participants in the Jackson Heart Study, a large community-based cohort of African Americans. Estimated glomerular filtration rate (eGFR) and urine albumin: creatinine ratio (ACR) were measured at baseline. We tested the association of eGFR and urine ACR with left ventricular mass (LVM), left ventricular ejection fraction (LVEF) and physician-adjudicated incident HF. Results. Among the 3332 participants in the study, 166 (5%) had eGFR <60 mL/min/1.73 m(2) and 405 (12%) had urine ACR >= 30 mg/g. In models adjusted for demographics, comorbidity and the alternative measure of kidney disease, lower eGFR and higher urine ACR were associated with higher LVM {beta-coefficient 1.54 [95% confidence interval (CI) 0.78-2.31] per 10 mL/min/1.73 m(2) decrease in eGFR and 2.87 (95% CI 1.85-3.88) per doubling of urine ACR}. There was no association of eGFR and urine ACR with LVEF [beta-coefficient -0.12 (95% CI -0.28-0.04) and -0.11 (95% CI -0.35-0.12), respectively]. There was no association of eGFR with the risk of incident HF [HR 1.02 (95% CI 0.91-1.14) per 10 mL/min/1.73 m(2) decrease], while there was a significant association of urine ACR [HR 2.22 (95% CI 1.29-3.84) per doubling of urine ACR]. This association was only modestly attenuated with adjustment for LVM [HR 1.95 (95% CI 1.09-3.49)]. Conclusions. Among a community-based cohort of African Americans, lower eGFR and higher ACR were associated with higher LVM. Furthermore, higher urine ACR was associated with incident HF, which was not entirely explained by the presence of left ventricular disease. C1 [Bansal, Nisha; Katz, Ronit; Himmelfarb, Jonathan; Afkarian, Maryam; Kestenbaum, Bryan; de Boer, Ian H.; Young, Bessie] Univ Washington, Div Nephrol, Kidney Res Inst, 908 Jefferson St,3rd Floor, Seattle, WA 98105 USA. [de Boer, Ian H.; Young, Bessie] Vet Affairs Puget Sound Hlth Care Syst, Nephrol Sect, Hosp & Specialty Med, Seattle, WA USA. RP Bansal, N (reprint author), Univ Washington, Div Nephrol, Kidney Res Inst, 908 Jefferson St,3rd Floor, Seattle, WA 98105 USA. EM nbansal@nephrology.washington.edu FU National Heart, Lung, and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities; Veterans Affairs Puget Sound Health Care System; [R01DK102134]; [K23DK088865] FX We thank all participants of the Jackson Heart Study for their time, effort and dedication toward this study. This study was supported by the following funding sources: R01DK102134 (B.Y.) and K23DK088865 (N.B.). The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C and HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. B.Y. and I.H.d.B. are also supported in part by funding from the Veterans Affairs Puget Sound Health Care System. NR 50 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 EI 1460-2385 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD DEC PY 2016 VL 31 IS 12 BP 2057 EP 2064 DI 10.1093/ndt/gfw218 PG 8 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA EJ2RV UT WOS:000393059700016 PM 27257276 ER PT J AU Nourazari, S Hoch, DB Capawanna, S Sipahi, R Benneyan, JC AF Nourazari, Sara Hoch, Daniel B. Capawanna, Soren Sipahi, Rifat Benneyan, James C. TI Can improved specialty access moderate emergency department overuse? Effect of neurology appointment delays on ED visits SO NEUROLOGY-CLINICAL PRACTICE LA English DT Article AB Background: Delayed access to specialty care may increase inappropriate emergency department (ED) visits. However, the details of this relationship after referral to a specialist are unknown. Methods: The correlations in an academic medical center between time to new neurology patient appointments and nonurgent ED use are explored in this study. Access was measured as the number of days between the scheduling and outpatient appointment dates. A series of statistical analyses including correlation analysis, regressions, and hypothesis tests were conducted to investigate possible associations between delayed access to specialty care and ED visits, as well as the effect of ED visits on specialty care cancellation and no-show rates. Results: Of 19,505 new neurology patients, 310 visited an ED prior to their appointment, 95.2% (295) of whom had poor access (defined here as exceeding 21 days). Patients with access >21 days for new visits were 6.6 times more likely to visit the ED before their appointment date, 19% within the first week after scheduling. Patients who visited the ED between their booking and appointment dates were 2.3 times more likely to cancel or fail to attend their appointment. Conclusion: These results suggest that long access delays in specialty referrals can significantly increase ED costs and congestion. Further studies in other specialties to explore this relationship are warranted. C1 [Nourazari, Sara; Benneyan, James C.] Healthcare Syst Engn Inst, Boston, MA 02115 USA. [Sipahi, Rifat] Northeastern Univ, Boston, MA 02115 USA. [Hoch, Daniel B.; Capawanna, Soren] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Benneyan, JC (reprint author), Healthcare Syst Engn Inst, Boston, MA 02115 USA. EM j.benneyan@neu.edu FU National Science Foundation (NSF) [IIP-1034990]; Center for Medicare and Medicaid Innovation (CMMI) [1C1CMS331050] FX Supported in part by the National Science Foundation (NSF) (IIP-1034990) and the Center for Medicare and Medicaid Innovation (CMMI) (1C1CMS331050). Any views or opinions presented herein are solely those of the authors and not the NSF or CMMI. NR 18 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2163-0402 EI 2163-0933 J9 NEUROL-CLIN PRACT JI Neurol.-Clin. Pract. PD DEC PY 2016 VL 6 IS 6 BP 498 EP 505 DI 10.1212/CPJ.0000000000000295 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EJ3HD UT WOS:000393102300010 ER PT J AU Arocho-Quinones, EV Pahapill, PA AF Arocho-Quinones, Elsa V. Pahapill, Peter A. TI Non-Infectious Peri-Electrode Edema and Contrast Enhancement Following Deep Brain Stimulation Surgery SO NEUROMODULATION LA English DT Article DE Brain edema; deep brain stimulation; gadolinium enhancement; peri-electrode; T2-weighted hyperintensity AB Background: Dramatic radiographic abnormalities seen after electrode placement (DRAAEP) in deep brain stimulation (DBS) surgery is rare and it has not been associated with infection or hemorrhage. It has consisted of peri-electrode low-attenuation signals on CT scans and extensive T2-hyperintense signals without associated contrast enhancement (CE) on MRI scans. Objective: Report on the management of a patient with Parkinson's disease (PD) presenting with a seizure and findings of DRAAEP with positive CE 12 days after the placement of a subthalamic nucleus (STN) DBS electrode. Methods: Head CT and contrasted brain MRI scans were completed on presentation. Standard laboratory work up was obtained to evaluate for infection. Operative exploration deep to the burr-hole site surrounding the electrode was performed and cultures were obtained. Serial contrasted MRI scans were completed to determine the abnormal signal duration. Results: A MRI revealed extensive T2-hyperintensity and positive CE concentrated around the burr-hole site surrounding the electrode. Intraoperative exploration revealed no evidence of infection and electrode revision was avoided. There was near resolution of the abnormal T2 signal and CE at six weeks from detection. The patient remained without signs of intracranial infection and responded well to DBS. Conclusion: To our knowledge, this is the first reported case of DRAAEP with positive gadolinium enhancement. Despite the extensive contrast enhancement, these DRAAEP appear to remain benign transient events that, in the absence of clinical signs of infection or neurologic decline, may warrant no further aggressive intervention such as hardware removal. C1 [Arocho-Quinones, Elsa V.; Pahapill, Peter A.] Med Coll Wisconsin, Dept Neurosurg, 9200 W Wisconsin Ave, Milwaukee, WI 53226 USA. [Arocho-Quinones, Elsa V.; Pahapill, Peter A.] US Dept Vet Affairs, Med Ctr, Dept Neurosurg, Milwaukee, WI USA. RP Arocho-Quinones, EV (reprint author), Med Coll Wisconsin, Dept Neurosurg, 9200 W Wisconsin Ave, Milwaukee, WI 53226 USA. EM earocho@mcw.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1094-7159 EI 1525-1403 J9 NEUROMODULATION JI Neuromodulation PD DEC PY 2016 VL 19 IS 8 BP 872 EP 876 DI 10.1111/ner.12432 PG 5 WC Medicine, Research & Experimental; Clinical Neurology SC Research & Experimental Medicine; Neurosciences & Neurology GA EI9IU UT WOS:000392822100021 PM 27098925 ER PT J AU Luberto, CM Hyland, KA Streck, JM Temel, B Park, ER AF Luberto, Christina M. Hyland, Kelly A. Streck, Joanna M. Temel, Brandon Park, Elyse R. TI Stigmatic and Sympathetic Attitudes Toward Cancer Patients Who Smoke: A Qualitative Analysis of an Online Discussion Board Forum SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID CELL-LUNG-CANCER; HELP-SEEKING BEHAVIOR; PUBLIC-HEALTH; TOBACCO DEPENDENCE; CIGARETTE-SMOKING; PROSTATE-CANCER; SOCIAL MEDIA; NECK CANCER; CESSATION; PERCEPTIONS AB Introduction: A significant minority of patients continue to smoke after a cancer diagnosis. Cancer patients who smoke experience stigma that can negatively impact health outcomes. We explored publicly shared perspectives about cancer patients who continued to smoke post-diagnosis. Methods: An online news article, published in January 2012, summarized the findings of smoking prevalence among patients with lung cancer and colorectal cancer enrolled in the Cancer Care Outcomes Research and Surveillance Consortium trial. In response, written comments were posted on the articles' public discussion board. Applying principles of grounded theory, we conducted a document analysis and established a conceptual framework to develop a model by which to explain factors underlying stigmatic and sympathetic attitudes toward cancer survivors who continue to smoke. Results: Personal experiences with cancer, smoking, and statistical literacy were found to influence beliefs about cancer and smoking, which in turn influenced stigmatic or sympathetic attitudes. More sympathetic attitudes were expressed by individuals who had personal experiences with smoking, believed cancer is multicausal, identified smoking as an addiction, or considered extrinsic factors responsible for smoking. Individuals who did not have personal experiences with cancer or smoking, had low statistical literacy, believed that smoking necessarily and directly causes cancer, and focused on intrinsic responsibilities for smoking tended to express more stigmatic attitudes. Conclusions: The current findings raise awareness and provide insight into stigma against cancer survivors who smoke and can help inform strategies for reducing stigma against this vulnerable group. Implications: This study helps raise awareness of stigma toward cancer patients who smoke and provides insight into the processes that may influence stigmatic as compared to sympathetic attitudes toward these patients. Results suggest that population-based strategies to educate the public regarding the nature of nicotine addiction, difficulty of quitting, and benefits of quitting for cancer patients may be useful for reducing stigma against cancer patients with a smoking history. C1 [Luberto, Christina M.; Park, Elyse R.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Luberto, Christina M.; Park, Elyse R.] Harvard Med Sch, Boston, MA USA. [Hyland, Kelly A.; Temel, Brandon; Park, Elyse R.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Hyland, Kelly A.; Temel, Brandon; Park, Elyse R.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Streck, Joanna M.] Univ Vermont, Dept Psychol Sci, Vermont Ctr Behav & Hlth, Burlington, VT USA. RP Luberto, CM (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, 15 Parkman St,ACC 812, Boston, MA 02114 USA. EM cluberto@mgh.harvard.edu FU National Center for Complementary and Integrative Health [NCCIH 2T32AT000051-6]; National Cancer Institute [1K24CA197382] FX This study was supported by funds from the National Center for Complementary and Integrative Health (NCCIH 2T32AT000051-6 to CML) and National Cancer Institute (1K24CA197382 to ERP) NR 94 TC 0 Z9 0 U1 3 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD DEC PY 2016 VL 18 IS 12 BP 2194 EP 2201 DI 10.1093/ntr/ntw166 PG 8 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA EJ4NF UT WOS:000393193300004 PM 27613953 ER PT J AU Turner-McGrievy, G Wang, X Popkin, B Tate, DF AF Turner-McGrievy, G. Wang, X. Popkin, B. Tate, D. F. TI Tasting profile affects adoption of caloric beverage reduction in a randomized weight loss intervention SO OBESITY SCIENCE & PRACTICE LA English DT Article DE Beverages; dietary adherence; tasting preference; water ID ALCOHOL DEPENDENCE; FOOD PREFERENCES; DIETARY-INTAKE; SWEET-LIKING; PREDICTORS; OBESITY; SUGAR; WATER; SENSITIVITY; PHENOTYPE AB Objective The aim of this study was to examine differences in rates of non-caloric beverage adoption by participants classified as sweet likers (SLs) or sweet dislikers (measured using a behavioural tasting task). Methods Data are a sub-study from a 6-month, three-group, randomized weight loss trial (CHOICE) (body mass index 36.3 +/- 5.8 kg m(-2), 84% female, aged 42.2 +/- 10.9 years, 53% African-American) comparing the replacement of caloric beverages with either non-caloric sweetened beverages (diet) or water (water) compared with a control group. This sub-study, which included participants within the water (n = 106) and diet (n = 103) groups only, examined whether SLs (n = 33 water; n = 37 diet) varied in their adherence to caloric beverage recommendations compared with sweet dislikers (n = 73 water; n = 76 diet) over the 6-month study. Results Diet intake and sweet-liking data collected on 190 (3 months) and 169 participants (6 months) were used for analysis. The interaction between SL status and beverage group (diet vs. water) approached significance (P = 0.06) at 3 months but not 6 months. Caloric beverage intake (% energy) at 3 months was significantly higher in SLs within the water group (9.7 +/- 1.4%) compared with SLs in the diet group (5.4 +/- 1.0%, P = 0.03). Conclusions Results suggest that SL status may affect the rate in reduction of caloric beverages when water is the recommended substitution. Future studies should explore tailoring beverage recommendations to tasting profile. C1 [Turner-McGrievy, G.] Univ South Carolina GTM, Arnold Sch Publ Hlth, Dept Hlth Promot Educ & Behav, Columbia, SC USA. [Wang, X.] Forsyth Inst, Ctr Clin & Translat Res Cambridge, Cambridge, MA USA. [Popkin, B.; Tate, D. F.] Univ North Carolina Chapel Hill, Dept Nutr, Chapel Hill, NC USA. [Tate, D. F.] Univ North Carolina Chapel Hill, Dept Hlth Behav & Hlth Educ, Chapel Hill, NC USA. [Tate, D. F.] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. RP Turner-McGrievy, G (reprint author), 915 Greene St,Room 529, Columbia, SC 29208 USA. EM brie@sc.edu FU Nestle Waters USA; UNC Interdisciplinary Obesity Center (NIH) [T32 MH075854] FX This study was supported by an investigator-initiated research grant to the University of North Carolina from Nestle Waters USA and also by the UNC Interdisciplinary Obesity Center (NIH T32 MH075854). Water was also provided by Nestle. NR 31 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2055-2238 J9 OBES SCI PRACT JI OBES. SCI. PRACT. PD DEC PY 2016 VL 2 IS 4 BP 392 EP 398 DI 10.1002/osp4.64 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EJ4NI UT WOS:000393193700008 PM 28090344 ER PT J AU Yonekawa, Y Qian, CX Patel, AV Kim, LA Eliott, D AF Yonekawa, Yoshihiro Qian, Cynthia X. Patel, Avni V. Kim, Leo A. Eliott, Dean TI Occult Perforating Globe Injury Caused by Intraocular Foreign Body SO OPHTHALMIC SURGERY LASERS & IMAGING RETINA LA English DT Editorial Material AB Intraocular foreign bodies (IOFBs) may be associated with occult exit wounds. The authors present a case of a man who sustained a zipper-tooth IOFB through the cornea from a car tire explosion. CT showed an IOFB within the vitreous cavity, but the IOFB was not identified during vitrectomy. Extension of the peritomy revealed an exit wound with the foreign body lodged in the extraocular space. This case demonstrates that IOFBs can rest within the vitreous cavity after creating an exit wound, but may escape detection by being driven back out of the globe during vitrectomy due to the pressurized eye. Coexistent ocular surface and intraocular pathology often limit intraoperative visualization, but a perforating through-and-through injury should be suspected if the IOFB cannot be identified during vitrectomy. C1 [Yonekawa, Yoshihiro; Qian, Cynthia X.; Patel, Avni V.; Kim, Leo A.; Eliott, Dean] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Retina Serv, Boston, MA USA. RP Eliott, D (reprint author), Massachusetts Eye & Ear Infirm, Retina Serv, 243 Charles St, Boston, MA 02114 USA.; Eliott, D (reprint author), Harvard Med Sch, 243 Charles St, Boston, MA 02114 USA. EM dean_eliott@meei.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 2325-8160 EI 2325-8179 J9 OSLI RETINA JI Ophthalmic Surg. Lasers Imag. Retin. PD DEC PY 2016 VL 47 IS 12 BP 1162 EP 1163 DI 10.3928/23258160-20161130-14 PG 2 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA EJ3ID UT WOS:000393104900014 PM 27977843 ER PT J AU Stern, TA AF Stern, Theodore A. TI The Interface of Cardiology and Psychiatry SO PSYCHIATRIC ANNALS LA English DT Editorial Material C1 [Stern, Theodore A.] Harvard Med Sch, Psychiat Field Psychosomat Med Consultat, Boston, MA 02115 USA. [Stern, Theodore A.] Massachusetts Gen Hosp, Avery Weisman Psychiat Consultat Serv, Boston, MA 02114 USA. [Stern, Theodore A.] Massachusetts Gen Hosp, Off Clin Careers, Boston, MA 02114 USA. [Stern, Theodore A.] Acad Psychosomat Med, Bethesda, MD USA. RP Stern, TA (reprint author), Harvard Med Sch, Psychiat Field Psychosomat Med Consultat, Boston, MA 02115 USA.; Stern, TA (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Warren Bldg,Room 606, Boston, MA 02114 USA. EM TStern@Partners.org NR 2 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 EI 1938-2456 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD DEC PY 2016 VL 46 IS 12 BP 674 EP 675 DI 10.3928/00485713-20161109-01 PG 2 WC Psychiatry SC Psychiatry GA EJ3QV UT WOS:000393127600005 ER PT J AU Ng, CY Mela, T AF Ng, Chee Yuan Mela, Theofanie TI A Primer on Cardiac Devices: Psychological and Pharmacological Considerations SO PSYCHIATRIC ANNALS LA English DT Article ID IMPLANTABLE-CARDIOVERTER-DEFIBRILLATOR; QUALITY-OF-LIFE; POSTTRAUMATIC-STRESS-DISORDER; HEART-FAILURE; RESYNCHRONIZATION THERAPY; RANDOMIZED-TRIAL; SHOCKS; INAPPROPRIATE; PREVENTION; AMIODARONE AB The placement of cardiac implantable electronic devices (CIEDs), such as implantable cardiac defibrillators (ICDs) and cardiac resynchronization therapy (CRT) devices, leads to a significant increase in survival for patients with cardiac arrhythmias. However, despite the survival benefits, patients with CIEDs may suffer from a lower quality of life, psychosocial distress, and posttraumatic stress syndrome associated with ICD shocks. This article describes the psychological concerns and considerations when managing a patient with a CIED. The care of a patient with a CIED requires a multidisciplinary approach that includes collaboration between cardiologists and mental health providers. C1 [Ng, Chee Yuan] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Mela, Theofanie] Harvard Med Sch, Med, Boston, MA USA. [Mela, Theofanie] Massachusetts Gen Hosp, Pacemaker & ICD Clin, Boston, MA 02114 USA. RP Ng, CY (reprint author), Massachusetts Gen Hosp, Corrigan Minehan Heart Ctr, 55 Fruit St, Boston, MA 02114 USA. EM cyng1@mgh.harvard.edu NR 60 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 EI 1938-2456 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD DEC PY 2016 VL 46 IS 12 BP 683 EP 690 DI 10.3928/00485713-20161107-01 PG 8 WC Psychiatry SC Psychiatry GA EJ3QV UT WOS:000393127600007 ER PT J AU Celano, CM Villegas, A Albanese, A Huffman, JC AF Celano, Christopher M. Villegas, Ana Albanese, Ariana Huffman, Jeff C. TI Heart Failure: Psychological and Pharmacological Considerations SO PSYCHIATRIC ANNALS LA English DT Article ID GENERALIZED ANXIETY DISORDER; RANDOMIZED-CONTROLLED-TRIAL; ACUTE MYOCARDIAL-INFARCTION; CORONARY-ARTERY-DISEASE; POSTTRAUMATIC-STRESS-DISORDER; MAJOR DEPRESSIVE DISORDER; QUALITY-OF-LIFE; COLLABORATIVE CARE; CARDIAC EVENTS; CLINICAL-TRIAL AB Among patients with heart failure (HF), depression and anxiety disorders are common and associated with poor functioning, frequent hospitalizations, and increased rates of mortality. Despite these associations, depression and anxiety disorders are underdiagnosed and undertreated in this high-risk cohort. Diagnosing depression or anxiety disorders in patients with HF is challenging due to the overlap between cardiac and psychiatric symptoms. We recommend diagnosis through the use of a clinical interview and adherence to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, criteria. Once a psychiatric diagnosis is confirmed, both pharmacological and psychotherapeutic interventions are available. Selective serotonin reuptake inhibitors are well-tolerated in patients with cardiovascular disease but have limited efficacy in patients with HF. Cognitive-behavioral therapy improves mental health outcomes in patients with HF but has not been shown to improve physical health. Finally, collaborative care programs may be considered for the management of uncomplicated depression and anxiety disorders. C1 [Celano, Christopher M.; Huffman, Jeff C.] Harvard Med Sch, Psychiat, Boston, MA USA. [Celano, Christopher M.; Villegas, Ana; Albanese, Ariana] Massachusetts Gen Hosp, Blake 11,55 Fruit St, Boston, MA 02114 USA. [Huffman, Jeff C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Celano, CM (reprint author), Massachusetts Gen Hosp, Blake 11,55 Fruit St, Boston, MA 02114 USA. EM ccelano@partners.org FU National Heart Lung and Blood Institute [K23HL123607] FX The time spent for article preparation was funded by the National Heart Lung and Blood Institute through grant K23HL123607 (to C.M.C.). NR 88 TC 0 Z9 0 U1 1 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 EI 1938-2456 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD DEC PY 2016 VL 46 IS 12 BP 691 EP 701 DI 10.3928/00485713-20161102-01 PG 11 WC Psychiatry SC Psychiatry GA EJ3QV UT WOS:000393127600008 ER PT J AU Ivkovic, A Puckett, J AF Ivkovic, Ana Puckett, Judith TI The Psychological and Pharmacological Correlations of Atrial Fibrillation SO PSYCHIATRIC ANNALS LA English DT Article ID QUALITY-OF-LIFE; COGNITIVE IMPAIRMENT; ORAL ANTICOAGULANTS; STROKE PREVENTION; DRUG INTERACTIONS; RHYTHM CONTROL; RISK-FACTOR; PATHOPHYSIOLOGY; STIMULATION; DEPRESSION AB Atrial fibrillation (AF) is an arrhythmia characterized by disorganized electrical activity of the atria, secondary to ectopic focal discharge, leading to ineffective contraction and rapid heart rate. AF is the most common cardiac arrhythmia and is seen in approximately 1% to 2% of the population. Risk factors connected with AF include age, male gender, hypertension, valve disease, obesity, heart failure, diabetes, sleep apnea, cardiac surgery, smoking, alcohol consumption, and psychosocial stress. AF is associated with increased morbidity and mortality primarily due to coronary heart disease, heart failure, and stroke and has been associated with cognitive impairment and psychological distress. Treatment of AF should be focused on mitigating stroke risk as well as rate or rhythm control. AF is linked with depression, anxiety, and mood disorders as well as poor quality of life, but evidence suggests that these features can be improved with appropriate management. Further investigation is needed to inform and guide clinicians in therapeutic options and nonpharmacologic interventions for both the physical and psychiatric ramifications of AF. C1 [Ivkovic, Ana] Harvard Med Sch, Psychiat, Boston, MA USA. [Ivkovic, Ana; Puckett, Judith] Massachusetts Gen Hosp, 55 Fruit St,Warren Bldg,Room 605, Boston, MA 02114 USA. [Puckett, Judith] McLean Hosp, Belmont, MA USA. RP Ivkovic, A (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Warren Bldg,Room 605, Boston, MA 02114 USA. EM aivkovic@partners.org NR 53 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 EI 1938-2456 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD DEC PY 2016 VL 46 IS 12 BP 702 EP 711 DI 10.3928/00485713-20161110-01 PG 10 WC Psychiatry SC Psychiatry GA EJ3QV UT WOS:000393127600009 ER PT J AU Lusk, R Lyubkin, M Chermack, ST Sanborn, ML Bowersox, NW AF Lusk, Rebecca Lyubkin, Mark Chermack, Stephen T. Sanborn, Michelle L. Bowersox, Nicholas W. TI Quasi-Experimental Evaluation of the Impact of a Cognitive Behavioral Pretreatment Intervention for Veterans Seeking Psychotherapy SO PSYCHOTHERAPY LA English DT Article DE pretreatment intervention; cognitive-behavioral therapy; psychotherapy; veteran ID MENTAL-HEALTH TREATMENT; DEPRESSION TREATMENT; PREPARING CLIENTS; THERAPY; METAANALYSIS; PTSD; CARE; STRATEGIES; MOTIVATION; ATTENDANCE AB Pretreatment interventions have documented efficacy for reducing initial therapy refusal and early therapy departure. However, these interventions have not been well-studied in diagnostically diverse patient populations or within Veterans Affairs (VA) health care settings. We designed a manualized 4-session group cognitive-behavioral therapy-based pretreatment intervention (PTI) for a diagnostically diverse population of Veterans referred for psychotherapy in a general mental health clinic (MHC) in a large VA hospital. Retrospective record review was used to collect patient data over a period of 6 months after their completion of the PTI. A sample of 50 Veterans who were referred for care at the MHC prior to the implementation of the PTI was used for comparison (NoPTI). Two hundred sixty-six Veterans participated in the PTI. Veterans who participated in the PTI were equally as likely to attend at least one psychotherapy session as NoPTI Veterans, but had more individual and group therapy sessions during the 6-month therapy tracking period. PTI participants were also less likely to have a psychiatric hospitalization during the 6-month therapy tracking period. Study findings suggest that PTIs are a good fit to a VA general mental health setting and effective in bolstering therapy attendance. Limitations and future directions are discussed. C1 [Lusk, Rebecca; Lyubkin, Mark; Chermack, Stephen T.; Sanborn, Michelle L.; Bowersox, Nicholas W.] VA Ann Arbor Healthcare Syst, US Dept Vet Affairs, Ann Arbor, MI USA. [Lusk, Rebecca; Lyubkin, Mark; Chermack, Stephen T.; Sanborn, Michelle L.; Bowersox, Nicholas W.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. RP Lusk, R (reprint author), VA Ann Arbor Healthcare Syst, 2215 Fuller Rd,116C, Ann Arbor, MI 48105 USA. EM rebecca.lusk@va.gov NR 48 TC 0 Z9 0 U1 1 U2 1 PU AMER PSYCHOLOGICAL ASSOC, DIV PSYCHOTHERAPY PI CORAL GABLES PA 1390 SOUTH DIXIE HIGHWAY, STE 2222, CORAL GABLES, FL 33146-2946 USA SN 0033-3204 EI 1939-1536 J9 PSYCHOTHERAPY JI Psychotherapy PD DEC PY 2016 VL 53 IS 4 SI SI BP 424 EP 432 DI 10.1037/pst0000088 PG 9 WC Psychology, Clinical SC Psychology GA EJ4VL UT WOS:000393215000005 PM 27918190 ER PT J AU Palmer, WE AF Palmer, William E. TI Spinal Injections for Pain Management SO RADIOLOGY LA English DT Article ID EPIDURAL STEROID INJECTIONS; LOW-BACK-PAIN; NERVE ROOT BLOCKS; FACET-JOINT INJECTION; CERVICAL TRANSFORAMINAL INJECTIONS; CT FLUOROSCOPIC GUIDANCE; COMPUTED-TOMOGRAPHY; MEDICARE POPULATION; NUCLEUS PULPOSUS; CORTICOSTEROID INJECTIONS AB Image-guided spinal injection is commonly performed in symptomatic patients to decrease pain severity, confirm the pain generator, and delay or avoid surgery. This article focuses on the radiologist as spine interventionist and addresses the following four topics relevant to the radiologist who performs corticosteroid injections for pain management: (a) the rationale behind corticosteroid injection, (b) the interaction with patients, (c) the role of imaging in procedural selection and planning, and (d) the pearls and pitfalls of fluoroscopically guided injections. Factors that contribute to the success of a pain management service include communication skills and risk mitigation. A critical factor is the correlation of clinical symptoms with magnetic resonance (MR) imaging findings. Radiologists can leverage their training in MR image interpretation to distinguish active pain generators in the spine from incidental abnormalities. Knowledge of fluoroscopic anatomy and patterns of contrast material flow guide the planning and execution of safe and effective needle placement. (C) RSNA, 2016 C1 [Palmer, William E.] Massachusetts Gen Hosp, Dept Musculoskeletal Radiol, 55 Fruit St,YAW 6030, Boston, MA 02114 USA. RP Palmer, WE (reprint author), Massachusetts Gen Hosp, Dept Musculoskeletal Radiol, 55 Fruit St,YAW 6030, Boston, MA 02114 USA. EM wpalmer@mgh.harvard.edu NR 130 TC 0 Z9 0 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD DEC PY 2016 VL 281 IS 3 BP 669 EP 688 DI 10.1148/radiol.2016152055 PG 20 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EJ4QI UT WOS:000393201500003 PM 27870618 ER PT J AU Kumamaru, KK Kumamaru, H Bateman, BT Gronsbell, J Cai, TX Liu, J Higgins, LD Aoki, S Ohtomo, K Rybicki, FJ Patorno, E AF Kumamaru, Kanako K. Kumamaru, Hiraku Bateman, Brian T. Gronsbell, Jessica Cai, Tianxi Liu, Jun Higgins, Laurence D. Aoki, Shigeki Ohtomo, Kuni Rybicki, Frank J. Patorno, Elisabetta TI Limited Hospital Variation in the Use and Yield of CT for Pulmonary Embolism in Patients Undergoing Total Hip or Total Knee Replacement Surgery SO RADIOLOGY LA English DT Article ID EMERGENCY-DEPARTMENT; VENOUS THROMBOEMBOLISM; UNITED-STATES; D-DIMER; ARTHROPLASTY; ANGIOGRAPHY; RISK; THROMBOSIS; OUTCOMES; RATES AB Purpose: To evaluate the variation among U.S. hospitals in overall use and yield of in-hospital computed tomographic (CT) pulmonary angiography (PA) in patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery. Materials and Methods: Patients in the Premier Research Database who underwent elective TKR or THR between 2007 and 2011 were enrolled in this HIPAA-compliant, institutional review board-approved retrospective observational study. The informed consent requirement was waived. Hospitals were categorized into low, medium, and high tertiles of CT PA use to compare baseline patient- and hospital-level characteristics and pulmonary embolism (PE) positivity rates. To further investigate between-hospital variation in CT PA use, a hierarchical logistic regression model that included hospital-specific random effects and fixed patient and hospital-level effects was used. The intraclass correlation coefficient (ICC) was used to measure the amount of variability in CT PA use attributable to between-hospital variation. Results: The cohort included 205 198 patients discharged from 178 hospitals (median of 734.5 patients discharged per hospital; interquartile range, 316-1461 patients) with 3647 CT PA studies (1.8%). The crude frequency of CT PA scans among the hospitals ranged from 0% to 6.2% (median, 1.6%); more than 90% of the hospitals performed CT PA in less than 3% of their patients. The mean hospital-level PE positivity rate was 12.3% (median, 9.1%); there was no significant difference in PE positivity rate across low through high CT PA use tertiles (11.3%, 11.9%, 12.9%, P = .37). After adjustment for hospital- and patient-level factors, the remaining amount of interhospital variation was relatively low (ICC, 9.0%). Conclusion: Limited interhospital variation in use and yield of in-hospital CT PA was observed among patients undergoing TKR or THR in the United States. (C) RSNA, 2016 C1 [Kumamaru, Kanako K.; Rybicki, Frank J.] Brigham & Womens Hosp, Dept Radiol, Appl Imaging Sci Lab, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA. [Kumamaru, Hiraku; Bateman, Brian T.; Liu, Jun; Patorno, Elisabetta] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA. [Higgins, Laurence D.] Brigham & Womens Hosp, Dept Orthoped, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA. Harvard Med Sch, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA. [Kumamaru, Kanako K.; Aoki, Shigeki] Juntendo Univ, Dept Radiol, Tokyo, Japan. [Bateman, Brian T.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Gronsbell, Jessica; Cai, Tianxi] Harvard Univ, Dept Biostat, Boston, MA 02115 USA. [Ohtomo, Kuni] Univ Tokyo, Dept Radiol, Tokyo, Japan. RP Patorno, E (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA. EM epatorno@partners.org FU Bayer Yakuhin [KJ-26-9]; Japan Radiological Society FX Supported by the Japan Radiological Society and Bayer Yakuhin (KJ-26-9). NR 36 TC 0 Z9 0 U1 1 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD DEC PY 2016 VL 281 IS 3 BP 826 EP 834 DI 10.1148/radiol.2016152765 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EJ4QI UT WOS:000393201500016 PM 27228331 ER PT J AU Pandharipande, PV Alabre, CI Coy, DL Zaheer, A Miller, CM Herring, MS Tramontano, AC Dowling, EC Eisenberg, JD Ashar, BH Halpern, EF Donelan, K Gazelle, GS AF Pandharipande, Pari V. Alabre, Claude I. Coy, David L. Zaheer, Atif Miller, Chad M. Herring, Maurice S. Tramontano, Angela C. Dowling, Emily C. Eisenberg, Jonathan D. Ashar, Bimal H. Halpern, Elkan F. Donelan, Karen Gazelle, G. Scott TI Changes in Physician Decision Making after CT: A Prospective Multicenter Study in Primary Care Settings SO RADIOLOGY LA English DT Article ID DIAGNOSTIC-IMAGING UTILIZATION; UNINTENTIONAL WEIGHT-LOSS; ACADEMIC-MEDICAL-CENTER; SUPPORT; TRENDS; APPROPRIATENESS; MANAGEMENT; GUIDELINE; ADULTS; ACT AB Purpose: To determine the effect of computed tomography (CT) results on physician decision making in three common clinical scenarios in primary care. Materials and Methods: This research was approved by the institutional review board (IRB) and was HIPAA compliant. All physicians consented to participate with an opt- in or opt-out mechanism; patient consent was waived with IRB approval. In this prospective multicenter observational study, outpatients referred by primary care providers (PCPs) for CT evaluation of abdominal pain, hematuria, or weight loss were identified. Prior to CT, PCPs were surveyed to elicit their leading diagnosis, confidence in that diagnosis (confidence range, 0%- 100%), a rule-out diagnosis, and a management plan if CT were not available. Surveys were repeated after CT. Study measures were the proportion of patients in whom leading diagnoses and management changed (PCP management vs specialist referral vs emergency department transfer), median changes in diagnostic confidence, and the proportion of patients in whom CT addressed rule-out diagnoses. Regression analyses were used to identify associations between study measures and site and participant characteristics. Specifically, logistic regression analysis was used for binary study measures (change in leading diagnosis, change in management), and linear regression analysis was used for the continuous study measure (change in diagnostic confidence). Accrual began on September 5, 2012, and ended on June 28, 2014. Results: In total, 91 PCPs completed pre- and post-CT surveys in 373 patients. In patients with abdominal pain, hematuria, or weight loss, leading diagnoses changed after CT in 53% (131 of 246), 49% (36 of 73), and 57% (27 of 47) of patients, respectively. Management changed in 35% (86 of 248), 27% (20 of 74), and 54% (26 of 48) of patients, respectively. Median absolute changes in diagnostic confidence were substantial and significant (+20%, +20%, and +19%, respectively; P <= .001 for all); median confidence after CT was high (90%, 88%, and 80%, respectively). PCPs reported CT was helpful in confirming or excluding rule-out diagnoses in 98% (184 of 187), 97% (59 of 61), and 97% (33 of 34) of patients, respectively. Significant associations between primary measures and site and participant characteristics were not identified. Conclusion: Changes in PCP leading diagnoses and management after CT were common, and diagnostic confidence increased substantially. (C) RSNA, 2016 C1 [Pandharipande, Pari V.; Halpern, Elkan F.; Gazelle, G. Scott] Massachusetts Gen Hosp, Dept Radiol, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. [Pandharipande, Pari V.; Herring, Maurice S.; Tramontano, Angela C.; Dowling, Emily C.; Eisenberg, Jonathan D.; Halpern, Elkan F.; Gazelle, G. Scott] Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. [Alabre, Claude I.] Massachusetts Gen Hosp, Dept Med, Div Internal Med, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. [Donelan, Karen] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Dept Med, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. [Coy, David L.] Virginia Mason Med Ctr, Dept Radiol, Seattle, WA 98101 USA. [Zaheer, Atif] Johns Hopkins Med Inst, Dept Radiol, Baltimore, MD 21205 USA. [Ashar, Bimal H.] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. [Miller, Chad M.] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. [Eisenberg, Jonathan D.] Yale Sch Med, Dept Med, New Haven, CT USA. RP Pandharipande, PV (reprint author), Massachusetts Gen Hosp, Dept Radiol, 101 Merrimac St,10th Floor, Boston, MA 02114 USA.; Pandharipande, PV (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM pari@mgh-ita.org FU National Electrical Manufacturers Association, Medical Imaging and Technology Alliance Division FX Supported by National Electrical Manufacturers Association, Medical Imaging and Technology Alliance Division. NR 19 TC 0 Z9 0 U1 3 U2 3 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD DEC PY 2016 VL 281 IS 3 BP 835 EP 846 DI 10.1148/radiol.2016152887 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EJ4QI UT WOS:000393201500017 PM 27479641 ER PT J AU Wick, MJ Loomis, ZL Harral, JW Le, M Wehling, CA Miller, YE Dempsey, EC AF Wick, Marilee J. Loomis, Zoe L. Harral, Julie W. Le, Mysan Wehling, Carol A. Miller, York E. Dempsey, Edward C. TI Protection against vascular leak in neprilysin transgenic mice with complex overexpression pattern SO TRANSGENIC RESEARCH LA English DT Article DE Neprilysin; Transgenic mouse; Vascular leak; Evans blue; Duodenum; Rosa26 promoter ID ANGIOTENSIN-CONVERTING ENZYME; NEUTRAL ENDOPEPTIDASE; PLASMA EXTRAVASATION; SUBSTANCE-P; PERMEABILITY; EXPRESSION; PROTEOLYSIS; INHIBITION; BRADYKININ; PATHOLOGY AB Neprilysin (NEP) is a cell surface metallopeptidase found in many tissues. Based mostly on pharmacological manipulations, NEP has been thought to protect blood vessels from plasma extravasation. We have suggested that NEP may protect against pulmonary vascular injury. However, these prior studies did not utilize mice which overexpress NEP. The aims of the present investigation were to develop and characterize doubly transgenic (DT) mice that overexpress NEP universally and conditionally, and to investigate the protective effect that overexpressed NEP may have against plasma extravasation in the vasculature. The duodenum, which is often used to assess vascular permeability, and in which the NEP protein was overexpressed in our DT mice two-fold, was selected as our experimental preparation. We found that substance P-induced plasma extravasation was decreased substantially (3.5-fold) in the duodenums of our doxycycline-treated DT mice, giving independent evidence of NEP's protective effects against plasma extravasation. Transgenic lung NEP protein was not stably expressed in the DT mice, so we were not able to test the effect of NEP overexpression in the lung. Although initially overexpressed nearly nine-fold at that site, pulmonary NEP protein overexpression eventually dissipated. Surprisingly, at a time when there was no lung transgenic NEP protein overexpression, lung NEP mRNA expression was still increased 23-fold, indicating that the expression defect probably is not transcriptional. These studies help to characterize our complex transgenic model of NEP overexpression and further demonstrate NEP's protective effects against plasma extravasation. C1 [Wick, Marilee J.; Loomis, Zoe L.; Harral, Julie W.; Dempsey, Edward C.] Univ Colorado Denver, Cardiovasc Pulm Res Lab, RC-2,Box B-133,12700 E 19th Ave, Aurora, CO 80045 USA. [Wick, Marilee J.; Loomis, Zoe L.; Harral, Julie W.; Miller, York E.; Dempsey, Edward C.] Univ Colorado Denver, Div Pulm Sci & Crit Care Med, Aurora, CO 80045 USA. [Le, Mysan; Wehling, Carol A.; Miller, York E.; Dempsey, Edward C.] Denver VA Med Ctr, Denver, CO 80220 USA. RP Wick, MJ (reprint author), Univ Colorado Denver, Cardiovasc Pulm Res Lab, RC-2,Box B-133,12700 E 19th Ave, Aurora, CO 80045 USA.; Wick, MJ (reprint author), Univ Colorado Denver, Div Pulm Sci & Crit Care Med, Aurora, CO 80045 USA. EM Marilee.wick@ucdenver.edu FU National Heart, Lung and Blood Institute [NHLBI RO1 HL078929, PPG HL14985, RO3 HL095439]; Department of Veterans' Affairs; NCI [P50 CA058187, P30 CA046934] FX Supported by Grants received from the National Heart, Lung and Blood Institute (NHLBI RO1 HL078929, PPG HL14985 and RO3 HL095439) and the Department of Veterans' Affairs (Merit Review to ECD). YEM is supported by NCI P50 CA058187 and NCI P30 CA046934. The authors wish to thank Dr. James West (Vanderbilt University) for the FVB/N Rosa26- rtTA2-M2 singly transgenic mice, Dr. Lou Hersh (University of Kentucky) for the NEP-pCSC-SP-PW lentiviral vector, and Dr Jeffrey Whitsett (Cincinnati Children's Hospital) for the reengineered Tet-O-CMV vector and FVB/N SP-C-rtTA transgenic mice. The authors also wish to thank Sandra Walchak and Andy Poczobutt for expert technical and administrative assistance. NR 38 TC 0 Z9 0 U1 1 U2 1 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 DEC PY 2016 VL 25 IS 6 BP 773 EP 784 DI 10.1007/s11248-016-9969-x PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA EJ5AQ UT WOS:000393229300002 PM 27369050 ER PT J AU Baan, M Krentz, KJ Fontaine, DA Davis, DB AF Baan, Mieke Krentz, Kathleen J. Fontaine, Danielle A. Davis, Dawn Belt TI Successful in vitro fertilization and generation of transgenics in Black and Tan Brachyury (BTBR) mice SO TRANSGENIC RESEARCH LA English DT Article DE BTBR; In vitro fertilization; Embryo transfer; Transgenic mouse model; Diabetes mellitus; Autism ID METHYL-BETA-CYCLODEXTRIN; AUTISM SPECTRUM DISORDERS; C57BL/6 MOUSE SPERM; DIABETIC-NEPHROPATHY; CELL PROLIFERATION; OB/OB MICE; MODEL; EXPRESSION; FERTILITY; IMPROVES AB The Black and Tan Brachyury (BTBR) mouse strain is a valuable model for the study of long-term complications from obesity-induced type 2 diabetes mellitus and autism spectrum disorder. Due to technical difficulties with assisted reproduction, genetically modified animals on this background have previously been generated through extensive back-crossing, which is expensive and time-consuming. We successfully generated two separate transgenic mouse lines after direct zygote microinjection into this background strain. Additionally, we developed in vitro fertilization (IVF) methods for the BTBR mouse. We found low rates of fertilization and implantation in this strain, and identified the BTBR oocyte as the primary culprit of low success with BTBR IVF. We achieved an increase in live born pups from 5.9 to 35.6% with IVF in the BTBR strain by use of BTBR females at a younger age (18-25 days), collection of oocytes 15-17 h after superovulation, and the use of supplemented fertilization media. This method eliminates the need for time consuming assisted embryo manipulations that are otherwise required for success with BTBR oocytes. This advancement provides an exciting opportunity to directly generate BTBR transgenics and gene-edited mice using both traditional and emerging genomic editing techniques, such as CRISPR/Cas9. These methods also allow effective colony preservation and rederivation with these strains. To our knowledge, this is the first report describing embryo manipulations in BTBR mice. C1 [Baan, Mieke; Fontaine, Danielle A.; Davis, Dawn Belt] Univ Wisconsin, Dept Med, Div Endocrinol Diabet & Metab, 4147 MFCB,1685 Highland Ave, Madison, WI 53705 USA. [Krentz, Kathleen J.] Univ Wisconsin, Ctr Biotechnol, 425 Henry Mall, Madison, WI 53706 USA. [Davis, Dawn Belt] William S Middleton Mem Vet Adm Med Ctr, 2500 Overlook Terrace, Madison, WI 53705 USA. RP Davis, DB (reprint author), Univ Wisconsin, Dept Med, Div Endocrinol Diabet & Metab, 4147 MFCB,1685 Highland Ave, Madison, WI 53705 USA.; Davis, DB (reprint author), William S Middleton Mem Vet Adm Med Ctr, 2500 Overlook Terrace, Madison, WI 53705 USA. EM dbd@medicine.wisc.edu FU National Institutes of Health [T32 RR023916, T32 OD010423]; National Institute of Aging [T32 AG000213]; University of Wisconsin-Madison Science and Medicine Graduate Research Scholars Program; NIDDK [DK083442]; University of Wisconsin Department of Medicine FX This work was supported by the National Institutes of Health training grants T32 RR023916 and T32 OD010423 (MB). DAF was supported by National Institute of Aging Training Grant T32 AG000213 and by the University of Wisconsin-Madison Science and Medicine Graduate Research Scholars Program. DBD is supported by NIDDK DK083442 and the University of Wisconsin Department of Medicine. This work was performed with resources from the William S. Middleton Memorial Veterans Hospital. This work does not represent the views of the Department of Veterans Affairs or the United States Government. NR 37 TC 0 Z9 0 U1 1 U2 1 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 DEC PY 2016 VL 25 IS 6 BP 847 EP 854 DI 10.1007/s11248-016-9974-0 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA EJ5AQ UT WOS:000393229300008 PM 27515175 ER PT J AU Millstein, RA Woodruff, SI Linton, LS Edwards, CC Sallis, JF AF Millstein, Rachel A. Woodruff, Susan I. Linton, Leslie S. Edwards, Christine C. Sallis, James F. TI A pilot study evaluating the effects of a youth advocacy program on youth readiness to advocate for environment and policy changes for obesity prevention SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article DE Childhood obesity; Built environment; Nutrition; Physical activity; Policy ID SCHOOL PHYSICAL-EDUCATION; PSYCHOLOGICAL EMPOWERMENT; TOBACCO CONTROL; SELF-EFFICACY; SCREENING MEASURE; PRIMARY-CARE; PARTICIPATION; INTERVENTION; ADOLESCENTS; HEALTH AB Youth advocacy for obesity prevention is a promising but under-evaluated intervention. The aims of this study are to evaluate a youth advocacy program's outcomes related to youth perceptions and behaviors, develop an index of youth advocacy readiness, and assess potential predictors of advocacy readiness. Youth ages 9-22 in an advocacy training program (n = 92 matched pairs) completed surveys before and after training. Youth outcomes and potential predictors of advocacy readiness were assessed with evaluated scales. All 20 groups who completed the evaluation study presented their advocacy projects to a decision maker. Two of six perception subscales increased following participation in the advocacy program: self-efficacy for advocacy behaviors (p < .001) and participation in advocacy (p < .01). Four of five knowledge and skills subscales increased: assertiveness (p < .01), health advocacy history (p < .001), knowledge of resources (p < .01), and social support for health behaviors (p < .001). Youth increased days of meeting physical activity recommendations ( p < .05). In a mixed regression model, four subscales were associated with the advocacy readiness index: optimism for change (B = 1.46, 95 % CI = .49-2.44), sports and physical activity enjoyment (B = .55, 95 % CI = .05-1.05), roles and participation (B = 1.81,95 % CI =.60- 3.02), and advocacy activities (B= 1.49,95 % CI =.64-2.32). The youth advocacy readiness index is a novel way to determine the effects of multiple correlates of advocacy readiness. Childhood obesity-related advocacy training appeared to improve youths' readiness for advocacy and physical activity. C1 [Millstein, Rachel A.] San Diego State Univ Univ Calif San Diego Joint D, San Diego, CA 92103 USA. [Millstein, Rachel A.] Massachusetts Gen Hosp, Dept Psychiat, 55 Fruit St,Warren 1220, Boston, MA 02114 USA. [Woodruff, Susan I.] San Diego State Univ, Sch Social Work, San Diego, CA 92182 USA. [Linton, Leslie S.; Edwards, Christine C.] Hlth Policy Consulting Grp, San Diego, CA USA. [Sallis, James F.] Univ Calif San Diego, Dept Family Med & Publ Hlth, San Diego, CA 92103 USA. RP Millstein, RA (reprint author), San Diego State Univ Univ Calif San Diego Joint D, San Diego, CA 92103 USA.; Millstein, RA (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 55 Fruit St,Warren 1220, Boston, MA 02114 USA. EM rmillstein@gmail.com FU Active Living Research program of the Robert Wood Johnson Foundation [68508] FX This paper was supported by a grant (# 68508) from the Active Living Research program of the Robert Wood Johnson Foundation. NR 37 TC 0 Z9 0 U1 27 U2 27 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD DEC PY 2016 VL 6 IS 4 BP 648 EP 658 DI 10.1007/s13142-016-0408-6 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ5YU UT WOS:000393296000018 PM 27246954 ER PT J AU Grimes, BS Krysan, K Tran, LM Park, SJ Aberle, DR Spira, AE Dubinett, SM AF Grimes, Brandon S. Krysan, Kostyantyn Tran, Linh M. Park, Stacy J. Aberle, Denise R. Spira, Avrum E. Dubinett, Steven M. TI Indolence versus aggression in non-small cell lung cancer: defining heterogeneity to impact clinical outcomes SO TRANSLATIONAL CANCER RESEARCH LA English DT Editorial Material ID SURVIVAL PREDICTION; VALIDATION; EXPRESSION; ADENOCARCINOMA C1 [Grimes, Brandon S.; Krysan, Kostyantyn; Tran, Linh M.; Park, Stacy J.; Dubinett, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Pulm & Crit Care Med, 10833 Le Conte Ave,37-131 CHS, Los Angeles, CA 90095 USA. [Krysan, Kostyantyn; Tran, Linh M.; Park, Stacy J.; Aberle, Denise R.; Dubinett, Steven M.] Jonsson Comprehens Canc Ctr, Los Angeles, CA 90034 USA. [Aberle, Denise R.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol, Los Angeles, CA 90095 USA. [Spira, Avrum E.] Boston Univ, Dept Med, Pulm Ctr, Boston, MA 02215 USA. [Spira, Avrum E.] Boston Univ, Dept Pathol & Lab Med, Boston, MA 02215 USA. [Spira, Avrum E.] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. [Dubinett, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Dubinett, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Dubinett, Steven M.] VA Greater Los Angeles Hlth Care Ctr, Los Angeles, CA USA. RP Dubinett, SM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Pulm & Crit Care Med, 10833 Le Conte Ave,37-131 CHS, Los Angeles, CA 90095 USA. EM SDubinett@mednet.ucla.edu FU National Institutes of Health [1U01CA196408-01] FX Supported by the National Institutes of Health 1U01CA196408-01. NR 17 TC 0 Z9 0 U1 0 U2 0 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2218-676X EI 2219-6803 J9 TRANSL CANCER RES JI Transl. Cancer Res. PD DEC PY 2016 VL 5 SU 7 BP S1315 EP S1319 DI 10.21037/tcr.2016.12.24 PG 5 WC Oncology SC Oncology GA EJ6KY UT WOS:000393329400003 ER PT J AU Ng, MR Jain, RK AF Ng, Mei Rosa Jain, Rakesh K. TI Hypoxia-induced DNA hypermethylation: another reason to normalize tumor vessels SO TRANSLATIONAL CANCER RESEARCH LA English DT Editorial Material ID TET ENZYMES; CANCER; THERAPY; EPIGENETICS C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs Tumor Biol, Boston, MA 02114 USA. [Jain, Rakesh K.] Harvard Med Sch, Boston, MA 02115 USA. RP Jain, RK (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA. EM Jain@steele.mgh.harvard.edu FU US Department of Defense Breast Cancer Research Program Postdoctoral Fellowship [W81XWH-14-1-0034]; NIH National Cancer Institute [P01-CA080124, R35-CA197743] FX Funding: MR Ng was supported by a US Department of Defense Breast Cancer Research Program Postdoctoral Fellowship (W81XWH-14-1-0034). RK Jain was supported by the Program Project Grant (P01-CA080124) and Outstanding Investigator Award (R35-CA197743) from the NIH National Cancer Institute. NR 26 TC 0 Z9 0 U1 2 U2 2 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2218-676X EI 2219-6803 J9 TRANSL CANCER RES JI Transl. Cancer Res. PD DEC PY 2016 VL 5 SU 7 BP S1358 EP S1362 DI 10.21037/tcr.2016.12.72 PG 5 WC Oncology SC Oncology GA EJ6KY UT WOS:000393329400013 ER PT J AU Kremer, J Muschitz, GK Aumayr, K Moser, P Szabo, G Weymann, A Zuckermann, A Podesser, BK AF Kremer, Jamila Muschitz, Gabriela K. Aumayr, Klaus Moser, Philipp Szabo, Gabor Weymann, Alexander Zuckermann, Andreas Podesser, Bruno K. TI Influence of antithymocyte globulin treatment of brain-dead organ donor on inflammatory response in cardiac grafts: an experimental study in mice SO TRANSPLANT INTERNATIONAL LA English DT Article; Proceedings Paper CT 43rd Annual Meeting of the German-Society-for-Thoracic-and-Cardiovascular-Surgery CY FEB 09-12, 2014 CL Freiburg, GERMANY SP German Soc Thorac & Cardiovascular Surg DE antithymocyte globulin; brain death; inflammation; organ quality; transplantation ID ISCHEMIA-REPERFUSION INJURY; ANTI-THYMOCYTE GLOBULINS; NONHUMAN PRIMATE MODEL; LIVING UNRELATED DONORS; ADHESION MOLECULES; INTERLEUKIN-6 IL-6; TRANSPLANTATION; EXPRESSION; CYTOKINE; SURVIVAL AB The expression of proinflammatory cytokines in donor hearts after antithymocyte globulin (ATG) treatment given prior to organ removal was evaluated to analyze changes in inflammatory response. Adult female OF-1 mice were randomized into brain death (BD) groups (BD Control, BD ATG) with or without treatment, and Controls (Control, ATG). BD induction was performed through gradual inflation of an intracranial positioned balloon catheter. At the end of a 6-h observation period, ATG (1 mg/kg BW) was given intravenously. After 45 min, the donor hearts were removed. Proinflammatory markers IL-2 and IL-6 were examined using ELISA and immunohistochemistry staining. After single administration of ATG, the inflammatory reaction in the myocardium showed a significant reduction in IL-2 expression (BD Control vs. BD ATG, P = 0.033). Our investigation showed expected increase in proinflammatory mediators after BD. This increase was abolished by single infusion of ATG, indicated by significant reduction in IL-2 levels in the myocardium. We observed a reduction of IL-6 deposition in media cells in ATG-treated specimens. Further research is necessary to evaluate the role of ATG in donor management considering a potentially positive effect of ATG on IL-2-directed inflammatory response and possible reduction of IL-6-mediated vascular changes. C1 [Kremer, Jamila; Szabo, Gabor; Weymann, Alexander] Heidelberg Univ, Heart & Marfan Ctr, Dept Cardiac Surg, Heidelberg, Germany. [Kremer, Jamila; Muschitz, Gabriela K.; Moser, Philipp; Podesser, Bruno K.] Med Univ Vienna, Core Unit Biomed Res, Ludwig Boltzmann Cluster Cardiovasc Res, Vienna, Austria. [Muschitz, Gabriela K.] Med Univ Vienna, Dept Surg, Div Plast & Reconstruct Surg, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. [Aumayr, Klaus] Med Univ Vienna, Dept Clin Pathol, Vienna, Austria. [Moser, Philipp] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Zuckermann, Andreas] Med Univ Vienna, Div Cardiac Surg, Dept Surg, Vienna, Austria. RP Muschitz, GK (reprint author), Med Univ Vienna, Dept Surg, Div Plast & Reconstruct Surg, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. EM gabriela.muschitz@meduniwien.ac.at NR 43 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0934-0874 EI 1432-2277 J9 TRANSPL INT JI Transpl. Int. PD DEC PY 2016 VL 29 IS 12 BP 1329 EP 1336 DI 10.1111/tri.12851 PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA EJ4RF UT WOS:000393203800009 PM 27571572 ER PT J AU Ueno, T Jung, K Yeung, MY McGrath, MM Shimizu, T Kim, P Sayegh, MH Chandraker, A Yun, SH AF Ueno, Takuya Jung, Keehoon Yeung, Melissa Y. McGrath, Martina M. Shimizu, Tetsunosuke Kim, Pilhan Sayegh, Mohamed H. Chandraker, Anil Yun, Seok H. TI Imaging cell biology in transplantation SO TRANSPLANT INTERNATIONAL LA English DT Letter ID IN-VIVO C1 [Ueno, Takuya; Yeung, Melissa Y.; McGrath, Martina M.; Shimizu, Tetsunosuke; Sayegh, Mohamed H.; Chandraker, Anil] Harvard Med Sch, Brigham & Womens Hosp, Div Renal, Transplantat Res Ctr, Boston, MA 02115 USA. [Jung, Keehoon; Kim, Pilhan; Yun, Seok H.] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Dept Dermatol, Boston, MA USA. RP Ueno, T (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Renal, Transplantat Res Ctr, Boston, MA 02115 USA. EM ueno.takuya@mgh.harvard.edu NR 7 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0934-0874 EI 1432-2277 J9 TRANSPL INT JI Transpl. Int. PD DEC PY 2016 VL 29 IS 12 BP 1349 EP 1351 DI 10.1111/tri.12852 PG 3 WC Surgery; Transplantation SC Surgery; Transplantation GA EJ4RF UT WOS:000393203800011 PM 27570933 ER PT J AU Vasterling, JJ Aslan, M Proctor, SP Ko, J Marx, BP Jakupcak, M Schnurr, PP Gleason, T Huang, GD Concato, J AF Vasterling, Jennifer J. Aslan, Mihaela Proctor, Susan P. Ko, John Marx, Brian P. Jakupcak, Matthew Schnurr, Paula P. Gleason, Theresa Huang, Grant D. Concato, John TI Longitudinal Examination of Posttraumatic Stress Disorder as a Long-Term Outcome of Iraq War Deployment SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Iraq War; longitudinal study; military deployment; prospective study; PTSD prevalence ID MENTAL-HEALTH-SERVICES; MILITARY SERVICE; PTSD; SOLDIERS; US; VETERANS; SYMPTOMS; AFGHANISTAN; RESILIENCE; COHORT AB The mental health toll of the Iraq and Afghanistan Wars on military veterans has been considerable, yet little is known about the persistence of these adverse outcomes, especially relative to predeployment status. We prospectively examined posttraumatic stress disorder (PTSD) as a long-term consequence of warzone deployment, integrating data collected from 2003-2014. In the Neurocognition Deployment Health Study, we measured PTSD symptoms in US Army soldiers before and shortly after Iraq War deployment. We used the PTSD Checklist-Civilian Version and a structured clinical interview (i.e., Clinician-Administered PTSD Scale) to reassess PTSD in 598 service members and military veterans a median of 7.9 years (interquartile range, 7.2-8.5 years) after an index Iraq deployment. At long-term follow-up, 24.7% (95% confidence interval (CI): 21.5, 28.4) of participants met the case definition for PTSD, which was an absolute increase of 14.2% from the percentage assessed post-deployment (10.5%; 95% CI: 7.8, 13.7) and of 17.3% from the percentage assessed predeployment (7.4%; 95% CI: 5.5, 9.8). These findings highlight that PTSD is an enduring consequence of warzone participation among contemporary military personnel and veterans. The largest increase in PTSD cases occurred between the post-deployment and long-term follow-up assessments, which suggests that adverse stress reactions cannot necessarily be expected to dissipate over time and actually may increase. C1 [Vasterling, Jennifer J.; Marx, Brian P.] VA Boston Healthcare Syst, Natl Ctr, Boston, MA USA. [Vasterling, Jennifer J.] VA Boston Healthcare Syst, Psychol Serv, Boston, MA USA. [Vasterling, Jennifer J.; Marx, Brian P.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Aslan, Mihaela; Ko, John; Concato, John] Clin Epidemiol Res Ctr, VA Cooperat Studies Program, West Haven, CT USA. [Aslan, Mihaela; Concato, John] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. [Proctor, Susan P.] US Army, Environm Med Res Inst, Natick, MA 01760 USA. [Proctor, Susan P.] VA Boston Healthcare Syst, Res Serv, Boston, MA USA. [Proctor, Susan P.] Boston Univ, Dept Environm Hlth, Sch Publ Hlth, Boston, MA USA. [Jakupcak, Matthew] VA Puget Sound Healthcare Syst, Seattle, WA USA. [Jakupcak, Matthew] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Schnurr, Paula P.] Natl Ctr PTSD, White River Jct, VT USA. [Schnurr, Paula P.] Dartmouth Coll, Dept Psychiat, Geisel Sch Med, Hanover, NH 03755 USA. [Gleason, Theresa] VA Off Res & Dev, Washington, DC USA. [Huang, Grant D.] Cent Off, VA Cooperat Studies Program, Washington, DC USA. RP Vasterling, JJ (reprint author), VA Boston Healthcare Syst, Psychol 116B, 150 S Huntington Ave, Boston, MA 02130 USA. EM jennifer.vasterling@va.gov FU Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) [566] FX The work was supported by the Department of Veterans Affairs (VA) Cooperative Studies Program (CSP#566). Support for previous collection of archived data used in this study's longitudinal analyses was provided by the US Army Medical Research and Materiel Command (DAMD 17-030020) and VA Clinical Sciences Research and Development. NR 36 TC 1 Z9 1 U1 3 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 1 PY 2016 VL 184 IS 11 BP 796 EP 805 DI 10.1093/aje/kww151 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EI8AC UT WOS:000392725400003 PM 27852604 ER PT J AU Holmes, SE Esterlis, I Mazure, CM Lim, YY Ames, D Rainey-Smith, S Martins, RN Salvado, O Dore, V Villemagne, VL Rowe, CC Laws, SM Masters, CL Maruff, P Pietrzak, RH AF Holmes, Sophie E. Esterlis, Irina Mazure, Carolyn M. Lim, Yen Ying Ames, David Rainey-Smith, Stephanie Martins, Ralph N. Salvado, Olivier Dore, Vincent Villemagne, Victor L. Rowe, Christopher C. Laws, Simon M. Masters, Colin L. Maruff, Paul Pietrzak, Robert H. CA Australian Imaging Biomarkers TI beta-Amyloid, APOE and BDNF Genotype, and Depressive and Anxiety Symptoms in Cognitively Normal Older Women and Men SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE amyloid; APOE; BDNF; depression; anxiety; elderly ID ALZHEIMERS-DISEASE; ALLELE AB Objective: To examine how beta-amyloid (A beta), APOE and BDNF genotypes, and cortisol relate to depressive and anxiety symptoms in cognitively normal older women and men. Methods: Cross-sectional data were analyzed from 423 older adults from the Australian Imaging Biomarkers and Lifestyle study. Analyses of covariance evaluated associations between A beta, APOE and BDNF genotype, and cortisol in relation to severity of depressive and anxiety symptoms. Results: Among-A beta+ older adults, APOE epsilon 4 carriage was associated with greater severity of anxiety symptoms (d = 0.55); and in the full sample, APOE epsilon 4 carriagewas linked togreater severity of depressive (d = 0.26) and anxiety (d = 0.21) symptoms. Among A beta+ women, epsilon 4 carriers reported greater anxiety symptoms than non-epsilon 4 carriers (d = 0.83), and female BDNF rs6265 Val66 Met allele carriers reported greater depressive symptoms (d = 0.29). Conclusion: Sex moderated the relationship between A beta, APOE genotype, and BDNF genotype in predicting severity of anxiety and depressive symptoms in cognitively normal older adults. C1 [Holmes, Sophie E.; Esterlis, Irina; Mazure, Carolyn M.; Pietrzak, Robert H.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Lim, Yen Ying; Villemagne, Victor L.; Masters, Colin L.; Maruff, Paul] Univ Melbourne, Florey Inst, Parkville, Vic, Australia. [Ames, David] Univ Melbourne, Dept Psychiat, St Vincents Hlth, Acad Unit Psychiat Old Age, Kew, Vic, Australia. [Ames, David] Natl Ageing Res Inst, Parkville, Vic, Australia. [Rainey-Smith, Stephanie; Martins, Ralph N.; Laws, Simon M.] Edith Cowan Univ, Sch Med & Hlth Sci, Ctr Excellence Alzheimers Dis Res & Care, Joondalup, WA, Australia. [Martins, Ralph N.] Hollywood Private Hosp, Sir James McCusker Alzheimers Dis Res Unit, Perth, WA, Australia. [Salvado, Olivier; Dore, Vincent] Commonwealth Sci & Ind Res Org, Canberra, ACT, Australia. [Dore, Vincent; Villemagne, Victor L.; Rowe, Christopher C.] Austin Hlth, Dept Nucl Med, Heidelberg, Vic, Australia. [Dore, Vincent; Villemagne, Victor L.; Rowe, Christopher C.] Austin Hlth, Ctr PET, Heidelberg, Vic, Australia. [Laws, Simon M.] Curtin Univ, Curtin Hlth Innovat Res Inst, Fac Hlth Sci, Sch Biomed Sci, Perth, WA, Australia. [Maruff, Paul] Cogstate Ltd, Melbourne, Vic, Australia. [Pietrzak, Robert H.] VA Connecticut Healthcare Syst, Clin Neurosci Div, Natl Ctr Posttraumat Stress Disorder, US Dept Vet Affairs, West Haven, CT USA. RP Holmes, SE (reprint author), Yale Translat Brain Imaging Program, 2 Church St South,Suite 511, New Haven, CT 06511 USA. EM sophie.holmes@yale.edu FU Commonwealth Scientific Industrial and research Organization; Edith Cowan University; Mental Health Research Institute; National Ageing Research Institute; Austin Health; CogState Ltd.; National Health and Medical Research Council Australia [APP1009292]; Science and Industry Endowment Fund; Cooperative Research Centre for Mental Health, an Australian Government Initiative; National Institutes of Health [5R01MH104459, 1K01MH092681]; U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder FX Funding for the study was provided in part by the study partners (Commonwealth Scientific Industrial and research Organization, Edith Cowan University, Mental Health Research Institute, National Ageing Research Institute, Austin Health, and CogState Ltd.). The study received support from the National Health and Medical Research Council Australia via a project grant (APP1009292) awarded to S.M.L. and R.N.M., the Science and Industry Endowment Fund, and the Cooperative Research Centre for Mental Health, an Australian Government Initiative. Drs. Holmes and Esterlis are supported by National Institutes of Health grants 5R01MH104459 and 1K01MH092681. Dr. Pietrzak is supported in part by the U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder. NR 11 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD DEC PY 2016 VL 24 IS 12 BP 1191 EP 1195 DI 10.1016/j.jagp.2016.08.007 PG 5 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EI8AU UT WOS:000392727300010 PM 27742526 ER PT J AU Naples, JG Kotlarczyk, MP Perera, S Greenspan, SL Hanlon, JT AF Naples, Jennifer G. Kotlarczyk, Mary P. Perera, Subashan Greenspan, Susan L. Hanlon, Joseph T. TI Non-tricyclic and Non-selective Serotonin Reuptake Inhibitor Antidepressants and Recurrent Falls in Frail Older Women SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE antidepressants; older adults; recurrent falls; long-term care; frailty ID NURSING-HOME RESIDENTS; PRIMARY-CARE DATABASE; LONG-TERM-CARE; ELDERLY PATIENTS; RISK; DEPRESSION; PEOPLE; ADULTS; DRUGS; SAFETY AB Objective: To determine the risk of recurrent falls associated with antidepressants other than tricyclics (TCAs) and selective serotonin reuptake inhibitors (SSRIs) among frail older women. Methods: This is a secondary analysis of the Zoledronic acid in frail Elders to STrengthen bone, or ZEST, trial data treated as a longitudinal cohort in 181 frail, osteoporotic women aged >= 65 years in long-term care. The primary exposure was individual non-TCA/non-SSRI antidepressants (i.e., serotonin norepinephrine reuptake inhibitors, mirtazapine, trazodone, and bupropion) at baseline and 6 months. The main outcome was recurrent (at least two) falls within 6 months after antidepressant exposure. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were derived using a generalized estimating equations model. Results: At least 15% of women experienced recurrent falls between 0-6 and 6-12 months. At baseline and 6 months, 18.2% and 6.9% had a non-TCA/non-SSRI antidepressant, respectively. Adjusting for demographics, health status, and other drugs that increase risk of falls, non-TCA/non-SSRI antidepressant exposure significantly increased the risk of recurrent falls (AOR: 2.14; 95% CI: 1.01-4.54). Fall risk further increased after removing bupropion from the non-TCA/non-SSRI antidepressant group in sensitivity analyses (AOR: 2.73; 95% CI: 1.24-6.01). Conclusions: Other antidepressant classes may not be safer than TCAs/SSRIs with respect to recurrent falls in frail older women. C1 [Naples, Jennifer G.; Kotlarczyk, Mary P.; Perera, Subashan; Greenspan, Susan L.; Hanlon, Joseph T.] Univ Pittsburgh, Sch Med, Dept Med, Div Geriatr, Pittsburgh, PA 15213 USA. [Naples, Jennifer G.; Hanlon, Joseph T.] Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Pittsburgh, PA 15261 USA. [Perera, Subashan] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. [Hanlon, Joseph T.] Vet Affairs Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. RP Hanlon, JT (reprint author), Dept Med, Div Geriatr, 3471 Fifth Ave,Suite 500, Pittsburgh, PA 15213 USA. EM jth14@pitt.edu FU National Institutes on Aging [R01-AG028086, R01-AG05123, T32-AG021885, P30-AG02482706]; Donoghue Foundation; Agency for Health Research and Quality [R18-HS023779]; Lilly; Amgen FX Supported in part by grants from the National Institutes on Aging (R01-AG028086, R01-AG05123, T32-AG021885, and P30-AG02482706), the Donoghue Foundation, and Agency for Health Research and Quality (R18-HS023779). The University of Pittsburgh receives grant funding from Lilly and Amgen for research. Dr. Greenspan is on an advisory board for Merck. For the remaining authors, no conflicts of interest were declared. NR 36 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD DEC PY 2016 VL 24 IS 12 BP 1221 EP 1227 DI 10.1016/j.jagp.2016.08.008 PG 7 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EI8AU UT WOS:000392727300015 PM 27743842 ER PT J AU Xia, D Hasserjian, RP AF Xia, Daniel Hasserjian, Robert P. TI Molecular testing for JAK2, MPL, and CALR in myeloproliferative neoplasms SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID MINIMAL-RESIDUAL-DISEASE; THROMBOPOIETIN RECEPTOR; POLYCYTHEMIA-VERA; CALRETICULIN MUTANTS; JAK2-V617F MUTATION; PERIPHERAL-BLOOD; BONE-MARROW; DIGITAL PCR; MYELOFIBROSIS; RUXOLITINIB AB Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are myeloproliferative neoplasms characterized by recurrent somatic mutations in JAK2, CALR, and MPL. This short review addresses (1) the spectrum of mutations seen in PV, ET, and PMF, (2) the emerging genotype-phenotype correlations, (3) the current role of molecular testing in disease classification and management, and (4) several important considerations for selecting an appropriate molecular test. In our view, sequential testing algorithms and simultaneous assessment of multiple mutations by next-generation sequencing are both valid approaches to testing. (C) 2016 Wiley Periodicals, Inc. C1 [Xia, Daniel; Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, Warren Bldg 225,55 Fruit St, Boston, MA 02114 USA. RP Xia, D (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren Bldg 225,55 Fruit St, Boston, MA 02114 USA. EM yxia8@partners.org NR 32 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD DEC PY 2016 VL 91 IS 12 BP 1277 EP 1280 DI 10.1002/ajh.24578 PG 4 WC Hematology SC Hematology GA EI8BY UT WOS:000392730900031 PM 27727468 ER PT J AU Phillips, KM Hoehle, LP Caradonna, DS Gray, ST Sedaghat, AR AF Phillips, Katie M. Hoehle, Lloyd P. Caradonna, David S. Gray, Stacey T. Sedaghat, Ahmad R. TI Association of severity of chronic rhinosinusitis with degree of comorbid asthma control SO ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY LA English DT Article ID ENDOSCOPIC SINUS SURGERY; ALLERGIC RHINITIS; NASAL POLYPS; RISK-FACTORS; EXACERBATIONS; PREVALENCE; VALIDITY; CHILDREN AB Background: Comorbid chronic rhinosinusitis (CRS) is associated with worse asthma control. However, no study has investigated whether CRS severity affects the degree of asthma control. Objective: To determine the effect size of an association between CRS severity and asthma control. Methods: A pilot study with a prospective cross-sectional design. Adult patients with CRS and asthma were recruited. CRS severity was measured using the 22-item Sinonasal Outcomes Test (SNOT-22), and asthma control was measured using the Asthma Control Test (ACT). Poor asthma control was defined as an ACT score of 19 or less. In addition to age and sex, we also assessed the participants' history of smoking, aeroallergen hypersensitivity, the presence of polyps, and current use of a corticosteroid-containing asthma inhaler. The association between SNOT-22 and ACT was assessed using univariate and multivariable linear regression. Results: A total of 40 patients were recruited. The mean (SD) SNOT-22 score was 43.6 (23.6), and the mean (SD) ACT score was 20.6 (4.8). We found that the SNOT-22 score was associated with the ACT score (adjusted beta = -0.07; 95% confidence interval [CI], -0.13 to -0.02; P = .02) and with having poor asthma control (adjusted odds ratio, 1.06; 95% CI, 1.01-1.11; P = .02). A SNOT-22 cutoff score of 45 or higher had the greatest association with uncontrolled asthma (adjusted odds ratio, 14.96; 95% CI, 1.93-115.89; P = .01). Conclusion: CRS severity is negatively associated with asthma control in patients with asthma and CRS. On the basis of this pilot study, further study is warranted to elucidate the effect of CRS severity on asthma control and to determine whether reduction in CRS severity translates to improvement in asthma control. (C) 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. C1 [Phillips, Katie M.; Hoehle, Lloyd P.; Gray, Stacey T.; Sedaghat, Ahmad R.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. [Phillips, Katie M.; Hoehle, Lloyd P.; Caradonna, David S.; Gray, Stacey T.; Sedaghat, Ahmad R.] Harvard Med Sch, Dept Otolaryngol, Boston, MA USA. [Caradonna, David S.; Sedaghat, Ahmad R.] Beth Israel Deaconess Med Ctr, Div Otolaryngol, Boston, MA 02215 USA. [Sedaghat, Ahmad R.] Boston Childrens Hosp, Dept Otolaryngol & Commun Enhancement, Boston, MA USA. RP Sedaghat, AR (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM ahmad_sedaghat@meei.harvard.edu NR 39 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 1081-1206 EI 1534-4436 J9 ANN ALLERG ASTHMA IM JI Ann. Allergy Asthma Immunol. PD DEC PY 2016 VL 117 IS 6 BP 651 EP 654 DI 10.1016/j.anai.2016.09.439 PG 4 WC Allergy; Immunology SC Allergy; Immunology GA EI9GK UT WOS:000392815700014 PM 27979022 ER PT J AU Albers, AD Asafu-Adjei, J Delaney, MK Kelly, KE Gomez-Isla, T Blacker, D Johnson, KA Sperling, RA Hyman, BT Betensky, RA Hastings, L Albers, MW AF Albers, Alefiya Dhilla Asafu-Adjei, Josephine Delaney, Mary K. Kelly, Kathleen E. Gomez-Isla, Teresa Blacker, Deborah Johnson, Keith A. Sperling, Reisa A. Hyman, Bradley T. Betensky, Rebecca A. Hastings, Lloyd Albers, Mark W. TI Episodic Memory of Odors Stratifies Alzheimer Biomarkers in Normal Elderly SO ANNALS OF NEUROLOGY LA English DT Article ID IDENTIFICATION ABILITY; COGNITIVE DECLINE; DISEASE; DEMENTIA; SCALE; NEURODEGENERATION; INDIVIDUALS; ASSOCIATION; CENTERS; ADULTS AB Objective: The objective of this study was to relate a novel test of identifying and recalling odor percepts to biomarkers of Alzheimer's disease (AD) in well-characterized elderly individuals, ranging from cognitively normal to demented. Methods: One hundred eighty-three participants (cognitively normal: n=70; subjective cognitive concerns: n=74; mild cognitive impairment [MCI]: n=29, AD dementia: n=10) were administered novel olfactory tests: the Odor Percept IDentification (OPID) and the Percepts of Odor Episodic Memory (POEM) tests. Univariate cross-sectional analyses of performance across diagnoses; logistic regression modeling, including covariates of age, sex, education, APOE genotype, and neuropsychological test scores; and linear mixed modeling of longitudinal cognitive scores were performed. Amyloid deposition and MRI volumetrics were analyzed in a subset of participants. Results: Accuracy of identification and episodic memory of odor percepts differed significantly across diagnosis and age, with progressively worse performance across degrees of impairment. Among the participants who were cognitively normal or had subjective cognitive concerns, poorer than expected performance on the POEM test (based on the same individual's performance on the OPID and odor discrimination tests) was associated with higher frequencies of the APOE epsilon 4 allele, thinner entorhinal cortices, and worse longitudinal trajectory of Logical Memory scores. Interpretation: Selective impairment of episodic memory of odor percepts, relative to identification and discrimination of odor percepts revealed by this novel POEM battery, is associated with biomarkers of AD in a well-characterized pre-MCI population. These affordable, noninvasive olfactory tests offer potential to identify clinically normal individuals who have greater likelihood of future cognitive decline. C1 [Albers, Alefiya Dhilla; Delaney, Mary K.; Kelly, Kathleen E.; Gomez-Isla, Teresa; Sperling, Reisa A.; Hyman, Bradley T.; Albers, Mark W.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Albers, Alefiya Dhilla] Endicott Coll, Dept Psychol, Beverly, MA USA. [Asafu-Adjei, Josephine] Univ North Carolina Chapel Hill, Sch Nursing, Dept Biostat, Chapel Hill, NC USA. [Blacker, Deborah] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Johnson, Keith A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Betensky, Rebecca A.] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Hastings, Lloyd] Osmic Enterprises, Cincinnati, OH USA. RP Albers, MW (reprint author), MassGeneral Inst Neurodegenerat Dis, 114 16th St,2003, Boston, MA 02129 USA. EM albers.mark@mgh.harvard.edu FU NIH [DP2-OD000662, P30-AG036449, P50-AG005134, T32NS048005]; Wilkens Foundation; MGH ECOR grant; Harvard NeuroDiscovery Center FX Supported by NIH DP2-OD000662 (awarded to M.W.A), P30-AG036449 (awarded to R.A.S.), P50-AG005134 (awarded to B.T.H.), and T32NS048005 (awarded to R.A.B.), the Wilkens Foundation (awarded to M.W.A), MGH ECOR grant (awarded to M.W.A), and the Harvard NeuroDiscovery Center. NR 32 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD DEC PY 2016 VL 80 IS 6 BP 846 EP 857 DI 10.1002/ana.24792 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EI9IR UT WOS:000392821800007 ER PT J AU Tinhofer, I Stenzinger, A Eder, T Konschak, R Niehr, F Endris, V Distel, L Hautmann, MG Mandic, R Stromberger, C Weichert, W Budach, V AF Tinhofer, I. Stenzinger, A. Eder, T. Konschak, R. Niehr, F. Endris, V. Distel, L. Hautmann, M. G. Mandic, R. Stromberger, C. Weichert, W. Budach, V. TI Targeted next-generation sequencing identifies molecular subgroups in squamous cell carcinoma of the head and neck with distinct outcome after concurrent chemoradiation SO ANNALS OF ONCOLOGY LA English DT Article DE targeted next-generation sequencing; molecular risk stratification; concurrent chemoradiation; mutation profile; oropharyngeal carcinoma; hypopharyngeal carcinoma ID GROWTH-FACTOR RECEPTOR; HUMAN-PAPILLOMAVIRUS; OROPHARYNGEAL CANCER; LUNG-CANCER; STEM-CELLS; NOTCH; RADIOSENSITIVITY; SURVIVAL; EXPRESSION; RESISTANCE AB Background: Based on epidemiological (HPV status, smoking habits) and clinical risk factors (T/N stage), three subgroups of patients suffering from locally advanced oropharyngeal carcinoma with significantly different outcome after concurrent chemoradiation (cCRTX) can be distinguished. Mutational profiling by targeted next-generation sequencing (NGS) might further improve risk stratification. Patients and methods: Patients with stage IV squamous cell carcinoma of the oropharynx and hypopharynx who had been enrolled in a randomized phase III trial (ARO-0401) comparing two regimens of cCRTX and from whom archival tumor specimens were available were included. The HPV status was determined by p16 immunostaining and detection of HPV DNA. Targeted NGS covering 45 genes frequently altered in squamous cell carcinoma of the head and neck (SCCHN) was applied for detection of non-synonymous somatic and germline mutations. Interference of mutational profiles with cCRTX efficacy was determined. Results: The prognostic value of the 'Ang' risk model could be confirmed in the total biomarker study cohort (N = 175) as well as the patient subgroup for which mutational profiles could be established (N = 97). Mutations in genes involved in phosphoinositide 3-kinase (PI3K), receptor tyrosine kinase (RTK), and p53 signaling pathways were significantly enriched in the low-(N = 7), intermediate-(N = 20), and high-risk group (N = 70), respectively. Mutations in TP53 identified a subgroup of high-risk patients with dismal outcome after cCRTX. No prognostic relevance was observed for mutations in PI3K and RTK signaling pathways in the low-and intermediate-risk groups, respectively. Mutated NOTCH1 and two functional KDR germline variants (rs2305948, rs1870377) were associated with improved outcome in all risk groups. All genetic markers (TP53, NOTCH1, KDR) remained independent prognosticators of OS in the multivariate model. Conclusion: A potential of targeted NGS for risk classification of SCCHN cases beyond HPV status and clinical factors was demonstrated. C1 [Tinhofer, I.; Eder, T.; Konschak, R.; Niehr, F.; Stromberger, C.; Budach, V.] Charite, Dept Radiooncol & Radiotherapy, Berlin, Germany. [Tinhofer, I.; Eder, T.; Konschak, R.; Niehr, F.] German Canc Res Ctr, Heidelberg, Germany. [Tinhofer, I.; Eder, T.; Konschak, R.; Niehr, F.] German Canc Consortium DKTK, Partner Site Berlin, Berlin, Germany. [Stenzinger, A.; Endris, V.; Weichert, W.] Univ Hosp, Inst Pathol, Heidelberg, Germany. [Stenzinger, A.; Endris, V.; Weichert, W.] Natl Ctr Tumor Dis, Heidelberg, Germany. [Stenzinger, A.] Harvard Med Sch, Dept Pathol, Ctr Integrated Diagnost, Massachusetts Gen Hosp, Boston, MA USA. [Distel, L.] Univ Hosp Erlangen Nurnberg, Dept Radiat Oncol, Erlangen, Germany. [Hautmann, M. G.] Univ Hosp Regensburg, Dept Radiotherapy, Regensburg, Germany. [Mandic, R.] Univ Hosp Giessen Marburg, Dept Otorhinolaryngol Head & Neck Surg, Marburg, Germany. [Weichert, W.] Tech Univ Munich, Inst Pathol, Munich, Germany. [Weichert, W.] German Canc Res Ctr, Heidelberg, Germany. [Weichert, W.] German Canc Consortium DKTK, Partner Site Munich, Munich, Germany. RP Tinhofer, I (reprint author), Charite, Dept Radiooncol & Radiotherapy, Charite Pl 1, D-10117 Berlin, Germany. EM ingeborg.tinhofer@charite.de FU German Cancer Aid [DKH70-3103, DKH110217]; NCT-Heidelberg School of Oncology (NCT-HSO) FX This work has been supported by two grants of the German Cancer Aid (DKH70-3103 to V.B.; DKH110217 to I.T. and W.W.). A.S. is fully supported by a fellowship of the NCT-Heidelberg School of Oncology (NCT-HSO). NR 28 TC 0 Z9 0 U1 4 U2 4 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 DEC PY 2016 VL 27 IS 12 BP 2262 EP 2268 DI 10.1093/annonc/mdw426 PG 8 WC Oncology SC Oncology GA EI9JW UT WOS:000392825100019 PM 27681865 ER PT J AU Musuuza, JS Safdar, N AF Musuuza, Jackson S. Safdar, Nasia TI Every other day bathing with chlorhexidine gluconate: what is the evidence? SO ANNALS OF TRANSLATIONAL MEDICINE LA English DT Editorial Material ID CARE-ASSOCIATED INFECTIONS; ACQUIRED INFECTION; RANDOMIZED-TRIALS; PREVENTION; INTERVENTIONS; METAANALYSIS; STATEMENT; QUALITY; IMPACT; COSTS C1 [Musuuza, Jackson S.; Safdar, Nasia] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Musuuza, Jackson S.; Safdar, Nasia] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Div Infect Dis, Madison, WI USA. EM ns2@medicine.wisc.edu FU Agency for Healthcare Research and Quality [R18HS024039]; VA FX This work was supported by grant number R18HS024039 from the Agency for Healthcare Research and Quality. Nasia Safdar is also supported by a VA-funded Patient Safety Center of Inquiry. NR 26 TC 0 Z9 0 U1 0 U2 0 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2305-5839 EI 2305-5847 J9 ANN TRANSL MED JI ANN. TRANSL. MED. PD DEC PY 2016 VL 4 IS 24 AR 506 DI 10.21037/atm.2016.11.83 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EI7DE UT WOS:000392656900028 PM 28149868 ER PT J AU Zhao, V Das, S AF Zhao, Vanessa Das, Saumya TI Professor Saumya Das: my experience on cardiology disease and views on it in China SO ANNALS OF TRANSLATIONAL MEDICINE LA English DT Editorial Material C1 [Das, Saumya] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Das, Saumya] Beth Israel Deaconess Med Ctr, Cardiovasc Genet Ctr, Boston, MA 02215 USA. [Das, Saumya] MGH, Resynchronizat & Adv Cardiac Therapeut Program, Boston, MA 02114 USA. [Das, Saumya] Harvard Med Sch, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2305-5839 EI 2305-5847 J9 ANN TRANSL MED JI ANN. TRANSL. MED. PD DEC PY 2016 VL 4 IS 24 AR 556 DI 10.21037/atm.2016.12.50 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EI7DE UT WOS:000392656900078 PM 28149917 ER PT J AU Soble, JR Sordahl, JA Critchfield, EA Highsmith, JM Gonzalez, DA Ashish, D Marceaux, JC O'Rourke, JJF McCoy, KJM AF Soble, Jason R. Sordahl, Jeffrey A. Critchfield, Edan A. Highsmith, Jonathan M. Gonzalez, David Andres Ashish, Dev Marceaux, Janice C. O'Rourke, Justin J. F. McCoy, Karin J. M. TI Slow and Steady Does Not Always Win the Race: Investigating the Effect of Processing Speed across Five Naming Tests SO ARCHIVES OF CLINICAL NEUROPSYCHOLOGY LA English DT Article DE Language and language disorders; Assessment; Intelligence ID FALSE DISCOVERY RATE; PERFORMANCE; ABILITY AB Objective: This retrospective study investigated the effect of processing speed on confrontation naming performance via five naming tests with varying time components. Method: The effect of processing speed, as measured by the Wechsler Adult Intelligence Scale-Fourth Edition Processing Speed Index (PSI), and cognitive impairment were examined using Boston Naming Test, Neuropsychological Assessment Battery Naming Test, Visual Naming Test (VNT), Auditory Naming Test (ANT), and Woodcock-Johnson III Rapid Picture Naming (RPN) performance among a mixed clinical sample of 115 outpatient veterans. Results: PSI scores accounted for 5%-26% of the total variance in naming test performances. Comparison of cognitively impaired versus unimpaired participants found significant differences and medium to large effect sizes (eta(2) = .08-.20) for all naming measures except ANT tip-of-the-tongue responses. After controlling for the effect processing speed, VNT tip-of-the-tongue responses also became non-significant, whereas significant group differences remained present for all other naming test scores, albeit with notably smaller effects sizes (eta(2) = .06-.10). Conclusions: Confrontation naming test performance is related to cognitive processing speed, although the magnitude of this effect varies by the demands of each naming test (i.e., largest for RPN; smallest for VNT). Thus, results argue that processing speed is important to consider for accurate clinical interpretation of naming tests, especially in the context of cognitive impairment. C1 [Soble, Jason R.; Critchfield, Edan A.; Highsmith, Jonathan M.; Gonzalez, David Andres; Ashish, Dev; Marceaux, Janice C.; O'Rourke, Justin J. F.; McCoy, Karin J. M.] South Texas Vet Hlth Care Syst, Psychol Serv, San Antonio, TX USA. [Sordahl, Jeffrey A.] Boise VA Med Ctr, Neuropsychol Clin, Boise, ID USA. RP Soble, JR (reprint author), South Texas Vet Hlth Care Syst, Psychol Serv 116B, 7400 Merton Minter, San Antonio, TX 78229 USA. EM Jason.Soble@va.gov NR 26 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0887-6177 EI 1873-5843 J9 ARCH CLIN NEUROPSYCH JI Arch. Clin. Neuropsychol. PD DEC PY 2016 VL 31 IS 8 BP 976 EP 982 DI 10.1093/arclin/acw073 PG 7 WC Psychology, Clinical; Psychology SC Psychology GA EJ1MM UT WOS:000392974600014 ER PT J AU Fishel, AK AF Fishel, Anne K. TI Harnessing the Power of Family Dinners to Create Change in Family Therapy SO AUSTRALIAN AND NEW ZEALAND JOURNAL OF FAMILY THERAPY LA English DT Article DE adolescents; children; family dinner; family therapy; food; mealtimes ID MENTAL-HEALTH; ADOLESCENTS; CHILDREN; MEALS; BEHAVIORS; EAT; FREQUENCY; ASTHMA; PARENT; FOOD AB Family dinner and family therapy confer many similar benefits to family members and they are both settings in which families can connect and interact as a group, in a designated space and time. Over the last 20 years, a large body of research documents the physical, academic, and mental health benefits of family dinners. Research links regular family meals with healthier eating habits and lower obesity rates, lower rates of substance abuse, teen pregnancy, depression, stress, and anxiety, as well as stronger self-esteem, parent-child connectedness, resilience, and even better vocabularies. Family therapists can harness these benefits in four ways. First, by asking screening questions of families to determine whether and how often they are sharing meals and then discussing solutions to overcoming common obstacles. Second, by asking about or enacting a family dinner to obtain a snapshot of a family's organisation and functioning, in terms of their gender roles, division of labour, expression of affect and conflict, capacity to have fun, and tolerance of difference. Third, by playing non-competitive games in therapy that promote conversation, games that can also be played at the dinner table. Fourth, using family dinner as an annex to therapy as a place to experiment with new roles, behaviours, and patterns of communication, which can be enacted on a nightly basis after being discussed in therapy. Two case examples are presented to illustrate the ways that dinner can be a place for change, begun in therapy, and implemented at home. C1 [Fishel, Anne K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. EM anne.fishel@gmail.com FU Family Dinner Project, Cambridge, Massachusetts FX The author would like to acknowledge the support of and collaboration with The Family Dinner Project, Cambridge, Massachusetts. NR 33 TC 0 Z9 0 U1 14 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0814-723X EI 1467-8438 J9 AUST NZ J FAM THER JI Aust. N. Z. J. Fam. Ther. PD DEC PY 2016 VL 37 IS 4 SI SI BP 514 EP 527 DI 10.1002/anzf.1185 PG 14 WC Family Studies SC Family Studies GA EI7BL UT WOS:000392652000008 ER PT J AU van Veluw, SJ Charidimou, A van der Kouwe, AJ Lauer, A Reijmer, YD Costantino, I Gurol, ME Biessels, GJ Frosch, MP Viswanathan, A Greenberg, SM AF van Veluw, Susanne J. Charidimou, Andreas van der Kouwe, Andre J. Lauer, Arne Reijmer, Yael D. Costantino, Isabel Gurol, M. Edip Biessels, Geert Jan Frosch, Matthew P. Viswanathan, Anand Greenberg, Steven M. TI Microbleed and microinfarct detection in amyloid angiopathy: a high-resolution MRI-histopathology study SO BRAIN LA English DT Article DE small vessel disease; post-mortem MRI; histology; microbleeds; microinfarcts ID SMALL VESSEL DISEASE; CEREBRAL MICROBLEEDS; CORTICAL MICROINFARCTS; ALZHEIMERS-DISEASE; INTRACEREBRAL HEMORRHAGE; IN-VIVO; 7T MRI; BRAIN; VALIDATION; IMAGES AB Cerebral amyloid angiopathy is a common neuropathological finding in the ageing human brain, associated with cognitive impairment. Neuroimaging markers of severe cerebral amyloid angiopathy are cortical microbleeds and microinfarcts. These parenchymal brain lesions are considered key contributors to cognitive impairment. Therefore, they are important targets for therapeutic strategies and may serve as surrogate neuroimaging markers in clinical trials. We aimed to gain more insight into the pathological basis of magnetic resonance imaging-defined microbleeds and microinfarcts in cerebral amyloid angiopathy, and to explore the pathological burden that remains undetected, by using high and ultra-high resolution ex vivo magnetic resonance imaging, as well as detailed histological sampling. Brain samples from five cases (mean age 85 +/- 6 years) with pathology-proven cerebral amyloid angiopathy and multiple microbleeds on in vivo clinical magnetic resonance imaging were subjected to high-resolution ex vivo 7T magnetic resonance imaging. On the obtained high-resolution (200 km isotropic voxels) ex vivo magnetic resonance images, 171 microbleeds were detected compared to 66 microbleeds on the corresponding in vivo magnetic resonance images. Of 13 sampled microbleeds that were matched on histology, five proved to be acute and eight old microhaemorrhages. The iron-positive old microhaemorrhages appeared approximately four times larger on magnetic resonance imaging compared to their size on histology. In addition, 48 microinfarcts were observed on ex vivo magnetic resonance imaging in three out of five cases (two cases exhibited no microinfarcts). None of them were visible on in vivo 1.5T magnetic resonance imaging after a retrospective analysis. Of nine sampled microinfarcts that were matched on histology, five were confirmed as acute and four as old microinfarcts. Finally, we explored the proportion of microhaemorrhage and microinfarct burden that is beyond the detection limits of ex vivo magnetic resonance imaging, by scanning a smaller sample at ultra-high resolution, followed by serial sectioning. At ultra-high resolution (75 mu m isotropic voxels) magnetic resonance imaging we observed an additional 48 microbleeds (compared to high resolution), which proved to correspond to vasculopathic changes (i.e. morphological changes to the small vessels) instead of frank haemorrhages on histology. After assessing the serial sections of this particular sample, no additional haemorrhages were observed that were missed on magnetic resonance imaging. In contrast, nine microinfarcts were found in these sections, of which six were only retrospectively visible at ultra-high resolution. In conclusion, these findings suggest that microbleeds on in vivo magnetic resonance imaging are specific for microhaemorrhages in cerebral amyloid angiopathy, and that increasing the resolution of magnetic resonance images results in the detection of more 'non-haemorrhagic' pathology. In contrast, the vast majority of microinfarcts currently remain under the detection limits of clinical in vivo magnetic resonance imaging. C1 [van Veluw, Susanne J.; Charidimou, Andreas; Lauer, Arne; Reijmer, Yael D.; Gurol, M. Edip; Viswanathan, Anand; Greenberg, Steven M.] Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. [van Veluw, Susanne J.; Charidimou, Andreas; Lauer, Arne; Reijmer, Yael D.; Costantino, Isabel; Gurol, M. Edip; Frosch, Matthew P.; Viswanathan, Anand; Greenberg, Steven M.] Harvard Med Sch, Boston, MA USA. [van Veluw, Susanne J.; Biessels, Geert Jan] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol, Utrecht, Netherlands. [van der Kouwe, Andre J.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Res, Charlestown, MA USA. [van der Kouwe, Andre J.] Harvard Med Sch, Charlestown, MA USA. [Costantino, Isabel; Frosch, Matthew P.] Massachusetts Gen Hosp, Neuropathol Serv, CS Kubik Lab Neuropathol, Boston, MA 02114 USA. RP van Veluw, SJ (reprint author), Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. EM svanveluw@mgh.harvard.edu FU Alzheimer Nederland fellowship [WE 15-2013-07]; Van Leersum grant of the Royal Dutch Academy of Sciences [2467-VLB-519]; NIH [R21AG046657, R01AG047975, P50AG005134, K23AG028726, R01AG26484]; VIDI grant from ZonMw, The Netherlands Organization for Health Research and Development [91711384] FX This work was supported by an Alzheimer Nederland fellowship [WE 15-2013-07] and a Van Leersum grant of the Royal Dutch Academy of Sciences [2467-VLB-519] to S.J.v.V., an NIH grant [R21AG046657] to A.J.v.d.K., a VIDI grant from ZonMw, The Netherlands Organization for Health Research and Development [91711384] to G.J.B., NIH grants [R01AG047975], [P50AG005134], and [K23AG028726] to A.V., and an NIH grant [R01AG26484] to A.V. and S.M.G. NR 41 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD DEC PY 2016 VL 139 BP 3151 EP 3162 DI 10.1093/brain/aww229 PN 12 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EI7US UT WOS:000392709800017 PM 27645801 ER PT J AU Wachinger, C Salat, DH Weiner, M Reuter, M AF Wachinger, Christian Salat, David H. Weiner, Michael Reuter, Martin CA Alzheimer's Dis Neuroimaging TI Whole-brain analysis reveals increased neuroanatomical asymmetries in dementia for hippocampus and amygdala SO BRAIN LA English DT Article DE brain asymmetry; Alzheimer's disease; longitudinal shape analysis; mixed effects models; survival analysis ID MILD COGNITIVE IMPAIRMENT; LONGITUDINAL NEUROIMAGE DATA; SURFACE-BASED ANALYSIS; ALZHEIMERS-DISEASE; CORTICAL SURFACE; COORDINATE SYSTEM; MRI; ATROPHY; MCI; BIOMARKERS AB Structural magnetic resonance imaging data are frequently analysed to reveal morphological changes of the human brain in dementia. Most contemporary imaging biomarkers are scalar values, such as the volume of a structure, and may miss the localized morphological variation of early presymptomatic disease progression. Neuroanatomical shape descriptors, however, can represent complex geometric information of individual anatomical regions and may demonstrate increased sensitivity in association studies. Yet, they remain largely unexplored. In this article, we introduce a novel technique to study shape asymmetries of neuroanatomical structures across subcortical and cortical brain regions. We demonstrate that neurodegeneration of subcortical structures in Alzheimer's disease is not symmetric. The hippocampus shows a significant increase in asymmetry longitudinally and both hippocampus and amygdala show a significantly higher asymmetry cross-sectionally concurrent with disease severity above and beyond an ageing effect. Our results further suggest that the asymmetry in these structures is undirectional and that primarily the anterior hippocampus becomes asymmetric. Based on longitudinal asymmetry measures we subsequently study the progression from mild cognitive impairment to dementia, demonstrating that shape asymmetry in hippocampus, amygdala, caudate and cortex is predictive of disease onset. The same analyses on scalar volume measurements did not produce any significant results, indicating that shape asymmetries, potentially induced by morphometric changes in subnuclei, rather than size asymmetries are associated with disease progression and can yield a powerful imaging biomarker for the early presymptomatic classification and prediction of Alzheimer's disease. Because literature has focused on contralateral volume differences, subcortical disease lateralization may have been overlooked thus far. C1 [Wachinger, Christian; Salat, David H.; Reuter, Martin] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Wachinger, Christian] Ludwig Maximilians Univ Munchen, Dept Child & Adolescent Psychiat, Psychosomat & Psychotherapy, Munich, Germany. [Wachinger, Christian; Reuter, Martin] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Salat, David H.; Reuter, Martin] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Weiner, Michael] Univ Calif San Francisco, San Francisco VA Med Ctr, San Francisco, CA 94121 USA. RP Wachinger, C (reprint author), Waltherstr 23, D-80337 Munich, Germany.; Reuter, M (reprint author), 149 Thirteenth St,Suite 2301, Charlestown, MA 02129 USA. EM wachinger@gmail.com; mreuter@nmr.mgh.harvard.edu FU Humboldt foundation; National Cancer Institute [1K25CA181632-01]; Massachusetts Alzheimer's Disease Research Center [5P50AG005134]; MGH Neurology Clinical Trials Unit; Harvard NeuroDiscovery Center; Genentech Foundation [G-40819]; SAP SE; NVIDIA hardware award; A.A. Martinos Center for Biomedical Imaging [P41RR014075, P41EB015896, U24RR021382]; Shared Instrumentation Grants [1S10RR023401, 1S10RR019307, 1S10RR023043]; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; DOD ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research FX Support for this research was provided in part by the Humboldt foundation, the National Cancer Institute (1K25CA181632-01), the Massachusetts Alzheimer's Disease Research Center (5P50AG005134), the MGH Neurology Clinical Trials Unit, the Harvard NeuroDiscovery Center, the Genentech Foundation (G-40819), SAP SE, and an NVIDIA hardware award. Further support was provided by the A.A. Martinos Center for Biomedical Imaging (P41RR014075, P41EB015896, U24RR021382), and Shared Instrumentation Grants (1S10RR023401, 1S10RR019307, 1S10RR023043). Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. NR 60 TC 0 Z9 0 U1 3 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD DEC PY 2016 VL 139 BP 3253 EP 3266 DI 10.1093/brain/aww243 PN 12 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EI7US UT WOS:000392709800024 PM 27913407 ER PT J AU Shen, ZL Feng, Y Muthupalani, S Sheh, A Cheaney, LE Kaufman, CA Gong, GY Paster, BJ Fox, JG AF Shen, Zeli Feng, Yan Muthupalani, Sureshkumar Sheh, Alexander Cheaney, Lenzie E. Kaufman, Christian A. Gong, Guanyu Paster, Bruce J. Fox, James G. TI Novel Helicobacter species H.japonicum isolated from laboratory mice from Japan induces typhlocolitis and lower bowel carcinoma in C57BL/129 IL10(-/-) mice SO CARCINOGENESIS LA English DT Article ID CHOLESTEROL GALLSTONE FORMATION; INDUCED GASTRIC PATHOLOGY; HEPATICUS INFECTION; DNA-DAMAGE; INTESTINAL INFLAMMATION; GASTROINTESTINAL-TRACT; COLONIC INFLAMMATION; BILIS INFECTION; A/JCR MICE; CANCER AB A novel Helicobacter species Helicobacter japonicum was isolated from the stomach and intestines of clinically normal mice received from three institutes from Japan. The novel Helicobacter sp. was microaerobic, grew at 37 degrees C and 42 degrees C, was catalase and oxidase positive, but urease negative. It is most closely related to the 16S rRNA gene of H. muridarum (98.6%); to the 23S rRNA gene of H. hepaticus (97.9%); to the hsp60 gene of H. typhlonius (87%). The novel Helicobacter sp. has in vitro cytolethal distending toxin (CDT) activity; its cdtB gene sequence has 83.8% identity with that of H. hepaticus. The whole genome sequence of H. japonicum MIT 01-6451 has a 2.06-Mb genome length with a 37.5% G + C content. When the organism was inoculated into C57BL/129 IL10(-/-) mice, it was cultured from the stomach, colon and cecum of infected mice at 6 and 10 weeks post-infection. The cecum had the highest H. japonicum colonization levels by quantitative PCR. The histopathology of the lower bowel was characterized by moderate to severe inflammation, mild edema, epithelial defects, mild to severe hyperplasia, dysplasia and carcinoma. Inflammatory cytokines IFN gamma, TNF alpha and IL17a, as well as iNOS were significantly upregulated in the cecal tissue of infected mice. These results demonstrate that the novel H. japonicum can induce inflammatory bowel disease and carcinoma in IL10(-/-) mice and highlights the importance of identifying novel Helicobacter spp. especially when they are introduced from outside mouse colonies from different geographic locations. C1 [Shen, Zeli; Feng, Yan; Muthupalani, Sureshkumar; Sheh, Alexander; Cheaney, Lenzie E.; Kaufman, Christian A.; Fox, James G.] MIT, Div Comparat Med, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Gong, Guanyu; Fox, James G.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Paster, Bruce J.] Forsyth Inst, Cambridge, MA 02139 USA. RP Fox, JG (reprint author), MIT, Div Comparat Med, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Fox, JG (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM jgfox@mit.edu FU National Institutes of Health [P30-ES002109, R01-OD01141, T32-OD010978] FX National Institutes of Health (P30-ES002109, R01-OD01141, T32-OD010978 all to J.G.F). NR 52 TC 0 Z9 0 U1 2 U2 2 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 DEC PY 2016 VL 37 IS 12 BP 1190 EP 1198 DI 10.1093/carcin/bgw101 PG 9 WC Oncology SC Oncology GA EI9MN UT WOS:000392832300009 PM 27655833 ER PT J AU Bowles, DW Kochenderfer, M Cohn, A Sideris, L Nguyen, N Cline-Burkhardt, V Schnadig, I Choi, M Nabell, L Chaudhry, A Ruxer, R Ucar, A Hausman, D Walker, L Spira, A Jimeno, A AF Bowles, Daniel W. Kochenderfer, Mark Cohn, Allen Sideris, Lucas Nguyen, Nghia Cline-Burkhardt, Vivian Schnadig, Ian Choi, Minsig Nabell, Lisle Chaudhry, Arvind Ruxer, Robert Ucar, Antonio Hausman, Diana Walker, Luke Spira, Alexander Jimeno, Antonio TI A Randomized, Phase II Trial of Cetuximab With or Without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients With Metastatic Colorectal Carcinoma SO Clinical Colorectal Cancer LA English DT Article DE Combination therapy; EGFR; KRAS; PI3K; PIK3CA ID ADVANCED SOLID TUMORS; CELL LUNG-CANCER; OPEN-LABEL; MULTICENTER PHASE-1; PLUS IRINOTECAN; PI3K INHIBITORS; PIK3CA; MUTATIONS; PANITUMUMAB; RESISTANCE AB The phosphotidyinositol-3 kinase (PI3K) pathway in frequently activated on metastatic colorectal carcinoma (CRC). We combined a novel PI3K inhibitor, PX-866, with cetuximab for patients with KRAS codon 12 wide type metastatic CRC. Patients receiving PX-866 plus cetuximab did not improvement in response rate, progression-free survival, or overall survival compared to cetuximab alone. Toxicity, especially gastrointestinal, was higher in the combination arm. Background: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in colorectal cancer (CRC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. This randomized phase II study evaluated cetuximab with or without PX-866 in patients with metastatic, antiepidermal growth factor receptor-naive, KRAS codon 12 and 13 wild-type CRC. Patients and Methods: Patients with metastatic CRC who had received both oxaliplatin and irinotecan were randomized (1: 1) to cetuximab (400 mg/m(2) loading then 250 mg/m(2) weekly) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, overall survival (OS), toxicity, and correlation of relevant biomarkers with efficacy outcomes. Results: A total of 85 patients were enrolled. The median PFS was 59 days versus 104 days for arms A (cetuximab + PX-866) and B (cetuximab alone), respectively (P = 77). OS between the 2 arms (266 vs. 333 days for arm A vs. B) were similar (P = 83). Overall toxicity, including treatment-related toxicity, was higher in arm A compared with arm B, especially in terms of all-grade nausea (66% vs. 37%), vomiting (50% vs. 29%), diarrhea (64% vs. 18%), and rash (66% vs. 37%). Grade 3 diarrhea occurred in 19% of patients in Arm A and 0% in Arm B. PIK3CA mutations and PTEN loss by immunohistochemistry were infrequently seen. Conclusion: The addition of PX-866 to cetuximab did not improve PFS, objective response rate, or OS in patients with metastatic CRC. The combination arm had greater toxicity and may have been harmful in this study. C1 [Bowles, Daniel W.] Denver Vet Affairs Med Ctr, Denver, CO USA. [Bowles, Daniel W.; Jimeno, Antonio] Univ Colorado, Div Med Oncol, Sch Med, Aurora, CO USA. [Kochenderfer, Mark] Oncol & Hematol Associates SW Virginia, Roanoke, VA USA. [Cohn, Allen] Rocky Mt Canc Ctr, Denver, CO USA. [Sideris, Lucas] Maisonneuve Rosemont Hosp, Montreal, PQ, Canada. [Nguyen, Nghia] Champlin Charles LeMoyne, Ctr Sante & Serv Soc, Longueuil, PQ, Canada. [Cline-Burkhardt, Vivian] Texas Oncol, Austin, TX USA. [Schnadig, Ian] Northwest Canc Specialists, Vancouver, WA USA. [Choi, Minsig] Karmanos Canc Inst, Detroit, MI USA. [Nabell, Lisle] Univ Alabama Birmingham, Birmingham, AL USA. [Chaudhry, Arvind] Med Oncol Associates, Spokane, WA USA. [Ruxer, Robert] Texas Oncol Ft Worth, Ft Worth, TX USA. [Ucar, Antonio] Adv Med Specialties, Miami, FL USA. [Hausman, Diana; Walker, Luke] Oncothryeron Inc, Seattle, WA USA. [Spira, Alexander] Virginia Canc Specialists, Fairfax, VA USA. RP Bowles, DW (reprint author), Univ Colorado, Sch Med, Div Med Oncol, Med, 12801 East 17th Ave,MS8117, Aurora, CO 80045 USA. EM daniel.bowles@ucdenver.edu FU Oncothyreon Inc. FX This clinical trial was sponsored by Oncothyreon Inc. No funding was received from the National Institutes of Health, Wellcome Trust, or Howard Hughes Medical Institute. NR 40 TC 0 Z9 0 U1 0 U2 0 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1533-0028 EI 1938-0674 J9 CLIN COLORECTAL CANC JI Clin. Colorectal Canc. PD DEC PY 2016 VL 15 IS 4 BP 337 EP + DI 10.1016/j.dcc.2016.03.004 PG 10 WC Oncology SC Oncology GA EI7VQ UT WOS:000392712600021 PM 27118441 ER PT J AU Zullig, LL Smith, VA Jackson, GL Danus, S Schnell, M Lindquist, J Provenzale, D Weinberger, M Kelley, MJ Bosworth, HB AF Zullig, Leah L. Smith, Valerie A. Jackson, George L. Danus, Susanne Schnell, Merritt Lindquist, Jennifer Provenzale, Dawn Weinberger, Morris Kelley, Michael J. Bosworth, Hayden B. TI Colorectal Cancer Statistics From the Veterans Affairs Central Cancer Registry SO Clinical Colorectal Cancer LA English DT Article DE Colorectal; Incidence; Mortality; Neoplasms; US Department of Veterans Affairs ID HEALTH-CARE-SYSTEM; REPORTING DELAY; PREVALENCE; QUALITY; IMPACT; VA AB We describe the patient and tumor characteristics of those with colorectal cancer (CRC) among Veterans Affairs (VA) healthcare system users. This is important because CRC is common and the VA data have not been uniformly included in national cancer reports. Using the VA Central Cancer Registry, we identified VA CRC cases and compared them with those in national data sources. We concluded that the incidence of CRC among VA users is similar to that in the U.S. CRC population. Background: Colorectal cancer (CRC) is a common and potentially deadly disease. Although the United States has robust cancer data reporting, information from the Department of Veterans Affairs (VA) healthcare system has often been underrepresented in national cancer data sources. We describe veterans with incident CRC in terms of their patient and tumor characteristics and mortality. Patients and Methods: Patients diagnosed or treated with CRC at any VA institution in the fiscal years 2009 to 2012 were identified using 3 data sources: (1) VA Central Cancer Registry (VACCR); (2) VA Corporate Data Warehouse; and (3) VA Reports and Measures Portal. The CRC frequencies within the VA population and survival curves were examined descriptively and compared with the national projections using Surveillance, Epidemiology, and End Results program data. Results: A total of 12,551 veterans with CRC were included in the present analysis. The median age at diagnosis was 65.5 years. Approximately 97% (n = 12,229) of the CRC cases were diagnosed among men. Approximately 44% (n = 5517) of the patients were diagnosed with localized disease. The 3-year survival rate was associated with age (P < .01) and stage (P < .01) at diagnosis. We identified a possible decrease in VA CRC incidence over time. Conclusion: Although the VA CRC patient population was heavily skewed toward the male gender, the patient and tumor characteristics were similar between the incident CRC cases reported by the VACCR and those reported to the Surveillance, Epidemiology, and End Results program. This suggests that research findings resulting from the VACCR might have applicability beyond the VA healthcare system setting. C1 [Zullig, Leah L.; Smith, Valerie A.; Jackson, George L.; Danus, Susanne; Schnell, Merritt; Lindquist, Jennifer; Provenzale, Dawn; Weinberger, Morris; Bosworth, Hayden B.] Durham Vet Affairs Med Ctr, Ctr Hlth Serv Res Primary Care, 508 Fulton St 152, Durham, NC 27705 USA. [Zullig, Leah L.; Smith, Valerie A.; Jackson, George L.; Bosworth, Hayden B.] Duke Univ, Med Ctr, Div Gen Internal Med, Durham, NC 27710 USA. [Provenzale, Dawn] Epidemiol Ctr, Cooperat Studies Program, Durham, NC USA. [Provenzale, Dawn] Duke Univ, Med Ctr, Div Gastroenterol, Durham, NC 27710 USA. [Kelley, Michael J.] US Dept Vet Affairs, Off Patient Care Serv, Washington, DC USA. [Kelley, Michael J.] Durham Vet Affairs Med Ctr, Hematol Oncol Serv, Durham, NC USA. [Kelley, Michael J.] Duke Univ, Med Ctr, Div Med Oncol, Durham, NC USA. [Bosworth, Hayden B.] Duke Univ, Sch Nursing, Dept Psychiat & Behav Sci, Durham, NC USA. RP Zullig, LL (reprint author), Durham Vet Affairs Med Ctr, Ctr Hlth Serv Res Primary Care, 508 Fulton St 152, Durham, NC 27705 USA. EM leah.zullig@va.gov FU Veterans Affairs Health Services Research and Development Career Development Award [CDA 13025]; Senior Research Career Scientist awards from Veterans Affairs Health Services Research and Development [RCS 08-027, RCS 91-408] FX Dr. Zullig is supported by a Veterans Affairs Health Services Research and Development Career Development Award (CDA 13025). Drs. Bosworth (RCS 08-027) and Weinberger (RCS 91-408) are supported by Senior Research Career Scientist awards from Veterans Affairs Health Services Research and Development. The views expressed in this article are those of the authors and do not necessarily represent the position or policy of the U.S. Department of Veterans Affairs of the United States Government. We thank the Veterans Affairs cancer registrars for their data collection and related efforts. NR 27 TC 1 Z9 1 U1 0 U2 0 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1533-0028 EI 1938-0674 J9 CLIN COLORECTAL CANC JI Clin. Colorectal Canc. PD DEC PY 2016 VL 15 IS 4 BP E199 EP E204 DI 10.1016/j.clcc.2016.04.005 PG 6 WC Oncology SC Oncology GA EI7VQ UT WOS:000392712600008 PM 27301717 ER PT J AU Salinas, JL Rentsch, C Marconi, VC Tate, J Budoff, M Butt, AA Freiberg, MS Gibert, CL Goetz, MB Leaf, D Rodriguez-Barradas, MC Justice, AC Rimland, D AF Salinas, Jorge L. Rentsch, Christopher Marconi, Vincent C. Tate, Janet Budoff, Matthew Butt, Adeel A. Freiberg, Matthew S. Gibert, Cynthia L. Goetz, Matthew Bidwell Leaf, David Rodriguez-Barradas, Maria C. Justice, Amy C. Rimland, David TI Baseline, Time-Updated, and Cumulative HIV Care Metrics for Predicting Acute Myocardial Infarction and All-Cause Mortality SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE acute myocardial infarction; HIV; mortality; VACS Index ID VETERANS AGING COHORT; COMBINATION ANTIRETROVIRAL THERAPY; CARDIOVASCULAR-DISEASE; INFECTED PATIENTS; RISK-FACTORS; INDEX; IMMUNODEFICIENCY; HOSPITALIZATION; INDIVIDUALS; VIREMIA AB Background. After adjustment for cardiovascular risk factors and despite higher mortality, those with human immunodeficiency virus (HIV+) have a greater risk of acute myocardial infarction (AMI) than uninfected individuals. Methods. We included HIV+ individuals who started combination antiretroviral therapy (cART) in the Veterans Aging Cohort Study (VACS) from 1996 to 2012. We fit multivariable proportional hazards models for baseline, time-updated and cumulative measures of HIV-1 RNA, CD4 counts, and the VACS Index. We used the trapezoidal rule to build the following cumulative measures: viremia copy-years, CD4-years, and VACS Index score-years, captured 180 days after cART initiation until AMI, death, last clinic visit, or 30 September 2012. The primary outcomes were incident AMI (Medicaid, Medicare, and Veterans Affairs International Classification of Diseases-9 codes) and death. Results. A total of 8168 HIV+ individuals (53 861 person-years) were analyzed with 196 incident AMIs and 1710 deaths. Controlling for known cardiovascular risk factors, 6 of the 9 metrics predicted AMI and all metrics predicted mortality. Time-updated VACS Index had the lowest Akaike information criterion among all models for both outcomes. A time-updated VACS Index score of 55+ was associated with a hazard ratio (HR) of 3.31 (95% confidence interval [CI], 2.11-5.20) for AMI and a HR of 31.77 (95% CI, 26.17-38.57) for mortality. Conclusions. Time-updated VACS Index provided better AMI and mortality prediction than CD4 count and HIV-1 RNA, suggesting that current health determines risk more accurately than prior history and that risk assessment can be improved by biomarkers of organ injury. C1 [Salinas, Jorge L.; Marconi, Vincent C.; Rimland, David] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Salinas, Jorge L.; Marconi, Vincent C.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Rentsch, Christopher; Marconi, Vincent C.; Rimland, David] Atlanta Vet Affairs Med Ctr, Decatur, GA USA. [Rentsch, Christopher; Tate, Janet; Justice, Amy C.] West Haven Vet Adm, Med Ctr, New Haven, CT USA. [Rentsch, Christopher; Tate, Janet; Justice, Amy C.] Yale Univ, Sch Med, New Haven, CT USA. [Rentsch, Christopher; Tate, Janet; Justice, Amy C.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Budoff, Matthew; Goetz, Matthew Bidwell; Leaf, David] Univ Calif Los Angeles, Vet Affairs Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. [Budoff, Matthew; Goetz, Matthew Bidwell; Leaf, David] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Butt, Adeel A.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. [Butt, Adeel A.] Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15260 USA. [Butt, Adeel A.] Weill Cornell Med Coll, Doha, Qatar. [Butt, Adeel A.] Weill Cornell Med Coll, New York, NY USA. [Butt, Adeel A.] Hamad Med Corp, Hamad Healthcare Qual Inst, Doha, Qatar. [Freiberg, Matthew S.] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Gibert, Cynthia L.] Wasington DC VA Med Ctr, Washington, DC USA. [Gibert, Cynthia L.] George Washington Univ, Sch Med, Washington, DC USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Infect Dis Sect, Michael E DeBakey VA Med Ctr, Houston, TX 77030 USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. RP Justice, AC (reprint author), Yale Univ, Sch Med, VA Connecticut Healthcare Syst, 950 Campbell Ave,Bldg 35a Rm 2-212 11 ACSLG, West Haven, CT 06516 USA. EM amy.justice2@va.gov FU Agency for Healthcare Research and Quality [R01-HS018372]; National Institute on Alcohol Abuse and Alcoholism [U24-AA020794, U01-AA020790, U01-AA020795, U01-AA020799, U24-AA022001, U24 AA022007, U10 AA013566]; National Heart, Lung, and Blood Institute [R01HL095136, R01-HL090342]; National Institute of Allergy and Infectious Diseases [U01-A1069918]; Fogarty International Center [R25TW009337]; National Institute of Mental Health [P30-MH062294]; National Institute on Drug Abuse [R01DA035616]; National Cancer Institute [R01 CA173754]; Veterans Health Administration Office of Research and Development [VA REA 08-266]; Veterans Health Administration Office of Research and Development (VA IRR Merit Award); Office of Academic Affiliations (Medical Informatics Fellowship) FX This work was supported by the following: Agency for Healthcare Research and Quality (R01-HS018372); National Institute on Alcohol Abuse and Alcoholism (U24-AA020794, U01-AA020790, U01-AA020795, U01-AA020799, U24-AA022001, U24 AA022007, U10 AA013566 completed); National Heart, Lung, and Blood Institute (R01HL095136, R01-HL090342); National Institute of Allergy and Infectious Diseases (U01-A1069918); Fogarty International Center (R25TW009337); National Institute of Mental Health (P30-MH062294); National Institute on Drug Abuse (R01DA035616); National Cancer Institute (R01 CA173754), Veterans Health Administration Office of Research and Development (VA REA 08-266, VA IRR Merit Award), and Office of Academic Affiliations (Medical Informatics Fellowship). NR 32 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 1 PY 2016 VL 63 IS 11 BP 1423 EP 1430 DI 10.1093/cid/ciw564 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EI7WA UT WOS:000392713900005 PM 27539575 ER PT J AU Xia, FD Cremer, J Butler, DC AF Xia, Fandi Cremer, Julia Butler, Daniel C. TI Dermatology Medications in Older Adults: Common Medications and Considerations SO Current Geriatrics Reports LA English DT Article DE Dermatogeriatrics; Geriatrics; Adverse effects; Medication interactions; Antihistamines; Antimicrobials; Systemic corticosteroids; Methotrexate; Immunosuppressives ID RENAL-FAILURE; METHOTREXATE; DRUG AB Purpose of review Medication management in the elderly population is a common challenge for dermatologists. This review aims to discuss clinical considerations when using common dermatologic classes of drugs in the elderly population. Recent findings A review of the relevant dermatologic and geriatric literature was conducted. Summary Drug classes discussed include H1-antihistamines, antimicrobials, and immunosuppressive medications with focus on systemic corticosteroids and methotrexate. The review examines the possible side-effects and drug interactions of these medications in the context of physiologic changes and comorbidities present in the elderly. C1 [Xia, Fandi] Harvard Med Sch, 25 Shattuck St, Boston, MA 02115 USA. [Cremer, Julia] Stanford Univ, Dept Med, 300 Pasteur Dr, Stanford, CA 94305 USA. [Butler, Daniel C.] Massachusetts Gen Hosp, Dept Dermatol, 55 Fruit St, Boston, MA 02114 USA. RP Butler, DC (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 55 Fruit St, Boston, MA 02114 USA. EM fandi_xia@hms.harvard.edu; juliakcremer@gmail.com; dbutler8@partners.org NR 33 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 2196-7865 J9 CURR GERIATR REP JI Curr. Geriatr. Rep. PD DEC PY 2016 VL 5 IS 4 BP 259 EP 265 DI 10.1007/s13670-016-0188-3 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA EI9TB UT WOS:000392850900004 ER PT J AU Gnanadesigan, M Kameyama, T Karanasos, A van Ditzhuijzen, NS van der Sijde, JN van Geuns, RJ Ligthart, J Witberg, K Ughi, GJ van der Steen, AFW Regar, E van Soest, G AF Gnanadesigan, Muthukaruppan Kameyama, Takeyoshi Karanasos, Antonios van Ditzhuijzen, Nienke S. van der Sijde, Johannes N. van Geuns, Robert-Jan Ligthart, Jurgen Witberg, Karen Ughi, Giovanni J. van der Steen, Antonius F. W. Regar, Evelyn van Soest, Gijs TI Automated characterisation of lipid core plaques in vivo by quantitative optical coherence tomography tissue type imaging SO EUROINTERVENTION LA English DT Article DE attenuation; lipid core plaque; optical coherence tomography ID NEAR-INFRARED SPECTROSCOPY; PERIPROCEDURAL MYOCARDIAL-INFARCTION; PERCUTANEOUS CORONARY INTERVENTION; FIBROUS CAP THICKNESS; INTRAVASCULAR ULTRASOUND; SCATTERING MEDIA; RICH PLAQUE; HIGH-RISK; ELEVATION; CATHETER AB Aims: Qualitative criteria for plaque tissue characterisation by OCT are well established, but quantitative methods lack systematic validation in vivo. High optical attenuation coefficient mu(t) has been associated with unstable plaque features, such as lipid core. The purpose of this study was to validate optical coherence tomography (OCT) attenuation imaging for tissue characterisation in vivo, specifically to detect lipid core in coronary atherosclerotic plaques, and to evaluate quantitatively the ability of OCT attenuation imaging to differentiate thin-cap (TCFA) and thick-cap fibroatheroma (FA). Methods and results: We prospectively enrolled 85 patients undergoing imaging of a native coronary segment by both OCT and near-infrared spectroscopy and intravascular ultrasound (NIRS-IVUS). Ninety-eight NIRS-positive 4 mm plaque segments were selected and matched to the OCT data. Two experienced OCT readers classified the plaque type using OCT criteria. A cap thickness of 65 mu m was used to differentiate TCFA and FA. We computed an index of plaque attenuation (IPA) in the 4 mm blocks, and assessed the association of this index with plaque type. IPA differentiated between TCFA and FA (AUC=0.82 in ROC analysis; p<0.0001). LCBI was numerically, but not significantly, higher in TCFA compared to FA (p=0.097). Conclusions: IPA is an unbiased reproducible measure of tissue optical properties. The fraction of pixels with attenuation coefficient >= 11 mm(-1) can identify TCFA. C1 [Gnanadesigan, Muthukaruppan; Kameyama, Takeyoshi; Karanasos, Antonios; van Ditzhuijzen, Nienke S.; van der Sijde, Johannes N.; van Geuns, Robert-Jan; Ligthart, Jurgen; Witberg, Karen; van der Steen, Antonius F. W.; Regar, Evelyn; van Soest, Gijs] Erasmus Univ, Med Ctr, Thoraxctr, Rotterdam, Netherlands. [Kameyama, Takeyoshi] Tohoku Univ, Biomed Imaging Lab, Grad Sch Biomed Engn, Sendai, Miyagi, Japan. [Ughi, Giovanni J.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [van der Steen, Antonius F. W.] Netherlands Heart Inst, Utrecht, Netherlands. [van der Steen, Antonius F. W.] Delft Univ Technol, Dept Imaging Phys, Delft, Netherlands. EM g.vansoest@erasmusmc.nl RI van Soest, Gijs/B-4881-2008 FU Dutch Heart Foundation [2010B064] FX The authors acknowledge funding from the Dutch Heart Foundation (2010B064). The authors would also like to acknowledge Prof. Dr Yoshifumi Saijo, Dr Frank Gijsen, Dr Jolanda Wentzel and Dr Pieter Kruizinga for their contributions in the discussions. We thank Dr Thomas Johnson for critical commenting on the manuscript. NR 33 TC 0 Z9 0 U1 1 U2 1 PU EUROPA EDITION PI TOULOUSE CEDEX 6 PA 19 ALLEES JEAN JAURES B P 61508, TOULOUSE CEDEX 6, 31015, FRANCE SN 1774-024X EI 1969-6213 J9 EUROINTERVENTION JI EuroIntervention PD DEC PY 2016 VL 12 IS 12 BP 1490 EP 1497 DI 10.4244/EIJ-D-15-00320 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI7OX UT WOS:000392688700011 PM 27998841 ER PT J AU Jackson, RJ Rudinskiy, N Herrmann, AG Croft, S Kim, JM Petrova, V Ramos-Rodriguez, JJ Pitstick, R Wegmann, S Garcia-Alloza, M Carlson, GA Hyman, BT Spires-Jones, TL AF Jackson, Rosemary J. Rudinskiy, Nikita Herrmann, Abigail G. Croft, Shaun Kim, JeeSoo Monica Petrova, Veselina Jose Ramos-Rodriguez, Juan Pitstick, Rose Wegmann, Susanne Garcia-Alloza, Monica Carlson, George A. Hyman, Bradley T. Spires-Jones, Tara L. TI Human tau increases amyloid beta plaque size but not amyloid beta-mediated synapse loss in a novel mouse model of Alzheimer's disease SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE Alzheimer; amyloid beta; plaque; synapse; tau ID LONG-TERM POTENTIATION; SOLUBLE-A-BETA; TRANSGENIC MICE; IN-VIVO; MULTIPHOTON MICROSCOPY; ARRAY TOMOGRAPHY; PATHOLOGICAL TAU; TANGLE FORMATION; ENDOGENOUS TAU; P-TAU AB Alzheimer's disease is characterized by the presence of aggregates of amyloid beta (A beta) in senile plaques and tau in neurofibrillary tangles, as well as marked neuron and synapse loss. Of these pathological changes, synapse loss correlates most strongly with cognitive decline. Synapse loss occurs prominently around plaques due to accumulations of oligomeric A beta. Recent evidence suggests that tau may also play a role in synapse loss but the interactions of A beta and tau in synapse loss remain to be determined. In this study, we generated a novel transgenic mouse line, the APP/PS1/rTg21221 line, by crossing APP/PS1 mice, which develop A beta-plaques and synapse loss, with rTg21221 mice, which overexpress wild-type human tau. When compared to the APP/PS1 mice without human tau, the cross-sectional area of ThioS+ dense core plaques was increased by similar to 50%. Along with increased plaque size, we observed an increase in plaque-associated dystrophic neurites containing misfolded tau, but there was no exacerbation of neurite curvature or local neuron loss around plaques. Array tomography analysis similarly revealed no worsening of synapse loss around plaques, and no change in the accumulation of A beta at synapses. Together, these results indicate that adding human wild-type tau exacerbates plaque pathology and neurite deformation but does not exacerbate plaque-associated synapse loss. C1 [Jackson, Rosemary J.; Herrmann, Abigail G.; Croft, Shaun; Kim, JeeSoo Monica; Petrova, Veselina; Spires-Jones, Tara L.] Univ Edinburgh, Ctr Cognit & Neural Syst, 1 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland. [Jackson, Rosemary J.; Herrmann, Abigail G.; Croft, Shaun; Kim, JeeSoo Monica; Petrova, Veselina; Spires-Jones, Tara L.] Univ Edinburgh, Ctr Dementia Prevent, 1 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland. [Rudinskiy, Nikita; Wegmann, Susanne; Hyman, Bradley T.] Massachusetts Gen Hosp, Charlestown, MA USA. [Rudinskiy, Nikita; Wegmann, Susanne; Hyman, Bradley T.] Harvard Med Sch, Charlestown, MA USA. [Jose Ramos-Rodriguez, Juan; Garcia-Alloza, Monica] Univ Cadiz, Cadiz, Spain. [Pitstick, Rose; Carlson, George A.] McLaughlin Res Inst, Great Falls, MT USA. RP Spires-Jones, TL (reprint author), Univ Edinburgh, Ctr Cognit & Neural Syst, 1 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland.; Spires-Jones, TL (reprint author), Univ Edinburgh, Ctr Dementia Prevent, 1 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland. EM tara.spires-jones@ed.ac.uk FU Alzheimer's Research UK; Scottish Government; Alzheimer's Society; University of Edinburgh Wellcome Trust ISSF FX We thank Dominic Walsh and Peter Davies for providing antibodies. Funding was provided by Alzheimer's Research UK, the Scottish Government, the Alzheimer's Society, a University of Edinburgh Wellcome Trust ISSF, and an anonymous foundation. NR 49 TC 1 Z9 1 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X EI 1460-9568 J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD DEC PY 2016 VL 44 IS 12 BP 3056 EP 3066 DI 10.1111/ejn.13442 PG 11 WC Neurosciences SC Neurosciences & Neurology GA EJ1CS UT WOS:000392948500009 PM 27748574 ER PT J AU Prendergast, JM Eavarone, D Starbuck, K Stein, J Foster, R Behrens, J Rueda, BR AF Prendergast, Jillian M. Eavarone, David Starbuck, Kristen Stein, Jenna Foster, Rosemary Behrens, Jeff Rueda, Bo R. TI Novel anti-Sialyl-Tn monoclonal antibodies and antibody drug conjugates (ADCs) target a cancer stem cell population and demonstrate in vitro and in vivo anti-tumor efficacy SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Glycobiology CY NOV 19-22, 2016 CL New Orleans, LA SP Soc Glycobiol C1 [Prendergast, Jillian M.; Eavarone, David; Stein, Jenna; Behrens, Jeff] Siamab Therapeut, Newton, MA USA. [Starbuck, Kristen; Foster, Rosemary; Rueda, Bo R.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Starbuck, Kristen; Foster, Rosemary; Rueda, Bo R.] Harvard Med Sch, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD DEC PY 2016 VL 26 IS 12 MA 183 BP 1449 EP 1449 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EJ0XX UT WOS:000392935600186 ER PT J AU Niederwieser, C Nicolet, D Carroll, AJ Kolitz, JE Powell, BL Kohlschmidt, J Stone, RM Byrd, JC Mrozek, K Bloomfield, CD AF Niederwieser, Christian Nicolet, Deedra Carroll, Andrew J. Kolitz, Jonathan E. Powell, Bayard L. Kohlschmidt, Jessica Stone, Richard M. Byrd, John C. Mrozek, Krzysztof Bloomfield, Clara D. TI Chromosome abnormalities at onset of complete remission are associated with worse outcome in patients with acute myeloid leukemia and an abnormal karyotype at diagnosis: CALGB 8461 (Alliance) SO HAEMATOLOGICA LA English DT Article ID MINIMAL RESIDUAL DISEASE; STEM-CELL TRANSPLANTATION; CYTOGENETIC ABNORMALITIES; PROGNOSTIC-SIGNIFICANCE; ADULT PATIENTS; AML; INDUCTION; CANCER; PERSISTENCE; SURVIVAL AB Achievement of complete remission is essential for long-term survival of acute myeloid leukemia patients. We evaluated the prognostic significance of cytogenetics at complete remission in 258 adults with de novo acute myeloid leukemia and abnormal pre-treatment karyotypes, treated on Cancer and Leukemia Group B front-line studies, with cytogenetic data at onset of morphological complete remission. Thirty-two patients had abnormal karyotypes at time of initial complete remission. Of these, 28 had at least 1 abnormality identified pre-treatment, and 4 acute myeloid leukemia-related abnormalities not detected pre-treatment. Two hundred and twenty-six patients had normal remission karyotypes. Patients with abnormal remission karyotypes were older (P<0.001), had lower pre-treatment white blood counts (P=0.002) and blood blast percentages (P=0.004), were less often classified as Favorable and more often as Adverse among European LeukemiaNet Genetic Groups (P<0.001), and had shorter disease-free survival (median 0.6 vs. 0.9 years; P<0.001) and overall survival (median 1.2 vs. 2.2 years; P<0.001) than patients with normal remission karyotypes. Sixteen patients with normal remission karyotypes also harbored non-clonal abnormalities unrelated to pre-treatment karyotypes. They had shorter overall survival than 210 patients with only normal metaphases (P=0.04). Forty-eight patients with any clonal or non-clonal chromosome abnormality at complete remission had worse disease-free survival (median 0.6 vs. 1.0 years; P<0.001) and overall survival (median 1.2 vs. 2.5 years; P<0.001) than 210 patients with exclusively normal metaphases. In multivariable analyses, after adjustment for age, the presence of any remission abnormality was associated with shorter disease-free survival (P=0.03) and overall survival (P=0.01). We conclude that detection of any abnormality at complete remission is an adverse prognostic factor. (clinicaltrials.gov identifier: 00048958) C1 [Niederwieser, Christian; Nicolet, Deedra; Kohlschmidt, Jessica; Mrozek, Krzysztof; Bloomfield, Clara D.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Nicolet, Deedra; Kohlschmidt, Jessica] Mayo Clin, Alliance Clin Trials Oncol Stat, Rochester, MN USA. [Carroll, Andrew J.] Univ Alabama Birmingham, Birmingham, AL USA. [Kolitz, Jonathan E.] Hofstra North Shore Long Isl Jewish Sch Med, Monter Canc Ctr, Lake Success, NY USA. [Powell, Bayard L.] Wake Forest Univ, Ctr Comprehens Canc, Winston Salem, NC 27109 USA. [Stone, Richard M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Byrd, John C.] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA. RP Mrozek, K; Bloomfield, CD (reprint author), Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. EM krzysztof.mrozek@osumc.edu; clara.bloomfield@osumc.edu FU National Cancer Institute of the National Institutes of Health [U10CA180821, U10CA180882, U10CA101140, U10CA077658, U10CA180861, P50CA140158, P30CA016058]; Leukemia Clinical Research Foundation FX The authors would like to thank Lisa J. Sterling and Christine Finks for data management. This work was supported in part by the National Cancer Institute of the National Institutes of Health [grants: U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), U10CA101140, U10CA077658, U10CA180861, P50CA140158, P30CA016058], and the Leukemia Clinical Research Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 30 TC 0 Z9 0 U1 3 U2 3 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD DEC PY 2016 VL 101 IS 12 BP 1516 EP 1523 DI 10.3324/haematol.2016.149542 PG 8 WC Hematology SC Hematology GA EI6DE UT WOS:000392584400011 PM 27470602 ER PT J AU Marshall, AL Scarpone, R De Greef, M Bird, R Kuter, DJ AF Marshall, Ariela L. Scarpone, Roberta De Greef, Melanie Bird, Robert Kuter, David J. TI Remissions after long-term use of romiplostim for immune thrombocytopenia SO HAEMATOLOGICA LA English DT Letter DE platelets; immune thrombocytopenic purpura; romiplostim; thrombopoietin ID PLATELET PRODUCTION; CHRONIC ITP; PURPURA; EFFICACY; THROMBOPOIETIN; SAFETY C1 [Marshall, Ariela L.] Mayo Clin, Div Hematol, Rochester, MN 55905 USA. [Scarpone, Roberta; Kuter, David J.] Massachusetts Gen Hosp, Ctr Hematol, Boston, MA 02114 USA. [De Greef, Melanie] Princess Alexandra Hosp, Oncol Pharm, Brisbane, Qld, Australia. [Bird, Robert] Princess Alexandra Hosp, Div Canc Serv, Brisbane, Qld, Australia. RP Marshall, AL (reprint author), Mayo Clin, Div Hematol, Rochester, MN 55905 USA. EM marshall.ariela@mayo.edu NR 15 TC 0 Z9 0 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD DEC PY 2016 VL 101 IS 12 BP E476 EP E478 DI 10.3324/haematol.2016.151886 PG 3 WC Hematology SC Hematology GA EI6DE UT WOS:000392584400023 PM 27587382 ER PT J AU Fadlallah, A Zhu, H Arafat, S Kochevar, I Melki, S Ciolino, JB AF Fadlallah, Ali Zhu, Hong Arafat, Samer Kochevar, Irene Melki, Samir Ciolino, Joseph B. TI Corneal Resistance to Keratolysis After Collagen Crosslinking With Rose Bengal and Green Light SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE crosslinking; rose bengal; green light ID ENZYMATIC DIGESTION; III COLLAGENS; UV-A; KERATOCONUS; RIBOFLAVIN; OXYGEN; KINETICS; EFFICACY; MODEL; CXL AB PURPOSE. The purpose of this study was to evaluate the resistance to degradation by collagenase A of corneas that have been crosslinked with Rose Bengal and green light (RGX). METHODS. The ex vivo crosslinking procedure was performed on enucleated rabbit corneas. Corneas were deepithelialized after applying 30% alcohol. Corneas were stained with Rose Bengal (RB, 0.1%) for 2 minutes and then exposed to green light (532 nm) at 0.25 W/cm(2) for times to deliver doses of 50, 100, 150, or 200 J/cm(2) (n = 5 per group). Five corneas were pretreated with riboflavin solution (0.1% riboflavin) for 15 minutes and irradiated with ultraviolet A (UVA) light (370 nm, 3 mW/cm(2)) for 30 minutes. Five corneas underwent only de-epithelialization and were otherwise untreated. Five corneas were stained with RB without light exposure. The central corneas of each group was removed with a 8.5-mm trephine and incubated at 378 degrees C in 0.3% collagenase A solution. Time to dissolution of each cornea was compared across treatments. RESULTS. Corneas treated with RGX were treated with light fluences of 50, 100, 150, and 200 J/cm(2); these corneas dissolved completely at 8.3 +/- 1.2, 11.1 +/- 1.4, 12.4 +/- 1.7, and 15.7 +/- 1.8 hours, respectively. Corneas treated by riboflavin and UVA light dissolved at 15.7 +/- 1.7 hours, and nontreated corneas dissolved at 6.1 +/- 1.3 hours. Corneas treated with only RB (no green light) dissolved at 9.3 +/- 1.7 hours. Compared with the untreated corneas, all of the RB groups and the riboflavin-UVA-treated group of corneas degraded statistically significantly slower than untreated corneas (P < 0.05). CONCLUSIONS. Crosslinking with RGX increased corneal resistance to digestion by collagenase comparable to that produced by riboflavin and UVA treatment. C1 [Fadlallah, Ali; Arafat, Samer; Melki, Samir; Ciolino, Joseph B.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Fadlallah, Ali; Melki, Samir] Boston Eye Grp, Brookline, MA USA. [Fadlallah, Ali; Zhu, Hong; Kochevar, Irene] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA USA. [Zhu, Hong] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 1, Dept Ophthalmol, Shanghai, Peoples R China. RP Melki, S; Ciolino, JB (reprint author), Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv, 243 Charles St, Boston, MA 02114 USA. EM samir_melki@meei.harvard.edu; Joseph_Ciolino@meei.harvard.edu FU Department of Ophthalmology, Harvard Medical School, from Research to Prevent Blindness, New York, New York FX Supported by an unrestricted grant to the Department of Ophthalmology, Harvard Medical School, from Research to Prevent Blindness, New York, New York (JBC). NR 28 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD DEC PY 2016 VL 57 IS 15 BP 6610 EP 6614 DI 10.1167/iovs.15-18764 PG 5 WC Ophthalmology SC Ophthalmology GA EJ0VR UT WOS:000392929500015 PM 27926752 ER PT J AU Lammer, J Prager, SG Cheney, MC Ahmed, A Radwan, SH Burns, SA Silva, PS Sun, JK AF Lammer, Jan Prager, Sonja G. Cheney, Michael C. Ahmed, Amel Radwan, Salma H. Burns, Stephen A. Silva, Paolo S. Sun, Jennifer K. TI Cone Photoreceptor Irregularity on Adaptive Optics Scanning Laser Ophthalmoscopy Correlates With Severity of Diabetic Retinopathy and Macular Edema SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE diabetic retinopathy; adaptive optics scanning laser ophthalmoscopy; cones; photoreceptor morphology ID IN-VIVO; COHERENCE TOMOGRAPHY; PACKING DENSITY; FUNDUS CAMERA; VISION; ELECTRORETINOGRAM; IMAGES; DEGENERATION; SENSITIVITY; DYSTROPHY AB PURPOSE. To determine whether cone density, spacing, or regularity in eyes with and without diabetes (DM) as assessed by high-resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) correlates with presence of diabetes, diabetic retinopathy (DR) severity, or presence of diabetic macular edema (DME). METHODS. Participants with type 1 or 2 DM and healthy controls underwent AOSLO imaging of four macular regions. Cone assessment was performed by independent graders for cone density, packing factor (PF), nearest neighbor distance (NND), and Voronoi tile area (VTA). Regularity indices (mean/SD) of NND (RI-NND) and VTA (RI-VTA) were calculated. RESULTS. Fifty-three eyes (53 subjects) were assessed. Mean +/- SD age was 44 +/- 12 years; 81% had DM (duration: 22 +/- 13 years; glycated hemoglobin [HbA1c]: 8.0 +/- 1.7%; DM type 1: 72%). No significant relationship was found between DM, HbA1c, or DR severity and cone density or spacing parameters. However, decreased regularity of cone arrangement in the macular quadrants was correlated with presence of DM (RI-NND: P = 0.04; RI-VTA: P = 0.04), increasing DR severity (RI-NND: P = 0.04), and presence of DME (RI-VTA: P = 0.04). Eyes with DME were associated with decreased density (P = 0.04), PF (P = 0.03), and RI-VTA (0.04). CONCLUSIONS. Although absolute cone density and spacing don't appear to change substantially in DM, decreased regularity of the cone arrangement is consistently associated with the presence of DM, increasing DR severity, and DME. Future AOSLO evaluation of cone regularity is warranted to determine whether these changes are correlated with, or predict, anatomic or functional deficits in patients with DM. C1 [Lammer, Jan; Prager, Sonja G.; Cheney, Michael C.; Ahmed, Amel; Radwan, Salma H.; Silva, Paolo S.; Sun, Jennifer K.] Joslin Diabet Ctr, Beetham Eye Inst, One Joslin Pl, Boston, MA 02215 USA. [Lammer, Jan; Prager, Sonja G.] Med Univ Vienna, Dept Ophthalmol, Vienna, Austria. [Ahmed, Amel] Assiut Univ, Dept Histol & Cell Biol, Fac Med, Assiut, Egypt. [Radwan, Salma H.] Cairo Univ, Dept Ophthalmol, Cairo, Egypt. [Burns, Stephen A.] Indiana Univ, Sch Optometry, Bloomington, IN USA. [Silva, Paolo S.; Sun, Jennifer K.] Harvard Med Sch, Dept Ophthalmol, Boston, MA USA. RP Sun, JK (reprint author), Joslin Diabet Ctr, Beetham Eye Inst, One Joslin Pl, Boston, MA 02215 USA. EM jennifer.sun@joslin.harvard.edu RI Burns, Stephen/D-9259-2011 OI Burns, Stephen/0000-0001-5348-035X FU National Eye Institute [R01 EY024702, R44 EY016295, P30EY019008]; JDRF [3-SRA-2014-264-M-R, 17-2011-359]; Eleanor Chesterman Beatson Childcare Ambassador Program Foundation; NIDDK [5 P30 DK036836-24 PF]; Massachusetts Lion Eye Research Fund, Inc. FX Supported by grants from National Eye Institute, R01 EY024702, R44 EY016295, and P30EY019008; JDRF 3-SRA-2014-264-M-R and 17-2011-359; Eleanor Chesterman Beatson Childcare Ambassador Program Foundation Grant, NIDDK 5 P30 DK036836-24 P&F Grant, Massachusetts Lion Eye Research Fund, Inc. NR 52 TC 2 Z9 2 U1 1 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD DEC PY 2016 VL 57 IS 15 BP 6624 EP 6632 DI 10.1167/iovs.16-19537 PG 9 WC Ophthalmology SC Ophthalmology GA EJ0VR UT WOS:000392929500017 PM 27926754 ER PT J AU Werling, D Reglodi, D Banks, WA Salameh, TS Kovacs, K Kvarik, T Vaczy, A Kovacs, L Mayer, F Danyadi, B Lokos, E Tamas, A Toth, G Biro, Z Atlasz, T AF Werling, Dora Reglodi, Dora Banks, William A. Salameh, Therese S. Kovacs, Krisztina Kvarik, Timea Vaczy, Alexandra Kovacs, Laszlo Mayer, Flora Danyadi, Bese Lokos, Emese Tamas, Andrea Toth, Gabor Biro, Zsolt Atlasz, Tamas TI Ocular Delivery of PACAP1-27 Protects the Retina From Ischemic Damage in Rodents SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE eye drops; ischemia; retina; neuropeptide ID CYCLASE-ACTIVATING POLYPEPTIDE; DIABETIC-RETINOPATHY; SIGNALING PATHWAYS; DEGENERATION; LESION; BRAIN; RATS; INVOLVEMENT; SECRETION; APOPTOSIS AB PURPOSE. Pituitary adenylate cyclase activating polypeptide (PACAP) is neuroprotective in neuronal injuries. Bilateral common carotid artery occlusion (BCCAO) causes chronic hypoperfusion-induced degeneration in the rat retina, where we proved the retinoprotective effect of intravitreal PACAP. Although this route of administration is a common clinical practice in several diseases, easier routes are clinically important. Our aim was to investigate the potential retinoprotective effects of PACAP eye drops in BCCAO-induced ischemic retinopathy. METHODS. After performing BCCAO in rats, the right eyes were treated with PACAP1-27 eye drops (1 mu g/drop, 2 3 1 drops/day for 5 days), containing different vehicles: saline, water for injections, thiomersal or benzalkonium solution for ophthalmic use (SOCB). Histology and immunohistochemistry were performed 2 weeks after surgery, while molecular analysis was performed 24 hours after BCCAO. Passage of PACAP1-27 through the ocular layers was tested with radioactive PACAP-SOCB in mice. RESULTS. Bilateral common carotid artery occlusion led to a severe degeneration of all retinal layers. Solution for ophthalmic use was the most effective vehicle for delivering PACAP (PACAP-SOCB), significantly ameliorating BCCAO-induced damage. The massive upregulation of GFAP was not observed in retinas treated with PACAP-SOCB eye drops. PACAP-SOCB treatment also increased activation of the protective Akt and ERK1/2 in hypoperfused retinas. The cytokine profile showing upregulation in different cytokines was attenuated by PACAP-SOCB. Radioactive PACAP reached the retina when delivered in SOCB-containing eye drops. CONCLUSIONS. PACAP1-27, delivered in the SOCB vehicle as eye drops, was retinoprotective in ischemic retinopathy, providing the basis for future therapeutic administration. C1 [Werling, Dora; Reglodi, Dora; Kvarik, Timea; Vaczy, Alexandra; Kovacs, Laszlo; Mayer, Flora; Danyadi, Bese; Lokos, Emese; Tamas, Andrea; Atlasz, Tamas] Univ Pecs, Dept Anat, Pecs, Hungary. [Werling, Dora; Biro, Zsolt] Univ Pecs, Dept Ophthalmol, Pecs, Hungary. [Banks, William A.; Salameh, Therese S.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Banks, William A.; Salameh, Therese S.] Univ Washington, Sch Med, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. [Kovacs, Krisztina] Univ Pecs, Dept Biochem & Med Chem, Pecs, Hungary. [Toth, Gabor] Univ Szeged, Dept Med Chem, Szeged, Hungary. [Atlasz, Tamas] Univ Pecs, Dept Sportbiol, Pecs, Hungary. [Atlasz, Tamas] Univ Pecs, Janos Szentagothai Res Ctr, Pecs, Hungary. RP Atlasz, T (reprint author), Univ Pecs, Fac Sci, Dept Sportbiol, Ifjusag St 6, H-7624 Pecs, Hungary. EM attam@gamma.ttk.pte.hu FU National Scientific Research Fund (OTKA, Budapest, Hungary) [K104984, K119759]; Arimura Foundation (New Orleans, LA, USA); Bolyai Scholarship of the Hungarian Academy of Sciences (Budapest, Hungary); PTE AOK KA Research Grant (Pecs, Hungary); National Brain Research Programme (Budapest, Hungary) [KTIA_13_NAP-A-III/5]; Centre for Neuroscience (Pecs, Hungary); New National Excellence Program of the Ministry of Human Capacites (Budapest, Hungary) [UNKP-16-3-IV, UNKP-16-4-III] FX Supported by grants from the National Scientific Research Fund (OTKA K104984, K119759; Budapest, Hungary), Arimura Foundation (New Orleans, LA, USA), Bolyai Scholarship of the Hungarian Academy of Sciences (Budapest, Hungary), PTE AOK KA Research Grant (Pecs, Hungary), National Brain Research Programme (KTIA_13_NAP-A-III/5; Budapest, Hungary), Centre for Neuroscience (Pecs, Hungary), and The UNKP-16-3-IV, UNKP-16-4-III New National Excellence Program of the Ministry of Human Capacites (Budapest, Hungary). NR 51 TC 0 Z9 0 U1 2 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD DEC PY 2016 VL 57 IS 15 BP 6683 EP 6691 DI 10.1167/iovs.16-20630 PG 9 WC Ophthalmology SC Ophthalmology GA EJ0VR UT WOS:000392929500024 PM 27936470 ER PT J AU Dean, SM Gilmore-Bykovskyi, A Buchanan, J Ehlenfeldt, B Kind, AJH AF Dean, Shannon M. Gilmore-Bykovskyi, Andrea Buchanan, Joel Ehlenfeldt, Brad Kind, Amy J. H. TI Design and Hospitalwide Implementation of a Standardized Discharge Summary in an Electronic Health Record SO Joint Commission Journal on Quality and Patient Safety LA English DT Article ID PATIENT OUTCOMES; CARE; PHYSICIANS; QUALITY; COMMUNICATION; MEDICINE; TRANSITIONS; TIMELINESS; CONTINUITY; PROVIDERS AB Background: The hospital discharge summary is the primary method used to communicate a patient's plan of care to the next provider(s). Despite the existence of regulations and guidelines outlining the optimal content for the discharge summary and its importance in facilitating an effective transition to posthospital care, incomplete discharge summaries remain a common problem that may contribute to poor posthospital outcomes. Electronic health records (EHRs) are regularly used as a platform on which standardization of content and format can be implemented. The feasibility of designing and implementing a standardized discharge summary hospitalwide using an EHR was examined-to the -authors' knowledge, for the first time. Methods: This large-scale project at the University of Wisconsin Hospital and Clinics was led by a task force that had been assembled to develop best practices for EHR notes. The evidence-based Replicating Effective Programs (REP) model was employed to guide the development and implementation during the project. REP outlines four stages in clinical health service intervention implementation: preconditions, preimplementation, implementation, and maintenance. Results: At 18 months postimplementation, 90% of all hospital discharge summaries were written using the standardized format. Hospital providers found the template helpful and easy to use, and recipient providers perceived an improvement in the quality of discharge summaries compared to those previously sent from the hospital. Conclusion: Discharge summaries can be standardized and implemented hospitalwide with both author and recipient provider satisfaction, particularly if evidence-based implementation strategies are employed. The use of EHR tools to guide clinicians in writing comprehensive discharge summaries holds promise in improving the existing deficits in communication at transitions of care. C1 [Dean, Shannon M.] Univ Wisconsin, Pediat, Div Hosp Med, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Dean, Shannon M.; Ehlenfeldt, Brad] UW Hlth, Madison, WI 53705 USA. [Gilmore-Bykovskyi, Andrea] William S Middleton Mem Vet Affairs Hosp, Madison, WI USA. [Gilmore-Bykovskyi, Andrea] Univ Wisconsin Madison, Sch Nursing, Madison, WI USA. [Buchanan, Joel] Univ Wisconsin, Med, Div Gen Internal Med, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Buchanan, Joel] Univ Wisconsin, Sch Med & Publ Hlth, Informat Technol Serv Strateg Projects, Madison, WI 53706 USA. [Kind, Amy J. H.] Univ Wisconsin, Sch Med & Publ Hlth, Med, Div Geriatr, Madison, WI 53706 USA. [Kind, Amy J. H.] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI USA. RP Dean, SM (reprint author), Univ Wisconsin, Pediat, Div Hosp Med, Sch Med & Publ Hlth, Madison, WI 53706 USA.; Dean, SM (reprint author), UW Hlth, Madison, WI 53705 USA. EM SDean@uwhealth.org FU NCRR NIH HHS [UL1 RR025011]; NIA NIH HHS [K23 AG034551] NR 28 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1553-7250 EI 1938-131X J9 JT COMM J QUAL PATIE JI Jt. Comm. J. Qual. Patient Saf. PD DEC PY 2016 VL 42 IS 12 BP 555 EP + PG 18 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EJ1NX UT WOS:000392978600005 PM 28334559 ER PT J AU Bates, KE Shea, JA Bird, GL Field, C Nandi, D Shaddy, RE Metlay, JP AF Bates, Katherine E. Shea, Judy A. Bird, Geoffrey L. Field, Cynthia Nandi, Deipanjan Shaddy, Robert E. Metlay, Joshua P. TI Development and Preliminary Testing of the Coordination Process Error Reporting Tool (CPERT), a Prospective Clinical Surveillance Mechanism for Teamwork Errors in the Pediatric Cardiac ICU SO Joint Commission Journal on Quality and Patient Safety LA English DT Article ID INTENSIVE-CARE-UNIT; ADVERSE EVENTS; COMMUNICATION; MORBIDITY; OUTCOMES AB Background: Patient safety reporting systems (PSRSs) may not detect teamwork or coordination process errors that affect all dimensions of quality defined by the Institute of Medicine. This study aimed to develop and observe the performance of a novel tool, the Coordination Process Error Reporting Tool (CPERT), as a prospective clinical surveillance mechanism for teamwork errors in the pediatric cardiac ICU. Methods: Providers and parents used the qualitative nominal group technique to identify coordination process error examples. Using categories developed from these discussions, the CPERT was designed and observed to assess agreement among providers and with the PSRS. For each patient at the end of each observed shift, the nurse, frontline clinician, and attending physician were invited to complete the CPERT online. Responses among providers were compared to assess interobserver agreement. Patients with errors identified by the CPERT were matched 1: 1 with patients without CPERT errors within the same shift. The PSRS and medical record were reviewed to judge whether a coordination process error occurred and whether patients with CPERT errors differed from controls. Results: Eight categories of errors were identified and incorporated into the CPERT. During 10 shifts (218 patients), the CPERT completion rate was 74%. Fifty-one patient shifts had errors identified by the CPERT (23%); these patients did not differ significantly from those without CPERT-reported errors. Only 5 CPERT-reported errors (10%) were identified by two or more providers. Of the 51 CPERT-reported errors, 43 (84%) were not documented in the PSRS. Conclusion: The CPERT detects coordination process -errors not identified through PSRS, making it or similar tools potentially useful for improvement efforts. C1 [Bates, Katherine E.; Nandi, Deipanjan] Childrens Hosp Philadelphia, Div Cardiol, Cardiac Ctr, Philadelphia, PA 19104 USA. [Bates, Katherine E.] Univ Michigan Hlth Syst, Congenital Heart Ctr, Ann Arbor, MI 48109 USA. [Bates, Katherine E.] Univ Michigan Hlth Syst, Qual, CS Mott Childrens Hosp, Ann Arbor, MI 48109 USA. [Shea, Judy A.; Metlay, Joshua P.] Univ Penn, Div Gen Internal Med, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Shea, Judy A.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Bird, Geoffrey L.] Childrens Hosp Philadelphia, Cardiac Ctr, Dept Anesthesia & Crit Care Med, Philadelphia, PA 19104 USA. [Bird, Geoffrey L.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Field, Cynthia] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Shaddy, Robert E.] Childrens Hosp Philadelphia, Div Cardiol, Philadelphia, PA 19104 USA. [Shaddy, Robert E.] Childrens Hosp Philadelphia, Cardiac Ctr, Philadelphia, PA 19104 USA. [Shaddy, Robert E.] Childrens Hosp Philadelphia, Pediat, Philadelphia, PA 19104 USA. [Metlay, Joshua P.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Metlay, Joshua P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Bates, KE (reprint author), Childrens Hosp Philadelphia, Div Cardiol, Cardiac Ctr, Philadelphia, PA 19104 USA.; Bates, KE (reprint author), Univ Michigan Hlth Syst, Congenital Heart Ctr, Ann Arbor, MI 48109 USA.; Bates, KE (reprint author), Univ Michigan Hlth Syst, Qual, CS Mott Childrens Hosp, Ann Arbor, MI 48109 USA. EM kebates@med.umich.edu FU National Institutes of Health (NIH) [NICHD/T32 HD060550]; NIH Mid-Career Investigator Award in Patient-Oriented Research [K24-AI073957] FX Dr. Bates was supported in part by National Institutes of Health (NIH) grant funding (NICHD/T32 HD060550). Dr. Metlay was supported by an NIH Mid-Career Investigator Award in Patient-Oriented Research (K24-AI073957). The authors thank the provider and parent participants for their enthusiasm for and participation in this study. NR 18 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1553-7250 EI 1938-131X J9 JT COMM J QUAL PATIE JI Jt. Comm. J. Qual. Patient Saf. PD DEC PY 2016 VL 42 IS 12 BP 562 EP + PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EJ1NX UT WOS:000392978600006 PM 28334560 ER PT J AU Paula, LF Wellman, TJ Winkler, T Spieth, PM Guldner, A Venegas, JG de Abreu, MG Carvalho, AR Melo, MFV AF Paula, Luis Felipe Wellman, Tyler J. Winkler, Tilo Spieth, Peter M. Gueldner, Andreas Venegas, Jose G. de Abreu, Marcelo Gama Carvalho, Alysson R. Melo, Marcos F. Vidal TI Regional tidal lung strain in mechanically ventilated normal lungs SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE anesthesia; computed tomography; mechanical ventilation; regional ventilation; strain measurements ID RESPIRATORY-DISTRESS-SYNDROME; ALVEOLAR EPITHELIAL PERMEABILITY; END-EXPIRATORY PRESSURE; VOLUME CHANGE; COMPUTED-TOMOGRAPHY; GAS-EXCHANGE; SHEEP; INFLAMMATION; RECRUITMENT; STRESS AB Parenchymal strain is a key determinant of lung injury produced by mechanical ventilation. However, imaging estimates of volumetric tidal strain (epsilon = regional tidal volume/reference volume) present substantial conceptual differences in reference volume computation and consideration of tidally recruited lung. We compared current and new methods to estimate tidal volumetric strains with computed tomography, and quantified the effect of tidal volume (V-T) and positive end-expiratory pressure (PEEP) on strain estimates. Eight supine pigs were ventilated with V-T = 6 and 12 ml/kg and PEEP = 0, 6, and 12 cmH(2)O. End-expiratory and end-inspiratory scans were analyzed in eight regions of interest along the ventral-dorsal axis. Regional reference volumes were computed at end-expiration (with/without correction of regional VT for intratidal recruitment) and at resting lung volume (PEEP = 0) corrected for intratidal and PEEP-derived recruitment. All strain estimates demonstrated vertical heterogeneity with the largest tidal strains in middependent regions (P < 0.01). Maximal strains for distinct estimates occurred at different lung regions and were differently affected by V-T-PEEP conditions. Values consistent with lung injury and inflammation were reached regionally, even when global measurements were below critical levels. Strains increased with VT and were larger in middependent than in nondependent lung regions. PEEP reduced tidal-strain estimates referenced to end-expiratory lung volumes, although it did not affect strains referenced to resting lung volume. These estimates of tidal strains in normal lungs point to middependent lung regions as those at risk for ventilator-induced lung injury. The different conditions and topography at which maximal strain estimates occur allow for testing the importance of each estimate for lung injury. C1 [Paula, Luis Felipe; Wellman, Tyler J.; Winkler, Tilo; Venegas, Jose G.; Melo, Marcos F. Vidal] Massachusetts Gen Hosp, Dep Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. [Paula, Luis Felipe; Carvalho, Alysson R.] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Physiol Resp Lab, Rio De Janeiro, Brazil. [Spieth, Peter M.; Gueldner, Andreas; de Abreu, Marcelo Gama; Carvalho, Alysson R.] Univ Hosp Carl Gustav Carus, Dept Anesthesiol & Intens Care Therapy, Pulmonary Engn Grp, Dresden, Germany. [Carvalho, Alysson R.] Univ Fed Rio de Janeiro, Alberto Luiz Coimbra Inst Post Grad & Res Engn, Lab Pulm Engn, Rio De Janeiro, Brazil. RP Melo, MFV (reprint author), Massachusetts Gen Hosp, Dep Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM mvidalmelo@partners.org RI Spieth, Peter/C-2928-2011 FU National Heart, Lung, and Blood Institute Grant [RO1 HL-121228]; Research Support Foundation of the State of Rio de Janeiro; Brazilian National Council for Scientific and Technological Development; German Research Foundation FX This work was supported by National Heart, Lung, and Blood Institute Grant RO1 HL-121228 (to M. F. Vidal Melo), and by Research Support Foundation of the State of Rio de Janeiro, Brazilian National Council for Scientific and Technological Development, and German Research Foundation. NR 33 TC 0 Z9 0 U1 1 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 EI 1522-1601 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD DEC PY 2016 VL 121 IS 6 BP 1335 EP 1347 DI 10.1152/japplphysiol.00861.2015 PG 13 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA EI9QY UT WOS:000392845000008 PM 27445302 ER PT J AU Menendez, ME Lu, N Huybrechts, KF Ring, D Barnes, CL Ladha, K Bateman, BT AF Menendez, Mariano E. Lu, Na Huybrechts, Krista F. Ring, David Barnes, C. Lowry Ladha, Karim Bateman, Brian T. TI Variation in Use of Blood Transfusion in Primary Total Hip and Knee Arthroplasties SO JOURNAL OF ARTHROPLASTY LA English DT Article DE total joint arthroplasty; variation; blood transfusion; quality; policy ID TOTAL JOINT ARTHROPLASTY; TRANEXAMIC ACID; UNITED-STATES; CELL TRANSFUSION; ORTHOPEDIC-SURGERY; METAANALYSIS; REPLACEMENT; STRATEGY; DISEASES; OUTCOMES AB Background: There is growing clinical and policy emphasis on minimizing transfusion use in elective joint arthroplasty, but little is known about the degree to which transfusion rates vary across US hospitals. This study aimed to assess hospital-level variation in use of allogeneic blood transfusion in patients undergoing elective joint arthroplasty and to characterize the extent to which variability is attributable to differences in patient and hospital characteristics. Methods: The study population included 228,316 patients undergoing total knee arthroplasty (TKA) at 922 hospitals and 88,081 patients undergoing total hip arthroplasty (THA) at 606 hospitals from January 1, 2009 to December 31, 2011 in the Nationwide Inpatient Sample database, a 20% stratified sample of US community hospitals. Results: The median hospital transfusion rates were 11.0% (interquartile range, 3.5%-18.5%) in TKA and 15.9% (interquartile range, 5.4%-26.2%) in THA. After fully adjusting for patient- and hospital-related factors using mixed-effects logistic regression models, the average predicted probability of blood transfusion use in TKA was 6.3%, with 95% of the hospitals having a predicted probability between 0.37% and 55%. For THA, the average predicted probability of blood transfusion use was 9.5%, with 95% of the hospitals having a predicted probability between 0.57% and 66%. Hospital transfusion rates were inversely associated with hospital procedure volume and directly associated with length of stay. Conclusion: The use of blood transfusion in elective joint arthroplasty varied widely across US hospitals, largely independent of patient case-mix and hospital characteristics. (C) 2016 Elsevier Inc. All rights reserved. C1 [Menendez, Mariano E.] Tufts Univ, Sch Med, Dept Orthopaed Surg, Boston, MA 02111 USA. [Lu, Na] Boston Univ, Sch Med, Clin Epidemiol Unit, Boston, MA 02118 USA. [Lu, Na] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Lu, Na; Huybrechts, Krista F.; Bateman, Brian T.] Harvard Med Sch, Boston, MA USA. [Huybrechts, Krista F.; Bateman, Brian T.] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA. [Ring, David] Univ Texas Austin, Dell Med Sch, Dept Surg & Perioperat Care, Austin, TX 78712 USA. [Barnes, C. Lowry] Univ Arkansas Med Sci, Dept Orthopaed Surg, Little Rock, AR 72205 USA. [Ladha, Karim; Bateman, Brian T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. NR 42 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD DEC PY 2016 VL 31 IS 12 BP 2757 EP + DI 10.1016/j.arth.2016.05.022 PG 9 WC Orthopedics SC Orthopedics GA EI6QY UT WOS:000392622100020 PM 27325367 ER PT J AU Liow, MHL Dimitriou, D Tsai, TY Kwon, YM AF Liow, Ming Han Lincoln Dimitriou, Dimitris Tsai, Tsung-Yuan Kwon, Young-Min TI Preoperative Risk Factors Associated With Poor Outcomes of Revision Surgery for "Pseudotumors" in Patients With Metal-on-Metal Hip Arthroplasty SO JOURNAL OF ARTHROPLASTY LA English DT Article DE revision hip arthroplasty; metal-on-metal; clinical outcomes; metal ion levels; pseudotumors ID RESURFACING ARTHROPLASTY; ADVERSE-REACTION; REPLACEMENT; FAILURE; MANAGEMENT; DEBRIS; WEAR; MRI AB Background: Revision surgery of failed metal-on-metal (MoM) total hip arthroplasty (THA) for adverse tissue reaction (pseudotumor) can be challenging as a consequence of soft tissue and muscle necrosis. The aims of this study were to (1) report the revision outcomes of patients who underwent revision surgery for failed MoM hip arthroplasty due to symptomatic pseudotumor and (2) identify preoperative risk factors associated with revision outcomes. Methods: Between January 2011 and January 2013, a total of 102 consecutive large head MoM hip arthroplasties in 97 patients (male: 62, female: 35), who underwent revision surgery were identified from the database of a multidisciplinary referral center. Results: At minimum follow-up of 2 years (range: 26-52 months), at least one complication had occurred in 14 of 102 revisions (14%). Prerevision radiographic loosening (P = .01), magnetic resonance imaging (MRI) findings of solid lesions with abductor deficiency on MRI (P < .001), and intraoperative grading of adverse tissue reactions (P = .05) were correlated with post-revision complications. The reoperation rate of revised MoM THA was 7% (7 of 102 hips). Implant survivorship was 88% at 3 years. Metal ion levels declined in most patients after removal of MoM articulation. Conclusion: Revision outcomes of revision surgery for failed MoM THA due to symptomatic pseudotumor demonstrated 14% complication rate and 7% re-revision rate at 30-month follow-up. Our study identified prerevision radiographic loosening, solid lesions/abductor deficiency on MRI, and high grade intraoperative tissue damage as risk factors associated with poorer revision outcomes. This provides clinically useful information for preoperative planning and perioperative counseling of MoM THA patients undergoing revision surgery. (C) 2016 Elsevier Inc. All rights reserved. C1 [Liow, Ming Han Lincoln; Dimitriou, Dimitris; Tsai, Tsung-Yuan; Kwon, Young-Min] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. NR 29 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD DEC PY 2016 VL 31 IS 12 BP 2835 EP 2842 DI 10.1016/j.arth.2016.05.034 PG 8 WC Orthopedics SC Orthopedics GA EI6QY UT WOS:000392622100035 PM 27387480 ER PT J AU Kwon, YM Antoci, V Eisemon, E Tsai, TY Yan, Y Liow, MHL AF Kwon, Young-Min Antoci, Valentin, Jr. Eisemon, Eric Tsai, Tsung-Yuan Yan, Yu Liow, Ming Han Lincoln TI "Top-Out" Removal of Well-Fixed Dual-Taper Femoral Stems: Surgical Technique and Radiographic Risk Factors SO JOURNAL OF ARTHROPLASTY LA English DT Article DE top-out technique; modular neck femoral stems; revision total hip arthroplasty; taper corrosion; adverse local tissue reaction ID TOTAL HIP-ARTHROPLASTY; EXTENDED TROCHANTERIC OSTEOTOMY; LOCAL TISSUE REACTION; MODULAR-NECK; FOLLOW-UP; REVISION; CORROSION; REJUVENATE; COMPONENT; IMPLANTS AB Background: Contemporary "dual-taper" modular femoral neck-stem designs have been associated with taper corrosionerelated adverse local tissue reaction (ALTR) requiring revision surgery and stem removal. Extended trochanteric osteotomy is recognized as the workhorse procedure for revision hip surgery. The aim of our study is to describe our "top-out" stem removal surgical technique and identify preoperative radiographic risk factors associated with periprosthetic fractures when using this technique. Methods: This is a single-center, single-surgeon, retrospective case series. Operative and clinic records were reviewed for patients with dual-taper modular femoral neck-stem junction who underwent revision surgery for taper tribocorrosionerelated ALTR. Results: Eighty-three patients (36 men and 47 women; mean age, 61.8 +/- 10.3; body mass index, 30.2 +/- 8.6) were revised using the top-out technique. Significant improvements in postoperative Harris hip score (P = .004), EuroQol 5-dimension questionnaire (EQ-5D; P < .001), and EQ-5D US-adjusted scores (P < .001) were observed at 19-months follow-up. Our study reports periprosthetic fracture incidence of 14% and reoperation rate of 7%. Periprosthetic fractures were positively correlated with radiographic parameters such as overhang distance (R = 0.376; P = .002) and overhang ratio (R = 0.312; P = .01) and negatively correlated with radiographic implant medial calcar prominence (R = -0.299; P = .01). Conclusion: Removal of well-fixed femoral components can be challenging, and the burden of revision surgery for taper tribocorrosionerelated ALTR of these femoral stems is likely to rise. A top-out technique with systematic preoperative planning with radiographs provides a viable, alternative surgical option to remove well-fixed femoral component while preserving the femoral bony envelope. (C) 2016 Elsevier Inc. All rights reserved. C1 [Kwon, Young-Min; Antoci, Valentin, Jr.; Eisemon, Eric; Tsai, Tsung-Yuan; Yan, Yu; Liow, Ming Han Lincoln] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. NR 28 TC 0 Z9 0 U1 1 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD DEC PY 2016 VL 31 IS 12 BP 2843 EP 2849 DI 10.1016/j.arth.2016.05.046 PG 7 WC Orthopedics SC Orthopedics GA EI6QY UT WOS:000392622100036 PM 27444847 ER PT J AU Apiou-Sbirlea, G Evans, CL Kelly, KM Tromberg, BJ AF Apiou-Sbirlea, Gabriela Evans, Conor L. Kelly, Kristen M. Tromberg, Bruce J. TI Translational biophotonics SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Editorial Material C1 [Apiou-Sbirlea, Gabriela; Evans, Conor L.] Massachusetts Gen Hosp, Res Inst, Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA. [Apiou-Sbirlea, Gabriela; Evans, Conor L.] Harvard Med Sch, Dept Dermatol, 40 Blossom St, Boston, MA 02114 USA. [Kelly, Kristen M.; Tromberg, Bruce J.] Univ Calif Irvine, Beckman Laser Inst, 1002 Hlth Sci Rd East, Irvine, CA 92612 USA. RP Apiou-Sbirlea, G (reprint author), Massachusetts Gen Hosp, Res Inst, Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA.; Apiou-Sbirlea, G (reprint author), Harvard Med Sch, Dept Dermatol, 40 Blossom St, Boston, MA 02114 USA. NR 14 TC 0 Z9 0 U1 0 U2 0 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 EI 1560-2281 J9 J BIOMED OPT JI J. Biomed. Opt. PD DEC PY 2016 VL 21 IS 12 AR 124002 DI 10.1117/1.JBO.21.12.124002 PG 2 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA EJ0QG UT WOS:000392914600016 ER PT J AU Tromberg, BJ Anderson, RR Birngruber, R Brinkmann, R Berns, MW Parrish, JA Apiou-Sbirlea, G AF Tromberg, Bruce J. Anderson, R. Rox Birngruber, Reginald Brinkmann, Ralf Berns, Michael W. Parrish, John A. Apiou-Sbirlea, Gabriela TI Biomedical optics centers: forty years of multidisciplinary clinical translation for improving human health SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE translational research origins; biophotonics; biomedical optics; clinical problem driven innovation; multidisciplinary research ID LASER AB Despite widespread government and public interest, there are significant barriers to translating basic science discoveries into clinical practice. Biophotonics and biomedical optics technologies can be used to overcome many of these hurdles, due, in part, to offering new portable, bedside, and accessible devices. The current JBO special issue highlights promising activities and examples of translational biophotonics from leading laboratories around the world. We identify common essential features of successful clinical translation by examining the origins and activities of three major international academic affiliated centers with beginnings traceable to the mid-late 1970s: The Wellman Center for Photomedicine (Mass General Hospital, USA), the Beckman Laser Institute and Medical Clinic (University of California, Irvine, USA), and the Medical Laser Center Lubeck at the University of Lubeck, Germany. Major factors driving the success of these programs include visionary founders and leadership, multidisciplinary research and training activities in light-based therapies and diagnostics, diverse funding portfolios, and a thriving entrepreneurial culture that tolerates risk. We provide a brief review of how these three programs emerged and highlight critical phases and lessons learned. Based on these observations, we identify pathways for encouraging the growth and formation of similar programs in order to more rapidly and effectively expand the impact of biophotonics and biomedical optics on human health. (C) 2016 Society of Photo-Optical Instrumentation Engineers (SPIE) C1 [Tromberg, Bruce J.; Berns, Michael W.] Univ Calif Irvine, Beckman Laser Inst, 1002 Hlth Sci Rd East, Irvine, CA 92612 USA. [Anderson, R. Rox; Birngruber, Reginald; Apiou-Sbirlea, Gabriela] Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA. [Anderson, R. Rox; Birngruber, Reginald; Apiou-Sbirlea, Gabriela] Harvard Med Sch, Massachusetts Gen Hosp, Res Inst, Dept Dermatol, 40 Blossom St, Boston, MA 02114 USA. [Birngruber, Reginald; Brinkmann, Ralf] Med Laser Ctr Lubeck, Peter Monnik Weg 4, D-23562 Lubeck, Germany. [Parrish, John A.] Ctr Integrat Med & Innovat Technol, 125 Nashua St, Boston, MA 02114 USA. RP Tromberg, BJ (reprint author), Univ Calif Irvine, Beckman Laser Inst, 1002 Hlth Sci Rd East, Irvine, CA 92612 USA.; Apiou-Sbirlea, G (reprint author), Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA.; Apiou-Sbirlea, G (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Res Inst, Dept Dermatol, 40 Blossom St, Boston, MA 02114 USA. EM bjtrombe@uci.edu; gapiou@mgh.harvard.edu NR 19 TC 1 Z9 1 U1 2 U2 2 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 EI 1560-2281 J9 J BIOMED OPT JI J. Biomed. Opt. PD DEC PY 2016 VL 21 IS 12 AR 124001 DI 10.1117/1.JBO.21.12.124001 PG 6 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA EJ0QG UT WOS:000392914600015 ER PT J AU Hamblin, MR AF Hamblin, Michael R. TI Photobiomodulation or low-level laser therapy SO Journal of Biophotonics LA English DT Editorial Material C1 [Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hamblin, Michael R.] Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA.; Hamblin, MR (reprint author), Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA.; Hamblin, MR (reprint author), Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. EM hamblin@helix.mgh.harvard.edu FU NIAID NIH HHS [R01 AI050875, R21 AI121700] NR 9 TC 0 Z9 0 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1864-063X EI 1864-0648 J9 J BIOPHOTONICS JI J. Biophotonics PD DEC PY 2016 VL 9 IS 11-12 SI SI BP 1122 EP 1124 DI 10.1002/jbio.201670113 PG 3 WC Biochemical Research Methods; Biophysics; Optics SC Biochemistry & Molecular Biology; Biophysics; Optics GA EJ0QS UT WOS:000392915800001 PM 27973730 ER PT J AU Cerdeira, CD Brigagao, MRPL de Carli, ML Ferreira, CD Moraes, GDI Hadad, H Hanemann, JAC Hamblin, MR Sperandio, FF AF Cerdeira, Claudio Daniel Pereira Lima Brigagao, Maisa Ribeiro de Carli, Marina Lara Ferreira, Claudia de Souza Isac Moraes, Gabriel de Oliveira Hadad, Henrique Costa Hanemann, Joao Adolfo Hamblin, Michael R. Sperandio, Felipe Fornias TI Low-level laser therapy stimulates the oxidative burst in human neutrophils and increases their fungicidal capacity SO Journal of Biophotonics LA English DT Article DE low-level laser therapy; photobiomodulation; neutrophils; reactive oxygen species; oxidative burst; Candida albicans ID HELIUM-NEON LASER; PHOTODYNAMIC THERAPY; IN-VITRO; CANDIDA-ALBICANS; WOUND REPAIR; CHEMILUMINESCENCE; ACTIVATION; CELLS; MODEL; PHOSPHORYLATION AB Low-level laser therapy (LLLT) is known to enhance mitochondrial electron transfer and ATP production; thus, this study asked whether LLLT could stimulate the oxidative burst in human neutrophils (PMN) and improve their ability to kill microorganisms. Blood from healthy human subjects was collected and PMN were isolated from the samples. PMN were treated in vitro with 660 nm or 780 nm CW laser light at 40 mW power and increasing energies up to 19.2 J and were subsequently incubated with Candida albicans cells. Generation of hydroxyl radicals, hypochlorite anions and superoxide anions by PMN were checked using fluorescent probes and chemiluminescence assays; a microbicidal activity assay against C. albicans was also performed. LLLT excited PMN to a higher functional profile, which was translated as superior production of reactive oxygen species (ROS) and increased fungicidal capacity. The most efficacious energy was 19.2 J and, interestingly, the 660 nm light was even more efficacious than 780 nm at increasing the respiratory burst of PMN and the fungicidal capacity. [GRAPHICS] . Human neutrophils (PMN) were stimulated in vitro with 660 nm or 780 nm CW laser light at 40 mW of power and a total energy of 19.2 J. Low-level laser therapy (LLLT) excited PMN to a higher functional profile, which was translated as a superior production of reactive oxygen species (ROS) such as hydroxyl radicals (HO center dot) and hypochlorite anions (ClO-) (Figure) and increased fungicidal capacity against Candida albicans cells. C1 [Cerdeira, Claudio Daniel; Pereira Lima Brigagao, Maisa Ribeiro; Ferreira, Claudia de Souza; Isac Moraes, Gabriel de Oliveira] Fed Univ Alfenas UNIFAL MG, Dept Biochem, Inst Biomed Sci, BR-37130000 Alfenas, MG, Brazil. [de Carli, Marina Lara; Hadad, Henrique; Costa Hanemann, Joao Adolfo] Fed Univ Alfenas UNIFAL MG, Sch Dent, Dept Clin & Surg, BR-37130000 Alfenas, MG, Brazil. [Hamblin, Michael R.; Sperandio, Felipe Fornias] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hamblin, Michael R.; Sperandio, Felipe Fornias] Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Sperandio, Felipe Fornias] Fed Univ Alfenas UNIFAL MG, Inst Biomed Sci, Dept Pathol & Parasitol, BR-37130000 Alfenas, MG, Brazil. RP Sperandio, FF (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA.; Sperandio, FF (reprint author), Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA.; Sperandio, FF (reprint author), Fed Univ Alfenas UNIFAL MG, Inst Biomed Sci, Dept Pathol & Parasitol, BR-37130000 Alfenas, MG, Brazil. EM ff.sperandio@gmail.com FU Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior [CAPES AUX PE PNPD 2386/2011]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq-INCT of Redox Processes in Biomedicine - Redoxoma); US NIH [R01AI050875] FX The authors are grateful to Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES AUX PE PNPD 2386/2011) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq-INCT of Redox Processes in Biomedicine - Redoxoma) for financially supporting this study. MR Hamblin was supported by US NIH grant R01AI050875. NR 50 TC 1 Z9 1 U1 4 U2 4 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1864-063X EI 1864-0648 J9 J BIOPHOTONICS JI J. Biophotonics PD DEC PY 2016 VL 9 IS 11-12 SI SI BP 1180 EP 1188 DI 10.1002/jbio.201600035 PG 9 WC Biochemical Research Methods; Biophysics; Optics SC Biochemistry & Molecular Biology; Biophysics; Optics GA EJ0QS UT WOS:000392915800007 PM 27243910 ER PT J AU Xuan, WJ Huang, LY Hamblin, MR AF Xuan, Weijun Huang, Liyi Hamblin, Michael R. TI Repeated transcranial low-level laser therapy for traumatic brain injury in mice: biphasic dose response and long-term treatment outcome SO Journal of Biophotonics LA English DT Article DE Traumatic brain injury; controlled cortical impact mouse model; photobiomodulation; LLLT; biphasic dose response; Morris water maze; glial fibrillary acidic protein; reactive gliosis ID FIBRILLARY ACIDIC PROTEIN; LIGHT THERAPY; NEUROLOGICAL DEFICITS; CEREBRAL-ISCHEMIA; UNITED-STATES; GFAP; SYNAPTOGENESIS; ACTIVATION; ASTROCYTES; RECOVERY AB We previously showed that near-infrared laser photobiomodulation (PBM) (810 nm, CW, 18 J/cm(2), 25 mW/cm(2)) delivered to the mouse daily for 3-days after a controlled cortical impact traumatic brain injury (TBI) gave a significant improvement in neurological/cognitive function. However the same parameters delivered 14X daily gave significantly less benefit. This biphasic dose response intrigued us, and we decided to follow the mice that received 3X or 14X laser treatments out to 56-days post-TBI. We found the 14X group showed worse neurological function than the no-treatment TBI group at 2-weeks, but started to improve steadily during the next 6-weeks, and by 56-days were significantly better than the no-treatment TBI mice, but still worse than the 3X mice. A marker of activated glial cells (GFAP) was significantly increased in the brain regions (compared to both untreated TBI and 3X groups) at 4-weeks in the 14X group, but the GFAP had fallen to low levels in both 3X and 14X groups by 8-weeks. We conclude that an excessive number of laser-treatments delivered to mice can temporarily inhibit the process of brain repair stimulated by tPBM, but then the inhibitory effect ceases, and brain repair can resume. The mechanism may be temporary induction of reactive gliosis. [GRAPHICS] . C1 [Xuan, Weijun] Guangxi Univ Chinese Med, Dept Otorhinolaryngol Head & Neck Surg, Ruikang Clin Med Coll, Nanning, Peoples R China. [Xuan, Weijun; Huang, Liyi; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Xuan, Weijun; Huang, Liyi; Hamblin, Michael R.] Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA.; Hamblin, MR (reprint author), Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA.; Hamblin, MR (reprint author), Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. EM Hamblin@helix.mgh.harvard.edu FU Air Force Office of Scientific Research [FA9550-13-1-0068]; US Army Medical Research Acquisition Activity [W81XWH-09-1-0514]; US Army Medical Research and Materiel Command [W81XWH-13-2-0067]; US NIH [R01AI050875] FX This work was supported by Air Force Office of Scientific Research grant FA9550-13-1-0068, by US Army Medical Research Acquisition Activity grant W81XWH-09-1-0514, and by US Army Medical Research and Materiel Command grant W81XWH-13-2-0067. MRH was supported by US NIH grant R01AI050875. We are grateful to Jie Zhao of the Photopathology Core of Wellman Center for Photomedicine for help with pathology. NR 54 TC 0 Z9 0 U1 2 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1864-063X EI 1864-0648 J9 J BIOPHOTONICS JI J. Biophotonics PD DEC PY 2016 VL 9 IS 11-12 SI SI BP 1263 EP 1272 DI 10.1002/jbio.201500336 PG 10 WC Biochemical Research Methods; Biophysics; Optics SC Biochemistry & Molecular Biology; Biophysics; Optics GA EJ0QS UT WOS:000392915800015 PM 26990361 ER PT J AU Ferraresi, C Huang, YY Hamblin, MR AF Ferraresi, Cleber Huang, Ying-Ying Hamblin, Michael R. TI Photobiomodulation in human muscle tissue: an advantage in sports performance? SO Journal of Biophotonics LA English DT Review DE photobiomodulation; LLLT; LEDT; fatigue; creatine kinase; delayed onset muscle soreness ID LEVEL LASER THERAPY; PLACEBO-CONTROLLED TRIAL; HIGH-INTENSITY EXERCISE; BIPHASIC DOSE-RESPONSE; LIGHT-EMITTING-DIODES; CYTOCHROME-C-OXIDASE; SKELETAL-MUSCLE; POSTMENOPAUSAL WOMEN; DOUBLE-BLIND; 830 NM AB Photobiomodulation (PBM) describes the use of red or near-infrared (NIR) light to stimulate, heal, and regenerate damaged tissue. Both preconditioning (light delivered to muscles before exercise) and PBM applied after exercise can increase sports performance in athletes. This review covers the effects of PBM on human muscle tissue in clinical trials in volunteers related to sports performance and in athletes. The parameters used were categorized into those with positive effects or no effects on muscle performance and recovery. Randomized controlled trials and case-control studies in both healthy trained and untrained participants, and elite athletes were retrieved from MEDLINE up to 2016. Performance metrics included fatigue, number of repetitions, torque, hypertrophy; measures of muscle damage and recovery such as creatine kinase and delayed onset muscle soreness. Searches retrieved 533 studies, of which 46 were included in the review (n = 1045 participants). Studies used single laser probes, cluster of laser diodes, LED clusters, mixed clusters (lasers and LEDs), and flexible LED arrays. Both red, NIR, and red/NIR mixtures were used. PBM can increase muscle mass gained after training, and decrease inflammation and oxidative stress in muscle biopsies. We raise the question of whether PBM should be permitted in athletic competition by international regulatory authorities. [GRAPHICS] . C1 [Ferraresi, Cleber; Huang, Ying-Ying; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Ferraresi, Cleber; Huang, Ying-Ying; Hamblin, Michael R.] Harvard Med Sch, Dept Dermatol, Boston, MA USA. [Ferraresi, Cleber] Univ Sagrado Coracao, Bauru, SP, Brazil. [Hamblin, Michael R.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA USA. RP Ferraresi, C (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA.; Ferraresi, C (reprint author), Harvard Med Sch, Dept Dermatol, Boston, MA USA.; Ferraresi, C (reprint author), Univ Sagrado Coracao, Bauru, SP, Brazil. EM cleber.ferraresi@gmail.com RI Ferraresi, Cleber/B-2458-2014 FU US NIH [AI050875]; CNPq, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [202313/2014-0] FX MRH was funded by US NIH grant AI050875. CF was supported by CNPq, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (Scholarship 202313/2014-0). NR 74 TC 0 Z9 0 U1 3 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1864-063X EI 1864-0648 J9 J BIOPHOTONICS JI J. Biophotonics PD DEC PY 2016 VL 9 IS 11-12 SI SI BP 1273 EP 1299 DI 10.1002/jbio.201600176 PG 27 WC Biochemical Research Methods; Biophysics; Optics SC Biochemistry & Molecular Biology; Biophysics; Optics GA EJ0QS UT WOS:000392915800016 PM 27874264 ER PT J AU Abou-Alfa, GK Andersen, JB Chapman, W Choti, M Forbes, SJ Gores, GJ Hong, TS Harding, JJ Vander Heiden, MG Javle, M Kelley, RK Kwong, LN Lowery, M Merrell, A Miyabe, K Rhim, A Saha, S Sia, D Tanasanvimon, S Venook, A Valle, JW Walesky, C Whetstine, J Willenbring, H Zhu, AX Mayer, D Stanger, BZ AF Abou-Alfa, Ghassan K. Andersen, Jesper B. Chapman, William Choti, Michael Forbes, Stuart J. Gores, Gregory J. Hong, Theodore S. Harding, James J. Vander Heiden, Matthew G. Javle, Milind Kelley, Robin K. Kwong, Lawrence N. Lowery, Maeve Merrell, Allyson Miyabe, Katsuyuki Rhim, Andrew Saha, Supriya Sia, Daniela Tanasanvimon, Suebpong Venook, Alan Valle, Juan W. Walesky, Chad Whetstine, Jonathan Willenbring, Holger Zhu, Andrew X. Mayer, Donna Stanger, Ben Z. TI Advances in cholangiocarcinoma research: report from the third Cholangiocarcinoma Foundation Annual Conference SO JOURNAL OF GASTROINTESTINAL ONCOLOGY LA English DT Article ID BILIARY-TRACT CANCER; INTRAHEPATIC CHOLANGIOCARCINOMA; HEPATOCELLULAR-CARCINOMA; EXTRAHEPATIC CHOLANGIOCARCINOMA; HEPATOCYTE PROLIFERATION; PHASE-2 TRIAL; ADULT MICE; OPEN-LABEL; GEMCITABINE; OXALIPLATIN C1 [Abou-Alfa, Ghassan K.; Harding, James J.; Lowery, Maeve] Mem Sloan Kettering Canc Ctr, 300 East 66th St, New York, NY 10065 USA. [Abou-Alfa, Ghassan K.; Harding, James J.; Lowery, Maeve] Weill Cornell Med Coll, New York, NY USA. [Andersen, Jesper B.] Univ Copenhagen, Biotech Res & Innovat Ctr, Dept Hlth & Med Sci, Copenhagen, Denmark. [Chapman, William] Washington Univ, St Louis, MO USA. [Choti, Michael] Southwestern Med Ctr, Dallas, TX USA. [Forbes, Stuart J.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Gores, Gregory J.; Miyabe, Katsuyuki] Mayo Clin, Rochester, MN USA. [Hong, Theodore S.; Whetstine, Jonathan; Zhu, Andrew X.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Vander Heiden, Matthew G.; Kwong, Lawrence N.] MIT, Koch Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Javle, Milind] MD Anderson, Houston, TX USA. [Kelley, Robin K.; Venook, Alan; Willenbring, Holger] UCSF, San Francisco, CA USA. [Merrell, Allyson; Stanger, Ben Z.] Univ Penn, Philadelphia, PA 19104 USA. [Rhim, Andrew] Univ Michigan, Ann Arbor, MI 48109 USA. [Saha, Supriya] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Sia, Daniela] Mt Sinai Hosp, New York, NY 10029 USA. [Tanasanvimon, Suebpong] Chulalongkorn Univ, Bangkok, Thailand. [Valle, Juan W.] Univ Manchester, Manchester, Lancs, England. [Walesky, Chad] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Mayer, Donna] Cholangiocarcinoma Fdn, Salt Lake City, UT USA. EM abou-alg@mskcc.org OI Lowery, Maeve/0000-0003-1354-7606 FU Cholangiocarcinoma Foundation FX This report is supported by an unrestricted education grant from the Cholangiocarcinoma Foundation. NR 39 TC 0 Z9 0 U1 2 U2 2 PU PIONEER BIOSCIENCE PUBL CO PI HONG KONG PA 9A GOLD SHINE TOWER, 346-348 QUEEN'S RD CENTRAL, SHEUNG WAN, HONG KONG, 00000, PEOPLES R CHINA SN 2078-6891 EI 2219-679X J9 J GASTROINTEST ONCOL JI J. Gastrointest. Oncol. PD DEC PY 2016 VL 7 IS 6 BP 819 EP 827 DI 10.21037/jgo.2016.11.11 PG 9 WC Oncology SC Oncology GA EI5QC UT WOS:000392548400001 PM 28078106 ER PT J AU Mawardi, H Enzinger, P McCleary, N Manon, R Villa, A Treister, N Woo, SB AF Mawardi, Hani Enzinger, Peter McCleary, Nadine Manon, Reshma Villa, Alessandro Treister, Nathaniel Woo, Sook-Bin TI Osteonecrosis of the jaw associated with ziv-aflibercept SO JOURNAL OF GASTROINTESTINAL ONCOLOGY LA English DT Article DE Osteonecrosis; jaw; ziv-aflibercept ID CANCER; BISPHOSPHONATES; UPDATE; RISK AB Medication-related osteonecrosis of the jaw (MRONJ) has been associated with medications that include bisphosphonates (BPs), denosumab, bevacizumab and sunitinib. Ziv-aflibercept is a recombinant human vascular endothelial growth factor (VEGF) receptor which has been used to treat patients with various advanced solid tumors. We report three patients without a history of the use of medications known to cause MRONJ presenting with jaw osteonecrosis typical for MRONJ following therapy with ziv-aflibercept. All patients had metastatic gastrointestinal cancer treated with ziv-aflibercept and were evaluated for MRONJ because of exposed bone in the oral cavity. None of the patients had received antiresorptive therapies or any other medication known to cause MRONJ, and none had received radiation therapy to the jaws. Patients were aged 43, 51, 63 and all were males. Patients received 7, 16 and 23 cycles of ziv-aflibercept treatment and developed necrotic bone. All three patients presented with mandibular involvement, with two reporting pain. Patients were managed with anti-microbial mouth rinse, antibiotics and non-surgical sequestrectomy and followed up for 1.5, 2, and 2 months; two patients became asymptomatic while one patient continued to have pain. These three reported patients with a history of ziv-aflibercept therapy and no reported use of other medications known to cause MRONJ developed exposed necrotic bone of the jaw. We believe that ziv-aflibercept is another medication that can potentially cause MRONJ probably through its anti-VEGF activity, similar to bevacizumab and sunitinib. C1 [Mawardi, Hani; Villa, Alessandro; Treister, Nathaniel; Woo, Sook-Bin] Brigham & Womens Hosp, Div Oral Med & Dent, Boston, MA 02215 USA. [Mawardi, Hani; Manon, Reshma; Villa, Alessandro; Treister, Nathaniel; Woo, Sook-Bin] Harvard Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02215 USA. [Mawardi, Hani; Manon, Reshma] King Abdulaziz Univ, Dept Oral Med Infect & Immun, Jeddah, Saudi Arabia. [Enzinger, Peter] Ctr Esophageal & Gastr Canc, Boston, MA 02215 USA. [McCleary, Nadine] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM hmawardi@gmail.com NR 30 TC 1 Z9 1 U1 1 U2 1 PU PIONEER BIOSCIENCE PUBL CO PI HONG KONG PA 9A GOLD SHINE TOWER, 346-348 QUEEN'S RD CENTRAL, SHEUNG WAN, HONG KONG, 00000, PEOPLES R CHINA SN 2078-6891 EI 2219-679X J9 J GASTROINTEST ONCOL JI J. Gastrointest. Oncol. PD DEC PY 2016 VL 7 IS 6 BP E81 EP E87 DI 10.21037/jgo.2016.05.07 PG 7 WC Oncology SC Oncology GA EI5QC UT WOS:000392548400027 PM 28078129 ER PT J AU Liu, FJ Wells, JW Porter, RM Glatt, V Shen, ZX Schinhan, M Ivkovic, A Vrahas, MS Evans, CH Ferreira, E AF Liu, Fangjun Wells, James W. Porter, Ryan M. Glatt, Vaida Shen, Zhenxin Schinhan, Martina Ivkovic, Alan Vrahas, Mark S. Evans, Christopher H. Ferreira, Elisabeth TI Interaction between living bone particles and rhBMP-2 in large segmental defect healing in the rat femur SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE autograft; INFUSE; RIA; xenograft; immunosuppression ID REAMER-IRRIGATOR-ASPIRATOR; GRAFT; COMPLICATIONS; FRACTURES; NONUNIONS; BMPS AB Orthopedic surgeons sometimes combine recombinant, human BMP-2 with autograft bone when dealing with problematic osseous fractures. Although some case reports indicate success with this off-label strategy, there have been no randomized controlled trials. Moreover, a literature search revealed only one pre-clinical study and this was in a cranial defect model. The present project examined the consequences of combining BMP-2 with particles of living bone in a rat femoral defect model. Human bone particles were recovered with a reamer-irrigator-aspirator (RIA). To allow acceptance of the xenograft as surrogate autograft, rats were administered an immunosuppressive cocktail that does not interfere with bone healing. Implantation of 200 mu g living bone particles generated a small amount of new bone and defects did not heal. Graded amounts of BMP-2 that alone provoked no healing (1.1 mu g), borderline healing (5.5 mu g), or full healing (11 mu g) were added to this amount of bone particles. Addition of BMP-2 (1.1 mu g) increased osteogenesis, and produced bridging in 2 of 7 defects. The combination of BMP-2 (5.5 mu g) and bone particles made healing more reliable and advanced the maturation of the regenerate. Bone formation with BMP-2 (11 mu g) and bone particles showed improved maturation. Thus, the combination of autograft and BMP-2 may be helpful clinically under conditions where the healing response is suboptimal. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2137-2145, 2016. Clinical significance These data support the clinical use of recombinant, human BMP-2 with autograft bone when treating large segmental osseous defects. The combination leads to greater bone formation and accelerates the maturation of the regenerate. C1 [Liu, Fangjun; Wells, James W.; Porter, Ryan M.; Glatt, Vaida; Shen, Zhenxin; Schinhan, Martina; Ivkovic, Alan; Evans, Christopher H.; Ferreira, Elisabeth] Harvard Med Sch, Ctr Adv Orthopaed Studies, Beth Israel Deaconess Med Ctr, 330,Brookline Ave RN 115, Boston, MA 02215 USA. [Liu, Fangjun; Wells, James W.; Porter, Ryan M.; Glatt, Vaida; Vrahas, Mark S.; Evans, Christopher H.; Ferreira, Elisabeth] AO Fdn, Collaborat Res Ctr, Davos, Switzerland. [Schinhan, Martina] Med Univ Vienna, Dept Orthopaed Surg, Vienna, Austria. [Vrahas, Mark S.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA USA. [Evans, Christopher H.] Mayo Clin, Rehabil Med Res Ctr, Rochester, MN 55905 USA. [Liu, Fangjun] WeiFang Med Univ, Inst Plast & Reconstruct Surg, Weifang, Shandong, Peoples R China. [Glatt, Vaida] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia. [Wells, James W.] Univ Queensland, Diamantina Inst, Brisbane, Qld, Australia. [Ivkovic, Alan] Univ Hosp Sveti Duh, Dept Orthopaed Surg, Zagreb, Croatia. EM evans.christopher@mayo.edu OI Ivkovic, Alan/0000-0003-0236-6244 FU NIH [RC1AR058776]; NIAMS; US Department of Defense [W81XWH-10-1-0888] FX Grant sponsor: NIH; Grant number: RC1AR058776; Grant sponsor: NIAMS and US Department of Defense; Grant number: W81XWH-10-1-0888. NR 19 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 EI 1554-527X J9 J ORTHOP RES JI J. Orthop. Res. PD DEC PY 2016 VL 34 IS 12 BP 2137 EP 2145 DI 10.1002/jor.23255 PG 9 WC Orthopedics SC Orthopedics GA EI5LQ UT WOS:000392536500013 PM 27037517 ER PT J AU Cohen, JR Danielson, CK Adams, ZW Ruggiero, KJ AF Cohen, Joseph R. Danielson, Carla Kmett Adams, Zachary W. Ruggiero, Kenneth J. TI Distress Tolerance and Social Support in Adolescence: Predicting Risk for Internalizing and Externalizing Symptoms Following a Natural Disaster SO JOURNAL OF PSYCHOPATHOLOGY AND BEHAVIORAL ASSESSMENT LA English DT Article DE Distress tolerance; Perceived social support; Natural disasters; Adolescence; Internalizing symptoms; Externalizing symptoms ID POSTTRAUMATIC-STRESS; REFUGEE ADOLESCENTS; HURRICANE-ANDREW; DEPRESSION; BEHAVIOR; TRAUMA; GENDER; ADULTS; PTSD; LIFE AB The purpose of the multi-measure, multi-wave, longitudinal study was to examine the interactive relation between behavioral distress tolerance (DT) and perceived social support (PSS) in 352 tornado-exposed adolescents aged 12-17 years (M = 14.44; SD = 1.74). At baseline, adolescents completed a computer-based task for DT, and self-report measures of PSS, depressed mood, posttraumatic stress disorder (PTSD), substance use, and interpersonal conflict. Symptoms also were assessed 4 and 12 months after baseline. Findings showed that lower levels of DT together with lower levels of PSS conferred risk for elevated symptoms of prospective depression (t(262) = -2.04, p = .04; r(effect size) = 0.13) and PTSD (t(195) = -2.08, p = .04; r(effect size) = 0.15) following a tornado. However, only PSS was significant in substance use t(139) = 2.20, p = .03; r(effect size=)0.18) and conflict (t(138) = -4.05, p < .0001; r(effect size=)0.33) in our sample. Implications regarding adolescent DT, the transdiagnostic nature of PSS, and the clinical applications of our findings in the aftermath of a natural disaster are discussed. C1 [Cohen, Joseph R.] Univ Illinois, Dept Psychol, Champaign, IL 61801 USA. [Danielson, Carla Kmett; Adams, Zachary W.] Med Univ South Carolina, Dept Psychiat & Behav Sci, Natl Crime Victims Res & Treatment Ctr, 67 President St,MSC 861,2nd Fl IOP South Bldg, Charleston, SC 29425 USA. [Ruggiero, Kenneth J.] Med Univ South Carolina, Coll Nursing, Technol Applicat Ctr Healthful Lifestyles, 67 President St,MSC 861,2nd Fl IOP South Bldg, Charleston, SC 29425 USA. [Ruggiero, Kenneth J.] Ralph H Johnson VAMC, Hlth Equ & Rural Outreach Innovat Ctr, Charleston, SC USA. EM cohenj@illinois.edu FU National Institute of Mental Health [R01MH081056, R21MH086313]; [R01DA031285]; [K12-DA031794]; [T32MH18869] FX The National Institute of Mental Health supported this study and the team of collaborators: data collection occurred via grants R01MH081056 to KJR and R21MH086313 to CKD. The preparation of this manuscript was partially supported by grant R01DA031285 to CKD, grant K12-DA031794 which supports ZWA, and T32MH18869 which supported JRC. NR 60 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0882-2689 EI 1573-3505 J9 J PSYCHOPATHOL BEHAV JI J. Psychopathol. Behav. Assess. PD DEC PY 2016 VL 38 IS 4 BP 538 EP 546 DI 10.1007/s10862-016-9545-y PG 9 WC Psychology, Clinical SC Psychology GA EI5ET UT WOS:000392517600003 PM 28163364 ER PT J AU Baldacci, F Lista, S Garaci, F Bonuccelli, U Toschi, N Hampel, H AF Baldacci, Filippo Lista, Simone Garaci, Francesco Bonuccelli, Ubaldo Toschi, Nicola Hampel, Harald TI Biomarker-guided classification scheme of neurodegenerative diseases SO Journal of Sport and Health Science LA English DT Editorial Material ID ALZHEIMERS-DISEASE; DIAGNOSTIC-CRITERIA; DEMENTIA C1 [Baldacci, Filippo; Bonuccelli, Ubaldo] Univ Pisa, Dept Clin & Expt Med, I-56126 Pisa, Italy. [Baldacci, Filippo; Hampel, Harald] Hop La Pitie Salpetriere, Inst Memory & Alzheimers Dis IM2A, Brain & Spine Inst ICM, UMR S 1127,Dept Neurol, F-75651 Paris, France. [Baldacci, Filippo; Hampel, Harald] Pierre & Marie Curie Univ, Sorbonne Univ, Paris VI, F-75005 Paris, France. [Lista, Simone; Hampel, Harald] AXA Res Fund, F-75005 Paris, France. [Lista, Simone; Hampel, Harald] Pierre & Marie Curie Univ Chair, F-75005 Paris, France. [Lista, Simone] Hop La Pitie Salpetriere, IHU A ICM Paris Inst Translat Neurosci, F-75651 Paris, France. [Garaci, Francesco; Toschi, Nicola] Univ Roma Tor Vergata, Dept Biomed & Prevent, Fac Med, I-00173 Rome, Italy. [Garaci, Francesco] San Raffaele Cassino Nursing Home, I-03043 Cassino, FR, Italy. [Toschi, Nicola] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Toschi, Nicola] Harvard Med Sch, Charlestown, MA 02129 USA. RP Hampel, H (reprint author), Hop La Pitie Salpetriere, Inst Memory & Alzheimers Dis IM2A, Brain & Spine Inst ICM, UMR S 1127,Dept Neurol, F-75651 Paris, France.; Hampel, H (reprint author), Pierre & Marie Curie Univ, Sorbonne Univ, Paris VI, F-75005 Paris, France.; Hampel, H (reprint author), AXA Res Fund, F-75005 Paris, France.; Hampel, H (reprint author), Pierre & Marie Curie Univ Chair, F-75005 Paris, France. EM harald.hampel@med.uni-muenchen.de FU AXA Research Fund; Fondation Universite Pierre et Marie Curie; Fondation pour la Recherche sur Alzheimer, Paris, France; program Investissements d'avenir (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6) [ANR-10-IAIHU-06] FX Harald Hampel is supported by the AXA Research Fund, the Fondation Universite Pierre et Marie Curie, and the Fondation pour la Recherche sur Alzheimer, Paris, France. The research leading to these results has received funding from the program Investissements d'avenir ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6). NR 25 TC 1 Z9 1 U1 1 U2 1 PU SHANGHAI UNIV SPORT PI SHANGHAI PA EDITORIAL BOARD, 650 QINGYUANHUAN RD, SHANGHAI, 200438, PEOPLES R CHINA SN 2095-2546 EI 2213-2961 J9 J SPORT HEALTH SCI JI J. Sport Health Sci. PD DEC PY 2016 VL 5 IS 4 BP 383 EP 387 DI 10.1016/j.jshs.2016.08.007 PG 5 WC Hospitality, Leisure, Sport & Tourism; Sport Sciences SC Social Sciences - Other Topics; Sport Sciences GA EJ0UA UT WOS:000392924800002 ER PT J AU Agrawal, V Coroller, TP Hou, Y Lee, SW Romano, JL Baldini, EH Chen, AB Jackman, DM Kozono, D Swanson, SJ Wee, JO Aerts, HJWL Mak, RH AF Agrawal, Vishesh Coroller, Thibaud P. Hou, Ying Lee, Stephanie W. Romano, John L. Baldini, Elizabeth H. Chen, Aileen B. Jackman, David M. Kozono, David Swanson, Scott J. Wee, Jon O. Aerts, Hugo J. W. L. Mak, Raymond H. TI Radiologic-pathologic correlation of response to chemoradiation in resectable locally advanced NSCLC SO LUNG CANCER LA English DT Article DE Non-small cell lung cancer; Quantitative imaging; Recist; Response assessment ID CELL LUNG-CANCER; GROSS TUMOR VOLUME; RANDOMIZED CONTROLLED-TRIAL; PHASE-II TRIAL; NEOADJUVANT CHEMOTHERAPY; PROGNOSTIC-FACTOR; PREOPERATIVE CHEMOTHERAPY; HISTOPATHOLOGIC RESPONSE; INDUCTION CHEMORADIATION; SURGICAL RESECTION AB Objectives: Accurate assessment of tumor response to chemoradiation has the potential to guide clinical decision-making regarding surgical resection and/or dose escalation for patients. Early assessment has implications for Optimal local therapy for operable locally advanced non-small cell lung cancer (LA-NSCLC) is controversial. This study evaluated quantitative CT-based tumor measurements to predict pathologic response. Materials and methods: Patients with operable LA-NSCLC treated with chemoradiation followed by surgical resection were assessed. Tumor diameter and volume were quantified from CT imaging obtained prior to chemoradiation and post-chemoradiation prior to surgical resection. Univariate and multivariate logistic regression were used to determine association with the primary endpoint of pathologic complete response (pCR). Overall survival, locoregional recurrence, and distant metastasis were assessed as secondary endpoints. Results: 101 LA-NSCLC patients were identified and treated with preoperative chemoradiation and surgical resection. The median RT dose was 54 Gy (range, 46-70) and 98% of patients received concurrent chemoradiation as part of their preoperative treatment. Reduction of CT-defined tumor volume was associated with pCR (OR 1.06 [1.02-1.09], p = 0.002) and LRR (HR 1.01 [1.00-1.02], p = 0.048). Conventional response assessment determined by RECIST (p = 0.213) was not associated with pCR or any secondary endpoints. Conclusion: CT-measured reductions in tumor volume after chemoradiation are associated with pCR and provide greater clinical information about tumor response than conventional response assessment (RECIST) or absolute tumor sizes or volumes. This study demonstrates that change in tumor volumes provides better radiologic-pathologic correlation and is thus an additional tool to assess tumor response following chemoradiation. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Agrawal, Vishesh; Coroller, Thibaud P.; Hou, Ying; Lee, Stephanie W.; Romano, John L.; Baldini, Elizabeth H.; Chen, Aileen B.; Kozono, David; Aerts, Hugo J. W. L.; Mak, Raymond H.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. [Agrawal, Vishesh; Baldini, Elizabeth H.; Chen, Aileen B.; Jackman, David M.; Kozono, David; Swanson, Scott J.; Wee, Jon O.; Aerts, Hugo J. W. L.; Mak, Raymond H.] Harvard Med Sch, Boston, MA USA. [Aerts, Hugo J. W. L.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Swanson, Scott J.; Wee, Jon O.] Brigham & Womens Hosp, Div Thorac Surg, 75 Francis St, Boston, MA 02115 USA. [Jackman, David M.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, 75 Francis St, Boston, MA 02115 USA. EM rmak@partners.org RI Aerts, Hugo/P-6350-2015 OI Aerts, Hugo/0000-0002-2122-2003 FU National Institute of Health [NIH-USA U24CA194354, NIH-USA U01CA190234]; Kaye Scholar Award FX This work was supported by National Institute of Health [NIH-USA U24CA194354, NIH-USA U01CA190234] and a Kaye Scholar Award. NR 35 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD DEC PY 2016 VL 102 BP 1 EP 8 DI 10.1016/j.lungcan.2016.10.002 PG 8 WC Oncology; Respiratory System SC Oncology; Respiratory System GA EI5VT UT WOS:000392565100001 PM 27987576 ER PT J AU Wong, ML McMurry, TL Stukenborg, GJ Francescatti, AB Amato-Martz, C Schumacher, JR Chang, GJ Greenberg, CC Winchester, DP McKellar, DP Walter, LC Kozower, BD AF Wong, Melisa L. McMurry, Timothy L. Stukenborg, George J. Francescatti, Amanda B. Amato-Martz, Carla Schumacher, Jessica R. Chang, George J. Greenberg, Caprice C. Winchester, David P. McKellar, Daniel P. Walter, Louise C. Kozower, Benjamin D. TI Impact of age and comorbidity on treatment of non-small cell lung cancer recurrence following complete resection: A nationally representative cohort study SO LUNG CANCER LA English DT Article DE Non-small cell lung cancer; Recurrence; Treatment; Geriatric oncology ID SUBSTANCE-ABUSE ISSUES; OLDER PATIENTS; EARLY-STAGE; PATIENT PREFERENCE; ELDERLY-PATIENTS; SEX-DIFFERENCES; UNITED-STATES; CHEMOTHERAPY; SURVIVAL; CARE AB Objective: Older patients with non-small cell lung cancer (NSCLC) are less likely to receive guideline recommended treatment at diagnosis, independent of comorbidity. However, national data on treatment of postoperative recurrence are limited. We evaluated the associations between age, comorbidity, and other patient factors and treatment of postoperative NSCLC recurrence in a national cohort. Materials and methods: We randomly selected 9001 patients with surgically resected stage I Ill NSCLC in 2006-2007 from the National Cancer Data Base. Patients were followed for 5 years or until first NSCLC recurrence, new primary cancer, or death, whichever came first. Perioperative comorbidities, first recurrence, treatment of recurrence, and survival were abstracted from medical records and merged with existing registry data. Factors associated with active treatment (chemotherapy, radiation, and/or surgery) versus supportive care only were analyzed using multivariable logistic regression. Results: Median age at initial diagnosis was 67; 69.7% had >1 comorbidity. At 5-year follow-up, 12.3% developed locoregional and 21.5% developed distant recurrence. Among patients with locoregional recurrence, 79.5% received active treatment. Older patients (OR 0.49 for age >75 compared with <55; 95% CI 0.27-0.88) and those with substance abuse (OR 0.43; 95% CI 0.23-0.81) were less likely to receive active treatment. Women (OR 0.62; 95% CI 0.43-0.89) and patients with symptomatic recurrence (OR 0.69; 95% CI 0.47-0.99) were also less likely to receive active treatment. Among those with distant recurrence, 77.3% received active treatment. Older patients (OR 0.42 for age >75 compared with <55; 95% CI 0.26-0.68) and those with any documented comorbidities (OR 0.59; 95% CI 0.38-0.89) were less likely to receive active treatment. Conclusion: Older patients independent of comorbidity, patients with substance abuse, and women were less likely to receive active treatment for postoperative NSCLC recurrence. Studies to further characterize these disparities in treatment of NSCLC recurrence are needed to identify barriers to treatment. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Wong, Melisa L.] Univ Calif San Francisco, Dept Med, Div Hematol Oncol, 505 Parnassus Ave,Mailbox 1270, San Francisco, CA 94143 USA. [Wong, Melisa L.] Univ Calif San Francisco, Dept Med, Div Geriatr, 505 Parnassus Ave,Mailbox 1270, San Francisco, CA 94143 USA. [Wong, Melisa L.] San Francisco VA Med Ctr, 505 Parnassus Ave,Mailbox 1270, San Francisco, CA 94143 USA. [McMurry, Timothy L.; Stukenborg, George J.] Univ Virginia Hlth Syst, Dept Publ Hlth Sci, POB 800717, Charlottesville, VA 22908 USA. [Francescatti, Amanda B.] Amer Coll Surg, 633 N St Clair St, Chicago, IL 60611 USA. [Amato-Martz, Carla] Alliance Clin Trials Oncol, 125 S Wacker Dr,Suite 1600, Chicago, IL 60606 USA. [Schumacher, Jessica R.; Greenberg, Caprice C.] Univ Wisconsin, Dept Surg, 600 Highland Ave,BX7375 Clin Sci Ctr, Madison, WI 53792 USA. [Chang, George J.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, 1515 Holcombe Blvd,Unit 444, Houston, TX 77030 USA. [Chang, George J.] Univ Texas MD Anderson Canc Ctr, Hlth Serv Res, 1515 Holcombe Blvd,Unit 444, Houston, TX 77030 USA. [Winchester, David P.] Amer Coll Surg, Canc Programs, 633 N St Clair St, Chicago, IL 60611 USA. [McKellar, Daniel P.] Amer Coll Surg, Commiss Canc, 633 N St Clair St, Chicago, IL 60611 USA. [Walter, Louise C.] Univ Calif San Francisco, Div Geriatr, Dept Med, 4150 Clement,181G, San Francisco, CA 94121 USA. [Walter, Louise C.] San Francisco VA Med Ctr, 4150 Clement,181G, San Francisco, CA 94121 USA. [Kozower, Benjamin D.] Washington Univ, Dept Surg, Div Cardiothorac Surg, One Barnes Jewish Hosp Plaza,Suite 3108, St Louis, MO 63110 USA. EM melisa.wong@ucsf.edu; tlm6w@eservices.virginia.edu; gjs6r@eservices.virginia.edu; afrancescatti@facs.org; cmartz@alliancefoundationtrials.org; schumacher@surgery.wisc.edu; GChang@mdanderson.org; greenberg@surgery.wisc.edu; DWinchester@facs.org; d.mckellar1958@gmail.com; Louise.Walter@ucsf.edu; kozowerb@wudosis.wustl.edu FU Patient-Centered Outcomes Research Institute (PCORI) [CE-1306-00727]; National Institute on Aging [T32AG000212, K24AG041180]; National Cancer Institute [UG1CA189823] FX This work was supported by the Patient-Centered Outcomes Research Institute (PCORI; CE-1306-00727, Kozower), the National Institute on Aging (T32AG000212, Wong and K24AG041180, Walter), and the National Cancer Institute (UG1CA189823, Alliance for Clinical Trials in Oncology NCORP Research Base). NR 47 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD DEC PY 2016 VL 102 BP 108 EP 117 DI 10.1016/j.lungcan.2016.11.002 PG 10 WC Oncology; Respiratory System SC Oncology; Respiratory System GA EI5VT UT WOS:000392565100018 PM 27987578 ER PT J AU Khan, NR VanLandingham, MA Fierst, TM Hymel, C Hoes, K Evans, LT Mayer, R Barker, F Klimo, P AF Khan, Nickalus R. VanLandingham, Matthew A. Fierst, Tamara M. Hymel, Caroline Hoes, Kathryn Evans, Linton T. Mayer, Rory Barker, Fred Klimo, Paul, Jr. TI Should Levetiracetam or Phenytoin Be Used for Posttraumatic Seizure Prophylaxis? A Systematic Review of the Literature and Meta-analysis SO NEUROSURGERY LA English DT Review DE Dilantin; Keppra; Levetiracetam; Meta-analysis; Phenytoin; Seizures; Trauma ID TRAUMATIC BRAIN-INJURY; CLINICAL-TRIALS; PREVENTION; EPILEPSY; QUALITY; BIAS AB BACKGROUND: Posttraumatic seizure (PTS) is a significant complication of traumatic brain injury (TBI). OBJECTIVE: To perform a systematic review and meta-analysis to compare levetiracetam with phenytoin for seizure prophylaxis in patients diagnosed with severe TBI. METHODS: An inclusive search of several electronic databases and bibliographies was conducted to identify scientific studies that compared the effect of levetiracetam and phenytoin on PTS. Independent reviewers obtained data and classified the quality of each article that met inclusion criteria. A random effects meta-analysis was then completed. RESULTS: During June and July 2015, a systematic literature search was performed that identified 6097 articles. Of these, 7 met inclusion criteria. A random-effects meta-analysis was performed. A total of 1186 patients were included. The rate of seizure was 35 of 654 (5.4%) in the levetiracetam cohort and 18 of 532 (3.4%) in the phenytoin cohort. Our meta-analysis revealed no change in the rate of early PTS with levetiracetam compared with phenytoin (relative risk, 1.02; 95% confidence interval, 0.53-1.95; P = .96). CONCLUSION: The lack of evidence on which antiepileptic drug to use in PTS is surprising given the number of patients prescribed an antiepileptic drug therapy for TBI. On the basis of currently available Level III evidence, patients treated with either levetiracetam or phenytoin have similar incidences of early seizures after TBI. C1 [Khan, Nickalus R.; VanLandingham, Matthew A.; Klimo, Paul, Jr.] Univ Tennessee, Ctr Hlth Sci, Dept Neurosurg, Memphis, TN 38163 USA. [Fierst, Tamara M.] Temple Univ, Sch Med, Dept Neurosurg, Philadelphia, PA 19122 USA. [Hymel, Caroline] Univ Memphis, Dept Psychol & Neurosci, Memphis, TN 38152 USA. [Hoes, Kathryn] Univ Texas Southwestern, Dept Neurosurg, Dallas, TX USA. [Evans, Linton T.] Dartmouth Hitchcock Hosp, Dept Neurosurg, Lebanon, NH USA. [Mayer, Rory] Baylor Coll Med, Dept Neurosurg, Houston, TX 77030 USA. [Barker, Fred] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Klimo, Paul, Jr.] Semmes Murphey Neurol & Spine Inst, 6325 Humphreys Blvd, Memphis, TN 38120 USA. EM pklimo@semmes-murphey.com NR 33 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 0148-396X J9 NEUROSURGERY JI Neurosurgery PD DEC PY 2016 VL 79 IS 6 BP 775 EP 781 DI 10.1227/NEU.0000000000001445 PG 7 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA EI6OH UT WOS:000392614700015 PM 27749510 ER PT J AU Collins, MW Kontos, AP Okonkwo, DO Almquist, J Bailes, J Barisa, M Bazarian, J Bloom, OJ Brody, DL Cantu, R Cardenas, J Clugston, J Cohen, R Echemendia, R Elbin, RJ Ellenbogen, R Fonseca, J Gioia, G Guskiewicz, K Heyer, R Hotz, G Iverson, GL Jordan, B Manley, G Maroon, J McAllister, T McCrea, M Mucha, A Pieroth, E Podell, K Pombo, M Shetty, T Sills, A Solomon, G Thomas, DG McLeod, TCV Yates, T Zafonte, R AF Collins, Michael W. Kontos, Anthony P. Okonkwo, David O. Almquist, Jon Bailes, Julian Barisa, Mark Bazarian, Jeffrey Bloom, O. Josh Brody, David L. Cantu, Robert Cardenas, Javier Clugston, Jay Cohen, Randall Echemendia, Ruben Elbin, R. J. Ellenbogen, Richard Fonseca, Janna Gioia, Gerard Guskiewicz, Kevin Heyer, Robert Hotz, Gillian Iverson, Grant L. Jordan, Barry Manley, Geoffrey Maroon, Joseph McAllister, Thomas McCrea, Michael Mucha, Anne Pieroth, Elizabeth Podell, Kenneth Pombo, Matthew Shetty, Teena Sills, Allen Solomon, Gary Thomas, Danny G. McLeod, Tamara C. Valovich Yates, Tony Zafonte, Ross TI Statements of Agreement From the Targeted Evaluation and Active Management (TEAM) Approaches to Treating Concussion Meeting Held in Pittsburgh, October 15-16, 2015 SO NEUROSURGERY LA English DT Article DE Concussion; mTBI; Rehabilitation; Treatment ID SPORT-RELATED CONCUSSION; TRAUMATIC BRAIN-INJURY; HIGH-SCHOOL FOOTBALL; RANDOMIZED CONTROLLED-TRIAL; POSTTRAUMATIC MIGRAINE CHARACTERISTICS; PREDICT PROTRACTED RECOVERY; FEMALE HIGH-SCHOOL; LOW-BACK-PAIN; NEUROCOGNITIVE PERFORMANCE; EMERGENCY-DEPARTMENT AB BACKGROUND: Conventional management for concussion involves prescribed rest and progressive return to activity. Recent evidence challenges this notion and suggests that active approaches may be effective for some patients. Previous concussion consensus statements provide limited guidance regarding active treatment. OBJECTIVE: To describe the current landscape of treatment for concussion and to provide summary agreements related to treatment to assist clinicians in the treatment of concussion. METHODS: On October 14 to 16, 2015, the Targeted Evaluation and Active Management (TEAM) Approaches to Treating Concussion meeting was convened in Pittsburgh, Pennsylvania. Thirty-seven concussion experts from neuropsychology, neurology, neurosurgery, sports medicine, physical medicine and rehabilitation, physical therapy, athletic training, and research and 12 individuals representing sport, military, and public health organizations attended the meeting. The 37 experts indicated their agreement on a series of statements using an audience response system clicker device. RESULTS: A total of 16 statements of agreement were supported covering (1) Summary of the Current Approach to Treating Concussion, (2) Heterogeneity and Evolving Clinical Profiles of Concussion, (3) TEAM Approach to Concussion Treatment: Specific Strategies, and (4) Future Directions: A Call to Research. Support (ie, response of agree or somewhat agree) for the statements ranged from to 97% to 100%. CONCLUSION: Concussions are characterized by diverse symptoms and impairments and evolving clinical profiles; recovery varies on the basis of modifying factors, injury severity, and treatments. Active and targeted treatments may enhance recovery after concussion. Research is needed on concussion clinical profiles, biomarkers, and the effectiveness and timing of treatments. C1 [Collins, Michael W.; Kontos, Anthony P.; Thomas, Danny G.] Univ Pittsburgh, UPMC Sports Med Concuss Program, Dept Orthopaed Surg, Pittsburgh, PA USA. [Okonkwo, David O.; Maroon, Joseph] Univ Pittsburgh, Dept Neurol Surg, Pittsburgh, PA 15260 USA. [Almquist, Jon] Fairfax Family Practice Comprehens Concuss Ctr, Fairfax, VA USA. [Bailes, Julian] NorthShore Univ Hlth Syst, Dept Neurosurg, Chicago, IL USA. [Barisa, Mark] Baylor Inst Rehabil, Frisco, TX USA. [Bazarian, Jeffrey] Univ Rochester, Dept Emergency Med, Rochester, NY USA. [Bloom, O. Josh; Fonseca, Janna] Carolina Sports Concuss Clin, Cary, NC USA. [Brody, David L.] Washington Univ, Dept Neurol, St Louis, MO USA. [Cantu, Robert] Boston Univ, Emerson Hosp, Robert C Cantu Concuss Ctr, Concord, MA USA. [Cardenas, Javier] Barrow Neurol Inst, Dept Neurol, Phoenix, AZ 85013 USA. [Clugston, Jay] Univ Florida, Community Hlth & Family Med, Gainesville, FL USA. [Cohen, Randall] Univ Arizona, Athlet Dept, Tucson, AZ USA. [Echemendia, Ruben] Psychol & Neurobehav Associates, State Coll, PA USA. [Elbin, R. J.] Univ Arkansas, Off Sports Concuss Res, Fayetteville, AR 72701 USA. [Ellenbogen, Richard] Univ Washington, Dept Neurol Surg, Seattle, WA 98195 USA. [Gioia, Gerard] Childrens Natl Hlth Syst, Div Neuropsychol, Washington, DC USA. [Guskiewicz, Kevin] Univ N Carolina, Coll Arts & Sci, Chapel Hill, NC USA. [Heyer, Robert] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Hotz, Gillian] Univ Miami, Miller Sch Med, Neurosci Ctr, Miami, FL 33136 USA. [Iverson, Grant L.] Harvard Med Sch, Brigham & Womens Hosp, Massachusetts Gen Hosp, Dept Phys Med & Rehabil,Spaulding Rehabil Hosp, Boston, MA USA. [Jordan, Barry] Burke Rehabil & Res, Neurorehabilitat, White Plains, NY USA. [Manley, Geoffrey] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [McAllister, Thomas] Indiana Univ, Dept Psychiat, Bloomington, IN USA. [McCrea, Michael; Thomas, Danny G.] Med Coll Wisconsin, Dept Neurol, Milwaukee, WI 53226 USA. [Mucha, Anne] Univ Pittsburgh, Med Ctr, Ctr Rehabil Serv, Pittsburgh, PA USA. [Pieroth, Elizabeth] NorthShore Univ Hlth Syst, Neurol Inst, Chicago, IL USA. [Podell, Kenneth] Houston Methodist Hosp, Houston Methodist Concuss Ctr, Houston, TX USA. [Pombo, Matthew] Emory Univ Healthcare, Dept Orthoped, Atlanta, GA USA. [Shetty, Teena] Weill Cornell Med Coll, Hosp Special Surg, Dept Neurol, New York, NY USA. [Solomon, Gary] Vanderbilt Univ, Dept Neurosurg, Vanderbilt Sports Concuss Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA. [Thomas, Danny G.] Childrens Hosp Wisconsin, Pediat Emergency Med, Wauwatosa, WI USA. [McLeod, Tamara C. Valovich] AT Still Univ, Dept Athlet Training, Kirksville, MO USA. [Yates, Tony] Pittsburgh Steelers, Pittsburgh, PA USA. EM collinsmw@upmc.edu FU National Football League; University of Pittsburgh Medical Center; DoD; NCAA; NIH; GE-NFL; Banyan Biomarkers; Brainscope; Health South; Pfizer; Arizona Super Bowl Host Committee grant; Banyan Biomarkers, Inc; NCAA-DoD CARE Consortium; Brainscope Co, Inc.; MCI; Neuro-Health Research and Rehabilitation, Inc; NeuroHealth LLC; Abbott; Pittsburgh Steelers; GE-NFL Head Health Challenge I; CE Speakers' Bureau-American Physical Therapy Association; Medbridge Education; ImPACT Applications, Inc; Brainsteps; Inova; GE-NFL Head Initiative and Brainscope; Chembio; National Institute on Disability, Independent Living, and Rehabilitation Research; NFL Players Association; National Operating Committee on Standards for Athletic Equipment; American Medical Society for Sports Medicine; New Jersey Commission on Brain Injury Research; NFL; USA Hockey; National Athletic Trainers' Association; NFL Benefits Association for Neurocognitive Disability Benefit; Innovative CEUs; NCAA-DoD FX The TEAM Approaches to Treating Concussion Meeting was supported by grants from the National Football League and University of Pittsburgh Medical Center. Dr Collins is a consultant for the Pittsburgh Steelers and Pittsburgh Penguins and a developer and shareholder in ImPACT (Immediate Post Concussion Assessment and Cognitive Testing) Applications Inc. He receives research funding from the DoD, NCAA, NIH, and GE-NFL. Dr Okonkwo receives research funding from the NIH, DoD, and GE-NFL. He is a paid consultant for Lanx. J. Almquist receives an honorarium for presentations from ImPACT Applications, Inc and is owner of JLA Consulting LLC and codeveloper of BrainTrax. Dr Barisa is on the ImPACT speakers' bureau. Dr Bazarian receives grant/research support from Banyan Biomarkers and Brainscope; is a consultant for Banyan Biomarkers and a virtual shares stockholder in Black Biometrics; and is on the data safety and monitoring board for Neuren Pharmaceuticals. Dr Brody receives grant/research support from Health South and Pfizer and is a consultant for Pfizer Inc, Intellectual Ventures, Signum Nutralogix, Kypha Inc, Sage Therapeutics, iPerian Inc, and Avid Radiopharmaceuticals (Eli Lily & Co). Dr Cantu serves as vice president for the National Operating Committee on Standards for Athletic Equipment; is cofounder, chairman, and medical director for Sports Legacy (SLI, Waltham, MA); and is senior advisor to the NFL's Head, Neck and Spine Committee, providing expert witness testimony in trials. Dr Cardenas has an Arizona Super Bowl Host Committee grant for a domestic violence program, is a consultant in the NFL unaffiliated neurotrauma consultant program, and serves on the ImPACT application scientific advisory board. Dr Clugston receives grant/research support from Banyan Biomarkers, Inc and the NCAA-DoD CARE Consortium. Dr Elbin receives grant/research support from Brainscope Co, Inc. Dr Ellenbogen receives grant/research support from NIH and MCI; is an unpaid consultant for NFL-GE and a member of the NFL Head, Neck and Spine Committee; and is a scientific consultant for the VICIS helmet company. J. Fonseca is a consultant for ImPACT Applications, Inc. Dr Gioia is a test author for Psychological Assessment Resources, Inc and a consultant for the Washington Capitals and Baltimore Ravens. Dr Heyer is a consultant for the Carolina Panthers and is president of the NFL Physicians Society. Dr Hotz receives grant/research support from GE-NFL. Dr Iverson receives grant/research support from several organizations for mTBI. He is a salaried as an independent practitioner in neuropsychology, including giving expert testimony, for Neuro-Health Research and Rehabilitation, Inc, NeuroHealth LLC. He receives reimbursements from government, professional scientific bodies, and commercial organizations for discussing/presenting mTBI. Dr Manley receives grant/research support from NIH, DoD, and Abbott. Dr Maroon is employed by the University of Pittsburgh Medical Center, which has received grants from the National Football League and the Pittsburgh Steelers. He is an unpaid consultant for the Pittsburgh Steelers football club. He has been the team neurosurgeon for the Pittsburgh Steelers since 1981 and the medical director for World Wrestling Entertainment Corp since 2008 for the management of spine and brain-related injury. He also has served on the NFL's Head, Neck and Spine Committee since 2007 and is currently a consultant to the committee.; He is a founder and shareholder in ImPACT, and the World Wrestling Entertainment has partnered with ImPACT to provide concussion management. He has served as an expert witness in medical legal cases involving concussions. Dr McCrea receives grant/ research support from GE-NFL Head Health Challenge I. He is a GE Healthcare consultant and a member of the NFL Head, Neck and Spine Committee. Dr Mucha has received speaker's fees/honoraria from CE Speakers' Bureau-American Physical Therapy Association, Medbridge Education, ImPACT Applications, Inc, Brainsteps, Inova, and various healthcare and/or educational societies. Dr Podell receives grant/research support from GE-NFL Head Initiative and Brainscope. Dr Shetty receives grant/research support from GE-NFL, Chembio, and Abbott and is on the GE-NFL Medical Advisory Board. Dr Solomon receives DoD grant/research support; is a consultant for the University of Tennessee Athletics, Tennessee Tech Athletics, Tennessee Titans, and Nashville Predators; and is on the Advisory Board of ImPACT Applications, Inc. He has received speaking honoraria from the American Academy of Neurology, American Medical Society for Sports Medicine, and American Associations of Neurological Surgeons. Dr Zafonte receives grant/ research support from NIH, DoD, National Institute on Disability, Independent Living, and Rehabilitation Research, and NFL Players Association and is a consultant for Harvard football. He has relationships with Oakstone Publishing, Demos Publishing, Oxeia Biopharma, and Myomo Orthotic Devices.; The following authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Dr Kontos receives research funding from the NIH, NCAA, DoD, and GE-NFL. Dr Bailes is chairman for the Pop Warner Football medical advisory board. Dr Bloom is a consultant for the Carolina Hurricanes. Dr Echemendia is a consultant to the NHL, Major League Soccer, the US Soccer Federation, and Princeton University. He is principal investigator or coprincipal investigator on grants funded by National Operating Committee on Standards for Athletic Equipment, American Medical Society for Sports Medicine, and the New Jersey Commission on Brain Injury Research. Dr Guskiewicz is a member of the NCAA Health and Safety Advisory Committee for Concussion, is a member of the NFL Head, Neck and Spine Committee, has given paid expert testimonials for TBI cases, and receives research funding from NIH, NCAA, NFL, USA Hockey, and National Athletic Trainers' Association. Dr Jordan is a paid consultant for NFL Benefits Association for Neurocognitive Disability Benefit. He receives compensation from Innovative CEUs for coaching their education program and is chief medical officer of the New York State Athletic Association. Dr McAllister receives research funding from the NCAA-DoD. Dr Pieroth is a consultant for the Chicago Bears, White Sox, and Blackhawks. Dr Sills is on the Medical Board of the Federation Equestrian Internationale; is an unpaid consultant for the US Equestrian Foundation, Southeastern Conference, and the Nashville Predators; and is an unaffiliated neurotrauma consultant for the NFL. Dr Yates is the team physician for the Pittsburgh Steelers and a member of the NFL Head, Neck and Spine Committee. Drs Cohen, Pombo, Thomas, and Valovich have no funding to disclose. NR 175 TC 1 Z9 1 U1 6 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD DEC PY 2016 VL 79 IS 6 BP 912 EP 929 DI 10.1227/NEU.0000000000001447 PG 18 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA EI6OH UT WOS:000392614700043 PM 27741219 ER PT J AU Babu, MA Heary, RF Nahed, BV AF Babu, Maya A. Heary, Robert F. Nahed, Brian V. TI Does the Open Payments Database Provide Sunshine on Neurosurgery? SO NEUROSURGERY LA English DT Article DE Conflicts of interest; Public policy; Transparency ID OF-INTEREST; ACT; TRANSPARENCY; PHYSICIANS; CONFLICTS AB BACKGROUND: The Open Payments Database (OPD) was launched by the Centers for Medicare & Medicaid Services in 2014. Through this online searchable database, the public can explore physician-industry interactions. To date, there is no published literature on the accuracy of the database for neurosurgeons or any physician specialty. OBJECTIVE: To study the accuracy of published records and scope of industry-neurosurgeon relationships between neurosurgeons and industry within the OPD. METHODS: We searched 4.3 million records in 2013 and 11.41 million records in 2014 in the OPD for board-certified neurosurgeons verified by the American Board of Neurological Surgery. Delimit software was used to condense these data, Microsoft Access for database queries, and STATA to perform descriptive analyses. RESULTS: Of the 3240 neurosurgeons in the OPD in 2013, 2020 were identified correctly as neurosurgeons within the database (62%). Of the 3593 neurosurgeons in the OPD in 2014, 2433 were identified correctly as neurosurgeons (68%). Within the OPD in 2013, there were 72 066 attributed records for neurosurgeons; within the 2014 OPD, there were 160 563 attributed records for neurosurgeons. Total payments to neurosurgeons in 2013 (for the 9 months published in OPD): $61 802 659.37; in 2014: $117 127 824.00. CONCLUSION: The OPD details physician interactions with industry and has multiple inaccuracies. Publicly availing inaccurate information through a searchable governmental website that can be accessed by patients and journalists alike has the potential to tarnish individual neurosurgeons and undermine professional credibility. C1 [Babu, Maya A.] Mayo Clin, Dept Neurol Surg, Rochester, MN USA. [Heary, Robert F.] Rutgers New Jersey Med Sch, Div Neurosurg, Newark, NJ USA. [Nahed, Brian V.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. EM babu.maya@mayo.edu FU DePuy Synthes; Zimmer FX Robert F. Heary, MD, receives royalty payments from DePuy Synthes and Zimmer. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. NR 19 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD DEC PY 2016 VL 79 IS 6 BP 933 EP 938 DI 10.1227/NEU.0000000000001417 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA EI6OH UT WOS:000392614700046 PM 27580479 ER PT J AU Maan, A Jorgensen, NW Mansour, M Dudley, S Jenny, NS Defilippi, C Szklo, M Alonso, A Refaat, MM Ruskin, J Heckbert, SR Heist, EK AF Maan, Abhishek Jorgensen, Neal W. Mansour, Moussa Dudley, Samuel, Jr. Jenny, Nancy S. Defilippi, Christopher Szklo, Moyses Alonso, Alvaro Refaat, Marwan M. Ruskin, Jeremy Heckbert, Susan R. Heist, E. Kevin TI Association between Heat Shock Protein-60 and Development of Atrial Fibrillation: Results from the Multi-Ethnic Study of Atherosclerosis (MESA) SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Article DE atrial fibrillation; heat shock protein; atrial stress response ID HEAT-SHOCK PROTEINS; STRESS-PROTEINS; THERAPY; MYOCARDIUM; INDUCTION; MORTALITY; ISCHEMIA; FIBROSIS; TARGETS; TRENDS AB BackgroundDuring atrial fibrillation (AF), a high rate of myocyte activation causes cellular stress and initiates the process of atrial remodeling, which further promotes persistence of AF. Although heat shock proteins (HSPs) have been shown to prevent atrial remodeling and suppress the occurrence of AF in cellular and animal experimental models, increased levels of HSP-60 have been observed in patients with postoperative AF, likely reflecting a response to cellular stress. To better understand the role of HSP-60 in relation to AF, we examined the association of HSP-60 levels in relation to the future development of AF in the Multi-Ethnic Study of Atherosclerosis (MESA). MethodsMESA is a cohort study that recruited 6,814 participants aged 45-84 years and free of known cardiovascular disease at baseline (2000-2002) from six field centers. We investigated 983 participants, selected at random from the total cohort, who had HSP-60 measured and were free of AF at baseline. We tested the association of HSP-60 levels with the incidence of AF using multivariate Cox models after adjustment for demographics, clinical characteristics, and biomarkers. ResultsDuring an average of 10.6 years of follow-up, 77 participants developed AF. We did not observe a significant association between the log-transformed HSP-60 levels and development of AF on either unadjusted or multivariate analysis (adjusted hazard ratio: 1.02 per unit difference on natural log scale, 95% confidence interval: 0.77-1.34 ln (ng/mL). ConclusionContrary to the findings from the preclinical studies, which demonstrated an important role of HSP-60 in the pathogenesis of AF, we did not observe a significant association between HSP-60 and occurrence of AF. C1 [Maan, Abhishek; Dudley, Samuel, Jr.] Brown Univ, Div Cardiol, Warren Alpert Med Sch, Providence, RI 02912 USA. [Jorgensen, Neal W.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Mansour, Moussa; Ruskin, Jeremy; Heist, E. Kevin] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Mansour, Moussa; Ruskin, Jeremy; Heist, E. Kevin] Massachusetts Gen Hosp, Ctr Heart, Boston, MA 02114 USA. [Jenny, Nancy S.] Univ Vermont, Coll Med, Lab Clin Biochem Res, Burlington, VT USA. [Defilippi, Christopher] Univ Maryland, Div Cardiovasc Med, Baltimore, MD 21201 USA. [Szklo, Moyses] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Szklo, Moyses] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Alonso, Alvaro] Univ Minnesota, Div Epidemiol & Publ Hlth, Minneapolis, MN USA. [Refaat, Marwan M.] Amer Univ Beirut, Med Ctr, Fac Med, Dept Internal Med Cardiol Cardiac Electrophysiol, Beirut, Lebanon. [Refaat, Marwan M.] Amer Univ Beirut, Med Ctr, Fac Med, Dept Biochem & Mol Genet, Beirut, Lebanon. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. EM kheist@mgh.harvard.edu RI Alonso, Alvaro/A-4917-2010 OI Alonso, Alvaro/0000-0002-2225-8323 FU National Heart Lung, and Blood Institute [N01-HC-95159, N01-HC-95166]; American Heart Association [16E1A26410001] FX This research was supported by the contracts N01-HC-95159, N01-HC-95166 from the National Heart Lung, and Blood Institute and by grant from the American Heart Association 16E1A26410001. NR 28 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0147-8389 EI 1540-8159 J9 PACE JI PACE-Pacing Clin. Electrophysiol. PD DEC PY 2016 VL 39 IS 12 BP 1373 EP 1378 DI 10.1111/pace.12969 PG 6 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA EI4XV UT WOS:000392498100015 PM 27807875 ER PT J AU Badour, CL Gros, DF Szafranski, DD Acierno, R AF Badour, Christal L. Gros, Daniel F. Szafranski, Derek D. Acierno, Ron TI Sexual Problems Predict PTSD and Depression Symptom Change Among Male OEF/OIF Veterans Completing Exposure Therapy SO PSYCHIATRY-INTERPERSONAL AND BIOLOGICAL PROCESSES LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; TREATING ERECTILE DYSFUNCTION; MENTAL-HEALTH PROBLEMS; SOCIAL SUPPORT; DOUBLE-BLIND; AFGHANISTAN; IRAQ; PREVALENCE; ASSOCIATION; SILDENAFIL AB Objective: A growing literature documents frequent sexual problems among Operations Enduring/Iraqi Freedom (OEF/OIF) veterans with post-traumatic stress disorder (PTSD). However, there has been no examination of how (1) sexual problems may be affected by evidenced-based psychotherapy for PTSD or (2) how the presence of sexual problems might impact effectiveness of evidenced-based psychotherapy for PTSD. As such, the present study investigated associations among symptoms of PTSD, depression, and problems with sexual desire and arousal among 45 male OEF/OIF veterans receiving behavioral activation and therapeutic exposure (BA-TE), an evidence-based behavior therapy targeting co-occurring symptoms of PTSD and depression. Method: Participants completed clinical interviews and several questionnaires including measures of sexual arousal, sexual desire, PTSD symptoms, and depression symptoms at baseline and after completion of 8 sessions of BA-TE treatment. A records review was also conducted to assess for relevant medication use. Results: Overall, sexual desire and sexual arousal problems did not improve during the course of treatment. Moreover, veterans with co-occurring sexual problems at baseline evidenced significantly less improvement in symptoms of PTSD and depression across treatment as compared to veterans without sexual problems. Conclusions: These findings suggest that veterans with co-occurring symptoms of PTSD and sexual problems may require additional assessment and treatment considerations in order to improve their treatment outcomes for both primary psychiatric symptoms as well as sexual problems. Future research on combination treatments of medication for sexual problems and psychotherapy for PTSD is needed. C1 [Badour, Christal L.] Univ Kentucky, 106B Kastle Hall, Lexington, KY 40506 USA. [Gros, Daniel F.; Szafranski, Derek D.; Acierno, Ron] Med Univ South Carolina, Charleston, SC USA. [Gros, Daniel F.; Szafranski, Derek D.; Acierno, Ron] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Badour, CL (reprint author), Univ Kentucky, 106B Kastle Hall, Lexington, KY 40506 USA. EM Christal.badour@uky.edu FU Department of Defense [W81XWH-07-PTSD-IIRA]; Department of Veteran Affairs Clinical Sciences Research and Development Career Development Award [CX000845]; South Carolina Clinical & Translational Research Institute; Medical University of South Carolina (NIH) [UL1 TR000062]; National Institute of Mental Health [T32 MH018869] FX This publication was supported, in part, by grants from the Department of Defense (W81XWH-07-PTSD-IIRA [PI: Acierno]), Department of Veteran Affairs Clinical Sciences Research and Development Career Development Award (CX000845 [PI: Gros]), and the South Carolina Clinical & Translational Research Institute, with an academic home at the Medical University of South Carolina (NIH Grant Number UL1 TR000062 [PI: Brady]). Dr. Badour is supported by a grant from the National Institute of Mental Health (T32 MH018869). Several authors are also core and affiliate members of the Ralph H. Johnson VA Centers of Innovation (PI: Egede), Charleston Health Equity and Rural Outreach Innovation 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, the National Institutes of Health, or the United States government. There are no conflicts of interest to disclose. NR 44 TC 0 Z9 0 U1 3 U2 3 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0033-2747 EI 1943-281X J9 PSYCHIATRY JI Psychiatry-Interpers. Biol. Process. PD WIN PY 2016 VL 79 IS 4 BP 403 EP 417 DI 10.1080/00332747.2016.1142774 PG 15 WC Psychiatry SC Psychiatry GA EJ2BE UT WOS:000393014100013 PM 27997327 ER PT J AU Mohamed, NE Pisipati, S Lee, CT Goltz, HH Latini, DM Gilbert, FS Wittmann, D Knauer, CJ Mehrazin, R Sfakianos, JP McWilliams, GW Quale, DZ Hall, SJ AF Mohamed, Nihal E. Pisipati, Sailaja Lee, Cheryl T. Goltz, Heather H. Latini, David M. Gilbert, Francis S. Wittmann, Daniela Knauer, Cynthia J. Mehrazin, Reza Sfakianos, John P. McWilliams, Glen W. Quale, Diane Z. Hall, Simon J. TI Unmet informational and supportive care needs of patients following cystectomy for bladder cancer based on age, sex, and treatment choices SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Urothelial carcinoma of the urinary bladder; Muscle-invasive bladder cancer; Cystectomy; Urinary diversion; Unmet need ID RADICAL CYSTECTOMY; URINARY-DIVERSION; CHEMOTHERAPY; CARCINOMA; DISTRESS AB Purpose: Assessing the unmet needs of cancer patients can help providers tailor health care services to patients' specific needs. This study examines whether the unmet informational and supportive care needs of the patients with muscle-invasive bladder cancer vary by the patients' age, sex, or individual treatment choices. Methods and materials: Participants (N = 30 survivors; 73.3% men) were recruited from the Mount Sinai Medical Center and through advertisements posted on a national Bladder Cancer Advocacy Network website between December 2011 and September 2012. Data were collected through individual interviews and electronic medical record review. A prior qualitative study of this cohort, using immersion/crystallization approach, confirmed the prevalence of unmet needs across the disease trajectory. This is a secondary quantitative analysis of the initial interview data we collected (i.e., quantitative analyses of transformed qualitative data using Chi-square and Fisher exact tests) to examine differences in unmet needs based on the patient's age, sex, and treatment choices. Results: Younger patients (<60 y) were less satisfied with the treatment information received presurgery and more likely to report posttreatment complications, choose a neobladder, and seek and receive professional support regarding sexual function, than were older patients (P < 0.05). More women than men reported difficulties with self-care and relied on themselves in disease self-management as opposed to relying on spousal support (P < 0.05). Patients with neobladder were more likely to report difficulties with urinary incontinence and deterioration in sexual function, whereas patients with ileal conduit were more likely to require spousal help with self-care. Patients who received chemotherapy were significantly more likely to report changes in everyday life (P < 0.05). Lastly, regardless of age, sex, or treatment choice, up to 50% of patients reported feeling depressed before or after treatment. Conclusions: Unmet informational and supportive needs of patients with muscle-invasive bladder cancer during survivorship, and vary by age, sex, and treatment choices. Educational and psychological assessments as well as clinical interventions should be tailored to a patient's specific unmet needs, and to specific clinical and demographic characteristics. (C) 2016 Elsevier Inc. All rights reserved. C1 [Mohamed, Nihal E.; Knauer, Cynthia J.; Mehrazin, Reza; Sfakianos, John P.; McWilliams, Glen W.] Icahn Sch Med Mt Sinai, Dept Urol & Oncol Sci, New York, NY 10029 USA. [Lee, Cheryl T.; Wittmann, Daniela] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. [Goltz, Heather H.] Univ Houston Downtown, Social Work Program, Houston, TX USA. [Goltz, Heather H.] Baylor Coll Med, Infect Dis Sect, Houston, TX 77030 USA. [Goltz, Heather H.] Baylor Coll Med, Infect Dis Sect, Houston, TX 77030 USA. [Latini, David M.] Baylor Coll Med, Scott Dept Urol, Houston, TX 77030 USA. [McWilliams, Glen W.] James J Peters Vet Affairs Med Ctr, Dept Urol, Bronx, NY USA. [Quale, Diane Z.] Bladder Canc Advocacy Network, Washington, DC USA. [Hall, Simon J.] Northwell Hlth Syst, Smith Inst Urol, Lake Success, NY USA. EM nihal.mohamed@mountsinai.org FU American Cancer Society [121193-MRSG-11-103-01-CPPB]; National Cancer Institute [1R03CA165768-01A1] FX Supported by mentored research scholar grants from the American Cancer Society (121193-MRSG-11-103-01-CPPB) and the National Cancer Institute (1R03CA165768-01A1). NR 26 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD DEC PY 2016 VL 34 IS 12 DI 10.1016/j.urolonc.2016.06.010 PG 8 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA EI6YL UT WOS:000392643500010 ER PT J AU Berdeja, JG Lin, Y Raje, N Siegel, D Munshi, N Turka, A Lam, LP Quigley, MT Kochenderfer, JN AF Berdeja, J. G. Lin, Y. Raje, N. Siegel, D. Munshi, N. Turka, A. Lam, L. P. Quigley, M. T. Kochenderfer, J. N. TI Clinical remissions and limited toxicity in a first-in-human multicenter study of bb2121, a novel anti-BCMA CAR T cell therapy for relapsed/refractory multiple myeloma SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Berdeja, J. G.] Sarah Cannon Res Inst, Nashville, TN USA. [Berdeja, J. G.] Tennessee Oncol, Nashville, TN USA. [Lin, Y.] Mayo Clin, Rochester, MN USA. [Raje, N.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Siegel, D.] Hackensack Univ, Med Ctr, Hackensack, NJ USA. [Munshi, N.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Turka, A.; Lam, L. P.; Quigley, M. T.] Bluebird Bio Inc, Cambridge, MA USA. [Kochenderfer, J. N.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 14LBA BP S5 EP S5 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500009 ER PT J AU Chen, A Conley, B Hamilton, S Williams, M O'Dwyer, P Arteaga, C Gray, R McShane, L Li, S Rubinstein, L Patton, D Sazali, K Zwiebel, J Mitchell, E Smith, ML Dragaud, D Little, R Comis, R Abrams, J Flaherty, K AF Chen, A. Conley, B. Hamilton, S. Williams, M. O'Dwyer, P. Arteaga, C. Gray, R. McShane, L. Li, S. Rubinstein, L. Patton, D. Sazali, K. Zwiebel, J. Mitchell, E. Smith, M. L. Dragaud, D. Little, R. Comis, R. Abrams, J. Flaherty, K. TI NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) trial: A novel public-private partnership SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Chen, A.] NCI, Early Clin Trials Dev Program, Bethesda, MD 20892 USA. [Conley, B.] NCI, CDP, Bethesda, MD 20892 USA. [Hamilton, S.] MD Anderson, Pathol, Houston, TX USA. [Williams, M.] NCI, Mol Characterizat Lab, Frederick, MD 21701 USA. [O'Dwyer, P.] Univ Penn, Med, Philadelphia, PA 19104 USA. [Arteaga, C.] NCI, Med Hem Onc, Nashville, TN USA. [Gray, R.] Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02115 USA. [McShane, L.; Rubinstein, L.; Zwiebel, J.; Little, R.; Abrams, J.] NCI, CTEP, Rockville, MD USA. [Li, S.] Dana Farber, Hematol Oncol, Boston, MA USA. [Patton, D.] NCI, CBIIT, Rockville, MD USA. [Sazali, K.; Dragaud, D.; Comis, R.] ECOG ACRIN, Canc Res Grp, Philadelphia, PA USA. [Mitchell, E.] Thomas Jefferson Univ, Med Oncol, Philadelphia, PA USA. [Smith, M. L.] ECOG ACRIN, Cacner Advocacy Comm, Philadelphia, PA USA. [Flaherty, K.] Mass Gen Hosp, Ctr Canc, Boston, MA USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 418 BP S137 EP S137 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500401 ER PT J AU Erb, M Winter, G Dastjerdi, S Scott, T Sanjana, N Shalem, O Buckley, D Zhang, F Bradner, J AF Erb, M. Winter, G. Dastjerdi, S. Scott, T. Sanjana, N. Shalem, O. Buckley, D. Zhang, F. Bradner, J. TI Transcription control by,the ENL YEATS domain in acute leukemia SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Erb, M.; Dastjerdi, S.; Scott, T.; Buckley, D.] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. [Winter, G.] Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria. [Sanjana, N.] NYU, Dept Biol, New York, NY 10003 USA. [Shalem, O.; Zhang, F.] MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Shalem, O.; Zhang, F.] Harvard Univ, Cambridge, MA 02138 USA. [Bradner, J.] Novartis Inst Biomed Res, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 255 BP S85 EP S86 PG 2 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500245 ER PT J AU Heinrich, M Jones, R Schoffski, P Bauer, S von Mehren, M Eskens, F Cassier, P Mir, O Shi, H Alvarez-Diez, T Healy, ME Wolf, B George, S AF Heinrich, M. Jones, R. Schoffski, P. Bauer, S. von Mehren, M. Eskens, F. Cassier, P. Mir, O. Shi, H. Alvarez-Diez, T. Healy, M. E. Wolf, B. George, S. TI Preliminary safety and activity in a first-in-human phase 1 study of BLU-285, a potent, highly-selective inhibitor of KIT and PDGFR alpha activation loop mutants in advanced gastrointestinal stromal tumor (GIST) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Heinrich, M.] OHSU, Knight Canc Inst, Hematol & Med Oncol, Portland, OR USA. [Jones, R.] Royal Marsden Hosp, Inst Canc Res, London, England. [Schoffski, P.] Univ Hosp Leuven, Leuven Canc Inst, Dept Gen Med Oncol, Leuven, Belgium. [Bauer, S.] Univ Essen Gesamthsch, Med Oncol, Essen, Germany. [von Mehren, M.] Fox Chase Canc Ctr, Hematol & Med Oncol, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Eskens, F.] Erasmus MC Canc Inst, Med Oncol, Rotterdam, Netherlands. [Cassier, P.] Ctr Leon Berard, Med Oncol, Lyon, France. [Mir, O.] Inst Gustave Roussy, Canc Med & Early Drug Dev, Paris, France. [Shi, H.; Alvarez-Diez, T.; Healy, M. E.; Wolf, B.] Blueprint Med, Clin Dev, Cambridge, MA USA. [George, S.] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 6LBA BP S4 EP S4 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500007 ER PT J AU Isakoff, S Bahleda, R Saleh, M Bordoni, R Shields, A Dauer, J Curley, M Baum, J McClure, T Louis, CU Soria, JC AF Isakoff, S. Bahleda, R. Saleh, M. Bordoni, R. Shields, A. Dauer, J. Curley, M. Baum, J. McClure, T. Louis, C. U. Soria, J. C. TI A phase 1 study of MM-141, a novel tetravalent monoclonal antibody targeting IGF-1R and ErbB3, in relapsed or refractory solid tumors SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Isakoff, S.] Massachusetts Gen Hosp, Ctr Canc, Hematol Oncol, Boston, MA USA. [Bahleda, R.] Inst Gustave Roussy, Early Drug Dev DITEP, Villejuif, France. [Saleh, M.] Univ Alabama Birmingham, Ctr Comprehens Canc, UAB Phase Program 1, Birmingham, AL 35294 USA. [Bordoni, R.] Georgia Canc Specialists, Atlanta, GA USA. [Bordoni, R.] Northside Hosp Canc Inst, Hematol, Atlanta, GA USA. [Shields, A.] Karmanos Canc Inst, Oncol, Detroit, MI USA. [Dauer, J.; Curley, M.; McClure, T.; Louis, C. U.] Merrimack Pharmaceut, Discovery, Cambridge, MA USA. [Baum, J.] Merrimack Pharmaceut, Dev, Cambridge, MA USA. [Soria, J. C.] Inst Gustave Roussy, Drug Dev, Villejuif, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 420 BP S137 EP S138 PG 2 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500403 ER PT J AU Janku, F George, S Razak, A Gordon, M Brooks, D Flynn, DG Kaufman, M Pitman, J Smith, B Somaiah, N Gerstenberger, E Westwood, D Rosen, O AF Janku, F. George, S. Razak, A. Gordon, M. Brooks, D. Flynn, D. G. Kaufman, M. Pitman, J. Smith, B. Somaiah, N. Gerstenberger, E. Westwood, D. Rosen, O. TI DCC-2618, a pan KIT and PDGFR switch control inhibitor, achieves proof-of-concept in a first-in-human study SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Janku, F.] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX 77030 USA. [George, S.] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02215 USA. [Razak, A.] Princess Margaret Canc Ctr, Canc Clin Res Unit, Toronto, ON, Canada. [Gordon, M.] Pinnacle Oncol Hematol, Phase Unit 1, Scottsdale, AZ USA. [Brooks, D.; Pitman, J.; Westwood, D.; Rosen, O.] Deciphera Pharmaceut, Clin Res & Dev, Waltham, MA USA. [Flynn, D. G.; Kaufman, M.; Smith, B.] Deciphera Pharmaceut, Res, Lawrence, KS USA. [Somaiah, N.] Univ Texas MD Anderson Canc Ctr, Dept Sarcoma Med Oncol, Houston, TX 77030 USA. [Gerstenberger, E.] Veristat, Biostat, Southborough, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 7LBA BP S4 EP S4 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500008 ER PT J AU Janouskova, H El Tekle, G Udeshi, N Ulbricht, A Rinaldi, A Civenni, G Catapano, C Peter, M Carr, S Garraway, L Theurillat, JP AF Janouskova, H. El Tekle, G. Udeshi, N. Ulbricht, A. Rinaldi, A. Civenni, G. Catapano, C. Peter, M. Carr, S. Garraway, L. Theurillat, J. P. TI Opposing therapeutic efficacy of BET inhibitors is determined by cancer type-specific SPOP mutants SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Janouskova, H.; El Tekle, G.; Rinaldi, A.; Civenni, G.; Catapano, C.; Theurillat, J. P.] Southern Switzerland, IOR, Dept Oncol, Bellinzona, Switzerland. [Udeshi, N.; Carr, S.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Ulbricht, A.; Peter, M.] Eidgenoss Tech Hsch ETH Zurich, Inst Biochem, Zurich, Switzerland. [Garraway, L.] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 2LBA BP S2 EP S2 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500003 ER PT J AU Juric, D Lopez, J Rasco, D Mercade, TM Xu, Q Brittany, B Kuida, K Patel, C Neuwirth, R Enke, A Zohren, F Burris, HA AF Juric, D. Lopez, J. Rasco, D. Mercade, T. Macarulla Xu, Q. Brittany, B. Kuida, K. Patel, C. Neuwirth, R. Enke, A. Zohren, F. Burris, H. A., III TI A phase 1b multicenter, open-label study of investigational TAK-228 (MLN0128) plus TAK-117 (MLN1117) in adult patients with advanced nonhematologic malignancies SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Juric, D.] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. [Lopez, J.] Royal Marsden Hosp, Inst Canc Res, Drug Dev Unit, Sutton, Surrey, England. [Rasco, D.] START, Oncol, San Antonio, TX USA. [Mercade, T. Macarulla] Vall dHebron Univ Hosp, Dept Med Oncol, Barcelona, Spain. [Xu, Q.; Brittany, B.; Kuida, K.] Millennium Pharmaceut Inc, Translat Med, Cambridge, MA USA. [Patel, C.] Millennium Pharmaceut Inc, Clin Pharmacol, Cambridge, MA USA. [Neuwirth, R.] Millennium Pharmaceut Inc, Global Stat, Cambridge, MA USA. [Enke, A.] Millennium Pharmaceut Inc, Oncol Clin Res, Cambridge, MA USA. [Zohren, F.] Millennium Pharmaceut Inc, Early Clin Res & Dev, Oncol Therapeut Area Unit, Cambridge, MA USA. [Burris, H. A., III] Tennessee Oncol, Sarah Cannon Res Inst, Drug Dev Unit, Nashville, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 19 BP S11 EP S12 PG 2 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500020 ER PT J AU Langenberg, MH Gluck, L Weger, V Frank, R Eskens, F Blay, JY Soria, JC Chawla, S Gounder, M Wagner, A Zhang, Y Kambuj, P Loberg, R Henary, H AF Langenberg, M. H. Gluck, L. Weger, V. Frank, R. Eskens, F. Blay, J. Y. Soria, J. C. Chawla, S. Gounder, M. Wagner, A. Zhang, Y. Kambuj, P. Loberg, R. Henary, H. TI A phase I study of the MDM2 inhibitor AMG 232 in patients with advanced p53 wild type (p53WT) solid tumors or multiple myeloma SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Langenberg, M. H.] UMC Utrecht Canc Ctr, Netherlands Dept Med Oncol, Utrecht, Netherlands. [Gluck, L.] ITOR, Greenville, SC USA. [Weger, V.] Netherlands Canc Inst, Dept Clin Pharmacol, Div Med Oncol, Amsterdam, Netherlands. [Frank, R.] Whittingham Canc Ctr, Dept Med Oncol & Haematol, Norwal, CT USA. [Eskens, F.] Erasmus MC Canc Inst, Dpt Med Oncol, Rotterdam, Netherlands. [Blay, J. Y.] Ctr Leon Berard, Dept Med Oncol, Lyon, France. [Soria, J. C.] Inst Gustave Roussy, DITEP, Paris, France. [Chawla, S.] Canc Ctr Southern Calif, Sarcoma Oncol Ctr, Santa Monica, CA USA. [Gounder, M.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Wagner, A.] Harvard Med Sch, Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Dept Med, Boston, MA USA. [Zhang, Y.] Amgen Inc, Clin Pharmacol, Thousand Oaks, CA 91320 USA. [Kambuj, P.] Amgen Inc, Global Safety, Thousand Oaks, CA 91320 USA. [Loberg, R.] Amgen Inc, Clin Biomarkers, Thousand Oaks, CA 91320 USA. [Henary, H.] Amgen Inc, Oncol Early Dev, Thousand Oaks, CA 91320 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 82 BP S34 EP S34 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500077 ER PT J AU Lillian, S De Bono, J Higano, C Shapiro, G Brugger, W Mitchell, P Colebrook, S Klinowska, T Barry, S Dean, E Martin-Mills, J Wisinski, K Moorthy, G Mills, J Cruzalegui, F Tolaney, S Lang, J Luken, MJD Kunar, R Chatta, G AF Lillian, S. De Bono, J. Higano, C. Shapiro, G. Brugger, W. Mitchell, P. Colebrook, S. Klinowska, T. Barry, S. Dean, E. Martin-Mills, J. Wisinski, K. Moorthy, G. Mills, J. Cruzalegui, F. Tolaney, S. Lang, J. Luken, M. Jose De Miguel Kunar, R. Chatta, G. TI AZD8186 study 1: Phase I study to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumour activity of AZD8186 in patients with advanced castration resistant prostate cancer (CRPC), squamous non-small cell lung cancer, triple negative breast cancer and with PTEN-deficient/mutated or PIK3CB mutated/amplified malignancies, as monotherapy and in combination with vistusertib (AZD2014) or abiraterone acetate SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Lillian, S.] Princess Margaret Hosp, Oncol, Toronto, ON, Canada. [De Bono, J.; Luken, M. Jose De Miguel; Kunar, R.] Royal Marsden Hosp, Oncol, Sutton, Surrey, England. [Higano, C.; Chatta, G.] Univ Washington, Oncol, Seattle, WA 98195 USA. [Shapiro, G.] Dana Faber Canc Inst, Oncol, Boston, MA USA. [Brugger, W.; Colebrook, S.; Barry, S.] AstraZeneca, Oncol, Cambridge, England. [Mitchell, P.; Moorthy, G.] AstraZeneca, Oncol, Waltham, MA USA. [Klinowska, T.; Mills, J.; Cruzalegui, F.] AstraZeneca, Oncol, Alderley Pk, England. [Dean, E.] Christie NHS Fdn Trust, Onocol, Manchester, Lancs, England. [Martin-Mills, J.] Vall dHebron Inst Concol, Oncol, Barcelona, Spain. [Wisinski, K.; Lang, J.] Univ Wisconsin, Oncol, Madison, WI 53706 USA. [Tolaney, S.] Dana Farber Canc Inst, Oncol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 37 BP S19 EP S19 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500032 ER PT J AU Luo, F Cowley, G Garraway, L AF Luo, F. Cowley, G. Garraway, L. TI Molecular determinants of resistance to CDK4/6 inhibition in ER plus breast cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Luo, F.; Garraway, L.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Luo, F.; Garraway, L.] Broad Inst, Med Oncol, Boston, MA USA. [Cowley, G.] Janssen Pharmaceut Co, Johnson & Johnson, Funct Genom, Discovery Sci, Perkasie, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 224 BP S76 EP S76 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500214 ER PT J AU Meric-Bernstam, F Tannir, N Harding, J Voss, M Mier, J DeMichele, A Munster, P Patel, M Iliopoulos, O Owonikoko, T Whiting, S Orford, K Bennett, M Carvajal, R McKay, R Fan, A Telli, M Infante, J AF Meric-Bernstam, F. Tannir, N. Harding, J. Voss, M. Mier, J. DeMichele, A. Munster, P. Patel, M. Iliopoulos, O. Owonikoko, T. Whiting, S. Orford, K. Bennett, M. Carvajal, R. McKay, R. Fan, A. Telli, M. Infante, J. TI Phase 1 study of CB-839, a small molecule inhibitor of glutaminase, in combination with everolimus in patients (pts) with clear cell and papillary renal cell cancer (RCC) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Meric-Bernstam, F.] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX 77030 USA. [Tannir, N.] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA. [Harding, J.; Voss, M.] Mem Sloan Kettering Canc Ctr, Med Oncol, 1275 York Ave, New York, NY 10021 USA. [Mier, J.] Dana Farber Harvard Canc Ctr, Boston, MA USA. [DeMichele, A.] Univ Penn, Perelman Sch Med, Div Hematol & Oncol, Philadelphia, PA 19104 USA. [Munster, P.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Dept Med Hematol Oncol, San Francisco, CA 94143 USA. [Patel, M.] Florida Canc Specialist & Res Inst, Hematol Oncol, Sarasota, FL USA. [Iliopoulos, O.] Massachusetts Gen Hosp, Dana Farber Harvard Canc Ctr, Boston, MA 02114 USA. [Owonikoko, T.] Emory Univ, Sch Med, Dept Hematol & Med Oncol, Atlanta, GA USA. [Whiting, S.; Orford, K.] Calithera Biosci Clin Dev, San Francisco, CA USA. [Bennett, M.] Calithera Biosci, Res, San Francisco, CA USA. [Carvajal, R.] Columbia Univ, Med Ctr, Div Hematol Oncol, New York, NY USA. [McKay, R.] Dana Farber Canc Inst, Dept Breast Oncol, Boston, MA 02115 USA. [Fan, A.; Telli, M.] Stanford Univ, Med Ctr, Med Oncol, Stanford, CA 94305 USA. [Infante, J.] Tennessee Oncol, Oncol, Nashville, TN USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 26 BP S12 EP S13 PG 2 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500021 ER PT J AU Moran, D Okada, Y Kernstock, R Spira, A Horn, L Weiss, J West, H Giaccone, G Evans, T Kelly, R Sakagami, H Desai, B Poondru, S Keating, A Oxnard, GR AF Moran, D. Okada, Y. Kernstock, R. Spira, A. Horn, L. Weiss, J. West, H. Giaccone, G. Evans, T. Kelly, R. Sakagami, H. Desai, B. Poondru, S. Keating, A. Oxnard, G. R. TI Serial plasma genotyping of patients with EGFR-mutant lung cancer treated with ASP8273 demonstrates acquired resistance mediated by EGFR C797S SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Moran, D.; Poondru, S.] Astellas Pharma US Inc, Clin Pharmacol & Exploratory Dev, Northbrook, IL USA. [Okada, Y.] Astellas Pharma, Drug Discovery Res, Chuo Ku, Tokyo, Japan. [Kernstock, R.] Astellas Pharma, Global Dev, Northbrook, IL USA. [Spira, A.] Virginia Canc Specialists, Oncol Hematol, Fairfax, VA USA. [Horn, L.] Vanderbilt Ingram Canc Ctr, Med, Nashville, TN USA. [Weiss, J.] UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [West, H.] Swedish Canc Inst, Thorac Oncol, Seattle, WA USA. [Giaccone, G.] Georgetown Univ, Med Ctr, Med Oncol, Washington, DC 20007 USA. [Evans, T.] Abramson Canc Ctr, Med, Philadelphia, PA USA. [Kelly, R.] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Oncol, Bethesda, MD USA. [Sakagami, H.] Astellas Pharma, Drug Discovery Res, Tokyo, Japan. [Desai, B.; Keating, A.] Astellas Pharma US Inc, Astellas Pharma Global Dev, Northbrook, IL USA. [Oxnard, G. R.] Dana Farber Canc Inst, Thorac Oncol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 60 BP S27 EP S27 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500055 ER PT J AU O'Connor, MJ Odedra, R Palakurthi, S Hughes, A Lai, Z Kirschmeier, P Zeng, Q Zhou, S Dharma, S Ivanova, E Wang, A Pierce, AJ Yates, J Powell, S Dougherty, B Barrett, JC English, J Jewsbury, P Matulonis, UA Liu, JF AF O'Connor, M. J. Odedra, R. Palakurthi, S. Hughes, A. Lai, Z. Kirschmeier, P. Zeng, Q. Zhou, S. Dharma, S. Ivanova, E. Wang, A. Pierce, A. J. Yates, J. Powell, S. Dougherty, B. Barrett, J. C. English, J. Jewsbury, P. Matulonis, U. A. Liu, J. F. TI Antitumor activity of the WEE1 inhibitor AZD1775 as a monotherapy and in combination with the PARP inhibitor olaparib in patient-derived explant (PDX) models SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [O'Connor, M. J.; Hughes, A.; Wang, A.; Pierce, A. J.; Yates, J.; Powell, S.] AstraZeneca, Innovat Med & Early Dev, Cambridge, England. [Odedra, R.; Jewsbury, P.] AstraZeneca, Innovat Med & Early Dev, Macclesfield, Cheshire, England. [Palakurthi, S.; Zeng, Q.; Zhou, S.; Dharma, S.; Ivanova, E.] Belfer Ctr Appl Canc Sci, Boston, MA USA. [Palakurthi, S.; Zeng, Q.; Zhou, S.; Dharma, S.; Ivanova, E.] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. [Lai, Z.; Dougherty, B.; Barrett, J. C.] AstraZeneca, Innovat Med & Early Dev, Waltham, MA USA. [Kirschmeier, P.; English, J.] Belfer Ctr Appl Canc Sci, Boston, MA USA. [Kirschmeier, P.] Dana Farber Canc Inst, Canc Therapeut, Boston, MA 02115 USA. [English, J.] Dana Farber Canc Inst, Discovery Res, Boston, MA 02115 USA. [Matulonis, U. A.; Liu, J. F.] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 436 BP S142 EP S142 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500418 ER PT J AU Parikh, A Kwak, E Goyal, L Blaszkowsky, L Hazar-Rethinam, M Siravegna, G Russo, M Van Seventer, E Nadres, B Shahzade, H Clark, J Allen, J Iafrate, AJ Bardellli, A Ryan, D Murphy, J Zhu, A Hong, T Corcoran, R AF Parikh, A. Kwak, E. Goyal, L. Blaszkowsky, L. Hazar-Rethinam, M. Siravegna, G. Russo, M. Van Seventer, E. Nadres, B. Shahzade, H. Clark, J. Allen, J. Iafrate, A. J. Bardellli, A. Ryan, D. Murphy, J. Zhu, A. Hong, T. Corcoran, R. TI A systematic liquid biopsy program identifies novel and heterogeneous mechanisms of acquired resistance in gastrointestinal (GI) cancer patients SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Parikh, A.; Kwak, E.; Goyal, L.; Blaszkowsky, L.; Hazar-Rethinam, M.; Van Seventer, E.; Nadres, B.; Shahzade, H.; Clark, J.; Allen, J.; Iafrate, A. J.; Ryan, D.; Murphy, J.; Zhu, A.; Hong, T.; Corcoran, R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Siravegna, G.; Russo, M.; Bardellli, A.] Univ Turin, Candiolo Canc Ctr, Turin, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 4LBA BP S3 EP S3 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500005 ER PT J AU Roberts, P He, S Schvartsman, G Patil, T Sorrentio, J Bisi, J Hoyer, R Schuster, S Strum, J Heymach, J Ferrarotto, R Sharpless, N Shapiro, G Malik, R AF Roberts, P. He, S. Schvartsman, G. Patil, T. Sorrentio, J. Bisi, J. Hoyer, R. Schuster, S. Strum, J. Heymach, J. Ferrarotto, R. Sharpless, N. Shapiro, G. Malik, R. TI G1T28, a CDK4/6 inhibitor, preserves T lymphocyte function from damage by cytotoxic chemotherapy SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Roberts, P.; Sorrentio, J.; Bisi, J.; Strum, J.; Malik, R.] G1 Therapeut Inc, Res & Dev, Res Triangle Pk, NC USA. [He, S.; Sharpless, N.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Schvartsman, G.; Heymach, J.; Ferrarotto, R.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Patil, T.] Univ Colorado, Sch Med, Aurora, CO USA. [Hoyer, R.] Univ Colorado Hlth, Mem Hosp, Colorado Springs, CO USA. [Schuster, S.] Univ Colorado Hlth, Ft Collins, CO USA. [Shapiro, G.] Harvard Univ, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 439 BP S143 EP S144 PG 2 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500421 ER PT J AU Shapiro, G Bedard, R Infante, J Bauer, T Prawira, A Laksin, O Weetall, M Baird, J Branstrom, A O'Mara, E Spiegel, R AF Shapiro, G. Bedard, R. Infante, J. Bauer, T. Prawira, A. Laksin, O. Weetall, M. Baird, J. Branstrom, A. O'Mara, E. Spiegel, R. TI Phase 1 results of PTC596, a novel small molecule targeting cancer stem cells (CSCs) by reducing levels of BMI1 protein SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Shapiro, G.] Dana Farber Canc Inst, Early Drug Dev Ctr, Boston, MA 02115 USA. [Bedard, R.; Prawira, A.] Princess Margaret Canc Ctr, Div Med Oncol, Toronto, ON, Canada. [Infante, J.; Bauer, T.] Sarah Cannon Res Inst, Drug Dev Program, Nashville, TN USA. [Laksin, O.; Baird, J.; O'Mara, E.; Spiegel, R.] PTC Therapeut, Clin, South Plainfield, NJ USA. [Weetall, M.; Branstrom, A.] PTC Therapeut, Res, South Plainfield, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 452 BP S148 EP S148 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500434 ER PT J AU Stinson, S He, J Hollenback, D Jia, J Kaplan, J Venkataramani, C Babusis, D Guevara, F Nelson, T Cavanaugh, J Asahina, H Ray, A Sicinska, E Fuchs, C Barbie, D Wong, KK Ng, K Dornan, D AF Stinson, S. He, J. Hollenback, D. Jia, J. Kaplan, J. Venkataramani, C. Babusis, D. Guevara, F. Nelson, T. Cavanaugh, J. Asahina, H. Ray, A. Sicinska, E. Fuchs, C. Barbie, D. Wong, K. K. Ng, K. Dornan, D. TI Anti-tumor activity of a TBK1/IKBKE inhibitor in combination with a MEK inhibitor in KRAS mutant colorectal and non-small cell lung cancer models SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Stinson, S.; He, J.; Hollenback, D.; Jia, J.; Kaplan, J.; Venkataramani, C.; Babusis, D.; Ray, A.; Dornan, D.] Gilead Sci Inc, Res, 353 Lakeside Dr, Foster City, CA 94404 USA. [Guevara, F.; Nelson, T.; Cavanaugh, J.; Asahina, H.; Sicinska, E.; Fuchs, C.; Barbie, D.; Wong, K. K.; Ng, K.] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 446 BP S146 EP S146 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500428 ER PT J AU Winter, G Buckley, D Mayer, A Roderick, J Kelliher, M Churchman, S Bradner, J AF Winter, G. Buckley, D. Mayer, A. Roderick, J. Kelliher, M. Churchman, S. Bradner, J. TI Global disruption of productive transcriptional elongation via targeted BET protein degradation SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Winter, G.] Res Ctr Mol Med, Chem Biol Oncogen Gene Regulat, CeMM, Vienna, Austria. [Buckley, D.] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. [Mayer, A.; Churchman, S.] Harvard Med Sch, Genet, Boston, MA USA. [Roderick, J.; Kelliher, M.] UMASS Med Sch, Worcester, MA USA. [Bradner, J.] NIBR Novartis Inst Biomed Res, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 271 BP S90 EP S90 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500261 ER PT J AU Yang, W Lightfoot, H Bignell, G Behan, F Cokelear, T Haber, D Engelman, J Stratton, M Benes, C McDermott, U Garnett, M AF Yang, W. Lightfoot, H. Bignell, G. Behan, F. Cokelear, T. Haber, D. Engelman, J. Stratton, M. Benes, C. McDermott, U. Garnett, M. TI Genomics of Drug Sensitivity in Cancer (GDSC): A resource for biomarker discovery in cancer cells SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Yang, W.; Lightfoot, H.; Bignell, G.; Behan, F.; Cokelear, T.; Stratton, M.; McDermott, U.; Garnett, M.] Wellcome Trust Sanger Inst, Canc Genome Project, Cambridge, England. [Haber, D.; Engelman, J.; Benes, C.] Harvard Med Sch, Ctr Canc, Massachusetts Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 244 BP S82 EP S82 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500234 ER PT J AU Rajabi, H Tagde, A Kufe, D AF Rajabi, Hasan Tagde, Ashujit Kufe, Donald TI MUC1-C drives DNA methylation in cancer SO AGING-US LA English DT Editorial Material DE MUC1-C; DNMT; DNA methylation; tumor suppressor genes; EMT ID ONCOPROTEIN; CELLS; DNMT1 C1 [Kufe, Donald] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Kufe, D (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02215 USA. EM donald_kufe@dfci.harvard.edu NR 7 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1945-4589 J9 AGING-US JI Aging-US PD DEC PY 2016 VL 8 IS 12 BP 3155 EP 3156 DI 10.18632/aging.101153 PG 2 WC Cell Biology SC Cell Biology GA EI5IP UT WOS:000392527800003 PM 28039441 ER PT J AU Des Roches, CA Vallila-Rohter, S Villard, S Tripodis, Y Caplan, D Kiran, S AF Des Roches, Carrie A. Vallila-Rohter, Sofia Villard, Sarah Tripodis, Yorghos Caplan, David Kiran, Swathi TI Evaluating Treatment and Generalization Patterns of Two Theoretically Motivated Sentence Comprehension Therapies SO AMERICAN JOURNAL OF SPEECH-LANGUAGE PATHOLOGY LA English DT Article ID AGRAMMATIC APHASIA; SYNTACTIC COMPLEXITY; PROCESSING DEFICITS; SEMANTIC COMPLEXITY; MOVEMENT STRUCTURES; MAPPING THERAPY; NAMING DEFICITS; LANGUAGE; REPLICATION; TYPICALITY AB Purpose: The current study examined treatment outcomes and generalization patterns following 2 sentence comprehension therapies: object manipulation (OM) and sentence-to-picture matching (SPM). Findings were interpreted within the framework of specific deficit and resource reduction accounts, which were extended in order to examine the nature of generalization following treatment of sentence comprehension deficits in aphasia. Method: Forty-eight individuals with aphasia were enrolled in 1 of 8 potential treatment assignments that varied by task (OM, SPM), complexity of trained sentences (complex, simple), and syntactic movement (noun phrase, wh-movement). Comprehension of trained and untrained sentences was probed before and after treatment using stimuli that differed from the treatment stimuli. Results: Linear mixed-model analyses demonstrated that, although both OM and SPM treatments were effective, OM resulted in greater improvement than SPM. Analyses of covariance revealed main effects of complexity in generalization; generalization from complex to simple linguistically related sentences was observed both across task and across movement. Conclusions: Results are consistent with the complexity account of treatment efficacy, as generalization effects were consistently observed from complex to simpler structures. Furthermore, results provide support for resource reduction accounts that suggest that generalization can extend across linguistic boundaries, such as across movement type. C1 [Des Roches, Carrie A.; Vallila-Rohter, Sofia; Villard, Sarah; Caplan, David; Kiran, Swathi] Boston Univ, Sargent Coll, Speech & Hearing Sci, Boston, MA 02215 USA. [Vallila-Rohter, Sofia] MGH Inst Hlth Profess, Dept Commun Sci & Disorders, Boston, MA USA. [Tripodis, Yorghos] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Caplan, David] Massachusetts Gen Hosp, Neuropsychol Lab, Boston, MA 02114 USA. RP Kiran, S (reprint author), Boston Univ, Sargent Coll, Speech & Hearing Sci, Boston, MA 02215 USA. EM kirans@bu.edu FU National Institute on Deafness and Other Communication Disorders Grant [4R33DC010461] FX This research was supported by National Institute on Deafness and Other Communication Disorders Grant 4R33DC010461. The authors thank the participants and their families and caregivers. They also thank Gloria Waters and Myrna Schwartz for their contributions and Chaleece Sandberg, Elsa Ascenso, Jason Lucas, Nadia Lonsdale, and Balaji Rangarathnam for their assistance in data collection. In addition, the authors thank Lauren Eiges, Melody Lo, Nicole Woody, Rasika Murali, Sophie Barry, and Zach Smith for their assistance at various stages of the project. NR 55 TC 0 Z9 0 U1 0 U2 0 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 2200 RESEARCH BLVD, #271, ROCKVILLE, MD 20850-3289 USA SN 1058-0360 EI 1558-9110 J9 AM J SPEECH-LANG PAT JI Am. J. Speech-Lang. Pathol. PD DEC PY 2016 VL 25 IS 4 SU S BP S743 EP S757 DI 10.1044/2016_AJSLP-15-0134 PG 15 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA EI1WC UT WOS:000392276100006 PM 27997950 ER PT J AU Hayes, RA Dickey, MW Warren, T AF Hayes, Rebecca A. Dickey, Michael Walsh Warren, Tessa TI Looking for a Location: Dissociated Effects of Event-Related Plausibility and Verb-Argument Information on Predictive Processing in Aphasia SO AMERICAN JOURNAL OF SPEECH-LANGUAGE PATHOLOGY LA English DT Article ID ADULT AGE-DIFFERENCES; LANGUAGE COMPREHENSION; SENTENCE COMPREHENSION; EYE-MOVEMENTS; KNOWLEDGE ACTIVATION; SYNTACTIC AMBIGUITY; CONTEXT; TIME; INTEGRATION; BIAS AB Purpose: This study examined the influence of verb-argument information and event-related plausibility on prediction of upcoming event locations in people with aphasia, as well as older and younger, neurotypical adults. It investigated how these types of information interact during anticipatory processing and how the ability to take advantage of the different types of information is affected by aphasia. Method: This study used a modified visual-world task to examine eye movements and offline photo selection. Twelve adults with aphasia (aged 54-82 years) as well as 44 young adults (aged 18-31 years) and 18 older adults (aged 50-71 years) participated. Results: Neurotypical adults used verb argument status and plausibility information to guide both eye gaze (a measure of anticipatory processing) and image selection (a measure of ultimate interpretation). Argument status did not affect the behavior of people with aphasia in either measure. There was only limited evidence of interaction between these 2 factors in eye gaze data. Conclusions: Both event-related plausibility and verb-based argument status contributed to anticipatory processing of upcoming event locations among younger and older neurotypical adults. However, event-related likelihood had a much larger role in the performance of people with aphasia than did verb-based knowledge regarding argument structure. C1 [Hayes, Rebecca A.; Dickey, Michael Walsh; Warren, Tessa] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Dickey, Michael Walsh] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Hayes, RA (reprint author), Univ Pittsburgh, Pittsburgh, PA 15260 USA. EM rahayes89@gmail.com FU National Institutes of Health [R01DC011520, UL1TR000005] FX This research was supported by the National Institutes of Health Grant R01DC011520 (awarded to Rebecca A. Hayes and Michael Walsh Dickey) and Grant UL1TR000005 (awarded to the Clinical and Translational Science Institute of the University of Pittsburgh, PA. This research was the result of work supported with resources and the use of facilities at the VA Pittsburgh Healthcare System, PA. NR 84 TC 0 Z9 0 U1 3 U2 3 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 2200 RESEARCH BLVD, #271, ROCKVILLE, MD 20850-3289 USA SN 1058-0360 EI 1558-9110 J9 AM J SPEECH-LANG PAT JI Am. J. Speech-Lang. Pathol. PD DEC PY 2016 VL 25 IS 4 SU S BP S758 EP S775 DI 10.1044/2016_AJSLP-15-0145 PG 18 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA EI1WC UT WOS:000392276100007 PM 27997951 ER PT J AU Partovi, S Ganguli, S AF Partovi, Sasan Ganguli, Suvranu TI Advanced venous imaging and image-guided venous interventions Preface SO CARDIOVASCULAR DIAGNOSIS AND THERAPY LA English DT Editorial Material C1 [Partovi, Sasan] Case Western Reserve Univ, Univ Hosp Cleveland, Med Ctr, Cleveland, OH 44106 USA. [Ganguli, Suvranu] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. RP Partovi, S (reprint author), Case Western Reserve Univ, Univ Hosp Cleveland, Med Ctr, Cleveland, OH 44106 USA. EM sxp509@case.edu; sganguli@mgh.harvard.edu NR 18 TC 0 Z9 0 U1 0 U2 0 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2223-3652 EI 2223-3660 J9 CARDIOVASC DIAGN THE JI Cardiovisc. Diagn. Ther. PD DEC PY 2016 VL 6 IS 6 BP 470 EP 472 DI 10.21037/cdt.2016.12.07 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI5QH UT WOS:000392548900001 PM 28123968 ER PT J AU Karande, GY Hedgire, SS Sanchez, Y Baliyan, V Mishra, V Ganguli, S Prabhakar, AM AF Karande, Gita Yashwantrao Hedgire, Sandeep S. Sanchez, Yadiel Baliyan, Vinit Mishra, Vishala Ganguli, Suvranu Prabhakar, Anand M. TI Advanced imaging in acute and chronic deep vein thrombosis SO CARDIOVASCULAR DIAGNOSIS AND THERAPY LA English DT Review DE Deep vein thrombosis (DVT); acute DVT; chronic DVT; computed tomography venography (CTV); magnetic resonance venography (MR venography) ID SUSPECTED PULMONARY-EMBOLISM; ENHANCED MR VENOGRAPHY; COMBINED CT VENOGRAPHY; LOWER-EXTREMITY VEINS; VENOUS THROMBOSIS; DOPPLER ULTRASONOGRAPHY; DIAGNOSTIC MANAGEMENT; COMPUTED-TOMOGRAPHY; CONTRAST VENOGRAPHY; F-18-FDG PET AB Deep venous thrombosis (DVT) affecting the extremities is a common clinical problem. Prompt imaging aids in rapid diagnosis and adequate treatment. While ultrasound (US) remains the workhorse of detection of extremity venous thrombosis, CT and MRI are commonly used as the problem-solving tools either to visualize the thrombosis in central veins like superior or inferior vena cava (IVC) or to test for the presence of complications like pulmonary embolism (PE). The cross-sectional modalities also offer improved visualization of venous collaterals. The purpose of this article is to review the established modalities used for characterization and diagnosis of DVT, and further explore promising innovations and recent advances in this field. C1 [Karande, Gita Yashwantrao] Changi Gen Hosp, Dept Radiol, S529889, Singapore, Singapore. [Hedgire, Sandeep S.; Prabhakar, Anand M.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiovasc Imaging, Boston, MA 02114 USA. [Sanchez, Yadiel] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Baliyan, Vinit; Mishra, Vishala] Harvard Med Sch, Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, Boston, MA 02114 USA. [Ganguli, Suvranu] Harvard Med Sch, Massachusetts Gen Hosp, Div Intervent Radiol, Boston, MA 02114 USA. RP Hedgire, SS (reprint author), Massachusetts Gen Hosp, Div Cardiovasc Imaging, 55 Fruit St, Boston, MA 02114 USA. EM Hedgire.Sandeep@mgh.harvard.edu NR 93 TC 1 Z9 1 U1 0 U2 0 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2223-3652 EI 2223-3660 J9 CARDIOVASC DIAGN THE JI Cardiovisc. Diagn. Ther. PD DEC PY 2016 VL 6 IS 6 BP 493 EP 507 DI 10.21037/cdt.2016.12.06 PG 15 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI5QH UT WOS:000392548900004 PM 28123971 ER PT J AU Oliveira, IS Hedgire, SS Li, WE Ganguli, S Prabhakar, AM AF Oliveira, Irai S. Hedgire, Sandeep S. Li, Weier Ganguli, Suvranu Prabhakar, Anand M. TI Blood pool contrast agents for venous magnetic resonance imaging SO CARDIOVASCULAR DIAGNOSIS AND THERAPY LA English DT Review DE Contrast media; magnetic resonance imaging; venous imaging ID ILIAC VEIN COMPRESSION; MAY-THURNER SYNDROME; NEPHROGENIC SYSTEMIC FIBROSIS; AORTOILIAC OCCLUSIVE DISEASE; ENHANCED MR VENOGRAPHY; GADOFOSVESET TRISODIUM; UROGENITAL-RADIOLOGY; NUTCRACKER SYNDROME; EUROPEAN-SOCIETY; PHASE-III AB Imaging of the venous system plays a vital role in the diagnosis and management of a wide range of clinically significant disorders. There have been great advances in venous imaging techniques, culminating in the use of magnetic resonance venography (MRV). Although MRV has distinct advantages in anatomic and quantitative cross sectional imaging without ionizing radiation, there are well-known challenges in acquisition timing and contrast administration in patients with renal impairment. The latest advancement involves the addition of new contrast media agents, which have emerged as valuable alternatives in these difficult scenarios. In this review, we will focus on a group of specific contrast agents called blood pool agents and discuss their salient features and clinical applications. C1 [Oliveira, Irai S.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging, Boston, MA USA. [Hedgire, Sandeep S.; Prabhakar, Anand M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Div Cardiovasc Imaging, 55 Fruit St,Gray Bldg,2nd Floor, Boston, MA 02114 USA. [Li, Weier] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Ganguli, Suvranu] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Div Intervent Radiol, Boston, MA USA. RP Hedgire, SS (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Div Cardiovasc Imaging, 55 Fruit St,Gray Bldg,2nd Floor, Boston, MA 02114 USA. EM hedgire.sandeep@mgh.harvard.edu FU Hospital Sirio-Libanes, Sao Paulo, Brazil FX Irai S. Oliveira would like to acknowledge the support from Hospital Sirio-Libanes, Sao Paulo, Brazil. NR 42 TC 1 Z9 1 U1 1 U2 1 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2223-3652 EI 2223-3660 J9 CARDIOVASC DIAGN THE JI Cardiovisc. Diagn. Ther. PD DEC PY 2016 VL 6 IS 6 BP 508 EP 518 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI5QH UT WOS:000392548900005 PM 28123972 ER PT J AU Zucker, EJ Ganguli, S Ghoshhajra, BB Gupta, R Prabhakar, AM AF Zucker, Evan J. Ganguli, Suvranu Ghoshhajra, Brian B. Gupta, Rajiv Prabhakar, Anand M. TI Imaging of venous compression syndromes SO CARDIOVASCULAR DIAGNOSIS AND THERAPY LA English DT Review DE Venous compression; May-Thurner syndrome (MTS); thoracic outlet syndrome (TOS); nutcracker syndrome (NCS); magnetic resonance venography (MRV) ID MAY-THURNER-SYNDROME; ILIAC VEIN COMPRESSION; THORACIC OUTLET SYNDROME; MULTIDETECTOR COMPUTED-TOMOGRAPHY; PAGET-SCHROETTER SYNDROME; NUTCRACKER SYNDROME; ENTRAPMENT SYNDROME; URINARY-BLADDER; THROMBOSIS; FERUMOXYTOL AB Venous compression syndromes are a unique group of disorders characterized by anatomical extrinsic venous compression, typically in young and otherwise healthy individuals. While uncommon, they may cause serious complications including pain, swelling, deep venous thrombosis (DVT), pulmonary embolism, and post-thrombotic syndrome. The major disease entities are May-Thurner syndrome (MTS), variant iliac vein compression syndrome (IVCS), venous thoracic outlet syndrome (VTOS)/Paget-Schroetter syndrome, nutcracker syndrome (NCS), and popliteal venous compression (PVC). In this article, we review the key clinical features, multimodality imaging findings, and treatment options of these disorders. Emphasis is placed on the growing role of noninvasive imaging options such as magnetic resonance venography (MRV) in facilitating early and accurate diagnosis and tailored intervention. C1 [Zucker, Evan J.; Ghoshhajra, Brian B.; Gupta, Rajiv; Prabhakar, Anand M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Div Cardiovasc Imaging, Boston, MA 02114 USA. [Zucker, Evan J.] Stanford Univ, Sch Med, Dept Radiol, 725 Welch Rd, Stanford, CA 94305 USA. [Ganguli, Suvranu] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Div Intervent Radiol, Boston, MA 02114 USA. [Gupta, Rajiv] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Div Neuroradiol, Boston, MA 02114 USA. RP Zucker, EJ (reprint author), Stanford Univ, Sch Med, Dept Radiol, 725 Welch Rd, Stanford, CA 94305 USA. EM zucker@post.harvard.edu NR 69 TC 1 Z9 1 U1 0 U2 0 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2223-3652 EI 2223-3660 J9 CARDIOVASC DIAGN THE JI Cardiovisc. Diagn. Ther. PD DEC PY 2016 VL 6 IS 6 BP 519 EP 532 DI 10.21037/cdt.2016.11.19 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI5QH UT WOS:000392548900006 PM 28123973 ER PT J AU Baliyan, V Tajmir, S Hedgire, SS Ganguli, S Prabhakar, AM AF Baliyan, Vinit Tajmir, Shahein Hedgire, Sandeep S. Ganguli, Suvranu Prabhakar, Anand M. TI Lower extremity venous reflux SO CARDIOVASCULAR DIAGNOSIS AND THERAPY LA English DT Review DE Venous reflux; venous incompetence; lower extremity ultrasound; ablation ID LONG SAPHENOUS-VEIN; ENDOVENOUS LASER TREATMENT; VARICOSE-VEINS; ARTERIOVENOUS-FISTULA; FASCIAL RELATIONSHIPS; VALVULAR REFLUX; VENOGRAPHY; THROMBOSIS; QUALITY; VALVES AB Venous incompetence in the lower extremity is a common clinical problem. Basic understanding of venous anatomy, pathophysiologic mechanisms of venous reflux is essential for choosing the appropriate treatment strategy. The complex interplay of venous pressure, abdominal pressure, venous valvular function and gravitational force determine the venous incompetence. This review is intended to provide a succinct review of the pathophysiology of venous incompetence and the current role of imaging in its management. C1 [Baliyan, Vinit] Massachusetts Gen Hosp, Div Abdominal Imaging, Boston, MA 02114 USA. [Tajmir, Shahein] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Hedgire, Sandeep S.; Prabhakar, Anand M.] Massachusetts Gen Hosp, Div Cardiovasc Imaging, 55 Fruit st, Boston, MA 02114 USA. [Ganguli, Suvranu] Massachusetts Gen Hosp, Div Intervent Radiol, Boston, MA 02114 USA. RP Hedgire, SS (reprint author), Massachusetts Gen Hosp, Div Cardiovasc Imaging, 55 Fruit st, Boston, MA 02114 USA. EM Hedgire.Sandeep@mgh.harvard.edu NR 60 TC 1 Z9 1 U1 0 U2 0 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2223-3652 EI 2223-3660 J9 CARDIOVASC DIAGN THE JI Cardiovisc. Diagn. Ther. PD DEC PY 2016 VL 6 IS 6 BP 533 EP 543 DI 10.21037/cdt.2016.11.14 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI5QH UT WOS:000392548900007 PM 28123974 ER PT J AU Kuyumcu, G Salazar, GM Prabhakar, A Ganguli, S AF Kuyumcu, Gokhan Salazar, Gloria Maria Prabhakar, Anand Ganguli, Suvranu TI Minimally invasive treatments for perforator vein insufficiency SO CARDIOVASCULAR DIAGNOSIS AND THERAPY LA English DT Review DE Perforator vein insufficiency; endovascular thermal ablation (EVTA); ultrasound guided sclerotherapy (USGS) ID ENDOVENOUS LASER-ABLATION; VENOUS LEG ULCERS; FOAM SCLEROTHERAPY; VARICOSE-VEINS; RADIOFREQUENCY ABLATION; DUPLEX ULTRASONOGRAPHY; RADIAL FIBER; INCOMPETENCE; ULCERATION; REFLUX AB Incompetent superficial veins are the most common cause of lower extremity superficial venous reflux and varicose veins; however, incompetent or insufficient perforator veins are the most common cause of recurrent varicose veins after treatment, often unrecognized. Perforator vein insufficiency can result in pain, skin changes, and skin ulcers, and often merit intervention. Minimally invasive treatments have replaced traditional surgical treatments for incompetent perforator veins. Current minimally invasive treatment options include ultrasound guided sclerotherapy (USGS) and endovascular thermal ablation (EVTA) with either laser or radiofrequency energy sources. Advantages and disadvantages of each modality and knowledge on these treatments are required to adequately address perforator venous disease. C1 [Kuyumcu, Gokhan] Cleveland Clin, Imaging Inst, A Bldg Crile Bldg,2049 E 100th St, Cleveland, OH 44195 USA. [Salazar, Gloria Maria; Prabhakar, Anand; Ganguli, Suvranu] Harvard Med Sch, Massachusetts Gen Hosp, Div Intervent Radiol, Dept Radiol, Boston, MA USA. RP Kuyumcu, G (reprint author), Cleveland Clin, Imaging Inst, A Bldg Crile Bldg,2049 E 100th St, Cleveland, OH 44195 USA. EM radiologistgokhan@gmail.com NR 46 TC 1 Z9 1 U1 0 U2 0 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2223-3652 EI 2223-3660 J9 CARDIOVASC DIAGN THE JI Cardiovisc. Diagn. Ther. PD DEC PY 2016 VL 6 IS 6 BP 593 EP 598 DI 10.21037/cdt.2016.11.12 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI5QH UT WOS:000392548900012 PM 28123979 ER PT J AU Kuyumcu, G Walker, TG AF Kuyumcu, Gokhan Walker, T. Gregory TI Inferior vena cava filter retrievals, standard and novel techniques SO CARDIOVASCULAR DIAGNOSIS AND THERAPY LA English DT Review DE Inferior vena cava (IVC); filter retrieval; complex; complications; retrievable ID EMBEDDED IVC FILTERS; VENOUS THROMBOEMBOLISM; ENDOBRONCHIAL FORCEPS; INITIAL-EXPERIENCE; ASSISTED REMOVAL; MANAGEMENT; COMPLICATIONS; PREVENTION; TRAPEASE; TRAUMA AB The placement of an inferior vena cava (IVC) filter is a well-established management strategy for patients with venous thromboembolism (VTE) disease in whom anticoagulant therapy is either contraindicated or has failed. IVC filters may also be placed for VTE prophylaxis in certain circumstances. There has been a tremendous growth in placement of retrievable IVC filters in the past decade yet the majority of the devices are not removed. Unretrieved IVC filters have several well-known complications that increase in frequency as the filter dwell time increases. These complications include caval wall penetration, filter fracture or migration, caval thrombosis and an increased risk for lower extremity deep vein thrombosis (DVT). Difficulty is sometimes encountered when attempting to retrieve indwelling filters, mainly because of either abnormal filter positioning or endothelization of filter components that are in contact with the IVC wall, thereby causing the filter to become embedded. The length of time that a filter remains indwelling also impacts the retrieval rate, as increased dwell times are associated with more difficult retrievals. Several techniques for difficult retrievals have been described in the medical literature. These techniques range from modifications of standard retrieval techniques to much more complex interventions. Complications related to complex retrievals are more common than those associated with standard retrieval techniques. The risks of complex filter retrievals should be compared with those of life-long anticoagulation associated with an unretrieved filter, and should be individualized. This article summarizes current techniques for IVC filter retrieval from a clinical point of view, with an emphasis on advanced retrieval techniques. C1 [Kuyumcu, Gokhan] Cleveland Clin, Imaging Inst, A Bldg,Crile Bldg,2049 E 100th St, Cleveland, OH 44195 USA. [Walker, T. Gregory] Massachusetts Gen Hosp, Dept Radiol, Div Intervent Radiol, Boston, MA USA. [Walker, T. Gregory] Harvard Med Sch, Boston, MA USA. RP Kuyumcu, G (reprint author), Cleveland Clin, Imaging Inst, A Bldg,Crile Bldg,2049 E 100th St, Cleveland, OH 44195 USA. EM radiologistgokhan@gmail.com NR 37 TC 1 Z9 1 U1 2 U2 2 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2223-3652 EI 2223-3660 J9 CARDIOVASC DIAGN THE JI Cardiovisc. Diagn. Ther. PD DEC PY 2016 VL 6 IS 6 BP 642 EP 650 DI 10.21037/cdt.2016.09.07 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI5QH UT WOS:000392548900017 PM 28123984 ER PT J AU Monteleone, PP Rosenfield, K Rosovsky, RP AF Monteleone, Peter P. Rosenfield, Kenneth Rosovsky, Rachel P. TI Multidisciplinary pulmonary embolism response teams and systems SO CARDIOVASCULAR DIAGNOSIS AND THERAPY LA English DT Article DE Pulmonary embolism (PE); deep vein thrombosis (DVT); rapid response team; pulmonary embolism response team (PERT); multidisciplinary; catheter directed thrombolysis (CDT); thrombosis; thrombolysis ID TRIAL AB Pulmonary embolism (PE) is a complex diagnosis that encompasses a wide range of clinical presentations. Often patients who present with PE have complicated medical histories which can make their management challenging. Many novel therapeutic strategies and tools are emerging to improve the care and outcomes of patients with PE. Pulmonary embolism response teams (PERTs) are developing at multiple centers to improve the decision making, efficiency and orchestration of these clinical strategies. Concordantly with development of PERT programs is the design and implementation of systems to allow for numerous specialists to convene and discuss complex PE patients in real time. The mechanisms to engage a multidisciplinary approach are proving to be an invaluable resource in the decision making processes and treatment of high risk PE patients. Ultimately, other multi-disciplinary teams may adopt these methods to better address their clinical needs. C1 [Monteleone, Peter P.; Rosenfield, Kenneth] Massachusetts Gen Hosp, Div Cardiol, Sect Vasc Med & Intervent, Boston, MA 02114 USA. [Rosovsky, Rachel P.] Massachusetts Gen Hosp, Dept Med, Div Hematol & Oncol, Boston, MA 02114 USA. RP Rosovsky, RP (reprint author), Massachusetts Gen Hosp, Div Hematol, 55 Fruit St, Boston, MA 02114 USA. EM rprosovsky@mgh.harvard.edu NR 11 TC 1 Z9 1 U1 0 U2 0 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2223-3652 EI 2223-3660 J9 CARDIOVASC DIAGN THE JI Cardiovisc. Diagn. Ther. PD DEC PY 2016 VL 6 IS 6 BP 662 EP 667 DI 10.21037/cdt.2016.11.05 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI5QH UT WOS:000392548900019 PM 28123986 ER PT J AU Luyster, FS Strollo, PJ Holguin, F Castro, M Dunican, EM Fahy, J Gaston, B Israel, E Jarjour, NN Mauger, DT Moore, WC Wenzel, SE AF Luyster, Faith S. Strollo, Patrick J., Jr. Holguin, Fernando Castro, Mario Dunican, Eleanor M. Fahy, John Gaston, Benjamin Israel, Elliot Jarjour, Nizar N. Mauger, David T. Moore, Wendy C. Wenzel, Sally E. TI Association Between Insomnia and Asthma Burden in the Severe Asthma Research Program (SARP) III SO CHEST LA English DT Article DE asthma; depression; health care utilization; insomnia; quality of life ID QUALITY-OF-LIFE; SLEEP DISTURBANCES; DEPRESSION SCALE; HOSPITAL ANXIETY; RISK-FACTORS; POPULATION; QUESTIONNAIRE; VALIDATION; SYMPTOMS; VALIDITY AB BACKGROUND: Sleep difficulties are commonly reported by patients with asthma; however, the prevalence of insomnia and its association with disease burden and well-being is unknown. We aimed to determine the prevalence of insomnia, defined as combined sleep-specific complaints with associated daytime symptoms, among a large sample of adults with asthma, and to compare well-being, asthma control, and asthma-related health care utilization in individuals with asthma and insomnia and those without insomnia. METHODS: Baseline data from adults with physician-confirmed asthma enrolled in the Severe Asthma Research Program III was used for analyses (N = 714). Participants completed the Insomnia Severity Index (ISI), Asthma Control Test, Asthma Quality of Life Questionnaire, and Hospital Anxiety and Depression Scale. RESULTS: Insomnia (ISI >= 10) was identified in 263 participants (37%). Presence of insomnia was associated with higher levels of depression and anxiety symptoms and poorer quality of life. Those with insomnia had a 2.4-fold increased risk for having not well-controlled asthma and a 1.5-fold increased risk for asthma-related health care utilization in the past year compared with those without insomnia. CONCLUSIONS: Insomnia is highly prevalent in asthma and is associated with adverse outcomes. Further studies are needed to gain a better understanding of the interaction between insomnia and asthma control. C1 [Luyster, Faith S.] Univ Pittsburgh, Sch Nursing, 3500 Vic St,Room 415, Pittsburgh, PA 15261 USA. [Strollo, Patrick J., Jr.; Holguin, Fernando; Wenzel, Sally E.] Univ Pittsburgh, Sch Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15261 USA. [Strollo, Patrick J., Jr.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Castro, Mario] Washington Univ, Sch Med, Div Pulm & Crit Care Med, St Louis, MO USA. [Dunican, Eleanor M.; Fahy, John] Univ Calif San Francisco, Sch Med, Div Pulm & Crit Care Med, San Francisco, CA 94143 USA. [Gaston, Benjamin] Univ Hosp Cleveland, Rainbow Babies & Childrens Hosp, Div Pediat Allergy & Immunol, Cleveland, OH 44106 USA. [Israel, Elliot] Brigham & Womens Hosp, Pulm Div, Boston, MA 02115 USA. [Jarjour, Nizar N.] Univ Wisconsin, Sch Med, Div Allergy Pulm & Crit Care Med, Madison, WI USA. [Mauger, David T.] Penn State Univ, Coll Med, Dept Publ Hlth Sci, Hershey, PA USA. [Moore, Wendy C.] Wake Forest Univ, Sch Med, Dept Med, Div Pulm Crit Care Allergy & Immunol Med, Winston Salem, NC 27109 USA. RP Luyster, FS (reprint author), Univ Pittsburgh, Sch Nursing, 3500 Vic St,Room 415, Pittsburgh, PA 15261 USA. EM luysterfs@upmc.edu FU National Institutes of Health [NIH] [U10HL 109164, U10HL 109257, U10HL 109250, U10HL 109172, U10HL 109168, U10HL 109152, U10HL 109046]; National Heart, Lung, and Blood Institute (NHLBI) [K23 HL105887] FX This study was funded by the National Institutes of Health [NIH U10HL 109164, U10HL 109257, U10HL 109250, U10HL 109172, U10HL 109168, U10HL 109152, U10HL 109046, U10HL 109046]. Support for the first author was provided by the National Heart, Lung, and Blood Institute (NHLBI) K23 HL105887. NR 37 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD DEC PY 2016 VL 150 IS 6 BP 1242 EP 1250 DI 10.1016/j.chest.2016.09.020 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EI1VQ UT WOS:000392274600024 PM 27720882 ER PT J AU Kadri, SS Miller, AC Hohmann, S Bonne, S Nielsen, C Wells, C Gruver, C Quraishi, SA Sun, JF Cai, RM Morris, PE Freeman, BD Holmes, JH Cairns, BA Suffredini, AF AF Kadri, Sameer S. Miller, Andrew C. Hohmann, Samuel Bonne, Stephanie Nielsen, Carrie Wells, Carmen Gruver, Courtney Quraishi, Sadeq A. Sun, Junfeng Cai, Rongman Morris, Peter E. Freeman, Bradley D. Holmes, James H. Cairns, Bruce A. Suffredini, Anthony F. CA US Critical Illness Injury Trials Smoke Inhalation Associated Acute TI Risk Factors for In-Hospital Mortality in Smoke Inhalation- Associated Acute Lung Injury Data From 68 United States Hospitals SO CHEST LA English DT Article DE adult respiratory distress syndrome; burns; epidemiology; risk factors; smoke inhalation ID BURN PATIENTS; MECHANICAL VENTILATION; RESUSCITATION; PROGNOSIS; OUTCOMES; SCORE AB BACKGROUND: Mortality after smoke inhalation-associated acute lung injury (SI-ALI) remains substantial. Age and burn surface area are risk factors of mortality, whereas the impact of patient-and center-level variables and treatments on survival are unknown. METHODS: We performed a retrospective cohort study of burn and non-burn centers at 68 US academic medical centers between 2011 and 2014. Adult inpatients with SI-ALI were identified using an algorithm based on a billing code for respiratory conditions from smoke inhalation who were mechanically ventilated by hospital day 4, with either a length-of-stay >= 5 days or death within 4 days of hospitalization. Predictors of in-hospital mortality were identified using logistic regression. The primary outcome was the odds ratio for in-hospital mortality. RESULTS: A total of 769 patients (52.9 +/- 18.1 years) with SI-ALI were analyzed. In-hospital mortality was 26% in the SI-ALI cohort and 50% in patients with >= 20% surface burns. In addition to age > 60 years (OR 5.1, 95% CI 2.53-10.26) and >= 20% burns (OR 8.7, 95% CI 4.55-16.75), additional risk factors of in-hospital mortality included initial vasopressor use (OR 5.0, 95% CI 3.16-7.91), higher diagnostic-related group-based risk-of-mortality assignment and lower hospital bed capacity (OR 2.3, 95% CI 1.23-4.15). Initial empiric antibiotics (OR 0.93, 95% CI 0.58-1.49) did not impact survival. These new risk factors improved mortality prediction by 9.9% (P < .001). CONCLUSIONS: In addition to older age and major surface burns, mortality in SI-ALI is predicted by initial vasopressor use, higher diagnostic-related group-based risk-of-mortality assignment, and care at centers with < 500 beds, but not by initial antibiotic therapy. C1 [Kadri, Sameer S.; Miller, Andrew C.; Sun, Junfeng; Cai, Rongman; Suffredini, Anthony F.] NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. [Kadri, Sameer S.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Miller, Andrew C.] West Virginia Univ, Dept Emergency Med, Morgantown, WV 26506 USA. [Hohmann, Samuel] Univ Hlth Syst Consortium, Chicago, IL USA. [Hohmann, Samuel] Rush Univ, Dept Hlth Syst Management, Chicago, IL 60612 USA. [Bonne, Stephanie; Freeman, Bradley D.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Nielsen, Carrie; Cairns, Bruce A.] Univ North Carolina Hosp, North Carolina Jaycee Burn Ctr, Chapel Hill, NC USA. [Wells, Carmen; Gruver, Courtney; Holmes, James H.] Wake Forest Sch Med, Wake Forest Med Ctr, Dept Gen Surg, Winston Salem, NC USA. [Quraishi, Sadeq A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anethesia Crit Care & Pain Med, Boston, MA 02114 USA. [Quraishi, Sadeq A.] Harvard Med Sch, Dept Anesthesia, Boston, MA USA. [Morris, Peter E.] Wake Forest Sch Med, Wake Forest Med Ctr, Div Pulm & Crit Care Med, Winston Salem, NC USA. RP Kadri, SS (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. EM sameer.kadri@nih.gov FU Intramural Research Program, National Institutes of Health FX This study was funded by the Intramural Research Program, National Institutes of Health. NR 30 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD DEC PY 2016 VL 150 IS 6 BP 1260 EP 1268 DI 10.1016/j.chest.2016.06.008 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EI1VQ UT WOS:000392274600026 PM 27316558 ER PT J AU Barnes, GD Kabrhel, C Courtney, DM Naydenov, S Wood, T Rosovsky, R Rosenfield, K Giri, J AF Barnes, Geoffrey D. Kabrhel, Christopher Courtney, D. Mark Naydenov, Soophia Wood, Todd Rosovsky, Rachel Rosenfield, Kenneth Giri, Jay CA Natl PERT Consortium Res Comm TI Diversity in the Pulmonary Embolism Response Team Model: An Organizational Survey of the National PERT Consortium Members SO CHEST LA English DT Letter C1 [Barnes, Geoffrey D.] Univ Michigan, Sch Med, Frankel Cardiovasc Ctr, Ann Arbor, MI 48109 USA. [Barnes, Geoffrey D.] Univ Michigan, Sch Med, Dept Internal Med, Inst Healthcare Policy & Innovat, Ann Arbor, MI USA. [Kabrhel, Christopher] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Vasc Emergencies, Dept Emergency Med, Boston, MA USA. [Courtney, D. Mark] Northwestern Univ, Feinberg Sch Med, Dept Emergency Med, Chicago, IL 60611 USA. [Naydenov, Soophia] St Louis Univ, Sch Med, Div Pulm Crit Care & Sleep Med, St Louis, MO 63103 USA. [Wood, Todd] Univ Penn Med, Lancaster Gen Hlth, Div Cardiol, Lancaster, PA USA. [Rosovsky, Rachel] Harvard Med Sch, Massachusetts Gen Hosp, Div Hematol & Oncol, Dept Med, Boston, MA USA. [Rosenfield, Kenneth] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Sect Vasc Med,Dept Med, Boston, MA USA. [Giri, Jay] Univ Penn, Perelman Sch Med, Penn Cardiovasc Outcomes Qual & Evaluat Res Ctr, Philadelphia, PA 19104 USA. RP Barnes, GD (reprint author), Univ Michigan, Frankel Cardiovasc Ctr, 2800 Plymouth Rd,Bldg 14-G101, Ann Arbor, MI 48109 USA. EM gbarnes@umich.edu FU NHLBI [T32-HL007853]; St. Jude Medical FX The authors have reported to CHEST the following: G. D. B. received support from NHLBI [grant T32-HL007853]. J. G. received modest research funds to the institution from St. Jude Medical. None declared (C. K., D. M. C., S. N., T. W., R. R., K. R.). NR 4 TC 1 Z9 1 U1 1 U2 1 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD DEC PY 2016 VL 150 IS 6 BP 1414 EP 1417 DI 10.1016/j.chest.2016.09.034 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EI1VQ UT WOS:000392274600051 PM 27938758 ER PT J AU Singh, P Garber, JJ AF Singh, Prashant Garber, John J. TI Implementation and adherence to osteoporosis screening guidelines among coeliac disease patients SO DIGESTIVE AND LIVER DISEASE LA English DT Article DE Bone mineral density; Coeliac disease; Dual-energy X-ray absorptiometry scanning; Osteoporosis; Osteopenia; Screening ID GLUTEN-FREE DIET; BONE HEALTH; CHILDREN; ADOLESCENTS; DENSITY AB Background: There are no studies evaluating the implementation of American Gastroenterological Association (AGA) guidelines on osteoporosis screening in coeliac disease. Aims: To investigate implementation of osteoporosis screening guidelines in coeliac disease patients and determine how often bone mineral density (BMD) assessment leads to therapeutic intervention. Methods: We screened all patients with biopsy-proven coeliac disease at our center from 2003 to 2013 and collected data on indication and results of dual energy X-ray absorptiometry scanning (DXA) and therapeutic interventions. Results: Of 222 adults with coeliac, only 80 (36%) underwent DXA after their diagnosis. Of those, 43 had DXA for osteoporosis screening specifically related to their coeliac diagnosis. Of these 43 patients, 28 (65.1%) had low BMD. A therapeutic intervention was made in the majority of these patients (21/28, 75%). Of 330 pediatric coeliac cases, 52 (15.8%) had DXA specifically in the context of the coeliac disease diagnosis with only 5 being complicated coeliac disease. Of these, 3 (5.8%) had low BMD and only 2 underwent therapeutic intervention. Conclusions: Osteoporosis screening guidelines are not followed in the majority of patients with coeliac disease but, when followed, frequently lead to therapeutic intervention. Osteoporosis screening guidelines in coeliac disease need to be updated, strengthened and publicized. (C) 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. C1 [Singh, Prashant; Garber, John J.] Harvard Med Sch, Dept Med, Boston, MA USA. [Singh, Prashant; Garber, John J.] Massachusetts Gen Hosp, Gastrointestinal Unit, 55 Fruit St,Jackson 712, Boston, MA 02114 USA. RP Garber, JJ (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, 55 Fruit St,Jackson 712, Boston, MA 02114 USA. EM jjgarber@mgh.harvard.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [K08 DK094966] FX Dr. Garber is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (K08 DK094966). NR 30 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 1590-8658 EI 1878-3562 J9 DIGEST LIVER DIS JI Dig. Liver Dis. PD DEC PY 2016 VL 48 IS 12 BP 1451 EP 1456 DI 10.1016/j.dld.2016.08.121 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EI6UI UT WOS:000392632300008 PM 27665261 ER PT J AU Basar, O Brugge, WR AF Basar, Omer Brugge, William R. TI Do molecular tests really differentiate malignant IPMNS from benign? SO ENDOSCOPY INTERNATIONAL OPEN LA English DT Editorial Material ID PAPILLARY MUCINOUS NEOPLASM; PANCREATIC CYST FLUID; KRAS MUTATION; DIAGNOSIS; METAANALYSIS; GNAS C1 [Basar, Omer; Brugge, William R.] Massachusetts Gen Hosp, Gastrointestinal Unit, Pancreas Biliary Ctr, Boston, MA 02114 USA. [Basar, Omer] Hacettepe Med Sch, Dept Gastroenterol, Ankara, Turkey. RP Basar, O (reprint author), Massachusetts Gen Hosp, GI Associates 3H, Zero Emerson Pl,Blossom St, Boston, MA 02114 USA. EM obasar@mgh.harvard.edu NR 13 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 2364-3722 EI 2196-9736 J9 ENDOSC INT OPEN JI Endosc. Int. Open PD DEC PY 2016 VL 4 IS 12 BP E1236 EP E1237 DI 10.1055/s-0042-121004 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EI5IL UT WOS:000392527400002 PM 27995181 ER PT J AU Do Valle, BG Cash, SS Sodini, CG AF Do Valle, Bruno G. Cash, Sydney S. Sodini, Charles G. TI Low-Power, 8-Channel EEG Recorder and Seizure Detector ASIC for a Subdermal Implantable System SO IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS LA English DT Article DE Biomedical electronics; biomedical signal processing; electroencephalography; epilepsy; implantable biomedical devices; microelectronic implants ID HIGH-FREQUENCY OSCILLATIONS; INSTRUMENTATION AMPLIFIER; CMOS AB EEG remains the mainstay test for the diagnosis and treatment of patients with epilepsy. Unfortunately, ambulatory EEG systems are far from ideal for patients who have infrequent seizures. These systems only last up to 3 days and if a seizure is not captured during the recordings, a definite diagnosis of the patient's condition cannot be given. This work aims to address this need by proposing a subdermal implantable, eight-channel EEG recorder and seizure detector that has two modes of operation: diagnosis and seizure counting. In the diagnosis mode, EEG is continuously recorded until a number of seizures are recorded. In the seizure counting mode, the system uses a low-power algorithm to track the number of seizures a patient has, providing doctors with a reliable count to help determine medication efficacy or other clinical endpoint. An ASIC that implements the EEG recording and seizure detection algorithm was designed and fabricated in a 0.18 mu m CMOS process. The ASIC includes eight EEG channels and is designed to minimize the system's power and size. The result is a power-efficient analog front end that requires 2.75 mu W per channel in diagnosis mode and 0.84 mu W per channel in seizure counting mode. Both modes have an input referred noise of approximately 1.1 mu Vrms. C1 [Do Valle, Bruno G.; Sodini, Charles G.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Cash, Sydney S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Do Valle, BG (reprint author), MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. EM brunogr@mit.edu; scash@partners.org; sodini@mtl.mit.edu OI Do Valle, Bruno/0000-0002-8645-1026 FU MIT Medical Electronics Device Realization Center; Center for Integrated Circuits and Systems FX This research was supported by MIT Medical Electronics Device Realization Center and the Center for Integrated Circuits and Systems. This paper was recommended by Associate Editor R. Genov. NR 36 TC 0 Z9 0 U1 2 U2 2 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1932-4545 EI 1940-9990 J9 IEEE T BIOMED CIRC S JI IEEE Trans. Biomed. Circuits Syst. PD DEC PY 2016 VL 10 IS 6 BP 1058 EP 1067 DI 10.1109/TBCAS.2016.2517039 PG 10 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA EI3UI UT WOS:000392417000003 PM 27116750 ER PT J AU Yu, T Zhao, SN Li, ZQ Wang, Y Xu, B Fang, DL Wang, FZ Zhang, Z He, LL Song, XR Yang, J AF Yu, Ting Zhao, Shengnan Li, Ziqiang Wang, Yi Xu, Bei Fang, Dailong Wang, Fazhan Zhang, Zhi He, Lili Song, Xiangrong Yang, Jian TI Enhanced and Extended Anti-Hypertensive Effect of VP5 Nanoparticles SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Article DE PLGA nanoparticles; antihypertensive peptide; oral administration; sustained release; continuously antihypertensive effect ID MODIFIED PLGA NANOPARTICLES; IN-VITRO; ORAL DELIVERY; PROTEIN DRUGS; PEPTIDE; RELEASE; FORMULATION; DESIGN; BIOAVAILABILITY; MACROMOLECULES AB Hypertension has become a significant global public health concern and is also one of the most common risk factors of cardiovascular disease. Recent studies have shown the promising result of peptides inhibiting angiotensin converting enzyme (ACE) in lowering the blood pressure in both animal models and humans. However, the oral bioavailability and continuous antihypertensive effectiveness require further optimization. Novel nanoparticle-based drug delivery systems are helpful to overcome these barriers. Therefore, a poly-(lactic-co-glycolic) acid nanoparticle (PLGANPs) oral delivery system, of the antihypertensive small peptides Val-Leu-Pro-Val-Pro (VLPVP, VP5) model, was developed in this study and its antihypertensive effect was investigated in spontaneously hypertensive rats (SHRs) for the first time. The obtained VP5 nanoparticles (VP5-NPs) showed a small particle size of 223.7 +/- 2.3 nm and high entrapment efficiency (EE%) of 87.37% +/- 0.92%. Transmission electronic microscopy (TEM) analysis showed that the nanoparticles were spherical and homogeneous. The optimal preparation of VP5-NPs exhibited sustained release of VP5 in vitro and a 96 h long-term antihypertensive effect with enhanced efficacy in vivo. This study illustrated that PLGANPs might be an optimal formulation for oral delivery of antihypertensive small peptides and VP5-NPs might be worthy of further development and use as a potential therapeutic strategy for hypertension in the future. C1 [Yu, Ting; Yang, Jian] Shenzhen Polytech, Sch Appl Chem & Biol Technol, Shenzhen 518055, Peoples R China. [Yu, Ting; Zhao, Shengnan; He, Lili] Southwest Univ Nationalities, Coll Pharm, Chengdu 610041, Peoples R China. [Yu, Ting; Zhao, Shengnan; Li, Ziqiang; Xu, Bei; Fang, Dailong; Wang, Fazhan; Zhang, Zhi; Song, Xiangrong] Sichuan Univ, State Key Lab Biotherapy, Chengdu 610041, Peoples R China. [Yu, Ting; Zhao, Shengnan; Li, Ziqiang; Xu, Bei; Fang, Dailong; Wang, Fazhan; Zhang, Zhi; Song, Xiangrong] Sichuan Univ, Ctr Canc, West China Hosp, Chengdu 610041, Peoples R China. [Yu, Ting; Zhao, Shengnan; Li, Ziqiang; Xu, Bei; Fang, Dailong; Wang, Fazhan; Zhang, Zhi; Song, Xiangrong] Sichuan Univ, Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China. [Wang, Yi] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wang, Yi] Harvard Med Sch, Boston, MA 02115 USA. RP Yang, J (reprint author), Shenzhen Polytech, Sch Appl Chem & Biol Technol, Shenzhen 518055, Peoples R China.; Song, XR (reprint author), Sichuan Univ, State Key Lab Biotherapy, Chengdu 610041, Peoples R China.; Song, XR (reprint author), Sichuan Univ, Ctr Canc, West China Hosp, Chengdu 610041, Peoples R China.; Song, XR (reprint author), Sichuan Univ, Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China. EM tingyu419@126.com; zhaoshn11@163.com; ziqiangli21@gmail.com; Yi_Wang@dfci.harvard.edu; xb1990625@126.com; fangdailongtwozero@126.com; FazhanWang_16@163.com; zhangzhi02@gmail.com; lilihes@163.com; songxr@scu.edu.cn; jiany@szpt.edu.cn FU Innovation Plan of the Science and Technology Plan of Shenzhen [JCYJ20130331151204151] FX This research has been received financial support from the Innovation Plan of the Science and Technology Plan of Shenzhen (JCYJ20130331151204151). NR 51 TC 0 Z9 0 U1 1 U2 1 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD DEC PY 2016 VL 17 IS 12 AR 1977 DI 10.3390/ijms17121977 PG 13 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA EI1XR UT WOS:000392280500021 ER PT J AU Wright, AA Bohlke, K Edelson, MI AF Wright, Alexi A. Bohlke, Kari Edelson, Mitchell I. TI Neoadjuvant Chemotherapy for Newly Diagnosed Advanced Ovarian Cancer: Society of Gynecologic Oncology and ASCO Clinical Practice Guideline Summary SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Editorial Material C1 Dana Farber Canc Inst, Boston, MA 02115 USA. [Bohlke, Kari] ASCO, 2318 Mill Rd,Ste 800, Alexandria, VA 22314 USA. Abington Jefferson Hlth, Abington, PA USA. RP Bohlke, K (reprint author), ASCO, 2318 Mill Rd,Ste 800, Alexandria, VA 22314 USA. EM guidelines@asco.org 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 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD DEC PY 2016 VL 12 IS 12 BP 1254 EP 1254 DI 10.1200/JOP.2016.016873 PG 1 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EI3II UT WOS:000392383200021 PM 27624951 ER PT J AU Neuss, MN Gilmore, TR Belderson, KM Billett, AL Conti-Kalchik, T Harvey, BE Hendricks, C LeFebvre, KB Mangu, P McNiff, K Olsen, M Schulmeister, L Von Gehr, A Polovich, M AF Neuss, Michael N. Gilmore, Terry R. Belderson, Kristin M. Billett, Amy L. Conti-Kalchik, Tara Harvey, Brittany E. Hendricks, Carolyn LeFebvre, Kristine B. Mangu, PamelaB. McNiff, Kristen Olsen, MiKaela Schulmeister, Lisa Von Gehr, Ann Polovich, Martha TI 2016 Updated American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Safety Standards, Including Standards for Pediatric Oncology SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Article ID MEDICATION ERRORS; ANTINEOPLASTIC DRUGS; CANCER-PATIENTS; ORDER ENTRY; PROGRAM; IMPLEMENTATION; SYSTEM AB Purpose To update the ASCO/Oncology Nursing Society (ONS) Chemotherapy Administration Safety Standards and to highlight standards for pediatric oncology. Methods The ASCO/ONS Chemotherapy Administration Safety Standards were first published in 2009 and updated in 2011 to include inpatient settings. A subsequent 2013 revision expanded the standards to include the safe administration and management of oral chemotherapy. A joint ASCO/ONS workshop with stakeholder participation, including that of the Association of Pediatric Hematology Oncology Nurses and American Society of Pediatric Hematology/Oncology, was held on May 12, 2015, to review the 2013 standards. An extensive literature search was subsequently conducted, and public comments on the revised draft standards were solicited. Results The updated 2016 standards presented here include clarification and expansion of existing standards to include pediatric oncology and to introduce new standards: most notably, two-person verification of chemotherapy preparation processes, administration of vinca alkaloids via minibags in facilities in which intrathecal medications are administered, and labeling of medications dispensed from the health care setting to be taken by the patient at home. The standards were reordered and renumbered to align with the sequential processes of chemotherapy prescription, preparation, and administration. Several standards were separated into their respective components for clarity and to facilitate measurement of adherence to a standard. Conclusion As oncology practice has changed, so have chemotherapy administration safety standards. Advances in technology, cancer treatment, and education and training have prompted the need for periodic review and revision of the standards. Additional information is available at http://www.asco.org/chemo-standards. C1 Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Gilmore, Terry R.] Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. Childrens Hosp Colorado, Aurora, CO USA. Dana Farber Canc Inst, Boston Childrens Canc & Blood Disorders Ctr, Boston, MA 02115 USA. Breast Ctr, Bethesda, MD USA. Oncol Nursing Soc, Pittsburgh, PA USA. Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Sidney Kimmel Comprehens Canc Ctr, New Orleans, LA USA. Permanente Med Grp Inc, San Jose, CA USA. Byrdine F Lewis Sch Nursing & Hlth Profess, Atlanta, GA USA. RP Gilmore, TR (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM terry.gilmore@asco.org NR 44 TC 1 Z9 1 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD DEC PY 2016 VL 12 IS 12 BP 1262 EP 1271 DI 10.1200/JOP.2016.017905 PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EI3II UT WOS:000392383200023 PM 27868581 ER PT J AU Siddiqui, B Greka, A Popovtzer, M Rennke, HG Jeselsohn, R AF Siddiqui, Bilal Greka, Anna Popovtzer, Mordecai Rennke, Helmut G. Jeselsohn, Rinath TI Immune Complex-Mediated Proliferative Glomerulonephritis Induced by Paclitaxel Treatment SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Editorial Material ID SYSTEMIC-LUPUS-ERYTHEMATOSUS C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Med Sch, Boston, MA USA. Southern Arizona Vet Affairs Hlth Care Syst, Tucson, AZ USA. Univ Arizona, Coll Med, Tucson, AZ USA. RP Jeselsohn, R (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Breast Oncol Ctr, 450 Brookline Ave, Boston, MA 02115 USA. EM rinath_jeselsohn@dfci.harvard.edu NR 6 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD DEC PY 2016 VL 12 IS 12 BP 1272 EP 1274 DI 10.1200/JOP.2016.016956 PG 3 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EI3II UT WOS:000392383200024 PM 27845869 ER EF