FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Kamdar, BB Martin, JL Needham, DM Ong, MK AF Kamdar, Biren B. Martin, Jennifer L. Needham, Dale M. Ong, Michael K. TI Promoting Sleep to Improve Delirium in the ICU SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE critical illness; delirium; intensive care unit; sleep C1 [Kamdar, Biren B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Pulm & Crit Care Med, Los Angeles, CA 90095 USA. [Martin, Jennifer L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Martin, Jennifer L.] VA Greater Los Angeles Healthcare Syst, Geriatr Res Educ & Clin Ctr, Los Angeles, CA USA. [Needham, Dale M.] Johns Hopkins Univ, Dept Phys Med & Rehabil, Div Pulm & Crit Care Med, Outcomes Crit Illness & Surg OACIS Grp, Baltimore, MD USA. [Ong, Michael K.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90095 USA. [Ong, Michael K.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Kamdar, BB (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Pulm & Crit Care Med, Los Angeles, CA 90095 USA. NR 16 TC 0 Z9 0 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2016 VL 44 IS 12 BP 2290 EP 2291 DI 10.1097/CCM.0000000000001982 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA EC3VZ UT WOS:000388056500029 PM 27858818 ER PT J AU Ferencik, M Akhavein, R Hoffmann, U AF Ferencik, Maros Akhavein, Reyhaneh Hoffmann, Udo TI The Potential Role of Combined Highly Sensitive Troponin and Coronary Computed Tomography Angiography in the Evaluation of Patients with Suspected Acute Coronary Syndrome in the Emergency Department SO CURRENT CARDIOVASCULAR IMAGING REPORTS LA English DT Article DE Acute coronary syndrome; Acute chest pain; Highly sensitive troponin; Coronary computed tomography angiography ID ACUTE CHEST-PAIN; FRACTIONAL FLOW RESERVE; ROMICAT-II TRIAL; ACCELERATED DIAGNOSTIC PROTOCOL; ACUTE MYOCARDIAL-INFARCTION; LEFT-VENTRICULAR FUNCTION; 3RD UNIVERSAL DEFINITION; CT ANGIOGRAPHY; CARDIAC TROPONIN; ARTERY-DISEASE AB The evaluation and triage of patients presenting to the emergency department (ED) with suspected acute coronary syndrome (ACS) remains to be challenging despite available guidelines and clinical evidence. The current guidelines in the USA recommend clinical risk assessment based on cardiovascular risk factors followed by serial electrocardiograms and conventional cardiac troponin measurements, which are supplemented by advanced non-invasive cardiac testing in the majority of patients. This approach is safe, but leads to a lengthy work-up and high cost of care. There is clinical need for diagnostic strategies that will lead to rapid and reliable triage of patients with suspected ACS. In this review, we will summarize the experience and evidence for the use of highly sensitive troponin (hsTn) in the rapid and efficient evaluation of patients with suspected ACS. We will also review the available literature on the use of coronary computed tomography angiography (CTA) in the rapid evaluation of patients with suspected ACS. We will discuss the opportunities for the combined use of hsTn and coronary CTA in this population. Finally, we will outline the possible implementation of combined use of hsTn and coronary CTA in the evaluation of patients with suspected ACS in the ED. C1 [Ferencik, Maros; Akhavein, Reyhaneh] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, 3180 SW Sam Jackson Pk Rd,Mail Code UHN62, Portland, OR 97239 USA. [Ferencik, Maros; Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Ferencik, Maros; Hoffmann, Udo] Harvard Med Sch, Boston, MA 02115 USA. [Ferencik, Maros; Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. RP Ferencik, M (reprint author), Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, 3180 SW Sam Jackson Pk Rd,Mail Code UHN62, Portland, OR 97239 USA.; Ferencik, M (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA.; Ferencik, M (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Ferencik, M (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. EM ferencik@ohsu.edu NR 72 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1941-9066 EI 1941-9074 J9 CURR CARDIOVASC IMAG JI CURR. CARDIOVASC. IMAGING REP. PD DEC PY 2016 VL 9 IS 12 AR 31 DI 10.1007/s12410-016-9393-x PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EC5UA UT WOS:000388200900001 ER PT J AU Dixon, LE Ahles, E Marques, L AF Dixon, Louise E. Ahles, Emily Marques, Luana TI Treating Posttraumatic Stress Disorder in Diverse Settings: Recent Advances and Challenges for the Future SO CURRENT PSYCHIATRY REPORTS LA English DT Review DE PTSD; Racial/ethnic minorities; Effectiveness; PTSD intervention; Cultural adaptation ID COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED-CONTROLLED-TRIAL; NARRATIVE EXPOSURE THERAPY; EVIDENCE-BASED INTERVENTIONS; NATIONAL COMORBIDITY SURVEY; MENTAL-HEALTH TREATMENTS; PROLONGED EXPOSURE; PROCESSING THERAPY; SOCIOCULTURAL EXPLANATIONS; RACIAL/ETHNIC DIFFERENCES AB Racial and ethnic minorities are at high risk for developing posttraumatic stress disorder (PTSD) after experiencing a traumatic event and are less likely to receive evidence-based treatment for their symptoms. There is a growing body of literature showing that culturally appropriate interventions result in greater uptake, symptom reduction, and sustained treatment gains. This article review explores new findings in the cultural understanding of PTSD among racial and ethnic minorities. We first review recent advances in the understanding of PTSD symptomotology. Next, we provide overview of trials demonstrating efficacy and effectiveness of cognitive processing therapy (CPT), prolonged exposure (PE), and trauma-focused cognitive-behavioral therapy (TF-CBT) in diverse communities. Then, we discuss specific implementation strategies common across intervention trials used to increase feasibility, acceptability, adoption, and sustainability. Last, we discuss areas for future research and dissemination efforts. C1 [Dixon, Louise E.] Univ Calif Los Angeles, Dept Psychol, 1285 Franz Hall,Box 951563, Los Angeles, CA 90095 USA. [Ahles, Emily] Massachusetts Gen Hosp, Dept Psychiat, 70 Everett Ave,Suite 516, Chelsea, MA 02150 USA. [Marques, Luana] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, 70 Everett Ave,Suite 516, Chelsea, MA 02150 USA. RP Marques, L (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, 70 Everett Ave,Suite 516, Chelsea, MA 02150 USA. EM ldixon7891@ucla.edu; eahles@mgh.harvard.edu; lmarques@mgh.harvard.edu NR 87 TC 0 Z9 0 U1 16 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 EI 1535-1645 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD DEC PY 2016 VL 18 IS 12 AR 108 DI 10.1007/s11920-016-0748-4 PG 10 WC Psychiatry SC Psychiatry GA EC5IY UT WOS:000388169300004 PM 27771824 ER PT J AU Simon, TG Corey, KE Chung, RT Giugliano, R AF Simon, Tracey G. Corey, Kathleen E. Chung, Raymond T. Giugliano, Robert TI Cardiovascular Risk Reduction in Patients with Nonalcoholic Fatty Liver Disease: The Potential Role of Ezetimibe SO DIGESTIVE DISEASES AND SCIENCES LA English DT Review DE Cholesterol; Nonalcoholic fatty liver disease; Acute coronary syndromes; Cardiovascular risk ID CORONARY-HEART-DISEASE; GAMMA-GLUTAMYL-TRANSFERASE; TYPE-2 DIABETIC-PATIENTS; POPULATION-BASED COHORT; PLASMA FETUIN-A; TERM-FOLLOW-UP; INSULIN-RESISTANCE; METABOLIC SYNDROME; UNITED-STATES; SUBCLINICAL ATHEROSCLEROSIS AB Nonalcoholic fatty liver disease (NAFLD) is widely considered to be the hepatic manifestation of the metabolic syndrome and is closely linked to dyslipidemia, obesity, and insulin resistance. Patients with NAFLD have increased mortality when compared to the general population, primarily related to cardiovascular disease or malignancy. The biologic mechanisms that link NAFLD to cardiovascular disease include expansion of visceral adipose tissue, atherogenic dyslipidemia, impaired insulin signaling, systemic inflammation, and endothelial dysfunction. Currently, there are no approved therapies for NAFLD. It has recently been hypothesized that reducing the delivery of dietary cholesterol using the hypolipidemic agent, ezetimibe, could benefit patients with NAFLD. By potently inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) sterol receptor on intestinal enterocytes and within the liver, ezetimibe blocks exogenous cholesterol absorption and has been shown to improve biochemical markers of NAFLD, improve insulin sensitivity and decrease hepatic steatosis. This review summarizes the clinical and epidemiological evidence for the relationship between NAFLD and cardiovascular risk and examines the potential therapeutic role of ezetimibe. C1 [Simon, Tracey G.; Corey, Kathleen E.; Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Div, Dept Med, Ctr Liver, Boston, MA USA. [Simon, Tracey G.; Corey, Kathleen E.; Chung, Raymond T.; Giugliano, Robert] Harvard Med Sch, Boston, MA USA. [Giugliano, Robert] Brigham & Womens Hosp, Cardiovasc Div, 350 Longwood Ave,1st Floor, Boston, MA 02215 USA. RP Giugliano, R (reprint author), Harvard Med Sch, Boston, MA USA.; Giugliano, R (reprint author), Brigham & Womens Hosp, Cardiovasc Div, 350 Longwood Ave,1st Floor, Boston, MA 02215 USA. EM rgiugliano@partners.org FU [K24DK078772]; [K23DK099422] FX Raymond T. Chung and Kathleen E. Corey have received financial support from K24DK078772 and K23DK099422, respectively. NR 89 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD DEC PY 2016 VL 61 IS 12 BP 3425 EP 3435 DI 10.1007/s10620-016-4330-z PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EC6DT UT WOS:000388227400010 PM 27714510 ER PT J AU Allegretti, AS Ortiz, G Kalim, S Wibecan, J Zhang, D Shan, HY Xu, D Chung, RT Karumanchi, SA Thadhani, RI AF Allegretti, Andrew S. Ortiz, Guillermo Kalim, Sahir Wibecan, Joshua Zhang, Dongsheng Shan, Hui Yi Xu, Dihua Chung, Raymond T. Karumanchi, S. Ananth Thadhani, Ravi I. TI Siglec-7 as a Novel Biomarker to Predict Mortality in Decompensated Cirrhosis and Acute Kidney Injury SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Cirrhosis; Hepatitis C; Liver immunology; Acute kidney injury; Hepatorenal syndrome ID NATURAL-KILLER-CELLS; SIALIC-ACID; HEPATORENAL-SYNDROME; INHIBITORY RECEPTOR; LIVER FIBROSIS; CLIF-SOFA; MANAGEMENT; RECOMMENDATIONS; IDENTIFICATION; MONOCYTES AB Patients with decompensated cirrhosis have high morbidity and are commonly hospitalized with acute kidney injury. We examined serum levels of Siglec-7, a transmembrane receptor that regulates immune activity, as a biomarker for mortality in patients with cirrhosis and acute kidney injury. Serum Siglec-7 was measured in hospitalized patients with cirrhosis and acute kidney injury, as well as in reference groups with acute liver injury/acute kidney injury, cirrhosis without acute kidney injury, and sepsis without liver disease. Clinical characteristics and subsequent outcomes were examined using univariate and multivariable analyses according to initial Siglec-7 levels. Primary outcome was death by 90 days. One hundred twenty-eight subjects were included, 92 of which had cirrhosis and acute kidney injury and were used in the primary analysis. Average Model for End-Stage Liver Disease (MELD) score was 24 [95 % CI 23, 26], and serum creatinine was 2.5 [2.2, 2.8] mg/dL at the time Siglec-7 was measured. After adjusting for age and MELD score, high serum Siglec-7 level predicted mortality with a hazard ratio of 1.96 [1.04, 3.69; p = 0.04]. There was no difference in Siglec-7 levels by etiology of AKI (p = 0.24). Addition of serum Siglec-7 to MELD score improved discrimination for 90-day mortality [category-free net reclassification index = 0.38 (p = 0.04); integrated discrimination increment = 0.043 (p = 0.04)]. Serum Siglec-7 was associated with increased mortality among hospitalized patients with cirrhosis and acute kidney injury. Addition of Siglec-7 to MELD score may increase discrimination to predict 90-day mortality. C1 [Allegretti, Andrew S.; Kalim, Sahir; Wibecan, Joshua; Xu, Dihua; Thadhani, Ravi I.] Massachusetts Gen Hosp, Div Nephrol, Dept Med, 55 Fruit St,GRB 1008, Boston, MA 02114 USA. [Ortiz, Guillermo] St Elizabeth Hosp, Dept Med, Boston, MA USA. [Zhang, Dongsheng; Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Div Nephrol, Dept Med, Boston, MA USA. [Shan, Hui Yi] Keck Sch Med USC, Div Nephrol & Hypertens, Dept Med, Los Angeles, CA USA. [Chung, Raymond T.] Massachusetts Gen Hosp, Liver Ctr & Gastrointestinal Div, Dept Med, Boston, MA 02114 USA. RP Allegretti, AS (reprint author), Massachusetts Gen Hosp, Div Nephrol, Dept Med, 55 Fruit St,GRB 1008, Boston, MA 02114 USA. EM aallegretti@partners.org; ortiz.sanjuan@gmail.com; skalim@partners.org; j.wibecan@gmail.com; dzhang4@bidmc.harvard.edu; shanh01@yahoo.com; DXU3@mgh.harvard.edu; chung.raymond@mgh.harvard.edu; sananth@bidmc.harvard.edu; RTHADHANI@mgh.harvard.edu FU NIH [5T32DK007540-30, K24DK078772, R01DK094486, K24DK094872]; Howard Hughes Medical Institute FX ASA is supported by NIH Grant 5T32DK007540-30. RTC is supported by NIH Grant K24DK078772. RIT is supported by NIH Grants R01DK094486 and K24DK094872. SAK was supported by funds from the Howard Hughes Medical Institute. NR 48 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD DEC PY 2016 VL 61 IS 12 BP 3609 EP 3620 DI 10.1007/s10620-016-4316-x PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EC6DT UT WOS:000388227400033 PM 27655105 ER PT J AU Chee, A Shi, P Cha, T Kao, TH Yang, SH Zhu, J Chen, D Zhang, YJ An, HS AF Chee, Ana Shi, Peng Cha, Thomas Kao, Ting-Hsien Yang, Shu-Hua Zhu, Jun Chen, Ding Zhang, Yejia An, Howard S. TI Cell Therapy with Human Dermal Fibroblasts Enhances Intervertebral Disk Repair and Decreases Inflammation in the Rabbit Model SO GLOBAL SPINE JOURNAL LA English DT Article DE cell therapy; human dermal fibroblast; disk degeneration; rabbit model ID MESENCHYMAL STEM-CELLS; EQUIVALENT ICX-SKN; CHONDROCYTE TRANSPLANTATION; IN-VIVO; CHONDROGENIC DIFFERENTIATION; CLINICAL-EXPERIENCE; PROTEOGLYCAN; THERAPEUTICS; DEGENERATION; REGENERATION AB Study DesignPilot study using the rabbit model. ObjectiveLow back pain is often associated with disk degeneration. Cell therapy for degenerating disks may promote tissue regeneration and repair. Human dermal fibroblasts, obtained from the patient's skin tissue or donated tissue, may be a promising cell therapy option for degenerating disks. The objective of these studies is to determine the effects of intradiscal transplantation of neonatal human dermal fibroblasts (nHDFs) on intervertebral disk (IVD) degeneration by measuring disk height, magnetic resonance imaging (MRI) signal intensity, gene expression, and collagen immunostaining. MethodsNew Zealand white rabbits (n=16) received an annular puncture to induce disk degeneration and were treated with nHDFs or saline 4 weeks later. At 2 and 8 weeks post-treatment, X-ray and MRI images were obtained. IVDs were isolated and examined for changes in collagen staining and gene expression. ResultsIn the nHDF-treated group, there was a 10% increase in the disk height index after 8 weeks of treatment (p0.05), and there was no significant difference in the saline-treated group. When compared with the saline-treated disks, disks treated with nHDFs showed reduced expression of inflammatory markers, a higher ratio of collagen type II over collagen type I gene expression, and more intense immunohistochemical staining for both collagen types I and II. ConclusionsHuman dermal fibroblast introduction into the disk reduced inflammation and promoted tissue rich in both type I and type II collagens. The results of this study suggest that nHDFs would be a feasible cell therapy option for disk degeneration. C1 [Chee, Ana; Shi, Peng; An, Howard S.] Rush Univ, Med Ctr, Dept Orthoped Surg, 1653 W Congress Pkwy, Chicago, IL 60612 USA. [Cha, Thomas] Massachusetts Gen Hosp, Dept Orthopaed, Yawkey Ctr Outpatient Care, Boston, MA 02114 USA. [Kao, Ting-Hsien] Lin Shin Hosp, Dept Neurosurg, Taichung, Taiwan. [Yang, Shu-Hua] Natl Taiwan Univ Hosp, Dept Orthoped, Taipei, Taiwan. [Yang, Shu-Hua] Natl Taiwan Univ, Coll Med, Taipei, Taiwan. [Zhu, Jun] First Peoples Hosp Huaihua, Dept Orthoped, Huaihua, Hunan, Peoples R China. [Zhu, Jun] Univ South China, Huaihua, Hunan, Peoples R China. [Chen, Ding] Cent S Univ, Xiangya Hosp 2, Dept Orthoped Surg, Changsha, Hunan, Peoples R China. [Zhang, Yejia] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Zhang, Yejia] Univ Penn, Dept Phys Med & Rehabil, Perelman Sch Med, Philadelphia, PA 19104 USA. RP An, HS (reprint author), Rush Univ, Med Ctr, Dept Orthoped Surg, 1653 W Congress Pkwy, Chicago, IL 60612 USA. EM howard.an@rushortho.com OI YANG, SHU-HUA/0000-0002-9879-0164 NR 34 TC 0 Z9 0 U1 5 U2 5 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 2192-5682 EI 2192-5690 J9 GLOB SPINE J JI Glob. Spine J. PD DEC PY 2016 VL 6 IS 8 BP 771 EP 779 DI 10.1055/s-0036-1582391 PG 9 WC Orthopedics SC Orthopedics GA ED1ZS UT WOS:000388644000007 PM 27853661 ER PT J AU Mima, K Nishihara, R Qian, ZR Cao, Y Sukawa, Y Nowak, JA Yang, JH Dou, RX Masugi, Y Song, MY Kostic, AD Giannakis, M Bullman, S Milner, DA Baba, H Giovannucci, EL Garraway, LA Freeman, GJ Dranoff, G Garrett, WS Huttenhower, C Meyerson, M Meyerhardt, JA Chan, AT Fuchs, CS Ogino, S AF Mima, Kosuke Nishihara, Reiko Qian, Zhi Rong Cao, Yin Sukawa, Yasutaka Nowak, Jonathan A. Yang, Juhong Dou, Ruoxu Masugi, Yohei Song, Mingyang Kostic, Aleksandar D. Giannakis, Marios Bullman, Susan Milner, Danny A. Baba, Hideo Giovannucci, Edward L. Garraway, Levi A. Freeman, Gordon J. Dranoff, Glenn Garrett, Wendy S. Huttenhower, Curtis Meyerson, Matthew Meyerhardt, Jeffrey A. Chan, Andrew T. Fuchs, Charles S. Ogino, Shuji TI Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis SO GUT LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; III COLON-CANCER; MICROSATELLITE INSTABILITY; BRAF MUTATION; PIK3CA MUTATION; GUT MICROBIOTA; FEATURES; DISEASE; ASSOCIATION AB Objective Accumulating evidence links the intestinal microbiota and colorectal carcinogenesis. Fusobacterium nucleatum may promote colorectal tumour growth and inhibit T cell-mediated immune responses against colorectal tumours. Thus, we hypothesised that the amount of F. nucleatum in colorectal carcinoma might be associated with worse clinical outcome. Design We used molecular pathological epidemiology database of 1069 rectal and colon cancer cases in the Nurses' Health Study and the Health Professionals Follow-up Study, and measured F. nucleatum DNA in carcinoma tissue. Cox proportional hazards model was used to compute hazard ratio (HR), controlling for potential confounders, including microsatellite instability (MSI, mismatch repair deficiency), CpG island methylator phenotype (CIMP), KRAS, BRAF, and PIK3CA mutations, and LINE-1 hypomethylation (low-level methylation). Results Compared with F. nucleatum-negative cases, multivariable HRs (95% CI) for colorectal cancer-specific mortality in F. nucleatum-low cases and F. nucleatum-high cases were 1.25 (0.82 to 1.92) and 1.58 (1.04 to 2.39), respectively, (p for trend=0.020). The amount of F. nucleatum was associated with MSI-high (multivariable odd ratio (OR), 5.22; 95% CI 2.86 to 9.55) independent of CIMP and BRAF mutation status, whereas CIMP and BRAF mutation were associated with F. nucleatum only in univariate analyses (p<0.001) but not in multivariate analysis that adjusted for MSI status. Conclusions The amount of F. nucleatum DNA in colorectal cancer tissue is associated with shorter survival, and may potentially serve as a prognostic biomarker. Our data may have implications in developing cancer prevention and treatment strategies through targeting GI microflora by diet, probiotics and antibiotics. C1 [Mima, Kosuke; Nishihara, Reiko; Qian, Zhi Rong; Sukawa, Yasutaka; Yang, Juhong; Dou, Ruoxu; Masugi, Yohei; Giannakis, Marios; Bullman, Susan; Garraway, Levi A.; Freeman, Gordon J.; Dranoff, Glenn; Garrett, Wendy S.; Meyerson, Matthew; Meyerhardt, Jeffrey A.; Fuchs, Charles S.; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Mima, Kosuke; Nishihara, Reiko; Qian, Zhi Rong; Sukawa, Yasutaka; Nowak, Jonathan A.; Yang, Juhong; Dou, Ruoxu; Masugi, Yohei; Kostic, Aleksandar D.; Giannakis, Marios; Bullman, Susan; Milner, Danny A.; Giovannucci, Edward L.; Garraway, Levi A.; Freeman, Gordon J.; Dranoff, Glenn; Garrett, Wendy S.; Huttenhower, Curtis; Meyerson, Matthew; Meyerhardt, Jeffrey A.; Chan, Andrew T.; Fuchs, Charles S.; Ogino, Shuji] Harvard Med Sch, Boston, MA USA. [Nishihara, Reiko; Cao, Yin; Song, Mingyang; Giovannucci, Edward L.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Nishihara, Reiko; Cao, Yin; Song, Mingyang; Giovannucci, Edward L.; Ogino, Shuji] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Nishihara, Reiko; Kostic, Aleksandar D.; Huttenhower, Curtis] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Nowak, Jonathan A.; Milner, Danny A.; Meyerson, Matthew; Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Yang, Juhong] Tianjin Med Univ, Metab Dis Hosp, Key Lab Hormone & Dev, Collaborat Innovat Ctr Tianjin Med Epigenet, Tianjin, Peoples R China. [Yang, Juhong] Tianjin Med Univ, Tianjin Inst Endocrinol, Tianjin, Peoples R China. [Kostic, Aleksandar D.; Giannakis, Marios; Bullman, Susan; Garraway, Levi A.; Garrett, Wendy S.; Huttenhower, Curtis; Meyerson, Matthew] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Kostic, Aleksandar D.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Giannakis, Marios; Garraway, Levi A.; Freeman, Gordon J.; Dranoff, Glenn] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Milner, Danny A.; Garrett, Wendy S.] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA. [Baba, Hideo] Kumamoto Univ, Grad Sch Med Sci, Dept Gastroenterol Surg, Kumamoto, Japan. [Giovannucci, Edward L.; Chan, Andrew T.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Dranoff, Glenn] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Huttenhower, Curtis] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. RP Ogino, S (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Room M422, Boston, MA 02215 USA. EM shuji_ogino@dfci.harvard.edu OI Kostic, Aleksandar/0000-0002-0837-4360 FU US National Institutes of Health (NIH) [P01 CA87969, UM1 CA186107, P01 CA55075, UM1 CA167552, P50 CA127003, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673]; Paula and Russell Agrusa Fund for Colorectal Cancer Research; Friends of the Dana-Farber Cancer Institute; Bennett Family Fund; Entertainment Industry Foundation through National Colorectal Cancer Research Alliance; Uehara Memorial Foundation; Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers from Japanese Society for the Promotion of Science FX This work was supported by US National Institutes of Health (NIH) grants (P01 CA87969 to S E Hankinson; UM1 CA186107 to M J Stampfer; P01 CA55075 and UM1 CA167552 to W C Willett; P50 CA127003 to CSF; R01 CA137178 to ATC; R01 CA151993 and R35 CA197735 to SO; and K07 CA190673 to RN); and by grants from The Paula and Russell Agrusa Fund for Colorectal Cancer Research, The Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. KM is supported by a fellowship grant from Uehara Memorial Foundation and a grant from Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers from Japanese Society for the Promotion of Science. NR 52 TC 11 Z9 11 U1 20 U2 20 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD DEC PY 2016 VL 65 IS 12 BP 1973 EP 1980 DI 10.1136/gutjnl-2015-310101 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EC4MV UT WOS:000388106600008 PM 26311717 ER PT J AU Scharpf, J Tuttle, M Wong, R Ridge, D Smith, R Hartl, D Levine, R Randolph, G AF Scharpf, Joseph Tuttle, Michael Wong, Richard Ridge, Drew Smith, Russell Hartl, Dana Levine, Robert Randolph, Gregory TI Comprehensive management of recurrent thyroid cancer: An American Head and Neck Society Consensus Statement AHNS Consensus Statement SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE thyroid cancer; recurrent thyroid cancer; reoperative thyroid surgery; thyroid cancer surveillance; nonoperative recurrent thyroid cancer management ID PERCUTANEOUS ETHANOL INJECTION; EXTERNAL-BEAM RADIOTHERAPY; METASTATIC LYMPH-NODES; SERUM THYROGLOBULIN; PARATHYROID SURGERY; REMNANT ABLATION; CARCINOMA; THERAPY; SURVEILLANCE; OUTCOMES AB This American Head and Neck Society (AHNS) consensus statement focuses on the detection and management of recurrent thyroid cancer. This document describes the radiologic approach to defining structural recurrent disease and the operative and nonoperative rationale in addressing identified structural disease to create equipoise in the personalized treatment strategy for the patient. The recommendations of this AHNS multidisciplinary consensus panel of the American Head and Neck Society are intended to help guide all multidisciplinary clinicians who diagnose or manage adult patients with thyroid cancer. The consensus panel is comprised of members of the American Head and Neck Society and its Endocrine Surgical Committee, and there is representation from medical endocrinology and both national and international surgical representation drawn from general/endocrine surgery and otolaryngology/head and neck surgery. Authors provided expertise for their respective sections, and consensus recommendations were made regarding the evaluation and treatment of recurrent thyroid cancer. Evidence-based literature support is drawn from thyroid cancer studies, recurrent thyroid cancer studies, and American Thyroid Association (ATA) guidelines. The manuscript was then distributed to members of the American Head and Neck Society Endocrine Committee and governing counsel for further feedback. (C) 2016 Wiley Periodicals, Inc. C1 [Scharpf, Joseph] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Tuttle, Michael; Wong, Richard] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Ridge, Drew] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Smith, Russell] Univ Nebraska, Med Ctr, Omaha, NE USA. [Hartl, Dana] Inst Cancerol Gustave Roussy, Villejuif, France. [Levine, Robert] Thyroid Ctr New Hampshire, Nashua, NH USA. [Randolph, Gregory] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Boston, MA USA. RP Scharpf, J (reprint author), Cleveland Clin Fdn, Head & Neck Inst, 8615 Euclid Ave, Cleveland, OH 44195 USA. EM Scharpj@ccf.org NR 33 TC 1 Z9 1 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 EI 1097-0347 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD DEC PY 2016 VL 38 IS 12 BP 1862 EP 1869 DI 10.1002/hed.24513 PG 8 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA EC8CI UT WOS:000388367400020 PM 27717219 ER PT J AU Abu Ghazal, Y Hinton, DE AF Abu Ghazal, Yazan Hinton, Devon E. TI Platzschwindel, agoraphobia and their influence on theories of anxiety at the end of the nineteenth century: theories of the role of biology and "representations' (Vorstellungen) SO HISTORY OF PSYCHIATRY LA English DT Article DE Agoraphobia; anxiety; history of psychiatry; representations; vertigo AB During the 1860s, Berlin's exterior physiognomy transformed radically. The city eroded the surrounding rural areas, and the frontiers of the old city centre were abolished. These transformations led to the disappearance of the visible frontiers that once demarcated the limits of the old residential Prussian city. In this context, the description of the clinical picture of agoraphobia by the Berlin psychiatrist Carl Westphal in 1872 marked a turning point, not only in psychiatric theories on anxiety but also in the conceptualization of our experience of space. In this paper, the authors trace the emergence of a new psychology-neurology episteme during the last third of the nineteenth century; and they argue that such an episteme became possible once the relations between anxiety and modern city-scape had been clearly articulated. C1 [Abu Ghazal, Yazan] Beaufort St,Banna Bldg, Beirut, Lebanon. [Hinton, Devon E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Abu Ghazal, Y (reprint author), Beaufort St,Banna Bldg, Beirut, Lebanon. EM yabughaz@gmail.com NR 39 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0957-154X EI 1740-2360 J9 HIST PSYCHIATR JI Hist. Psychiatr. PD DEC PY 2016 VL 27 IS 4 BP 425 EP 442 DI 10.1177/0957154X16657710 PG 18 WC History Of Social Sciences; Psychiatry SC Social Sciences - Other Topics; Psychiatry GA EC0BA UT WOS:000387761300003 ER PT J AU Gong, Y Zou, L Cen, DZ Chao, W Chen, DJ AF Gong, Yu Zou, Lin Cen, Dongzhi Chao, Wei Chen, Dunjin TI Reduced Expression of SARM in Mouse Spleen during Polymicrobial Sepsis SO INFLAMMATION LA English DT Article DE SARM; polymicrobial sepsis; splenocyte apoptosis ID INDUCED IMMUNOSUPPRESSION; AXON DEGENERATION; ADAPTER SARM; CELL-DEATH; ACTIVATION; MITOCHONDRIA; INFECTION; PROTEIN; TIME; IMMUNOTHERAPY AB Objective Immune dysfunction, including prominent apoptosis of immune cells and decreased functioning of the remaining immune cells, plays a central role in the pathogenesis of sepsis. Sterile alpha and HEAT/armadillo motif-containing protein (SARM) is implicated in the regulation of immune cell apoptosis. This study aimed to elucidate SARM contributes to sepsis-induced immune cell death and immunosuppression. Methods A mouse model of polymicrobial sepsis was generated by cecum ligation and puncture (CLP). SARM gene and protein expression, caspase 3 cleavage and intracellular ATP production were measured in the mouse spleens. Results CLP-induced polymicrobial sepsis specifically attenuated both the gene and protein expression of SARM in the spleens. Moreover, the attenuation of SARM expression synchronized with splenocyte apoptosis, as evidenced by increased caspase 3 cleavage and ATP depletion. Conclusions These findings suggest that SARM is a potential regulator of sepsis-induced splenocyte apoptosis. C1 [Gong, Yu] Guangzhou Med Univ, Affiliated Hosp 3, Biomed Res Ctr, 63 Duobao Rd, Guangzhou 510150, Guangdong, Peoples R China. [Gong, Yu] Guangzhou Med Univ, Affiliated Hosp 3, Key Lab Major Obstet Dis Guangdong Prov,Dept Surg, Key Lab Reprod & Genet Guangdong Higher Educ Inst, 63 Duobao Rd, Guangzhou 510150, Guangdong, Peoples R China. [Gong, Yu; Zou, Lin; Chao, Wei] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Cen, Dongzhi] Guangzhou Med Univ, Affiliated Hosp 3, Dept Oncol, Guangzhou, Guangdong, Peoples R China. [Chen, Dunjin] Guangzhou Med Univ, Affiliated Hosp 3, Key Lab Major Obstet Dis Guangdong Prov,Inst Gyne, Key Lab Reprod & Genet Guangdong Higher Educ Inst, 63 Duobao Rd, Guangzhou 510150, Guangdong, Peoples R China. RP Gong, Y (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA.; Chen, DJ (reprint author), Guangzhou Med Univ, Affiliated Hosp 3, Key Lab Major Obstet Dis Guangdong Prov,Inst Gyne, Key Lab Reprod & Genet Guangdong Higher Educ Inst, 63 Duobao Rd, Guangzhou 510150, Guangdong, Peoples R China. EM shirley_gong17@hotmail.com; djchen_gysy@sina.com FU Guangzhou Medical University [2011C43]; Third Affiliated Hospital of Guangzhou Medical University [2012Y20]; Department of Education of Guangdong Province [2015KQNCX137] FX This work was supported financially by Guangzhou Medical University (2011C43), the Third Affiliated Hospital of Guangzhou Medical University (2012Y20), and Department of Education of Guangdong Province (2015KQNCX137). NR 33 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0360-3997 EI 1573-2576 J9 INFLAMMATION JI Inflammation PD DEC PY 2016 VL 39 IS 6 BP 1930 EP 1938 DI 10.1007/s10753-016-0428-x PG 9 WC Cell Biology; Immunology SC Cell Biology; Immunology GA EC4MX UT WOS:000388106800009 PM 27590237 ER PT J AU Andrikopoulou, E Lloyd, SG Hage, FG AF Andrikopoulou, Efstathia Lloyd, Steven G. Hage, Fadi G. TI Ventricular tachycardia during regadenoson SPECT myocardial perfusion imaging SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Editorial Material ID ADENOSINE C1 [Andrikopoulou, Efstathia; Lloyd, Steven G.; Hage, Fadi G.] Univ Alabama Birmingham, Dept Med, Div Cardiovascular Dis, Cardiovascular Dis Fellowship Program, 1808 7th Ave South,BDB 201, Birmingham, AL 35294 USA. [Lloyd, Steven G.] Univ Alabama Birmingham, Dept Radiol, Birmingham, AL USA. [Lloyd, Steven G.; Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. RP Andrikopoulou, E (reprint author), Univ Alabama Birmingham, Dept Med, Div Cardiovascular Dis, Cardiovascular Dis Fellowship Program, 1808 7th Ave South,BDB 201, Birmingham, AL 35294 USA. EM eandrikopoulou@uabmc.edu OI Hage, Fadi/0000-0002-1397-4942 NR 4 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD DEC PY 2016 VL 23 IS 6 BP 1518 EP 1520 DI 10.1007/s12350-015-0339-5 PG 3 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EC5NI UT WOS:000388182100041 PM 26626781 ER PT J AU Watkins, BA Kim, J Tamez, H Wenger, J Thadhani, R Friedman, AN AF Watkins, Bruce A. Kim, Jeffrey Tamez, Hector Wenger, Julia Thadhani, Ravi Friedman, Allon N. TI Serum phospholipid fraction of polyunsaturated fatty acids is the preferred indicator for nutrition and health status in hemodialysis patients SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE Lipids; Human; PUFA; Serum; Fatty Acids; Phospholipids; Hemodialysis ID CARDIOVASCULAR-DISEASE; OMEGA-3-FATTY-ACIDS; DIACYLGLYCEROL; KINASE; LIPIDS; CELLS AB Long chain (LC) polyunsaturated fatty acids (PUFA) are major components of cell membrane phospholipids (PL) and serve as precursors for numerous bioactive lipid derivatives. Fatty acids (FA) are routinely analyzed in biological samples to assess composition of tissues, cells, and lipid fractions. In human studies, serum or plasma is often used because of their easy procurement. However, the lipid pool in serum and plasma is a mixture of triacylglycerol (TG), PL, cholesterol and its esters, and other components. Herein, we report findings from a serum FA analysis after fractionation of polar and neutral lipids by solid phase extraction in a large cohort of 400 hemodialysis patients. LC PUFA were found concentrated in the polar fraction compared to the total or the neutral lipid fraction. When correlated with clinical markers of disease, a greater number of significant correlations were found for PUFA in polar compared to total or the neutral fraction. We also observed that polar lipids are a reliable reflection of LC PUFA status compared to the total or neutral fractions because the latter are diluted by non-essential FA. The relative amounts of LC PUFA in the total and neutral fractions reflect the contribution of TG in blood that varies with diet, age, and physiologic state. Our data indicate that LC PUFA in the polar fraction are superior indicators of bioactive FA-status than in the total or the neutral fraction and should be used to establish important links between PUFA status, their bioactive substrates in hemodialysis patients. (C) 2016 Elsevier Inc. All rights reserved. C1 [Watkins, Bruce A.] Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA. [Tamez, Hector; Wenger, Julia; Thadhani, Ravi] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Friedman, Allon N.] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Watkins, Bruce A.] Indiana Univ Sch Med, Dept Anat & Cell Biol, Indianapolis, IN 46202 USA. [Watkins, Bruce A.; Kim, Jeffrey] Univ Connecticut, Ctr Hlth, Ctr Aging, Farmington, CT USA. RP Watkins, BA (reprint author), Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA. EM baw@purdue.edu FU NIH grant [DK084403]; National Kidney Foundation FX This work was supported by NIH grant DK084403 and the National Kidney Foundation. NR 27 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 0955-2863 EI 1873-4847 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD DEC PY 2016 VL 38 BP 18 EP 24 DI 10.1016/j.jnutbio.2016.07.021 PG 7 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA EC8ZG UT WOS:000388431000003 PM 27721114 ER PT J AU Kiwanuka, H Aycart, MA Gitlin, DF Devine, E Perry, BJ Win, TS Bueno, EM Alhefzi, M Krezdorn, N Pomahac, B AF Kiwanuka, Harriet Aycart, Mario A. Gitlin, David F. Devine, Elaine Perry, Bridget J. Win, Thet-Su Bueno, Ericka M. Alhefzi, Muayyad Krezdorn, Nicco Pomahac, Bohdan TI The role of face transplantation in the self-inflicted gunshot wound SO JOURNAL OF PLASTIC RECONSTRUCTIVE AND AESTHETIC SURGERY LA English DT Article DE Face transplantation; Vascularized composite allotransplantation; Self-inflicted gunshot wound; Conventional reconstruction; Psychosocial outcomes; Screening ID FORM HEALTH SURVEY; FACIAL TRANSPLANTATION; ACUTE REJECTION; OUTCOMES; ALLOTRANSPLANTATION; RECONSTRUCTION; RELIABILITY; INSTRUMENT; SELECTION; VALIDITY AB Background: Facial self-inflicted gunshot wounds (SIGSWs) cause a devastating midfacial defect and pose a challenging problem to the reconstructive surgeon. Face transplantation (FT) has the potential for near-normal restoration in otherwise nonreconstructible defects. Two out of 7 FT recipients at Brigham and Women's Hospital (BWH) sustained SIGSWs. In this study, we illustrate the role of FT in the management of SIGSWs through an aesthetic, functional, and psychosocial examination of outcomes. Methods: We performed a retrospective analysis of individuals with SIGSWs who were screened at BWH between 2008 and 2015. We then collected data of the injuries, modes of conventional reconstruction (CR), and deficits. For the FT recipients, we critically reviewed the psychosocial screening process and post-transplantation aesthetic, functional, and psychosocial outcomes. Results: A total of six individuals post-SIGSWs were screened for FT. All of them had undergone CR, with five receiving loco-regional flaps and free tissue transfers, and one undergoing serial debridement and primary soft-tissue repair. Following CR, all suffered from residual functional and aesthetic deficits. Two underwent partial FT and one is currently undergoing FT screening. We describe the pre-transplant psychosocial screening process and the aesthetic, functional, and psychosocial outcomes of the SIGSW FT recipients. Conclusions: We examined the facial SIGSW injury, outcomes of CR, and the mechanism of FT to offer a potential solution to the shortcomings of CR. More importantly, we highlight the critical nature of the psychosocial component of the multidisciplinary evaluation given the history of mental illness and suicidal behavior in this subset of patients. (C) 2016 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. C1 [Kiwanuka, Harriet; Aycart, Mario A.; Win, Thet-Su; Bueno, Ericka M.; Alhefzi, Muayyad; Krezdorn, Nicco; Pomahac, Bohdan] Harvard Med Sch, Brigham & Womens Hosp, Div Plast Surg, Dept Surg, 75 Francis St, Boston, MA 02115 USA. [Gitlin, David F.] Harvard Med Sch, Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. [Devine, Elaine] Harvard Med Sch, Brigham & Womens Hosp, Dept Social Work, 75 Francis St, Boston, MA 02115 USA. [Perry, Bridget J.] Massachusetts Gen Hosp, MGH Inst Hlth Profess, 55 Fruit St, Boston, MA 02114 USA. RP Pomahac, B (reprint author), Harvard Med Sch, Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM bpomahac@partners.org FU United States Department of Defense [W911QY-09-C-0216] FX None of the authors have a financial interest in any of the products, devices, or drugs mentioned in this manuscript. Drs. Pomahac, Bueno, and Krezdorn receive partial salary support from a research contract with the United States Department of Defense (#W911QY-09-C-0216). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. NR 43 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 1748-6815 EI 1878-0539 J9 J PLAST RECONSTR AES JI J. Plast. Reconstr. Aesthet. Surg. PD DEC PY 2016 VL 69 IS 12 BP 1636 EP 1647 DI 10.1016/j.bjps.2016.08.014 PG 12 WC Surgery SC Surgery GA EC7CP UT WOS:000388293700010 PM 27720683 ER PT J AU Goff, SL Youssef, Y Pekow, PS White, KO Guhn-Knight, H Lagu, T Mazor, KM Lindenauer, PK AF Goff, Sarah L. Youssef, Yara Pekow, Penelope S. White, Katharine O. Guhn-Knight, Haley Lagu, Tara Mazor, Kathleen M. Lindenauer, Peter K. TI Successful Strategies for Practice-Based Recruitment of Racial and Ethnic Minority Pregnant Women in a Randomized Controlled Trial: the IDEAS for a Healthy Baby Study SO JOURNAL OF RACIAL AND ETHNIC HEALTH DISPARITIES LA English DT Article DE Recruitment; Retention; Randomized controlled trial; Pregnant women; Low socioeconomic status; Racial and ethnicminority ID LOW-INCOME; INTERVENTION TRIAL; CLINICAL-TRIALS; HISPANIC WOMEN; CARE; PARTICIPATION; RETENTION; BARRIERS; CHILDREN; QUALITY AB Background Racial/ethnic minority patients are often under-represented in clinical trials. Efforts to address barriers to participation may improve representation, thus enhancing our understanding of how research findings apply to more diverse populations. Methods The IDEAS (Information, Description, Education, Assistance, and Support) for a Healthy Baby study was a randomized controlled trial (RCT) of an intervention to reduce barriers to using publicly reported quality data for low-income, racial/ethnic minority women. We used strategies grounded in a health equity framework to address barriers to recruitment and retention in three domains: preparation, process, and patient-centeredness. "Preparation" included teaching study staff about health inequities, role-playing skills to develop rapport and trust, and partnering with clinic staff. "Processes" included use of electronic registration systems to pre-screen potential candidates and determine when eligible participants were in clinic and an electronic database to track patients through the study. Use of a flexible protocol, stipends, and consideration of literacy levels promoted "patient-centeredness." Results We anticipated needing to recruit 800 women over 18 months to achieve a completion goal of 650. Using the recruitment and retention strategies outlined above, we recruited 746 women in 15 months, achieving higher recruitment (87.1 %) and retention rates (97.3 %) than we had anticipated. Discussion These successful recruitment and retention strategies used for a large RCT promoted inclusivity and accessibility. Researchers seeking to recruit racial and ethnic minority pregnant women in similar settings may find the preparation, process, and patient-centered strategies used in this study applicable for their own studies. C1 [Goff, Sarah L.; Guhn-Knight, Haley; Lagu, Tara; Lindenauer, Peter K.] Tufts Univ, Dept Med, Baystate Med Ctr, 759 Chestnut St, Springfield, MA 01199 USA. [Goff, Sarah L.; Pekow, Penelope S.; Guhn-Knight, Haley; Lagu, Tara; Lindenauer, Peter K.] Baystate Med Ctr, Ctr Qual Care Res, 759 Chestnut St, Springfield, MA 01199 USA. [Youssef, Yara; Pekow, Penelope S.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Amherst, MA 01003 USA. [Youssef, Yara] Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. [White, Katharine O.] Boston Univ, Med Ctr, Dept Obstet & Gynecol, 72 East Concord St, Boston, MA 02118 USA. [Mazor, Kathleen M.] Meyers Primary Care Inst, 630 Plantat St, Worcester, MA USA. [Mazor, Kathleen M.] Univ Massachusetts, Sch Med, Dept Internal Med, 55 Lake Ave N, Worcester, MA USA. RP Goff, SL (reprint author), Tufts Univ, Dept Med, Baystate Med Ctr, 759 Chestnut St, Springfield, MA 01199 USA.; Goff, SL (reprint author), Baystate Med Ctr, Ctr Qual Care Res, 759 Chestnut St, Springfield, MA 01199 USA. EM sarah.goffmd@baystatehealth.org; penny.pekow@baystatehealth.org FU AHRQ HHS [R21 HS021864, R21 HS021879]; NHLBI NIH HHS [K01 HL114745] NR 36 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2197-3792 EI 2196-8837 J9 J RACIAL ETHN HEALTH JI J. Racial Ethn. Health Disparities PD DEC PY 2016 VL 3 IS 4 BP 731 EP 737 DI 10.1007/s40615-015-0192-x PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EC5TN UT WOS:000388199400019 PM 27068662 ER PT J AU Carrera, ET Dias, HB Corbi, SCT Marcantonio, RAC Bernardi, ACA Bagnato, VS Hamblin, MR Rastelli, ANS AF Carrera, E. T. Dias, H. B. Corbi, S. C. T. Marcantonio, R. A. C. Bernardi, A. C. A. Bagnato, V. S. Hamblin, M. R. Rastelli, A. N. S. TI The application of antimicrobial photodynamic therapy (aPDT) in dentistry: a critical review SO LASER PHYSICS LA English DT Review DE photochemotherapy; bacteria; biofilms; photosensitizing agents ID STREPTOCOCCUS-MUTANS; METHYLENE-BLUE; IN-VITRO; AGGRESSIVE PERIODONTITIS; NONSURGICAL TREATMENT; LASER-RADIATION; CURCUMIN; BIOFILMS; PHOTOSENSITIZERS; CHEMOTHERAPY AB In recent years there have been an increasing number of in vitro and in vivo studies that show positive results regarding antimicrobial photodynamic therapy (aPDT) used in dentistry. These include applications in periodontics, endodontics, and mucosal infections caused by bacteria present as biofilms. Antimicrobial photodynamic therapy is a therapy based on the combination of a non-toxic photosensitizer (PS) and appropriate wavelength visible light, which in the presence of oxygen is activated to produce reactive oxygen species (ROS). ROS induce a series of photochemical and biological events that cause irreversible damage leading to the death of microorganisms. Many light-absorbing dyes have been mentioned as potential PS for aPDT and different wavelengths have been tested. However, there is no consensus on a standard protocol yet. Thus, the goal of this review was to summarize the results of research on aPDT in dentistry using the PubMed database focusing on recent studies of the effectiveness aPDT in decreasing microorganisms and microbial biofilms, and also to describe aPDT effects, mechanisms of action and applications. C1 [Carrera, E. T.; Dias, H. B.; Rastelli, A. N. S.] Univ Estadual Paulista, Araraquara Sch Dent, Dept Restorat Dent, 1680 Humaita St, BR-14801903 Araraquara, SP, Brazil. [Corbi, S. C. T.; Marcantonio, R. A. C.] Univ Estadual Paulista, Araraquara Sch Dent, Dept Diag & Surg, BR-14801903 Araraquara, SP, Brazil. [Bernardi, A. C. A.] Univ Ctr Araraquara UNIARA, Dept Biol & Hlth Sci, BR-14801340 Araraquara, SP, Brazil. [Bagnato, V. S.] Univ Sao Paulo, Dept Phys & Mat Sci, Phys Inst Sao Carlos IFSC, BR-13566590 Sao Carlos, SP, Brazil. [Hamblin, M. R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hamblin, M. R.] Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, M. R.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Rastelli, ANS (reprint author), Univ Estadual Paulista, Araraquara Sch Dent, Dept Restorat Dent, 1680 Humaita St, BR-14801903 Araraquara, SP, Brazil. EM alrastelli@foar.unesp.br RI Sao Carlos Institute of Physics, IFSC/USP/M-2664-2016 FU CAPES - Coordination for the Improvement of Higher Education Personnel; FAPEAM (Amazon State Research Foundation); FAPESP (Sao Paulo Research Foundation, Brazil) [2013/07276-1-CEPOF]; US NIH [R01AI050875] FX The authors would like to thank CAPES - Coordination for the Improvement of Higher Education Personnel, FAPEAM (Amazon State Research Foundation) and FAPESP (Sao Paulo Research Foundation, Brazil) for the following research grant (Process 2013/07276-1-CEPOF) and for the financial support for this study. Michael R Hamblin was supported by US NIH grant R01AI050875. NR 65 TC 0 Z9 0 U1 20 U2 20 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1054-660X EI 1555-6611 J9 LASER PHYS JI Laser Phys. PD DEC PY 2016 VL 26 IS 12 AR 123001 DI 10.1088/1054-660X/26/12/123001 PG 13 WC Optics; Physics, Applied SC Optics; Physics GA ED0EL UT WOS:000388515700001 ER PT J AU Liu, XW Perakakis, N Gong, HZ Chamberland, JP Brinkoetter, MT Hamnvik, OPR Mantzoros, CS AF Liu, Xiaowen Perakakis, Nikolaos Gong, Huizhi Chamberland, John P. Brinkoetter, Mary T. Hamnvik, Ole-Petter R. Mantzoros, Christos S. TI Adiponectin administration prevents weight gain and glycemic profile changes in diet-induced obese immune deficient Rag1-/- mice lacking mature lymphocytes SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article DE Adiponectin; Obesity; Diabetes; Lymphocyte; Immunity ID ACTIVE ANTIRETROVIRAL THERAPY; HIGH-FAT DIET; INSULIN-RESISTANCE; ADIPOSE-TISSUE; ENERGY HOMEOSTASIS; METABOLIC SYNDROME; INFECTED PATIENTS; PROTEIN-KINASE; DISEASE; LEPTIN AB Background. Obesity is associated with chronic low-grade inflammation leading to insulin resistance and diabetes. Adiponectin is an adipokine that regulates inflammatory responses. The aim of our study was to investigate whether any effects of adiponectin against obesity and insulin-resistance may depend on the adaptive immune system. Methods. We treated high-fat-diet fed Rag1-/- mice lacking mature lymphocytes with adiponectin over 7 weeks and investigated alterations in their metabolic outcome and inflammatory state. Results. Adiponectin protects from weight gain despite a small compensatory stimulation of energy intake in mice lacking an adaptive immune system. Additionally, adiponectin protects from dysglycemia. Minor alterations in the macrophage phenotype, but not in the circulating cytokine levels, may contribute to the protective role of adiponectin against hyperglycemia and diabetes. Conclusion. Adiponectin or agents increasing adiponectin may be a promising therapeutic option against obesity and hyperglycemia in immune-deficient populations. (C) 2016 Elsevier Inc. All rights reserved. C1 [Liu, Xiaowen; Perakakis, Nikolaos; Gong, Huizhi; Chamberland, John P.; Brinkoetter, Mary T.; Hamnvik, Ole-Petter R.; Mantzoros, Christos S.] Harvard Med Sch, Div Endocrinol Diabet & Metab, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Chamberland, John P.; Hamnvik, Ole-Petter R.; Mantzoros, Christos S.] Harvard Med Sch, Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA 02130 USA. [Hamnvik, Ole-Petter R.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Diabet & Hypertens, 75 Francis St, Boston, MA 02115 USA. [Hamnvik, Ole-Petter R.] Harvard Med Sch, Boston, MA USA. RP Perakakis, N (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Endocrinol, FD 876,330 Brookline Ave, Boston, MA 02215 USA. EM nperakak@bidmc.harvard.edu FU BIDMC; NIH [DK081913] FX Discretionary grant from BIDMC. This work is also supported in part by NIH DK081913. NR 39 TC 0 Z9 0 U1 3 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD DEC PY 2016 VL 65 IS 12 BP 1720 EP 1730 DI 10.1016/j.metabol.2016.09.003 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EC5FO UT WOS:000388158700003 PM 27832860 ER PT J AU Moore, JC Mulligan, TS Yordan, NT Castranova, D Pham, VN Tang, Q Lobbardi, R Anselmo, A Liwski, RS Berman, JN Sadreyev, RI Weinstein, BM Langenau, DM AF Moore, John C. Mulligan, Timothy S. Yordan, Nora Torres Castranova, Daniel Pham, Van N. Tang, Qin Lobbardi, Riadh Anselmo, Anthony Liwski, Robert S. Berman, Jason N. Sadreyev, Ruslan I. Weinstein, Brant M. Langenau, David M. TI T Cell Immune Deficiency in zap70 Mutant Zebrafish SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; TRANSGENIC ZEBRAFISH; VASCULAR DEVELOPMENT; TYROSINE KINASE; EMBRYONAL RHABDOMYOSARCOMA; SYK; ZAP-70; TRANSPLANTATION; EXPRESSION; MICE AB ZAP70 [zeta-chain (TCR)-associated protein kinase, 70-kDa], is required for T cell activation. ZAP70 deficiencies in humans and null mutations in mice lead to severe combined immune deficiency. Here, we describe a zap70 loss-of-function mutation in zebrafish (zap70(y442)) that was created using transcription activator-like effector nucleases (TALENs). In contrast to what has been reported for morphant zebrafish, zap70(y442) homozygous mutant zebrafish displayed normal development of blood and lymphatic vasculature. Hematopoietic cell development was also largely unaffected in mutant larvae. However, mutant fish had reduced lck: GFP(+) thymic T cells by 5 days postfertilization that persisted into adult stages. Morphological analysis, RNA sequencing, and single-cell gene expression profiling of whole kidney marrow cells of adult fish revealed complete loss of mature T cells in zap70(y442) mutant animals. T cell immune deficiency was confirmed through transplantation of unmatched normal and malignant donor cells into zap70(y442) mutant zebrafish, with T cell loss being sufficient for robust allogeneic cell engraftment. zap70 mutant zebrafish show remarkable conservation of immune cell dysfunction as found in mice and humans and will serve as a valuable model to study zap70 immune deficiency. C1 [Moore, John C.; Tang, Qin; Lobbardi, Riadh; Langenau, David M.] Massachusetts Gen Hosp, Mol Pathol, Charlestown, MA 02129 USA. [Moore, John C.; Tang, Qin; Lobbardi, Riadh; Langenau, David M.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Moore, John C.; Tang, Qin; Lobbardi, Riadh; Langenau, David M.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Moore, John C.; Yordan, Nora Torres; Tang, Qin; Lobbardi, Riadh; Langenau, David M.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Mulligan, Timothy S.; Castranova, Daniel; Pham, Van N.; Weinstein, Brant M.] NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Yordan, Nora Torres] Harvard Univ, Cambridge, MA 02138 USA. [Anselmo, Anthony; Sadreyev, Ruslan I.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Anselmo, Anthony] Harvard Med Sch, Dept Genet, Boston, MA USA. [Liwski, Robert S.; Berman, Jason N.] Dalhousie Univ, Izaak Walton Killam Hlth Ctr, Halifax, NS, Canada. [Sadreyev, Ruslan I.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sadreyev, Ruslan I.] Harvard Med Sch, Boston, MA USA. RP Langenau, DM (reprint author), Massachusetts Gen Hosp, Mol Pathol, Charlestown, MA 02129 USA.; Langenau, DM (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA.; Langenau, DM (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA.; Langenau, DM (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA.; Weinstein, BM (reprint author), NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. EM flyingfish2@nih.gov; dlangenau@mgh.harvard.edu FU HHS \ National Institutes of Health (NIH) [R01CA154923, U54CA168512]; HHS \ NIH \ NIH Office of the Director (OD) [R24OD016761]; HHS \ NIH \ Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [ZIA-HD008808] FX This work, including the efforts of John Moore, Nora Torres Yordan, Qin Tang, Riadh Lobbardi, and David Langenau, was funded by HHS vertical bar National Institutes of Health (NIH) (R01CA154923). This work, including the efforts of John Moore, Nora Torres Yordan, Qin Tang, Riadh Lobbardi, and David Langenau, was funded by HHS vertical bar National Institutes of Health (NIH) (U54CA168512). This work, including the efforts of John Moore, Nora Torres Yordan, Qin Tang, Riadh Lobbardi, and David Langenau, was funded by HHS vertical bar NIH vertical bar NIH Office of the Director (OD) (R24OD016761). This work, including the efforts of Timothy Mulligan, Daniel Castranova, Van Pham, and Brant Weinstein, was funded by HHS vertical bar NIH vertical bar Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (ZIA-HD008808). NR 41 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC PY 2016 VL 36 IS 23 BP 2868 EP 2876 DI 10.1128/MCB.00281-16 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EC9MU UT WOS:000388469500001 ER PT J AU Lee, PH Baker, JT Holmes, AJ Jahanshad, N Ge, T Jung, JY Cruz, Y Manoach, DS Hibar, DP Faskowitz, J McMahon, KL de Zubicaray, GI Martin, NH Wright, MJ Ongur, D Buckner, R Roffman, J Thompson, PM Smoller, JW AF Lee, P. H. Baker, J. T. Holmes, A. J. Jahanshad, N. Ge, T. Jung, J-Y Cruz, Y. Manoach, D. S. Hibar, D. P. Faskowitz, J. McMahon, K. L. de Zubicaray, G. I. Martin, N. H. Wright, M. J. Ongur, D. Buckner, R. Roffman, J. Thompson, P. M. Smoller, J. W. TI Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia SO MOLECULAR PSYCHIATRY LA English DT Article ID GENOME-WIDE ASSOCIATION; 1ST EPISODE SCHIZOPHRENIA; VOXEL-BASED MORPHOMETRY; SUPERIOR FRONTAL GYRUS; HUMAN CEREBRAL-CORTEX; DEFAULT MODE NETWORK; YOUNG-ADULT SMOKERS; CORTICAL THICKNESS; PREFRONTAL CORTEX; POLYGENIC RISK AB Schizophrenia is a devastating neurodevelopmental disorder with a complex genetic etiology. Widespread cortical gray matter loss has been observed in patients and prodromal samples. However, it remains unresolved whether schizophrenia-associated cortical structure variations arise due to disease etiology or secondary to the illness. Here we address this question using a partitioning-based heritability analysis of genome-wide single-nucleotide polymorphism (SNP) and neuroimaging data from 1750 healthy individuals. We find that schizophrenia-associated genetic variants explain a significantly enriched proportion of trait heritability in eight brain phenotypes (false discovery rate = 10%). In particular, intracranial volume and left superior frontal gyrus thickness exhibit significant and robust associations with schizophrenia genetic risk under varying SNP selection conditions. Cross-disorder comparison suggests that the neurogenetic architecture of schizophrenia-associated brain regions is, at least in part, shared with other psychiatric disorders. Our study highlights key neuroanatomical correlates of schizophrenia genetic risk in the general population. These may provide fundamental insights into the complex pathophysiology of the illness, and a potential link to neurocognitive deficits shaping the disorder. C1 [Lee, P. H.; Ge, T.; Cruz, Y.; Smoller, J. W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. [Lee, P. H.; Ge, T.; Smoller, J. W.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Lee, P. H.; Baker, J. T.; Ge, T.; Ongur, D.; Roffman, J.; Smoller, J. W.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Baker, J. T.; Ongur, D.] McLean Hosp, Psychot Disorders Div, Schizophrenia & Bipolar Disorder Program, 115 Mill St, Belmont, MA 02178 USA. [Holmes, A. J.; Ge, T.; Manoach, D. S.; Buckner, R.] Harvard Med Sch, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Holmes, A. J.] Yale Univ, Dept Psychol, New Haven, CT USA. [Jahanshad, N.; Hibar, D. P.; Faskowitz, J.; Thompson, P. M.] Univ Southern Calif, Keck Sch Med, Stevens Neuroimaging & Informat Inst, Imaging Genet Ctr, Marina Del Rey, CA USA. [Jung, J-Y] Stanford Univ, Dept Pediat, Div Syst Med, Stanford, CA 94305 USA. [Cruz, Y.] Harvard Grad Sch Educ, Cambridge, MA USA. [McMahon, K. L.; Wright, M. J.] Univ Queensland, Ctr Adv Imaging, Brisbane, Qld, Australia. [de Zubicaray, G. I.] Queensland Univ Technol, Fac Hlth, Brisbane, Qld, Australia. [de Zubicaray, G. I.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia. [Martin, N. H.] Queensland Inst Med Res QIMR Berghofer, Brisbane, Qld, Australia. [Wright, M. J.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Buckner, R.] Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA. [Buckner, R.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Roffman, J.] Massachusetts Gen Hosp, Schizophrenia Clin & Res Program, Boston, MA 02114 USA. RP Lee, PH (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. EM phlee@pngu.mgh.harvard.edu; jsmoller@hms.harvard.edu RI McMahon, Katie/C-6440-2009 OI McMahon, Katie/0000-0002-6357-615X FU Center for Brain Science Neuroinformatics Research Group; Athinoula A Martinos Center for Biomedical Imaging; Center for Human Genetic Research; Stanley Center for Psychiatric Research; NIH [R01 HD050735, U54 EB020403, K99MH101367, K23MH104515, K01MH099232, K24MH094614, R01 MH101486]; NHMRC [389875, 486682, 1009064] FX Neuroimaging genetics data were provided by the Brain Genomics Superstruct Project (GSP) of Harvard University and MGH, with support from the Center for Brain Science Neuroinformatics Research Group, Athinoula A Martinos Center for Biomedical Imaging, Center for Human Genetic Research, and Stanley Center for Psychiatric Research. Twenty individual investigators at Harvard and MGH generously contributed data to the overall project. The QTIM study is supported by grants from NIH (R01 HD050735) and the NHMRC (389875, 486682 and 1009064). We thank the twins and siblings for their participation, Marlene Grace and Ann Eldridge for twin recruitment, Aiman Al Najjar and other radiographers for scanning, Kerrie McAloney and Daniel Park for research support, and Anjali Henders and staff for DNA sample processing and preparation. PMT, NJ and MJW were supported in part by a Consortium grant (U54 EB020403 to PMT) from the NIH Institutes contributing to the Big Data to Knowledge (BD2K) Initiative. This research was also funded in part by NIH Grants K99MH101367 (to PHL); K23MH104515 (to JTB), K01MH099232 (to AJH); K24MH094614 and R01 MH101486 (to JWS); JWS is a Tepper Family MGH Research Scholar. NR 79 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD DEC PY 2016 VL 21 IS 12 BP 1680 EP 1689 DI 10.1038/mp.2016.164 PG 10 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA ED3AD UT WOS:000388720600007 PM 27725656 ER PT J AU Homann, OR Misura, K Lamas, E Sandrock, RW Nelson, P McDonough, SI DeLisi, LE AF Homann, O. R. Misura, K. Lamas, E. Sandrock, R. W. Nelson, P. McDonough, S. I. DeLisi, L. E. TI Whole-genome sequencing in multiplex families with psychoses reveals mutations in the SHANK2 and SMARCA1 genes segregating with illness SO MOLECULAR PSYCHIATRY LA English DT Article ID AUTISM SPECTRUM DISORDER; SCAFFOLDING PROTEIN SHANK3; NON-SYNONYMOUS VARIANTS; CHINESE HAN POPULATION; COPY NUMBER VARIATIONS; DE-NOVO MUTATIONS; SCHIZOPHRENIA; COMPLEX; ASSOCIATION; FRAMEWORK AB A current focus in psychiatric genetics is detection of multiple common risk alleles through very large genome-wide association study analyses. Yet families do exist, albeit rare, that have multiple affected members who are presumed to have a similar inherited cause to their illnesses. We hypothesized that within some of these families there may be rare highly penetrant mutations that segregate with illness. In this exploratory study, the genomes of 90 individuals across nine families were sequenced. Each family included a minimum of three available relatives affected with a psychotic illness and three available unaffected relatives. Twenty-six variants were identified that are private to a family, alter protein sequence, and are transmitted to all sequenced affected individuals within the family. In one family, seven siblings with schizophrenia spectrum disorders each carry a novel private missense variant within the SHANK2 gene. This variant lies within the consensus SH3 protein-binding motif by which SHANK2 may interact with post-synaptic glutamate receptors. In another family, four affected siblings and their unaffected mother each carry a novel private missense variant in the SMARCA1 gene on the X chromosome. Both variants represent candidates that may be causal for psychotic disorders when considered in the context of their transmission pattern and known gene and disease biology. C1 [Homann, O. R.; Misura, K.; McDonough, S. I.] Amgen Inc, Genome Anal Unit, San Francisco, CA USA. [Lamas, E.; Sandrock, R. W.] Amgen Inc, Genome Anal Unit, Thousand Oaks, CA USA. [Nelson, P.; DeLisi, L. E.] BVARI Fdn, VA Boston Healthcare Syst, Boston, MA USA. [DeLisi, L. E.] VA Boston Healthcare Syst, Boston, MA USA. [DeLisi, L. E.] Harvard Med Sch, Dept Psychiat, Bldg 2,Rm 204,940 Belmont Ave, Brockton, MA 02301 USA. RP DeLisi, LE (reprint author), Harvard Med Sch, Dept Psychiat, Bldg 2,Rm 204,940 Belmont Ave, Brockton, MA 02301 USA. EM Lynn.DeLisi@VA.gov FU NIMH [MHR01 44245]; Amgen FX The pedigree collections were partially supported by NIMH from 1992-1999 (MHR01 44245) and more recently by Amgen 2013-present. We acknowledge the patients and families who contributed samples and made this study possible. NR 57 TC 4 Z9 4 U1 9 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD DEC PY 2016 VL 21 IS 12 BP 1690 EP 1695 DI 10.1038/mp.2016.24 PG 6 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA ED3AD UT WOS:000388720600008 PM 27001614 ER PT J AU Levy, G Habib, N Guzzardi, MA Kitsberg, D Bomze, D Ezra, E Uygun, BE Uygun, K Trippler, M Schlaak, JF Shibolet, O Sklan, EH Cohen, M Timm, J Friedman, N Nahmias, Y AF Levy, Gahl Habib, Naomi Guzzardi, Maria Angela Kitsberg, Daniel Bomze, David Ezra, Elishai Uygun, Basak E. Uygun, Korkut Trippler, Martin Schlaak, Joerg F. Shibolet, Oren Sklan, Ella H. Cohen, Merav Timm, Joerg Friedman, Nir Nahmias, Yaakov TI Nuclear receptors control pro-viral and antiviral metabolic responses to hepatitis C virus infection SO NATURE CHEMICAL BIOLOGY LA English DT Article ID GENE-EXPRESSION; HEPATOCELLULAR-CARCINOMA; RNA REPLICATION; FLUX ANALYSIS; CULTURED-HEPATOCYTES; CORE PROTEIN; LIVER; MECHANISM; TARGET; ALPHA AB Viruses lack the basic machinery needed to replicate and therefore must hijack the host's metabolism to propagate. Virus-induced metabolic changes have yet to be systematically studied in the context of host transcriptional regulation, and such studies shoul offer insight into host-pathogen metabolic interplay. In this work we identified hepatitis C virus (HCV)-responsive regulators by coupling system-wide metabolic-flux analysis with targeted perturbation of nuclear receptors in primary human hepatocytes. We found HCV-induced upregulation of glycolysis, ketogenesis and drug metabolism, with glycolysis controlled by activation of HNF4 alpha, ketogenesis by PPAR alpha and FXR, and drug metabolism by PXR. Pharmaceutical inhibition of HNF4 alpha reversed HCV-induced glycolysis, blocking viral replication while increasing apoptosis in infected cells showing virus-induced dependence on glycolysis. In contrast, pharmaceutical inhibition of PPAR alpha or FXR reversed HCV-induced ketogenesis but increased viral replication, demonstrating a novel host antiviral response. Our results show that virus-induced changes to a host's metabolism can be detrimental to its life cycle, thus revealing a biologically complex relationship between virus and host. C1 [Levy, Gahl; Habib, Naomi; Guzzardi, Maria Angela; Kitsberg, Daniel; Bomze, David; Ezra, Elishai; Cohen, Merav; Friedman, Nir; Nahmias, Yaakov] Hebrew Univ Jerusalem, Benin Sch Comp Sci & Engn, Grass Ctr Bioengn, Jerusalem, Israel. [Levy, Gahl; Habib, Naomi; Kitsberg, Daniel; Bomze, David; Cohen, Merav; Friedman, Nir; Nahmias, Yaakov] Hebrew Univ Jerusalem, Silberman Inst Life Sci, Jerusalem, Israel. [Habib, Naomi] Broad Inst Harvard & MIT, Klarman Cell Observ, Cambridge, MA USA. [Guzzardi, Maria Angela] Natl Res Council CNR, Inst Clin Physiol, Pisa, Italy. [Ezra, Elishai] Jerusalem Coll Technol, Fac Engn, Jerusalem, Israel. [Uygun, Basak E.; Uygun, Korkut] Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. [Trippler, Martin; Schlaak, Joerg F.] Univ Duisburg Essen, Univ Hosp, Dept Gastroenterol & Hepatol, Essen, Germany. [Shibolet, Oren] Tel Aviv Med Ctr & Sch Med, Dept Gastroenterol, Liver Unit, Tel Aviv, Israel. [Shibolet, Oren] Sackler Fac Med, Tel Aviv, Israel. [Sklan, Ella H.] Tel Aviv Univ, Sackler Sch Med, Dept Clin Microbiol & Immunol, Tel Aviv, Israel. [Timm, Joerg] Univ Dusseldorf, Fac Med, Inst Virol, Dusseldorf, Germany. RP Nahmias, Y (reprint author), Hebrew Univ Jerusalem, Benin Sch Comp Sci & Engn, Grass Ctr Bioengn, Jerusalem, Israel.; Nahmias, Y (reprint author), Hebrew Univ Jerusalem, Silberman Inst Life Sci, Jerusalem, Israel. EM ynahmias@cs.huji.ac.il OI Nahmias, Yaakov/0000-0002-6051-616X; Ezra, Elishai/0000-0003-1304-8022 FU European Research Council [242699, 681870]; British Council BIRAX Regenerative Medicine award [06BX14SFYN] FX The authors thank M.-L. Izamis and M. Zimerman for technical support, K.J. Archer for providing GSE14323 phenotypic data, A. Regev for important insight, and the Rina and Samuel M. Frankel Family Foundation for its generous gift to the Nahmias lab. Some primary human hepatocytes were kindly provided by S.C. Strom (University of Pittsburgh, Pittsburg, Pennsylvania, USA). The Huh7.5.1 human hepatoma cell line was provided by F. Chisari (Scripps Research Institute, La Jolla, California, USA). Plasmids containing the JFH-1 full-length genome were kindly provided by T. Wakita (National Institute of Infectious Diseases, Tokyo, Japan); plasmids containing the JC1-RFP full-length genome were kindly provided by R. Bartenschlager (University of Heidelberg, Heidelberg, Germany). The PXR reporter construct was a kind gift from C. Liddle (University of Sydney, Australia). This work was funded by European Research Council Starting Grant TMIHCV (project 242699), European Research Council Consolidator Grant OCLD (project 681870) and the British Council BIRAX Regenerative Medicine award (project 06BX14SFYN). NR 60 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD DEC PY 2016 VL 12 IS 12 BP 1037 EP + DI 10.1038/NCHEMBIO.2193 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ED1CZ UT WOS:000388582900012 ER PT J AU Tanaka, M Roberts, JM Seo, HS Souza, A Paulk, J Scott, TG DeAngelo, SL Dhe-Paganon, S Bradner, JE AF Tanaka, Minoru Roberts, Justin M. Seo, Hyuk-Soo Souza, Amanda Paulk, Joshiawa Scott, Thomas G. DeAngelo, Stephen L. Dhe-Paganon, Sirano Bradner, James E. TI Design and characterization of bivalent BET inhibitors SO NATURE CHEMICAL BIOLOGY LA English DT Article ID BROMODOMAIN PROTEIN BRD4; ELONGATION-FACTOR B; CHEMICAL PROBES; P-TEFB; TARGET; TRANSCRIPTION; LEUKEMIA; BINDING; RIBONUCLEOPROTEIN; DEGRADATION AB Cellular signaling is often propagated by multivalent interactions. Multivalency creates avidity, allowing stable biophysical recognition. Multivalency is an attractive strategy for achieving potent binding to protein targets, as the affinity of bivalent ligands is often greater than the sum of monovalent affinities. The bromodomain and extraterminal domain (BET) family of transcriptional coactivators features tandem bromodomains through which BET proteins bind acetylated histones and transcription factors. All reported antagonists of the BET protein BRD4 bind in a monovalent fashion. Here we describe, to our knowledge for the first time, a bivalent BET bromodomain inhibitor-MT1-which has unprecedented potency. Biophysical and biochemical studies suggest MT1 is an intramolecular bivalent BRD4 binder that is more than 100-fold more potent, in cellular assays, than the corresponding monovalent antagonist, JQ1. MT1 significantly (P < 0.05) delayed leukemia progression in mice, as compared to JQ1. These data qualify a powerful chemical probe for BET bromodomains and a rationale for further development of multidomain inhibitors of epigenetic reader proteins. C1 [Tanaka, Minoru; Roberts, Justin M.; Souza, Amanda; Paulk, Joshiawa; Scott, Thomas G.; DeAngelo, Stephen L.; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Tanaka, Minoru; Bradner, James E.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Seo, Hyuk-Soo; DeAngelo, Stephen L.; Dhe-Paganon, Sirano] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Bradner, James E.] Novartis Inst Biomed Res, Cambridge, MA 02139 USA. RP Bradner, JE (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Bradner, JE (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA.; Bradner, JE (reprint author), Novartis Inst Biomed Res, Cambridge, MA 02139 USA. EM james_bradner@dfci.harvard.edu FU William Lawrence and Blanche Hughes Foundation; Leukemia and Lymphoma Society; US National Institutes of Health [CA066996-01A1] FX We thank J.A. Perry for critical reading of the manuscript and discussions. NMC797 cells were a gift from C. French (Brigham and Women's Hospital). Crystallographic work was based on research conducted at the Advanced Photon Source on the Northeastern Collaborative Access Team beamlines. We thank Mitsubishi Tanabe Pharma Corporation for nonresearch support of M.T. This research was supported by the William Lawrence and Blanche Hughes Foundation (J.E.B.), the Leukemia and Lymphoma Society (J.E.B.) and the US National Institutes of Health (CA066996-01A1, J.E.B.). NR 45 TC 2 Z9 2 U1 17 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD DEC PY 2016 VL 12 IS 12 BP 1089 EP + DI 10.1038/NCHEMBIO.2209 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ED1CZ UT WOS:000388582900019 PM 27775715 ER PT J AU Ishiyama, A Doherty, J Ishiyama, G Quesnel, AM Lopez, I Linthicum, FH AF Ishiyama, Akira Doherty, Joni Ishiyama, Gail Quesnel, Alicia M. Lopez, Ivan Linthicum, Fred H. TI Post Hybrid Cochlear Implant Hearing Loss and Endolymphatic Hydrops SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Endolymphatic hydrops; Hearing preservation; Hybrid cochlear implantation; Temporal bone histopathology ID ACOUSTIC STIMULATION; RESIDUAL HEARING; TISSUE FORMATION; AUDITORY-SYSTEM; ROUND WINDOW; COCHLEOSTOMY; BONE; EAR AB Objective: To evaluate for potential causes of delayed loss of residual hearing that variably occurs with hybrid cochlear implants. Study Design: Histopathological evaluation of 29 human temporal bone (HTB) with cochlear implant (CI). Setting: The Neurotology and House HTB Laboratory of UCLA (House-UCLA). Subjects and Methods: HTB from CI patients from the House-UCLA HTB Laboratory (n = 28) and one courtesy of Massachusetts Eye and Ear Infirmary (MEEI). Histopathological analysis to identify the location of cochleostomy, fibrosis, and bone formation in the scala vestibuli and tympani, and endolymphatic hydrops. Spiral ganglion neuron counts were obtained. Statistical analysis compared presence of cochleostomy and location with the histopathological findings. Results: Seventeen of 29 bones with fibrosis in the scala vestibule (SV) and tympani had evidence of a cochleostomy involving the SV containing the ductus reunions, all of which had hydrops. Ten of 11 bones had no SV fibrosis, and a cochleostomy limited to the scala tympani, of which all had no hydrops. One HTB had moderate SV fibrosis not involving the ductus reuniens, and was without hydrops. One HTB had a SV cochleostomy but the electrode ruptured Reissner's membrane, and was without hydrops. Cochleostomy was significantly associated with SV fibrosis and hydrops (p < 0.01), those without hydrops had no SV atrophy (p < 0.01). Round window insertion was associated with no fibrosis and no hydrops. Conclusion: We hypothesize that cochleostomies involving scala vestibuli incite fibrosis, compromising the ductus reuniens, causing hydrops which may cause the delayed loss of residual low frequency hearing in CI. C1 [Ishiyama, Akira; Lopez, Ivan; Linthicum, Fred H.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Head & Neck Surg, Los Angeles, CA 90095 USA. [Doherty, Joni] Shohet Ear Associates Med Grp, Seal Beach, CA USA. [Doherty, Joni] Shohet Ear Associates Med Grp, Newport Beach, CA USA. [Ishiyama, Gail] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Quesnel, Alicia M.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Boston, MA USA. RP Ishiyama, A (reprint author), Univ Calif Los Angeles, Neurotol & House Temporal Bone Lab, Rehabil Ctr, 1000 Vet Ave,Rm 32-28, West Los Angeles, CA 90096 USA. EM ishiyama@ucla.edu FU IRB [14-001753 UCLA]; NIDCD/NIH [U24DC011962-04] FX IRB# 14-001753 UCLA. Supported by NIDCD/NIH: U24DC011962-04. NR 21 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 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD DEC PY 2016 VL 37 IS 10 BP 1516 EP 1521 DI 10.1097/MAO.0000000000001199 PG 6 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA EC5OI UT WOS:000388185000016 PM 27608418 ER PT J AU Creighton, FX Guan, XY Park, S Kymissis, I Nakajima, HH Olson, ES AF Creighton, Francis (Pete) X. Guan, Xiying Park, Steve Kymissis, Ioannis (John) Nakajima, Hideko Heidi Olson, Elizabeth S. TI An Intracochlear Pressure Sensor as a Microphone for a Fully Implantable Cochlear Implant SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Cochlear implants; Hearing prosthesis; Implantable microphones; Intracochlear pressure measurement ID HUMAN TEMPORAL BONES; INNER-EAR; MIDDLE; STIMULATION; DEVICE AB Objective: To validate an intracochlear piezoelectric sensor for its ability to detect intracochlear pressure and function as a microphone for a fully implantable cochlear implant. Methods: A polyvinylidene fluoride (PVDF) piezoelectric pressure sensor was inserted into a human fresh cadaveric round window at varying depths. An external sound pressure stimulus was applied to the external auditory canal (EAC). EAC pressure, stapes velocity, and piezoelectric sensor voltage output were recorded. Results: The PVDF sensor was able to detect the intracochlear sound pressure response to an acoustic input to the EAC. The frequency response of the pressure measured with the intracochlear sensor was similar to that of the pressure at the EAC, with the expected phase delay of the middle ear transmission. The magnitude of the response increased and smoothened with respect to frequency as the sensor was inserted more deeply into the scala tympani. Artifact measurements, made with the sensor in air near the round window, showed flat frequency response in both magnitude and phase, which were distinct from those measured when the sensor was inserted in the round window. Conclusion: This study describes a novel method of measuring intracochlear pressure for an otologic microphone composed of a piezoelectric polymer, and demonstrates feasibility. Our next goal is to improve device sensitivity and bandwidth. Our long-term objective is to imbed the piezoelectric sensor within a conventional cochlear implant electrode, to enable a device to both measure intracochlear sound pressure and deliver electrical stimulus to the cochlea, for a fully implantable cochlear implant. C1 [Creighton, Francis (Pete) X.; Guan, Xiying; Nakajima, Hideko Heidi] Harvard Med Sch, Dept Otolaryngol, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Nakajima, Hideko Heidi] Harvard Program Speech & Hearing Biosci & Technol, Cambridge, MA USA. [Park, Steve; Kymissis, Ioannis (John)] Columbia Univ, Dept Elect Engn, Med Ctr, New York, NY 10027 USA. [Olson, Elizabeth S.] Columbia Univ, Dept Otolaryngol Head & Neck Surg, Med Ctr, New York, NY USA. [Park, Steve] Columbia Univ, Dept Biomed Engn, New York, NY USA. [Olson, Elizabeth S.] Korea Adv Inst Sci & Technol, Daejon, South Korea. RP Creighton, FX (reprint author), Harvard Med Sch, Dept Otolaryngol, Massachusetts Eye & Ear, ENT Educ Off, 243 Charles St, Boston, MA 02114 USA. EM francis_creighton@meei.harvard.edu FU Advanced Bionics FX Dr. Nakajima has a gift from Advanced Bionics to support parts of this research. NR 25 TC 0 Z9 0 U1 6 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD DEC PY 2016 VL 37 IS 10 BP 1596 EP 1600 DI 10.1097/MAO.0000000000001209 PG 5 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA EC5OI UT WOS:000388185000029 PM 27631834 ER PT J AU van Tilburg, MJ Herrmann, BS Guinan, JJ Rauch, SD AF van Tilburg, Mark J. Herrmann, Barbara S. Guinan, John J., Jr. Rauch, Steven D. TI Serial cVEMP Testing is Sensitive to Disease Progression in Meniere Patients SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Cervical vestibular evoked myogenic potential; Meniere's disease; Migraine associated vertigo ID EVOKED MYOGENIC POTENTIALS; VEMP AB Objective: To assess the cervical vestibular evoked myogenic potentials (cVEMPs) ability to track disease progression in Meniere's disease patients over time and identify the most sensitive outcome measurement. Study Design: Retrospective. Setting: Large specialty hospital, department of otolaryngology. Subjects: Twenty nine Meniere's patients and seven migraine associated vertigo (MAV) patients. Intervention: All patients underwent two cervical vestibular evoked myogenic potential tests at 250, 500, 750, and 1000 Hz with a minimum test interval of 3 months. Main Outcome Measures: Threshold, peak-to-peak (PP) amplitude, interaural asymmetry ratio, and effect size. Results: In affected Meniere's ears all outcome measures were worse during the second test, for threshold this difference was statistically significant at 750 and 1000 Hz compared with the first test. Compared with young healthy ears the threshold was significantly worse at all frequencies. PP amplitude was significantly decreased at the second test at 750 Hz compared with the first test. In MAV no significant difference between tests was found at any frequency in PP amplitude or threshold. In Meniere's ears, threshold showed a higher first-to-second effect size at 500, 750, and 1000 Hz compared with PP amplitude. Conclusion: cVEMP is able to track progression in Meniere's disease over time. Thresholds were the most effective outcome measure to both track progression and to distinguish between MAV and Meniere's patients. C1 [van Tilburg, Mark J.; Rauch, Steven D.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. [Herrmann, Barbara S.; Guinan, John J., Jr.; Rauch, Steven D.] Harvard Med Sch, Dept Otolaryngol, Boston, MA USA. [Herrmann, Barbara S.] Massachusetts Eye & Ear Infirm, Dept Audiol, Boston, MA 02114 USA. [Guinan, John J., Jr.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. RP Rauch, SD (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM steven_rauch@meei.harvard.edu NR 12 TC 0 Z9 0 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD DEC PY 2016 VL 37 IS 10 BP 1614 EP 1619 DI 10.1097/MAO.0000000000001213 PG 6 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA EC5OI UT WOS:000388185000032 PM 27668791 ER PT J AU McFarland, DH Martin-Harris, B Fortin, AJ Humphries, K Hill, E Armeson, K AF McFarland, D. H. Martin-Harris, B. Fortin, A. -J. Humphries, K. Hill, E. Armeson, K. TI Respiratory-swallowing coordination in normal subjects: Lung volume at swallowing initiation SO RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY LA English DT Article DE Respiration; Deglutition; Lung volume; Respiratory-swallow coordination ID HEALTHY-YOUNG ADULTS; SWALLOW/RESPIRATORY PHASE-RELATIONSHIPS; UPPER ESOPHAGEAL SPHINCTER; SUBGLOTTIC AIR-PRESSURE; BOLUS VOLUME; APNEA DURATION; DYSPHAGIC PATIENTS; STRAW DRINKING; AGE; PHARYNGEAL AB This study was designed to investigate the significance of bolus types and volumes, delivery methods and swallowing instructions on lung volume at swallowing initiation in normal subjects in a single experiment using a multifactorial approach. Our broad range goal was to determine optimal lung volume range associated with swallowing initiation to provide training targets for dysphagic patients with disordered respiratory-swallow coordination. Our hypothesis was that swallows would be initiated within a limited range of quiet breathing lung volumes regardless of bolus volume, consistency or task. Results confirmed this hypothesis and revealed that swallows were initiated at mean lung volume = 244 ml. Cued swallows were initiated at lower quiet breathing volumes than un-cued swallows (cued =201 ml; uncued =367 ml). Water boluses were initiated at slightly higher quiet breathing volumes than solids. Data suggest that swallows occur within a restricted range of lung volumes with variation due to instructions, bolus type and other experimental variables. (C) 2016 Elsevier B.V. All rights reserved. C1 [McFarland, D. H.; Fortin, A. -J.] Univ Montreal, Fac Med, Ecole Orthophonie & Audiol, CP 6128,Succ Ctr Ville, Montreal, PQ H3C 2J7, Canada. [McFarland, D. H.] McGill Univ, Fac Med, Sch Commun Sci & Disorders, McGill Coll 2001, 8th Floor, Montreal, PQ H3A 1G1, Canada. [Martin-Harris, B.; Humphries, K.; Hill, E.; Armeson, K.] Med Univ South Carolina, 171 Ashley Ave, Charleston, SC 19425 USA. [Martin-Harris, B.] Ralph H Johnson VAMC, 109 Bee St, Charleston, SC 29401 USA. [Martin-Harris, B.; Humphries, K.] Dept Otolaryngol Head & Neck Surg, 135 Rutledge Ave,MSC 550, Charleston, SC 29425 USA. [Martin-Harris, B.; Humphries, K.] Evelyn Trammell Inst Voice & Swallowing, 135 Rutledge Ave,MSC 550, Charleston, SC 29425 USA. [Martin-Harris, B.; Hill, E.; Armeson, K.] Dept Publ Hlth Sci, 135 Cannon St,Suite 303,MSC 835, Charleston, SC 29425 USA. [Martin-Harris, B.] Northwestern Univ, Roxelyn & Richard Pepper Dept Commun Sci & Disord, 70 Arts Circle Dr, Evanston, IL 60208 USA. RP McFarland, DH (reprint author), Univ Montreal, Fac Med, CP 6128,Succ Ctr Ville, Montreal, PQ H3C 2J7, Canada. EM david.mcfarland@umontreal.ca; bonnie.martinharris@northwestern.edu; annie-joelle.fortin@umontreal.ca; humphrik@musc.edu; hille@musc.edu; armeson@musc.edu FU National Institutes of Health [NIDCD1K24DC1281, NIDCD1R21DC010480-A1]; United States Department of Veteran Affairs [RRDC7135R] FX This work was funded by the National Institutes of Health NIDCD1K24DC1281 and NIDCD1R21DC010480-A1; the United States Department of Veteran Affairs RR&DC7135R. NR 69 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-9048 EI 1878-1519 J9 RESP PHYSIOL NEUROBI JI Respir. Physiol. Neuro. PD DEC PY 2016 VL 234 BP 89 EP 96 DI 10.1016/j.resp.2016.09.004 PG 8 WC Physiology; Respiratory System SC Physiology; Respiratory System GA EC3XQ UT WOS:000388060800011 PM 27612587 ER PT J AU Restrepo, MI Reyes, LF Anzueto, A AF Restrepo, Marcos I. Reyes, Luis F. Anzueto, Antonio TI Complication of Community-Acquired Pneumonia (Including Cardiac Complications) SO SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review DE pneumonia; sepsis; complications; multiple organ dysfunction ID INTENSIVE-CARE-UNIT; RANDOMIZED CLINICAL-TRIAL; IN-HOSPITAL MORTALITY; D-DIMER LEVELS; CARDIOVASCULAR-DISEASE; PLEURAL EFFUSION; RISK-FACTORS; PARAPNEUMONIC EFFUSION; PNEUMOCOCCAL PNEUMONIA; CHLAMYDIA-PNEUMONIAE AB Community-acquired pneumonia (CAP) represents an important public health problem and carries significant morbidity, mortality, and costs. The incidence of CAP is highest among children and elderly patients, but the mortality is much higher in patients older than 65 years. Despite the advances in medicine, the administration of antimicrobials, and the overall better care, there are still patients with CAP dying due to systemic complications all over the world. A continuum of CAP disease progression may involve multiple organs beyond the pulmonary parenchyma. These pulmonary and nonpulmonary complications are associated not only with mortality but also with the development of clinical failure, prolonged hospitalization, and the need for more intensive level of care. In this review, we present the characteristics of several CAP-related pulmonary and nonpulmonary organ dysfunction, such as those affecting the heart, kidneys, hematological, neurological, endocrine systems. Multiple severity of illness scores identified a series of systemic findings that indicate the organ dysfunctions and the associated related outcomes. However, further research is required to address the mechanisms, the management, and prevention of organ dysfunction in patients with CAP. C1 [Restrepo, Marcos I.; Reyes, Luis F.; Anzueto, Antonio] South Texas Vet Hlth Care Syst, Div Pulm Dis & Crit Care Med, ALMD 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. [Restrepo, Marcos I.; Reyes, Luis F.; Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, Div Pulm Dis & Crit Care Med, San Antonio, TX 78229 USA. RP Restrepo, MI (reprint author), South Texas Vet Hlth Care Syst, Div Pulm Dis & Crit Care Med, ALMD 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM restrepom@uthscsa.edu FU National Heart, Lung, and Blood Institute [K23HL096054] FX MIR'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 Heart, Lung, And Blood Institute or the National Institutes of Health nor the Department of Veterans Affairs. NR 82 TC 0 Z9 0 U1 2 U2 2 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1069-3424 EI 1098-9048 J9 SEMIN RESP CRIT CARE JI Semin. Respir. Crit. Care Med. PD DEC PY 2016 VL 37 IS 6 BP 897 EP 904 DI 10.1055/s-0036-1593754 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EC6MR UT WOS:000388250900011 PM 27960213 ER PT J AU Hobai, IA Aziz, K Buys, ES Brouckaert, P Siwik, DA Colucci, WS AF Hobai, Ion A. Aziz, Kanwal Buys, Emmanuel S. Brouckaert, Peter Siwik, Deborah A. Colucci, Wilson S. TI DISTINCT MYOCARDIAL MECHANISMS UNDERLIE CARDIAC DYSFUNCTION IN ENDOTOXEMIC MALE AND FEMALE MICE SO SHOCK LA English DT Article DE Calcium handling; excitation contraction coupling; myofilaments; sepsis; sepsis-induced cardiomyopathy; septic shock; SERCA ID INDUCED CONTRACTILE DYSFUNCTION; NITRIC-OXIDE; RADICAL SCAVENGER; GUANYLYL CYCLASE; SEPSIS; EXPRESSION; CGMP; RESPONSIVENESS; PATHWAY; MODELS AB In male mice, sepsis-induced cardiomyopathy develops as a result of dysregulation of myocardial calcium (Ca2+) handling, leading to depressed cellular Ca2+ transients (Delta Cai). DCai depression is partially due to inhibition of sarcoplasmic reticulum Ca2+ ATP-ase (SERCA) via oxidative modifications, which are partially opposed by cGMP generated by the enzyme soluble guanylyl cyclase (sGC). Whether similar mechanisms underlie sepsis-induced cardiomyopathy in female mice is unknown. Male and female C57Bl/6J mice (WT), and mice deficient in the sGC alpha(1) subunit activity (sGC alpha(-/-)(1)), were challenged with lipopolysaccharide (LPS, ip). LPS induced mouse death and cardiomyopathy (manifested as the depression of left ventricular ejection fraction by echocardiography) to a similar degree in WT male, WT female, and sGC alpha(-/-)(1) male mice, but significantly less in sGC alpha(-/-)(1) female mice. We measured sarcomere shortening and Delta Ca-i in isolated, externally paced cardiomyocytes, at 37 degrees C. LPS depressed sarcomere shortening in both WT male and female mice. Consistent with previous findings, in male mice, LPS induced a decrease in Delta Ca-i (to 30 +/- 2% of baseline) and SERCA inhibition (manifested as the prolongation of the time constant of Ca2+ decay, tau(Ca), to 150 +/- 5% of baseline). In contrast, in female mice, the depression of sarcomere shortening induced by LPS occurred in the absence of any change in Delta Ca-i, or SERCA activity. This suggested that, in female mice, the causative mechanism lies downstream of the Ca2+ transients, such as a decrease in myofilament sensitivity for Ca2+. The depression of sarcomere shortening shortening after LPS was less severe in female sGC alpha(-/-)(1) mice than in WT female mice, indicating that cGMP partially mediates cardiomyocyte dysfunction. These results suggest, therefore, that LPS-induced cardiomyopathy develops through distinct sex-specific myocardial mechanisms. While in males LPS induces sGC-independent decrease in Delta Ca-i, in female mice LPS acts downstream of Delta Ca-i, possibly via sGC-dependent myofilament dysfunction. C1 [Hobai, Ion A.; Aziz, Kanwal; Siwik, Deborah A.; Colucci, Wilson S.] Boston Univ, Med Ctr, Dept Med, Cardiovasc Med, Boston, MA 02118 USA. [Hobai, Ion A.; Buys, Emmanuel S.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Hobai, Ion A.; Buys, Emmanuel S.] Harvard Univ, Boston, MA 02115 USA. [Brouckaert, Peter] Univ Ghent, Dept Biomed Mol Biol, Ghent, Belgium. [Brouckaert, Peter] Flanders Inst Biotechnol VIB, Inflammat Res Ctr, Ghent, Belgium. RP Hobai, IA (reprint author), Boston Univ, Med Ctr, Evans Basic Res Bldg,650 Albany St,X740, Boston, MA 02118 USA. EM ihobai@partners.org FU NHLBI NIH HHS [N01HV28178, R01 HL064750, R01 HL061639]; NIGMS NIH HHS [K08 GM096082] NR 31 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 1073-2322 EI 1540-0514 J9 SHOCK JI Shock PD DEC PY 2016 VL 46 IS 6 BP 713 EP 722 DI 10.1097/SHK.0000000000000679 PG 10 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA EC9XP UT WOS:000388497900016 PM 27405063 ER PT J AU Taylor, JB Ferris, TG Weilburg, JB Alpert, JE AF Taylor, John B. Ferris, Timothy G. Weilburg, Jeffrey B. Alpert, Jonathan E. TI Behavioral Health Integration: Challenges and Opportunities for Academic Medical Centers SO ACADEMIC PSYCHIATRY LA English DT Article ID CARVE-OUT C1 [Taylor, John B.; Ferris, Timothy G.; Weilburg, Jeffrey B.; Alpert, Jonathan E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Taylor, John B.; Ferris, Timothy G.; Weilburg, Jeffrey B.; Alpert, Jonathan E.] Harvard Med Sch, Boston, MA 02115 USA. RP Taylor, JB (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA.; Taylor, JB (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM taylor.john@mgh.harvard.edu NR 12 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1042-9670 EI 1545-7230 J9 ACAD PSYCHIATR JI Acad. Psych. PD DEC PY 2016 VL 40 IS 6 BP 874 EP 879 DI 10.1007/s40596-016-0584-1 PG 6 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA EB9CV UT WOS:000387690200003 PM 27472931 ER PT J AU Lokko, HN Chen, JA Parekh, RI Stern, TA AF Lokko, Hermioni N. Chen, Justin A. Parekh, Ranna I. Stern, Theodore A. TI Racial and Ethnic Diversity in the US Psychiatric Workforce: A Perspective and Recommendations SO ACADEMIC PSYCHIATRY LA English DT Editorial Material ID PRIMARY-CARE; RACE; DISPARITIES; DOCTOR C1 [Lokko, Hermioni N.; Chen, Justin A.; Stern, Theodore A.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Parekh, Ranna I.] Amer Psychiat Assoc, Arlington, VA USA. RP Lokko, HN (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM hlokko@partners.org NR 27 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1042-9670 EI 1545-7230 J9 ACAD PSYCHIATR JI Acad. Psych. PD DEC PY 2016 VL 40 IS 6 BP 898 EP 904 DI 10.1007/s40596-016-0591-2 PG 7 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA EB9CV UT WOS:000387690200007 PM 27421839 ER PT J AU Sacks, GD Dawes, AJ Ettner, SL Brook, RH Fox, CR Russell, MM Ko, CY Maggard-Gibbons, M AF Sacks, Greg D. Dawes, Aaron J. Ettner, Susan L. Brook, Robert H. Fox, Craig R. Russell, Marcia M. Ko, Clifford Y. Maggard-Gibbons, Melinda TI Impact of a Risk Calculator on Risk Perception and Surgical Decision Making A Randomized Trial SO ANNALS OF SURGERY LA English DT Article DE risk calculator; risk perception; surgical decision-making; variations in care ID CLINICAL-ASSESSMENT; INFORMED-CONSENT; SURGERY; BENEFITS; TALK; CARE AB Objective: The aim of this study was to determine whether exposure to data from a risk calculator influences surgeons' assessments of risk and in turn, their decisions to operate. Background: Little is known about how risk calculators inform clinical judgment and decision-making. Methods: We asked a national sample of surgeons to assess the risks (probability of serious complications or death) and benefits (recovery) of operative and nonoperative management and to rate their likelihood of recommending an operation (5-point scale) for 4 detailed clinical vignettes wherein the best treatment strategy was uncertain. Surgeons were randomized to the clinical vignettes alone (control group; n = 384) or supplemented by data from a risk calculator (risk calculator group; n = 395). We compared surgeons' judgments and decisions between the groups. Results: Surgeons exposed to the risk calculator judged levels of operative risk that more closely approximated the risk calculator value (RCV) compared with surgeons in the control group [mesenteric ischemia: 43.7% vs 64.6%, P < 0.001 (RCV = 25%); gastrointestinal bleed: 47.7% vs 53.4%, P < 0.001 (RCV = 38%); small bowel obstruction: 13.6% vs 17.5%, P < 0.001 (RCV = 14%); appendicitis: 13.4% vs 24.4%, P < 0.001 (RCV = 5%)]. Surgeons exposed to the risk calculator also varied less in their assessment of operative risk (standard deviations: mesenteric ischemia 20.2% vs 23.2%, P = 0.01; gastrointestinal bleed 17.4% vs 24.1%, P < 0.001; small bowel obstruction 10.6% vs 14.9%, P < 0.001; appendicitis 15.2% vs 21.8%, P < 0.001). However, averaged across the 4 vignettes, the 2 groups did not differ in their reported likelihood of recommending an operation (mean 3.7 vs 3.7, P = 0.76). Conclusions: Exposure to risk calculator data leads to less varied and more accurate judgments of operative risk among surgeons, and thus may help inform discussions of treatment options between surgeons and patients. Interestingly, it did not alter their reported likelihood of recommending an operation. C1 [Sacks, Greg D.; Dawes, Aaron J.; Russell, Marcia M.; Ko, Clifford Y.; Maggard-Gibbons, Melinda] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Sacks, Greg D.; Dawes, Aaron J.; Russell, Marcia M.; Ko, Clifford Y.; Maggard-Gibbons, Melinda] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Sacks, Greg D.; Dawes, Aaron J.; Ettner, Susan L.; Brook, Robert H.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. [Ettner, Susan L.; Brook, Robert H.; Fox, Craig R.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Brook, Robert H.] RAND Corp, Los Angeles, CA USA. [Fox, Craig R.] Univ Calif Los Angeles, Anderson Sch Management, Los Angeles, CA USA. [Fox, Craig R.] Univ Calif Los Angeles, Dept Psychol, Coll Letters & Sci, Los Angeles, CA USA. RP Sacks, GD (reprint author), Univ Calif Los Angeles, Dept Surg, 10833 Le Conte Ave,72-227 CHS, Los Angeles, CA 90095 USA. EM gsacks@mednet.ucla.edu FU Robert Wood Johnson Clinical Scholars program FX Two of the authors (G.D.S. and A.J.D.) received support from the Robert Wood Johnson Clinical Scholars program. NR 31 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 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD DEC PY 2016 VL 264 IS 6 BP 889 EP 895 DI 10.1097/SLA.0000000000001750 PG 7 WC Surgery SC Surgery GA EC2UB UT WOS:000387978500008 PM 27192347 ER PT J AU Sacks, GD Dawes, AJ Ettner, SL Brook, RH Fox, CR Maggard-Gibbons, M Ko, CY Russell, MM AF Sacks, Greg D. Dawes, Aaron J. Ettner, Susan L. Brook, Robert H. Fox, Craig R. Maggard-Gibbons, Melinda Ko, Clifford Y. Russell, Marcia M. TI Surgeon Perception of Risk and Benefit in the Decision to Operate SO ANNALS OF SURGERY LA English DT Article DE behavioral science: perception; risk and benefit; surgical decision making; variations ID CLINICAL JUDGMENT; SURGICAL QUALITY; RELIABILITY; RATES AB Objective: To determine how surgeons' perceptions of treatment risks and benefits influence their decisions to operate. Background: Little is known about what makes one surgeon choose to operate on a patient and another chooses not to operate. Methods: Using an online study, we presented a national sample of surgeons (N = 767) with four detailed clinical vignettes (mesenteric ischemia, gastrointestinal bleed, bowel obstruction, appendicitis) where the best treatment option was uncertain and asked them to: (1) judge the risks (probability of serious complications) and benefits (probability of recovery) for operative and nonoperative management and (2) decide whether or not they would recommend an operation. Results: Across all clinical vignettes, surgeons varied markedly in both their assessments of the risks and benefits of operative and nonoperative management (narrowest range 4%-100% for all four predictions across vignettes) and in their decisions to operate (49%-85%). Surgeons were less likely to operate as their perceptions of operative risk increased [absolute difference (AD) = -29.6% from 1.0 standard deviation below to 1.0 standard deviation above mean (95% confidence interval, CI: -31.6, -23.8)] and their perceptions of nonoperative benefit increased [AD = -32.6% (95% CI: -32.8,- -28.9)]. Surgeons were more likely to operate as their perceptions of operative benefit increased [AD = 18.7% (95% CI: 12.6, 21.5)] and their perceptions of nonoperative risk increased [AD = 32.7% (95% CI: 28.7, 34.0)]. Differences in risk/benefit perceptions explained 39% of the observed variation in decisions to operate across the four vignettes. Conclusions: Given the same clinical scenarios, surgeons' perceptions of treatment risks and benefits vary and are highly predictive of their decisions to operate. C1 [Sacks, Greg D.; Dawes, Aaron J.; Maggard-Gibbons, Melinda; Ko, Clifford Y.; Russell, Marcia M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, 10833 Le Conte Ave,72-227 CHS, Los Angeles, CA 90095 USA. [Sacks, Greg D.; Dawes, Aaron J.; Maggard-Gibbons, Melinda; Ko, Clifford Y.; Russell, Marcia M.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Sacks, Greg D.; Dawes, Aaron J.; Ettner, Susan L.; Brook, Robert H.] Univ Calif Los Angeles, Dept Hlth Policy & Management, Fielding Sch Publ Hlth, Los Angeles, CA USA. [Ettner, Susan L.; Brook, Robert H.; Fox, Craig R.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Brook, Robert H.] RAND Corp, Los Angeles, CA USA. [Fox, Craig R.] Univ Calif Los Angeles, Anderson Sch Management, Los Angeles, CA USA. [Fox, Craig R.] Univ Calif Los Angeles, Dept Psychol, Coll Letters & Sci, Los Angeles, CA USA. RP Sacks, GD (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, 10833 Le Conte Ave,72-227 CHS, Los Angeles, CA 90095 USA. EM gsacks@mednet.ucla.edu FU Robert Wood Johnson/Veterans Affairs Clinical Scholars program FX Two of the authors (G.D.S and A.J.D.) received support from the Robert Wood Johnson/Veterans Affairs Clinical Scholars program. NR 30 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 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD DEC PY 2016 VL 264 IS 6 BP 896 EP 903 DI 10.1097/SLA.0000000000001784 PG 8 WC Surgery SC Surgery GA EC2UB UT WOS:000387978500009 PM 27192348 ER PT J AU Cohen, ME Liu, YM Huffman, KM Ko, CY Hall, BL AF Cohen, Mark E. Liu, Yaoming Huffman, Kristopher M. Ko, Clifford Y. Hall, Bruce L. TI On-demand Reporting of Risk-adjusted and Smoothed Rates for Quality Profiling in ACS NSQIP SO ANNALS OF SURGERY LA English DT Article DE ACS NSQIP; on-demand; risk adjustment; smoothed rates; surgical quality improvement ID SURGICAL QUALITY; HOSPITALS; SURGEONS AB Background: Surgical quality improvement depends on hospitals having accurate and timely information about comparative performance. Profiling accuracy is improved by risk adjustment and shrinkage adjustment to stabilize estimates. These adjustments are included in ACS NSQIP reports, where hospital odds ratios (OR) are estimated using hierarchical models built on contemporaneous data. However, the timeliness of feedback remains an issue. Study Design: We describe an alternative, nonhierarchical approach, which yields risk-and shrinkage-adjusted rates. In contrast to our "Traditional" NSQIP method, this approach uses preexisting equations, built on historical data, which permits hospitals to have near immediate access to profiling results. We compared our traditional method to this new "on-demand" approach with respect to outlier determinations, kappa statistics, and correlations between logged OR and standardized rates, for 12 models (4 surgical groups by 3 outcomes). Results: When both methods used the same contemporaneous data, there were similar numbers of hospital outliers and correlations between logged OR and standardized rates were high. However, larger differences were observed when the effect of contemporaneous versus historical data was added to differences in statistical methodology. Conclusions: The on-demand, nonhierarchical approach provides results similar to the traditional hierarchical method and offers immediacy, an "overtime" perspective, application to a broader range ofmodels and data subsets, and reporting of more easily understood rates. Although the nonhierarchical method results are now available "on-demand" in a web-based application, the hierarchical approach has advantages, which support its continued periodic publication as the gold standard for hospital profiling in the program. C1 [Cohen, Mark E.; Liu, Yaoming; Huffman, Kristopher M.; Ko, Clifford Y.; Hall, Bruce L.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL USA. [Ko, Clifford Y.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Hall, Bruce L.] Washington Univ, Dept Surg, St Louis, MO 63130 USA. [Hall, Bruce L.] Washington Univ, Ctr Hlth Policy, St Louis, MO 63130 USA. [Hall, Bruce L.] Washington Univ, Olin Business Sch, St Louis, MO 63130 USA. [Hall, Bruce L.] John Cochran Vet Affairs Med Ctr, St Louis, MO USA. [Hall, Bruce L.] BJC Healthcare, St Louis, MO USA. RP Cohen, ME (reprint author), Amer Coll Surg, 633 N St Clair St,22nd Floor, Chicago, IL 60611 USA. EM markcohen@facs.org NR 16 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 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD DEC PY 2016 VL 264 IS 6 BP 966 EP 972 DI 10.1097/SLA.0000000000001551 PG 7 WC Surgery SC Surgery GA EC2UB UT WOS:000387978500021 PM 27115903 ER PT J AU Zenteno, AC Carnes, T Levi, R Daily, BJ Dunn, PF AF Zenteno, Ana Cecilia Carnes, Tim Levi, Retsef Daily, Bethany J. Dunn, Peter F. TI Systematic OR Block Allocation at a Large Academic Medical Center Comprehensive Review on a Data-driven Surgical Scheduling Strategy SO ANNALS OF SURGERY LA English DT Article DE data-driven analysis; mathematical modeling; operations research; surgical scheduling ID HEALTH; OCCUPANCY; CAPACITY AB Objective: To alleviate the surgical patient flow congestion in the perioperative environment without additional resources. Background: Massachusetts General Hospital experienced increasing overcrowding of the perioperative environment in 2008. The Post-Anesthesia Care Unit would often be at capacity, forcing patients to wait in the operating room. The cause of congestion was traced back to significant variability in the surgical inpatient-bed occupancy across the days of the week due to elective surgery scheduling practices. Methods: We constructed an optimization model to find a rearrangement of the elective block schedule to smooth the average inpatient census by reducing the maximum average occupancy throughout the week. The model was revised iteratively as it was used in the organizational change process that led to an implementable schedule. Results: Approximately 21% of the blocks were rearranged. The setting of study is very dynamic. We constructed a hypothetical scenario to analyze the patient population most representative of the circumstances under which the model was built. For this group, the patient volume remained constant, the average census peak decreased by 3.2% (P < 0.05), and the average weekday census decreased by 2.8% (P < 0.001). When considering all patients, the volume increased by 9%, the census peak increased 1.6% (P < 0.05), and the average weekday census increased by 2% (P < 0.001). Conclusions: This work describes the successful implementation of a data-driven scheduling strategy that increased the effective capacity of the surgical units. The use of the model as an instrument for change and strong managerial leadership was paramount to implement and sustain the new scheduling practices. C1 [Zenteno, Ana Cecilia; Carnes, Tim; Levi, Retsef] MIT, Sloan Sch Management, Operat Management, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Daily, Bethany J.; Dunn, Peter F.] Massachusetts Gen Hosp, Perioperat Adm, Boston, MA 02114 USA. RP Dunn, PF (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM pdunn@mgh.harvard.edu FU NSF [DMS-0732175, CMMI-0846554]; AFOSR [FA9550-11-1-0150, FA9550-08-1-0369]; Massachusetts General Hospital [2011P001124]; Massachusetts Institute of Technology [1201004856]; Massachusetts General Hospital; Massachusetts Institute of Technology Sloan School of Management FX Professor Levi is partially supported by NSF grants DMS-0732175 and CMMI-0846554 (CAREER Award) and AFOSR awards FA9550-11-1-0150 and FA9550-08-1-0369. This research project was conducted under protocols #2011P001124 (Massachusetts General Hospital) and #1201004856 (Massachusetts Institute of Technology). Support was provided by Massachusetts General Hospital and Massachusetts Institute of Technology Sloan School of Management. The views expressed herein do not represent the views of either institution. The remaining authors have no conflicts of interest or financial disclosures to make. NR 24 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 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD DEC PY 2016 VL 264 IS 6 BP 973 EP 981 DI 10.1097/SLA.0000000000001560 PG 9 WC Surgery SC Surgery GA EC2UB UT WOS:000387978500022 PM 26910199 ER PT J AU Lee, CNH Ubel, PA Deal, AM Blizard, LB Sepucha, KR Ollila, DW Pignone, MP AF Lee, Clara Nan-hi Ubel, Peter Anthony Deal, Allison M. Blizard, Lillian Burdick Sepucha, Karen R. Ollila, David W. Pignone, Michael Patrick TI How Informed Is the Decision About Breast Reconstruction After Mastectomy? A Prospective, Cross-sectional Study SO ANNALS OF SURGERY LA English DT Article DE breast cancer; breast reconstruction; breast surgery; decision; decision making; decision quality; informed decision making; medical decision making; patient knowledge; risk communication; shared decision making ID CANCER-TREATMENT; QUALITY; PATIENT; IMMEDIATE; OUTCOMES; COMPLICATIONS; DETERMINANTS; SATISFACTION; RADIOTHERAPY; PHYSICIANS AB Objective: To assess how informed patients are about breast reconstruction, and how involved they are in decision making. Summary Background Data: Breast reconstruction is an important treatment option for patients undergoing mastectomy. Wide variations in who gets reconstruction, however, have led to concerns about decision making. Methods: We conducted a prospective cross-sectional study of patients planning mastectomy at a single site, over 20 months. Before surgery, patients completed a survey with validated scales to assess knowledge about breast reconstruction and involvement in decision making. Factors associated with knowledge were examined in a multivariable linear regression model. Results: A total of 145 patients enrolled (77% enrollment rate), and 126 remained eligible. The overall knowledge score was 58.5% (out of 100%). Knowledge about risk of complications was especially low at 14.3%. Knowledge did not differ by treatment (reconstruction or not). On multivariable analysis, non-white race was independently associated with lower knowledge. Most patients (92.1%) reported some discussion with a provider about reconstruction, and most (90.4%) reported being asked their preference. More patients reported discussing the advantages of reconstruction (57.9%) than the disadvantages (27.8%). Conclusions: Women undergoing mastectomy in this sample were highly involved in decision making, but had major deficits in knowledge about the procedure. Knowledge about the risk of complications was particularly low. Providers seemed to have discussed the advantages of reconstruction more than its disadvantages. C1 [Lee, Clara Nan-hi; Ollila, David W.] Univ North Carolina Chapel Hill, Sch Med, Dept Surg, Chapel Hill, NC USA. [Lee, Clara Nan-hi] Univ North Carolina Chapel Hill, Sch Publ Hlth, Dept Hlth Policy & Management, Chapel Hill, NC USA. [Lee, Clara Nan-hi; Ollila, David W.; Pignone, Michael Patrick] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Ubel, Peter Anthony] Duke Univ, Fuqua Sch Business, Dept Mkt, Durham, NC 27706 USA. [Deal, Allison M.] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Biostat Core Facil, Chapel Hill, NC USA. [Blizard, Lillian Burdick] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Sepucha, Karen R.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Sepucha, Karen R.] Harvard Med Sch, Dept Med, Boston, MA USA. [Pignone, Michael Patrick] Univ North Carolina Chapel Hill, Sch Med, Dept Med, Chapel Hill, NC USA. RP Lee, CNH (reprint author), UNC Plast Surg, CB 7195, Chapel Hill, NC 27599 USA. EM cnlee@med.unc.edu FU National Institutes of Health (National Cancer Institute) [1K07CA154850-01A1] FX National Institutes of Health 1K07CA154850-01A1 Cancer Prevention, Control, Behavioral, and Population Sciences Career Development Award (National Cancer Institute); Lineberger Comprehensive Cancer Center Population Sciences Cancer Research Award; North Carolina Translational and Clinical Sciences Institute Pilot Award. NR 36 TC 0 Z9 0 U1 9 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD DEC PY 2016 VL 264 IS 6 BP 1103 EP 1109 DI 10.1097/SLA.0000000000001561 PG 7 WC Surgery SC Surgery GA EC2UB UT WOS:000387978500040 PM 26727092 ER PT J AU Mueller, N Murthy, S Tainter, CR Lee, J Riddell, K Fintelmann, FJ Grabitz, SD Timm, FP Levi, B Kurth, T Eikermann, M AF Mueller, Noomi Murthy, Sushila Tainter, Christopher R. Lee, Jarone Riddell, Kathleen Fintelmann, Florian J. Grabitz, Stephanie D. Timm, Fanny P. Levi, Benjamin Kurth, Tobias Eikermann, Matthias TI Can Sarcopenia Quantified by Ultrasound of the Rectus Femoris Muscle Predict Adverse Outcome of Surgical Intensive Care Unit Patients as well as Frailty? A Prospective, Observational Cohort Study SO ANNALS OF SURGERY LA English DT Article DE frailty; risk prediction; sarcopenia; surgical intensive care unit; ultrasound ID ELDERLY ICU PATIENTS; LENGTH-OF-STAY; CRITICALLY-ILL; CO-MORBIDITY; OLDER-ADULTS; HEALTH-CARE; MORTALITY; SURGERY; DIFFERENTIATION; COMPLICATIONS AB Objective: To compare sarcopenia and frailty for outcome prediction in surgical intensive care unit (SICU) patients. Background: Frailty has been associated with adverse outcomes and describes a status of muscle weakness and decreased physiological reserve leading to increased vulnerability to stressors. However, frailty assessment depends on patient cooperation. Sarcopenia can be quantified by ultrasound and the predictive value of sarcopenia at SICU admission for adverse outcome has not been defined. Methods: We conducted a prospective, observational study of SICU patients. Sarcopenia was diagnosed by ultrasound measurement of rectus femoris cross-sectional area. Frailty was diagnosed by the Frailty Index Questionnaire based on 50 variables. Relationship between variables and outcomes was assessed by multivariable regression analysis NCT02270502. Results: Sarcopenia and frailty were quantified in 102 patients and observed in 43.1% and 38.2%, respectively. Sarcopenia predicted adverse discharge disposition (discharge to nursing facility or in-hospital mortality, odds ratio 7.49; 95% confidence interval 1.47-38.24; P = 0.015) independent of important clinical covariates, as did frailty (odds ratio 8.01; 95% confidence interval 1.82-35.27; P = 0.006); predictive ability did not differ between sarcopenia and frailty prediction model, reflected by chi(2) values of 21.74 versus 23.44, respectively, and a net reclassification improvement (NRI) of -0.02 (P = 0.87). Sarcopenia and frailty predicted hospital length of stay and the frailty model had a moderately better predictive accuracy for this outcome. Conclusions: Bedside diagnosis of sarcopenia by ultrasound predicts adverse discharge disposition in SICU patients equally well as frailty. Sarcopenia assessed by ultrasound may be utilized as rapid beside modality for risk stratification of critically ill patients. C1 [Mueller, Noomi; Murthy, Sushila; Riddell, Kathleen; Grabitz, Stephanie D.; Timm, Fanny P.; Levi, Benjamin; Eikermann, Matthias] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. [Mueller, Noomi; Murthy, Sushila; Lee, Jarone; Riddell, Kathleen; Fintelmann, Florian J.; Grabitz, Stephanie D.; Timm, Fanny P.; Levi, Benjamin; Eikermann, Matthias] Harvard Med Sch, Boston, MA USA. [Tainter, Christopher R.] Univ Calif San Diego, Div Crit Care, Dept Emergency Med, San Diego, CA 92103 USA. [Tainter, Christopher R.] Univ Calif San Diego, Div Crit Care, Dept Anesthesiol, San Diego, CA 92103 USA. [Lee, Jarone] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Lee, Jarone] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Fintelmann, Florian J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Levi, Benjamin] Univ Michigan, Sch Med, Dept Surg, Ann Arbor, MI USA. [Kurth, Tobias] Univ Bordeaux, Coll Hlth Sci, Inserm Res Ctr Epidemiol & Biostat U897, Team Neuroepidemiol, Bordeaux, France. [Kurth, Tobias] Univ Bordeaux, Coll Hlth Sci, Bordeaux, France. [Eikermann, Matthias] Univ Duisburg Essen, Dept Anesthesia & Crit Care Med, Essen, Germany. RP Eikermann, M (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM meikermann@partners.org RI Kurth, Tobias/A-9243-2012 OI Kurth, Tobias/0000-0001-7169-2620 FU Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital; NIH NIGMS [1K08GM109105-01]; Plastic Surgery Foundation National Endowment Award; French National Research Agency; US National Institutes of Health FX Departmental funding was received from the Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital. Benjamin Levi is funded by NIH NIGMS 1K08GM109105-01 and the Plastic Surgery Foundation National Endowment Award. Tobias Kurth is funded by the French National Research Agency, the US National Institutes of Health and has received honoraria from the BMJ and Cephalalgia for editorial services. NR 52 TC 2 Z9 2 U1 6 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD DEC PY 2016 VL 264 IS 6 BP 1116 EP 1124 DI 10.1097/SLA.0000000000001546 PG 9 WC Surgery SC Surgery GA EC2UB UT WOS:000387978500042 PM 26655919 ER PT J AU Mason, SA Nathens, AB Finnerty, CC Gamelli, RL Gibran, NS Arnoldo, BD Tompkins, RG Herndon, DN Jeschke, MG AF Mason, Stephanie A. Nathens, Avery B. Finnerty, Celeste C. Gamelli, Richard L. Gibran, Nicole S. Arnoldo, Brett D. Tompkins, Ronald G. Herndon, David N. Jeschke, Marc G. CA Inflammation Host Response Injury TI Hold the Pendulum: Rates of Acute Kidney Injury are Increased in Patients Who Receive Resuscitation Volumes Less than Predicted by the Parkland Equation SO ANNALS OF SURGERY LA English DT Article DE acute kidney injury; burn injury; resuscitation ID ACUTE-RENAL-FAILURE; FLUID RESUSCITATION; MAJOR-BURN; ADVERSE OUTCOMES; THERMAL-INJURY; ASSOCIATION; MORTALITY; FORMULA; MANAGEMENT; CREEP AB Objective: To determine whether restrictive fluid resuscitation results in increased rates of acute kidney injury (AKI) or infectious complications. Background: Studies demonstrate that patients often receive volumes in excess of those predicted by the Parkland equation, with potentially detrimental sequelae. However, the consequences of under-resuscitation are not well-studied. Methods: Data were collected from a multicenter prospective cohort study. Adults with greater than 20% total burned surface area injury were divided into 3 groups on the basis of the pattern of resuscitation in the first 24 hours: volumes less than (restrictive), equal to, or greater than (excessive) standard resuscitation (4 to 6 cc/kg/% total burned surface area). Multivariable regression analysis was employed to determine the effect of fluid group on AKI, burn wound infections (BWIs), and pneumonia. Results: Among 330 patients, 33% received restrictive volumes, 39% received standard resuscitation volumes, and 28% received excessive volumes. The standard and excessive groups had higher mean baseline APACHE scores (24.2 vs 16, P<0.05 and 22.3 vs 16, P<0.05) than the restrictive group, but were similar in other characteristics. After adjustment for confounders, restrictive resuscitation was associated with greater probability of AKI [odds ratio (OR) 3.25, 95% confidence interval (95% CI) 1.18-8.94]. No difference in the probability of BWI or pneumonia among groups was found (BWI: restrictive vs standard OR 0.74, 95% CI 0.39-1.40, excessive vs standard OR 1.40, 95% CI 0.75-2.60, pneumonia: restrictive vs standard, OR 0.52, 95% CI 0.26-1.05; excessive vs standard, OR 1.12, 95% CI 0.58-2.14). Conclusions: Restrictive resuscitation is associated with increased AKI, without changes in infectious complications. C1 [Mason, Stephanie A.; Nathens, Avery B.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Surg, Toronto, ON, Canada. [Mason, Stephanie A.; Nathens, Avery B.] Univ Toronto, Div Gen Surg, Toronto, ON, Canada. [Finnerty, Celeste C.] Univ Texas Med Branch, Shriners Hosp Children Galveston, Galveston, TX 77555 USA. [Finnerty, Celeste C.] Univ Texas Med Branch, Dept Surg, Galveston, TX 77555 USA. [Finnerty, Celeste C.; Herndon, David N.] Univ Texas Med Branch, Sealy Ctr Mol Med, Galveston, TX 77555 USA. [Finnerty, Celeste C.; Herndon, David N.] Univ Texas Med Branch, Inst Translat Sci, Galveston, TX 77555 USA. [Gamelli, Richard L.] Loyola Univ, Stritch Sch Med, Dept Surg, Maywood, IL 60153 USA. [Gibran, Nicole S.] Univ Washington, Harborview Med Ctr, Sch Med, Dept Surg, Seattle, WA 98104 USA. [Arnoldo, Brett D.] Univ Texas Southwestern Med Sch, Dept Surg, Dallas, TX USA. [Tompkins, Ronald G.] Harvard Med Sch, Shriners Hosp Children, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Jeschke, Marc G.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Ross Tilley Burn Ctr, Toronto, ON, Canada. [Jeschke, Marc G.] Univ Toronto, Div Plast Surg, Toronto, ON, Canada. RP Mason, SA (reprint author), 2075 Bayview Ave,Suite D704, Toronto, ON M4N 3M5, Canada. EM stephanie.mason@mail.utoronto.ca FU National Institute of General Medical Sciences [U54 GM62119, P50 GM060338, R01 GM056687, T32 GM0008256, R01 GM087285]; Shriners Hospitals for Children [71008, 84080]; Canadian Institutes of Health Research [123336]; CFI Leader's Opportunity Fund [25407]; Institute for Translational Science at the University of Texas Medical Branch; Clinical and Translational Science Award from the National Center for Advancing Translational Science, National Institutes of Health [UL1TR000071]; DeSouza Chair in Trauma Research; [KL2RR029875]; [UL1RR029876] FX This study was supported by a Large-Scale Collaborative Research Grant from the National Institute of General Medical Sciences (U54 GM62119) awarded to Ronald G. Tompkins at the Massachusetts General Hospital, Boston, MA, and by research grants awarded to David N. Herndon at the University of Texas Medical Branch, Galveston, TX, by the National Institute of General Medical Sciences (P50 GM060338, R01 GM056687, T32 GM0008256) and Shriners Hospitals for Children (71008, 84080) as well as to Marc G. Jeschke by the National Institute of General Medical Sciences (R01 GM087285), Canadian Institutes of Health Research (#123336), and CFI Leader's Opportunity Fund (Project #25407). CCF is an Institute for Translational Sciences Career Development Scholar supported, in part, by KL2RR029875 and UL1RR029876. This study was conducted with the support of the Institute for Translational Science at the University of Texas Medical Branch, supported in part by a Clinical and Translational Science Award (UL1TR000071) from the National Center for Advancing Translational Science, National Institutes of Health. Dr. Nathens is supported by the DeSouza Chair in Trauma Research. NR 32 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 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD DEC PY 2016 VL 264 IS 6 BP 1142 EP 1147 DI 10.1097/SLA.0000000000001615 PG 6 WC Surgery SC Surgery GA EC2UB UT WOS:000387978500045 PM 27828823 ER PT J AU Hodin, RA AF Hodin, Richard Aaron TI Trans-oral Vestibular Endocrine Surgery: A New Technique in the United States SO ANNALS OF SURGERY LA English DT Editorial Material C1 [Hodin, Richard Aaron] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Hodin, RA (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM rhodin@mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD DEC PY 2016 VL 264 IS 6 BP E17 EP E17 DI 10.1097/SLA.0000000000002010 PG 1 WC Surgery SC Surgery GA EC2UB UT WOS:000387978500002 PM 27643929 ER PT J AU Yeh, DD AF Yeh, Daniel Dante TI Transhepatic Feeding: Safe and Effective SO ANNALS OF SURGERY LA English DT Editorial Material C1 [Yeh, Daniel Dante] Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. RP Yeh, DD (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. EM Dyeh2@partners.org NR 4 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD DEC PY 2016 VL 264 IS 6 BP E23 EP E23 DI 10.1097/SLA.0000000000001812 PG 1 WC Surgery SC Surgery GA EC2UB UT WOS:000387978500006 PM 27232246 ER PT J AU Manikandan, S Nillni, YI Zvolensky, MJ Rohan, KJ Carkeek, KR Leyro, TM AF Manikandan, Sanjana Nillni, Yael I. Zvolensky, Michael J. Rohan, Kelly J. Carkeek, Krystle R. Leyro, Teresa M. TI The role of emotion regulation in the experience of menstrual symptoms and perceived control over anxiety-related events across the menstrual cycle SO ARCHIVES OF WOMENS MENTAL HEALTH LA English DT Article DE Emotion regulation; Menstrual symptoms; Perceived control; Menstrual cycle; Anxiety ID PREMENSTRUAL DYSPHORIC DISORDER; BIOLOGICAL CHALLENGE; MOOD; PSYCHOPATHOLOGY; DYSREGULATION; MINDFULNESS; SENSITIVITY; SUPPRESSION; VALIDATION; AVOIDANCE AB Hormonal variation throughout the menstrual cycle is posited to impact various physical and mental health symptoms; however, this is not observed in all women and mechanisms are not well understood. Difficulty in emotion regulation may elucidate differences that women experience in physical and mental health functioning between menstrual phases. We examined the moderating role of difficulty in emotion regulation in the relation between menstrual phase and menstrual symptom severity and perceived control over anxiety-related events, in healthy, regularly menstruating women. The participants were 37 women (M-age = 26.5, SD = 9.6). A series of regression analyses were used to examine whether individual differences in emotion regulation difficulties moderate the relation between menstrual phase and our outcomes, severity of menstrual symptoms and perceived control over anxiety-related events, using a within-subjects design. The analyses revealed that difficulty in emotion regulation significantly moderated the relation between menstrual phase and perceived control over anxiety-related events (beta = -0.42, p < .05), but not menstrual symptom severity. Women who reported higher emotion regulation difficulty experienced greater differences in perceived control over anxiety-related events between menstrual phases. Specifically, women with lower difficulty in emotion regulation report greater increase in control over anxiety during the late luteal phase compared to women with higher emotion regulation difficulty. Difficulty in emotion regulation may play an important role in understanding differences in menstrual phase-associated impairments, thereby informing the development of targeted interventions for vulnerable women. C1 [Manikandan, Sanjana; Carkeek, Krystle R.; Leyro, Teresa M.] Rutgers State Univ, New Brunsick, NJ 08901 USA. [Zvolensky, Michael J.] Univ Houston, Houston, TX USA. [Zvolensky, Michael J.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Rohan, Kelly J.] Univ Vermont, Burlington, VT 05405 USA. [Nillni, Yael I.] VA Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA USA. [Nillni, Yael I.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Leyro, TM (reprint author), Rutgers State Univ, New Brunsick, NJ 08901 USA. EM teresa.leyro@rutgers.edu FU National Institute of Mental Health [1R36MH086170-01A1] FX This project was conducted as a part of a larger study funded under Yael I. Nillni by National Institute of Mental Health-1R36MH086170-01A1 NR 37 TC 0 Z9 0 U1 7 U2 7 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 1434-1816 EI 1435-1102 J9 ARCH WOMEN MENT HLTH JI Arch. Womens Ment. Health PD DEC PY 2016 VL 19 IS 6 BP 1109 EP 1117 DI 10.1007/s00737-016-0661-1 PG 9 WC Psychiatry SC Psychiatry GA EB8QT UT WOS:000387656600019 PM 27562823 ER PT J AU Wassermann, D Makris, N Rathi, Y Shenton, M Kikinis, R Kubicki, M Westin, CF AF Wassermann, Demian Makris, Nikos Rathi, Yogesh Shenton, Martha Kikinis, Ron Kubicki, Marek Westin, Carl-Fredrik TI The white matter query language: a novel approach for describing human white matter anatomy SO BRAIN STRUCTURE & FUNCTION LA English DT Article DE Diffusion MRI; Tractography; White matter fascicles; Automatic classification of white matter tracts; Computational neuroanatomy ID HUMAN BRAIN; IN-VIVO; LONGITUDINAL FASCICULUS; FUNCTIONAL CONNECTIVITY; TRACTOGRAPHY METHODS; IMAGE REGISTRATION; ARCUATE FASCICULUS; DIFFUSION; SEGMENTATION; ATLAS AB We have developed a novel method to describe human white matter anatomy using an approach that is both intuitive and simple to use, and which automatically extracts white matter tracts from diffusion MRI volumes. Further, our method simplifies the quantification and statistical analysis of white matter tracts on large diffusion MRI databases. This work reflects the careful syntactical definition of major white matter fiber tracts in the human brain based on a neuroanatomist's expert knowledge. The framework is based on a novel query language with a near-to-English textual syntax. This query language makes it possible to construct a dictionary of anatomical definitions that describe white matter tracts. The definitions include adjacent gray and white matter regions, and rules for spatial relations. This novel method makes it possible to automatically label white matter anatomy across subjects. After describing this method, we provide an example of its implementation where we encode anatomical knowledge in human white matter for ten association and 15 projection tracts per hemisphere, along with seven commissural tracts. Importantly, this novel method is comparable in accuracy to manual labeling. Finally, we present results applying this method to create a white matter atlas from 77 healthy subjects, and we use this atlas in a small proof-of-concept study to detect changes in association tracts that characterize schizophrenia. C1 [Wassermann, Demian; Rathi, Yogesh; Kubicki, Marek; Westin, Carl-Fredrik] Harvard Med Sch, Brigham & Womens Hosp, Lab Math Imaging, 1249 Boylston, Boston, MA 02215 USA. [Wassermann, Demian; Makris, Nikos; Rathi, Yogesh; Shenton, Martha; Kubicki, Marek] Harvard Med Sch, Brigham & Womens Hosp, Psychiat Neuroimaging Lab, 1249 Boylston, Boston, MA 02215 USA. [Wassermann, Demian; Kikinis, Ron] Harvard Med Sch, Brigham & Womens Hosp, Surg Planning Lab, 1249 Boylston, Boston, MA 02215 USA. [Makris, Nikos; Kubicki, Marek] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Morphometr Anal, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. [Wassermann, Demian] INRIA Sophia Antipolis Mediterranee, Athena Project Team, 2004 Route Lucioles, F-06902 Sophia Antipolis, France. [Shenton, Martha] Harvard Med Sch, Dept Psychiat, VA Boston Healthcare Syst, Brockton, MA USA. RP Wassermann, D (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Lab Math Imaging, 1249 Boylston, Boston, MA 02215 USA.; Wassermann, D (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Psychiat Neuroimaging Lab, 1249 Boylston, Boston, MA 02215 USA.; Wassermann, D (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Surg Planning Lab, 1249 Boylston, Boston, MA 02215 USA.; Wassermann, D (reprint author), INRIA Sophia Antipolis Mediterranee, Athena Project Team, 2004 Route Lucioles, F-06902 Sophia Antipolis, France. EM demian.wassermann@inria.fr; nikos@cma.mgh.harvard.edu; yogesh@bwh.harvard.edu; shenton@bwh.harvard.edu; kikinis@bwh.harvard.edu; kubicki@bwh.harvard.edu; westin@bwh.harvard.edu OI Wassermann, Demian/0000-0001-5194-6056 FU NIH [R01MH074794, R01MH092862, P41RR013218, R01MH097979, P41EB015902]; VA Boston Healthcare System, Boston, MA; Swedish Research Council (VR) [2012-3682] FX This work has been supported by NIH grants: R01MH074794, R01MH092862, P41RR013218, R01MH097979, P41EB015902, VA Boston Healthcare System, Boston, MA and Swedish Research Council (VR) Grant 2012-3682. Demian Wassermann wishes to thank Dr. Maxime Descoteaux for helpful discussions. NR 66 TC 2 Z9 2 U1 5 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2653 EI 1863-2661 J9 BRAIN STRUCT FUNCT JI Brain Struct. Funct. PD DEC PY 2016 VL 221 IS 9 BP 4705 EP 4721 DI 10.1007/s00429-015-1179-4 PG 17 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA EB8QZ UT WOS:000387657200026 PM 26754839 ER PT J AU Pardesi, O Bittner, EA AF Pardesi, Omar Bittner, Edward A. TI Leukocyte larceny: a cause of pseudohypoxemia SO CANADIAN JOURNAL OF ANESTHESIA-JOURNAL CANADIEN D ANESTHESIE LA English DT Editorial Material ID SPURIOUS HYPOXEMIA C1 [Pardesi, Omar; Bittner, Edward A.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Pardesi, O (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM opardesi@partners.org NR 3 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0832-610X EI 1496-8975 J9 CAN J ANESTH JI Can. J. Anesth. PD DEC PY 2016 VL 63 IS 12 BP 1374 EP 1375 DI 10.1007/s12630-016-0691-1 PG 2 WC Anesthesiology SC Anesthesiology GA EB6PA UT WOS:000387505800008 PM 27351710 ER PT J AU Miller, KA Chaand, M Gregoire, S Yoshida, T Beck, LA Ivanov, AI Dziejman, M AF Miller, Kelly A. Chaand, Mudit Gregoire, Stacy Yoshida, Takeshi Beck, Lisa A. Ivanov, Andrei I. Dziejman, Michelle TI Characterization of V. cholerae T3SS-dependent cytotoxicity in cultured intestinal epithelial cells SO CELLULAR MICROBIOLOGY LA English DT Article ID III SECRETION SYSTEM; ENTEROPATHOGENIC ESCHERICHIA-COLI; VIBRIO-CHOLERAE; VIRULENCE FACTORS; HOSPITALIZED-PATIENTS; MOLECULAR ANALYSIS; PROTEIN-KINASES; PORE FORMATION; UNITED-STATES; ENDEMIC AREA AB AM-19226 is a pathogenic, non-O1/non-O139 serogroup strain of Vibrio cholerae that uses a Type 3 Secretion System (T3SS) mediated mechanism to colonize host tissues and disrupt homeostasis, causing cholera. Co-culturing the Caco2-BBE human intestinal epithelial cell line with AM-19226 in the presence of bile results in rapid mammalian cell death that requires a functional T3SS. We examined the role of bile, sought to identify the mechanism, and evaluated the contributions of T3SS translocated effectors in in vitro cell death. Our results suggest that Caco2-BBE cytotoxicity does not proceed by apoptotic or necrotic mechanisms, but rather displays characteristics consistent with osmotic lysis. Cell death was preceded by disassembly of epithelial junctions and reorganization of the cortical membrane skeleton, although neither cell death nor cell-cell disruption required VopM or VopF, two effectors known to alter actin dynamics. Using deletion strains, we identified a subset of AM-19226 Vops that are required for host cell death, which were previously assigned roles in protein translocation and colonization, suggesting that they function other than to promote cytotoxicity. The collective results therefore suggest that cooperative Vop activities are required to achieve cytotoxicity in vitro, or alternatively, that translocon pores destabilize the membrane in a bile dependent manner. C1 [Miller, Kelly A.; Chaand, Mudit; Gregoire, Stacy; Dziejman, Michelle] Univ Rochester, Sch Med & Dent, Dept Microbiol & Immunol, Rochester, NY 14642 USA. [Yoshida, Takeshi; Beck, Lisa A.] Univ Rochester, Sch Med & Dent, Dept Dermatol, Rochester, NY 14642 USA. [Ivanov, Andrei I.] Univ Rochester, Sch Med & Dent, Dept Med, Div Gastroenterol & Hepatol, Rochester, NY 14642 USA. [Miller, Kelly A.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Chaand, Mudit] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA. [Ivanov, Andrei I.] Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA USA. [Ivanov, Andrei I.] Virginia Commonwealth Univ, Inst Mol Med, Richmond, VA USA. RP Dziejman, M (reprint author), Univ Rochester, Sch Med & Dent, Dept Microbiol & Immunol, Rochester, NY 14642 USA. EM michelle_dziejman@urmc.rochester.edu FU NIH [R01 AI0737085, T32 AI007362, R21 AR062357, R01 DK083968, DK084953] FX We thank David Yule for sharing reagents, Linda Callahan and the Imaging Core for expert assistance, Michael Elliott, John Frelinger, and members of the Dziejman laboratory for helpful discussions. This work was supported by NIH R01 AI0737085 (M.D.), NIH T32 AI007362 (K.A.M), NIH R21 AR062357 (L.A.B.), and NIH R01 DK083968 and DK084953 (A.I.I.). The authors declare no conflicts of interest. NR 90 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-5814 EI 1462-5822 J9 CELL MICROBIOL JI Cell Microbiol. PD DEC PY 2016 VL 18 IS 12 BP 1857 EP 1870 DI 10.1111/cmi.12629 PG 14 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA EC1PZ UT WOS:000387880200013 PM 27302486 ER PT J AU Di Zazzo, A Tahvildari, M Florakis, GJ Dana, R AF Di Zazzo, Antonio Tahvildari, Maryam Florakis, George J. Dana, Reza TI Ocular Manifestations of Inherited Phospholipase-C gamma 2-Associated Antibody Deficiency and Immune Dysregulation SO CORNEA LA English DT Article DE PLAID; IL-1 beta; cornea; inflammation ID RECEPTOR ANTAGONIST; EYE DISEASE; IMMUNODEFICIENCY; PLCG2 AB Purpose: To report the ocular manifestations of phospholipase-C gamma 2-associated antibody deficiency and immune dysregulation (PLAID). Methods: Case report and literature review. Results: A 21-year-old woman diagnosed with PLAID was referred for evaluation of repeated episodes of ocular inflammation resulting in bilateral peripheral corneal pannus with episcleritis and corneal scarring accompanied by systemic manifestations including epidermolysis bullosa and interstitial lung disease. Systemic immunosuppression with corticosteroids and interleukin-1 (IL-1) receptor antagonist (anakinra) was supplemented with topical anakinra to avoid systemic side effects, which resulted in partial improvement of the ocular symptoms. Oral prednisone was restarted to treat active lesions during bouts of inflammation. Conclusions: Ocular PLAID is a bilateral chronic or recurrent inflammatory disease of the ocular surface leading to severe and early cicatricial ocular surface and corneal involvement because of high IL-1 production. Management of PLAID may require both topical and systemic immunomodulatory treatments, potentially including targeted local anti-IL-1 therapy. C1 [Di Zazzo, Antonio; Tahvildari, Maryam; Dana, Reza] Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA USA. [Florakis, George J.] Columbia Univ, Edward S Harkness Eye Inst, New York, NY USA. RP Dana, R (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM Reza_Dana@meei.harvard.edu NR 8 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 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD DEC PY 2016 VL 35 IS 12 BP 1656 EP 1657 PG 2 WC Ophthalmology SC Ophthalmology GA EC1KK UT WOS:000387863300035 ER PT J AU Albaghdadi, M Jang, IK AF Albaghdadi, Mazen Jang, Ik-Kyung TI Flow and plaque phenotype SO CORONARY ARTERY DISEASE LA English DT Editorial Material ID OPTICAL COHERENCE TOMOGRAPHY; INTRAVASCULAR ULTRASOUND; SPATIAL-DISTRIBUTION; CORONARY; DISEASE; LESIONS C1 [Albaghdadi, Mazen; Jang, Ik-Kyung] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA USA. [Jang, Ik-Kyung] Kyung Hee Univ, Div Cardiol, Dept Med, Seoul, South Korea. RP Jang, IK (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, GRB 800,55 Fruit St, Boston, MA 02114 USA. EM ijang@mgh.harvard.edu NR 13 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 0954-6928 EI 1473-5830 J9 CORONARY ARTERY DIS JI Coronary Artery Dis. PD DEC PY 2016 VL 27 IS 8 BP 621 EP 622 DI 10.1097/MCA.0000000000000431 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EB6JM UT WOS:000387489000001 PM 27798412 ER PT J AU Gin, AL Vergallo, R Minami, Y Ong, DS Hou, JB Jia, HB Soeda, T Hu, SN Zhang, SS Lee, H Yu, B Jang, IK AF Gin, Amy L. Vergallo, Rocco Minami, Yoshiyasu Ong, Daniel S. Hou, Jingbo Jia, Haibo Soeda, Tsunenari Hu, Sining Zhang, Shaosong Lee, Hang Yu, Bo Jang, Ik-Kyung TI Changes in coronary plaque morphology in patients with acute coronary syndrome versus stable angina pectoris after initiation of statin therapy SO CORONARY ARTERY DISEASE LA English DT Article DE acute coronary syndrome; intravascular ultrasound; optical coherence tomography; statin ID OPTICAL COHERENCE TOMOGRAPHY; INTRAVASCULAR ULTRASOUND; FIBROUS-CAP; ATORVASTATIN; INFLAMMATION; ATHEROSCLEROSIS; ACQUISITION; STANDARDS; CONSENSUS; DISEASE AB Objectives The aim of this study was to examine coronary plaque morphology after initiation of statins and compare changes in plaque morphology in patients presenting with acute coronary syndrome (ACS) versus stable angina pectoris (SAP). Background ACS is associated with a pan-inflammatory state, and intraplaque features of inflammation correlate with coronary plaque progression. Statins have known anti-inflammatory properties that may contribute toward their beneficial cardiovascular effects. Methods Sixty-nine statin-naive patients (ACS, n= 55; SAP, n= 14) underwent baseline imaging with optical coherence tomography and intravascular ultrasound. Repeat imaging was performed at 6 and 12 months. A total of 97 nonculprit plaques were analyzed (ACS, n= 74; SAP, n= 23). Results Fibrous cap thickness increased in both ACS and SAP patients (all P< 0.001 compared with the baseline); the ACS group showed greater percent change in fibrous cap thickness at 12 months (192.8 +/- 148.9% in ACS vs. 128.2 +/- 88.7% in SAP, P= 0.018). The ACS group also showed a significant decrease in plaque microvessels (44.6% at baseline vs. 26.6% at 12 months, P= 0.0386). Conclusion Compared with patients with SAP, patients presenting with ACS show more favorable changes in plaque morphology after starting statin treatment. This supports a potential additive benefit of statins in the inflammatory state of ACS and reaffirms the clinical importance of statin therapy for coronary atherosclerosis. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Gin, Amy L.; Vergallo, Rocco; Minami, Yoshiyasu; Ong, Daniel S.; Jia, Haibo; Soeda, Tsunenari; Hu, Sining; Lee, Hang; Jang, Ik-Kyung] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gin, Amy L.; Vergallo, Rocco; Minami, Yoshiyasu; Ong, Daniel S.; Jia, Haibo; Soeda, Tsunenari; Hu, Sining; Jang, Ik-Kyung] Harvard Med Sch, Div Cardiol, Boston, MA USA. [Lee, Hang] Harvard Med Sch, Ctr Biostat, Boston, MA USA. [Hou, Jingbo; Jia, Haibo; Hu, Sining; Zhang, Shaosong; Yu, Bo] Harbin Med Univ, Chinese Minist Educ, Affiliated Hosp 2, Key Lab Myocardial Ischemia,Dept Cardiol, Harbin, Peoples R China. [Soeda, Tsunenari] Nara Med Univ, Dept Med 1, Nara, Japan. [Zhang, Shaosong] Goodman Co Ltd, Nagoya, Aichi, Japan. [Jang, Ik-Kyung] Kyung Hee Univ, Div Cardiol, Seoul, South Korea. RP Jang, IK (reprint author), Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St,GRB 800, Boston, MA 02114 USA. EM ijang@mgh.harvard.org FU Allan Gill Gray; Italian Society of Cardiology; 'Enrico ed Enrica Sovena' Foundation of Rome, Italy FX Dr Jang's work was supported by Michael A. Park and Allan & Gill Gray. Dr Vergallo was supported in part by the 2013 Italian Society of Cardiology Award for Research Abroad and the 'Enrico ed Enrica Sovena' Foundation of Rome, Italy. NR 23 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 0954-6928 EI 1473-5830 J9 CORONARY ARTERY DIS JI Coronary Artery Dis. PD DEC PY 2016 VL 27 IS 8 BP 629 EP 635 DI 10.1097/MCA.0000000000000415 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EB6JM UT WOS:000387489000003 PM 27468140 ER PT J AU Xie, ZL Hou, JB Yu, H Jia, HB Du, HW Lee, H Yu, B Tian, JW Jang, IK AF Xie, Zulong Hou, Jingbo Yu, Huai Jia, Haibo Du, Hongwei Lee, Hang Yu, Bo Tian, Jinwei Jang, Ik-Kyung TI Patterns of coronary plaque progression: phasic versus gradual. A combined optical coherence tomography and intravascular ultrasound study SO CORONARY ARTERY DISEASE LA English DT Article DE atherosclerosis; intravascular ultrasound; optical coherence tomography; plaque progression ID THIN-CAP FIBROATHEROMA; ARTERY-DISEASE; ATHEROSCLEROTIC PLAQUE; VULNERABILITY; ATHEROMA; BURDEN; RUPTURE AB Objective Some plaques grow slowly in a linear manner, whereas others undergo a rapid phasic progression. However, the detailed in-vivo relationship between plaque characteristics and plaque progression pattern has not been reported. The current study aimed to investigate the plaque progression patterns with serial intravascular ultrasound (IVUS) examinations, and to correlate baseline plaque characteristics assessed by optical coherence tomography and IVUS with plaque progression patterns. Methods A total of 248 coronary lesions from 157 patients were identified and imaged by both optical coherence tomography and IVUS at baseline. IVUS examination was repeated at 6 and 12 months. Plaque progression was defined as greater than or equal to 5% increase in percent atheroma volume by IVUS. The progression patterns were divided into three groups: no progression, rapid phasic progression, and gradual progression. Results Among 248 lesions, 190 (77%) showed no progression. Among 58 lesions with progression, 20 (34%) showed gradual progression, whereas 38 (66%) showed rapid phasic progression. Multivariate analysis indicated that thin-cap fibroatheroma [odds ratio (OR)= 5.24, 95% confidence interval (CI) 2.04-13.4; P= 0.001], microvessel (OR= 2.20, 95% CI 1.10-4.79; P= 0.045), and positive remodeling (OR= 2.64, 95% CI 1.19-5.81; P= 0.016) were associated independently with rapid phasic progression. Conclusion Three-quarters of coronary plaques did not progress over time with contemporary medical treatment. Among the lesions with progression, one-third showed a gradual pattern and two-thirds showed a rapid phasic pattern. The presence of thin-cap fibroatheroma, microvessel, and positive remodeling were the independent predictors for rapid phasic pattern progression of coronary atherosclerotic plaques. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Xie, Zulong; Hou, Jingbo; Yu, Huai; Jia, Haibo; Du, Hongwei; Yu, Bo; Tian, Jinwei] Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, 246 Xuefu Rd, Harbin 150086, Peoples R China. [Xie, Zulong; Hou, Jingbo; Yu, Huai; Jia, Haibo; Du, Hongwei; Yu, Bo; Tian, Jinwei] Chinese Minist Educ, Key Lab Myocardial Ischemia, 246 Xuefu Rd, Harbin, Peoples R China. [Lee, Hang] Harvard Med Sch, Massachusetts Gen Hosp, Dept Biostat, Boston, MA USA. [Jang, Ik-Kyung] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA. [Jang, Ik-Kyung] Kyung Hee Univ Seoul, Div Cardiol, Seoul, South Korea. RP Tian, JW (reprint author), Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, 246 Xuefu Rd, Harbin 150086, Peoples R China.; Tian, JW (reprint author), Chinese Minist Educ, Key Lab Myocardial Ischemia, 246 Xuefu Rd, Harbin, Peoples R China. EM tianjinweidr2009@163.com FU National Natural Science Foundation of China [81571749]; National Youth Top-notch Talent Support Program of China; St Jude Medical FX This study was supported by the National Natural Science Foundation of China (Grant No. 81571749 to J. T.), and the National Youth Top-notch Talent Support Program of China (J. T.). Dr Jang has received a research grant from St Jude Medical. NR 28 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 0954-6928 EI 1473-5830 J9 CORONARY ARTERY DIS JI Coronary Artery Dis. PD DEC PY 2016 VL 27 IS 8 BP 658 EP 666 DI 10.1097/MCA.0000000000000420 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EB6JM UT WOS:000387489000006 PM 27580090 ER PT J AU Keenan, HA Maddaloni, E AF Keenan, Hillary A. Maddaloni, Ernesto TI Bone Microarchitecture in Type 1 Diabetes: It Is Complicated SO CURRENT OSTEOPOROSIS REPORTS LA English DT Review DE Bone quality; Microarchitecture; Type 1 diabetes; Diabetes; Complications; Bone fragility ID ENDOTHELIAL GROWTH-FACTOR; CORONARY-ARTERY-DISEASE; MINERAL DENSITY; TRABECULAR BONE; CARDIOVASCULAR-DISEASE; FRACTURE RISK; AORTIC CALCIFICATION; GLYCEMIC CONTROL; YOUNG-PATIENTS; ADYNAMIC BONE AB Patients with type 1 diabetes (T1DM) experience a disproportionate number of fractures for their bone mineral density (BMD). Differences in bone microarchitecture from those without the disease are thought to be responsible. However, the literature is inconclusive. New studies of the microarchitecture using three-dimensional imaging have the advantage of providing in vivo estimates of "bone quality," rather than examining areal BMD alone. There are drawbacks in that most studies have been done on those with less than a 30-year duration of T1DM, and the techniques used to measure vary as do the sites assessed. In addition to the rise in these imaging techniques, very recent literature presents evidence of an intimate relationship between skeletal health and vascular complications in T1DM. The following review provides an overview of the available studies of the bone microarchitecture in T1DM with a discussion of the burgeoning field of complications and skeletal health. C1 [Keenan, Hillary A.; Maddaloni, Ernesto] Harvard Med Sch, Div Res, Joslin Diabet Ctr, One Joslin Pl, Boston, MA 02215 USA. [Maddaloni, Ernesto] Univ Campus Biomed Rome, Dept Med, Unit Endocrinol & Diabet, Rome, Italy. RP Keenan, HA (reprint author), Harvard Med Sch, Div Res, Joslin Diabet Ctr, One Joslin Pl, Boston, MA 02215 USA. EM hillary.keenan@joslin.harvard.edu; e.maddaloni@unicampus.it FU NIDDK NIH HHS [U24 DK076169] NR 70 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1544-2241 J9 CURR OSTEOPOROS REP JI Curr. Osteoporos. Rep. PD DEC PY 2016 VL 14 IS 6 BP 351 EP 358 DI 10.1007/s11914-016-0338-8 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EC1KW UT WOS:000387864600012 PM 27704394 ER PT J AU Atassi, N Beghi, E Blanquer, M Boulis, NM Cantello, R Caponnetto, C Chio, A Dunnett, SB Feldman, EL Vescovi, A Mazzini, L AF Atassi, Nazem Beghi, Ettore Blanquer, Miguel Boulis, Nicholas M. Cantello, Roberto Caponnetto, Claudia Chio, Adriano Dunnett, Stephen B. Feldman, Eva L. Vescovi, Angelo Mazzini, Letizia CA Attendees Int Workshop Progres TI Intraspinal stem cell transplantation for amyotrophic lateral sclerosis: Ready for efficacy clinical trials? SO CYTOTHERAPY LA English DT Article DE ALS; clinical trials; stem cells; transplantation ID PHASE-I TRIAL; PARKINSONS-DISEASE; MOUSE MODEL; SAFETY; DISORDERS; THERAPY; ALS AB Intraspinal stem cell (SC) transplantation represents a new therapeutic approach for amyotrophic lateral sclerosis (ALS) clinical trials. There are considerable difficulties in designing future efficacy trials, some related to the field of ALS and some that are specific to SCs or the mode of delivery. In October 2015, the most controversial points on SC transplantation were addressed during an international workshop intended to bring together international SC and ALS researchers in a public discussion on a topic for which expertise is limited. During the meeting, a discussion was started on the basic structure of the ideal clinical trial testing the efficacy and safety of SC transplantation. The current document includes a number of consensus points reflecting the design of phase II/III clinical trials. C1 [Atassi, Nazem] Massachusetts Gen Hosp, Dept Neurol, NCRI, Boston, MA 02114 USA. [Beghi, Ettore] IRCCS Inst Pharmacol Res Mario Negri, Dept Neurosci, Milan, Italy. [Blanquer, Miguel] Univ Murcia, Virgen de la Arrixaca Univ Hosp IMIB, Transplant & Cell Therapy Unit, Murcia, Spain. [Boulis, Nicholas M.] Emory Univ, Sch Med, Dept Neurosurg, Atlanta, GA USA. [Cantello, Roberto] Eastern Piedmont Univ, Dept Neurol, Novara, Italy. [Caponnetto, Claudia] IRCCS AOU S Martino IST, UO Neurol, Genoa, Italy. [Chio, Adriano] Univ Turin, ALS Ctr Rita Levi Montalcini, Dept Neurosci, Neurol 2, Turin, Italy. [Dunnett, Stephen B.] Cardiff Univ, Sch Biosci, Brain Repair Grp, Museum Ave, Cardiff, S Glam, Wales. [Feldman, Eva L.] Univ Michigan, Dept Neurol, Ann Arbor, MI USA. [Vescovi, Angelo] IRCCS Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy. [Vescovi, Angelo] Bicocca Univ, Biotechnol & Biosci Dept, Milan, Italy. [Mazzini, Letizia] Maggiore della Carita Univ Hosp, Dept Neurol, ALS Ctr, Corso Mazzini 18, I-28100 Novara, Italy. RP Mazzini, L (reprint author), Maggiore della Carita Univ Hosp, Dept Neurol, ALS Ctr, Corso Mazzini 18, I-28100 Novara, Italy. EM mazzini.l@libero.it RI La Bella, Vincenzo/H-4532-2012; OI Bendotti, Caterina/0000-0003-1055-1271 FU Uniti Ricerca Sclerosi Larerale Amiotrofica (URSLA)-Novara Onlus Association FX The workshop was generously funded by the Uniti Ricerca Sclerosi Larerale Amiotrofica (URSLA)-Novara Onlus Association. NR 23 TC 1 Z9 1 U1 7 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD DEC PY 2016 VL 18 IS 12 BP 1471 EP 1475 DI 10.1016/j.jcyt.2016.08.005 PG 5 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA EB6XU UT WOS:000387529700002 PM 27720637 ER PT J AU Prentice, JC Pizer, SD Conlin, PR AF Prentice, J. C. Pizer, S. D. Conlin, P. R. TI Identifying the independent effect of HbA(1c) variability on adverse health outcomes in patients with Type 2 diabetes SO DIABETIC MEDICINE LA English DT Article ID GLYCEMIC VARIABILITY; ADMINISTRATIVE DATA; OXIDATIVE STRESS; COMPLICATIONS; MORTALITY; RISK; HYPERGLYCEMIA; HYPOGLYCEMIA; PRESSURE; VETERANS AB AimsTo characterize the relationship between HbA(1c) variability and adverse health outcomes among US military veterans with Type 2 diabetes. MethodsThis retrospective cohort study used Veterans Affairs and Medicare claims for veterans with Type 2 diabetes taking metformin who initiated a second diabetes medication (n = 50 861). The main exposure of interest was HbA(1c) variability during a 3-year baseline period. HbA(1c) variability, categorized into quartiles, was defined as standard deviation, coefficient of variation and adjusted standard deviation, which accounted for the number and mean number of days between HbA(1c) tests. Cox proportional hazard models predicted mortality, hospitalization for ambulatory care-sensitive conditions, and myocardial infarction or stroke and were controlled for mean HbA(1c) levels and the direction of change in HbA(1c) levels during the baseline period. ResultsOver a mean 3.3 years of follow-up, all HbA(1c) variability measures significantly predicted each outcome. Using the adjusted standard deviation measure for HbA(1c) variability, the hazard ratios for the third and fourth quartile predicting mortality were 1.14 (95% CI 1.04, 1.25) and 1.42 (95% CI 1.28, 1.58), for myocardial infarction and stroke they were 1.25 (95% CI 1.10, 1.41) and 1.23 (95% CI 1.07, 1.42) and for ambulatory-care sensitive condition hospitalization they were 1.10 (95% CI 1.03, 1.18) and 1.11 (95% CI 1.03, 1.20). Higher baseline HbA(1c) levels independently predicted the likelihood of each outcome. ConclusionsIn veterans with Type 2 diabetes, greater HbA(1c) variability was associated with an increased risk of adverse long-term outcomes, independently of HbA(1c) levels and direction of change. Limiting HbA(1c) fluctuations over time may reduce complications. C1 [Prentice, J. C.; Pizer, S. D.; Conlin, P. R.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Prentice, J. C.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Pizer, S. D.] Northwestern Univ, Boston, MA USA. [Conlin, P. R.] Harvard Med Sch, Boston, MA USA. RP Prentice, JC (reprint author), VA Boston Healthcare Syst, Boston, MA 02130 USA.; Prentice, JC (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. EM jprentic@bu.edu FU Department of Veterans Affairs Health Services Research and Development Service [IIR 10-136]; Agency for Healthcare Research and Quality [R01 HS019708] FX This study was supported by research grants (IIR 10-136) from the Department of Veterans Affairs Health Services Research and Development Service and from the Agency for Healthcare Research and Quality (R01 HS019708). NR 30 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0742-3071 EI 1464-5491 J9 DIABETIC MED JI Diabetic Med. PD DEC PY 2016 VL 33 IS 12 BP 1640 EP 1648 DI 10.1111/dme.13166 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EC1MZ UT WOS:000387871300008 PM 27279250 ER PT J AU Taylor, PA Alhamud, A van der Kouwe, A Saleh, MG Laughton, B Meintjes, E AF Taylor, Paul A. Alhamud, A. van der Kouwe, Andre Saleh, Muhammad G. Laughton, Barbara Meintjes, Ernesta TI Assessing the performance of different DTI motion correction strategies in the presence of EPI distortion correction SO HUMAN BRAIN MAPPING LA English DT Article DE diffusion tensor imaging; motion correction; echo planar imaging volumetric navigator; fractional anisotropy; tractography ID IN-DIFFUSION MRI; SUBJECT-MOTION; WHITE-MATTER; HEAD MOTION; SPIN-ECHO; TRACTOGRAPHY; REPRODUCIBILITY; ARTIFACTS; IMAGES; BRAIN AB Diffusion tensor imaging (DTI) is susceptible to several artifacts due to eddy currents, echo planar imaging (EPI) distortion and subject motion. While several techniques correct for individual distortion effects, no optimal combination of DTI acquisition and processing has been determined. Here, the effects of several motion correction techniques are investigated while also correcting for EPI distortion: prospective correction, using navigation; retrospective correction, using two different popular packages (FSL and TORTOISE); and the combination of both methods. Data from a pediatric group that exhibited incidental motion in varying degrees are analyzed. Comparisons are carried while implementing eddy current and EPI distortion correction. DTI parameter distributions, white matter (WM) maps and probabilistic tractography are examined. The importance of prospective correction during data acquisition is demonstrated. In contrast to some previous studies, results also show that the inclusion of retrospective processing also improved ellipsoid fits and both the sensitivity and specificity of group tractographic results, even for navigated data. Matches with anatomical WM maps are highest throughout the brain for data that have been both navigated and processed using TORTOISE. The inclusion of both prospective and retrospective motion correction with EPI distortion correction is important for DTI analysis, particularly when studying subject populations that are prone to motion. Hum Brain Mapp 37:4405-4424, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Taylor, Paul A.; Alhamud, A.; Saleh, Muhammad G.; Meintjes, Ernesta] Univ Cape Town, Dept Human Biol, Fac Hlth Sci, MRC UCT Med Imaging Res Unit, Cape Town, South Africa. [Taylor, Paul A.] African Inst Math Sci, Muizenberg, Western Cape, South Africa. [Taylor, Paul A.] NIH, Sci & Stat Comp Core, Bldg 10, Bethesda, MD 20892 USA. [van der Kouwe, Andre] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Laughton, Barbara] Univ Stellenbosch, Dept Paediat & Child Hlth, Childrens Infect Dis Clin Res Unit, Stellenbosch, South Africa. RP Taylor, PA (reprint author), Univ Cape Town, Fac Hlth Sci, Dept Human Biol, ZA-7925 Cape Town, South Africa. EM neon.taylor@gmail.com FU NRF/DST South African Research Chairs Initiative; NIH [R01HD071664, R21MH096559]; NRF [CPR20110614000019421]; Medical Research Council (MRC); NIMH; NINDS Intramural Research Programs of the NIH FX Contract grant sponsor: NRF/DST South African Research Chairs Initiative; Contract grant sponsor: NIH; Contract grant number: R01HD071664 and R21MH096559; Contract grant sponsor: NRF; Contract grant number: CPR20110614000019421; Contract grant sponsor: The Medical Research Council (MRC); Contract grant sponsor: NIMH and NINDS Intramural Research Programs of the NIH NR 44 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 DEC PY 2016 VL 37 IS 12 BP 4405 EP 4424 DI 10.1002/hbm.23318 PG 20 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EB5FL UT WOS:000387399200014 PM 27436169 ER PT J AU Takaya, S Liu, HS Greve, DN Tanaka, N Leveroni, C Cole, AJ Stufflebeam, SM AF Takaya, Shigetoshi Liu, Hesheng Greve, Douglas N. Tanaka, Naoaki Leveroni, Catherine Cole, Andrew J. Stufflebeam, Steven M. TI Altered anterior-posterior connectivity through the arcuate fasciculus in temporal lobe epilepsy SO HUMAN BRAIN MAPPING LA English DT Article DE Broca's area; Freesurfer; function; language; MRI; psychophysiological interaction; reorganization; semantic; structure; tractography ID WHITE-MATTER MICROSTRUCTURE; INTERICTAL GLUCOSE HYPOMETABOLISM; INFERIOR PREFRONTAL CORTEX; HUMAN CEREBRAL-CORTEX; HUMAN BRAIN; LANGUAGE LATERALIZATION; FUNCTIONAL MRI; CORTICAL SURFACE; HIPPOCAMPAL SCLEROSIS; SEMANTIC KNOWLEDGE AB How the interactions between cortices through a specific white matter pathway change during cognitive processing in patients with epilepsy remains unclear. Here, we used surface-based structural connectivity analysis to examine the change in structural connectivity with Broca's area/the right Broca's homologue in the lateral temporal and inferior parietal cortices through the arcuate fasciculus (AF) in 17 patients with left temporal lobe epilepsy (TLE) compared with 17 healthy controls. Then, we investigated its functional relevance to the changes in task-related responses and task-modulated functional connectivity with Broca's area/the right Broca's homologue during a semantic classification task of a single word. The structural connectivity through the AF pathway and task-modulated functional connectivity with Broca's area decreased in the left midtemporal cortex. Furthermore, task-related response decreased in the left mid temporal cortex that overlapped with the region showing a decrease in the structural connectivity. In contrast, the region showing an increase in the structural connectivity through the AF overlapped with the regions showing an increase in task-modulated functional connectivity in the left inferior parietal cortex. These structural and functional changes in the overlapping regions were correlated. The results suggest that the change in the structural connectivity through the left frontal-temporal AF pathway underlies the altered functional networks between the frontal and temporal cortices during the language-related processing in patients with left TLE. The left frontal-parietal AF pathway might be employed to connect anterior and posterior brain regions during language processing and compensate for the compromised left frontal-temporal AF pathway. Hum Brain Mapp 37:4425-4438, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Takaya, Shigetoshi; Liu, Hesheng; Greve, Douglas N.; Tanaka, Naoaki; Stufflebeam, Steven M.] Massachusetts Gen Hosp, MGH HST Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Takaya, Shigetoshi; Liu, Hesheng; Greve, Douglas N.; Tanaka, Naoaki; Leveroni, Catherine; Cole, Andrew J.; Stufflebeam, Steven M.] Harvard Med Sch, Boston, MA USA. [Leveroni, Catherine] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Cole, Andrew J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Takaya, S (reprint author), Kyoto Univ, Grad Sch Med, Dept Neurol, Human Brain Res Ctr, Kyoto 6068507, Japan. EM shig.t@kuhp.kyoto-u.ac.jp FU National Institute of Health [R01-NS069696, P41-EB015896, U01-MH093765, T32-EB001680]; National Science Foundation [NFSDMS-1042134]; Uehara Memorial Foundation; SNMMI (Wagner-Torizuka Fellowship); Department of Energy [DE-SC0008430] FX Contract grant sponsor: National Institute of Health; Contract grant numbers: R01-NS069696, P41-EB015896, U01-MH093765, T32-EB001680; Contract grant sponsor: National Science Foundation grant; Contract grant number: NFSDMS-1042134; Contract grant sponsors: Uehara Memorial Foundation, the SNMMI (Wagner-Torizuka Fellowship); Contract grant sponsor: Department of Energy; Contract grant number: DE-SC0008430 NR 97 TC 0 Z9 0 U1 7 U2 7 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 DEC PY 2016 VL 37 IS 12 BP 4425 EP 4438 DI 10.1002/hbm.23319 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EB5FL UT WOS:000387399200015 PM 27452151 ER PT J AU Karami, S Han, Y Pande, M Cheng, I Rudd, J Pierce, BL Nutter, EL Schumacher, FR Kote-Jarai, Z Lindstrom, S Witte, JS Fang, S Han, J Kraft, P Hunter, DJ Song, F Hung, RJ McKay, J Gruber, SB Chanock, SJ Risch, A Shen, H Haiman, CA Boardman, L Ulrich, CM Casey, G Peters, U Al Olama, AA Berchuck, A Berndt, SI Bezieau, S Brennan, P Brenner, H Brinton, L Caporaso, N Chan, AT Chang-Claude, J Christiani, DC Cunningham, JM Easton, D Eeles, RA Eisen, T Gala, M Gallinger, SJ Gayther, SA Goode, EL Gronberg, H Henderson, BE Houlston, R Joshi, AD Kury, S Landi, MT Le Marchand, L Muir, K Newcomb, PA Permuth-Wey, J Pharoah, P Phelan, C Potter, JD Ramus, SJ Risch, H Schildkraut, J Slattery, ML Song, H Wentzensen, N White, E Wiklund, F Zanke, BW Sellers, TA Zheng, W Chatterjee, N Amos, CI Doherty, JA AF Karami, Sara Han, Younghun Pande, Mala Cheng, Iona Rudd, James Pierce, Brandon L. Nutter, Ellen L. Schumacher, Fredrick R. Kote-Jarai, Zsofia Lindstrom, Sara Witte, John S. Fang, Shenying Han, Jiali Kraft, Peter Hunter, David J. Song, Fengju Hung, Rayjean J. McKay, James Gruber, Stephen B. Chanock, Stephen J. Risch, Angela Shen, Hongbing Haiman, Christopher A. Boardman, Lisa Ulrich, Cornelia M. Casey, Graham Peters, Ulrike Al Olama, Ali Amin Berchuck, Andrew Berndt, Sonja I. Bezieau, Stephane Brennan, Paul Brenner, Hermann Brinton, Louise Caporaso, Neil Chan, Andrew T. Chang-Claude, Jenny Christiani, David C. Cunningham, Julie M. Easton, Douglas Eeles, Rosalind A. Eisen, Timothy Gala, Manish Gallinger, Steven J. Gayther, Simon A. Goode, Ellen L. Gronberg, Henrik Henderson, Brian E. Houlston, Richard Joshi, Amit D. Kury, Sebastien Landi, Mari T. Le Marchand, Loic Muir, Kenneth Newcomb, Polly A. Permuth-Wey, Jenny Pharoah, Paul Phelan, Catherine Potter, John D. Ramus, Susan J. Risch, Harvey Schildkraut, Joellen Slattery, Martha L. Song, Honglin Wentzensen, Nicolas White, Emily Wiklund, Fredrik Zanke, Brent W. Sellers, Thomas A. Zheng, Wei Chatterjee, Nilanjan Amos, Christopher I. Doherty, Jennifer A. CA GECCO GAME-ON Network CORECT CORECT DRIVE ELLIPSE FOCI TRICL TI Telomere structure and maintenance gene variants and risk of five cancer types SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE telomere structure; telomere maintenance; cancer risk; GWAS; meta-analysis; lung cancer; breast cancer; ovarian cancer; prostate cancer; colorectal cancer ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; COLORECTAL-CANCER; OVARIAN-CANCER; IDENTIFIES 3; METAANALYSIS; LENGTH; IMPUTATION; BREAST; REGIONS AB Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs <= 3.08 X 10(-5)). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk. C1 [Karami, Sara; Rudd, James; Nutter, Ellen L.; Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Dept Epidemiol, Lebanon, NH USA. [Han, Younghun; Amos, Christopher I.] Geisel Sch Med Dartmouth, Dept Biomed Data Sci, Lebanon, NH USA. [Pande, Mala] Univ Texas MD Anderson Canc Ctr, Dept Gastroenterol Hepatol & Nutr, Houston, TX 77030 USA. [Cheng, Iona] Canc Prevent Inst Calif, Fremont, CA USA. [Cheng, Iona] Stanford Canc Inst, Stanford, CA USA. [Pierce, Brandon L.] Univ Chicago, Dept Publ Hlth Sci, Chicago, IL 60637 USA. [Pierce, Brandon L.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Pierce, Brandon L.] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA. [Schumacher, Fredrick R.; Gruber, Stephen B.; Haiman, Christopher A.; Casey, Graham; Gayther, Simon A.; Henderson, Brian E.; Ramus, Susan J.] Univ Southern Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA USA. [Kote-Jarai, Zsofia; Eeles, Rosalind A.] Inst Canc Res, Oncogenet Team, London, England. [Kote-Jarai, Zsofia; Eeles, Rosalind A.] Royal Marsden NHS Fdn Trust, London, England. [Lindstrom, Sara; Christiani, David C.] Harvard TH Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA. [Witte, John S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, Div Genet & Canc Epidemiol, San Francisco, CA 94143 USA. [Witte, John S.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Fang, Shenying] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Han, Jiali] Indiana Univ, Dept Epidemiol, Fairbanks Sch Publ Hlth, Simon Canc Ctr, Indianapolis, IN 46204 USA. [Kraft, Peter; Hunter, David J.; Joshi, Amit D.] Harvard Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. [Song, Fengju] Tianjin Med Univ, Canc Inst & Hosp, Natl Clin Res Ctr Canc, Dept Epidemiol & Biostat,Key Lab Canc Prevent & T, Tianjin, Peoples R China. [Hung, Rayjean J.; Gallinger, Steven J.] Univ Toronto, Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [McKay, James; Brennan, Paul] Int Agcy Res Canc, Genet Epidemiol Grp, Genet Canc Susceptibil Grp, Lyon, France. [Chanock, Stephen J.; Berndt, Sonja I.; Brinton, Louise; Caporaso, Neil; Landi, Mari T.; Wentzensen, Nicolas; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Risch, Angela] German Canc Res Ctr, Div Epigen & Canc Risk Factors, Heidelberg, Germany. [Risch, Angela] German Ctr Lung Res DZL, TLRC H, Heidelberg, Germany. [Shen, Hongbing] Nanjing Med Univ, Dept Epidemiol & Biostat, Collaborat Innovat Ctr Canc Med,Sch Publ Hlth, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Nanjing, Jiangsu, Peoples R China. [Boardman, Lisa; Cunningham, Julie M.; Goode, Ellen L.] Mayo Clin, Rochester, MN USA. [Ulrich, Cornelia M.; Slattery, Martha L.] Huntsman Canc Inst, Salt Lake City, UT USA. [Ulrich, Cornelia M.; Peters, Ulrike; Newcomb, Polly A.; Potter, John D.; White, Emily] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Al Olama, Ali Amin; Easton, Douglas] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Berchuck, Andrew] Duke Univ, Dept Obstet & Gynecol, Durham, NC USA. [Bezieau, Stephane; Kury, Sebastien] CHU Nantes, Serv Genet Med, Nantes, France. [Brenner, Hermann] Deutsch Krebsforschungszentrum, Klin Epidemiol & Alternsforsch, Heidelberg, Germany. [Chan, Andrew T.; Gala, Manish] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Chan, Andrew T.] Harvard Med Sch, Boston, MA USA. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Easton, Douglas; Pharoah, Paul; Song, Honglin] Univ Cambridge, Dept Oncol, Cambridge, England. [Eisen, Timothy] Addenbrookes Hosp, Cambridge Biomed Campus, Cambridge, England. [Gronberg, Henrik; Wiklund, Fredrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Houlston, Richard] Inst Canc Res, London, England. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Div Epidemiol, Honolulu, HI 96822 USA. [Muir, Kenneth] Univ Warwick, Warwick Med Sch, Coventry, W Midlands, England. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Permuth-Wey, Jenny; Phelan, Catherine; Sellers, Thomas A.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Risch, Harvey] Yale Sch Publ Hlth, New Haven, CT USA. [Schildkraut, Joellen] Univ Virginia, Charlottesville, VA USA. [Zanke, Brent W.] Univ Ottawa, Ottawa Hosp, Res Inst, Div Hematol, Ottawa, ON, Canada. [Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Zheng, Wei] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37212 USA. RP Doherty, JA (reprint author), Geisel Sch Med Dartmouth, Dept Community & Family Med, Dept Epidemiol, One Med Ctr Dr,7927 Rubin Bldg,Room 853, Lebanon, NH 03756 USA. EM Jennifer.A.Doherty@Dartmouth.edu RI Gallinger, Steven/E-4575-2013; Brenner, Hermann/B-4627-2017; Risch, Angela/H-2669-2013; OI Brenner, Hermann/0000-0002-6129-1572; Risch, Angela/0000-0002-8026-5505; Pierce, Brandon/0000-0002-7829-952X; Houlston, Richard/0000-0002-5268-0242 FU National Institutes of Health (NIH), National Cancer Institute (NCI) [R01 CA151989]; European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; (COGS), Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defense [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; US NCI GAME-ON Post-GWAS Initiative [U19-CA148112]; TRICL (Transdisciplinary Research for Cancer of Lung): NIH [U19 CA148127-01]; Canadian Cancer Society Research Institute [020214]; DRIVE (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer): NIH [U19 CA148065]; CORECT (ColoRectal Transdisciplinary Study): NIH [U19 CA148107, R01 CA81488, P30 CA014089]; ELLIPSE (ELLIPSE, Elucidating Loci in Prostate Cancer Susceptibility); GAMEON U19 initiative for prostate cancer (ELLIPSE) [U19 CA148537]; FOCI (Transdisciplinary Cancer Genetic Association and Interacting Studies) [NIH U19 CA148112-01, R01-CA122443, P50-CA136393, P30-CA15083]; Cancer Research UK [C490/A8339, C490/A16561, C490/A10119, C490/A10124]; GECCO: NCI, NIH, U.S. Department of Health and Human Services (DHHS) [U01 CA137088, R01 CA059045]; ASTERISK: a Hospital Clinical Research Program (PHRC); Regional Council of Pays de la Loire; Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC); Association Anne de Bretagne Genetique; Ligue Regionale Contre le Cancer (LRCC); COLO23: NIH [R01 CA60987]; DACHS: German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; NIH [R01 CA48998, P01 CA 055075, UM1 CA167552, R01 137178, R01 CA151993, P50 CA127003, UM1 CA186107, R01 CA137178, P01 CA87969, R01 CA042182]; MEC: NIH [R37 CA54281, P01 CA033619, R01 CA63464]; Ontario Registry for Studies of Familial Colorectal Cancer (OFCCR: NIH) [U01 CA074783]; Ontario Research Fund; Canadian Institutes of Health Research; Ontario Institute for Cancer Research (OFCCR); Ontario Ministry of Research and Innovation; PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, NCI, NIH, DHHS; Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS; Nat Genet; Colon CGEMS pancreatic cancer scan (PanScan); NIH, Genes, Environment and Health Initiative (GEI) [Z01 CP 010200, NIH U01 HG004446, NIH GEI U01 HG 004438]; GENEVA Coordinating Center; Johns Hopkins University Center for Inherited Disease Research; PMH: NIH [R01 CA076366]; VITAL: NIH [K05 CA154337]; WHI: National Heart, Lung, and Blood Institute, NIH, DHHS (The WHI program) [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; MD Anderson: NCI [NIH K07CA160753] FX Grant sponsor: The National Institutes of Health (NIH), National Cancer Institute (NCI); Grant number: R01 CA151989; Grant sponsor: European Community's Seventh Framework Programme under grant agreement no 223175; Grant number: HEALTH-F2-2009-223175; Grant sponsor: (COGS), Cancer Research UK; Grant numbers: C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/ A8384, C5047/A15007, C5047/A10692, C8197/A16565; Grant sponsor: National Institutes of Health; Grant number: CA128978; Grant sponsor: Post-Cancer GWAS initiative; Grant numbers: 1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 -the GAME-ON initiative; Grant sponsor: Department of Defense; Grant number: W81XWH-10-1-0341; Grant sponsors: Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund; Grant sponsor: US NCI GAME-ON Post-GWAS Initiative; Grant number: U19-CA148112; Grant sponsor: TRICL (Transdisciplinary Research for Cancer of Lung): NIH U19 CA148127-01 (PI: Amos); Grant sponsors: Canadian Cancer Society Research Institute (no. 020214, PI: Hung); DRIVE (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer): NIH U19 CA148065; CORECT (ColoRectal Transdisciplinary Study): NIH U19 CA148107; R01 CA81488, P30 CA014089; ELLIPSE (ELLIPSE, Elucidating Loci in Prostate Cancer Susceptibility); Grant sponsors: GAMEON U19 initiative for prostate cancer (ELLIPSE); Grant number: U19 CA148537; Grant sponsor: FOCI (Transdisciplinary Cancer Genetic Association and Interacting Studies); Grant numbers: NIH U19 CA148112-01 (PI: Sellers), R01-CA122443, P50-CA136393, P30-CA15083 (PI: Goode); Grant sponsor: Cancer Research UK; Grant numbers: C490/A8339, C490/A16561, C490/A10119, C490/A10124 (PI: Pharoah); Grant sponsor: GECCO: NCI, NIH, U.S. Department of Health and Human Services (DHHS); Grant numbers: U01 CA137088, R01 CA059045; Grant sponsors: ASTERISK: a Hospital Clinical Research Program (PHRC); Regional Council of Pays de la Loire, the Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Genetique and the Ligue Regionale Contre le Cancer (LRCC); COLO2&3: NIH (R01 CA60987); Grant sponsor: DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS: NIH (R01 CA48998 to M. L. Slattery); Grant sponsor: NIH (HPFS); Grant numbers: P01 CA 055075, UM1 CA167552, R01 137178, R01 CA151993, P50 CA127003; Grant sponsor: NIH (NHS); Grant numbers: UM1 CA186107, R01 CA137178, P01 CA87969, R01 CA151993 and P50 CA127003; Grant sponsors: NIH (PHS); Grant number: R01 CA042182; Grant sponsor: MEC: NIH; Grant numbers: R37 CA54281, P01 CA033619 and R01 CA63464; Grant sponsor: Ontario Registry for Studies of Familial Colorectal Cancer (OFCCR: NIH); Grant number: U01 CA074783; Grant sponsors: Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research (OFCCR), Ontario Ministry of Research and Innovation; Grant sponsors: PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and Division of Cancer Prevention, NCI, NIH, DHHS; Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS (Yeager, M et al.; Genome-wide association study of prostate cancer identifies a second risk locus at 8q24; Grant sponsors: Nat Genet 2007 May; 39(5): 645-9), Colon CGEMS pancreatic cancer scan (PanScan) (Amundadottir, L et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet. 2009 Sep; 41(9): 986-90, and Petersen, GM et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010 Mar; 42(3): 224-8), and the Lung Cancer and Smoking study (Landi MT, et al. A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet. 2009 Nov; 85(5): 679-91); the prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems. cancer. gov/data/) accession numbers phs000207. v1. p1 and phs000206. v3. p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www. ncbi. nlm. nih. gov/gap) through accession number phs000093.v2.p2; Grant sponsor: NIH, Genes, Environment and Health Initiative (GEI) (Lung Cancer and Smoking study); Grant numbers: Z01 CP 010200, NIH U01 HG004446 and NIH GEI U01 HG 004438; Grant sponsors: GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping; Grant sponsor: PMH: NIH; Grant number: R01 CA076366 to P. A. Newcomb; Grant sponsors: VITAL: NIH; Grant numbers: K05 CA154337; Grant sponsors: WHI: National Heart, Lung, and Blood Institute, NIH, DHHS (The WHI program); Grant numbers: HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C; Grant sponsor: MD Anderson: NCI; Grant number: NIH K07CA160753 (PI: Pande) NR 47 TC 0 Z9 0 U1 21 U2 21 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 DEC PY 2016 VL 139 IS 12 BP 2655 EP 2670 DI 10.1002/ijc.30288 PG 16 WC Oncology SC Oncology GA EB8CU UT WOS:000387619400003 PM 27459707 ER PT J AU Qazi, H Shi, ZD Song, JW Cancel, LM Huang, PG Zeng, Y Roberge, S Munn, LL Tarbell, JM AF Qazi, Henry Shi, Zhong-Dong Song, Jonathan W. Cancel, Limary M. Huang, Peigen Zeng, Ye Roberge, Sylvie Munn, Lance L. Tarbell, John M. TI Heparan sulfate proteoglycans mediate renal carcinoma metastasis SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE metastasis; glycocalyx; NDST1; mechanobiology; interstitial flow ID INTERSTITIAL FLOW; CELL GLYCOCALYX; CANCER; INVASION; ANGIOGENESIS; MODEL; MECHANOTRANSDUCTION; MIGRATION; DEPLETION; SURVIVAL AB The surface proteoglycan/glycoprotein layer (glycocalyx) on tumor cells has been associated with cellular functions that can potentially enable invasion and metastasis. In addition, aggressive tumor cells with high metastatic potential have enhanced invasion rates in response to interstitial flow stimuli in vitro. Our previous studies suggest that heparan sulfate (HS) in the glycocalyx plays an important role in this flow mediated mechanostransduction and upregulation of invasive and metastatic potential. In this study, highly metastatic renal cell carcinoma cells were genetically modified to suppress HS production by knocking down its synthetic enzyme NDST1. Using modified Boyden chamber and microfluidic assays, we show that flow-enhanced invasion is suppressed in HS deficient cells. To assess the ability of these cells to metastasize in vivo, parental or knockdown cells expressing fluorescence reporters were injected into kidney capsules in SCID mice. Histological analysis confirmed that there was a large reduction (95%) in metastasis to distant organs by tumors formed from the NDST1 knockdown cells compared to control cells with intact HS. The ability of these cells to invade surrounding tissue was also impaired. The substantial inhibition of metastasis and invasion upon reduction of HS suggests an active role for the tumor cell glycocalyx in tumor progression. C1 [Qazi, Henry; Cancel, Limary M.; Zeng, Ye; Tarbell, John M.] CUNY City Coll, Dept Biomed Engn, Wallace H Coulter Lab, New York, NY 10032 USA. [Shi, Zhong-Dong] Sloan Kettering Inst, Dev Biol Program, New York, NY 10065 USA. [Song, Jonathan W.] Ohio State Univ, Dept Mech & Aerosp Engn, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Huang, Peigen; Roberge, Sylvie; Munn, Lance L.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs Tumor Biol, Charlestown, MA 02129 USA. [Huang, Peigen; Roberge, Sylvie; Munn, Lance L.] Harvard Med Sch, Charlestown, MA 02129 USA. [Zeng, Ye] Sichuan Univ, Inst Biomed Engn, Sch Preclin & Forens Med, Chengdu, Peoples R China. RP Tarbell, JM (reprint author), CUNY City Coll, Dept Biomed Engn, Steinman Hall,T-404C,Convent Ave & 140th St, New York, NY 10031 USA.; Munn, LL (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, 149 13th St,3409, Charlestown, MA 02129 USA. EM lmunn@mgh.harvard.edu; tarbell@ccny.cuny.edu OI Song, Jonathan/0000-0002-6991-5298 NR 45 TC 0 Z9 0 U1 11 U2 11 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 DEC PY 2016 VL 139 IS 12 BP 2791 EP 2801 DI 10.1002/ijc.30397 PG 11 WC Oncology SC Oncology GA EB8CU UT WOS:000387619400017 PM 27543953 ER PT J AU Stapleton, CJ Torok, CM Patel, AB AF Stapleton, Christopher J. Torok, Collin M. Patel, Aman B. TI Early experience with the Penumbra SMART coil in the endovascular treatment of intracranial aneurysms: Safety and efficacy SO INTERVENTIONAL NEURORADIOLOGY LA English DT Article DE Endovascular coil embolization; intracranial aneurysm; subarachnoid hemorrhage ID RUPTURED CEREBRAL ANEURYSMS; SACCULAR ANEURYSMS; CLINICAL ARTICLE; TRIAL ISAT; EMBOLIZATION; OUTCOMES; ELECTROTHROMBOSIS; OCCLUSION; TRENDS AB Background: Penumbra SMART coils differ from traditional microcoils used for endovascular coil embolization of intracranial aneurysms (IAs) in that they (1) become progressively softer from their distal to proximal end, rather than being of uniform stiffness, (2) have a tight conformational structure, and (3) have a more robust stretch-resistance platform. These properties aid in preventing microcatheter prolapse and coil herniation during coil deployment and in filling small pockets of the aneurysm sac. Objective/Methods: To determine the safety and efficacy of this device, the records of 17 consecutive patients with IAs treated with SMART coils were retrospectively analyzed. Results: Thirteen female and four male patients were identified. Eleven patients presented with subarachnoid hemorrhage, four had recurrent aneurysms, and two had incidentally discovered aneurysms. Twelve aneurysms (two of which were recurrent) were treated with stand-alone coiling, three were treated with stent-assisted coiling, and two with flow diversion with adjuvant coiling. Microcatheter prolapse occurred in one case of a recurrent aneurysm, due to mechanical limitations imposed by a stent placed during prior coiling. Raymond-Roy Occlusion Classification (RROC) I or II occlusion was achieved in 12 aneurysms, including all 10 undergoing primary stand-alone coiling. Of the five RROC III occlusions, two were expected given treatment with flow diversion, while the other three occurred in complex, recurrent aneurysms. One patient suffered a thromboembolic complication of unclear clinical significance. Conclusions: The Penumbra SMART coil is a safe and effective device for the endovascular treatment of IAs. Follow-up studies are required to establish long-term results. C1 [Stapleton, Christopher J.; Patel, Aman B.] Massachusetts Gen Hosp, Dept Neurosurg, 15 Parkman St,Wang 745, Boston, MA 02114 USA. [Stapleton, Christopher J.; Torok, Collin M.; Patel, Aman B.] Harvard Med Sch, Boston, MA USA. [Stapleton, Christopher J.; Torok, Collin M.; Patel, Aman B.] Massachusetts Gen Hosp, Neuroendovasc Program, Boston, MA 02114 USA. RP Patel, AB (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 15 Parkman St,Wang 745, Boston, MA 02114 USA. EM abpatel@mgh.harvard.edu NR 20 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1591-0199 EI 2385-2011 J9 INTERV NEURORADIOL JI Interv. Neuroradiol. PD DEC PY 2016 VL 22 IS 6 BP 654 EP 658 DI 10.1177/1591019916663479 PG 5 WC Clinical Neurology; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EB8OL UT WOS:000387650400006 PM 27609753 ER PT J AU Torok, CM Nogueira, RG Yoo, AJ Leslie-Mazwi, TM Hirsch, JA Stapleton, CJ Patel, AB Rabinov, JD AF Torok, Collin M. Nogueira, Raul G. Yoo, Albert J. Leslie-Mazwi, Thabele M. Hirsch, Joshua A. Stapleton, Christopher J. Patel, Aman B. Rabinov, James D. TI Transarterial venous sinus occlusion of dural arteriovenous fistulas using ONYX SO INTERVENTIONAL NEURORADIOLOGY LA English DT Article DE Dural arteriovenous fistula; embolization; ONYX ID SIGMOID SINUSES; EMBOLIZATION; DRAINAGE; SHUNTS; TRANSVERSE; EXPERIENCE; MANAGEMENT; SWINE AB Purpose: The purpose of this article is to present a case series of transarterial venous sinus occlusion for dural arteriovenous fistulas (DAVFs) of the transverse and sigmoid sinuses. Materials and methods: From 2006 to 2012, 11 patients with DAVF of the transverse and sigmoid sinuses were treated with transarterial closure of the affected venous sinus using ethylene vinyl alcohol copolymer (ONYX). The consecutive retrospective cohort included six female and five male patients with an age range of 30-79. Patients presented with stroke, intracranial hemorrhage, seizure, headache, focal neurologic deficit or cognitive change. Lesions were categorized as Cognard II a+b (n = 5) or Cognard II b (n = 6). Four of this latter group consisted of isolated sinus segments. Selection criteria for dural sinus occlusion included direct multi-hole fistulas involving a broad surface in length or circumference of the sinus wall. External carotid artery (ECA) branches were directly embolized when considered safe. High-risk arterial supply from ICA, PICA, AICA or ECA cranial nerve branches were closed via retrograde approach during sinus occlusion. Results: DAVF closure was accomplished in all 11 patients with a total of 17 embolization procedures using ONYX. High-risk arterial collaterals were closed via artery-artery or artery-sinus-artery embolization. The vein of Labbe was spared in the four cases with initial antegrade flow. No neurologic complications occurred, and DAVF closures were durable on three-month angiography. Conclusion: Transarterial closure of the transverse and sigmoid sinuses. C1 [Torok, Collin M.; Leslie-Mazwi, Thabele M.; Hirsch, Joshua A.; Stapleton, Christopher J.; Patel, Aman B.; Rabinov, James D.] Massachusetts Gen Hosp, Neurointervent Serv, Boston, MA 02114 USA. [Nogueira, Raul G.] Grady Mem Hosp, Intervent Neurol, Atlanta, GA USA. [Yoo, Albert J.] Texas Stroke Inst, Plano, TX USA. RP Rabinov, JD (reprint author), Massachusetts Gen Hosp, Neurointervent Serv Gray 241, 55 Fruit St, Boston, MA 02114 USA. EM jrabinov@partners.org NR 22 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1591-0199 EI 2385-2011 J9 INTERV NEURORADIOL JI Interv. Neuroradiol. PD DEC PY 2016 VL 22 IS 6 BP 711 EP 716 DI 10.1177/1591019916663478 PG 6 WC Clinical Neurology; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EB8OL UT WOS:000387650400018 PM 27530138 ER PT J AU Conrad, C Kutlu, OC Dasari, A Chan, JA Vauthey, JN Adams, DB Kim, M Fleming, JB Katz, MHG Lee, JE AF Conrad, Claudius Kutlu, Onur C. Dasari, Arvind Chan, Jennifer A. Vauthey, Jean-Nicolas Adams, David B. Kim, Michael Fleming, Jason B. Katz, Matthew H. G. Lee, Jeffrey E. TI Prognostic Value of Lymph Node Status and Extent of Lymphadenectomy in Pancreatic Neuroendocrine Tumors Confined To and Extending Beyond the Pancreas SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Pancreatic neuroendocrine tumor; pNET; Lymph node status; Lymph node metastasis; Extend of lymphadenectomy; SEER; Prognostication ID RESECTION; SURVIVAL; CANCER; IMPACT; CLASSIFICATION; EXPERIENCE; PREDICTORS AB The impact of lymph node (LN) status and lymphadenectomy (LA) on survival in pancreatic neuroendocrine tumors (pNETs) remains controversial. We evaluated the impact of tumor extension and grade on nodal metastasis and survival. Surgical pNET patients were queried in the Surveillance Epidemiology and End Results (SEER) database (1998-2012, N = 981). Factors associated with LN status were analyzed by logistic regression and by Cox analyses. For T1-T2 tumors, N status was associated only with tumor size. N status (p = 0.001), grade (p < 0.001), age (p = 0.001), and sex (p = 0.007) predicted overall survival (OS). For T3-T4, grade (p < 0.001), sex (p = 0.004), size (p = 0.013), and age (p = 0.007) but not N status (p = 0.789) predicted OS. For T1-T2, disease-specific survival (DSS; p = 0.003) and OS (p = 0.008) were longer for N0 vs N1, while N0 vs NX had similar OS (p = 0.59) and DSS (p = 0.80). While a difference was seen in DSS for NX vs N1 (p = 0.04), no significant difference in OS was seen (p = 0.08). For T3-T4, N status did not affect DSS (p = 0.365) or OS (p = 0.454). For all T groups and any N status, extended LA (aeyen10 nodes resected) was not associated with OS. While in T1-T2 pNET N1 status is a predictor of negative OS, similar outcome between NX and N0 supports limited LN resection in selected patients. Extended LA is unlikely to be helpful in T3-T4. C1 [Conrad, Claudius; Vauthey, Jean-Nicolas; Kim, Michael; Fleming, Jason B.; Katz, Matthew H. G.; Lee, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Sect Hepatopancreatobiliary Surg, Dept Surg Oncol, Unit 1484, 1400 Pressler, Houston, TX 77030 USA. [Kutlu, Onur C.; Adams, David B.] Med Univ South Carolina, Div Gastrointestinal & Laparoscop Surg, Charleston, SC USA. [Dasari, Arvind] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Chan, Jennifer A.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. RP Conrad, C (reprint author), Univ Texas MD Anderson Canc Ctr, Sect Hepatopancreatobiliary Surg, Dept Surg Oncol, Unit 1484, 1400 Pressler, Houston, TX 77030 USA. EM cconrad1@mdanderson.org NR 23 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD DEC PY 2016 VL 20 IS 12 BP 1966 EP 1974 DI 10.1007/s11605-016-3243-7 PG 9 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA EC1MJ UT WOS:000387869300006 PM 27714644 ER PT J AU Cruz-Oliver, DM Sanchez-Reilly, S AF Cruz-Oliver, Dulce M. Sanchez-Reilly, Sandra TI Barriers to Quality End-of-Life Care for Latinos Hospice Health Care Professionals' Perspective SO JOURNAL OF HOSPICE & PALLIATIVE NURSING LA English DT Article DE EOL care; focus group; health care providers; Hispanic; hospice; Latinos ID OLDER LATINOS; CAREGIVERS; EXPERIENCE; WHITE AB Hospice is an option that serves the care needs of terminally ill patients. However, promoting awareness of pursuing end-of-life (EOL) care among Hispanics is challenging. Hispanics are the fastest growing ethnic minority group in the United States but the most unlikely to use hospice services for EOL. This project was intended to identify health care providers' (HCPs') self-perceived barriers/solutions to improve use of hospice among Latino patients in both Hispanic-predominant and white-predominant communities. Focus groups were conducted at 2 hospice agencies to compare views on Hispanic EOL care. Two HCP groups from VITAS hospice in Texas (n = 9, 12) and 1 in Missouri (n = 24) participated. Qualitative analysis was performed. Across groups, all HCPs had similar distributions of professions (predominantly nursing). Despite the differences in ethnicity and few Hispanic patients in Missouri, common EOL barriers were identified, including language, religion, and family culture. Potential solutions identified included education in Spanish to families, the use of community religious leaders, and use of media ("telenovelas = soap operas") to bring the concept of Hospice to Hispanic homes. From the perspective of HCPs, this study identifies barriers and solutions with potential health care implications to improve hospice care among growing Hispanic communities in a culturally appropriate manner. C1 [Cruz-Oliver, Dulce M.] St Louis Univ, Div Geriatr Med, Internal Med, 1402 South Grand Blvd M238, St Louis, MO 63104 USA. [Sanchez-Reilly, Sandra] Univ Texas Hlth Sci Ctr San Antonio, GEC, San Antonio, TX 78229 USA. [Sanchez-Reilly, Sandra] South Texas Vet Hlth Care Syst, GRECC, San Antonio, TX USA. RP Cruz-Oliver, DM (reprint author), St Louis Univ, Dept Internal Med, Div Geriatr, 1402 South Grand Blvd M238, St Louis, MO 63104 USA. EM dcruzoli@slu.edu FU Health Resources and Services Administration (HRSA) Geriatric Academic Career Award [K01HP20479-03-00] FX This work was supported by the Health Resources and Services Administration (HRSA) Geriatric Academic Career Award K01HP20479-03-00. NR 17 TC 0 Z9 0 U1 12 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1522-2179 EI 1539-0705 J9 J HOSP PALLIAT NURS JI J. Hosp. Palliat. Nurs. PD DEC PY 2016 VL 18 IS 6 BP 505 EP 511 DI 10.1097/NJH.0000000000000277 PG 7 WC Nursing SC Nursing GA EB9AE UT WOS:000387682700004 ER PT J AU Ting, BL Kalish, LA Waters, PM Bae, DS AF Ting, Beverlie L. Kalish, Leslie A. Waters, Peter M. Bae, Donald S. TI Reducing Cost and Radiation Exposure During the Treatment of Pediatric Greenstick Fractures of the Forearm SO JOURNAL OF PEDIATRIC ORTHOPAEDICS LA English DT Article DE forearm fractures; greenstick fractures; radiation; reducing costs; reducing radiation; closed treatment greenstick fractures of the forearm ID CHILDREN; RADIOGRAPHS; RADIUS AB Background: We hypothesize that after successful closed reduction of pediatric greenstick fractures of the forearm, there is a low rate of lost reduction requiring intervention. By reducing the frequency of clinical and radiographic follow-up, we can reduce costs and radiation exposure. Methods: A retrospective analysis was performed on patients aged 2 to 16 years treated with closed reduction and cast immobilization for greenstick fractures of the forearm at our institution between 2003 and 2013. The primary endpoint was a healed fracture with acceptable alignment at the final radiographic evaluation. Time-derived activity-based costing was used for cost analysis. We estimated radiation exposure in consultation with our hospital's radiation safety office. Results: One hundred and nine patients with an average age of 6.9 years (range, 2 to 15 y) met the inclusion criteria. The initial maximal fracture angulation of the affected radius and/or ulna averaged 19.3 (SD= +/- 8.7) degrees (range, 2 to 55 degrees). Patients were followed for an average of 60 days (range, 19 to 635 d). On average, patients received 3.6 follow-up clinical visits and 3.5 sets of radiographs following immediate emergency department care. Ninety-four percent of patients met criteria for acceptable radiographic alignment. Only 1 patient (0.9%; 95% confidence interval, 0.2%-5.0%) underwent rereduction, as determined by the treating physician. If clinical follow-up were limited to 2 visits and 3 sets of radiographs total, there would be a 14.3% reduction in total cost of fracture care and a 41% reduction in radiation exposure. Conclusions: This retrospective study suggests that pediatric greenstick fractures of the forearm rarely require intervention after initial closed reduction. We propose that 2 clinical follow-up visits and 3 sets of radiographs would reduce overall care costs and radiation exposure without compromising clinical results. Level of Evidence: Level IV-economic and decision analyses. C1 [Ting, Beverlie L.] Massachusetts Gen Hosp, Harvard Combined Orthopaed Residency Program, Boston, MA 02114 USA. [Kalish, Leslie A.] Boston Childrens Hosp, Clin Res Ctr, Boston, MA USA. [Waters, Peter M.; Bae, Donald S.] Boston Childrens Hosp, Dept Orthopaed Surg, 300 Longwood Ave,Hunnewell 2, Boston, MA 02115 USA. RP Bae, DS (reprint author), Boston Childrens Hosp, Dept Orthopaed Surg, 300 Longwood Ave,Hunnewell 2, Boston, MA 02115 USA. EM donald.bae@childrens.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 0271-6798 EI 1539-2570 J9 J PEDIATR ORTHOPED JI J. Pediatr. Orthop. PD DEC PY 2016 VL 36 IS 8 BP 816 EP 820 DI 10.1097/BPO.0000000000000560 PG 5 WC Orthopedics; Pediatrics SC Orthopedics; Pediatrics GA EC3EK UT WOS:000388008100013 PM 26057068 ER PT J AU Spence, RT Hampton, M Pluke, K Kahn, M Chinyepi, N Elmusbahi, M van Wyngaard, T Panieri, E AF Spence, Richard Trafford Hampton, Mark Pluke, Kent Kahn, Miriam Chinyepi, Nkhabe Elmusbahi, Mohamed van Wyngaard, Tirsa Panieri, Eugenio TI Factors associated with adverse events after emergency laparotomy in Cape Town, South Africa: identifying opportunities for quality improvement SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Global Surgery; Quality Improvement; Trauma; Gastrointestinal ID NECROTIZING PANCREATITIS; AMERICAN-COLLEGE; PROGRAM; CLASSIFICATION; INTERVENTION; SURGERY; TRAUMA; CARE AB Background: Surgical outcomes research is limited in areas of the world with the greatest unmet surgical need and likely greatest variation in outcomes. Measurement alone may improve outcomesdthe so-called Hawthorne effect. The purpose of this multicenter cohort study was to identify factors that are both feasible to collect and are associated with a major adverse event following a targeted procedure in Cape Town, South Africa. Methods: A collaborative of four acute care surgical units was formed to develop a data set with minimal data burden describing outcomes after an emergency exploratory laparotomy during a 3-mo period (February-April 2015). Controlling for patient, problem, provider, procedure and process predictors, multivariate models were built to identify risk factors for a major adverse event and higher resource use after surgery in our collaborative. Results: The outcomes of 450 exploratory laparotomies from the four participating hospitals were audited, 319 (70.9%) were for non-trauma and 131 (29.1%) were for trauma. The major adverse event rate was 15.7% (95% CI 12.6-19.4). In the multivariate analysis, factors associated with the primary outcome included age, American Society of Anesthesia score of greater than 2, bowel resection, preoperative CT scan, and a nontherapeutic laparotomy. A major adverse event was associated with all three outcomes assessing increased resource utilization. Conclusions: This study supports the comparative outcome assessment of a high-volume or high-risk procedure as a proxy for measuring the quality of care provided in a surgical collaborative. Such an exercise can identify opportunities for quality improvement. (C) 2016 Elsevier Inc. All rights reserved. C1 [Spence, Richard Trafford] Massachusetts Gen Hosp, Dept Surg, Codman Ctr Clin Effectiveness, Boston, MA 02114 USA. [Spence, Richard Trafford; Pluke, Kent; Kahn, Miriam; Chinyepi, Nkhabe; Elmusbahi, Mohamed; van Wyngaard, Tirsa; Panieri, Eugenio] Univ Cape Town, Groote Schuur Hosp, Dept Surg, Cape Town, South Africa. [Hampton, Mark] Victoria Hosp, Dept Gen Surg, Cape Town, South Africa. [Spence, Richard Trafford] Groote Schuur Hosp, Dept Gen Surg, Main Rd, ZA-7935 Cape Town, South Africa. RP Spence, RT (reprint author), Codman Ctr Clin Effectiveness Surg, Charles River Plaza,Suite 403,165 Cambridge St, Boston, MA 02114 USA. EM spnric004@myuct.ac.za NR 24 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 0022-4804 EI 1095-8673 J9 J SURG RES JI J. Surg. Res. PD DEC PY 2016 VL 206 IS 2 BP 363 EP 370 DI 10.1016/j.jss.2016.08.025 PG 8 WC Surgery SC Surgery GA EC2VY UT WOS:000387983600013 PM 27884330 ER PT J AU Cheng, LS Graham, HK Pan, WH Nagy, N Carreon-Rodriguez, A Goldstein, AM Hotta, R AF Cheng, Lily S. Graham, Hannah K. Pan, Wei Hua Nagy, Nandor Carreon-Rodriguez, Alfonso Goldstein, Allan M. Hotta, Ryo TI Optimizing neurogenic potential of enteric neurospheres for treatment of neurointestinal diseases SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Enteric nervous system; Enteric neural stem cells; Neurospheres; Glial cell line-derived neurotrophic factor; Endothelin-3 ID NEURAL CREST CELLS; NERVOUS-SYSTEM; IN-VIVO; HIRSCHSPRUNGS-DISEASE; PROGENITOR CELLS; NEURONS; GUT; TRANSPLANTATION; GLIA; DIFFERENTIATION AB Background: Enteric neurospheres derived from postnatal intestine represent a promising avenue for cell replacement therapy to treat Hirschsprung disease and other neurointestinal diseases. We describe a simple method to improve the neuronal yield of spontaneously formed gut-derived neurospheres. Materials and methods: Enteric neurospheres were formed from the small and large intestines of mouse and human subjects. Neurosphere size, neural crest cell content, cell migration, neuronal differentiation, and neuronal proliferation in culture were analyzed. The effect of supplemental neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF) and endothelin-3, was also assessed. Results: Mouse small intestineederived neurospheres contained significantly more P75-expressing neural crest-derived cells (49.9 +/- 15.3% versus 21.6 +/- 11.9%, P < 0.05) and gave rise to significantly more Tuj1-expressing neurons than colon-derived neurospheres (69.9 +/- 8.6% versus 46.2 +/- 15.6%, P < 0.05). A similar pattern was seen in neurospheres isolated from human small and large intestine (32.6 +/- 17.5% versus 10.2 +/- 8.2% neural crest cells, P < 0.05; 29.7 +/- 16.4% versus 16.0 +/- 13.5% enteric neurons, P < 0.05). The addition of GDNF to the culture media further improved the neurogenic potential of small intestinal neurospheres (75.9 +/- 4.0% versus 67.8 +/- 5.8%, P < 0.05) whereas endothelin-3 had no effect. Conclusions: Enteric neurospheres formed from small intestine and supplemented with GDNF yield an enriched population of neural crest-derived progenitor cells and give rise to a high density of enteric neurons. (C) 2016 Elsevier Inc. All rights reserved. C1 [Cheng, Lily S.; Graham, Hannah K.; Pan, Wei Hua; Nagy, Nandor; Carreon-Rodriguez, Alfonso; Goldstein, Allan M.; Hotta, Ryo] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pediat Surg, Boston, MA USA. [Cheng, Lily S.] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. [Pan, Wei Hua] Shanghai Jiao Tong Univ, Xinhua Hosp, Dept Pediat Surg, Sch Med, Shanghai, Peoples R China. [Nagy, Nandor] Semmelweis Univ, Dept Anat Histol & Embryol, Fac Med, Budapest, Hungary. [Carreon-Rodriguez, Alfonso] Inst Nacl Salud Publ, Ctr Invest Salud Poblac, Cuernavaca, Morelos, Mexico. RP Hotta, R (reprint author), Massachusetts Gen Hosp, Pediat Surg Res Labs, Dept Pediat Surg, 185 Cambridge St,CPZN 6215, Boston, MA 02114 USA. EM rhotta@partners.org FU Society of University Surgeons Ethicon Surgical Research Fellowship Award; Tosteson Fund for Medical Discovery at Massachusetts General Hospital; REACHirschsprung Foundation; American Neurogastroenterology and Motility Society; National Institutes of Health [R01DK103785] FX L.S.C. is supported by the Society of University Surgeons Ethicon Surgical Research Fellowship Award. R.H. is supported by grants from the Tosteson Fund for Medical Discovery at Massachusetts General Hospital, the REACHirschsprung Foundation, and the American Neurogastroenterology and Motility Society. A.M.G. is supported by the National Institutes of Health (R01DK103785). NR 24 TC 1 Z9 1 U1 4 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 EI 1095-8673 J9 J SURG RES JI J. Surg. Res. PD DEC PY 2016 VL 206 IS 2 BP 451 EP 459 DI 10.1016/j.jss.2016.08.035 PG 9 WC Surgery SC Surgery GA EC2VY UT WOS:000387983600025 PM 27884342 ER PT J AU Aliberti, S Reyes, LF Faverio, P Sotgiu, G Dore, S Rodriguez, AH Soni, NJ Restrepo, MI AF Aliberti, Stefano Reyes, Luis F. Faverio, Paola Sotgiu, Giovanni Dore, Simone Rodriguez, Alejandro H. Soni, Nilam J. Restrepo, Marcos I. CA GLIMP Invest TI Global initiative for meticillin-resistant Staphylococcus aureus pneumonia (GLIMP): an international, observational cohort study SO LANCET INFECTIOUS DISEASES LA English DT Article ID CARE-ASSOCIATED PNEUMONIA; INFECTIOUS-DISEASES SOCIETY; COMMUNITY; GUIDELINES; MRSA; HOSPITALIZATION; PATHOGENS; OUTCOMES; THERAPY; AMERICA AB Background Antibiotic resistance is a major global health problem and pathogens such as meticillin-resistant Staphylococcus aureus (MRSA) have become of particular concern in the management of lower respiratory tract infections. However, few data are available on the worldwide prevalence and risk factors for MRSA pneumonia. We aimed to determine the point prevalence of MRSA pneumonia and identify specific MRSA risk factors in community-dwelling patients hospitalised with pneumonia. Methods We did an international, multicentre study of community-dwelling, adult patients admitted to hospital with pneumonia who had microbiological tests taken within 24 h of presentation. We recruited investigators from 222 hospitals in 54 countries to gather point-prevalence data for all patients admitted with these characteristics during 4 days randomly selected during the months of March, April, May, and June in 2015. We assessed prevalence of MRSA pneumonia and associated risk factors through logistic regression analysis. Findings 3702 patients hospitalised with pneumonia were enrolled, with 3193 patients receiving microbiological tests within 24 h of admission, forming the patient population. 1173 (37%) had at least one pathogen isolated (culture-positive population). The overall prevalence of confirmed MRSA pneumonia was 3.0% (n=95), with differing prevalence between continents and countries. Three risk factors were independently associated with MRSA pneumonia: previous MRSA infection or colonisation (odds ratio 6.21,95% CI 3.25-11.85), recurrent skin infections (2.87,1.10-7.45), and severe pneumonia disease (2.39,1.55-3.68). Interpretation This multicountry study shows low prevalence of MRSA pneumonia and specific MRSA risk factors among community-dwelling patients hospitalised with pneumonia. C1 [Aliberti, Stefano] Univ Milan, Dept Pathophysiol & Transplantat, Cardiothorac Unit, Milan, Italy. [Aliberti, Stefano] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Adult Cyst Fibrosis Ctr, Milan, Italy. [Reyes, Luis F.; Soni, Nilam J.; Restrepo, Marcos I.] Univ Texas Hlth Sci Ctr San Antonio, Div Pulm Dis & Crit Care Med, San Antonio, TX 78229 USA. [Soni, Nilam J.; Restrepo, Marcos I.] South Texas Vet Hlth Care Syst, Div Pulm Dis & Crit Care Med, San Antonio, TX USA. [Faverio, Paola] Univ Milano Bicocca, AO San Gerardo, Sch Med & Surg, Monza, Italy. [Sotgiu, Giovanni; Dore, Simone] Univ Sassari, Clin Epidemiol & Med Stat Unit, Dept Biomed Sci, Res Med Educ & Profess Dev Unit,AOU Sassari, Sassari, Italy. [Rodriguez, Alejandro H.] Hosp Univ Joan XXIII, Crit Care Med, Tarragona, Spain. RP Restrepo, MI (reprint author), South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. FU National Heart, Lung, and Blood Institute [K23HL096054]; Asociacion Latinoamerican de Torax; European Respiratory Society; World Federation of Societies of Intensive and Critical Care Medicine; American College of Chest Physicians FX MIR'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 Heart, Lung, And Blood Institute or the National Institutes of Health nor the Department of Veterans Affairs. We would like to thank the Asociacion Latinoamerican de Torax, European Respiratory Society, World Federation of Societies of Intensive and Critical Care Medicine, and American College of Chest Physicians for their support of this project. NR 26 TC 1 Z9 1 U1 8 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD DEC PY 2016 VL 16 IS 12 BP 1364 EP 1376 DI 10.1016/S1473-3099(16)30267-5 PG 13 WC Infectious Diseases SC Infectious Diseases GA EC3YK UT WOS:000388062800046 PM 27593581 ER PT J AU Tang, M Ryman, DC McDade, E Jasielec, MS Buckles, VD Cairns, NJ Fagan, AM Goate, A Marcus, DS Xiong, C Allegri, RF Chhatwal, JP Danek, A Farlow, MR Fox, NC Ghetti, B Graff-Radford, NR Laske, C Martins, RN Masters, CL Mayeux, RP Ringman, JM Rossor, MN Salloway, SP Schofield, PR Morris, JC Bateman, RJ AF Tang, Mengxuan Ryman, Davis C. McDade, Eric Jasielec, Mateusz S. Buckles, Virginia D. Cairns, Nigel J. Fagan, Anne M. Goate, Alison Marcus, Daniel S. Xiong, Chengjie Allegri, Ricardo F. Chhatwal, Jasmeer P. Danek, Adrian Farlow, Martin R. Fox, Nick C. Ghetti, Bernardino Graff-Radford, Neill R. Laske, Christopher Martins, Ralph N. Masters, Colin L. Mayeux, Richard P. Ringman, John M. Rossor, Martin N. Salloway, Stephen P. Schofield, Peter R. Morris, John C. Bateman, Randall J. CA Dominantly Inherited Alzheimer TI Neurological manifestations of autosomal dominant familial Alzheimer's disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) SO LANCET NEUROLOGY LA English DT Article ID AGE-OF-ONSET; AMYLOID ANGIOPATHY; SEIZURES; MUTATIONS; PRESENILIN-1; METAANALYSIS; DEPOSITION; PHENOTYPE; DEMENTIA; GENOTYPE AB Background Autosomal dominant familial Alzheimer's disease (ADAD) is a rare disorder with non-amnestic neurological symptoms in some clinical presentations. We aimed to compile and compare data from symptomatic participants in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) with those reported in the literature to estimate the prevalences of non-amnestic neurological symptoms in participants with ADAD. Methods We prospectively collected data from the DIAN-OBS database, which recruited participants from study centres in the USA, Europe, and Australia, between Feb 29,2008, and July 1,2014. We also did a systematic review of publications to extract individual-level clinical data for symptomatic participants with ADAD. We used data for age of onset (from first report of cognitive decline), disease course from onset to death, and the presence of 13 neurological findings that have been reported in association with ADAD. Using multivariable linear regression, we investigated the prevalences of various non-amnestic neurological symptoms and the contributions of age of onset and specific mutation type on symptoms. Findings The DIAN-OBS dataset included 107 individuals with detailed clinical data (forming the DIAN-OBS cohort). Our systematic review yielded 188 publications reporting on 1228 symptomatic individuals, with detailed neurological examination descriptions available for 753 individuals (forming the published data cohort). The most prevalent nonamnestic cognitive manifestations in participants in the DIAN-OBS cohort were those typical of mild to moderate Alzheimer's disease, including visual agnosia (55.1%, 95% CI 45-7-64.6), aphasia (57.9%, 48.6-67-3), and behavioural changes (61.7%, 51.5-70.0). Non-amnestic cognitive manifestations were less prevalent in the published data cohort (eg, visual agnosia [5.6%, 3.9-7-2], aphasia [23.0%, 20.0-26-0], and behavioural changes [31.7%, 28.4-35.1]). Prevalence of non-cognitive neurological manifestations in the DIAN-OBS cohort was low, including myodonus and spasticity (9.3%, 95% CI 3-8-15.0), and seizures (2.8%, 0.5-5-9) and moderate for parkinsonism (11.2%, 5-3-17.1). By constrast, prevalence was higher in the published data cohort for myodonus and spasticity (19.4%, 16-6-22.2 and 15.0%, 12.5-17-6, respectively), parldnsonism (12.5%, 10-1-15- 0), and seizures (20.3%, 17.4-23-2). In an analysis of the published data cohort, ischaemic stroke was more prevalent at older ages of onset of symptoms of ADAD (odds ratio 1.09 per 1 year increase in age of onset, 95% CI 1.04-144, p=0.0003); and motor symptoms were more common at younger age of onset (myodonus 0.93, 0.90-0.97, p=0.0007; seizures 0.95, 0.92-0.98, p=0.0018; corticobulbar deficits 0.91, 0.86-0.96, p=0.0012; and cerebellar ataxia 0.82, 0.74-0-91, p=0.0002). In the DIAN-OBS cohort, non-cognitive symptoms were more common at more severe stages of disease. Interpretation The non-cognitive clinical manifestations of Alzheimer's disease seem to affect a small proportion of participants with mild to moderate ADAD, and are probably influenced by disease severity, environmental, and genetic factors. When evaluating patients with potential ADAD, clinicians should note that cognitive symptoms typical of sporadic Alzheimer's disease are the most consistent finding, with some patients manifesting non-cognitive neurological symptoms. Future work is needed to determine the environmental and genetic factors that cause these neurological symptoms. C1 [Tang, Mengxuan; Ryman, Davis C.; McDade, Eric; Buckles, Virginia D.; Cairns, Nigel J.; Fagan, Anne M.; Morris, John C.; Bateman, Randall J.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Jasielec, Mateusz S.; Xiong, Chengjie] Washington Univ, Sch Med, Dept Biostat, St Louis, MO USA. [Goate, Alison] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Marcus, Daniel S.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Allegri, Ricardo F.] Neurol Res Inst Raul Carrea, Buenos Aires, DF, Argentina. [Chhatwal, Jasmeer P.] Brigham & Womens Hosp, Ctr Alzheimer Res & Treatment, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Chhatwal, Jasmeer P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Danek, Adrian] Ludwig Maximilians Univ Munchen, Neurol Klin, Munich, Germany. [Danek, Adrian] German Ctr Neurodegenerat Dis, Munich, Germany. [Farlow, Martin R.] Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN 46202 USA. [Ghetti, Bernardino] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA. [Fox, Nick C.; Rossor, Martin N.] UCL, Inst Neurol, Dementia Res Ctr, London, England. [Graff-Radford, Neill R.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Laske, Christopher] German Ctr Neurodegenerat Dis, Tubingen, Germany. [Laske, Christopher] Hertie Inst Clin Brain Res, Tubingen, Germany. [Martins, Ralph N.] Edith Cowan Univ, Sch Exercise Biomed & Hlth Sci, Ctr Excellence Alzheimers Dis Res & Care, Perth, WA, Australia. [Masters, Colin L.] Univ Melbourne, Mental Hlth Res Inst, Parkville, Vic, Australia. [Mayeux, Richard P.] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA. [Ringman, John M.] Univ Southern Calif, Keck Sch Med, Memory & Aging Ctr, Los Angeles, CA 90033 USA. [Salloway, Stephen P.] Brown Univ, Warren Alpert Med Sch, Butler Hosp, Dept Neurol, Providence, RI 02912 USA. [Schofield, Peter R.] Neurosci Res Australia, Sydney, NSW, Australia. [Schofield, Peter R.] Univ New South Wales, Sydney, NSW, Australia. RP Bateman, RJ (reprint author), Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. EM batemanr@wustl.edu RI Fox, Nick/B-1319-2009; Danek, Adrian/G-7339-2011 OI Fox, Nick/0000-0002-6660-657X; Danek, Adrian/0000-0001-8857-5383 FU National Institutes of Health; German Center for Neurodegenerative Diseases FX National Institutes of Health and German Center for Neurodegenerative Diseases. NR 31 TC 2 Z9 2 U1 6 U2 6 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 DEC PY 2016 VL 15 IS 13 BP 1317 EP 1325 DI 10.1016/S1474-4422(16)30229-0 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA EB6XV UT WOS:000387529800017 PM 27777020 ER PT J AU Gibbs, WS Weber, RA Schnellmann, RG Adkins, DL AF Gibbs, Whitney S. Weber, Rachel A. Schnellmann, Rick G. Adkins, DeAnna L. TI Disrupted mitochondrial genes and inflammation following stroke SO LIFE SCIENCES LA English DT Article DE Cerebral ischemia; Respiratory complexes; Oxidative stress; Sensorimotor cortex; Et-1 ID ACUTE KIDNEY INJURY; OXIDATIVE STRESS; NEURODEGENERATIVE DISEASES; UNCOUPLING PROTEINS; CELL-DEATH; BIOGENESIS; CASPASE-3; APOPTOSIS; ISCHEMIA; CORTEX AB Aims: Determine the subacute time course of mitochondria disruption, cell death, and inflammation in a rat model of unilateral motor cortical ischemic stroke. Main methods: Rats received unilateral ischemia of the motor cortex and were tested on behavioral tasks to determine impairments. Animals were euthanized at 24 h, 72 h and 144 h and mRNA expression of key mitochondria proteins and indicators of inflammation, apoptosis and potential regenerative processes in ipsilesion cortex and striatum, using RT-qPCR. Mitochondrial proteins were examined at 144 h using immunoblot analysis. Key findings: Rats with stroke induced-behavioral deficits had sustained, 144 h post-lesion, decreases in mitochondrial-encoded electron transport chain proteins NADH dehydrogenase subunit-1 and cytochrome c oxidase subunit-1 (mRNA and protein) and mitochondrial DNA content in perilesion motor and sensory cortex. Uncoupling-protein-2 gene expression, but not superoxide dismutase-2, remained elevated in ipsilateral cortex and striatumat this time. Cortical inflammatory cytokine, interleukin-6, was increased early and was followed by increased macrophage marker F4/80 after stroke. Cleaved caspase-3 activation was elevated in cortex and growth associated protein-43 was elevated in the cortex and striatum six days post-lesion. Significance: We identified a relationship between three disrupted pathways, (1) sustained loss of mitochondrial proteins and mitochondrial DNA copy number in the cortex linked to decreased mitochondrial gene transcription; (2) early inflammatory response mediated by interleukin-6 followed by macrophages; (3) apoptosis in conjunction with the activation of regenerative pathways. The stroke-induced spatial and temporal profiles lay the foundation to target pharmacological therapeutics to these three pathways. (C) 2016 Elsevier Inc. All rights reserved. C1 [Gibbs, Whitney S.] Med Univ South Carolina, Dept Drug Discovery & Biomed Sci, Charleston, SC USA. [Weber, Rachel A.; Adkins, DeAnna L.] Med Univ South Carolina, Dept Neurosci, Charleston, SC USA. [Adkins, DeAnna L.] Med Univ South Carolina, Ctr Biomed Imaging, Charleston, SC USA. [Adkins, DeAnna L.] Med Univ South Carolina, Hlth Sci & Res, Coll Hlth Profess, Charleston, SC USA. [Schnellmann, Rick G.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Schnellmann, Rick G.] Univ Arizona, Coll Pharm, Dept Pharm & Toxicol, Tucson, AZ 85721 USA. RP Schnellmann, RG; Adkins, DL (reprint author), Univ Arizona, Coll Pharm, Drachman Hall,1295 N Martin Ave POB 210202, Tucson, AZ 85721 USA. EM schnell@pharmacy.arizona.edu; adkinsdl@musc.edu FU MUSC Neuroscience Institute Pilot Grant; National Institutes of Health National Institute of General Medical Science [GM084147]; Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs [BX-000851]; Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health [P20GM12345]; National Institutes of Health Ruth L. Kirschstein National Research Service Award [5T32-DK083262] FX This study was funded by MUSC Neuroscience Institute Pilot Grant (D.L.A), National Institutes of Health National Institute of General Medical Sciences: GM084147 (R.G.S), the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs: BX-000851 (R.G.S.), Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health: P20GM12345 (D.L.A), and the National Institutes of Health Ruth L. Kirschstein National Research Service Award: Grant 5T32-DK083262 (W.S.G.) NR 63 TC 1 Z9 1 U1 5 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 EI 1879-0631 J9 LIFE SCI JI Life Sci. PD DEC 1 PY 2016 VL 166 BP 139 EP 148 DI 10.1016/j.lfs.2016.09.021 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA EC4LK UT WOS:000388101300019 PM 27693381 ER PT J AU Salah, M Nishimoto, Y Kohno, S Kondoh, A Kitajima, S Muranaka, H Nishiuchi, T Ibrahim, A Yoshida, A Takahashi, C AF Salah, Mohammed Nishimoto, Yuuki Kohno, Susumu Kondoh, Atsushi Kitajima, Shunsuke Muranaka, Hayato Nishiuchi, Takumi Ibrahim, Ahmed Yoshida, Akiyo Takahashi, Chiaki TI An in vitro system to characterize prostate cancer progression identified signaling required for self-renewal SO MOLECULAR CARCINOGENESIS LA English DT Article DE Rb; Pten; prostasphere; prostate cancer ID LYSYL OXIDASE; RETINOBLASTOMA GENE; RB DEFICIENCY; BASAL-CELLS; GROWTH; PTEN; STAT3; INTERLEUKIN-6; INHIBITION; PATHWAY AB Mutations in RB and PTEN are linked to castration resistance and poor prognosis in prostate cancer. Identification of genes that are regulated by these tumor suppressors in a context that recapitulates cancer progression may be beneficial for discovering novel therapeutic targets. Although various genetically engineered mice thus far provided tumor models with various pathological stages, they are not ideal for detecting dynamic changes in gene transcription. Additionally, it is difficult to achieve an effect specific to tumor progression via gain of functions of these genes. In this study, we developed an in vitro model to help identify RB- and PTEN-loss signatures during the malignant progression of prostate cancers. Trp53(-/-); Rb-f/f, Trp53(-/-); Pten(f/f), and Trp53(-/-); Rb-f/f; Pten(f/f) prostate epithelial cells were infected with AD-LacZ or AD-Cre. We found that deletion of Rb, Pten or both stimulated prostasphere formation and tumor development in immune-compromised mice. The GO analysis of genes affected by the deletion of Rb or Pten in Trp53(-/-) prostate epithelial cells identified a number of genes encoding cytokines, chemokines and extracellular matrix remodeling factors, but only few genes related to cell cycle progression. Two genes (Il-6 and Lox) were further analyzed. Blockade of Il-6 signaling and depletion of Lox significantly attenuated prostasphere formation in 3D culture, and in the case of IL-6, strongly suppressed tumor growth in vivo. These findings suggest that our in vitro model may be instrumental in identifying novel therapeutic targets of prostate cancer progression, and further underscore IL-6 and LOX as promising therapeutic targets. (c) 2015 Wiley Periodicals, Inc. C1 [Salah, Mohammed; Ibrahim, Ahmed] South Valley Univ, Dept Biochem, Fac Vet Med, Qena, Egypt. [Salah, Mohammed; Nishimoto, Yuuki; Kohno, Susumu; Kondoh, Atsushi; Kitajima, Shunsuke; Muranaka, Hayato; Yoshida, Akiyo; Takahashi, Chiaki] Kanazawa Univ, Canc Res Inst, Div Oncol & Mol Biol, Kanazawa, Ishikawa, Japan. [Kitajima, Shunsuke] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Nishiuchi, Takumi] Kanazawa Univ, Div Funct Genom, Adv Sci Res Ctr, Kanazawa, Ishikawa, Japan. [Ibrahim, Ahmed] South Valley Univ, Dept Poultry Dis, Fac Vet Med, Qena, Egypt. [Yoshida, Akiyo] Kanazawa Univ, Grad Sch Med Sci, Dept Cellular Transplantat Biol, Kanazawa, Ishikawa, Japan. RP Takahashi, C (reprint author), Kanazawa Univ, Canc Res Inst, Div Oncol & Mol Biol, Kanazawa, Ishikawa, Japan. EM chtakaha@staff.kanazawa-u.ac.jp FU Next Generation World-Leading Researchers; Astellas Foundation; Takeda Science Foundation; Naito Foundation; Daiichi-Sankyo Foundation; NOVARTIS Foundation FX Grant sponsor: Next Generation World-Leading Researchers; Grant sponsor: Grant-in-Aid for Scientific Research; Grant sponsor: Astellas Foundation; Grant sponsor: Takeda Science Foundation; Grant sponsor: Naito Foundation; Grant sponsor: Daiichi-Sankyo Foundation; Grant sponsor: NOVARTIS Foundation NR 40 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD DEC PY 2016 VL 55 IS 12 BP 1974 EP 1989 DI 10.1002/mc.22444 PG 16 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA EC1GY UT WOS:000387854100008 PM 26621780 ER PT J AU Cheng, G Werner, TJ Newberg, A Alavi, A AF Cheng, Gang Werner, Thomas J. Newberg, Andrew Alavi, Abass TI Failed PET Application Attempts in the Past, Can We Avoid Them in the Future? SO MOLECULAR IMAGING AND BIOLOGY LA English DT Editorial Material DE Positron emission tomography (PET); Computed tomography (CT); Noninvasive imaging; Radiopharmaceuticals ID POSITRON-EMISSION-TOMOGRAPHY; BETA-CELL MASS; IN-VIVO EVALUATION; ESTROGEN-RECEPTOR-BETA; VESICULAR MONOAMINE TRANSPORTER-2; METASTATIC BREAST-CANCER; BIOLOGICAL EVALUATION; DIABETES-MELLITUS; HUMAN PANCREAS; RADIOLIGANDS C1 [Cheng, Gang] Philadelphia VA Med Ctr, Dept Radiol, 3900 Woodland Ave, Philadelphia, PA 19104 USA. [Cheng, Gang; Werner, Thomas J.; Alavi, Abass] Hosp Univ Penn, Dept Radiol, 3400 Spruce St, Philadelphia, PA 19104 USA. [Newberg, Andrew] Thomas Jefferson Univ, Myrna Brind Ctr Integrat Med, 925 Chestnut St, Philadelphia, PA 19107 USA. RP Alavi, A (reprint author), Hosp Univ Penn, Dept Radiol, 3400 Spruce St, Philadelphia, PA 19104 USA. EM abass.alavi@uphs.upenn.edu NR 81 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 EI 1860-2002 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD DEC PY 2016 VL 18 IS 6 BP 797 EP 802 DI 10.1007/s11307-016-1017-y PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EB4TQ UT WOS:000387367100001 PM 27730470 ER PT J AU Luis, TC Luc, S Mizukami, T Boukarabila, H Thongjuea, S Woll, PS Azzoni, E Giustacchini, A Lutteropp, M Bouriez-Jones, T Vaidya, H Mead, AJ Atkinson, D Boiers, C Carrelha, J Macaulay, IC Patient, R Geissmann, F Nerlov, C Sandberg, R de Bruijn, MFTR Blackburn, CC Godin, I Jacobsen, SEW AF Luis, Tiago C. Luc, Sidinh Mizukami, Takuo Boukarabila, Hanane Thongjuea, Supat Woll, Petter S. Azzoni, Emanuele Giustacchini, Alice Lutteropp, Michael Bouriez-Jones, Tiphaine Vaidya, Harsh Mead, Adam J. Atkinson, Deborah Boiers, Charlotta Carrelha, Joana Macaulay, Iain C. Patient, Roger Geissmann, Frederic Nerlov, Claus Sandberg, Rickard de Bruijn, Marella F. T. R. Blackburn, C. Clare Godin, Isabelle Jacobsen, Sten Eirik W. TI Initial seeding of the embryonic thymus by immune-restricted lympho-myeloid progenitors SO NATURE IMMUNOLOGY LA English DT Article ID T-CELL DEVELOPMENT; STEM-CELLS; FETAL THYMUS; LINEAGE; LYMPHOPOIESIS; ORGANOGENESIS; COMMITMENT; PRECURSORS AB The final stages of restriction to the T cell lineage occur in the thymus after the entry of thymus-seeding progenitors (TSPs). The identity and lineage potential of TSPs remains unclear. Because the first embryonic TSPs enter a non-vascularized thymic rudiment, we were able to directly image and establish the functional and molecular properties of embryonic thymopoiesis-initiating progenitors (T-IPs) before their entry into the thymus and activation of Notch signaling. T-IPs did not include multipotent stem cells or molecular evidence of T cell restricted progenitors. Instead, single-cell molecular and functional analysis demonstrated that most fetal T-IPs expressed genes of and had the potential to develop into lymphoid as well as myeloid components of the immune system. Moreover, studies of embryos deficient in the transcriptional regulator RBPJ demonstrated that canonical Notch signaling was not involved in pre-thymic restriction to the T cell lineage or the migration of T-IPs. C1 [Luis, Tiago C.; Luc, Sidinh; Mizukami, Takuo; Boukarabila, Hanane; Thongjuea, Supat; Woll, Petter S.; Giustacchini, Alice; Lutteropp, Michael; Bouriez-Jones, Tiphaine; Mead, Adam J.; Atkinson, Deborah; Carrelha, Joana; Macaulay, Iain C.; Jacobsen, Sten Eirik W.] Univ Oxford, Weatherall Inst Mol Med, John Radcliffe Hosp, Haematopoiet Stem Cell Lab, Oxford, England. [Luc, Sidinh] Lund Univ, Lund Stem Cell Ctr, Hematopoiet Stem Cell Lab, Lund, Sweden. [Luc, Sidinh; Thongjuea, Supat; Azzoni, Emanuele; Lutteropp, Michael; Patient, Roger; Nerlov, Claus; de Bruijn, Marella F. T. R.; Jacobsen, Sten Eirik W.] Univ Oxford, Weatherall Inst Mol Med, MRC Mol Haematol Unit, Oxford, England. [Vaidya, Harsh; Blackburn, C. Clare] Univ Edinburgh, MRC Ctr Regenerat Med, Inst Stem Cell Res, Edinburgh, Midlothian, Scotland. [Boiers, Charlotta] Lund Univ, Div Mol Med & Gene Therapy, Lund Stem Cell Ctr, Lund, Sweden. [Geissmann, Frederic] Kings Coll London, Ctr Mol & Cellular Biol Inflammat, London, England. [Geissmann, Frederic] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Sandberg, Rickard] Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden. [Sandberg, Rickard] Ludwig Inst Canc Res, Stockholm, Sweden. [Godin, Isabelle] INSERM, Villejuif, France. [Godin, Isabelle] Univ Paris Saclay, Univ Paris Sud, Villejuif, France. [Godin, Isabelle] Gustave Roussy, Villejuif, France. [Jacobsen, Sten Eirik W.] Karolinska Inst, Wallenberg Inst Regenerat Med, Dept Cell & Mol Biol, Stockholm, Sweden. [Jacobsen, Sten Eirik W.] Karolinska Inst, Dept Med Huddinge, Ctr Hematol & Regenerat Med, Stockholm, Sweden. [Jacobsen, Sten Eirik W.] Karolinska Univ Hosp, Stockholm, Sweden. [Luc, Sidinh] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Luc, Sidinh] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA. RP Jacobsen, SEW (reprint author), Univ Oxford, Weatherall Inst Mol Med, John Radcliffe Hosp, Haematopoiet Stem Cell Lab, Oxford, England.; Jacobsen, SEW (reprint author), Univ Oxford, Weatherall Inst Mol Med, MRC Mol Haematol Unit, Oxford, England.; Jacobsen, SEW (reprint author), Karolinska Inst, Wallenberg Inst Regenerat Med, Dept Cell & Mol Biol, Stockholm, Sweden.; Jacobsen, SEW (reprint author), Karolinska Inst, Dept Med Huddinge, Ctr Hematol & Regenerat Med, Stockholm, Sweden.; Jacobsen, SEW (reprint author), Karolinska Univ Hosp, Stockholm, Sweden. EM sten.eirik.jacobsen@ki.se OI Azzoni, Emanuele/0000-0002-4572-5692; Cunha Luis, Tiago/0000-0002-6305-1257; Macaulay, Iain/0000-0002-6761-757X FU MRC HIU; MRC MHU [MC_UU_12009]; NIHR Oxford BRC; John Fell Fund [131/030, 101/517]; EPA fund [CF182, CF170]; WIMM Strategic Alliance awards [G0902418, MC_UU_12025]; MRC via the WIMM Strategic Alliance [G0902418]; MHU [MC_UU_12009]; HIU [MC_UU_12010]; Wolfson Foundation [18272]; MRC/BBSRC/EPSRC [MR/K015777X/1]; MIC-Nanoscopy Oxford (NanO): Novel Super-resolution Imaging Applied to Biomedical Sciences, Micron [107457/Z/15Z]; WIMM Strategic Alliance [G0902418, MC_UU_12025]; Medical Research Council UK [G0801073, MC_UU_12009/5]; Swedish Research Council; Knut och Alice Wallenberg Foundation (WIRM); Tobias Foundation; StratRegen, KI; EU-FP7 EuroSyStem Integrated projects; Swedish Research Council Linnaeus (Hemato-Linne grant); MRC (Molecular Haematology Unit core award); EMBO-LTF; Kay Kendall Leukaemia Fund; Leukaemia and Lymphoma Research FX We thank N. Sakaguchi (Kumamoto University) for the Rag1-GFP mouse line; M. Reth (Max Planck Institute of Immunobiology) for Cd79atm1(cre)Reth mice; S. Srinivas (University of Oxford) for R26-stop-eYFP mice; T. Rabbitts (University of Oxford) for Rag1-Cre mice; S. Cory (The Walter & Eliza Hall Institute of Medical Research) for vavP-Mcl1 trangenic mice; N. Iscove (Ontario Cancer Institute, University Health Network) for W41 mice; A. Cumano (Institut Pasteur) for OP9 and OP9-DL1 stromal cells; Biomedical Services at Oxford University for animal support; B. Wu for technical assistance; P. Sopp and S-A. Clark (WIMM FACS facility, supported by the MRC HIU; MRC MHU (MC_UU_12009); NIHR Oxford BRC and the John Fell Fund (131/030 and 101/517), the EPA fund (CF182 and CF170) and by WIMM Strategic Alliance awards G0902418 and MC_UU_12025); C. Lagerholm and D. Waithe (Wolfson Imaging Centre Oxford, supported by the MRC via the WIMM Strategic Alliance (G0902418), the MHU (MC_UU_12009), the HIU (MC_UU_12010), the Wolfson Foundation (18272), MRC/BBSRC/EPSRC (MR/K015777X/1), and MIC-Nanoscopy Oxford (NanO): Novel Super-resolution Imaging Applied to Biomedical Sciences, Micron (107457/Z/15Z)) and the WIMM Strategic Alliance (G0902418 and MC_UU_12025)). Supported by the Medical Research Council UK (G0801073 and MC_UU_12009/5 to S.E.W.J.), the Swedish Research Council (S.E.W.J.), the Knut och Alice Wallenberg Foundation (WIRM; S.E.W.J.), the Tobias Foundation (S.E.W.J.), StratRegen, KI (S.E.W.J.), EU-FP7 EuroSyStem Integrated projects (S.E.W.J., C.C.B.), the Swedish Research Council Linnaeus (Hemato-Linne grant to S.E.W.J.), the MRC (Molecular Haematology Unit core award to M.F.T.R.d.B.), EMBO-LTF (T.C.L.), Kay Kendall Leukaemia Fund (T.C.L.) and Leukaemia and Lymphoma Research (C.C.B. and A.J.M.). NR 44 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD DEC PY 2016 VL 17 IS 12 BP 1424 EP 1435 DI 10.1038/ni.3576 PG 12 WC Immunology SC Immunology GA EC3VY UT WOS:000388056400013 PM 27695000 ER PT J AU Sage, PT Ron-Harel, N Juneja, VR Sen, DR Maleri, S Sungnak, W Kuchroo, VK Haining, WN Chevrier, N Haigis, M Sharpe, AH AF Sage, Peter T. Ron-Harel, Noga Juneja, Vikram R. Sen, Debattama R. Maleri, Seth Sungnak, Waradon Kuchroo, Vijay K. Haining, W. Nicholas Chevrier, Nicolas Haigis, Marcia Sharpe, Arlene H. TI Suppression by T-FR\ cells leads to durable and selective inhibition of B cell effector function SO NATURE IMMUNOLOGY LA English DT Article ID FOLLICULAR HELPER-CELL; TRANSCRIPTIONAL REPRESSOR BCI6; GERMINAL CENTER; REGULATORY CELLS; C-MYC; IMMUNE-RESPONSES; DIFFERENTIATION; FH; SIGNATURE; ENHANCERS AB Follicular regulatory T cells (T-FR cells) inhibit follicular helper T cell (T-FH cell)-mediated antibody production. The mechanisms by which T-FR cells exert their key immunoregulatory functions are largely unknown. Here we found that T-FR cells induced a distinct suppressive state in T-FH cells and B cells, in which effector transcriptional signatures were maintained but key effector molecules and metabolic pathways were suppressed. The suppression of B cell antibody production and metabolism by T-FR cells was durable and persisted even in the absence of T-FR cells. This durable suppression was due in part to epigenetic changes. The cytokine IL-21 was able to overcome T-FR cell-mediated suppression and inhibited T-FR cells and stimulated B cells. By determining mechanisms of T-FR cell-mediated suppression, we have identified methods for modulating the function of T-FR cells and antibody production. C1 [Sage, Peter T.; Juneja, Vikram R.; Maleri, Seth; Sharpe, Arlene H.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Sage, Peter T.; Juneja, Vikram R.; Maleri, Seth; Sungnak, Waradon; Kuchroo, Vijay K.; Sharpe, Arlene H.] Harvard Med Sch, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA. [Sage, Peter T.; Juneja, Vikram R.; Maleri, Seth; Sungnak, Waradon; Kuchroo, Vijay K.; Sharpe, Arlene H.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Ron-Harel, Noga; Haigis, Marcia] Harvard Med Sch, Dept Cell Biol, Boston, MA USA. [Sen, Debattama R.; Haining, W. Nicholas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Sungnak, Waradon; Kuchroo, Vijay K.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Chevrier, Nicolas] Harvard Univ, FAS Ctr Syst Biol, Cambridge, MA 02138 USA. [Sharpe, Arlene H.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. RP Sharpe, AH (reprint author), Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA.; Sharpe, AH (reprint author), Harvard Med Sch, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA.; Sharpe, AH (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.; Sharpe, AH (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM arlene_sharpe@hms.harvard.edu FU US National Institute of Health [T32HL007627, R37AI38310, P01AI56299, P01AI065687]; Evergrande Center for Immunologic Diseases FX We thank the Nikon Imaging Center at Harvard Medical School for help with light microscopy and the MBIB flow cytometry core for help with flow cytometry. Supported by the US National Institute of Health (T32HL007627 to P.T.S.; and R37AI38310, P01AI56299 and P01AI065687 to A.H.S.) and the Evergrande Center for Immunologic Diseases. NR 47 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD DEC PY 2016 VL 17 IS 12 BP 1436 EP 1446 DI 10.1038/ni.3578 PG 11 WC Immunology SC Immunology GA EC3VY UT WOS:000388056400014 PM 27695002 ER PT J AU Gerriets, VA Kishton, RJ Johnson, M Cohen, S Siska, PJ Nichols, AG Warmoes, MO de Cubas, AA Maclver, NJ Locasale, JW Turka, LA Wells, AD Rathmell, JC AF Gerriets, Valerie A. Kishton, Rigel J. Johnson, Marc O. Cohen, Sivan Siska, Peter J. Nichols, Amanda G. Warmoes, Marc O. de Cubas, Aguirre A. Maclver, Nancie J. Locasale, Jason W. Turka, Laurence A. Wells, Andrew D. Rathmell, Jeffrey C. TI Foxp3 and Toll-like receptor signaling balance T-reg cell anabolic metabolism for suppression SO NATURE IMMUNOLOGY LA English DT Article ID EFFECTOR FUNCTION; INFLAMMATION; ACTIVATION; AKT; DIFFERENTIATION; GLYCOLYSIS; EXPRESSION; TOLERANCE; PROMOTES; PATHWAY AB CD4(+) effector T cells (T-eff cells) and regulatory T cells (T-reg cells) undergo metabolic reprogramming to support proliferation and immunological function. Although signaling via the lipid kinase PI(3)K (phosphatidylinositol-3-OH kinase), the serine-threonine kinase Akt and the metabolic checkpoint kinase complex mTORC1 induces both expression of the glucose transporter Glut1 and aerobic glycolysis for T-eff cell proliferation and inflammatory function, the mechanisms that regulate T-reg cell metabolism and function remain unclear. We found that Toll-like receptor (TLR) signals that promote T-reg cell proliferation increased PI(3)K-Akt-mTORC1 signaling, glycolysis and expression of Glut1. However, TLR-induced mTORC1 signaling also impaired T-reg cell suppressive capacity. Conversely, the transcription factor Foxp3 opposed PI(3)K-Akt-mTORC1 signaling to diminish glycolysis and anabolic metabolism while increasing oxidative and catabolic metabolism. Notably, Glut1 expression was sufficient to increase the number of T-reg cells, but it reduced their suppressive capacity and Foxp3 expression. Thus, inflammatory signals and Foxp3 balance mTORC1 signaling and glucose metabolism to control the proliferation and suppressive function of Treg cells. C1 [Gerriets, Valerie A.; Kishton, Rigel J.; Johnson, Marc O.; Cohen, Sivan; Nichols, Amanda G.; Locasale, Jason W.] Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC USA. [Johnson, Marc O.; Siska, Peter J.; Rathmell, Jeffrey C.] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Vanderbilt Ctr Immunobiol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Johnson, Marc O.] Univ Kentucky, Dept Toxicol & Canc Biol, Ctr Environm & Syst Biochem, Lexington, KY USA. [Johnson, Marc O.] Univ Kentucky, Markey Canc Ctr, Lexington, KY USA. [de Cubas, Aguirre A.] Vanderbilt Univ, Div Hematol & Oncol, Dept Med, Med Ctr, Nashville, TN USA. [Maclver, Nancie J.] Duke Univ, Div Pediat Endocrinol & Diabet, Durham, NC USA. [Turka, Laurence A.] Massachusetts Gen Hosp, Ctr Transplantat Sci, Boston, MA 02114 USA. [Wells, Andrew D.] Univ Penn, Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Wells, Andrew D.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Rathmell, JC (reprint author), Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Vanderbilt Ctr Immunobiol, 221 Kirkland Hall, Nashville, TN 37235 USA. EM jeff.rathmell@vanderbilt.edu OI Locasale, Jason/0000-0002-7766-3502 FU Crohn's and Colitis Foundation of America; Alliance for Lupus Research; US National Institutes of Health [R01HL 108006, R01105550DK, P01HL018646, F31CA183529, R00CA168997, R01AI070807, P01AI073489]; German Research Foundation (Deutsche Forschungsgemeinschaft) FX We thank members of the Rathmell and Wells laboratories for discussions, and the Immunological Genome Project. Supported by the Crohn's and Colitis Foundation of America (Senior Research Grant to J.C.R.), the Alliance for Lupus Research (J.C.R.), the US National Institutes of Health (R01HL 108006 and R01105550DK to J.C.R.; P01HL018646 to L.A.T. and J.C.R.; F31CA183529 to R.J.K.; R00CA168997 to J.W.L.; and R01AI070807 and P01AI073489 to A.D.W.), and the German Research Foundation (Deutsche Forschungsgemeinschaft; P.J.S.). NR 45 TC 6 Z9 6 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD DEC PY 2016 VL 17 IS 12 BP 1459 EP 1466 DI 10.1038/ni.3577 PG 8 WC Immunology SC Immunology GA EC3VY UT WOS:000388056400016 PM 27695003 ER PT J AU Zhou, YC Hu, XY Tang, ZM Ahn, AC AF Zhou, Yichao Hu, Xiyuan Tang, Zhenmin Ahn, Andrew C. TI Sparse representation-based ECG signal enhancement and QRS detection SO PHYSIOLOGICAL MEASUREMENT LA English DT Article DE ECG enhancement; QRS complex detection; sparse representation; dictionary learning ID EMPIRICAL MODE DECOMPOSITION; COMPLEX DETECTION; SHANNON ENERGY; ALGORITHM; ENVELOPE AB Electrocardiogram (ECG) signal enhancement and QRS complex detection is a critical preprocessing step for further heart disease analysis and diagnosis. In this paper, we propose a sparse representation-based ECG signal enhancement and QRS complex detection algorithm. Unlike traditional Fourier or wavelet transform-based methods, which use fixed bases, the proposed algorithm models the ECG signal as the superposition of a few inner structures plus additive random noise, where these structures (referred to here as atoms) can be learned from the input signal or a training set. Using these atoms and their properties, we can accurately approximate the original ECG signal and remove the noise and other artifacts such as baseline wandering. Additionally, some of the atoms with larger kurtosis values can be modified and used as an indication function to detect and locate the QRS complexes in the enhanced ECG signals. To demonstrate the robustness and efficacy of the proposed algorithm, we compare it with several state-of-the-art ECG enhancement and QRS detection algorithms using both simulated and real-life ECG recordings. C1 [Zhou, Yichao; Tang, Zhenmin] Nanjing Univ Sci & Technol, Sch Comp Sci, Nanjing 210094, Jiangsu, Peoples R China. [Zhou, Yichao; Hu, Xiyuan] Chinese Acad Sci, Inst Automat, High Technol Innovat Ctr HITIC, Beijing 100190, Peoples R China. [Ahn, Andrew C.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Ahn, Andrew C.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02215 USA. RP Hu, XY (reprint author), Chinese Acad Sci, Inst Automat, High Technol Innovat Ctr HITIC, Beijing 100190, Peoples R China. EM wingegg_313@126.com; xiyuan.hu@ia.ac.cn; aahn1@mgh.harvard.edu FU National Natural Science Foundation of China [61571438]; Institute for Integrative Health FX This work was partially supported by the National Natural Science Foundation of China with Grant No. 61571438. Dr Ahn was supported by The Institute for Integrative Health. The authors also would like to thank the reviewers for their insightful comments, which helped improve the quality of the paper significantly. NR 32 TC 0 Z9 0 U1 13 U2 13 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0967-3334 EI 1361-6579 J9 PHYSIOL MEAS JI Physiol. Meas. PD DEC PY 2016 VL 37 IS 12 BP 2093 EP 2110 DI 10.1088/0967-3334/37/12/2093 PG 18 WC Biophysics; Engineering, Biomedical; Physiology SC Biophysics; Engineering; Physiology GA EC1WY UT WOS:000387900700001 ER PT J AU Howard, LE De Hoedt, AM Aronson, WJ Kane, CJ Amling, CL Cooperberg, MR Terris, MK Divers, CH Valderrama, A Freedland, SJ AF Howard, L. E. De Hoedt, A. M. Aronson, W. J. Kane, C. J. Amling, C. L. Cooperberg, M. R. Terris, M. K. Divers, C. H. Valderrama, A. Freedland, S. J. TI Do skeletal-related events predict overall survival in men with metastatic castration-resistant prostate cancer? SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article ID BONE METASTASIS; BIOCHEMICAL RECURRENCE; RADICAL PROSTATECTOMY; MORTALITY; MEDICARE; TRIAL; PAIN; ENZALUTAMIDE; PREDNISONE; DOCETAXEL AB BACKGROUND: Skeletal-related events (SREs) including pathologic fracture, spinal cord compression, radiation to bone and surgery to bone, are common in men with bone metastatic castration-resistant prostate cancer (mCRPC). Men with mCRPC are at high risk of death. Whether SREs predict mortality is unclear. We tested the association between SREs and overall survival (OS) in a multiethnic cohort with bone mCRPC, controlling for key covariates unavailable in claims data such as bone pain, number of bone metastases and PSA doubling time (PSADT). METHODS: We collected data on 233 men diagnosed with nonmetastatic castration-resistant prostate cancer (CRPC) in 2000-2013 at two Veterans Affairs hospitals who later progressed to bone metastases. First occurrence of SRE and OS were collected from the medical records. Cox models were used to test the association between SRE and OS, treating SRE as a time-dependent variable. We adjusted for age, year, race, treatment center, biopsy Gleason, primary treatment to the prostate, PSA, PSADT, months from androgen deprivation therapy to CRPC, months from CRPC to metastasis and number of bone metastases at initial bone metastasis diagnosis. In a secondary analysis, we also adjusted for bone pain. RESULTS: During follow-up, 88 (38%) patients had an SRE and 198 (85%) died. After adjusting for risk factors, SRE was associated with increased mortality (hazard ratio (HR) = 1.67; 95% confidence interval (CI) 1.22-2.30; P = 0.001). When bone pain was added to the model, the association of SREs and OS was attenuated, but remained significant (HR = 1.42; 95% CI 1.01-1.99; P = 0.042). CONCLUSIONS: SREs are associated with increased mortality in men with bone mCRPC. Further studies on the impact of preventing SREs to increase survival are warranted. C1 [Howard, L. E.] Duke Univ, Sch Med, Dept Biostat & Bioinformat, Durham, NC USA. [Howard, L. E.; De Hoedt, A. M.; Freedland, S. J.] Vet Affairs Med Ctr, Dept Surg, Div Urol, Durham, NC USA. [Aronson, W. J.] Univ Calif Los Angeles, Sch Med, Dept Urol, Los Angeles, CA USA. [Aronson, W. J.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Surg, Urol Sect, Los Angeles, CA USA. [Kane, C. J.] Univ Calif San Diego Hlth Syst, Dept Urol, San Diego, CA USA. [Amling, C. L.] Oregon Hlth & Sci Univ, Dept Surg, Div Urol, Portland, OR USA. [Cooperberg, M. R.] UCSF Helen Diller Family Comprehens Canc Ctr, Dept Urol, San Francisco, CA USA. [Terris, M. K.] Vet Affairs Med Ctr, Dept Surg, Urol Sect, Augusta, GA USA. [Terris, M. K.] Med Coll Georgia, Dept Surg, Urol Sect, Augusta, GA 30912 USA. [Divers, C. H.; Valderrama, A.] Bayer Pharmaceut, US Hlth Econ, Whippany, NJ USA. [Freedland, S. J.] Cedars Sinai Med Ctr, Dept Surg, Div Urol, Samuel Oschin Comprehens Canc Inst, 8635 West 3rd St,Suite 1070W, Los Angeles, CA 90048 USA. RP Freedland, SJ (reprint author), Cedars Sinai Med Ctr, Dept Surg, Div Urol, Samuel Oschin Comprehens Canc Inst, 8635 West 3rd St,Suite 1070W, Los Angeles, CA 90048 USA. EM stephen.freedland@cshs.org FU Bayer HealthCare; NIH/NCI [P50CA09231] FX This study was funded by Bayer HealthCare and supported by the NIH/NCI under Award Number P50CA09231. NR 21 TC 1 Z9 1 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 EI 1476-5608 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD DEC PY 2016 VL 19 IS 4 BP 380 EP 384 DI 10.1038/pcan.2016.26 PG 5 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA EC3CO UT WOS:000388002500008 PM 27377207 ER PT J AU Mckay, RR Werner, L Fiorillo, M Nakabayashi, M Kantoff, PW Taplin, ME AF Mckay, R. R. Werner, L. Fiorillo, M. Nakabayashi, M. Kantoff, P. W. Taplin, M-E TI Predictors of duration of abiraterone acetate in men with castration-resistant prostate cancer SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article ID CLINICAL ACTIVITY; ENZALUTAMIDE MDV3100; ANTITUMOR-ACTIVITY; INCREASED SURVIVAL; PROGNOSTIC MODEL; DOCETAXEL; THERAPY; CHEMOTHERAPY; EFFICACY; ANDROGENS AB BACKGROUND: Androgen receptor signaling remains important in castration-resistant prostate cancer (CRPC) as demonstrated by the efficacy of abiraterone acetate (henceforth abiraterone) in phase III trials. Given that heterogeneous patient responses are observed, we sought to identify clinical factors associated with duration of abiraterone. METHODS: We retrospectively identified patients with CRPC treated with abiraterone in our database. Patient characteristics and types and duration of prostate cancer (PC) therapies were analyzed. These parameters were analyzed with duration of abiraterone in univariate and multivariable analyses. RESULTS: We identified 161 patients who had received abiraterone. All had received primary androgen-deprivation therapy (ADT), 86% prior secondary hormone therapy (SHT) and 33% prior chemotherapy. The median duration of primary ADT was 23 months, duration of SHT (excluding abiraterone) was 17 months and duration of chemotherapy was 8 months. We demonstrated that lower PSA at abiraterone initiation, longer primary ADT duration, no prior ketoconazole, no prior chemotherapy and longer chemotherapy duration were associated with a longer duration on abiraterone in univariate analysis. In multivariable analysis, duration of primary ADT (duration of abiraterone 9 versus 13 months for <= 12 versus >12 months, P = 0.03) and no use of prior chemotherapy (duration of abiraterone 16 versus 7 months for no versus yes prior chemotherapy, P<0.01) were associated with duration of abiraterone. CONCLUSIONS: Several clinical parameters, including type and duration of prior therapy, are predictive of responsiveness to abiraterone. These parameters are logical and correlate with smaller disease burden or less exposure to PC therapies. This information can help physicians counsel patients about the potential durability of efficacy of abiraterone. Identifying predictive biomarkers that inform patient selection for therapy is critical to optimizing treatment outcomes. C1 [Mckay, R. R.; Werner, L.; Fiorillo, M.; Nakabayashi, M.; Kantoff, P. W.; Taplin, M-E] Dana Farber Canc Inst, Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. [Kantoff, P. W.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. RP Mckay, RR (reprint author), Dana Farber Canc Inst, Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM rmckay5@partners.org FU Fairweather Family Fund at the Dana-Farber Cancer Institute FX This project was supported in part by the Fairweather Family Fund at the Dana-Farber Cancer Institute (to M-ET). NR 37 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 EI 1476-5608 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD DEC PY 2016 VL 19 IS 4 BP 398 EP 405 DI 10.1038/pcan.2016.31 PG 8 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA EC3CO UT WOS:000388002500012 PM 27502737 ER PT J AU Wadhwa, H Terris, MK Aronson, WJ Kane, CJ Amling, CL Cooperberg, MR Freedland, SJ Abern, MR AF Wadhwa, H. Terris, M. K. Aronson, W. J. Kane, C. J. Amling, C. L. Cooperberg, M. R. Freedland, S. J. Abern, M. R. TI Long-term oncological outcomes of apical positive surgical margins at radical prostatectomy in the Shared Equal Access Regional Cancer Hospital cohort SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article ID BIOCHEMICAL RECURRENCE; PROGNOSTIC-SIGNIFICANCE; ANTIGEN RECURRENCE; RISK-FACTORS; FOLLOW-UP; IMPACT; EXTENT; SPECIMENS; LOCATION; RADIOTHERAPY AB BACKGROUND: Approximately 29-38% of all positive surgical margins (PSMs) at radical prostatectomy (RP) involve the apex. The prognostic significance of apical PSM remains unclear. We therefore compared the long-term oncologic outcomes of men with apical PSMs to those with negative PSMs, apical and other PSMs, and other PSMs at RP. METHODS: The SEARCH (Shared Equal Access Regional Cancer Hospital) database was used to identify 4031 men with prostate cancer (PCa) managed with RP with complete pathologic grade and stage data. Margin status was categorized as negative, apex only, or other positive. Multivariable Cox regression models adjusted for pathologic stage and grade were developed to test the relationship between margin status and biochemical recurrence (BCR), metastases and PCa death. RESULTS: In the final cohort, 34.3% had PSMs, whereas 65.7% had negative margins. Univariable analysis showed that compared with negative margins, apex-only PSM was associated with BCR (hazard ratio (HR): 1.4 [1.1-1.8]), but not metastases or PCa death, whereas apex and other PSMs were associated with BCR (HR: 3.3 [2.8-4]) and metastases (HR: 1.8 [1.02-3.1]) but not PCa death. Nonapical PSMs were associated with BCR (HR: 2.7 [2.4-3.1]), metastases (1.7 [1.2-2.5)] and PCa death (1.8 [1.05-3]). On multivariable analysis, apex-only, apex and other, and nonapical PSMs were associated with BCR but margin status was not associated with metastases or PCa death. CONCLUSIONS: In a large cohort of men undergoing RP, those with PSMs at the prostatic apex had lower BCR, metastases, or PCa death compared with those with PSMs at other locations. When adjusted for pathologic stage and grade, however, PSMs were associated with BCR but not long-term oncologic outcomes. These data confirm that men with apex-only PSMs may not be ideal candidates for adjuvant therapy after RP. C1 [Wadhwa, H.; Abern, M. R.] Univ Illinois, Dept Urol, 820 South Wood St Suite 515, Chicago, IL 60612 USA. [Terris, M. K.] Vet Affairs Med Ctr, Urol Sect, Augusta, GA USA. [Terris, M. K.] Med Coll Georgia, Urol Sect, Augusta, GA 30912 USA. [Aronson, W. J.] Vet Affairs Greater Los Angeles Healthcare Syst, Urol Sect, Dept Surg, Los Angeles, CA USA. [Aronson, W. J.] Univ Calif Los Angeles, Sch Med, Dept Urol, Los Angeles, CA USA. [Kane, C. J.] Univ Calif San Diego, Div Urol, San Diego, CA 92103 USA. [Amling, C. L.] Oregon Hlth & Sci Univ, Dept Urol, Portland, OR USA. [Cooperberg, M. R.] Univ Calif San Francisco, Ctr Comprehens Canc, Dept Urol, San Francisco, CA 94143 USA. [Cooperberg, M. R.] Vet Affairs Med Ctr, Dept Surg, Urol Sect, San Francisco, CA 94121 USA. [Freedland, S. J.] Vet Affairs Med Ctr, Urol Sect, Durham, NC USA. [Freedland, S. J.] Cedars Sinai, Dept Surg, Div Urol Surg, Los Angeles, CA USA. RP Abern, MR (reprint author), Univ Illinois, Dept Urol, 820 South Wood St Suite 515, Chicago, IL 60612 USA. EM mabern1@uic.edu NR 48 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 1365-7852 EI 1476-5608 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD DEC PY 2016 VL 19 IS 4 BP 423 EP 428 DI 10.1038/pcan.2016.45 PG 6 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA EC3CO UT WOS:000388002500016 PM 27698440 ER PT J AU Verburg, JM Grassberger, C Dowdell, S Schuemann, J Seco, J Paganetti, H AF Verburg, Joost Mathijs Grassberger, Clemens Dowdell, Stephen Schuemann, Jan Seco, Joao Paganetti, Harald TI Automated Monte Carlo Simulation of Proton Therapy Treatment Plans SO TECHNOLOGY IN CANCER RESEARCH & TREATMENT LA English DT Article DE radiotherapy; proton therapy; Monte Carlo simulation; treatment planning; dose calculation ID CARBON-ION THERAPY; DOSE CALCULATION; BEAM THERAPY; RANGE UNCERTAINTIES; CLINICAL-PRACTICE; SCANNED PROTON; GEANT4; SCATTERING; DELIVERY; DISTRIBUTIONS AB Simulations of clinical proton radiotherapy treatment plans using general purpose Monte Carlo codes have been proven to be a valuable tool for basic research and clinical studies. They have been used to benchmark dose calculation methods, to study radiobiological effects, and to develop new technologies such as in vivo range verification methods. Advancements in the availability of computational power have made it feasible to perform such simulations on large sets of patient data, resulting in a need for automated and consistent simulations. A framework called MCAUTO was developed for this purpose. Both passive scattering and pencil beam scanning delivery are supported. The code handles the data exchange between the treatment planning system and the Monte Carlo system, which requires not only transfer of plan and imaging information but also translation of institutional procedures, such as output factor definitions. Simulations are performed on a high-performance computing infrastructure. The simulation methods were designed to use the full capabilities of Monte Carlo physics models, while also ensuring consistency in the approximations that are common to both pencil beam and Monte Carlo dose calculations. Although some methods need to be tailored to institutional planning systems and procedures, the described procedures show a general road map that can be easily translated to other systems. C1 [Verburg, Joost Mathijs; Grassberger, Clemens; Dowdell, Stephen; Schuemann, Jan; Seco, Joao; Paganetti, Harald] Massachusetts Gen Hosp, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA. [Verburg, Joost Mathijs; Grassberger, Clemens; Dowdell, Stephen; Schuemann, Jan; Seco, Joao; Paganetti, Harald] Harvard Med Sch, 30 Fruit St, Boston, MA 02114 USA. RP Verburg, JM (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA.; Verburg, JM (reprint author), Harvard Med Sch, 30 Fruit St, Boston, MA 02114 USA. EM jverburg@mgh.harvard.edu FU US Department of Health and Human Services, National Institutes of Health, National Cancer Institute [C06-CA059267] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: US Department of Health and Human Services, National Institutes of Health, National Cancer Institute C06-CA059267. NR 43 TC 0 Z9 0 U1 7 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1533-0346 EI 1533-0338 J9 TECHNOL CANCER RES T JI Technol. Cancer Res. Treat. PD DEC PY 2016 VL 15 IS 6 BP NP35 EP NP46 DI 10.1177/1533034615614139 PG 12 WC Oncology SC Oncology GA EC0AE UT WOS:000387759000005 PM 26596915 ER PT J AU Ttendo, SS Was, A Preston, MA Munyarugero, E Kerry, VB Firth, PG AF Ttendo, Stephen S. Was, Adam Preston, Mark A. Munyarugero, Emmanuel Kerry, Vanessa B. Firth, Paul G. TI Retrospective Descriptive Study of an Intensive Care Unit at a Ugandan Regional Referral Hospital SO WORLD JOURNAL OF SURGERY LA English DT Article ID LOW-INCOME COUNTRIES; SEVERE SEPSIS; DEVELOPING-WORLD; SEPTIC SHOCK; ANESTHESIA; MORTALITY; PATIENT; AFRICA; ZAMBIA; MEDICINE AB We describe delivery and outcomes of critical care at Mbarara Regional Referral Hospital, a Ugandan secondary referral hospital serving a large, widely dispersed rural population. Retrospective observational study of ICU admissions was performed from January 2008 to December 2011. Of 431 admissions, 239 (55.4 %) were female, and 142 (33.2 %) were children (< 18 years). The median length of stay was 2 (IQR 1-4) days, with 365 patients (85 %) staying less than 8 days. Indications for admission were surgical 49.3 % (n = 213), medical/pediatric 27.4 % (n = 118), or obstetrical/gynecological 22.3 % (n = 96). The overall mortality rate was 37.6 % (162/431) [adults 39.3 % (n = 113/287), children 33.5 % (n = 48/143), unspecified age 100 % (n = 1/1)]. Of the 162 deaths, 76 (46.9 %) occurred on the first, 20 (12.3 %) on the second, 23 (14.2 %) on the third, and 43 (26.5 %) on a subsequent day of admission. Mortality rates for common diagnoses were surgical abdomen 31.9 % (n = 29/91), trauma 45.5 % (n = 30/66), head trauma 59.6 % (n = 28/47), and poisoning 28.6 % (n = 10/35). The rate of mechanical ventilation was 49.7 % (n = 214/431). The mortality rate of ventilated patients was 73.5 % (n = 119/224). The multivariate odd ratio estimates of mortality were significant for ventilation [aOR 6.15 (95 % CI 3.83-9.87), p < 0.0001] and for length of stay beyond seven days [aOR 0.37 (95 % CI 0.19-0.70), p = 0.0021], but not significant for decade of age [aOR 1.06 (95 % CI 0.94-1.20), p = 0.33], gender [aOR 0.61(95 % CI 0.38-0.99), p = 0.07], or diagnosis type [medical vs. surgical aOR 1.08 (95 % CI 0. 63-1.84), medical vs. obstetric/gynecology aOR 0.73 (95 % CI 0.37-1.43), p = 0.49]. The ICU predominantly functions as an acute care unit for critically ill young patients, with most deaths occurring within the first 48 h of admission. Expansion of critical care capacity in low-income countries should be accompanied by measurement of the nature and impact of this intervention. C1 [Ttendo, Stephen S.; Munyarugero, Emmanuel] Mbarara Reg Referral Hosp, Dept Anaesthesia & Crit Care, Mbarara, Uganda. [Was, Adam] Lucile Packard Childrens Hosp Stanford, Dept Pediat, Palo Alto, CA USA. [Preston, Mark A.] Brigham & Womans Hosp, Dept Surg, Boston, MA USA. [Kerry, Vanessa B.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Firth, Paul G.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. RP Firth, PG (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM pfirth@partners.org FU MGH Global Health, Massachusetts General Hospital, Boston, MA, USA FX Funding was provided by MGH Global Health, Massachusetts General Hospital, Boston, MA, USA. NR 36 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 EI 1432-2323 J9 WORLD J SURG JI World J.Surg. PD DEC PY 2016 VL 40 IS 12 BP 2847 EP 2856 DI 10.1007/s00268-016-3644-5 PG 10 WC Surgery SC Surgery GA EB9JG UT WOS:000387709300003 PM 27506722 ER PT J AU Carlson, LC Stewart, BT Hatcher, KW Kabetu, C VanderBurg, R Magee, WP AF Carlson, Lucas C. Stewart, Barclay T. Hatcher, Kristin W. Kabetu, Charles VanderBurg, Richard Magee, William P., Jr. TI A Model of the Unmet Need for Cleft Lip and Palate Surgery in Low- and Middle-Income Countries SO WORLD JOURNAL OF SURGERY LA English DT Article ID SURGICAL CARE; GLOBAL BURDEN; EXPERIENCE; DISEASE; REPAIR; IMPACT AB There is a significant unmet need for the cleft lip and/or palate (CL/P) care in low- and middle-income countries (LMICs) ; however, country-level estimates that can be used to inform local and international cleft care program strategies are lacking. Using data from Operation Smile surgical programs in twelve LMICs and country-level indicators from the World Health Organization and World Bank, we developed a model to estimate the proportion of individuals with CL/Ps older than respective surgery age targets for cleft lip and cleft palate surgery (1 and 2 years, respectively). After extrapolating this model to other LMICs with available indicator data, we combined these findings with estimates of CL/P prevalence among live births to estimate the total number of unrepaired CL/P cases in LMICs worldwide. The models were constructed from a total of 887 cases of cleft palate and 576 cases of cleft lip across the twelve countries. From these, we estimated that there are 616,655 cases of unrepaired CL/P (95 % CI 564,893-678,503) in the 113 countries with available data for extrapolation. The rate of unrepaired CL/Ps ranged from 2.5 per 100,000 population in Romania to 28.5 per 100,000 in Cambodia, respectively (median rate 10.7 per 100,000 population). Our model provides marked insight into the global surgical backlog due to cleft lip and palate. While the most populated LMICs have the largest number of unrepaired CL/Ps, low-income countries with relatively less healthcare infrastructure have exceptionally high rates (e.g., Cambodia, Afghanistan, and Nepal). These estimates can be used by local and international cleft care organizations to set program priorities, estimate resource requirements, and inform strategies to support cleft care. C1 [Carlson, Lucas C.] Brigham & Womens Hosp, Dept Emergency Med, 10 Vining St,Neville House 2nd Floor, Boston, MA 02115 USA. [Carlson, Lucas C.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Stewart, Barclay T.] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Stewart, Barclay T.] Kwame Nkrumah Univ Sci & Technol, Sch Med Sci, Kumasi, Ghana. [Stewart, Barclay T.] Univ Stellenbosch, Dept Interdisciplinary Hlth Sci, Cape Town, South Africa. [Hatcher, Kristin W.; VanderBurg, Richard; Magee, William P., Jr.] Operat Smile Inc, Virginia Beach, VA USA. [Kabetu, Charles] Kenyatta Natl Hosp, Dept Anesthesiol, Nairobi, Kenya. RP Carlson, LC (reprint author), Brigham & Womens Hosp, Dept Emergency Med, 10 Vining St,Neville House 2nd Floor, Boston, MA 02115 USA.; Carlson, LC (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. EM lccarlson@partners.org FU Fogarty International Center, US National Institutes of Health [R25-TW009345] FX Data analysis and manuscript preparation was partially supported by the Grant R25-TW009345 from the Fogarty International Center, US National Institutes of Health. NR 18 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 EI 1432-2323 J9 WORLD J SURG JI World J.Surg. PD DEC PY 2016 VL 40 IS 12 BP 2857 EP 2867 DI 10.1007/s00268-016-3637-4 PG 11 WC Surgery SC Surgery GA EB9JG UT WOS:000387709300004 PM 27417108 ER PT J AU Fitzler, S Raia, P Buckley, FO Wang, M AF Fitzler, Sandra Raia, Paul Buckley, Fredrick O., Jr. Wang, Mei TI Does Nursing Facility Use of Habilitation Therapy Improve Performance on Quality Measures? SO AMERICAN JOURNAL OF ALZHEIMERS DISEASE AND OTHER DEMENTIAS LA English DT Article DE habilitation therapy; interdisciplinary behavior team; nursing home; quality measures AB The purpose of the project, Centers for Medicare & Medicaid Services (CMS) Innovation study, was to evaluate the impact on 12 quality measures including 10 Minimum Data Set (MDS) publicly reported measures and 2 nursing home process measures using habilitation therapy techniques and a behavior team to manage dementia-related behaviors. A prospective design was used to assess the changes in the measures. A total of 30 Massachusetts nursing homes participated in the project over a 12-month period. Project participation required the creation of an interdisciplinary behavior team, habilitation therapy training, facility visit by the program coordinator, attendance at bimonthly support and sharing calls, and monthly collection of process measure data. Participating facilities showed improvement in 9 of the 12 reported measures. Findings indicate potential quality improvement in having nursing homes learn habilitation therapy techniques and know how to use the interdisciplinary team to manage problem behaviors. C1 [Fitzler, Sandra] Healthcentr Advisors, 500 West Cummings Pk,Suite 4000, Woburn, MA 01801 USA. [Raia, Paul] Alzheimers Assoc, Watertown, MA USA. [Buckley, Fredrick O., Jr.] Massachusetts Gen Phys Org, Boston, MA USA. [Wang, Mei] Ctr Medicare Serv, Boston, MA USA. [Wang, Mei] Ctr Medicaid Serv, Boston, MA USA. RP Fitzler, S (reprint author), Healthcentr Advisors, 500 West Cummings Pk,Suite 4000, Woburn, MA 01801 USA. EM sfitzler@comcast.net FU Centers for Medicare & Medicaid Services (CMS); US Department of Health and Human Services (DHHS) [HHSM-500-2011-MA] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the Centers for Medicare & Medicaid Services (CMS), an agency of the US Department of Health and Human Services (DHHS), under Contract Number HHSM-500-2011-MA, titled "Improving Dementia Care in Skilled Nursing Facilities" in the state of Massachusetts. NR 4 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1533-3175 EI 1938-2731 J9 AM J ALZHEIMERS DIS JI Am. J. Alzheimers Dis. Other Dement. PD DEC PY 2016 VL 31 IS 8 BP 687 EP 692 DI 10.1177/1533317516662335 PG 6 WC Geriatrics & Gerontology; Clinical Neurology SC Geriatrics & Gerontology; Neurosciences & Neurology GA EB6IP UT WOS:000387485900010 PM 27650126 ER PT J AU Pasalic, D Gazelka, HM Topazian, RJ Buchhalter, LC Ottenberg, AL Webster, TL Swetz, KM Mueller, PS AF Pasalic, Dario Gazelka, Halena M. Topazian, Rachel J. Buchhalter, Lillian C. Ottenberg, Abigale L. Webster, Tracy L. Swetz, Keith M. Mueller, Paul S. TI Palliative Care Consultation and Associated End-of-Life Care After Pacemaker or Implantable Cardioverter-Defibrillator Deactivation SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Article DE cardiac pacemaker; cardiovascular implantable electronic device; end of life; implantable cardioverter-defibrillator; medical ethics; palliative care ID TERMINALLY-ILL PATIENTS; ADVANCE DIRECTIVES; DECISION-MAKING; MANAGEMENT; ATTITUDES; COMMUNICATION; OUTCOMES; RELIGION; SUICIDE; THERAPY AB The presence of cardiac pacemakers and defibrillators complicates making end-of-life (EOL) medical decisions. Palliative care/medicine consultation (PCMC) may benefit patients and primary providers, but data are lacking. We retrospectively reviewed 150 charts of patients who underwent device deactivation at our tertiary care center (between November 1, 2008, and September 1, 2012), assessing for PCMC and outcomes. Overall, 42% of patients received a PCMC, and 68% of those PCMCs specifically addressed device deactivation. Median survival following deactivation was 2 days, with 42% of deaths occurring within 1 day of deactivation. There was no difference in survival between the groups. The EOL care for patients with implanted cardiac devices is complex, but PCMC may assist with symptom management and clarification of goals of care for such patients. C1 [Pasalic, Dario; Buchhalter, Lillian C.] Mayo Clin, Coll Med, Mayo Med Sch, Rochester, MN 55905 USA. [Gazelka, Halena M.] Mayo Clin, Div Pain Med, 200 First St SW, Rochester, MN 55905 USA. [Topazian, Rachel J.; Swetz, Keith M.; Mueller, Paul S.] Mayo Clin, Biomed Eth Program, Rochester, MN 55905 USA. [Topazian, Rachel J.; Swetz, Keith M.; Mueller, Paul S.] Mayo Clin, Div Gen Internal Med, Rochester, MN 55905 USA. [Topazian, Rachel J.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Ottenberg, Abigale L.; Mueller, Paul S.] Mayo Clin, Program Professionalism & Eth, Rochester, MN 55905 USA. [Ottenberg, Abigale L.] SSH Hlth Miss Legal & Govt Affairs, St Louis, MO USA. [Webster, Tracy L.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN 55905 USA. [Swetz, Keith M.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Gazelka, HM (reprint author), Mayo Clin, Div Pain Med, 200 First St SW, Rochester, MN 55905 USA. EM gazelka.halena@mayo.edu NR 34 TC 0 Z9 0 U1 6 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-9091 EI 1938-2715 J9 AM J HOSP PALLIAT ME JI Am. J. Hosp. Palliat. Med. PD DEC PY 2016 VL 33 IS 10 BP 966 EP 971 DI 10.1177/1049909115595017 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EB2ZJ UT WOS:000387230800009 PM 26169518 ER PT J AU Burnett, YJ Echevarria, K Traugott, KA AF Burnett, Yvonne J. Echevarria, Kelly Traugott, Kristi A. TI Ceftaroline as Salvage Monotherapy for Persistent MRSA Bacteremia SO ANNALS OF PHARMACOTHERAPY LA English DT Review DE ceftaroline; MRSA; methicillin-resistant Staphylococcus aureus; bacteremia; salvage therapy; salvage ID STAPHYLOCOCCUS-AUREUS BACTEREMIA; AWARE SURVEILLANCE PROGRAM; METHICILLIN-RESISTANT; INTEGRATED ANALYSIS; PLUS CEFTAROLINE; UNITED-STATES; CASE SERIES; VANCOMYCIN; INFECTIONS; THERAPY AB Objective: To summarize published data regarding the use of ceftaroline as salvage monotherapy for persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Data Sources: PubMed (January 1980-June 2016) was searched using combinations of the search terms methicillin-resistant Staphylococcus aureus, MRSA, bacteremia, ceftaroline, refractory, and persistent. Supplemental references were generated through review of identified literature citations. Study Selection and Data Extraction: Available English-language, full-text articles pertaining to the use of ceftaroline for persistent MRSA bacteremia (MRSAB) were included. Data Synthesis: The PubMed search yielded 23 articles for evaluation. There are no randomized controlled trials to dateonly case series and reports. Four retrospective case series detailing the use of ceftaroline as monotherapy for persistent MRSAB were included. Most patients received at least 4 days of an appropriate anti-MRSA antimicrobial prior to ceftaroline and were able to clear bacteremia within 3 days. The most common rationales for ceftaroline use were progression of disease or nonresponse to current therapy. Higher off-label dosing of ceftaroline is often utilized to achieve optimal pharmacokinetic/pharmacodynamic parameters. Adverse events are not well described due to lack of follow-up; however, neutropenia has been associated with prolonged use. Conclusions: Treatment options for persistent MRSAB remain few and far between. Ceftaroline is an effective agent for the salvage treatment of MRSAB. Off-label doses up to 600 mg every 8 hours are often used to achieve optimal pharmacokinetic/pharmacodynamic parameters. Because of lack of follow-up in these reports, the incidence of adverse effects of prolonged use of ceftaroline is not well defined. C1 [Burnett, Yvonne J.] St Louis Coll Pharm, 4588 Parkview Pl,Acad & Res Bldg,Room 333, St Louis, MO 63110 USA. [Burnett, Yvonne J.] Washington Univ, Sch Med, St Louis, MO USA. [Echevarria, Kelly] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Echevarria, Kelly; Traugott, Kristi A.] Univ Texas Austin, Austin, TX USA. [Echevarria, Kelly; Traugott, Kristi A.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Traugott, Kristi A.] Univ Hlth Syst, San Antonio, TX USA. RP Burnett, YJ (reprint author), St Louis Coll Pharm, 4588 Parkview Pl,Acad & Res Bldg,Room 333, St Louis, MO 63110 USA. EM yvonne.burnett@stlcop.edu NR 55 TC 2 Z9 2 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1060-0280 EI 1542-6270 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD DEC PY 2016 VL 50 IS 12 BP 1051 EP 1059 DI 10.1177/1060028016664361 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EB4FR UT WOS:000387326200008 PM 27520326 ER PT J AU Graffeo, R Livraghi, L Pagani, O Goldhirsch, A Partridge, AH Garber, JE AF Graffeo, Rossella Livraghi, Luca Pagani, Olivia Goldhirsch, Aron Partridge, Ann H. Garber, Judy E. TI Time to incorporate germline multigene panel testing into breast and ovarian cancer patient care SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Review DE Cancer genetic counseling; Breast and ovarian cancer; BRCA; Surveillance; Multiple-gene panel testing; Genetic counselors ID PEUTZ-JEGHERS-SYNDROME; DIFFUSE GASTRIC-CANCER; HEREDITARY COLORECTAL-CANCER; BRCA2 MUTATION CARRIERS; PROPHYLACTIC TOTAL GASTRECTOMY; REVISED BETHESDA GUIDELINES; FAMILIAL PANCREATIC-CANCER; METASTATIC PROSTATE-CANCER; SOCIETY TASK-FORCE; LYNCH-SYNDROME AB Genetic evaluation is increasingly becoming an integral part of the management of women with newly diagnosed breast and ovarian cancer (OC), and of individuals at high risk for these diseases. Genetic counseling and testing have been incorporated into oncological care to help and complete management and treatment strategies. Risk assessment and early detection strategies in individuals with BRCA1/2 mutations and with Lynch syndrome have been quite extensively studied, whereas much less is known about the management of mutation carriers with less common high-penetrance cancer susceptibility genes (PTEN, TP53, STK11, CDH1), and particularly those who carry mutations in moderate-penetrance genes (e.g., PALB2, CHEK2, ATM, NF1, RAD51C, RAD51D, BRIP1). The latter patient groups represent important ongoing research opportunities to enable informed counseling about appropriate clinical management. We summarize the current guidelines for the management of high and moderate-penetrance mutations for breast and OC susceptibility. Continuous updating of guidelines for proper clinical management of these individuals is ongoing because of rapid advances in technology and knowledge in this field. Thus, we exhort the use of multigene panels for the assessment of cancer risk beyond the classic predisposition syndromes as a new standard of care in cancer genetics. We further support an increase of genetic counselors in Europe and use of their expertise to support genetic testing in specialist multidisciplinary teams. C1 [Graffeo, Rossella; Goldhirsch, Aron] European Inst Oncol, Dept Med Oncol, Milan, Italy. [Livraghi, Luca] ASST Papa Giovanni XXIII, Med Oncol Unit, Bergamo, Italy. [Graffeo, Rossella; Pagani, Olivia] Inst Oncol Southern Switzerland IOSI, Bellinzona, Switzerland. [Graffeo, Rossella; Pagani, Olivia] Breast Unit Southern Switzerland CSSI, Bellinzona, Switzerland. [Partridge, Ann H.; Garber, Judy E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Graffeo, R (reprint author), European Inst Oncol, Dept Med Oncol, Milan, Italy.; Graffeo, R (reprint author), Inst Oncol Southern Switzerland IOSI, Bellinzona, Switzerland.; Graffeo, R (reprint author), Breast Unit Southern Switzerland CSSI, Bellinzona, Switzerland. EM rossella.graffeogalbiati@eoc.ch; llivraghi@asst-pg23.it; Olivia.Pagani@eoc.ch; aaron.goldhirsch@ieo.it; Ann_Partridge@dfci.harvard.edu; Judy_Garber@dfci.harvard.edu NR 147 TC 0 Z9 0 U1 22 U2 22 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD DEC PY 2016 VL 160 IS 3 BP 393 EP 410 DI 10.1007/s10549-016-4003-9 PG 18 WC Oncology SC Oncology GA EB4LH UT WOS:000387342800002 PM 27734215 ER PT J AU Cheng, FX Zhao, JF Hanker, AB Brewer, MR Arteaga, CL Zhao, ZM AF Cheng, Feixiong Zhao, Junfei Hanker, Ariella B. Brewer, Monica Red Arteaga, Carlos L. Zhao, Zhongming TI Transcriptome- and proteome-oriented identification of dysregulated eIF4G, STAT3, and Hippo pathways altered by PIK3CA (H1047R) in HER2/ER-positive breast cancer SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE PIK3CA; Bioinformatics; Synergistic interactions; HER2; ER; Breast cancer ID DRUG-SENSITIVITY; SOMATIC MUTATIONS; SIGNALING PATHWAY; GENOMICS APPROACH; MAMMARY-TUMORS; UP-REGULATION; GROWTH; YAP; TUMORIGENESIS; KINASE AB Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in human breast cancer. Furthermore, PIK3CA mutations are commonly associated with resistance to anti-epidermal growth factor receptor 2 (HER2) or anti-estrogen receptor (ER) agents in HER2 or ER positive (HER2(+)/ER+) breast cancer. Hence, deciphering the underlying mechanisms of PIK3CA mutations in HER2(+)/ER+ breast cancer would provide novel insights into elucidating resistance to anti-HER2/ER therapies. In this study, we systematically investigated the biological consequences of PIK3CA (H1047R) in HER2(+)/ER+ breast cancer by uniquely incorporating mRNA transcriptomic data from The Cancer Genome Atlas and proteomic data from reverse-phase protein arrays. Our integrative bioinformatics analyses revealed that several important pathways such as STAT3 and VEGF/hypoxia were selectively altered by PIK3CA (H1047R) in HER2(+)/ER+ breast cancer. Protein differential expression analysis indicated that an elevated eIF4G might promote tumor angiogenesis and growth via regulation of the hypoxia-activated switch in HER2(+) PIK3CA (H1047R) breast cancer. We observed hypo-phosphorylation of EGFR in HER2(+) PIK3CA (H1047R) breast cancer versus HER2(+)PIK3CA(wild-type) (PIK3CA (WT)). In addition, ER and PIK3CA (H1047R) might cooperate to activate STAT3, MAPK, AKT, and Hippo pathways in ER+ PIK3CA (H1047R) breast cancer. A higher YAP(pS127) level was observed in ER+ PIK3CA (H1047R) patients than that in an ER+ PIK3CA (WT) subgroup. By examining breast cancer cell lines having both microarray gene expression and drug treatment data from the Genomics of Drug Sensitivity in Cancer and the Stand Up to Cancer datasets, we found that the elevated YAP1 mRNA expression was associated with the resistance of BCL-2 family inhibitors, but with the sensitivity to MEK/MAPK inhibitors in breast cancer cells. In summary, these findings shed light on the functional consequences of PIK3CA (H1047R)-driven breast tumorigenesis and resistance to the existing therapeutic agents in HER2(+)/ER+ breast cancer. C1 [Cheng, Feixiong; Zhao, Junfei; Zhao, Zhongming] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN 37203 USA. [Zhao, Junfei; Zhao, Zhongming] Univ Texas Hlth Sci Ctr Houston, Sch Biomed Informat, Ctr Precis Hlth, Houston, TX 77030 USA. [Hanker, Ariella B.; Brewer, Monica Red; Arteaga, Carlos L.] Vanderbilt Univ, Dept Med, Vanderbilt Ingram Canc Ctr, Med Ctr, Nashville, TN 37232 USA. [Arteaga, Carlos L.; Zhao, Zhongming] Vanderbilt Univ, Dept Canc Biol, Vanderbilt Ingram Canc Ctr, Med Ctr, Nashville, TN 37232 USA. [Arteaga, Carlos L.; Zhao, Zhongming] Vanderbilt Univ, Breast Canc Res Program, Vanderbilt Ingram Canc Ctr, Med Ctr, Nashville, TN 37232 USA. [Cheng, Feixiong] Harvard Med Sch, Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA. [Cheng, Feixiong] Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA. RP Zhao, ZM (reprint author), Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN 37203 USA.; Zhao, ZM (reprint author), Univ Texas Hlth Sci Ctr Houston, Sch Biomed Informat, Ctr Precis Hlth, Houston, TX 77030 USA.; Arteaga, CL (reprint author), Vanderbilt Univ, Dept Med, Vanderbilt Ingram Canc Ctr, Med Ctr, Nashville, TN 37232 USA.; Arteaga, CL; Zhao, ZM (reprint author), Vanderbilt Univ, Dept Canc Biol, Vanderbilt Ingram Canc Ctr, Med Ctr, Nashville, TN 37232 USA.; Arteaga, CL; Zhao, ZM (reprint author), Vanderbilt Univ, Breast Canc Res Program, Vanderbilt Ingram Canc Ctr, Med Ctr, Nashville, TN 37232 USA. EM carlos.arteaga@vanderbilt.edu; zhongming.zhao@uth.tmc.edu FU National Institutes of Health (NIH) [R01LM011177]; Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation; Ingram Professorship Funds; NIH Breast Cancer SPORE pilot project FX We thank Barbara O'Brien for improving the English in an early version of the manuscript. This work was partially supported by National Institutes of Health (NIH) grants (R01LM011177), The Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, Ingram Professorship Funds (to Z.Z.), and a NIH Breast Cancer SPORE pilot project (to Z.Z.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 0 Z9 0 U1 13 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD DEC PY 2016 VL 160 IS 3 BP 457 EP 474 DI 10.1007/s10549-016-4011-9 PG 18 WC Oncology SC Oncology GA EB4LH UT WOS:000387342800007 PM 27771839 ER PT J AU Wu, ZR Lu, WQ Wu, D Luo, AQ Bian, HP Li, J Li, WH Liu, GX Huang, J Cheng, FX Tang, Y AF Wu, Zengrui Lu, Weiqiang Wu, Dang Luo, Anqi Bian, Hanping Li, Jie Li, Weihua Liu, Guixia Huang, Jin Cheng, Feixiong Tang, Yun TI In silico prediction of chemical mechanism of action via an improved network-based inference method SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article ID TARGET INTERACTION PREDICTION; ESTROGEN-RECEPTOR BETA; YEAST 2-HYBRID ASSAY; CONCISE GUIDE; SYSTEMS PHARMACOLOGY; SEROTONIN RECEPTORS; IUPHAR/BPS GUIDE; DRUG DEVELOPMENT; CANCER-CELL; DISCOVERY AB Background and PurposeDeciphering chemical mechanism of action (MoA) enables the development of novel therapeutics (e.g. drug repositioning) and evaluation of drug side effects. Development of novel computational methods for chemical MoA assessment under a systems pharmacology framework would accelerate drug discovery and development with greater efficiency and low cost. Experimental ApproachIn this study, we proposed an improved network-based inference method, balanced substructure-drug-target network-based inference (bSDTNBI), to predict MoA for old drugs, clinically failed drugs and new chemical entities. Specifically, three parameters were introduced into network-based resource diffusion processes to adjust the initial resource allocation of different node types, the weighted values of different edge types and the influence of hub nodes. The performance of the method was systematically validated by benchmark datasets and bioassays. Key ResultsHigh performance was yielded for bSDTNBI in both 10-fold and leave-one-out cross validations. A global drug-target network was built to explore MoA of anticancer drugs and repurpose old drugs for 15 cancer types/subtypes. In a case study, 27 predicted candidates among 56 commercially available compounds were experimentally validated to have binding affinities on oestrogen receptor with IC50 or EC50 values 10M. Furthermore, two dual ligands with both agonistic and antagonistic activities 1M would provide potential lead compounds for the development of novel targeted therapy in breast cancer or osteoporosis. Conclusion and ImplicationsIn summary, bSDTNBI would provide a powerful tool for the MoA assessment on both old drugs and novel compounds in drug discovery and development. C1 [Wu, Zengrui; Wu, Dang; Luo, Anqi; Bian, Hanping; Li, Jie; Li, Weihua; Liu, Guixia; Huang, Jin; Tang, Yun] East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, 130 Meilong Rd, Shanghai 200237, Peoples R China. [Lu, Weiqiang] East China Normal Univ, Shanghai Key Lab Regulatory Biol, Inst Biomed Sci, Shanghai, Peoples R China. [Lu, Weiqiang] East China Normal Univ, Shanghai Key Lab Regulatory Biol, Sch Life Sci, Shanghai, Peoples R China. [Cheng, Feixiong] Sichuan Univ, West China Med Sch, Collaborat Innovat Ctr Biotherapy, State Key Lab Biotherapy,West China Hosp, Chengdu 610041, Sichuan, Peoples R China. [Cheng, Feixiong] Harvard Med Sch, Dana Farber Canc Inst, CCSB, Boston, MA USA. [Cheng, Feixiong] Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA. RP Huang, J; Tang, Y (reprint author), East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, 130 Meilong Rd, Shanghai 200237, Peoples R China.; Cheng, FX (reprint author), Sichuan Univ, West China Med Sch, Collaborat Innovat Ctr Biotherapy, State Key Lab Biotherapy,West China Hosp, Chengdu 610041, Sichuan, Peoples R China. EM huangjin@ecust.edu.cn; fxcheng1985@gmail.com; ytang234@ecust.edu.cn FU National Natural Science Foundation of China [81373328, 81573020, 81673356]; National Key Research and Development Program [2016YFA0502304]; 111 Project [B07023] FX This work was supported by the National Natural Science Foundation of China (grants 81373328, 81573020 and 81673356), the National Key Research and Development Program (grant 2016YFA0502304) and the 111 Project (grant B07023). NR 71 TC 2 Z9 2 U1 17 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD DEC PY 2016 VL 173 IS 23 BP 3372 EP 3385 DI 10.1111/bph.13629 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EB4NP UT WOS:000387348900007 ER PT J AU Wang, W Erbe, AK Gallenberger, M Kim, K Carmichael, L Hess, D Mendonca, EA Song, YQ Hank, JA Cheng, SC Signoretti, S Atkins, M Carlson, A Weiss, JM Mier, J Panka, D McDermott, DF Sondel, PM AF Wang, Wei Erbe, Amy K. Gallenberger, Mikayla Kim, KyungMann Carmichael, Lakeesha Hess, Dustin Mendonca, Eneida A. Song, Yiqiang Hank, Jacquelyn A. Cheng, Su-Chun Signoretti, Sabina Atkins, Michael Carlson, Alexander Weiss, Jonathan M. Mier, James Panka, David McDermott, David F. Sondel, Paul M. TI Killer immunoglobulin-like receptor (KIR) and KIR-ligand genotype do not correlate with clinical outcome of renal cell carcinoma patients receiving high-dose IL2 SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE Renal cell carcinoma; High-dose IL2; Killer immunoglobulin-like receptors; HLA; NK cells ID ACUTE MYELOGENOUS LEUKEMIA; UNLICENSED NK CELLS; RECOMBINANT INTERLEUKIN-2; HLA-C; UNRELATED TRANSPLANTATION; NEUROBLASTOMA PATIENTS; IN-VITRO; ANTIBODY; MISMATCH; TUMOR AB NK cells play a role in many cancer immunotherapies. NK cell activity is tightly regulated by killer immunoglobulin-like receptor (KIR) and KIR-ligand interactions. Inhibitory KIR-ligands have been identified as HLA molecules, while activating KIR-ligands are largely unknown. Individuals that have not inherited the corresponding KIR-ligand for at least one inhibitory KIR gene are termed the "KIR-ligand missing" genotype, and they are thought to have a subset of NK cells that express inhibitory KIRs for which the corresponding KIR-ligand is missing on autologous tissue, and thus will not be inhibited through KIR-ligand recognition. In some settings where an anticancer immunotherapeutic effect is likely mediated by NK cells, individuals with a KIR-ligand missing genotype have shown improved clinical outcome compared to individuals with an "all KIR-ligands present" genotype. In addition, patients receiving hematopoietic stem cell transplants for leukemia may do better if their donor has more activating KIR genes (i.e., KIR haplotype-B). In a recent multi-institution clinical trial of patients with metastatic renal cell carcinoma receiving high-dose IL2 (HD-IL2), 25 % of patients showed a complete or partial tumor response to this therapy. We genotyped KIR and KIR-ligand genes for these patients (n = 107) and tested whether KIR/KIR-ligand genotypes correlated with patient clinical outcomes. In these analyses, we did not find any significant association of KIR/KIR-ligand genotype (either KIR-ligand missing or the presence of KIR haplotype-B) with patient outcome in response to the HD-IL2 therapy. C1 [Wang, Wei; Erbe, Amy K.; Gallenberger, Mikayla; Hess, Dustin; Hank, Jacquelyn A.; Sondel, Paul M.] Univ Wisconsin, Dept Human Oncol, 4159 WIMR Bldg UW Madison Campus, Madison, WI 53705 USA. [Kim, KyungMann; Carmichael, Lakeesha; Mendonca, Eneida A.; Song, Yiqiang] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI USA. [Cheng, Su-Chun] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Signoretti, Sabina] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Atkins, Michael; Mier, James; McDermott, David F.] Cytokine Working Grp, Rockville, MD USA. [Atkins, Michael] Georgetown Univ, Dept Med, Washington, DC USA. [Carlson, Alexander; Mier, James; Panka, David; McDermott, David F.] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Weiss, Jonathan M.] NCI, Biol Resources Branch, Frederick, MD 21701 USA. [Mendonca, Eneida A.; Sondel, Paul M.] Univ Wisconsin, Dept Pediat, Madison, WI 53792 USA. RP Sondel, PM (reprint author), Univ Wisconsin, Dept Human Oncol, 4159 WIMR Bldg UW Madison Campus, Madison, WI 53705 USA.; Sondel, PM (reprint author), Univ Wisconsin, Dept Pediat, Madison, WI 53792 USA. EM pmsondel@humonc.wisc.edu FU Hyundai Hope on Wheels Grant; Midwest Athletes Against Childhood; Stand Up 2 Cancer; The St. Baldrick's Foundation; American Association of Cancer Research; University of Wisconsin-Madison Carbone Cancer Center; NCI-Cytokine Working Group; Public Health Service Grants from the National Cancer Institute [CA014520, CA021115, CA023318, CA066636, CA180820, CA180794, CA021076, CA180799, CA14958, CA180816, CA166105, CA197078]; National Institutes of Health; Department of Health and Human Services FX The authors thank the medical and nursing staff that participated in the care of patients in this study, and especially all patients participating in this study. Thanks also to Bartosz Grzywacz and Patrick Reville for their helpful discussions and input. This research was supported by Hyundai Hope on Wheels Grant; Midwest Athletes Against Childhood; Stand Up 2 Cancer; The St. Baldrick's Foundation; American Association of Cancer Research; University of Wisconsin-Madison Carbone Cancer Center; by NCI-Cytokine Working Group and supported in part by Public Health Service Grants CA014520, CA021115, CA023318, CA066636, CA180820, CA180794, CA021076, CA180799, CA14958, CA180816, CA166105 and CA197078, from the National Cancer Institute; the National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. NR 38 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 EI 1432-0851 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD DEC PY 2016 VL 65 IS 12 BP 1523 EP 1532 DI 10.1007/s00262-016-1904-8 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA EB7UB UT WOS:000387595000008 PM 27695964 ER PT J AU Li, AN Wu, Y Linnoila, J Pulli, B Wang, CH Zeller, M Ali, M Lewandrowski, GK Li, JH Tricot, B Keliher, E Wojtkiewicz, GR Fulci, G Feng, XY Tannous, BA Yao, ZW Chen, JW AF Li, Anning Wu, Yue Linnoila, Jenny Pulli, Benjamin Wang, Cuihua Zeller, Matthias Ali, Muhammad Lewandrowski, Grant K. Li, Jinghui Tricot, Benoit Keliher, Edmund Wojtkiewicz, Gregory R. Fulci, Giulia Feng, Xiaoyuan Tannous, Bakhos A. Yao, Zhenwei Chen, John W. TI Surface biotinylation of cytotoxic T lymphocytes for in vivo tracking of tumor immunotherapy in murine models SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE Biotin; Cytotoxic T lymphocytes; Tumor; Immunotherapy ID NEAR-INFRARED FLUORESCENCE; CELLS; CANCER; ANTIGEN; XENOGRAFTS; THERAPY; GENE; MRI AB Currently, there is no stable and flexible method to label and track cytotoxic T lymphocytes (CTLs) in vivo in CTL immunotherapy. We aimed to evaluate whether the sulfo-hydroxysuccinimide (NHS)-biotin-streptavidin (SA) platform could chemically modify the cell surface of CTLs for in vivo tracking. CD8+ T lymphocytes were labeled with sulfo-NHS-biotin under different conditions and then incubated with SA-Alexa647. Labeling efficiency was proportional to sulfo-NHS-biotin concentration. CD8+ T lymphocytes could be labeled with higher efficiency with sulfo-NHS-biotin in DPBS than in RPMI (P < 0.05). Incubation temperature was not a key factor. CTLs maintained sufficient labeling for at least 72 h (P < 0.05), without altering cell viability. After co-culturing labeled CTLs with mouse glioma stem cells (GSCs) engineered to present biotin on their surface, targeting CTLs could specifically target biotin-presenting GSCs and inhibited cell proliferation (P < 0.01) and tumor spheres formation. In a biotin-presenting GSC brain tumor model, targeting CTLs could be detected in biotin-presenting gliomas in mouse brains but not in the non-tumor-bearing contralateral hemispheres (P < 0.05). In vivo fluorescent molecular tomography imaging in a subcutaneous U87 mouse model confirmed that targeting CTLs homed in on the biotin-presenting U87 tumors but not the control U87 tumors. PET imaging with Zr-89-deferoxamine-biotin and SA showed a rapid clearance of the PET signal over 24 h in the control tumor, while only minimally decreased in the targeted tumor. Thus, sulfo-NHS-biotin-SA labeling is an efficient method to noninvasively track the migration of adoptive transferred CTLs and does not alter CTL viability or interfere with CTL-mediated cytotoxic activity. C1 [Li, Anning; Wu, Yue; Feng, Xiaoyuan; Yao, Zhenwei] Fudan Univ, Huashan Hosp, Dept Radiol, 12 Urumchi Rd, Shanghai 200040, Peoples R China. [Li, Anning; Wu, Yue; Linnoila, Jenny; Pulli, Benjamin; Wang, Cuihua; Zeller, Matthias; Ali, Muhammad; Li, Jinghui; Tricot, Benoit; Keliher, Edmund; Wojtkiewicz, Gregory R.; Chen, John W.] Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA. [Li, Anning; Wu, Yue; Linnoila, Jenny; Pulli, Benjamin; Wang, Cuihua; Zeller, Matthias; Ali, Muhammad; Li, Jinghui; Tricot, Benoit; Keliher, Edmund; Wojtkiewicz, Gregory R.; Chen, John W.] Harvard Med Sch, 185 Cambridge St, Boston, MA 02114 USA. [Pulli, Benjamin; Chen, John W.] Massachusetts Gen Hosp, Dept Radiol, Inst Innovat Imaging, Boston, MA 02114 USA. [Lewandrowski, Grant K.; Tannous, Bakhos A.] Ctr Neurosci, Mol Neurogenet Unit, 149 13th St, Charlestown, MA 02129 USA. [Fulci, Giulia] Massachusetts Gen Hosp, Brain Tumor Res Ctr, Neurosurg Serv, Simches Res Bldg, Boston, MA 02114 USA. [Li, Anning] Shandong Univ, Qilu Hosp, Dept Radiol, 107 West Wenhua Rd, Jinan 250012, Peoples R China. RP Yao, ZW (reprint author), Fudan Univ, Huashan Hosp, Dept Radiol, 12 Urumchi Rd, Shanghai 200040, Peoples R China.; Chen, JW (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA.; Chen, JW (reprint author), Harvard Med Sch, 185 Cambridge St, Boston, MA 02114 USA.; Chen, JW (reprint author), Massachusetts Gen Hosp, Dept Radiol, Inst Innovat Imaging, Boston, MA 02114 USA. EM aocnhnr@126.com; jwchen@mgh.harvard.edu FU US National Institute of Health [R01-NS070835, R01-NS072167]; National Natural Science Foundation of China [81271633] FX This work was supported by the US National Institute of Health (R01-NS070835 and R01-NS072167), National Natural Science Foundation of China (Grant 81271633). We thank the Memorial Sloan Kettering Cancer Center for providing [89Zr] Zr-oxalate. NR 28 TC 0 Z9 0 U1 12 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 EI 1432-0851 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD DEC PY 2016 VL 65 IS 12 BP 1545 EP 1554 DI 10.1007/s00262-016-1911-9 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA EB7UB UT WOS:000387595000010 PM 27722909 ER PT J AU Liu, JF Wang, WL Liu, M Su, LM Zhou, H Xia, Y Ran, JH Lin, HY Yang, BX AF Liu, Jiangfeng Wang, Weiling Liu, Ming Su, Limin Zhou, Hong Xia, Yin Ran, Jianhua Lin, Herbert Y. Yang, Baoxue TI Repulsive guidance molecule b inhibits renal cyst development through the bone morphogenetic protein signaling pathway SO CELLULAR SIGNALLING LA English DT Article DE PKD; Tubule branching; Smad1/5/8; Renal cyst; Kidney disease ID POLYCYSTIC KIDNEY-DISEASE; BRANCHING MORPHOGENESIS; IN-VITRO; E-CADHERIN; CELL; APOPTOSIS; DRAGON; GROWTH; TUBULOGENESIS; ACTIVATION AB Autosomal dominant polycystic kidney disease (ADPKD) is a monogenetic disease that still lacks effective therapy. Repulsive guidance molecule b (RGMb), a co-receptor for bone morphogenetic proteins (BMPs) and a ligand for neogenin, is expressed in renal tubular epithelial cells. Previous studies showed that RGMb plays negative roles in several types of tumors and prevents the immune system from over activation. The present study was designed to explore the effects of RGMb in ADPKD development. We found that expression of RGMb in kidney was less in PKD mice than wild-type mice. With stimulation of 8-bromo-cAMP, RGMb-null embryonic kidneys had greater cyst index, though their ureteric bud branched less than wild-type mice at E13.5. Postnatal RGMb-null kidneys showed interstitial hyperplasia and decreased tubular structures, especially in the boundary area of renal cortex and medulla. RGMb overexpression dramatically inhibited cyst development and promoted tubulogenesis in MDCK cells grown in 3D collagen gels. Biochemical analysis showed increased p-Smad1/5/8 and decreased p-ERK in RGMb-overexpressing MDCK cells, suggesting modulated BMP signaling. Specific inhibition of p-Smad1/5/8 by LDN193189 reversed the suppression of RGMb on MDCK cyst model. These results reveal RGMb as a novel regulator for ADPKD by promoting renal tubule branching and regulating BMP signaling pathway. Elevating RGMb and enhancing p-Smad1/5/8 are promising new strategies to treat ADPKD. (C) 2016 Elsevier Inc. All rights reserved. C1 [Liu, Jiangfeng; Wang, Weiling; Liu, Ming; Su, Limin; Zhou, Hong; Yang, Baoxue] Peking Univ, Sch Basic Med Sci, Dept Pharmacol, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China. [Xia, Yin] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Ran, Jianhua] Chongqing Med Univ, Dept Anat, Chongqing, Peoples R China. [Ran, Jianhua] Chongqing Med Univ, Neurosci Ctr, Chongqing, Peoples R China. [Lin, Herbert Y.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol,Renal Div, Boston, MA USA. RP Yang, BX (reprint author), Peking Univ, Sch Basic Med Sci, Dept Pharmacol, 38 Xueyuan Lu, Beijing 100191, Peoples R China. EM baoxue@bjmu.edu.cn FU National Natural Science Foundation of China grants (NSFC) [31200869, 81330074, 81170632, N_CUHK432/12, 81261160507]; Hong Kong Research Grant Council (RGC); Research Fund for the Doctoral Program of Higher Education [20100001110047]; 111 Project FX This work was supported by National Natural Science Foundation of China grants (NSFC) 31200869, 81330074 and 81170632, the Hong Kong Research Grant Council (RGC) and NSFC joint grants N_CUHK432/12 (Y. X.) and 81261160507 (B. Y.), the Research Fund for the Doctoral Program of Higher Education 20100001110047, and the 111 Project. NR 59 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 0898-6568 EI 1873-3913 J9 CELL SIGNAL JI Cell. Signal. PD DEC PY 2016 VL 28 IS 12 BP 1842 EP 1851 DI 10.1016/j.cellsig.2016.08.015 PG 10 WC Cell Biology SC Cell Biology GA EB2NP UT WOS:000387199400004 PM 27575743 ER PT J AU Lin, DJ Hermann, KL Schmahmann, JD AF Lin, David J. Hermann, Katherine L. Schmahmann, Jeremy D. TI The Diagnosis and Natural History of Multiple System Atrophy, Cerebellar Type SO CEREBELLUM LA English DT Article DE Multiple system atrophy; Cerebellum; Ataxia; Idiopathic late-onset cerebellar ataxia; Sporadic adult-onset ataxia; Parkinsonism; Pathologic laughing and crying; REM sleep behavior disorder; Autonomic neuropathy; Urinary incontinence; Erectile dysfunction; Pons; Middle cerebellar peduncle; Atrophy ID GLIAL CYTOPLASMIC INCLUSIONS; COGNITIVE-AFFECTIVE SYNDROME; ADULT-ONSET ATAXIA; PARKINSONS-DISEASE; ALPHA-SYNUCLEIN; LEWY BODIES; OLIVOPONTOCEREBELLAR ATROPHY; CONSENSUS STATEMENT; SLEEP DISORDERS; WHITE-MATTER AB The objective of this study was to identify key features differentiating multiple system atrophy cerebellar type (MSA-C) from idiopathic late-onset cerebellar ataxia (ILOCA). We reviewed records of patients seen in the Massachusetts General Hospital Ataxia Unit between 1992 and 2013 with consensus criteria diagnoses of MSA-C or ILOCA. Twelve patients had definite MSA-C, 53 had possible/probable MSA-C, and 12 had ILOCA. Autonomic features, specifically urinary urgency, frequency, and incontinence with erectile dysfunction in males, differentiated MSA-C from ILOCA throughout the disease course (p = 0.005). Orthostatic hypotension developed later and differentiated MSA-C from ILOCA (p < 0.01). REM sleep behavior disorder (RBD) occurred early in possible/probable MSA-C (p < 0.01). Late MSA-C included pathologic laughing and crying (PLC, p < 0.01), bradykinesia (p = 0.01), and corticospinal findings (p = 0.01). MRI distinguished MSA-C from ILOCA by atrophy of the brainstem (p < 0.01) and middle cerebellar peduncles (MCP, p = 0.02). MSA-C progressed faster than ILOCA: by 6 years, MSA-C walker dependency was 100 % and ILOCA 33 %. MSA-C survival was 8.4 +/- 2.5 years. Mean length of ILOCA illness to date is 15.9 +/- 6.4 years. A sporadic onset, insidiously developing cerebellar syndrome in midlife, with autonomic features of otherwise unexplained bladder dysfunction with or without erectile dysfunction in males, and atrophy of the cerebellum, brainstem, and MCP points strongly to MSA-C. RBD and postural hypotension confirm the diagnosis. Extrapyramidal findings, corticospinal tract signs, and PLC are helpful but not necessary for diagnosis. Clarity in early MSA-C diagnosis can prevent unnecessary investigations and facilitate therapeutic trials. C1 [Lin, David J.; Hermann, Katherine L.; Schmahmann, Jeremy D.] Harvard Med Sch, Massachusetts Gen Hosp, Lab Neuroanat & Cerebellar Neurobiol, Ataxia Unit,Cognit Behav Neurol Unit,Dept Neurol, Boston, MA 02114 USA. RP Schmahmann, JD (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Lab Neuroanat & Cerebellar Neurobiol, Ataxia Unit,Cognit Behav Neurol Unit,Dept Neurol, Boston, MA 02114 USA. EM jschmahmann@mgh.harvard.edu FU Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Research Resources); National Center for Advancing Translational Sciences, National Institutes of Health [UL1 TR001102]; Harvard University and its affiliated academic health-care centers; Birmingham Foundation; MINDlink Foundation FX The authors gratefully acknowledge the helpful discussions regarding statistical analysis with Hang Lee, PhD of the MGH Department of Biostatistics; the assistance of Jason MacMore, BA; and the clinical care and coordination of the patients in this study by Marygrace Neal, MA. The neuropathological studies were performed, and reports generated, by Dr. E. Tessa Hedley-Whyte and Dr. Matthew P. Frosch of the MGH Department of Neuropathology. This work was conducted with support 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 health-care centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health-care centers, or the National Institutes of Health. This work was supported in part by the Birmingham Foundation and the MINDlink Foundation. This study is dedicated to our patients in the MGH Ataxia Unit and their families, without whose commitment to research into MSA-C and related ataxias this study could not have been performed. NR 83 TC 2 Z9 2 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1473-4222 EI 1473-4230 J9 CEREBELLUM JI Cerebellum PD DEC PY 2016 VL 15 IS 6 BP 663 EP 679 DI 10.1007/s12311-015-0728-y PG 17 WC Neurosciences SC Neurosciences & Neurology GA EB7BC UT WOS:000387539000002 PM 26467153 ER PT J AU Hoche, F Guell, X Sherman, JC Vangel, MG Schmahmann, JD AF Hoche, Franziska Guell, Xavier Sherman, Janet C. Vangel, Mark G. Schmahmann, Jeremy D. TI Cerebellar Contribution to Social Cognition SO CEREBELLUM LA English DT Article DE Cerebellum; Cerebellar cognitive affective syndrome; Emotion attribution; Dysmetria of thought; Social cognition; Social perception ID OBSESSIVE-COMPULSIVE DISORDER; EMOTION RECOGNITION; HUNTINGTONS-DISEASE; FACIAL EXPRESSIONS; CEREBROCEREBELLAR SYSTEM; SPINOCEREBELLAR ATAXIA; FUNCTIONAL TOPOGRAPHY; NEURAL RESPONSES; RHESUS-MONKEY; AUTISM AB Emotion attribution (EA) from faces is key to social cognition, and deficits in perception of emotions from faces underlie neuropsychiatric disorders in which cerebellar pathology is reported. Here, we test the hypothesis that the cerebellum contributes to social cognition through EA from faces. We examined 57 patients with cerebellar disorders and 57 healthy controls. Thirty-one patients had complex cerebrocerebellar disease (complex cerebrocerebellar disease group (CD)); 26 had disease isolated to cerebellum (isolated cerebellar disease group (ID)). EA was measured with the Reading the Mind in the Eyes test (RMET), and informants were administered a novel questionnaire, the Cerebellar Neuropsychiatric Rating Scale (CNRS). EA was impaired in all patients (CD p < 0.001, ID p < 0.001). When analyzed for valence categories, both CD and ID missed more positive and negative stimuli. Positive targets produced the highest deficit (CD p < 0.001, ID p = 0.004). EA impairments correlated with CNRS measures of deficient social skills (p < 0.05) and autism spectrum behaviors (p < 0.005). Patients had difficulties with emotion regulation (CD p < 0.001, ID p < 0.001), autism spectrum behaviors (CD p < 0.049, ID p < 0.001), and psychosis spectrum symptoms (CD p < 0.021, ID p < 0.002). ID informants endorsed deficient social skills (CD p < 0.746, ID p < 0.003) and impaired attention regulation (CD p < 0.144, ID p < 0.001). Within the psychosis spectrum domain, CD patients were worse than controls for lack of empathy (CD p = 0.05; ID p = 0.49). Thus, patients with cerebellar damage were impaired on an EA task associated with deficient social skills and autism spectrum behaviors and experienced psychosocial difficulties on the CNRS. This has relevance for ataxias, the cerebellar cognitive affective/Schmahmann syndrome, and neuropsychiatric disorders with cerebellar pathology. C1 [Hoche, Franziska; Guell, Xavier; Schmahmann, Jeremy D.] Massachusetts Gen Hosp, Lab Neuroanat & Cerebellar Neurobiol, Cognit Behav Neurol Unit, Ataxia Unit,Dept Neurol, 175 Cambridge St, Boston, MA 02114 USA. [Hoche, Franziska; Guell, Xavier; Sherman, Janet C.; Vangel, Mark G.; Schmahmann, Jeremy D.] Harvard Med Sch, 175 Cambridge St, Boston, MA 02114 USA. [Sherman, Janet C.] Massachusetts Gen Hosp, Dept Psychiat, Psychol Assessment Ctr, Boston, MA 02114 USA. [Vangel, Mark G.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Hoche, F; Schmahmann, JD (reprint author), Massachusetts Gen Hosp, Lab Neuroanat & Cerebellar Neurobiol, Cognit Behav Neurol Unit, Ataxia Unit,Dept Neurol, 175 Cambridge St, Boston, MA 02114 USA.; Hoche, F; Schmahmann, JD (reprint author), Harvard Med Sch, 175 Cambridge St, Boston, MA 02114 USA. EM fhoche@mgh.harvard.edu; jschmahmann@mgh.harvard.edu FU National Ataxia Foundation; Cerebellar Research Consortium for the Spinocerebellar Ataxias [RC1 NS068897-02]; Birmingham Foundation; MINDlink Foundation FX This work was supported in part by the National Ataxia Foundation, the Cerebellar Research Consortium for the Spinocerebellar Ataxias (RC1 NS068897-02), and the Birmingham and MINDlink Foundations. NR 102 TC 1 Z9 1 U1 10 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1473-4222 EI 1473-4230 J9 CEREBELLUM JI Cerebellum PD DEC PY 2016 VL 15 IS 6 BP 732 EP 743 DI 10.1007/s12311-015-0746-9 PG 12 WC Neurosciences SC Neurosciences & Neurology GA EB7BC UT WOS:000387539000009 PM 26585120 ER PT J AU Beard, C Fuchs, C Asnaani, A Schulson, M Schofield, CA Clerkin, EM Weisberg, RB AF Beard, Courtney Fuchs, Cara Asnaani, Anu Schulson, Molly Schofield, Casey A. Clerkin, Elise M. Weisberg, Risa B. TI A Pilot Open Trial of Cognitive Bias Modification for Panic Disorder SO COGNITIVE THERAPY AND RESEARCH LA English DT Article DE Panic disorder; Cognitive bias modification; Attention; Interpretation ID SOCIAL ANXIETY DISORDER; ATTENTION BIAS; SEVERITY SCALE; EFFICACY; PHOBIA; INDIVIDUALS; RELIABILITY; HYPOTHESIS; STIMULI; THREAT AB Although cognitive biases are involved in the maintenance of panic disorder (PD), cognitive bias modification (CBM) has not been tested in PD. The current study developed and piloted a combined CBM-attention/CBM-interpretation PD treatment to determine initial acceptability and efficacy. Ten individuals diagnosed with PD (nine with Agoraphobia) were asked to complete 8, 20-min sessions of a CBM-A (Dot Probe task with fearful faces) and CBM-I (Word-Sentence Association Paradigm) intervention. Cognitive bias, panic symptom severity, and anxiety during interoceptive exercises were assessed at pre- and post-assessments. At post-treatment, participants showed increased benign interpretations, reduced threat interpretations of ambiguous panic situations, and reported significantly less severe panic symptoms with six individuals meeting criteria for remission. Anticipatory anxiety for interoceptive exercises decreased following treatment, but duration of exercises and anxiety following the exercises did not. Results suggest that further testing of the treatment and putative mechanisms of action is warranted. C1 [Beard, Courtney] Harvard Med Sch, McLean Hosp, 115 Mill St,Mailstop 113, Belmont, MA 02478 USA. [Beard, Courtney; Fuchs, Cara; Schulson, Molly; Weisberg, Risa B.] Brown Univ, Alpert Med Sch, Dept Psychiat, Providence, RI 02912 USA. [Fuchs, Cara] Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. [Asnaani, Anu] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Schofield, Casey A.] Skidmore Coll, Dept Psychol, Saratoga Springs, NY 12866 USA. [Clerkin, Elise M.] Miami Univ, Dept Psychol, Oxford, OH 45056 USA. [Weisberg, Risa B.] VA Boston Healthcare Syst, Boston, MA USA. [Weisberg, Risa B.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Beard, C (reprint author), Harvard Med Sch, McLean Hosp, 115 Mill St,Mailstop 113, Belmont, MA 02478 USA.; Beard, C (reprint author), Brown Univ, Alpert Med Sch, Dept Psychiat, Providence, RI 02912 USA. EM cbeard@mclean.harvard.edu FU Department of Psychiatry and Human Behavior of Alpert Medical School of Brown University FX This study was supported by funds from the Department of Psychiatry and Human Behavior of Alpert Medical School of Brown University. NR 34 TC 0 Z9 0 U1 9 U2 9 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0147-5916 EI 1573-2819 J9 COGNITIVE THER RES JI Cogn. Ther. Res. PD DEC PY 2016 VL 40 IS 6 BP 792 EP 798 DI 10.1007/s10608-016-9790-0 PG 7 WC Psychology, Clinical SC Psychology GA EB1DT UT WOS:000387088200006 ER PT J AU Basden, SL Orr, SP Otto, MW AF Basden, Shawnee L. Orr, Scott P. Otto, Michael W. TI Impaired De Novo Fear Conditioning in Opiate-Dependent Outpatients SO COGNITIVE THERAPY AND RESEARCH LA English DT Article DE Fear conditioning; Substance use; Opiate dependence; Neuropsychological functioning; Methadone ID POSTTRAUMATIC-STRESS-DISORDER; ANXIETY DISORDERS; COCAINE-USERS; ADDICTION; ABUSE; RAT; CONSEQUENCES; METAANALYSIS; INDIVIDUALS; COMORBIDITY AB Substance use disorders are characterized by excessive seeking and taking of drugs in the face of adverse consequences. Impaired learning of contingencies around negative outcomes may influence such drug-use patterns. To our knowledge, no studies to date have examined fear conditioning in drug-dependent humans, nor have they investigated the association between fear conditioning outcomes and neuropsychological functioning. The current study compared de novo fear conditioning in a sample of opiate-dependent outpatients to that in a healthy and an affective-disordered sample in an attempt to isolate the contribution of substance dependence on conditioning outcomes, relative to the substantial comorbidity present in substance using samples. Additionally, a brief neuropsychological battery was completed in the substance dependent sample. We found consistent evidence across three indices of fear acquisition-simple conditioning, differential conditioning, and contingency awareness-that the opiate-dependent learned the cue association less well than the control groups. Some of these deficits were significantly related to impairments in attention and memory. As such, substance use and/or associated neuropsychological impairments may make associative learning difficult, and may contribute to the persistence of maladaptive patterns and the failure to change behavior in response to aversive outcomes. C1 [Basden, Shawnee L.; Otto, Michael W.] Boston Univ, Dept Psychol & Brain Sci, 648 Beacon St,Floor 6, Boston, MA 02215 USA. [Orr, Scott P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Orr, Scott P.] Harvard Med Sch, Boston, MA USA. RP Otto, MW (reprint author), Boston Univ, Dept Psychol & Brain Sci, 648 Beacon St,Floor 6, Boston, MA 02215 USA. EM mwotto@bu.edu FU NIDA [DA017904]; NIMH [MH072165] FX Work on this project was supported in part by a NIDA minority supplement to the first author through DA017904. Work by the second and third authors was supported by NIMH MH072165 to the third author. NIDA and the NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the manuscript for publication. NR 28 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0147-5916 EI 1573-2819 J9 COGNITIVE THER RES JI Cogn. Ther. Res. PD DEC PY 2016 VL 40 IS 6 BP 824 EP 830 DI 10.1007/s10608-016-9786-9 PG 7 WC Psychology, Clinical SC Psychology GA EB1DT UT WOS:000387088200009 ER PT J AU Amalakuhan, B Habib, SA Mangat, M Reyes, LF Rodriguez, AH Hinojosa, CA Soni, NJ Gilley, RP Bustamante, CA Anzueto, A Levine, SM Peters, JI Aliberti, S Sibila, O Chalmers, JD Torres, A Waterer, GW Martin-Loeches, I Bordon, J Blanquer, J Sanz, F Marcos, PJ Rello, J Ramirez, J Sole-Violan, J Luna, CM Feldman, C Witzenrath, M Wunderink, RG Stolz, D Wiemken, TL Shindo, Y Dela Cruz, CS Orihuela, CJ Restrepo, MI AF Amalakuhan, Bravein Habib, Sheila A. Mangat, Mandeep Reyes, Luis F. Rodriguez, Alejandro H. Hinojosa, Cecilia A. Soni, Nilam J. Gilley, Ryan P. Bustamante, Carlos A. Anzueto, Antonio Levine, Stephanie M. Peters, Jay I. Aliberti, Stefano Sibila, Oriol Chalmers, James D. Torres, Antoni Waterer, Grant W. Martin-Loeches, Ignacio Bordon, Jose Blanquer, Jose Sanz, Francisco Marcos, Pedro J. Rello, Jordi Ramirez, Julio Sole-Violan, Jordi Luna, Carlos M. Feldman, Charles Witzenrath, Martin Wunderink, Richard G. Stolz, Daiana Wiemken, Tim L. Shindo, Yuichiro Dela Cruz, Charles S. Orihuela, Carlos J. Restrepo, Marcos I. TI Endothelial adhesion molecules and multiple organ failure in patients with severe sepsis SO CYTOKINE LA English DT Article DE Biomarkers; Sepsis; Shock; Mortality; Multiple organ failure; Intracellular Adhesion Molecule-1; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor ID SEPTIC SHOCK; GROWTH-FACTOR; POLYMICROBIAL SEPSIS; PATHOGENESIS; DYSFUNCTION; ACTIVATION; MORTALITY; ICAM-1; DEFINITIONS; BIOMARKERS AB Objective: To determine if serum levels of endothelial adhesion molecules were associated with the development of multiple organ failure (MOF) and in-hospital mortality in adult patients with severe sepsis. Design: This study was a secondary data analysis of a prospective cohort study. Setting: Patients were admitted to two tertiary intensive care units in San Antonio, TX, between 2007 and 2012. Patients: Patients with severe sepsis at the time of intensive care unit (ICU) admission were enrolled. Inclusion criteria were consistent with previously published criteria for severe sepsis or septic shock in adults. Exclusion criteria included immunosuppressive medications or conditions. Interventions: None. Measurements: Baseline serum levels of the following endothelial cell adhesion molecules were measured within the first 72 h of ICU admission: Intracellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule-1 (VCAM-1), and Vascular Endothelial Growth Factor (VEGF). The primary and secondary outcomes were development of MOF ( organ dysfunction) and in-hospital mortality, respectively. Main results: Forty-eight patients were enrolled in this study, of which 29 (60%) developed MOF. Patients that developed MOF had higher levels of VCAM-1 (p = 0.01) and ICAM-1 (p = 0.01), but not VEGF (p = 0.70) compared with patients without MOF (single organ failure only). The area under the curve (AUC) to predict MOF according to VCAM-1, ICAM-1 and VEGF was 0.71, 0.73, and 0.54, respectively. Only increased VCAM-1 levels were associated with in-hospital mortality (p = 0.03). These associations were maintained even after adjusting for APACHE and SOFA scores using logistic regression. Conclusions: High levels of serum ICAM-1 was associated with the development of MOF. High levels of VCAM-1 was associated with both MOF and in-hospital mortality. Published by Elsevier Ltd. C1 [Amalakuhan, Bravein; Habib, Sheila A.; Mangat, Mandeep; Reyes, Luis F.; Hinojosa, Cecilia A.; Soni, Nilam J.; Gilley, Ryan P.; Anzueto, Antonio; Levine, Stephanie M.; Peters, Jay I.; Orihuela, Carlos J.; Restrepo, Marcos I.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Reyes, Luis F.; Soni, Nilam J.; Anzueto, Antonio; Levine, Stephanie M.; Peters, Jay I.; Restrepo, Marcos I.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Bustamante, Carlos A.] Camino Dist Univ Adelita Char, Barranquilla, Colombia. [Aliberti, Stefano] Univ Milano Bicocca, Clin Pneumol, Monza, Italy. [Sibila, Oriol] Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Med, Serv Pneumol, Barcelona, Spain. [Rodriguez, Alejandro H.] Joan XXIII Univ Hosp, Crit Care Dept, Tarragona, Spain. [Rodriguez, Alejandro H.] CIBERES, Pere Virgili Hlth Inst, Tarragona, Spain. [Chalmers, James D.] Univ Dundee, Dundee, Scotland. [Anzueto, Antonio] Univ Barcelona, Hosp Clin, Serv Pneumol, Barcelona, Spain. [Waterer, Grant W.] Univ Western Australia, Royal Perth Hosp Unit, Sch Med & Pharmacol, Perth, WA, Australia. [Martin-Loeches, Ignacio] St James Hosp, Trinity Ctr Hlth Sci, CIBERES, Dublin, Ireland. [Bordon, Jose] Providence Hosp, Infect Dis Sect, Dept Med, Washington, DC USA. [Blanquer, Jose] Hosp Clin Univ, Unidad Cuidados Intens Resp, Valencia, Spain. [Sanz, Francisco] Consorci Hosp Gen Univ Valencia, Dept Pulmonol, Valencia, Spain. [Marcos, Pedro J.] Univ Coruna UDC, CHUAC, Inst Invest Biomed A Coruna INIBIC, Serv Neumol, La Coruna, Spain. [Rello, Jordi] Hosp Univ Vall dHebron, Crit Care Dept, CIBERES, Barcelona, Spain. [Ramirez, Julio; Wiemken, Tim L.] Univ Louisville, Div Infect Dis, Louisville, KY 40292 USA. [Sole-Violan, Jordi] Hosp Univ Dr Negrin, Intens Care Unit, CIBERES, Las Palmas Gran Canaria, Spain. [Luna, Carlos M.] Univ Buenos Aires, Div Pulmonol, Hosp Clin, Div Pulm Med,Dept Med, Buenos Aires, DF, Argentina. [Feldman, Charles] Charlotte Maxeke Johannesburg Acad Hosp, Dept Internal Med, Johannesburg, South Africa. [Feldman, Charles] Univ Witwatersrand, Fac Hlth Sci, Johannesburg, South Africa. [Witzenrath, Martin] Charite Univ Med Berlin, Dept Infect Dis & Pulm Med, Berlin, Germany. [Witzenrath, Martin] SFB TR84 Innate Immun Lung, Berlin, Germany. [Wunderink, Richard G.] Northwestern Univ, Dept Med, Div Pulm & Crit Care Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Stolz, Daiana] Univ Basel Hosp, Clin Pulm Med & Resp Cell Res, Basel, Switzerland. [Shindo, Yuichiro] Nagoya Univ, Grad Sch Med, Inst Adv Res, Nagoya, Aichi, Japan. [Shindo, Yuichiro] Nagoya Univ, Grad Sch Med, Dept Resp Med, Nagoya, Aichi, Japan. [Dela Cruz, Charles S.] Yale Univ, Sch Med, Sect Pulm Crit Care & Sleep Med, New Haven, CT USA. [Orihuela, Carlos J.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. RP Restrepo, MI (reprint author), South Texas Vet Hlth Care Syst ALMD, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM restrepom@uthscsa.edu OI Wunderink, Richard/0000-0002-8527-4195 FU National Heart, Lung, and Blood Institute [K23HL096054]; Carlos III Health Institute from Spain [M-BAE 15/00063] FX All authors have no conflicts of interest. Dr. Restrepo's time is partially protected by Award Number K23HL096054 from the National Heart, Lung, and Blood Institute. Dr. Rodriguez's time is protected by grant M-BAE 15/00063 from Carlos III Health Institute from Spain. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, And Blood Institute or the National Institutes of Health or the Department of Veterans Affairs. NR 25 TC 0 Z9 0 U1 6 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD DEC PY 2016 VL 88 BP 267 EP 273 DI 10.1016/j.cyto.2016.08.028 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA EA8CE UT WOS:000386862100034 PM 27701021 ER PT J AU Trentalange, M Bielawski, M Murphy, TE Lessard, K Brandt, C Bean-Mayberry, B Maisel, NC Wright, SM Allore, H Skanderson, M Reyes-Harvey, E Gaetano, V Haskell, S Bastian, LA AF Trentalange, Mark Bielawski, Mark Murphy, Terrence E. Lessard, Katarzyna Brandt, Cynthia Bean-Mayberry, Bevanne Maisel, Natalya C. Wright, Steven M. Allore, Heather Skanderson, Melissa Reyes-Harvey, Evelyn Gaetano, Vera Haskell, Sally Bastian, Lori A. TI Patient Perception of Enough Time Spent With Provider Is a Mechanism for Improving Women Veterans' Experiences With VA Outpatient Health Care SO EVALUATION & THE HEALTH PROFESSIONS LA English DT Article DE women; veterans; experiences with health care; primary care; nurse practitioners; structural equation model ID NURSE-PRACTITIONERS; DESIGNATION; MODELS AB We postulated that associations between two specific provider characteristics, class (nurse practitioner relative to physician) and primary care providers who are proficient and interested in women's health (designated women's provider relative to nondesignated) and overall satisfaction with provider, were mediated through women veterans' perception of enough time spent with the provider. A national patient experience survey was administered to 7,620 women veterans. Multivariable models of overall patient satisfaction with provider were compared with and without the proposed mediator. A structural equation model (SEM) of the mediation of the two provider characteristics was also evaluated. Without the mediator, associations of provider class and designation with overall patient satisfaction were significant. With the proposed mediator, these associations became nonsignificant. An SEM showed that the majority (>80%) of the positive associations between provider class and designation and the outcome were exerted through patient perception of enough time spent with provider. Higher ratings of overall satisfaction with provider exhibited by nurse practitioners and designated women's health providers were exerted through patient perception of enough time spent with provider. Future research should examine what elements of provider training can be developed to improve provider-patient communication and patient satisfaction with their health care. C1 [Trentalange, Mark; Murphy, Terrence E.; Allore, Heather] Yale Sch Med, Dept Internal Med, New Haven, CT USA. [Bielawski, Mark; Lessard, Katarzyna; Bastian, Lori A.] VA Connecticut Healthcare Syst, Newington, CT USA. [Brandt, Cynthia] VA Connecticut Healthcare Syst, West Haven, CT USA. [Bean-Mayberry, Bevanne] VA Greater Los Angeles Healthcare Syst, Vet Hlth Adm Hlth Serv Res & Dev, Ctr Study Healthcare Innovat Implementat & Policy, Sepulveda, CA USA. [Maisel, Natalya C.] VA Palo Alto Hlth Care Syst, Ctr Innovat Implementat, Menlo Pk, CA USA. [Wright, Steven M.] Dept Vet Affairs, VHA Off Analyt & Business Intelligence, Off Performance Measurement, Providence, RI USA. [Allore, Heather] Yale Sch Publ Hlth, Dept Biostat, New Haven, CT USA. [Skanderson, Melissa] Dept Vet Affairs, Pittsburgh, PA USA. [Reyes-Harvey, Evelyn] VHA Off Analyt & Business Intelligence, Off Performance Measurement, Durham, NC USA. [Gaetano, Vera] VA Connecticut HSR&D Pain Res Informat Multimorbi, West Haven, CT USA. [Haskell, Sally] Yale Sch Med, VA Connecticut Healthcare Syst, VA Cent Off, Womens Hlth Serv,Patient Care Serv, West Haven, CT USA. RP Trentalange, M (reprint author), Yale Sch Med, Dept Internal Med, Yale Program Aging, 300 George St Suite 775, New Haven, CT 06511 USA. EM mark.trentalange@yale.edu FU Yale University Claude D. Pepper Older Americans Independence Center grant [P30AG21342] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The research was funded in part by a Yale University Claude D. Pepper Older Americans Independence Center grant (P30AG21342). NR 30 TC 1 Z9 1 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0163-2787 EI 1552-3918 J9 EVAL HEALTH PROF JI Eval. Health Prof. PD DEC PY 2016 VL 39 IS 4 BP 460 EP 474 DI 10.1177/0163278716629523 PG 15 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA EB6KD UT WOS:000387490900004 PM 26908572 ER PT J AU Bromberger, JT Kravitz, HM Youk, A Schott, LL Joffe, H AF Bromberger, Joyce T. Kravitz, Howard M. Youk, Ada Schott, Laura L. Joffe, Hadine TI Patterns of depressive disorders across 13 years and their determinants among midlife women: SWAN mental health study SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Longitudinal; Depressive disorders; Midlife women; Risk factors ID STRUCTURED CLINICAL INTERVIEW; NATIONAL EPIDEMIOLOGIC SURVEY; QUALITY-OF-LIFE; MAJOR DEPRESSION; GENERAL-POPULATION; PHYSICAL-ACTIVITY; COMMUNITY SAMPLE; SURVEY SF-36; CHILD-ABUSE; RELIABILITY AB Background: Little is known about the course of depression in midlife women. This study aims to identify factors that distinguish risk factors for persistent or recurrent depression from those of a milder course across 13-years of follow-up. Methods: 297 Black and White premenopausal women aged 42-52 were enrolled at the Study of Women's Health Across the Nation Pittsburgh site. Psychiatric interviews obtained information on lifetime psychiatric diagnoses at baseline and occurrences of depression annually. We identified four depression patterns: 91(31%) had Persistent/recurrent major depressive disorder (MDD), 27(9%) Single Episode MDD, 35 (12%) Minor Depression (minD) only, 144(48%) No Depression. We compared baseline risk factors for the Persistent/recurrent MDD group with each of the other three. Results: A lifetime history of major or minor depression (p-values =.001-.08) and 2+ very upsetting life events in the previous year (p-values=.003-.04) were more likely to be reported by women in the Persistent/recurrent group than in the other three. The Persistent/recurrent group was more likely to report a family history of depression (p=.03) than the MinD group, and to report current sleep problems (p=.002) at baseline than the Single Episode MDD group. Limitations: Small numbers of women with minD or a Single Episode MDD. Childhood maltreatment and family depression history were retrospectively reported. Conclusions: A Persistent/recurrent depression course is common during midlife. In addition to personal and family histories of depression, providers of midlife health care should recognize that current sleep problems and recent very upsetting events are strong risk factors for a pernicious depression course. (C) 2016 Elsevier B.V. All rights reserved. C1 [Bromberger, Joyce T.; Youk, Ada; Schott, Laura L.] Univ Pittsburgh, Dept Epidemiol, 3811 OHara St, Pittsburgh, PA 15261 USA. [Bromberger, Joyce T.] Univ Pittsburgh, Dept Psychiat, 3811 OHara St, Pittsburgh, PA 15260 USA. [Kravitz, Howard M.] Rush Univ, Med Ctr, Dept Psychiat, Chicago, IL 60612 USA. [Kravitz, Howard M.] Rush Univ, Med Ctr, Dept Prevent Med, Chicago, IL 60612 USA. [Joffe, Hadine] Harvard Med Sch, Brigham & Womens Hosp, Dept Psychiat, Boston, MA USA. [Joffe, Hadine] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. RP Bromberger, JT (reprint author), Univ Pittsburgh, Dept Epidemiol, 3811 OHara St, Pittsburgh, PA 15261 USA.; Bromberger, JT (reprint author), Univ Pittsburgh, Dept Psychiat, 3811 OHara St, Pittsburgh, PA 15260 USA. EM brombergerjt@upmc.edu FU National Institutes of Health (NIH); Department of Health and Human Services (HHS), through the National Institute on Aging (NIA); National Institute of Nursing Research (NINR); NIH Office of Research on Women's Health (ORWH) [U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495]; National Institute of Mental Health [R01MH59689]; Merck Company FX The Study of Women's Health Across the Nation (SWAN) was supported by the National Institutes of Health (NIH), Department of Health and Human Services (HHS), through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women's Health (ORWH) (Grants U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, and U01AG012495). The SWAN Mental Health Study has grant support from the National Institute of Mental Health (R01MH59689). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NIMH, ORWH or the NIH.; (HJ) This work was supported by Merck & Company. NR 48 TC 1 Z9 1 U1 7 U2 7 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 DEC PY 2016 VL 206 BP 31 EP 40 DI 10.1016/j.jad.2016.07.005 PG 10 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EB2LK UT WOS:000387193500006 PM 27455356 ER PT J AU Richards, C McIntyre, RS Weisler, R Sambunaris, A Brawman-Mintzer, O Gao, J Geibel, B Dauphin, M Madhoo, M AF Richards, Cynthia McIntyre, Roger S. Weisler, Richard Sambunaris, Angelo Brawman-Mintzer, Olga Gao, Joseph Geibel, Brooke Dauphin, Matthew Madhoo, Manisha TI Lisdexamfetamine dimesylate augmentation for adults with major depressive disorder and inadequate response to antidepressant monotherapy: Results from 2 phase 3, multicenter, randomized, double-blind, placebo-controlled studies SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Augmentation; Lisdexamfetamine dimesylate; Major depressive disorder; Selective serotonin reuptake inhibitors; Serotonin-norepinephrine reuptake inhibitors; Amphetamine ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; STAR-ASTERISK-D; CONTROLLED-TRIAL; PSYCHOMETRIC EVALUATION; EFFICACY; METHYLPHENIDATE; SAFETY; OUTPATIENTS; SLEEPINESS; MODAFINIL AB Background: The efficacy, safety, and tolerability of lisdexamfetamine dimesylate (LDX) augmentation of antidepressant monotherapy in adults with major depressive disorder (MDD) from two phase 3 studies are reported. Methods: Across study 1 (placebo, n=201; LDX, n=201) and study 2 (placebo, n=213; LDX, n=211), most participants (placebo and LDX) in the safety analysis set were female (study 1: 66.2% and 64.2%; study 2: 67.1% and 66.8%); mean +/- SD ages were 41.8 +/- 12.04 with placebo and 42.2 +/- 12.32 with LDX in study 1 and 42.6 +/- 11.41 with placebo and 42.0 +/- 11.63 with LDX in study 2. Participants (18-65 y) had DSM-IV-TR-diagnosed MDD and lead-in baseline Montgomery-Asberg Depression Rating Scale (MADRS) total scores >= 24. Eight-week antidepressant lead-in phases prospectively assessed antidepressant response. Then, 8 weeks of randomized (1:1), double-blind treatment with dose-optimized LDX (20-70 mg) or placebo in participants exhibiting inadequate antidepressant monotherapy responses (augmentation baseline MADRS total scores >= 18 and < 50% MADRS total score reductions from lead-in baseline to augmentation baseline) was initiated. The primary endpoint was MADRS total score change from augmentation baseline to week 16. Safety and tolerability measures included the occurrence of treatment-emergent adverse events (TEAE5). Results: Least squares mean (95% CI) treatment differences (LDX-placebo) for MADRS total score changes from augmentation baseline to week 16 were not statistically significant in study 1 (0.1 [-1.7, 2.0], P=0.883) or study 2 (-0.5 [-23, 1.3], P=0.583). The only TEAE reported by > 5% of LDX participants at twice the placebo rate in both studies was dry mouth. Limitations: Limitations include the exclusion of participants with psychiatric comorbidities/active medical disorders, the inability to assess specific MDD symptom domains (eg, anhedonia, cognition) or subtypes, the use of telephone-based depression assessments, and the potential influence of placebo response. Conclusion: Contrary to expectations, LDX augmentation was not superior to placebo in reducing C1 [Richards, Cynthia; Gao, Joseph; Geibel, Brooke; Dauphin, Matthew; Madhoo, Manisha] Shire, 300 Shire Way, Lexington, MA 02421 USA. [McIntyre, Roger S.] Univ Toronto, Toronto, ON, Canada. [Weisler, Richard] Duke Univ, Med Ctr, Durham, NC USA. [Weisler, Richard] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Sambunaris, Angelo] Atlanta Inst Med & Res, Atlanta, GA USA. [Brawman-Mintzer, Olga] Med Univ South Carolina, Charleston, SC USA. [Brawman-Mintzer, Olga] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Madhoo, M (reprint author), Shire, 300 Shire Way, Lexington, MA 02421 USA. EM mmadhoo@shire.com NR 32 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD DEC PY 2016 VL 206 BP 151 EP 160 DI 10.1016/j.jad.2016.07.006 PG 10 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EB2LK UT WOS:000387193500020 PM 27474961 ER PT J AU Aydin, B Yurt, A Gokmen, N Renshaw, P Olson, D Yildiz, A AF Aydin, Burc Yurt, Aysegul Gokmen, Necati Renshaw, Perry Olson, David Yildiz, Aysegul TI Trait-related alterations of N-acetylaspartate in euthymic bipolar patients: A longitudinal proton magnetic resonance spectroscopy study SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE N-acetylaspartate; Magnetic resonance spectroscopy; Mania; Euthymia; Dorsomedial prefrontal cortex ID DORSOLATERAL PREFRONTAL CORTEX; ACETYL-ASPARTATE; MITOCHONDRIAL DYSFUNCTION; DISORDER; MANIA; SCALE; SCHIZOPHRENIA; METAANALYSIS; ILLNESS; BRAIN AB Background: Neurochemical changes are responsible for bipolar disorder (BD) pathophysiology. Despite current progress in BD research, mood- and trait-related alterations in BD continue to elicit further investigation. Methods: In this study, we report a longitudinal proton magnetic resonance spectroscopy study evaluating dorsomedial prefrontal cortex (DMPFC) metabolites N-acetylaspartate (NAA), creatine plus phosphocreatine (total creatine [tCr]), phosphorylcholine plus glycerophosphocholine, myo-inositol, and glutamate plus glutamine levels of manic and euthymic adult BD type I patients (n=48) treated with standard antimanic medicines, compared to matching healthy controls (n=44). Results: DMPFC NAA values and NAA/tCr ratio were significantly lower in euthymic BD patients when compared with healthy controls with similar levels of other metabolites in all groups, indicating a trait related NAA abnormality in euthymic BD patients. Limitations: of our study include a relatively low (1.5 T) magnetic resonance field strength and variable drugs administered to achieve euthymia despite the best efforts to standardize the open fashion treatment. Conclusions: Our study contributes to the integrating models of trait-related metabolite alterations observed in euthymia since NAA is considered as a marker of neuronal viability and mitochondria] energy metabolism. In light of supporting and conflicting results reported previously, future studies with longitudinal designs and larger patient groups are warranted to better define both state- and trait-related cerebral metabolic alterations associated with BD pathophysiology. (C) 2016 Elsevier B.V. All rights reserved. C1 [Aydin, Burc] Dokuz Eylul Univ, Sch Med, Dept Med Pharmacol, TR-35340 Izmir, Turkey. [Yurt, Aysegul] Dokuz Eylul Univ, Hlth Sci Inst, Dept Med Phys, Izmir, Turkey. [Gokmen, Necati] Dokuz Eylul Univ, Sch Med, Dept Anesthesiol & Reanimat, Izmir, Turkey. [Renshaw, Perry] Univ Utah, Inst Brain, Salt Lake City, UT USA. [Renshaw, Perry] Univ Utah, Dept Psychiat, Salt Lake City, UT USA. [Olson, David] Harvard Med Sch, McLean Hosp, Brain Imaging Ctr, Belmont, MA USA. [Yildiz, Aysegul] Dokuz Eylul Univ, Sch Med, Dept Psychiat, Izmir, Turkey. [Yildiz, Aysegul] Massachusetts Gen Hosp, Int Consortium Bipolar Disorder Res, Boston, MA 02114 USA. [Yildiz, Aysegul] Massachusetts Gen Hosp, Psychopharmacol Program, McLean Div, Boston, MA 02114 USA. RP Aydin, B (reprint author), Dokuz Eylul Univ, Sch Med, Dept Med Pharmacol, TR-35340 Izmir, Turkey. EM burcaydin@gmail.com FU Stanley Medical Research Institute Grant [02T-162]; American Psychiatric Association/Astra Zeneca Young Minds in Psychiatry Award; Harvard Medical School Stanley Foundation Bipolar Disorders Research Center, Belmont, Massachusetts; International Sleep Research Foundation, Houston, Texas; National Institute of Mental Health Grant [MH58681] FX This study was supported by the Stanley Medical Research Institute Grant No. 02T-162 (to A. Yildiz), American Psychiatric Association/Astra Zeneca Young Minds in Psychiatry Award (to A. Yildiz), Harvard Medical School Stanley Foundation Bipolar Disorders Research Center, Belmont, Massachusetts (to A. Yildiz), International Sleep Research Foundation, Houston, Texas (to A. Yildiz), and National Institute of Mental Health Grant No. MH58681 (to P.R.). Funding sources had no role in study design, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication. NR 30 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD DEC PY 2016 VL 206 BP 315 EP 320 DI 10.1016/j.jad.2016.09.002 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EB2LK UT WOS:000387193500043 PM 27662572 ER PT J AU Antshel, KM Biederman, J Spencer, TJ Faraone, SV AF Antshel, Kevin M. Biederman, Joseph Spencer, Thomas J. Faraone, Stephen V. TI The Neuropsychological Profile of Comorbid Post-Traumatic Stress Disorder in Adult ADHD SO JOURNAL OF ATTENTION DISORDERS LA English DT Article DE attention deficit disorder (ADD); ADHD; post-traumatic stress disorder (PTSD); neuropsychology ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; QUALITY-OF-LIFE; DEFICIT HYPERACTIVITY DISORDER; SHORT-TERM-MEMORY; SUBTHRESHOLD DIAGNOSES; LATE-ONSET; VIETNAM VETERANS; COMBAT VETERANS; DYSFUNCTION; DEPRESSION AB Objective: ADHD and post-traumatic stress disorder (PTSD) are often comorbid yet despite the increased comorbidity between the two disorders, to our knowledge, no data have been published regarding the neuropsychological profile of adults with comorbid ADHD and PTSD. Likewise, previous empirical studies of the neuropsychology of PTSD did not control for ADHD status. We sought to fill this gap in the literature and to assess the extent to which neuropsychological test performance predicted psychosocial functioning, and perceived quality of life. Method: Participants were 201 adults with ADHD attending an outpatient mental health clinic between 1998 and 2003 and 123 controls without ADHD. Participants completed a large battery of self-report measures and psychological tests. Diagnoses were made using data obtained from structured psychiatric interviews (i.e., Structured Clinical Interview for DSM-IV, Schedule for Affective Disorders and Schizophrenia for School-Age Children Epidemiologic Version). Results: Differences emerged between control participants and participants with ADHD on multiple neuropsychological tests. Across all tests, control participants outperformed participants with ADHD. Differences between the two ADHD groups emerged on seven psychological subtests including multiple Wechsler Adult Intelligence ScaleThird edition and Rey-Osterrieth Complex Figure Test measures. These test differences did not account for self-reported quality of life differences between groups. Conclusion: The comorbidity with PTSD in adults with ADHD is associated with weaker cognitive performance on several tasks that appear related to spatial/perceptual abilities and fluency. Neuropsychological test performances may share variance with the quality of life variables yet are not mediators of the quality of life ratings. C1 [Antshel, Kevin M.] Syracuse Univ, Psychol, Syracuse, NY USA. [Antshel, Kevin M.] Syracuse Univ, Clin Psychol Program, Syracuse, NY USA. [Biederman, Joseph] Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. [Biederman, Joseph] Massachusetts Gen Hosp, Clin & Res Program Adult ADHD, Boston, MA 02114 USA. [Biederman, Joseph] Massachusetts Gen Hosp, Alan & Lorraine Bressler Clin & Res Program Autis, Boston, MA 02114 USA. [Biederman, Joseph] Harvard Med Sch, Psychiat, Boston, MA USA. [Spencer, Thomas J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Spencer, Thomas J.] Harvard Med Sch, Boston, MA USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA. RP Faraone, SV (reprint author), SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, 750 East Adams St, Syracuse, NY 13210 USA. EM sfaraone@childpsychresearch.org FU National Institute of Health [R01MH57934] FX The author(s) declared receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a grant to S.V. Faraone from the National Institute of Health (R01MH57934). NR 48 TC 3 Z9 3 U1 10 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0547 EI 1557-1246 J9 J ATTEN DISORD JI J. Atten. Disord. PD DEC PY 2016 VL 20 IS 12 BP 1047 EP 1055 DI 10.1177/1087054714522512 PG 9 WC Psychology, Developmental; Psychiatry SC Psychology; Psychiatry GA EB6CD UT WOS:000387467500007 PM 24567364 ER PT J AU Poghosyan, H Darwish, SA Kim, SS Cooley, ME AF Poghosyan, Hermine Darwish, Sabreen A. Kim, Sun S. Cooley, Mary E. TI The association between social support and smoking status in cancer survivors with frequent and infrequent mental distress: results from 10 US states, 2010 SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Smoking; Social support; Mental distress; Cancer survivors ID QUALITY-OF-LIFE; FACTOR SURVEILLANCE SYSTEM; EMOTIONAL SUPPORT; HEALTH BEHAVIORS; QUIT SMOKING; CESSATION; ILLNESS; METAANALYSIS; PREDICTORS; PATTERNS AB This study examined the association between social support and smoking status among adult cancer survivors, with special emphasis on mental health differences using data from 10 US states. Cross-sectional data from the 2010 Behavioral Risk Factor Surveillance System, Cancer Survivorship module on 8055 cancer survivors were analyzed. Sample weights were applied for the generalization of results to 2.6 million cancer survivors. In 2010, 15.6 % (418,700) were current, 38.4 % (1.03 million) former, and 46.0 % (1.2 million) never smokers. About 18.0 % of cancer survivors reported receiving the lowest level of social support and 12.1 % reported experiencing frequent mental distress in the past 30 days. Participants' mean age at the time of the first cancer diagnosis was 51.0 (standard error (SE) = 0.33) and mean time since their diagnosis was 11.3 years (SE = 0.18). Compared to those with infrequent mental distress, cancer survivors with frequent mental distress were diagnosed at a younger age (45.0 vs. 51.8), more likely to be current smokers (36.8 vs. 12.7 %), and less likely to always receive social support they needed (33.4 vs. 56.3 %). Cancer survivors who received higher levels of social support were less likely to be current smokers than those who received the lowest level of social support they needed. Among cancer survivors who reported frequent mental distress, non-Hispanic blacks were more likely to be current smokers than non-Hispanic whites. Rates of current smokers were lower among cancer survivors who received social support and reported infrequent mental distress. Psychosocial screening may help health care professional identify smokers with frequent mental distress who require more intensive smoking cessation interventions. C1 [Poghosyan, Hermine] Northeastern Univ, Sch Nursing, Boston, MA 02115 USA. [Poghosyan, Hermine] Northeastern Univ, Bouve Coll Hlth Sci, Boston, MA 02115 USA. [Darwish, Sabreen A.; Kim, Sun S.] Univ Massachusetts, Coll Nursing & Hlth Sci, 100 Morrissey Blvd, Boston, MA 02125 USA. [Cooley, Mary E.] Dana Farber Canc Inst, Phyllis F Cantor Ctr Res Nursing & Patient Care S, Boston, MA 02115 USA. RP Poghosyan, H (reprint author), Northeastern Univ, Sch Nursing, Boston, MA 02115 USA.; Poghosyan, H (reprint author), Northeastern Univ, Bouve Coll Hlth Sci, Boston, MA 02115 USA. EM h.poghosyan@neu.edu NR 50 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD DEC PY 2016 VL 10 IS 6 BP 1078 EP 1088 DI 10.1007/s11764-016-0551-6 PG 11 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA EB4JO UT WOS:000387337700012 PM 27236586 ER PT J AU Berkowitz, SA Fabreau, GE Raghavan, S Kentoffio, K Chang, Y He, W Atlas, SJ Percac-Lima, S AF Berkowitz, Seth A. Fabreau, Gabriel E. Raghavan, Sridharan Kentoffio, Katherine Chang, Yuchiao He, Wei Atlas, Steven J. Percac-Lima, Sanja TI Risk of Developing Diabetes Among Refugees and Immigrants: A Longitudinal Analysis SO JOURNAL OF COMMUNITY HEALTH LA English DT Article DE Immigration; Refugees; Diabetes incidence; Diabetes prevention ID LIFE-STYLE INTERVENTION; COUNTRY-OF-ORIGIN; UNITED-STATES; PRIMARY-CARE; NATIONAL-HEALTH; CHRONIC DISEASE; ATHEROSCLEROSIS; POPULATION; PREVALENCE; PREVENTION AB To determine the difference in risk of developing diabetes for refugees, immigrants, and American-born participants living in the same communities, and to explore potential mediators of that difference. Retrospective longitudinal cohort from January 1, 2003 and December 31, 2013. Refugees aged aeyen18 years were matched in a 1:3 ratio by age, gender, and date of care initiation to (1) Spanish-speaking non-refugee immigrants, and (2) English-speaking controls receiving care in the same community health center. We used proportional hazards regression to estimate the risk of incident diabetes. We tested whether differences in education or baseline obesity mediated diabetes risk using counterfactual mediation analysis. We included 3174 participants. Among refugee participants, the most common countries of origin were Somalia (17.8 %), Iraq (16.7 %) and Bhutan (8.8 %). Diabetes incidence rate was 1.94, 1.91, and 1.22 cases per 100 person-years follow-up for refugees, immigrants, and controls, respectively. In adjusted models, both refugee (HR 2.08 95 % CI 1.32-3.30) and immigrant (HR 1.51 95 % CI 1.01-2.24) statuses were associated with increased diabetes risk compared with controls. Risk between refugees and immigrants did not differ (adjusted HR for refugees 1.37 95 % CI 0.91-2.06). In mediation analyses, educational attainment mediated 36 % (p = 0.007) of the difference in diabetes risk between refugees/immigrants and controls. Baseline obesity did not mediate difference in diabetes risk (proportion mediated 1 %, p = 0.84). Refugees and immigrants had significantly increased risk for diabetes, partially mediated by education. Education-based lifestyle interventions may be a promising strategy to prevent diabetes for these vulnerable patients. C1 [Berkowitz, Seth A.; Raghavan, Sridharan; Chang, Yuchiao; He, Wei; Atlas, Steven J.; Percac-Lima, Sanja] Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. [Berkowitz, Seth A.] Massachusetts Gen Hosp, Diabet Populat Hlth Unit, Boston, MA USA. [Berkowitz, Seth A.; Raghavan, Sridharan; Kentoffio, Katherine; Chang, Yuchiao; Atlas, Steven J.; Percac-Lima, Sanja] Harvard Med Sch, Boston, MA USA. [Fabreau, Gabriel E.] Univ Calgary, Cumming Sch Med, Fac Med & Community Hlth Sci, Div Gen Internal Med, Calgary, AB, Canada. RP Berkowitz, SA (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM SABerkowitz@partners.org OI Berkowitz, Seth/0000-0003-1030-4297 FU SA Berkowitz FX SA Berkowitz was supported the Division of General Internal Medicine and Diabetes Population Health Unit at Massachusetts General Hospital. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of data; or preparation, review, or approval of the manuscript, or decisions to submit for publication. A prior version of this work was presented at the Society for General Internal Medicine Regional (27 March 2015) and National (22 April 2015) research meetings. NR 39 TC 1 Z9 1 U1 11 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0094-5145 EI 1573-3610 J9 J COMMUN HEALTH JI J. Community Health PD DEC PY 2016 VL 41 IS 6 BP 1274 EP 1281 DI 10.1007/s10900-016-0216-4 PG 8 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EB2WU UT WOS:000387224100023 PM 27363825 ER PT J AU Hayden, RP Bennett, NE Tanrikut, C AF Hayden, Russell P. Bennett, Nelson E. Tanrikut, Cigdem TI Hematocrit Response and Risk Factors for Significant Hematocrit Elevation with Implantable Testosterone Pellets SO JOURNAL OF UROLOGY LA English DT Article DE hypogonadism; testosterone; polycythemia; hematocrit ID HYPOGONADAL MEN; OLDER MEN; THERAPY; SAFETY; REPLACEMENT; POLYCYTHEMIA; EFFICACY AB Purpose: We studied the incidence and risk factors for the development of erythrocytosis with implantable testosterone pellets. Materials and Methods: A multi-institutional retrospective database analysis was used to evaluate men treated with testosterone pellets between 2009 and 2014. Inclusion criteria consisted of adult, hypogonadal males who had a full complement of pretreatment and posttreatment surveillance studies. Pretreatment and posttreatment values were compared with Wilcoxon signed rank tests. Multiple linear regression was used to identify potential risk factors for significant hematocrit elevation. Results: A total of 97 patients were included in the study. The average age of the cohort was 52 years (range 24 to 80). Mean hematocrit before and after pellet implantation was 43.9% and 46.1%, respectively, corresponding to an increase of 2.2% (CI 1.4-2.9, p <0.001). The average increase in testosterone was 145.3 ng/dl from an initial mean of 278.9 ng/dl (CI 105.7-184.9, p <0.001). Multiple linear regression demonstrated that pretreatment hematocrit was inversely related to the expected change in hematocrit. Pretreatment comorbidity status (ie the presence of hypertension, hyperlipidemia, obesity or diabetes) was not associated with a significant increase in posttreatment hematocrit. Conclusions: Although the data demonstrate a statistically significant increase in hematocrit, an increment of 2.2% is unlikely to translate into clinical relevance. Thus, for this cohort of patients implantable testosterone pellets appear safe in terms of the risk of polycythemia. Pretreatment hematocrit may serve as a predictor of a significant hematocrit increase after the initiation of therapy. C1 [Hayden, Russell P.; Tanrikut, Cigdem] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Bennett, Nelson E.] Northwestern Univ, Feinberg Sch Med, Dept Urol, Chicago, IL 60611 USA. RP Tanrikut, C (reprint author), MGH Fertil Ctr, 55 Fruit St,YAW 10A, Boston, MA 02114 USA. EM ctanrikut@mgh.harvard.edu NR 23 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 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD DEC PY 2016 VL 196 IS 6 BP 1715 EP 1720 DI 10.1016/j.juro.2016.05.110 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA EB5QS UT WOS:000387436000052 PM 27287525 ER PT J AU Appelboom, G Detappe, A LoPresti, M Kunjachan, S Mitrasinovic, S Goldman, S Chang, SD Tillement, O AF Appelboom, Geoff Detappe, Alexandre LoPresti, Melissa Kunjachan, Sijumon Mitrasinovic, Stefan Goldman, Serge Chang, Steve D. Tillement, Olivier TI Stereotactic modulation of blood-brain barrier permeability to enhance drug delivery SO NEURO-ONCOLOGY LA English DT Article DE electroporation; focused ultrasound; microbubbles; photodynamic therapy; vascular permeability ID GUIDED FOCUSED ULTRASOUND; IN-VIVO; CAVITATION THRESHOLD; RADIATION-THERAPY; DISRUPTION; TUMORS; GLIOBLASTOMA; HYPERTHERMIA; TRANSPORT; CANCER AB Drug delivery in the CNS is limited by endothelial tight junctions forming the impermeable blood-brain barrier. The development of new treatment paradigms has previously been hampered by the restrictiveness of the blood-brain barrier to systemically administered therapeutics. With recent advances in stereotactic localization and noninvasive imaging, we have honed the ability to modulate, ablate, and rewire millimetric brain structures to precisely permeate the impregnable barrier. The wide range of focused radiations offers endless possibilities to disrupt endothelial permeability with different patterns and intensity following 3-dimensional coordinates offering a new world of possibilities to access the CNS, as well as to target therapies. We propose a review of the current state of knowledge in targeted drug delivery using noninvasive image-guided approaches. To this end, we focus on strategies currently used in clinics or in clinical trials such as targeted radiotherapy and magnetic resonance guided focused ultrasound, but also on more experimental approaches such as magnetically heated nanoparticles, electric fields, and lasers, techniques which demonstrated remarkable results both in vitro and in vivo. We envision that biodistribution and efficacy of systemically administered drugs will be enhanced with further developments of these promising strategies. Besides therapeutic applications, stereotactic platforms can be highly valuable in clinical applications for interventional strategies that can improve the targetability and efficacy of drugs and macromolecules. It is our hope that by showcasing and reviewing the current state of this field, we can lay the groundwork to guide future research in this realm. C1 [Appelboom, Geoff; Chang, Steve D.] Stanford Med Ctr, Dept Neurosurg, Stanford, CA 94305 USA. [Detappe, Alexandre; Kunjachan, Sijumon] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA USA. [Detappe, Alexandre; Tillement, Olivier] Univ Claude Bernard Lyon 1, Inst Lumiere Matiere, Villeurbanne, France. [LoPresti, Melissa] Baylor Coll Med, Dept Neurosurg, Houston, TX 77030 USA. [Mitrasinovic, Stefan] Columbia Univ, Med Ctr, Dept Neurol Surg, New York, NY USA. [Goldman, Serge] Univ Libre Bruxelles, Hop Erasme, Dept Nucl Med, Brussels, Belgium. RP Appelboom, G (reprint author), Stanford Med Ctr, Dept Neurosurg, Stanford, CA 94305 USA. EM ga@neuro-digital.com OI Mitrasinovic, Stefan/0000-0001-9681-8808; Detappe, Alexandre/0000-0001-9364-1621 NR 70 TC 2 Z9 2 U1 12 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD DEC PY 2016 VL 18 IS 12 BP 1601 EP 1609 DI 10.1093/neuonc/now137 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA EB4HL UT WOS:000387331500004 PM 27407134 ER PT J AU Wefel, JS Noll, KR Rao, G Cahill, DP AF Wefel, Jeffrey S. Noll, Kyle R. Rao, Ganesh Cahill, Daniel P. TI Neurocognitive function varies by IDH1 genetic mutation status in patients with malignant glioma prior to surgical resection SO NEURO-ONCOLOGY LA English DT Article DE brain tumor; cognition; glioma; genetic marker; neuropsychology ID ISOCITRATE DEHYDROGENASE 1; CELLULAR-METABOLISM; DIFFUSE GLIOMAS; BRAIN-TUMORS; GLIOBLASTOMA; CLASSIFICATION; ASTROCYTOMAS; PROGRESSION; SURVIVAL; CANCER AB Background. Patients with malignant gliomas present with variation in neurocognitive function (NCF) not attributable to lesion size or location alone. A potential contributor is the rate at which tumors grow, or "lesion momentum." Isocitrate dehydrogenase 1 wild type (IDH1-WT) are more proliferative and aggressive than IDH1-mutant (IDH1-M) tumors. We hypothesized that patients with IDH1-WT would exhibit worse NCF than patients with IDH1-M tumors. Methods. Comprehensive NCF testing was completed in 119 patients with malignant glioma prior to surgical resection. IDH1 status was determined with immunohistochemistry and sequencing. Rates of impairment and mean test performances were compared by IDH1. Results. NCF impairment was significantly more frequent in patients with IDH1-WT tumors in memory, processing speed, visuoconstruction, language, executive functioning, and manual dexterity. Mean performances of patients with IDH1-WT were also significantly lower than those with IDH1-M tumors on measures of learning and memory, processing speed, language, executive functioning, and dexterity. Lesion volume was not statistically different between IDH1-WT and IDH1-M tumors. Tumor and lesion volume on T1-weighted and fluid attenuated inversion recovery MRI were significantly associated with most NCF tests in patients with IDH1-WT, but only significantly associated with a single measure in patients with IDH1-M tumors. Conclusion. Patients with IDH1-WT show reduced NCF compared with those with IDH1-M malignant gliomas. Lesion volume is inversely associated with NCF for patients with IDH1-WT, but not IDH1-M tumors. These findings are consistent with the hypothesis that patients with IDH1-WT tumors present with more severe NCF impairment due to greater lesion momentum, which may impede compensatory neuroplasticity and cerebral reorganization. C1 [Wefel, Jeffrey S.; Noll, Kyle R.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, 1515 Holcombe Blvd,Unit 431, Houston, TX 77030 USA. [Rao, Ganesh] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, 1515 Holcombe Blvd,Unit 431, Houston, TX 77030 USA. [Cahill, Daniel P.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA USA. RP Wefel, JS (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, 1515 Holcombe Blvd,Unit 431, Houston, TX 77030 USA. EM wefel@mdanderson.org FU National Institutes of Health through the National Institute of Nursing Research [R01NR014195]; National Institutes of Neurological Disorders and Stroke [K08NS070928]; National Cancer Institute SPORE award [P50CA165962]; Burroughs Wellcome Fund Career Award; National Institutes of Health or Burroughs Wellcome Fund FX Research reported in this publication was supported by the National Institutes of Health through the National Institute of Nursing Research award number R01NR014195 (J.S.W.), National Institutes of Neurological Disorders and Stroke award number K08NS070928 (G.R.), and National Cancer Institute SPORE award number P50CA165962 (D.P.C.). Additional support was received from the Burroughs Wellcome Fund Career Award (D.P.C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or Burroughs Wellcome Fund. NR 34 TC 1 Z9 1 U1 5 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD DEC PY 2016 VL 18 IS 12 BP 1656 EP 1663 DI 10.1093/neuonc/now165 PG 8 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA EB4HL UT WOS:000387331500009 PM 27576872 ER PT J AU Chang, K Zhang, BQ Guo, XT Zong, M Rahman, R Sanchez, D Winder, N Reardon, DA Zhao, BS Wen, PY Huang, RY AF Chang, Ken Zhang, Biqi Guo, Xiaotao Zong, Min Rahman, Rifaquat Sanchez, David Winder, Nicolette Reardon, David A. Zhao, Binsheng Wen, Patrick Y. Huang, Raymond Y. TI Multimodal imaging patterns predict survival in recurrent glioblastoma patients treated with bevacizumab SO NEURO-ONCOLOGY LA English DT Article DE bevacizumab; glioblastoma; machine learning; recurrent; survival ID APPARENT DIFFUSION-COEFFICIENT; ANTI-ANGIOGENIC THERAPY; HISTOGRAM ANALYSIS; PERFUSION MRI; MULTIFORME; GLIOMAS; MAPS; MULTICENTER; BIOMARKER; IMPROVE AB Background. Bevacizumab is a humanized antibody against vascular endothelial growth factor approved for treatment of recurrent glioblastoma. There is a need to discover imaging biomarkers that can aid in the selection of patients who will likely derive the most survival benefit from bevacizumab. Methods. The aim of the study was to examine if pre- and posttherapy multimodal MRI features could predict progression-free survival and overall survival (OS) for patients with recurrent glioblastoma treated with bevacizumab. The patient population included 84 patients in a training cohort and 42 patients in a testing cohort, separated based on pretherapy imaging date. Tumor volumes of interest were segmented from contrast-enhanced T1-weighted and fluid attenuated inversion recovery images and were used to derive volumetric, shape, texture, parametric, and histogram features. A total of 2293 pretherapy and 9811 posttherapy features were used to generate the model. Results. Using standard radiographic assessment criteria, the hazard ratio for predicting OS was 3.38 (P< .001). The hazard ratios for pre- and posttherapy features predicting OS were 5.10 (P<.001) and 3.64 (P< .005) for the training and testing cohorts, respectively. Conclusion. With the use of machine learning techniques to analyze imaging features derived from pre- and posttherapy multimodal MRI, we were able to develop a predictive model for patient OS that could potentially assist clinical decision making. C1 [Chang, Ken; Zhang, Biqi; Rahman, Rifaquat; Sanchez, David; Winder, Nicolette; Huang, Raymond Y.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Guo, Xiaotao; Zong, Min; Zhao, Binsheng] Columbia Univ, Coll Phys & Surg, Dept Radiol, New York, NY USA. [Reardon, David A.; Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA USA. RP Huang, RY (reprint author), Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. EM ryhuang@partners.org FU ARRS/ASNR Scholar Award FX The work is supported by the ARRS/ASNR Scholar Award (foundation grant). NR 46 TC 0 Z9 0 U1 6 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD DEC PY 2016 VL 18 IS 12 BP 1680 EP 1687 DI 10.1093/neuonc/now086 PG 8 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA EB4HL UT WOS:000387331500012 PM 27257279 ER PT J AU Kopacz, MS Bryan, CJ AF Kopacz, Marek S. Bryan, Craig J. TI If Intergenerational Transmission Is the Problem, Then What Is the Solution? SO NEUROPSYCHOPHARMACOLOGY LA English DT Letter C1 [Kopacz, Marek S.] US Dept Vet Affairs, VISN Ctr Excellence Suicide Prevent 2, 400 Ft Hill Ave, Canandaigua, NY 14424 USA. [Bryan, Craig J.] Univ Utah, Natl Ctr Vet Studies, Salt Lake City, UT USA. RP Kopacz, MS (reprint author), US Dept Vet Affairs, VISN Ctr Excellence Suicide Prevent 2, 400 Ft Hill Ave, Canandaigua, NY 14424 USA. EM marek.kopacz@va.gov OI Bryan, Craig/0000-0002-9714-0733 NR 5 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2016 VL 41 IS 13 BP 2965 EP 2965 DI 10.1038/npp.2016.23 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EB7MC UT WOS:000387570700002 PM 27818520 ER PT J AU Spielberg, JM Beall, EB Hulvershorn, LA Altinay, M Karne, H Anand, A AF Spielberg, Jeffrey M. Beall, Erik B. Hulvershorn, Leslie A. Altinay, Murat Karne, Harish Anand, Amit TI Resting State Brain Network Disturbances Related to Hypomania and Depression in Medication-Free Bipolar Disorder SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID BEHAVIORAL-APPROACH SYSTEM; RATING-SCALE; SPECTRUM DISORDERS; MANIA; CONNECTIVITY; SCHIZOPHRENIA; METAANALYSIS; SYMPTOMS; EUTHYMIA; AMYGDALA AB Research on resting functional brain networks in bipolar disorder (BP) has been unable to differentiate between disturbances related to mania or depression, which is necessary to understand the mechanisms leading to each state. Past research has also been unable to elucidate the impact of BP-related network disturbances on the organizational properties of the brain (eg, communication efficiency). Thus, the present work sought to isolate network disturbances related to BP, fractionate these into components associated with manic and depressive symptoms, and characterize the impact of disturbances on network function. Graph theory was used to analyze resting functional magnetic resonance imaging data from 60 medication-free patients meeting the criteria for BP and either a current hypomanic (n= 30) or depressed (n= 30) episode and 30 closely age/sex-matched healthy controls. Correction for multiple comparisons was carried out. Compared with controls, BP patients evidenced hyperconnectivity in a network involving right amygdala. Fractionation revealed that (hypo) manic symptoms were associated with hyperconnectivity in an overlapping network and disruptions in the brain's 'small-world' network organization. Depressive symptoms predicted hyperconnectivity in a network involving orbitofrontal cortex along with a less resilient global network organization. Findings provide deeper insight into the differential pathophysiological processes associated with hypomania and depression, along with the particular impact these differential processes have on network function. C1 [Spielberg, Jeffrey M.] Univ Delaware, Dept Psychol & Brain Sci, Newark, DE USA. [Spielberg, Jeffrey M.] VA Boston Healthcare Syst, Neuroimaging Res Vet Ctr, Boston, MA USA. [Beall, Erik B.] Cleveland Clin Fdn, Imaging Inst, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Hulvershorn, Leslie A.] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. [Altinay, Murat; Karne, Harish; Anand, Amit] Cleveland Clin Fdn, Ctr Behav Hlth, Cleveland Clin Main Campus,9500 Euclid Ave P57, Cleveland, OH 44195 USA. RP Anand, A (reprint author), Cleveland Clin Fdn, Ctr Behav Hlth, Cleveland Clin Main Campus,9500 Euclid Ave P57, Cleveland, OH 44195 USA. EM ANANDA@ccf.org OI Spielberg, Jeffrey/0000-0001-8348-7157 FU NIMH [R01MH075025] FX This project was funded by a NIMH grant to AA (R01MH075025). NR 40 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2016 VL 41 IS 13 BP 3016 EP 3024 DI 10.1038/npp.2016.112 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EB7MC UT WOS:000387570700008 PM 27356764 ER PT J AU Hanlon, CA Dowdle, LT Moss, H Canterberry, M George, MS AF Hanlon, Colleen A. Dowdle, Logan T. Moss, Hunter Canterberry, Melanie George, Mark S. TI Mobilization of Medial and Lateral Frontal-Striatal Circuits in Cocaine Users and Controls: An Interleaved TMS/BOLD Functional Connectivity Study SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; DORSOLATERAL PREFRONTAL CORTEX; DEFAULT-MODE NETWORKS; MOTOR CORTEX; BOLD-FMRI; ORBITOFRONTAL CORTEX; ANTERIOR CINGULATE; DOPAMINE RELEASE; BRAIN ACTIVATION; DRUG-ADDICTION AB The integrity of frontal-striatal circuits is an area of great interest in substance dependence literature, particularly as the field begins to develop neural circuit-specific brain stimulation treatments for these individuals. Prior research indicates that frontal-striatal connectivity is disrupted in chronic cocaine users in a baseline (resting) state. It is unclear, however, if this is also true when these circuits are mobilized by an external source. In this study, we measured the functional and structural integrity of frontal-striatal circuitry involved in limbic arousal and executive control in 36 individuals-18 cocaine-dependent individuals with a history of failed quit attempts and 18 age-matched controls. This was achieved by applying a transcranial magnetic stimulation to the medial prefrontal cortex (Brodmann area 10) and the dorsolateral prefrontal cortex (lateral Brodmann 9) while participants rested in the MRI scanner (TMS/BOLD imaging). Relative to the controls, cocaine users had a lower ventral striatal BOLD response to MPFC stimulation. The dorsal striatal BOLD response to DLPFC stimulation however was not significantly different between the groups. Among controls, DLPFC stimulation led to a reciprocal attenuation of MPFC activity (BA 10), but this pattern did not exist in cocaine users. No relationship was found between regional diffusion metrics and functional activity. Considered together these data suggest that, when engaged, cocaine users can mobilize their executive control system similar to controls, but that the 'set point' for mobilizing their limbic arousal system has been elevated-an interpretation consistent with opponent process theories of addiction. C1 [Hanlon, Colleen A.; Dowdle, Logan T.; Moss, Hunter; Canterberry, Melanie; George, Mark S.] Med Univ South Carolina, Dept Psychiat & Behav Sci, Charleston, SC USA. [Hanlon, Colleen A.; George, Mark S.] Med Univ South Carolina, Dept Neurosci, Charleston, SC USA. [Hanlon, Colleen A.; George, Mark S.] Med Univ South Carolina, Ctr Biomed Imaging, Charleston, SC USA. [George, Mark S.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Hanlon, CA (reprint author), Med Univ South Carolina, Ctr Adv Imaging Res, Dept Psychiat, Charleston, SC 29425 USA.; Hanlon, CA (reprint author), Med Univ South Carolina, Ctr Adv Imaging Res, Dept Neurosci, Charleston, SC 29425 USA. EM hanlon@musc.edu FU National Institutes of Health; Department of Defense; Veterans Administration; [R01DA0036617]; [T32DA007288]; [R25DA020537]; [UL1 TR001450] FX We would like to thank William DeVries for assisting in participant screening, Jayce Doose for engineering support, James Purl for MRI acquisition support, Dr Truman S. Brown for data quality assessment and interleaved TMS/BOLD imaging sequence optimization, and Scott Henderson for editorial support. This work was supported by R01DA0036617, T32DA007288, R25DA020537, and UL1 TR001450. Dr Hanlon's work has been funded exclusively by the National Institutes of Health. MSG has received funding from the National Institutes of Health, the Department of Defense, and the Veterans Administration. He has also served as a consultant to several major TMS device companies including MagStim, Neuronetics, Magventure, and Brainsway. NR 59 TC 1 Z9 1 U1 2 U2 2 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 DEC PY 2016 VL 41 IS 13 BP 3032 EP 3041 DI 10.1038/npp.2016.114 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EB7MC UT WOS:000387570700010 PM 27374278 ER PT J AU Kahle, KT Khanna, AR Duan, JJ Staley, KJ Delpire, E Poduri, A AF Kahle, Kristopher T. Khanna, Arjun R. Duan, JingJing Staley, Kevin J. Delpire, Eric Poduri, Annapurna TI The KCC2 Cotransporter and Human Epilepsy: Getting Excited About Inhibition SO NEUROSCIENTIST LA English DT Article DE KCC2; epilepsy; neurogenetics; cation-chloride cotransport; antiepileptic therapy ID CATION-CHLORIDE COTRANSPORTERS; IN-VIVO; CL; TRANSPORTERS; EXPRESSION; PHOSPHORYLATION; MUTATIONS; POTASSIUM; ONSET; HYPEREXCITABILITY AB The cation-Cl- cotransporter KCC2, encoded by SLC12A5, is required for the emergence and maintenance of GABAergic fast synaptic inhibition in organisms across evolution. These findings have suggested that KCC2 deficiency might play a role in the pathogenesis human epilepsy, but this has only recently been substantiated by two lines of genetic evidence. The first is the discovery of heterozygous missense polymorphisms in SLC12A5, causing decreased KCC2-dependent Cl- extrusion capacity, in an Australian family with inherited febrile seizures and in a French-Canadian cohort with severe genetic generalized epilepsy (GGE). The second is the discovery of recessive loss-of-function mutations in SLC12A5 in patients with a severe, early-onset Mendelian disease termed epilepsy of infancy with migrating focal seizures (EIMFS). These findings collectively support the paradigm that precisely regulated KCC2 activity is required for synaptic inhibition in humans, and that genetically encoded impairment of KCC2 function, due to effects on gene dosage, intrinsic activity, or extrinsic regulation, can influence epilepsy phenotypes in patients. Accordingly, KCC2 could be a target for a novel antiepileptic strategies that aims to restore GABA inhibition by facilitating Cl- extrusion. Such drugs could have relevance for pharmaco-resistant epilepsies and possibly other diseases characterized by synaptic hyperexcitability, such as the spectrum autism disorders. C1 [Kahle, Kristopher T.] Yale Univ, Dept Neurosurg, Yale Program Neurogenet, Sch Med, New Haven, CT USA. [Kahle, Kristopher T.] Yale Univ, Sch Med, Dept Pediat, Yale Program Neurogenet, New Haven, CT 06510 USA. [Kahle, Kristopher T.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, Yale Program Neurogenet, New Haven, CT 06510 USA. [Kahle, Kristopher T.] Yale Univ, Sch Med, Ctr Mendelian Genom, New Haven, CT USA. [Khanna, Arjun R.; Duan, JingJing] Harvard Med Sch, Boston Childrens Hosp, Dept Neurosurg, Boston, MA USA. [Staley, Kevin J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Delpire, Eric] Vanderbilt Univ, Sch Med, Dept Anesthesiol, Nashville, TN 37212 USA. [Poduri, Annapurna] Boston Childrens Hosp, Div Epilepsy & Clin Elect, Dept Neurol, Boston, MA USA. RP Kahle, KT (reprint author), Yale Univ, Sch Med, 333 Cedar St, New Haven, CT 06510 USA. EM kristopher.kahle@yale.edu NR 53 TC 3 Z9 3 U1 4 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 EI 1089-4098 J9 NEUROSCIENTIST JI Neuroscientist PD DEC PY 2016 VL 22 IS 6 BP 555 EP 562 DI 10.1177/1073858416645087 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EB4BF UT WOS:000387313300005 PM 27130838 ER PT J AU Borsook, D Veggeberg, R Erpelding, N Borra, R Linnman, C Burstein, R Becerra, L AF Borsook, David Veggeberg, Rosanna Erpelding, Nathalie Borra, Ronald Linnman, Clas Burstein, Rami Becerra, Lino TI The Insula: A "Hub of Activity" in Migraine SO NEUROSCIENTIST LA English DT Review DE interoception; pain; autonomic function; brain connectivity; salience network; headache; functional networks; sensory processing; emotional processing; brain imaging; fMRI; PET; lateral sulcus ID STATE FUNCTIONAL CONNECTIVITY; AUTONOMIC NERVOUS-SYSTEM; VON ECONOMO NEURONS; COGNITIVE-BEHAVIORAL THERAPY; CEREBRAL GLUCOSE-METABOLISM; ANTERIOR CINGULATE CORTEX; BRAIN-STEM ACTIVATION; VESTIBULAR MIGRAINE; SLEEP-DEPRIVATION; PLACEBO ANALGESIA AB The insula, a cortical hub buried within the lateral sulcus, is involved in a number of processes including goal-directed cognition, conscious awareness, autonomic regulation, interoception, and somatosensation. While some of these processes are well known in the clinical presentation of migraine (i.e., autonomic and somatosensory alterations), other more complex behaviors in migraine, such as conscious awareness and error detection, are less well described. Since the insula processes and relays afferent inputs from brain areas involved in these functions to areas involved in higher cortical function such as frontal, temporal, and parietal regions, it may be implicated as a brain region that translates the signals of altered internal milieu in migraine, along with other chronic pain conditions, through the insula into complex behaviors. Here we review how the insula function and structure is altered in migraine. As a brain region of a number of brain functions, it may serve as a model to study new potential clinical perspectives for migraine treatment. C1 [Borsook, David; Veggeberg, Rosanna; Erpelding, Nathalie; Borra, Ronald; Linnman, Clas; Becerra, Lino] Harvard Med Sch, Boston Childrens Hosp, Dept Anesthesia, PAIN Grp,Ctr Pain & Brain, Waltham, MA USA. [Borsook, David; Becerra, Lino] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Borsook, David; Becerra, Lino] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. [Borsook, David; Becerra, Lino] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA USA. [Burstein, Rami] Harvard Med Sch, Beth Israel Deaconess Hosp, Dept Anesthesia, Boston, MA USA. RP Borsook, D (reprint author), Boston Childrens Hosp, Ctr Pain & Brain, 1 Autumn St, Boston, MA 02115 USA. EM david.borsook@childrens.harvard.edu FU NIH [NINDS K24 NS064050, R01 R01NS056195] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by NIH R01 (NINDS K24 NS064050 and R01 R01NS056195). NR 249 TC 3 Z9 3 U1 13 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 EI 1089-4098 J9 NEUROSCIENTIST JI Neuroscientist PD DEC PY 2016 VL 22 IS 6 BP 632 EP 652 DI 10.1177/1073858415601369 PG 21 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EB4BF UT WOS:000387313300011 PM 26290446 ER PT J AU Sharma, S Brennan, B Naden, R Whelan, P AF Sharma, Sapna Brennan, Barbara Naden, Ray Whelan, Patrick TI A case of Degos disease in pregnancy SO OBSTETRIC MEDICINE LA English DT Article DE General medicine; high-risk pregnancy ID MALIGNANT ATROPHIC PAPULOSIS; LUPUS-ERYTHEMATOSUS AB Degos disease is characterized as a rare systemic vaso-occlusive disorder, although the exact pathophysiology is uncertain. Fewer than 200 patients have been reported in the literature, and only two reports describe the course of the disease during pregnancy. Here, we present the first reported case of the course of pregnancy in a woman with the systemic form of Degos disease. The patient had been diagnosed with Degos prior to pregnancy and was monitored throughout the duration of the pregnancy. Her presentation and treatment are described. There was no further exacerbation secondary to the pregnancy itself; the pregnancy course was uncomplicated and the baby unaffected to date. C1 [Sharma, Sapna; Brennan, Barbara] McMaster Univ, Div Maternal Fetal Med, Dept Obstet & Gynecol, Hamilton, ON, Canada. [Naden, Ray] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Whelan, Patrick] MassGen Hosp Children, Div Rheumatol, Boston, MA USA. [Whelan, Patrick] Harvard Med Sch, Boston, MA USA. [Whelan, Patrick] Heritage Provider Network, Los Angeles, CA USA. RP Sharma, S (reprint author), McMaster Childrens Hosp, Rm HSC 4F,1200 Main St W, Hamilton, ON L8N 3Z5, Canada. EM ssharma2009@gmail.com NR 14 TC 0 Z9 0 U1 3 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1753-495X EI 1753-4968 J9 OBSTET MED JI Obstet. Med. PD DEC PY 2016 VL 9 IS 4 BP 167 EP 168 DI 10.1177/1753495X16652006 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EB5UU UT WOS:000387446900007 PM 27829877 ER PT J AU Plant, AS Chi, SN Frazier, L AF Plant, Ashley S. Chi, Susan N. Frazier, Lindsay TI Pediatric malignant germ cell tumors: A comparison of the neuro-oncology and solid tumor experience SO PEDIATRIC BLOOD & CANCER LA English DT Review DE autologous stem cell transplant; chemotherapy; germ cell tumor; growing teratoma syndrome; immature teratoma; radiation therapy ID HIGH-DOSE CHEMOTHERAPY; CENTRAL-NERVOUS-SYSTEM; STAGE-I SEMINOMA; CHILDRENS ONCOLOGY GROUP; C-KIT GENE; BONE-MARROW-TRANSPLANTATION; RANDOMIZED-TRIAL; INTRACRANIAL GERMINOMAS; PROGNOSTIC-FACTORS; BRAIN-TUMORS AB Malignant germ cell tumors (GCT) arise from abnormal migration of primordial germ cells and are histologically identical whether they occur inside or outside the central nervous system (CNS). However, the treatment strategy for GCTs varies greatly depending on the location of the tumor. These differences are in part due to the increased morbidity of surgery in the CNS but may also reflect differential sensitivity of the tumors to chemotherapy and radiation therapy (RT) or not-yet-understood biologic differences between these tumors. Historically, specialists caring for extracranial and intracranial GCT in the United States have practiced separately without much cross communication. The focus of this review is a discussion of differences between the management of CNS and extra-CNS GCTs and opportunities for collaboration and future research. C1 [Plant, Ashley S.; Frazier, Lindsay] Dana Farber Canc Inst, Brain Tumors Ctr, Pediat Hematol Oncol, Boston, MA 02115 USA. [Chi, Susan N.] Dana Farber Canc Inst, Pediat Hematol Oncol, Solid Tumor Ctr, Boston, MA 02115 USA. RP Plant, AS (reprint author), 450 Brookline Ave, Boston, MA 02215 USA. EM Ashley.plant@childrens.harvard.edu NR 81 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2016 VL 63 IS 12 BP 2086 EP 2095 DI 10.1002/pbc.26165 PG 10 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA EB0HE UT WOS:000387023900004 PM 27554756 ER PT J AU Watkins, LE Harpaz-Rotem, I Sippel, LM Krystal, JH Southwick, SM Pietrzak, RH AF Watkins, Laura E. Harpaz-Rotem, Ilan Sippel, Lauren M. Krystal, John H. Southwick, Steven M. Pietrzak, Robert H. TI Hostility and telomere shortening among US military veterans: Results from the National Health and Resilience in Veterans Study SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE Hostility; Aging; Telomere length; Veterans; Anger ID PHYSIOLOGICAL-RESPONSES; INFLAMMATORY MARKERS; PSYCHOSOCIAL FACTORS; CIGARETTE-SMOKING; PERCEIVED STRESS; HEART-DISEASE; LENGTH; ASSOCIATION; ADULTS; ANGER AB Chronic disorders of aging are critical concerns for the U.S. veteran population, which is, on average, two decades older than the non-veteran population. Characterization of risk factors that may accelerate biological aging is important in identifying targets for prevention and intervention. In the current study, we analyzed data from a contemporary, and nationally representative sample of U.S. veterans to evaluate the relationship between a broad range of sociodemographic, military, and clinical variables, and peripheral telomere length, which is an indicator of biological age and linked to risk for aging-related disorders and mortality. Data from 468 U.S. military veterans who participated in the National Health and Resilience in Veterans Study were analyzed. Telomere length was assessed from cells isolated from saliva using quantitative polymerase chain reaction methods. A multivariable binary logistic regression analysis was conducted to evaluate the relations between hostility and telomere length, while controlling for sociodemographic, military, and clinical variables. Greater scores on a measure of hostility were independently associated with telomere shortening, even after adjustment for a broad range of other variables (odds ratio (OR] =1.58, 95% confidence interval [CI] = 1.15-2.18). Secondary analyses revealed that this association was driven by difficulties controlling anger (OR = 1.72, 95%CI = 1.14-2.61), which reflect the external manifestation of hostility, rather than aggressive urges or impulses. Hostility, particularly difficulties controlling anger, is associated with peripheral telomere shortening in U.S. military veterans. Prevention and treatment efforts designed to reduce hostility may help mitigate risk for accelerated cellular aging in this growing segment of the U.S. population. Published by Elsevier Ltd. C1 [Watkins, Laura E.; Harpaz-Rotem, Ilan; Sippel, Lauren M.; Krystal, John H.; Southwick, Steven M.; Pietrzak, Robert H.] VA Connecticut Healthcare Syst, US Dept Vet Affairs, Natl Ctr Posttraumat Stress Disorder, Clin Neurosci Div, West Haven, CT USA. [Watkins, Laura E.; Harpaz-Rotem, Ilan; Sippel, Lauren M.; Krystal, John H.; Southwick, Steven M.; Pietrzak, Robert H.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. RP Watkins, LE (reprint author), VA Connecticut Healthcare Syst, 950 Campbell Ave 151D, West Haven, CT 06516 USA. EM laura.watkins@yale.edu NR 64 TC 0 Z9 0 U1 9 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD DEC PY 2016 VL 74 BP 251 EP 257 DI 10.1016/j.psyneuen.2016.09.006 PG 7 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA EB6VW UT WOS:000387524700029 PM 27689898 ER PT J AU Antoni, MH Bouchard, LC Jacobs, JM Lechner, SC Jutagir, DR Gudenkauf, LM Carver, CS Lutgendorf, S Cole, SW Lippman, M Blomberg, BB AF Antoni, Michael H. Bouchard, Laura C. Jacobs, Jamie M. Lechner, Suzanne C. Jutagir, Devika R. Gudenkauf, Lisa M. Carver, Charles S. Lutgendorf, Susan Cole, Steven W. Lippman, Marc Blomberg, Bonnie B. TI Stress management, leukocyte transcriptional changes and breast cancer recurrence in a randomized trial: An exploratory analysis SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE Conserved transcriptional response to adversity; Cognitive behavioral stress management; Leukocyte gene expression; Breast cancer recurrence; Disease-free survival ID GENE-EXPRESSION; OVARIAN-CARCINOMA; PSYCHOLOGICAL INTERVENTION; SOCIAL REGULATION; CLINICAL-TRIAL; FOLLOW-UP; SURVIVAL; IMMUNE; SYSTEM; BETA AB Purpose: Cognitive behavioral stress management (CBSM) is an empirically-validated group-based psychosocial intervention. CBSM is related to decreased self-reported indicators of psychological adversity during breast cancer treatment and greater disease-free survival (DFS) vs. a control condition. This study examined relationships between CBSM, DFS, and a potential biobehavioral pathway linking these variables in breast cancer patients through a gene expression composite representing the leukocyte conserved transcriptional response to adversity (CTRA). Design: Women with stage 0-IIIb breast cancer completed questionnaires and provided blood samples post-surgery. Participants were randomized to 10-week group-based CBSM or a psychoeducation control group and followed at 6 months, 12 months, and median 11 years. In total, 51 participants provided blood data for longitudinal analyses (CBSM n = 28; Control n = 23). Mixed model analyses examined CBSM effects on 6-12 month changes in CTRA expression (53 indicator genes representing pro-inflammatory, anti-viral and antibody production signaling). Cox regression models assessed the relationship between 6 and 12 month changes in CTRA expression and 11-year DFS. Results: Patients randomized to CBSM showed attenuated 6-12 month change in CTRA gene expression, whereas patients randomized to control showed increased CTRA expression (p = 0.014). Average DFS was 5.92 years (SD= 3.90). Greater 6-12 month CTRA increases predicted shorter 11-year DFS controlling for covariates (p = 0.007). Conclusions: CBSM attenuated CTRA gene expression during the initial year of breast cancer treatment. In turn, greater increases in CTRA gene expression predicted shorter long-term DFS. These findings identify a biobehavioral oncology pathway to examine in future work. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Antoni, Michael H.; Bouchard, Laura C.; Jutagir, Devika R.; Gudenkauf, Lisa M.; Carver, Charles S.] Univ Miami, Dept Psychol, 5665 Ponce de Leon Blvd, Coral Gables, FL 33124 USA. [Antoni, Michael H.; Lechner, Suzanne C.] Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, 1120 NW 14th St, Miami, FL 33136 USA. [Antoni, Michael H.; Lechner, Suzanne C.; Carver, Charles S.; Lippman, Marc; Blomberg, Bonnie B.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, 1475 NW 12th Ave, Miami, FL 33136 USA. [Jacobs, Jamie M.] Massachusetts Gen Hosp, Ctr Canc, Dept Psychiat, Ctr Psychiat Oncol & Behav Sci, 55 Fruit St, Boston, MA 02114 USA. [Lutgendorf, Susan] Univ Iowa, Dept Psychol & Brain Sci, E 11 Seashore Hall, Iowa City, IA 52242 USA. [Cole, Steven W.] Univ Calif Los Angeles, Sch Med, Dept Med, Div Hematol Oncol, 11-934 Factor Bldg, Los Angeles, CA 90095 USA. [Cole, Steven W.] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, 11-934 Factor Bldg, Los Angeles, CA 90095 USA. [Cole, Steven W.] Univ Calif Los Angeles, Norman Cousins Ctr, 11-934 Factor Bldg, Los Angeles, CA 90095 USA. [Lippman, Marc] Univ Miami, Miller Sch Med, Dept Med, 1600 NW 10th Ave,RMSB 3146A, Miami, FL 33136 USA. [Blomberg, Bonnie B.] Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, 1600 NW 10th Ave,RMSB 3146A, Miami, FL 33136 USA. RP Antoni, MH (reprint author), Univ Miami, Dept Psychol, 5665 Ponce De Leon Blvd, Coral Gables, FL 33146 USA. EM mantoni@miami.edu OI carver, charles/0000-0002-3688-8545 FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E, R01 CA064710] NR 48 TC 0 Z9 0 U1 5 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD DEC PY 2016 VL 74 BP 269 EP 277 DI 10.1016/j.psyneuen.2016.09.012 PG 9 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA EB6VW UT WOS:000387524700031 PM 27689900 ER PT J AU Meyer, JD Koltyn, KF Stegner, AJ Kim, JS Cook, DB AF Meyer, Jacob D. Koltyn, Kelli F. Stegner, Aaron J. Kim, Jee-Seon Cook, Dane B. TI Relationships between serum BDNF and the antidepressant effect of acute exercise in depressed women SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE Exercise; Brain-derived neurotrophic factor; Depression; Exercise intensity; Antidepressant response; Mood ID NEUROTROPHIC FACTOR BDNF; MAJOR DEPRESSION; PSYCHIATRIC OUTPATIENTS; SEROTONIN TRANSPORTER; AFFECTIVE-DISORDERS; PHYSICAL-ACTIVITY; MOOD STATES; DSM-IV; BRAIN; NEUROPLASTICITY AB Objective: Brain-derived neurotrophic factor (BDNF) has recently emerged as one potential mechanism with which exercise improves mood in major depressive disorder (MDD). This study examined the relationship between changes in serum total BDNF and mood following acute exercise in MDD. It was hypothesized that acute exercise would increase BDNF in an intensity-dependent manner and that changes in BDNF would be significantly related to improvement in depressed mood post-exercise. Methods: Twenty-four women (age: 38.6 +/- 14.0 years) with MDD exercised for 30 min on a stationary bicycle at light, moderate and hard exercise intensities and performed a quiet rest session using a within subjects, randomized and counter-balanced design. Before, 10 and 30 min after each session, participants completed the profile of mood states (POMS). Blood was drawn before and within 10 min after completion of each session and serum total BDNF (sBDNF) was measured by enzyme-linked immunosorbent assay. Acute exercise-induced changes in POMS Depression and sBDNF were analyzed via 4 session (quiet rest, light, moderate, hard) by 2 measurement (pre, post) ANOVA. Secondary analyses examined the effects of baseline mood and antidepressant usage on sBDNF. Results: Exercise resulted in an acute improvement in depressed mood that was not intensity dependent (p > 0.05), resulting in significant acute increases in sBDNF (p = 0.006) that were also not intensity dependent (p > 0.05). Acute changes in sBDNF were not significantly correlated to changes in POMS depression at 10m (r = -0.171, p = 0.161) or 30m (r = -0.151, p = 0.215) post-exercise. The fourteen participants taking antidepressant medications exhibited lower post-exercise sBDNF (p =0.015) than the participants not currently taking antidepressants, although mood responses were similar. Conclusion: Acute exercise is an effective mood-enhancing stimulus, although sBDNF does not appear to play a role in this short-term response. Patients who are not currently taking antidepressant medications and those who have greater pre-exercise depression may experience a greater sBDNF response to exercise, but the clinical significance of this is currently unclear. Circulating BDNF levels are unlikely to be altered by steady-state acute exercise in a linear dose-dependent manner. This does not eliminate its potential relevance in the antidepressant response to chronic exercise training, but suggests that other mechanisms are involved in the acute affective response to exercise in depression. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Stegner, Aaron J.; Cook, Dane B.] William S Middleton Mem Vet Adm Med Ctr, 2500 Overlook Terrace, Madison, WI 53705 USA. [Meyer, Jacob D.; Koltyn, Kelli F.; Stegner, Aaron J.; Cook, Dane B.] Univ Wisconsin, Dept Kinesiol, 2000 Observ Dr, Madison, WI 53706 USA. [Kim, Jee-Seon] Univ Wisconsin, Dept Educ Psychol, 1025 West Johnson St, Madison, WI 53706 USA. RP Meyer, JD (reprint author), Univ Wisconsin, Dept Kinesiol, 2000 Observ Dr, Madison, WI 53706 USA. EM jdmeyer3@wisc.edu 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 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD DEC PY 2016 VL 74 BP 286 EP 294 DI 10.1016/j.psyneuen.2016.09.022 PG 9 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA EB6VW UT WOS:000387524700033 PM 27697714 ER PT J AU Hilliard, S Bukusi, E Grabe, S Lu, T Hatcher, AM Kwena, Z Mwaura-Muiru, E Dworkin, SL AF Hilliard, Starr Bukusi, Elizabeth Grabe, Shelly Lu, Tiffany Hatcher, Abigail M. Kwena, Zachary Mwaura-Muiru, Esther Dworkin, Shari L. TI Perceived Impact of a Land and Property Rights Program on Violence Against Women in Rural Kenya: A Qualitative Investigation SO VIOLENCE AGAINST WOMEN LA English DT Article DE structural interventions; violence against women; land and property rights; gender inequality; Kenya ID INTIMATE-PARTNER VIOLENCE; HIV RISK BEHAVIOR; GENDER-BASED VIOLENCE; SOUTH-AFRICA; DOMESTIC VIOLENCE; STRUCTURAL INTERVENTIONS; RELATIONSHIP POWER; MARITAL VIOLENCE; PREVENTION; EMPOWERMENT AB The current study focuses on a community-led land and property rights program in two rural provinces in western Kenya. The program was designed to respond to women's property rights violations to reduce violence against women and HIV risks at the community level. Through in-depth interviews with 30 women, we examine the perceived impact that this community-level property rights program had on violence against women at the individual and community level. We also examine perceptions as to how reductions in violence were achieved. Finally, we consider how our findings may aid researchers in the design of structural violence-prevention strategies. C1 [Hilliard, Starr; Hatcher, Abigail M.] Univ Calif San Francisco, Sch Nursing, San Francisco, CA 94143 USA. [Dworkin, Shari L.] Univ Calif San Francisco, Sch Nursing, Sociol, San Francisco, CA 94143 USA. [Dworkin, Shari L.] Univ Calif San Francisco, Sch Nursing, Acad Affairs, San Francisco, CA 94143 USA. [Bukusi, Elizabeth] Kenya Govt Med Res Ctr, Res Training, Kisumu, Kenya. [Kwena, Zachary] Kenya Govt Med Res Ctr, Ctr Microbiol Reseach, Kisumu, Kenya. [Grabe, Shelly] Univ Calif Santa Cruz, Social Sci Div, Psychol, Santa Cruz, CA 95064 USA. [Lu, Tiffany] Massachusetts Gen Hosp, Internal Med, Boston, MA 02114 USA. [Hatcher, Abigail M.] Univ Witwatersrand, Johannesburg, South Africa. [Mwaura-Muiru, Esther] GROOTS Kenya, Women Organizing Together Sisterhood, Nairobi, Kenya. RP Dworkin, SL (reprint author), Univ Calif San Francisco, Ctr AIDS Prevent Studies, Dept Social & Behav Sci, 3333 Calif St,LHTS 455, San Francisco, CA 94118 USA. EM shari.dworkin@ucsf.edu FU National Institutes of Health, University of California, San Francisco Gladstone Institute of Virology & Immunology, Center for AIDS Research [P30-AI027763] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by a grant from the National Institutes of Health, University of California, San Francisco Gladstone Institute of Virology & Immunology, Center for AIDS Research, P30-AI027763. NR 93 TC 0 Z9 0 U1 14 U2 14 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1077-8012 EI 1552-8448 J9 VIOLENCE AGAINST WOM JI Violence Against Women PD DEC PY 2016 VL 22 IS 14 BP 1682 EP 1703 DI 10.1177/1077801216632613 PG 22 WC Women's Studies SC Women's Studies GA EB1QG UT WOS:000387128500002 ER PT J AU Chai, XQJ Hirshfeld-Becker, D Biederman, J Uchida, M Doehrmann, O Leonard, JA Salvatore, J Kenworthy, T Brown, A Kagan, E de los Angeles, C Gabrieli, JDE Whitfield-Gabrieli, S AF Chai, Xiaoqian J. Hirshfeld-Becker, Dina Biederman, Joseph Uchida, Mai Doehrmann, Oliver Leonard, Julia A. Salvatore, John Kenworthy, Tara Brown, Ariel Kagan, Elana de los Angeles, Carlo Gabrieli, John D. E. Whitfield-Gabrieli, Susan TI Altered Intrinsic Functional Brain Architecture in Children at Familial Risk of Major Depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Chidren; Default mode network; Depression; Familial risk; Resting-state fMRI; Subgenual ACC ID DEFAULT-MODE NETWORK; DORSOLATERAL PREFRONTAL CORTEX; COGNITIVE CONTROL NETWORK; GLOBAL SIGNAL REGRESSION; WORKING-MEMORY; CINGULATE CORTEX; MOOD DISORDERS; NEURAL BASIS; CONNECTIVITY; AMYGDALA AB BACKGROUND: Neuroimaging studies of patients with major depression have revealed abnormal intrinsic functional connectivity measured during the resting state in multiple distributed networks. However, it is unclear whether these findings reflect the state of major depression or reflect trait neurobiological underpinnings of risk for major depression. METHODS: We compared resting-state functional connectivity, measured with functional magnetic resonance imaging, between unaffected children of parents who had documented histories of major depression (at-risk, n = 27; 8-14 years of age) and age-matched children of parents with no lifetime history of depression (control subjects, n = 16). RESULTS: At-risk children exhibited hyperconnectivity between the default mode network and subgenual anterior cingulate cortex/orbital frontal cortex, and the magnitude of connectivity positively correlated with individual symptom scores. At-risk children also exhibited 1) hypoconnectivity within the cognitive control network, which also lacked the typical anticorrelation with the default mode network; 2) hypoconnectivity between left dorsolateral prefrontal cortex and subgenual anterior cingulate cortex; and 3) hyperconnectivity between the right amygdala and right inferior frontal gyrus, a key region for top-down modulation of emotion. Classification between at-risk children and control subjects based on resting-state connectivity yielded high accuracy with high sensitivity and specificity that was superior to clinical rating scales. CONCLUSIONS: Children at familial risk for depression exhibited atypical functional connectivity in the default mode, cognitive control, and affective networks. Such task-independent functional brain measures of risk for depression in children could be used to promote early intervention to reduce the likelihood of developing depression. C1 [Chai, Xiaoqian J.; Doehrmann, Oliver; Leonard, Julia A.; Salvatore, John; de los Angeles, Carlo; Gabrieli, John D. E.; Whitfield-Gabrieli, Susan] MIT, McGovern Inst Brain Res, Poitras Ctr Affect Disorders Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Chai, Xiaoqian J.; Doehrmann, Oliver; Leonard, Julia A.; Salvatore, John; de los Angeles, Carlo; Gabrieli, John D. E.; Whitfield-Gabrieli, Susan] MIT, Dept Brain & Cognit Sci, 43 Vassar St,46-5081,Bldg 46, Cambridge, MA 02139 USA. [Hirshfeld-Becker, Dina; Biederman, Joseph; Uchida, Mai; Kenworthy, Tara; Brown, Ariel; Kagan, Elana] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Biederman, Joseph; Uchida, Mai; Kenworthy, Tara; Brown, Ariel; Kagan, Elana] Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. [Gabrieli, John D. E.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Chai, XQJ (reprint author), MIT, Dept Brain & Cognit Sci, 43 Vassar St,46-5081,Bldg 46, Cambridge, MA 02139 USA. EM xiaoqian@-mit.edu FU Tommy Fuss Fund; Poitras Center for Affective Disorders Research; Massachusetts General Hospital Pediatric Psychopharmacology Council Fund; National Institutes of Health (NIH) [R01 HD036317, R01MH050657, R01 MH636833, R01 MH/CHD076923, R01 MH47077]; The Department of Defense; American Academy of Child and Adolescent Psychiatry; Alcobra; Forest Research Institute; Ironshore; Lundbeck; Magceutics Inc.; Merck; PamLab; Pfizer; Shire Pharmaceuticals Inc.; SPRITES; Sunovion; Vaya Pharma/Enzymotec; National Institutes of Health; Ingenix; Prophase; Shire; Bracket Global; Theravance FX This work was supported by the Tommy Fuss Fund, the Poitras Center for Affective Disorders Research, the Massachusetts General Hospital Pediatric Psychopharmacology Council Fund, and the National Institutes of Health (NIH) grants to JB (Grant Nos. R01 HD036317 and R01MH050657). The original participant recruitment was supported by NIH grants to DHB (Grant Nos. R01 MH636833 and R01 MH/CHD076923), and Grant No. R01 MH47077 (PI: Rosenbaum). The funding sources had no involvement in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.; Dr. Joseph Biederman is currently receiving research support from the following sources: The Department of Defense, American Academy of Child and Adolescent Psychiatry, Alcobra, Forest Research Institute, Ironshore, Lundbeck, Magceutics Inc., Merck, PamLab, Pfizer, Shire Pharmaceuticals Inc., SPRITES, Sunovion, Vaya Pharma/Enzymotec, and National Institutes of Health. In 2014, Dr. Joseph Biederman received honoraria from the MGH Psychiatry Academy for tuition-funded continuing medical education courses. He has a US Patent application pending (Provisional Number 61/233,686) through MGH corporate licensing on a method to prevent stimulant abuse. Dr. Biederman received departmental royalties from a copyrighted rating scale used for attention-deficit/hyperactivity disorder diagnoses, paid by Ingenix, Prophase, Shire, Bracket Global, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH. All other authors report no biomedical financial interests or potential conflicts of interest. NR 71 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 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD DEC 1 PY 2016 VL 80 IS 11 BP 849 EP 858 DI 10.1016/j.biopsych.2015.12.003 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EA9CK UT WOS:000386938400010 PM 26826874 ER PT J AU Bychkovsky, BL Dizon, DS Sikov, WM AF Bychkovsky, Brittany L. Dizon, Don S. Sikov, William M. TI Systemic Therapies for Nonmetastatic Breast Cancer: The Role of Neoadjuvant and Adjuvant Chemotherapy and the Use of Endocrine Therapy SO CLINICAL OBSTETRICS AND GYNECOLOGY LA English DT Article DE breast cancer; chemotherapy; endocrine therapy; biological agents; adjuvant therapy; neoadjuvant therapy ID PATHOLOGICAL COMPLETE RESPONSE; RANDOMIZED PHASE-3 TRIAL; PARALLEL HER2-NEGATIVE COHORT; CONTROLLED SUPERIORITY TRIAL; PACLITAXEL PLUS TRASTUZUMAB; OPEN-LABEL; COMPLETE REMISSION; FOLLOW-UP; II TRIAL; STAGE-II AB Breast cancer is a heterogenous disease, comprised of at least 3 major subtypes: hormone receptor-positive/HER2-(HR+), HER2+, and HR-/HER2-(triple negative) breast cancers. The medical management of each subype is distinct. In this article, we review contemporary data supporting the use of chemotherapy, endocrine therapy and biologic therapies, especially HER2-directed agents, in the adjuvant and neoadjuvant setting in patients with newly diagnosed nonmetastatic (stage I-III) breast cancer. C1 [Bychkovsky, Brittany L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bychkovsky, Brittany L.; Dizon, Don S.] Harvard Med Sch, Boston, MA USA. [Dizon, Don S.] Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St, Boston, MA 02114 USA. [Sikov, William M.] Brown Univ, Alpert Med Sch, Women & Infants Hosp Rhode Isl, Program Womens Oncol, Providence, RI 02912 USA. RP Dizon, DS (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St, Boston, MA 02114 USA. EM ddizon@mgh.harvard.edu NR 65 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-9201 EI 1532-5520 J9 CLIN OBSTET GYNECOL JI Clin. Obstet. Gynecol. PD DEC PY 2016 VL 59 IS 4 BP 756 EP 771 DI 10.1097/GRF.0000000000000237 PG 16 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EB0RH UT WOS:000387052200009 PM 27741213 ER PT J AU Marino, L Wissow, LS Davis, M Abrams, MT Dixon, LB Slade, EP AF Marino, Leslie Wissow, Lawrence S. Davis, Maryann Abrams, Michael T. Dixon, Lisa B. Slade, Eric P. TI Predictors of outpatient mental health clinic follow-up after hospitalization among Medicaid-enrolled young adults SO EARLY INTERVENTION IN PSYCHIATRY LA English DT Article DE Medicaid; mental health service; young adult ID MISSED 1ST APPOINTMENTS; PSYCHIATRIC-HOSPITALIZATION; SUBSTANCE-ABUSE; CARE; ILLNESS; SCHIZOPHRENIA; INTERVENTION; DEPRESSION; STRATEGIES; DISCHARGE AB AimTo assess demographic and clinical predictors of outpatient mental health clinic follow-up after inpatient psychiatric hospitalization among Medicaid-enrolled young adults. MethodsUsing logistic regression and administrative claims data from the Maryland public mental health system and Maryland Medicaid for young adults ages 18-26 who were enrolled in Medicaid (N = 1127), the likelihood of outpatient mental health follow-up within 30 days after inpatient psychiatric hospitalization was estimated . ResultsOnly 51% of the young adults had any outpatient mental health follow-up visits within 30 days of discharge. Being black and having a co-occurring substance use disorder diagnosis were associated with a lower probability of having a follow-up visit (OR=0.60, P<0.01 and OR=0.36, P<0.01, respectively). In addition, those who utilized any outpatient public mental health services during the 180 days prior to their index hospitalization (N=625, 55.4%) were more likely to have a follow-up visit than those without prior outpatient use (OR=2.45, P<0.01). Prior Medicaid-reimbursed primary care visits were not significantly associated with follow-up. ConclusionsIn this predominantly urban, low-income statewide sample of young adults hospitalized for serious psychiatric conditions, half did not connect with an outpatient mental healthcare provider following their discharge. Outpatient transition supports may be especially needed for young adults who were not receiving outpatient services prior to being admitted for psychiatric inpatient care, as well as for young adults with substance use disorders and African Americans. C1 [Marino, Leslie; Dixon, Lisa B.] Columbia Univ, Med Ctr, Dept Psychiat, New York State Psychiat Inst, New York, NY USA. [Wissow, Lawrence S.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. [Slade, Eric P.] Univ Maryland, Sch Med, Dept Psychiat, US Dept Vet Affairs,Capitol Healthcare Network VI, Baltimore, MD 21201 USA. [Abrams, Michael T.] Univ Maryland Baltimore Cty, HillTop Inst, Catonsville, MD USA. [Davis, Maryann] Univ Massachusetts, Sch Med, Dept Psychiat, Syst & Psychosocial Adv Res Ctr,Learning & Workin, Worcester, MA 01655 USA. RP Marino, L (reprint author), Columbia Univ, Med Ctr, Dept Psychiat, 1051 Riverside Dr,Box 93, New York, NY 10027 USA.; Marino, L (reprint author), New York State Psychiat Inst & Hosp, 1051 Riverside Dr,Box 93, New York, NY 10032 USA. EM marinol@nyspi.columbia.edu FU NIDA NIH HHS [T32 DA007294]; NIMH NIH HHS [R34 MH081303] NR 31 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1751-7885 EI 1751-7893 J9 EARLY INTERV PSYCHIA JI Early Interv. Psychiatry PD DEC PY 2016 VL 10 IS 6 BP 468 EP 475 DI 10.1111/eip.12206 PG 8 WC Psychiatry SC Psychiatry GA EA6TS UT WOS:000386762500002 PM 25639939 ER PT J AU Lopez, L Grant, RW Marceau, L Piccolo, R McKinlay, J Meigs, JB AF Lopez, Lenny Grant, Richard W. Marceau, Lisa Piccolo, Rebecca McKinlay, John B. Meigs, James B. TI Association of Acculturation and Health Literacy with Prevalent Dysglycemia and Diabetes Control Among Latinos in the Boston Area Community Health (BACH) Survey SO JOURNAL OF IMMIGRANT AND MINORITY HEALTH LA English DT Article DE Acculturation; Health literacy; Latinos; Type 2 diabetes ID CARDIOVASCULAR RISK-FACTORS; SAN-ANTONIO HEART; UNITED-STATES; INTERVIEW SURVEY; OUTCOMES; DISPARITIES; HISPANICS; OBESITY; BLACK AB This study assessed the effect of acculturation on type 2 diabetes and whether health literacy may mediate this association. The Boston Area Community Health cohort is a multi-stage stratified random sample of adults from Boston including 744 Latinos. We defined dysglycemia as a HbA1c aeyen5.7 %. Multivariable analyses examined the associations between acculturation and health literacy adjusting for demographic and clinical variables. Similar analyses were performed among participants with HbA1c aeyen7.0 % to assess the association between acculturation and diabetes control. Among an insured primarily foreign born Spanish speaking Latino population, with a long residence period in the US and good healthcare utilization, higher levels of acculturation were not associated with dysglycemia. Lower levels of acculturation were associated with worse diabetes control. Health literacy level did not modify these associations. Elucidating the components of heterogeneity among Latinos will be essential for understanding the influence of acculturation on diabetes. C1 [Lopez, Lenny] Univ Calif San Francisco, Div Hosp Med, San Francisco, CA 94143 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Grant, Richard W.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Marceau, Lisa; Piccolo, Rebecca; McKinlay, John B.] New England Res Inst, Boston, MA USA. RP Lopez, L (reprint author), Univ Calif San Francisco, Div Hosp Med, San Francisco, CA 94143 USA. EM lopezlenny77@gmail.com FU Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program; NIDDK [1K23DK098280-01, R01 DK080786, K24 DK 080140] FX Dr. Lenny Lopez acknowledges the support of the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program and NIDDK 1K23DK098280-01. This funding body was not involved in the design, data collection, analysis, interpretation nor the preparation of the manuscript. Also supported by NIDDK R01 DK080786: Upstream Contributors to Downstream Disparities in Type 2 Diabetes, and NIDDK K24 DK 080140 (J.B. Meigs). NR 40 TC 0 Z9 0 U1 12 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1912 EI 1557-1920 J9 J IMMIGR MINOR HEALT JI J. Immigr. Minor. Health PD DEC PY 2016 VL 18 IS 6 BP 1266 EP 1273 DI 10.1007/s10903-016-0362-x PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EA3JY UT WOS:000386499600002 PM 26898955 ER PT J AU Rhodes, CM Chang, YC Percac-Lima, S AF Rhodes, Corinne M. Chang, Yuchiao Percac-Lima, Sanja TI Development of Obesity and Related Diseases in African Refugees After Resettlement to United States SO JOURNAL OF IMMIGRANT AND MINORITY HEALTH LA English DT Article DE Refugee; Obesity; Hypertension; Diabetes; Hyperlipidemia ID EXCESS BODY-WEIGHT; FOOD INSECURITY; HEALTH-CARE; WOMEN; RISK; IMMIGRANTS; BEHAVIORS; AUSTRALIA; CHILDREN; FAT AB Despite increases in obesity and related diseases in developing nations, initial refugee clinical visits do not address these issues. We explored the development of obesity and related diseases in a longitudinal prospective cohort of African refugees resettling in northeastern US. Using state Department of Health data, refugees were linked to a health system. Body mass index, diabetes, hypertension, and hyperlipidemia status were extracted from charts. US regional controls from NAMCS/NHAMCS data were matched by age, sex, race, and visit year. African refugee BMI increased after resettlement at 1 (1.7 +/- 2.9, p < 0.0001) and 5 years (3.1 +/- 3.7, p < 0.0001), a different trend than matched regional controls (p = 0.01). Refugees had increased rates of diabetes (1.0 vs. 10.8 %, p < 0.0001), hypertension (16.7 vs. 21.6 %, p < 0.0001) and hyperlipidemia (3.9 vs. 10.8 %, p < 0.0001) at 5 years not observed in regional controls. Our findings emphasize the need for interventions during resettlement to prevent development of obesity and related disease in this vulnerable population. C1 [Rhodes, Corinne M.; Chang, Yuchiao; Percac-Lima, Sanja] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Rhodes, Corinne M.; Chang, Yuchiao; Percac-Lima, Sanja] Harvard Med Sch, Boston, MA 02115 USA. RP Rhodes, CM (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA.; Rhodes, CM (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM crhodes@mgh.harvard.edu OI rhodes, corinne/0000-0002-9894-1364 FU Institutional National Research Service Award [T32HP1025]; Tyoichi Sasakawa Fellowship Fund; Division of General Medicine at Massachusetts General Hospital FX C.M.R. receives current funding support from an Institutional National Research Service Award T32HP1025, the Tyoichi Sasakawa Fellowship Fund, and by the Division of General Medicine at Massachusetts General Hospital. NR 39 TC 0 Z9 0 U1 12 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1912 EI 1557-1920 J9 J IMMIGR MINOR HEALT JI J. Immigr. Minor. Health PD DEC PY 2016 VL 18 IS 6 BP 1386 EP 1391 DI 10.1007/s10903-015-0278-x PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EA3JY UT WOS:000386499600017 PM 26392397 ER PT J AU Molina, G Hull, MA Chen, YL DeLaney, TF Bernstein, KD Choy, E Cote, G Harmon, DC Mullen, JT Haynes, AB AF Molina, George Hull, Melissa A. Chen, Yen-Lin DeLaney, Thomas F. De Amorim Bernstein, Karen Choy, Edwin Cote, Gregory Harmon, David C. Mullen, John T. Haynes, Alex B. TI Preoperative radiation therapy combined with radical surgical resection is associated with a lower rate of local recurrence when treating unifocal, primary retroperitoneal liposarcoma SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Article DE retroperitoneal liposarcoma; radiotherapy; neoplasm recurrence; local ID SOFT-TISSUE SARCOMA; ELECTRON-BEAM RADIOTHERAPY; COMPETING RISK; SURGERY; MANAGEMENT; OUTCOMES; SERIES AB Background and ObjectivesLocal recurrence (LR) is the primary cause of death in patients with retroperitoneal liposarcoma (RP-LPS). The purpose of this study was to evaluate if the addition of preoperative radiation therapy (XRT) to radical resection for RP-LPS at a single institution was associated with improved LR. MethodsThis retrospective analysis included patients with unifocal, primary RP-LPS who underwent complete R0/R1 resection at a single institution between 1991 and 2013. Multiple patient, tumor, and surgeon characteristics were tested to evaluate their association to LR (recurrence in the retroperitoneal space). We used competing risk hazards regression to evaluate the effect of preoperative XRT on the probability of LR. ResultsThere were 41 patients with liposarcoma histology whose tumors included entirely well-differentiated (N=13), de-differentiated components (n=26), myxoid (n=1), and NOS (n=1). Preoperative XRT was significantly associated with a lower probability of LR (HR 0.11, 95%CI 0.01-0.91, P=0.04) and a higher 5-year local recurrence-free survival (95.6%, 95%CI 72.4-99.4%, vs. 75.0%, 95%CI 40.8-91.2%; P=0.0213), but not with 5-year distant recurrence-free survival or disease-specific survival. ConclusionsPreoperative XRT combined with complete R0/R1 resection for unifocal, primary RP-LPS was associated with improved LR and it should be considered in the multimodality treatment of RP-LPS. J. Surg. Oncol. 2016;114:814-820. (c) 2016 2016 Wiley Periodicals, Inc. C1 [Molina, George; Mullen, John T.; Haynes, Alex B.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Hull, Melissa A.] Virginia Commonwealth Univ, Div Surg Oncol, Sch Med, Richmond, VA USA. [Chen, Yen-Lin; DeLaney, Thomas F.; De Amorim Bernstein, Karen] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Choy, Edwin; Cote, Gregory; Harmon, David C.] Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA. RP Haynes, AB (reprint author), Massachusetts Gen Hosp, Yawkey Ctr Outpatient Care, 32 Fruit St, Boston, MA 02114 USA. EM abhaynes@mgh.harvard.edu OI Cote, Gregory/0000-0003-0181-886X FU Cassandra Moseley Berry Foundation; Kenneth Stanton Foundation; Jennifer Hunter Yates Sarcoma Foundation FX Grant sponsor: Cassandra Moseley Berry Foundation.; Grant sponsor: Kenneth Stanton Foundation.; Grant sponsor: Jennifer Hunter Yates Sarcoma Foundation. NR 23 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 1 PY 2016 VL 114 IS 7 BP 814 EP 820 DI 10.1002/jso.24427 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA EB0JA UT WOS:000387028900007 PM 27634478 ER PT J AU Crane, PK Walker, RL Sonnen, J Gibbons, LE Melrose, R Hassenstab, J Keene, CD Postupna, N Montine, TJ Larson, EB AF Crane, Paul K. Walker, Rod L. Sonnen, Joshua Gibbons, Laura E. Melrose, Rebecca Hassenstab, Jason Keene, C. Dirk Postupna, Nadia Montine, Thomas J. Larson, Eric B. TI Glucose levels during life and neuropathologic findings at autopsy among people never treated for diabetes SO NEUROBIOLOGY OF AGING LA English DT Article DE Glucose; Neuropathology; Neuritic plaques; Hippocampal sclerosis; Lewy bodies; Neurofibrillary tangles ID ALZHEIMERS ASSOCIATION GUIDELINES; PARKINSONS-DISEASE; HIPPOCAMPAL SCLEROSIS; NATIONAL INSTITUTE; DEMENTIA; RISK; DIAGNOSIS; PATHOLOGY; COHORT; CERAD AB We evaluated associations between glucose and dementia-related neuropathologic findings among people without diabetes treatment history to elucidate mechanisms of glucose's potential effect on dementia. We used glucose and hemoglobin A1c values to characterize glucose exposures over 5 years before death (primary) and age bands from 55-59 through 80-84 (secondary). Autopsy evaluations included Braak stage for neurofibrillary tangles, Consortium to Establish a Registry for Alzheimer's Disease grade for neuritic plaques, macroscopic infarcts including lacunar infarcts, Lewy bodies, cerebral microinfarcts, and hippocampal sclerosis. Of 529 who came to autopsy, we included 430 with no history of diabetes treatment. We found no associations between glucose levels and Braak stage or Consortium to Establish a Registry for Alzheimer's Disease grade. There was a suggestion of a relationship between glucose and hippocampal sclerosis, although this was inconsistent across analyses. There was higher risk of Lewy bodies in substantia nigra and locus ceruleus with higher glucose levels in age band analyses. We did not find interactions between glucose levels, neuropathologic findings, and dementia. The mechanism by which glucose may impact dementia risk is still unknown. (C) 2016 Elsevier Inc. All rights reserved. C1 [Crane, Paul K.; Gibbons, Laura E.] Univ Washington, Dept Med, Seattle, WA USA. [Walker, Rod L.; Larson, Eric B.] Grp Hlth Res Inst, Seattle, WA USA. [Sonnen, Joshua] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [Melrose, Rebecca] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Melrose, Rebecca] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Hassenstab, Jason] Washington Univ, Dept Neurol, St Louis, MO USA. [Keene, C. Dirk; Postupna, Nadia; Montine, Thomas J.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. RP Crane, PK (reprint author), Box 359780,325 Ninth Ave, Seattle, WA 98104 USA. EM pcrane@uw.edu OI Gibbons, Laura/0000-0001-5054-2543; Sonnen, Joshua/0000-0001-9267-8705 FU National Institute on Aging [U01 AG006781] FX This study was funded by National Institute on Aging (grant# U01 AG006781). Alzheimer's Disease Patient Registry is also known as the Adult Changes in Thought (ACT) study. Eric B. Larson, MD MPH, and Paul K. Crane, MD MPH, serve as multiple principal investigators for ACT. NR 53 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 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD DEC PY 2016 VL 48 BP 72 EP 82 DI 10.1016/j.neurobiolaging.2016.07.021 PG 11 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA EA9PW UT WOS:000386977300008 PM 27644076 ER PT J AU Wang, B Fintelmann, FJ Kamath, RS Kattapuram, SV Rosenthal, DI AF Wang, Benjamin Fintelmann, Florian J. Kamath, Ravi S. Kattapuram, Susan V. Rosenthal, Daniel I. TI Limited magnetic resonance imaging of the lumbar spine has high sensitivity for detection of acute fractures, infection, and malignancy SO SKELETAL RADIOLOGY LA English DT Article DE Limited protocol lumbar spine MRI; Low back pain; Health care costs; Health care value; Lumbar spine MRI ID LOW-BACK-PAIN; RADIOGRAPHS; PHYSICIANS; DIAGNOSIS AB The objective of this study is to determine how a limited protocol MR examination compares to a full conventional MR examination for the detection of non-degenerative pathology such as acute fracture, infection, and malignancy. A sample of 349 non-contrast MR exams was selected retrospectively containing a 3:1:1:1 distribution of negative/degenerative change only, acute fracture, infection, and malignancy. This resulted in an even distribution of pathology and non-pathology. A limited protocol MR exam was simulated by extracting T1-weighted sagittal and T2-weighted fat-saturated (or STIR) sagittal sequences from each exam and submitting them for blinded review by two experienced musculoskeletal radiologists. The exams were evaluated for the presence or absence of non-degenerative pathology. Interpretation of the limited exam was compared to the original report of the full examination. If either reader disagreed with the original report, the case was submitted for an unblinded adjudication process with the participation of a third musculoskeletal radiologist to establish a consensus diagnosis. There were five false negatives for a sensitivity of 96.9 % for the limited protocol MR exam. Infection in the psoas, paraspinal muscles, and sacroiliac joint, as well as acute fractures in transverse processes and sacrum were missed by one or more readers. No cases of malignancy were missed. Overall diagnostic accuracy was 96.0 % (335/349). MR imaging of the lumbar spine limited to sagittal T1-weighted and sagittal T2 fat-saturated (or STIR) sequences has high sensitivity for the detection of acute fracture, infection, or malignancy compared to a conventional MR examination. C1 [Wang, Benjamin; Fintelmann, Florian J.; Kamath, Ravi S.; Kattapuram, Susan V.; Rosenthal, Daniel I.] Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. RP Wang, B (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM bwang9@partners.org NR 16 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 EI 1432-2161 J9 SKELETAL RADIOL JI Skeletal Radiol. PD DEC PY 2016 VL 45 IS 12 BP 1687 EP 1693 DI 10.1007/s00256-016-2493-5 PG 7 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA EA4FE UT WOS:000386564800009 PM 27726015 ER PT J AU Sarosiek, S Shah, R Munshi, NC AF Sarosiek, Shayna Shah, Ruchit Munshi, Nikhil C. TI Review of siltuximab in the treatment of multicentric Castleman's disease SO THERAPEUTIC ADVANCES IN HEMATOLOGY LA English DT Review DE Castleman's disease; interleukin 6 antibody; siltuximab; tocilizumab ID ANTI-INTERLEUKIN-6 MONOCLONAL-ANTIBODY; DOUBLE-BLIND; OPEN-LABEL; INTERLEUKIN-6; THERAPY; LYMPHOMA; APPROVAL AB Castleman's disease (CD) is a rare lymphoproliferative disorder that has multiple histologic patterns, as well as two distinct clinical forms: unicentric or multicentric. Multicentric Castleman's disease (MCD) may have mild symptoms in some cases, but in others it can progress to severe pancytopenia, life-threatening infection, secondary malignancy, multiorgan failure, or death. Recent research has determined that the etiology of the disease signs and symptoms is related to elevated cytokines, including interleukin 6 (IL-6). Siltuximab is a monoclonal antibody that targets IL-6 and is currently the only US Food and Drug Administration approved therapy for idiopathic MCD. Clinical data have demonstrated significant efficacy and tolerance of siltuximab in patients with idiopathic CD. C1 [Shah, Ruchit; Munshi, Nikhil C.] Harvard Med Sch, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Sarosiek, Shayna] Boston Univ, Sch Med, Boston, MA 02118 USA. [Sarosiek, Shayna] Harvard Med Sch, VA Boston Healthcare Syst, Dept Med, Boston, MA USA. RP Munshi, NC (reprint author), Harvard Med Sch, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM nikhil_munshi@dfci.harvard.edu NR 27 TC 0 Z9 0 U1 3 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 2040-6207 EI 2040-6215 J9 THER ADV HEMATOL JI Ther. Adv. Hematol. PD DEC PY 2016 VL 7 IS 6 BP 360 EP 366 DI 10.1177/2040620716653745 PG 7 WC Hematology SC Hematology GA EA8YZ UT WOS:000386927600004 PM 27904739 ER PT J AU Pu, HJ Jiang, XY Hu, XM Xia, JC Hong, DD Zhang, WT Gao, YQ Chen, J Shi, YJ AF Pu, Hongjian Jiang, Xiaoyan Hu, Xiaoming Xia, Jinchao Hong, Dandan Zhang, Wenting Gao, Yanqin Chen, Jun Shi, Yejie TI Delayed Docosahexaenoic Acid Treatment Combined with Dietary Supplementation of Omega-3 Fatty Acids Promotes Long-Term Neurovascular Restoration After Ischemic Stroke SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Angiogenesis; Cognitive function; Glial scar; Hippocampus; Neurogenesis ID SPINAL-CORD-INJURY; FOCAL CEREBRAL-ISCHEMIA; CENTRAL-NERVOUS-SYSTEM; BRAIN-BARRIER DISRUPTION; VASCULAR NEURAL-NETWORK; FATTY-ACIDS; COGNITIVE IMPAIRMENT; RAT MODEL; INTRACEREBRAL HEMORRHAGE; CLINICAL TRANSLATION AB Prophylactic dietary intake of omega-3 polyunsaturated fatty acids (n-3 PUFAs) has been shown to remarkably ameliorate ischemic brain injury. However, the therapeutic efficacy of n-3 PUFA administration post-stroke, especially its impact on neurovascular remodeling and long-term neurological recovery, has not been fully characterized thus far. In this study, we investigated the effect of n-3 PUFA supplementation, as well as in combination with docosahexaenoic acid (DHA) injections, on long-term stroke outcomes. Mice were subjected to transient middle cerebral artery occlusion (MCAO) before randomly assigned to four groups to receive the following: (1) low dose of n-3 PUFAs as the vehicle control, (2) intraperitoneal DHA injections, (3) n-3 PUFA dietary supplement, or (4) combined treatment of (2) and (3). Neurological deficits and brain atrophy, neurogenesis, angiogenesis, and glial scar formation were assessed up to 28 days after MCAO. Results revealed that groups 2 and 3 showed only marginal reduction in post-stroke tissue loss and attenuation of cognitive deficits. Interestingly, group 4 exhibited significantly reduced tissue atrophy and improved cognitive functions compared to groups 2 and 3 with just a single treatment. Mechanistically, the combined treatment promoted post-stroke neurogenesis and angiogenesis, as well as reduced glial scar formation, all of which significantly correlated with the improved spatial memory in the Morris water maze. These results demonstrate an effective therapeutic regimen to enhance neurovascular restoration and long-term cognitive recovery in the mouse model of MCAO. Combined post-stroke DHA treatment and n-3 PUFA dietary supplementation thus may be a potential clinically translatable therapy for stroke or related brain disorders. C1 [Pu, Hongjian; Hu, Xiaoming; Chen, Jun; Shi, Yejie] Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15261 USA. [Jiang, Xiaoyan; Hu, Xiaoming; Zhang, Wenting; Gao, Yanqin; Chen, Jun] Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China. [Jiang, Xiaoyan; Hu, Xiaoming; Zhang, Wenting; Gao, Yanqin; Chen, Jun] Fudan Univ, Inst Brain Sci, Shanghai 200032, Peoples R China. [Pu, Hongjian; Jiang, Xiaoyan; Hu, Xiaoming; Xia, Jinchao; Hong, Dandan; Gao, Yanqin; Chen, Jun; Shi, Yejie] Univ Pittsburgh, Pittsburgh Inst Brain Disorders & Recovery, Pittsburgh, PA 15213 USA. [Pu, Hongjian; Jiang, Xiaoyan; Hu, Xiaoming; Xia, Jinchao; Hong, Dandan; Gao, Yanqin; Chen, Jun; Shi, Yejie] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA. RP Chen, J; Shi, YJ (reprint author), Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15261 USA.; Chen, J (reprint author), Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China.; Chen, J (reprint author), Fudan Univ, Inst Brain Sci, Shanghai 200032, Peoples R China.; Chen, J; Shi, YJ (reprint author), Univ Pittsburgh, Pittsburgh Inst Brain Disorders & Recovery, Pittsburgh, PA 15213 USA.; Chen, J; Shi, YJ (reprint author), Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA. EM chenj2@upmc.edu; shiy3@upmc.edu OI Shi, Yejie/0000-0001-7502-9201 FU US Department of Veterans Affairs (VA) RRD Merit Review [RX000420]; US National Institutes of Health [NS045048, NS091175, NS095671]; American Heart Association [13SDG14570025]; Chinese Natural Science Foundation [81529002, 81171149, 81371306, 81571285, 81100978]; VA Senior Research Career Scientist Award FX *H.P. and *X.J. contributed equally to this research. This project was supported by the US Department of Veterans Affairs (VA) RR&D Merit Review RX000420; the US National Institutes of Health grants NS045048, NS091175, and NS095671; the American Heart Association grant 13SDG14570025; and the Chinese Natural Science Foundation grants 81529002, 81171149, 81371306, 81571285, and 81100978. J.C. is a recipient of the VA Senior Research Career Scientist Award. The authors are indebted to Pat Strickler for excellent administrative support. The present address of J.X. is Cerebrovascular Center, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou 450003, China. NR 77 TC 0 Z9 0 U1 7 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD DEC PY 2016 VL 7 IS 6 BP 521 EP 534 DI 10.1007/s12975-016-0498-y PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EA1VJ UT WOS:000386379800008 PM 27566736 ER PT J AU Jiang, XY Pu, HJ Hu, XM Wei, ZS Hong, DD Zhang, WT Gao, YQ Chen, J Shi, YJ AF Jiang, Xiaoyan Pu, Hongjian Hu, Xiaoming Wei, Zhishuo Hong, Dandan Zhang, Wenting Gao, Yanqin Chen, Jun Shi, Yejie TI A Post-stroke Therapeutic Regimen with Omega-3 Polyunsaturated Fatty Acids that Promotes White Matter Integrity and Beneficial Microglial Responses after Cerebral Ischemia SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Myelin; Oligodendrogenesis; Corpus callosum; Microglial polarization ID TRAUMATIC BRAIN-INJURY; MICROGLIA/MACROPHAGE POLARIZATION DYNAMICS; VASCULAR COGNITIVE IMPAIRMENT; DOCOSAHEXAENOIC ACID; NEUROLOGICAL FUNCTION; FUNCTIONAL RECOVERY; MULTIPLE-SCLEROSIS; M2 MICROGLIA; RT-PA; STROKE AB White matter injury induced by ischemic stroke elicits sensorimotor impairments, which can be further deteriorated by persistent proinflammatory responses. We previously reported that delayed and repeated treatments with omega-3 polyunsaturated fatty acids (n-3 PUFAs) improve spatial cognitive functions and hippocampal integrity after ischemic stroke. In the present study, we report a post-stroke n-3 PUFA therapeutic regimen that not only confers protection against neuronal loss in the gray matter but also promotes white matter integrity. Beginning 2 h after 60 min of middle cerebral artery occlusion (MCAO), mice were randomly assigned to receive intraperitoneal docosahexaenoic acid (DHA) injections (10 mg/kg, daily for 14 days), alone or in combination with dietary fish oil (FO) supplements starting 5 days after MCAO. Sensorimotor functions, gray and white matter injury, and microglial responses were examined up to 28 days after MCAO. Our results showed that DHA and FO combined treatment-facilitated long-term sensorimotor recovery and demonstrated greater beneficial effect than DHA injections alone. Mechanistically, n-3 PUFAs not only offered direct protection on white matter components, such as oligodendrocytes, but also potentiated microglial M2 polarization, which may be important for white matter repair. Notably, the improved white matter integrity and increased M2 microglia were strongly linked to the mitigation of sensorimotor deficits after stroke upon n-3 PUFA treatments. Together, our results suggest that post-stroke DHA injections in combination with FO dietary supplement benefit white matter restoration and microglial responses, thereby dictating long-term functional improvements. C1 [Jiang, Xiaoyan; Hu, Xiaoming; Zhang, Wenting; Gao, Yanqin; Chen, Jun] Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China. [Jiang, Xiaoyan; Hu, Xiaoming; Zhang, Wenting; Gao, Yanqin; Chen, Jun] Fudan Univ, Inst Brain Sci, Shanghai 200032, Peoples R China. [Jiang, Xiaoyan; Pu, Hongjian; Hu, Xiaoming; Wei, Zhishuo; Hong, Dandan; Gao, Yanqin; Chen, Jun; Shi, Yejie] Univ Pittsburgh, Pittsburgh Inst Brain Disorders & Recovery, Pittsburgh, PA 15213 USA. [Jiang, Xiaoyan; Pu, Hongjian; Hu, Xiaoming; Wei, Zhishuo; Hong, Dandan; Gao, Yanqin; Chen, Jun; Shi, Yejie] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA. [Hu, Xiaoming; Chen, Jun; Shi, Yejie] Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15261 USA. RP Chen, J (reprint author), Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China.; Chen, J (reprint author), Fudan Univ, Inst Brain Sci, Shanghai 200032, Peoples R China.; Chen, J; Shi, YJ (reprint author), Univ Pittsburgh, Pittsburgh Inst Brain Disorders & Recovery, Pittsburgh, PA 15213 USA.; Chen, J; Shi, YJ (reprint author), Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA.; Chen, J; Shi, YJ (reprint author), Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15261 USA. EM chenj2@upmc.edu; shiy3@upmc.edu OI Shi, Yejie/0000-0001-7502-9201 FU US Department of Veterans Affairs (VA) RRD Merit Review [RX000420]; US National Institutes of Health [NS045048, NS091175, NS095671]; American Heart Association [13SDG14570025]; Chinese Natural Science Foundation [81529002, 81171149, 81371306, 81571285, 81100978]; VA Senior Research Career Scientist Award FX This project was supported by the US Department of Veterans Affairs (VA) RR&D Merit Review RX000420, the US National Institutes of Health grants NS045048, NS091175 and NS095671, the American Heart Association grant 13SDG14570025, and the Chinese Natural Science Foundation grants 81529002, 81171149, 81371306, 81571285 and 81100978. J.C. is a recipient of the VA Senior Research Career Scientist Award. The authors are indebted to Pat Strickler for excellent administrative support. NR 69 TC 0 Z9 0 U1 7 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD DEC PY 2016 VL 7 IS 6 BP 548 EP 561 DI 10.1007/s12975-016-0502-6 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EA1VJ UT WOS:000386379800010 PM 27714669 ER PT J AU Stauffer, CS Musinipally, V Suen, A Lynch, KL Shapiro, B Woolley, JD AF Stauffer, Christopher S. Musinipally, Vivek Suen, Angela Lynch, Kara L. Shapiro, Brad Woolley, Joshua D. TI A two-week pilot study of intranasal oxytocin for cocaine-dependent individuals receiving methadone maintenance treatment for opioid use disorder SO ADDICTION RESEARCH & THEORY LA English DT Article DE Cocaine; social; addiction; methadone; oxytocin ID TREATMENT RETENTION; SOCIAL ATTACHMENT; OPIATE ADDICTION; DRUG-USERS; STRESS; SEEKING; ASSOCIATION; IMPLICIT; BEHAVIOR; HEROIN AB About 30-60% of the patients receiving methadone for opioid use disorder (OUD) actively use cocaine. Cocaine use disorder (CUD) has no FDA-approved pharmacological treatment; existing psychosocial treatments are inadequate. Oxytocin (OT), a social neuropeptide, has preclinical promise as an adjunctive treatment for both OUD and CUD. Twenty-two individuals receiving methadone for OUD with co-occurring CUD were randomized to receive OT or placebo intranasally 40IU twice daily for two weeks. A priori aims were feasibility and safety. Exploratory effectiveness aims included laboratory-based measures of drug craving, drug-related implicit cognition, and drug use. High retention rates (93.5%), the absence of study-related adverse events, and the fact that OT was well tolerated in this population support the feasibility of larger trials. Two weeks of OT (but not placebo) significantly reduced cocaine craving at day 15 compared to baseline (mean change +/- SD: OT=-0.23 +/- 0.19, p=0.004; PL=-0.16 +/- 0.29, p=0.114). For heroin craving, the placebo group reported a trend-level increase over time while the OT group remained unchanged - with medium to large effect sizes between the groups (Cohen's d=0.71-0.90). OT led to a significant switch from implicit self-association with drugs to implicitly associating drugs with others (mean change +/- SD: 0.25 +/- 0.35, p=0.037) and a trend-level reduction in self-reported cocaine use over time (Z=-1.78, p=0.075). Furthermore, OT significantly increased the accuracy of self-reported cocaine use when correlated with quantitative urine levels of cocaine metabolite. This proof-of-concept study provides promising early evidence that OT may be an effective adjunct to the treatment of co-occurring CUD and OUD. Further investigation with larger trials is warranted. C1 [Stauffer, Christopher S.; Shapiro, Brad; Woolley, Joshua D.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Stauffer, Christopher S.; Musinipally, Vivek; Woolley, Joshua D.] San Francisco VA Med Ctr, Dept Mental Hlth, San Francisco, CA USA. [Musinipally, Vivek; Suen, Angela] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Lynch, Kara L.] Univ Calif San Francisco, Dept Pathol & Lab Med, San Francisco, CA 94143 USA. RP Stauffer, CS (reprint author), 4150 Clement St 116-C, San Francisco, CA 94121 USA. EM christopher.stauffer@ucsf.edu FU San Francisco Treatment Research Center at the University of California, San Francisco from National Institute on Drug Abuse [P50 DA009253]; National Institute of Mental Health [R25 MH060482] FX This project was supported by the San Francisco Treatment Research Center at the University of California, San Francisco via grant number P50 DA009253 from the National Institute on Drug Abuse. Additional support was provided by the National Institute of Mental Health via grant number R25 MH060482. NR 46 TC 1 Z9 1 U1 10 U2 10 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1606-6359 EI 1476-7392 J9 ADDICT RES THEORY JI Addict. Res. Theory PD DEC PY 2016 VL 24 IS 6 BP 490 EP 498 DI 10.3109/16066359.2016.1173682 PG 9 WC Substance Abuse; Social Issues SC Substance Abuse; Social Issues GA DZ4RW UT WOS:000385848200008 ER PT J AU Moss, ML Miller, MA Vujanovic, N Yoneyama, T Rasmussen, FH AF Moss, Marcia L. Miller, Miles A. Vujanovic, Nikola Yoneyama, Toshie Rasmussen, Fred H. TI Fluorescent substrates for ADAM15 useful for assaying and high throughput screening SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE ADAM15; Fluorescent substrate; FRET; TIMP; Metalloproteinase; Disintegrin ID IGE RECEPTOR CD23; METALLOPROTEINASE ADAM15; SIGNAL TRANSACTIVATION; CANCER PROGRESSION; CATALYTIC-ACTIVITY; CELL-MIGRATION; INHIBITION; PROSTATE; BREAST; DISINTEGRIN AB A disintegrin and metalloproteinase 15 (ADAM15), also known as metargidin, plays important roles in regulating inflammation, wound healing, neovascularization, and is an attractive drug target. Fluorescence resonance energy transfer (FRET)-based peptide substrates were tested to identify candidate reagents for high throughput screening and detection of ADAM15 in biological samples. ADAM15 exhibits a unique and diverse activity profile compared to other metalloproteinases. Two FRET substrates, Dabcyl-Gly-Pro-Leu-Gly-Met-Arg-Gly-Lys(FAM)-NH2 (PEPDAB011) and Dabcyl-Ala-Pro-Arg-Trp-Ile-Gln-AspLys(FAM)-NH2 (PEPDAB017), which also detect activities of several matrix metalloproteinases (MMPs -2, -9, and -13), were efficiently cleaved by ADAM15 with specificity constants of 5800 M-1 s(-1) and 4300 M-1 s-1, respectively. Additionally, ADAM15 efficiently processed Dabcyl-Leu-Arg-Glu-Gln-Gln-Arg-Leu-Lys-Ser-Lys(FAM)-NH2 (PEPDAB022), which is based on a physiological CD23 cleavage site, with a specificity constant (kcat/Km) of 5200 M-1 s(-1). PEPDAB022 was used to screen the ability of known metalloproteinase inhibitors including TAPI-2, marimastat, GI-254023, and the Tissue Inhibitor of Metalloproteinases(TIMPs) 1 and 3 to block ADAM15 activity. Even though ADAM15 exhibits similar substrate preferences to other metalloproteinases, many broad spectrum inhibitors failed to block ADAM15 activity at concentrations as high as 50 M. Thus, a clear need exists to develop potent and selective ADAM15 inhibitors, and the FRET substrates described herein should aid future research efforts towards this aim. (C) 2016 Elsevier Inc. All rights reserved. C1 [Moss, Marcia L.; Rasmussen, Fred H.] BioZyme Inc, 1513 Old White Oak Church Rd, Apex, NC 27523 USA. [Miller, Miles A.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Vujanovic, Nikola; Yoneyama, Toshie] Univ Pittsburgh, Dept Pathol, VA Healthcare Syst, Inst Canc, Pittsburgh, PA USA. RP Moss, ML (reprint author), BioZyme Inc, 1513 Old White Oak Church Rd, Apex, NC 27523 USA. EM mossscientist0@gmail.com FU VA Merit Award [1-I01-BX000993-01/VUJ-ONCA-053-12S] FX Portions of this work were funded by VA Merit Award Grant 1-I01-BX000993-01/VUJ-ONCA-053-12S. NR 36 TC 0 Z9 0 U1 11 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 EI 1096-0309 J9 ANAL BIOCHEM JI Anal. Biochem. PD DEC 1 PY 2016 VL 514 BP 42 EP 47 DI 10.1016/j.ab.2016.09.010 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DY9QW UT WOS:000385471200008 PM 27637923 ER PT J AU Siegel, DS Weisel, KC Dimopoulos, MA Baz, R Richardson, P Delforge, M Song, KW San Miguel, JF Moreau, P Goldschmidt, H Cavo, M Jagannath, S Yu, X Hong, K Sternas, L Zaki, M Palumbo, A AF Siegel, David S. Weisel, Katja C. Dimopoulos, Meletios A. Baz, Rachid Richardson, Paul Delforge, Michel Song, Kevin W. San Miguel, Jesus F. Moreau, Philippe Goldschmidt, Hartmut Cavo, Michele Jagannath, Sundar Yu, Xin Hong, Kevin Sternas, Lars Zaki, Mohamed Palumbo, Antonio TI Pomalidomide plus low-dose dexamethasone in patients with relapsed/refractory multiple myeloma and moderate renal impairment: a pooled analysis of three clinical trials SO LEUKEMIA & LYMPHOMA LA English DT Article DE IMiD; pomalidomide; relapsed/refractory multiple myeloma; renal impairment ID LENALIDOMIDE; AGENTS; REVERSIBILITY; BORTEZOMIB; SURVIVAL; FAILURE; IMPACT; CREATININE AB Renal impairment (RI) is a major comorbidity in patients with multiple myeloma (MM). Here we present the pooled safety and efficacy analysis of three clinical trials (MM-002, MM-003, and MM-010) of pomalidomide + low-dose dexamethasone (POM + LoDEX) in patients with moderate RI (creatinine clearance [CrCl] >= 30 to <60 mL/min) and without RI (>= 60 mL/min). Trial protocols were approved by the institutional review board of each site involved. Patients with RI were older than patients without RI, although other baseline characteristics were similar. The dosing and safety profile of POM + LoDEX was similar across RI subgroups. Median overall response rate, progression-free survival, time to progression, and duration of response were not significantly different between RI subgroups. However, patients with vs. without RI had significantly shorter median overall survival (10.5 vs. 14.0 months, respectively; p = .004). This analysis demonstrates that POM + LoDEX is a safe and effective treatment for patients with moderate RI. The trials were registered at ClinicalTrials.gov as NCT00833833 (MM-002), NCT01311687 (MM-003), and NCT01712789 (MM-010) and at EudraCT as 2010-019820-30 (MM-003) and 2012-001888-78 (MM-010). C1 [Siegel, David S.] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Div Multiple Myeloma, Hackensack, NJ USA. [Weisel, Katja C.] Univ Tubingen Hosp, Dept Hematol Oncol Immunol Rheumatol & Pulm, Tubingen, Germany. [Dimopoulos, Meletios A.] Univ Athens, Sch Med, Dept Clin Therapeut Univ, Athens, Greece. [Baz, Rachid] H Lee Moffitt Canc Ctr & Res Inst, Dept Malignant Hematol, Tampa, FL USA. [Richardson, Paul] Dana Farber Canc Inst, Myeloma Program, Boston, MA 02115 USA. [Delforge, Michel] Univ Hosp Leuven, Dept Hematol, Leuven, Belgium. [Song, Kevin W.] Vancouver Gen Hosp, Div Hematol, Vancouver, BC, Canada. [San Miguel, Jesus F.] Univ Navarra Clin, CIMA, IDISNA, Clin & Translat Med, Pamplona, Spain. [Moreau, Philippe] CHU Nantes, CHU Hotel Dieu, Dept Hematol, Nantes, France. [Goldschmidt, Hartmut] Heidelberg Univ, Dept Med 5, Heidelberg, Germany. [Cavo, Michele] Univ Bologna, Sch Med, Seragnoli Inst Hematol, Bologna, Italy. [Jagannath, Sundar] Mt Sinai Hosp, Tisch Canc Inst, New York, NY 10029 USA. [Yu, Xin; Hong, Kevin; Sternas, Lars; Zaki, Mohamed] Celgene Corp, Summit, NJ USA. [Palumbo, Antonio] Univ Turin, Dept Hematol, Turin, Italy. RP Siegel, DS (reprint author), Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Myeloma Div, 92 Second St,Suite 340, Hackensack, NJ 07601 USA. EM DSiegel@HackensackUMC.org RI richard, chrystelle/K-8595-2015 FU Celgene Corporation FX The authors acknowledge financial support for this study from Celgene Corporation. The authors received editorial assistance from MediTech Media (Skye Geherin, PhD, and Peter J. Simon, PhD), sponsored by Celgene Corporation. NR 33 TC 4 Z9 4 U1 4 U2 4 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 PD DEC PY 2016 VL 57 IS 12 BP 2833 EP 2838 DI 10.1080/10428194.2016.1177181 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA DY9QU UT WOS:000385471000014 PM 27267105 ER PT J AU Le, M Unkelbach, J Ayache, N Delingette, H AF Le, Matthieu Unkelbach, Jan Ayache, Nicholas Delingette, Herve TI Sampling image segmentations for uncertainty quantification SO MEDICAL IMAGE ANALYSIS LA English DT Article; Proceedings Paper CT 18th International Conference on Medical Image Computing and Computer-Assisted Intervention (MICCAI) CY OCT 05-09, 2015 CL Munich, GERMANY SP Tech Univ Munich, Friedrich Alexander Univ Erlangen Nuremberg DE Segmentation; Uncertainty; Gaussian process; Radiotherapy planning; Brain tumor ID GAUSSIAN-PROCESSES; MODEL; INFERENCE AB In this paper, we introduce a method to automatically produce plausible image segmentation samples from a single expert segmentation. A probability distribution of image segmentation boundaries is defined as a Gaussian process, which leads to segmentations which are spatially coherent and consistent with the presence of salient borders in the image. The proposed approach is computationally efficient, and generates visually plausible samples. The variability between the samples is mainly governed by a parameter which may be correlated with a simple Dice's coefficient, or easily set by the user from the definition of probable regions of interest. The method is extended to the case of several neighboring structures, but also to account for under or over segmentation, and the presence of excluded regions. We also detail a method to sample segmentations with more general non-stationary covariance functions which relies on supervoxels. Furthermore, we compare the generated segmentation samples with several manual clinical segmentations of a brain tumor. Finally, we show how this approach can have useful applications in the field of uncertainty quantification, and an illustration is provided in radiotherapy planning, where segmentation sampling is applied to both the clinical target volume and the organs at risk. (C) 2016 Published by Elsevier B.V. C1 [Le, Matthieu; Ayache, Nicholas; Delingette, Herve] Inria Sophia Antipolis, Asclepios Project, Valbonne, France. [Unkelbach, Jan] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Unkelbach, Jan] Harvard Med Sch, Boston, MA USA. RP Le, M (reprint author), Inria Sophia Antipolis, Asclepios Project, Valbonne, France. EM matthieu.le@inria.fr NR 31 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1361-8415 EI 1361-8423 J9 MED IMAGE ANAL JI Med. Image Anal. PD DEC PY 2016 VL 34 BP 42 EP 51 DI 10.1016/j.media.2016.04.005 PG 10 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DY7PE UT WOS:000385320800005 PM 27198913 ER PT J AU Biggs, ML Doody, DR Trabert, B Starr, JR Chen, C Schwartz, SM AF Biggs, Mary L. Doody, David R. Trabert, Britton Starr, Jacqueline R. Chen, Chu Schwartz, Stephen M. TI Consumption of alcoholic beverages in adolescence and adulthood and risk of testicular germ cell tumor SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE alcohol drinking; epidemiology; nonseminoma; seminoma; testicular germ cell tumor ID MARIJUANA USE; TESTIS CANCER; TRENDS; POPULATION; COHORT; ASSOCIATION; MORTALITY; HORMONES; SEX; AGE AB The etiology of testicular germ cell tumor (TGCT) remains obscure and accumulating evidence suggests that postnatal environmental or lifestyle factors may play a role. To investigate whether consumption of alcoholic beverages during adolescence or adulthood is associated with TGCT risk, we analyzed data from a USA population-based case-control study of 540 18-44 year-old TGCT cases and 1,280 age-matched controls. Participants were queried separately about consumption of beer, wine and liquor during grades 7-8, grades 9-12 and the 5 years before reference date (date of diagnosis for cases and corresponding date for controls). We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association of TGCT risk with alcoholic beverage consumption during the different periods, both total and by specific beverage types and separately for seminomas and nonseminomas. Compared with nondrinkers in the 5 years before reference date, the OR (95% CI) for 1-6, 7-13 and 14 drinks per week were 1.20 (0.85, 1.69), 1.23 (0.81, 1.85) and 1.56 (1.03, 2.37), respectively (p-trend=0.04). The corresponding results for alcohol consumption in grades 9-12 were 1.39 (1.06, 1.82), 1.07 (0.72, 1.60), 1.53 (1.01, 2.31) (p-trend=0.05). Alcohol consumption in grades 7-8 was uncommon and no statistically significant associations with TGCT were observed. Associations with alcohol consumption in the 5 years before reference date appeared stronger for nonseminomas than for seminomas, but the differences were not statistically significant (p0.10). Associations were similar across different alcoholic beverage types. Consumption of alcoholic beverages may be associated with an increased TGCT risk. What's new? Drinking alcohol appears to boost risk of testicular cancer, according to new analysis. Not much is known about the causes of TGCT and these authors wondered if alcohol consumption might play a role. They interviewed 540 cases and 1280 controls about their consumption of beer, wine and liquor during high school and in the 5 years prior to diagnosis (or a randomly assigned reference date, for controls). Those who imbibed two or more drinks per day, in either time period, increased their risk by 50% compared with nondrinkers. C1 [Biggs, Mary L.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Doody, David R.; Chen, Chu; Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, POB 19024, Seattle, WA 98109 USA. [Trabert, Britton] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Starr, Jacqueline R.; Chen, Chu; Schwartz, Stephen M.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Starr, Jacqueline R.] Forsyth Inst, Dept Appl Oral Sci, Cambridge, MA USA. [Starr, Jacqueline R.] Harvard Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, Boston, MA USA. RP Schwartz, SM (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, POB 19024, Seattle, WA 98109 USA. EM sschwart@fhcrc.org RI Trabert, Britton/F-8051-2015 FU U.S. National Cancer Institute [R01CA085914, N01PC067009, N01PC35142, T32ES007262] FX Grant sponsor: U.S. National Cancer Institute; Grant numbers: R01CA085914; N01PC067009; N01PC35142; T32ES007262 NR 32 TC 0 Z9 0 U1 33 U2 33 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 DEC 1 PY 2016 VL 139 IS 11 BP 2405 EP 2414 DI 10.1002/ijc.30368 PG 10 WC Oncology SC Oncology GA DX8NQ UT WOS:000384646200003 PM 27474852 ER PT J AU Senderovich, A Weidlich, M Yedidsion, L Gal, A Mandelbaum, A Kadish, S Bunnell, CA AF Senderovich, Arik Weidlich, Matthias Yedidsion, Liron Gal, Avigdor Mandelbaum, Avishai Kadish, Sarah Bunnell, Craig A. TI Conformance checking and performance improvement in scheduled processes: A queueing-network perspective SO INFORMATION SYSTEMS LA English DT Article; Proceedings Paper CT 27th International Conference on Advanced Information Systems Engineering (CAiSE) CY JUN 08-12, 2015 CL Stockholm, SWEDEN DE Scheduled processes; Conformance checking; Process improvement; Queueing networks; Process mining; Scheduling; Statistical inference ID FORK-JOIN NETWORKS; WAITING-TIMES; DISCOVERY; FRAMEWORK; BEHAVIOR; QUEUES AB Service processes, for example in transportation, telecommunications or the health sector, are the backbone of today's economies. Conceptual models of service processes enable operational analysis that supports, e.g., resource provisioning or delay prediction. In the presence of event logs containing recorded traces of process execution, such operational models can be mined automatically. In this work, we target the analysis of resource-driven, scheduled processes based on event logs. We focus on processes for which there exists a pre-defined assignment of activity instances to resources that execute activities. Specifically, we approach the questions of conformance checking (how to assess the conformance of the schedule and the actual process execution) and performance improvement (how to improve the operational process performance). The first question is addressed based on a queueing network for both the schedule and the actual process execution. Based on these models, we detect operational deviations and then apply statistical inference and similarity measures to validate the scheduling assumptions, thereby identifying root-causes for these deviations. These results are the starting point for our technique to improve the operational performance. It suggests adaptations of the scheduling policy of the service process to decrease the tardiness (non-punctuality) and lower the flow time. We demonstrate the value of our approach based on a real-world dataset comprising clinical pathways of an outpatient clinic that have been recorded by a real-time location system (RTLS). Our results indicate that the presented technique enables localization of operational bottlenecks along with their root-causes, while our improvement technique yields a decrease in median tardiness and flow time by more than 20%. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Senderovich, Arik; Yedidsion, Liron; Gal, Avigdor; Mandelbaum, Avishai] Technion Israel Inst Technol, Haifa, Israel. [Weidlich, Matthias] Humboldt Univ, Berlin, Germany. [Kadish, Sarah; Bunnell, Craig A.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Senderovich, A (reprint author), Technion Israel Inst Technol, Haifa, Israel.; Weidlich, M (reprint author), Humboldt Univ, Berlin, Germany. EM sariks@tx.technion.ac.il; matthias.weidlich@hu-berlin.de; lirony@ie.technion.ac.il; avigal@ie.technion.ac.il; avim@ie.technion.ac.il; sarah_kadish@dfci.harvard.edu; craig_bunnell@dfci.harvard.edu NR 56 TC 0 Z9 0 U1 22 U2 22 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4379 EI 1873-6076 J9 INFORM SYST JI Inf. Syst. PD DEC PY 2016 VL 62 BP 185 EP 206 DI 10.1016/j.is.2016.01.002 PG 22 WC Computer Science, Information Systems SC Computer Science GA DY0IM UT WOS:000384780500011 ER PT J AU Atem, FD Qian, J Maye, JE Johnson, KA Betensky, RA AF Atem, Folefac D. Qian, Jing Maye, Jacqueline E. Johnson, Keith A. Betensky, Rebecca A. TI Multiple imputation of a randomly censored covariate improves logistic regression analysis SO JOURNAL OF APPLIED STATISTICS LA English DT Article DE Alzheimer's disease; age of onset; complete case analysis; limit of detection; reverse survival regression ID MATERNAL FAMILY-HISTORY; ALZHEIMER-DISEASE; RISK; TRANSMISSION; DEMENTIA; EXPOSURE; CHILDREN; DECLINE AB Randomly censored covariates arise frequently in epidemiologic studies. The most commonly used methods, including complete case and single imputation or substitution, suffer from inefficiency and bias. They make strong parametric assumptions or they consider limit of detection censoring only. We employ multiple imputation, in conjunction with semi-parametric modeling of the censored covariate, to overcome these shortcomings and to facilitate robust estimation. We develop a multiple imputation approach for randomly censored covariates within the framework of a logistic regression model. We use the non-parametric estimate of the covariate distribution or the semi-parametric Cox model estimate in the presence of additional covariates in the model. We evaluate this procedure in simulations, and compare its operating characteristics to those from the complete case analysis and a survival regression approach. We apply the procedures to an Alzheimer's study of the association between amyloid positivity and maternal age of onset of dementia. Multiple imputation achieves lower standard errors and higher power than the complete case approach under heavy and moderate censoring and is comparable under light censoring. The survival regression approach achieves the highest power among all procedures, but does not produce interpretable estimates of association. Multiple imputation offers a favorable alternative to complete case analysis and ad hoc substitution methods in the presence of randomly censored covariates within the framework of logistic regression. C1 [Atem, Folefac D.; Betensky, Rebecca A.] Harvard TH Chan Sch Publ Hlth, Biostat, Boston, MA 02115 USA. [Qian, Jing] Univ Massachusetts, Publ Hlth, Amherst, MA 01003 USA. [Maye, Jacqueline E.] Univ Florida, Clin & Hlth Psychol, Gainesville, FL USA. [Johnson, Keith A.] Massachusetts Gen Hosp, Radiol, Boston, MA 02114 USA. RP Betensky, RA (reprint author), Harvard TH Chan Sch Publ Hlth, Biostat, Boston, MA 02115 USA. EM betensky@hsph.harvard.edu FU National Institutes of Health [5T32NS048005, 5P50AG005134, 5P01AG036694]; Harvard NeuroDiscovery Center FX This work was supported by National Institutes of Health grants [5T32NS048005, 5P50AG005134, 5P01AG036694]; Harvard NeuroDiscovery Center. NR 30 TC 0 Z9 0 U1 13 U2 13 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0266-4763 EI 1360-0532 J9 J APPL STAT JI J. Appl. Stat. PD DEC PY 2016 VL 43 IS 15 BP 2886 EP 2896 DI 10.1080/02664763.2016.1155110 PG 11 WC Statistics & Probability SC Mathematics GA DX3HA UT WOS:000384263000012 PM 27713593 ER PT J AU Epstein, AJ Nicholson, S Asch, DA AF Epstein, Andrew J. Nicholson, Sean Asch, David A. TI THE PRODUCTION OF AND MARKET FOR NEW PHYSICIANS' SKILL SO AMERICAN JOURNAL OF HEALTH ECONOMICS LA English DT Article DE physician skill production; market learning ID CARDIAC-SURGEONS; QUALITY; MORTALITY; SERVICES; OUTCOMES; VOLUME; CARE; REGRESSION; SELECTION; PATTERNS AB Our understanding of the determinants of physician skill and the extent to which skill is valued in the marketplace is superficial. Using a large, detailed panel of new obstetricians, we find that, even though physicians' maternal complication rates improve steadily with experience, initial skill (as measured by performance in a physician's first year of practice) explains more of the variation in physician performance over time than experience does. At the same time, we find that the trajectories of new physicians' delivery volume develop in a way consistent with Bayesian learning about physician quality. As physicians gain experience, their volume becomes increasingly sensitive to the information in their accumulated prior belief, while responses to information on recent performance are detectable in only selected settings (e.g., vaginal delivery, commercially insured patients). C1 [Epstein, Andrew J.; Asch, David A.] Philadelphia VAMC, Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA. [Epstein, Andrew J.; Asch, David A.] Univ Penn, Philadelphia, PA 19104 USA. [Nicholson, Sean] Cornell Univ, Ithaca, NY 14853 USA. RP Epstein, AJ (reprint author), Philadelphia VAMC, Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA.; Epstein, AJ (reprint author), Univ Penn, Philadelphia, PA 19104 USA. EM eandrew@mail.med.upenn.edu NR 36 TC 0 Z9 0 U1 11 U2 11 PU MIT PRESS PI CAMBRIDGE PA ONE ROGERS ST, CAMBRIDGE, MA 02142-1209 USA SN 2332-3493 EI 2332-3507 J9 AM J HEALTH ECON JI AM. J. HEALTH ECON. PD WIN PY 2016 VL 2 IS 1 BP 41 EP 65 DI 10.1162/ajhe_a_00033 PG 25 WC Economics; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA DS1PG UT WOS:000380367800002 ER PT J AU Iverson, GL AF Iverson, Grant L. TI Suicide and Chronic Traumatic Encephalopathy SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID MILD COGNITIVE IMPAIRMENT; STRESSFUL LIFE EVENTS; PROFESSIONAL FOOTBALL PLAYERS; MAJOR DEPRESSIVE DISORDER; BRAIN-INJURY; CHRONIC PAIN; PSYCHIATRIC-DISORDERS; ALZHEIMERS-DISEASE; PROSPECTIVE COHORT; RISK-FACTORS AB For nearly 80 years, suicidality was not considered to be a core clinical feature of chronic traumatic encephalopathy (CTE). In recent years, suicide has been widely cited as being associated with CTE, and now depression has been proposed to be one of three core diagnostic features alongside cognitive impairment and anger control problems. This evolution of the clinical features has been reinforced by thousands of media stories reporting a connection between mental health problems in former athletes and military veterans, repetitive neurotrauma, and CTE. At present, the science underlying the causal assumption between repetitive neurotrauma, depression, suicide, and the neuropathology believed to be unique to CTE is inconclusive. Epidemiological evidence indicates that former National Football League players, for example, are at lower, not greater, risk for suicide than men in the general population. This article aims to discuss the critical issues and literature relating to these possible relationships. C1 [Iverson, Grant L.] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Iverson, Grant L.] Spaulding Rehabil Hosp, Boston, MA USA. [Iverson, Grant L.] MassGen Hosp Children Sports Concuss Program, Boston, MA USA. [Iverson, Grant L.] Red Sox Fdn, Boston, MA USA. [Iverson, Grant L.] Massachusetts Gen Hosp, Home Base Program, Boston, MA 02114 USA. RP Iverson, GL (reprint author), Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA.; Iverson, GL (reprint author), Spaulding Rehabil Hosp, Boston, MA USA.; Iverson, GL (reprint author), MassGen Hosp Children Sports Concuss Program, Boston, MA USA.; Iverson, GL (reprint author), Red Sox Fdn, Boston, MA USA.; Iverson, GL (reprint author), Massachusetts Gen Hosp, Home Base Program, Boston, MA 02114 USA. EM giverson@mgh.harvard.edu NR 143 TC 3 Z9 3 U1 63 U2 271 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 EI 1545-7222 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD WIN PY 2016 VL 28 IS 1 BP 9 EP 16 DI 10.1176/appi.neuropsych.15070172 PG 8 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DM0PB UT WOS:000376046800013 PM 26449269 ER PT J AU Widge, AS Licon, E Zorowitz, S Corse, A Arulpragasam, AR Camprodon, JA Cusin, C Eskandar, EN Deckersbach, T Dougherty, DD AF Widge, Alik S. Licon, Ernesto Zorowitz, Samuel Corse, Andrew Arulpragasam, Amanda R. Camprodon, Joan A. Cusin, Cristina Eskandar, Emad N. Deckersbach, Thilo Dougherty, Darin D. TI Predictors of Hypomania During Ventral Capsule/Ventral Striatum Deep Brain Stimulation SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID OBSESSIVE-COMPULSIVE DISORDER; TREATMENT-RESISTANT DEPRESSION; MODEL; CURVES AB Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) is a novel therapy for neuropsychiatric disorders. Hypomania is a known complication of VC/VS DBS, but who is at risk is less understood. Factors such as family history, combined with details of DBS programming, might quantify that risk. The authors performed an iterative modeling procedure on a VC/VS DBS patient registry to identify key predictors. Hypomania was less common for men and for patients stimulated on the ventral right contact. It was more common with right monopolar stimulation. These findings may help to establish decision rules to reduce complications of VC/VS DBS. C1 [Widge, Alik S.; Zorowitz, Samuel; Corse, Andrew; Arulpragasam, Amanda R.; Camprodon, Joan A.; Cusin, Cristina; Deckersbach, Thilo; Dougherty, Darin D.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Eskandar, Emad N.] Massachusetts Gen Hosp, Dept Neurol Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Widge, Alik S.] MIT, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. [Licon, Ernesto] Texas A&M Hlth Sci Ctr, Bryan, TX USA. RP Widge, AS (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.; Widge, AS (reprint author), MIT, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. EM awidge@partners.org FU Picower Family Foundation; NIMH [MH076179]; University of California, San Diego Division of Geriatric Psychiatry M-STREAM program; Defense Advanced Research Projects Agency [W911NF-14-2-0045]; Medtronic; NIMH FX This research was supported by a Picower Family Foundation grant to Dr. Widge; NIMH grant MH076179 to Drs. Eskandar and Dougherty; University of California, San Diego Division of Geriatric Psychiatry M-STREAM program support to Dr. Licon; and Defense Advanced Research Projects Agency Cooperative Agreement W911NF-14-2-0045 to Drs. Widge, Zorowitz, Arulpragasam, Eskandar, Deckersbach, and Dougherty. The underlying clinical trials were supported through Medtronic and NIMH. The funding sources for this research had no direct role in the study design, analysis, or publication. The opinions expressed herein are those of the authors, not their funding agencies. NR 30 TC 0 Z9 0 U1 30 U2 52 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 EI 1545-7222 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD WIN PY 2016 VL 28 IS 1 BP 38 EP 44 DI 10.1176/appi.neuropsych.15040089 PG 7 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DM0PB UT WOS:000376046800017 PM 26404172 ER PT J AU Goetz, JM Pitman, SR Tanev, KS Pitman, RK Chemtob, CM AF Goetz, Jared M. Pitman, Seth R. Tanev, Kaloyan S. Pitman, Roger K. Chemtob, Claude M. TI Mixed-Handedness in Identical Twins Discordant for Combat Exposure in Vietnam: Relationship to Posttraumatic Stress Disorder SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID ADMINISTERED PTSD SCALE; LATERAL PREFERENCE; MENTAL-HEALTH AB This study evaluated the degree of mixed-handedness in predominantly right-handed Vietnam combat veteran twins and their identical, combat-unexposed cotwins. The "high-risk" cotwins of combat veterans with combat-related posttraumatic stress disorder (PTSD) had more mixed-handedness (i.e., less right-handedness) than the "low-risk" cotwins of combat veterans without PTSD. Self-reported combat exposure in combat-exposed twins was a mediator of the association between handedness in their unexposed cotwins and PTSD in the twins themselves. We conclude that mixed-handedness is a familial risk factor for combat-related PTSD. This risk may be mediated in part by a proclivity for mixed-handed soldiers and Marines to experience heavier combat. C1 [Goetz, Jared M.; Tanev, Kaloyan S.; Pitman, Roger K.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Goetz, Jared M.; Tanev, Kaloyan S.; Pitman, Roger K.] Harvard Univ, Sch Med, Boston, MA USA. [Pitman, Seth R.] Adelphi Univ, Derner Inst Adv Psychol Studies, Garden City, NY USA. [Chemtob, Claude M.] NYU, Dept Child Psychiat, New York, NY USA. RP Pitman, RK (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.; Pitman, RK (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM roger_pitman@hms.harvard.edu FU U.S. PHS [R01MH54636]; U.S. Department of Veterans Affairs FX This work was supported by U.S. PHS grant R01MH54636. The U.S. Department of Veterans Affairs provided financial support for the development and maintenance of the Vietnam Era Twin (VET) Registry. Through their support of the VET Registry, numerous other U.S. organizations also provided invaluable assistance, including the Department of Defense; National Personnel Records Center, National Archives and Records Administration; Internal Revenue Service; National Institutes of Health; National Opinion Research Center; National Research Council, National Academy of Sciences; and Institute for Survey Research, Temple University. NR 24 TC 0 Z9 0 U1 7 U2 32 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 EI 1545-7222 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD WIN PY 2016 VL 28 IS 1 BP 45 EP 48 DI 10.1176/appi.neuropsych.15040090 PG 4 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DM0PB UT WOS:000376046800018 PM 26404173 ER PT J AU Sarkis, RA Dickerson, BC Cole, AJ Chemali, ZN AF Sarkis, Rani A. Dickerson, Bradford C. Cole, Andrew J. Chemali, Zeina N. TI Clinical and Neurophysiologic Characteristics of Unprovoked Seizures in Patients Diagnosed With Dementia SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID ONSET ALZHEIMERS-DISEASE; EPILEPTIFORM ACTIVITY; ILAE COMMISSION; EPILEPSY; DEFINITION; PREDICTORS; CRITERIA AB Seizures are a common comorbid condition in patients with dementia, but their characteristics have been poorly described. The authors performed a retrospective chart review using ICD-9 diagnosis codes consistent with seizures and with dementia. Seventy-seven patients were identified. Average age at onset was 68.1 years for cognitive symptoms, 71.5 years for dementia, and 73.9 years for seizures. Seizures preceded or followed cognitive symptoms (4.3 years before and 18.7 years after). At last follow-up, 12% of patients continued to have seizures. Findings show that unprovoked seizures can precede or follow the onset of dementia, but these seizures are controlled with medications in the majority of patients. C1 [Sarkis, Rani A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Edward B Bromfield Epilepsy Ctr, Boston, MA 02115 USA. [Dickerson, Bradford C.] Massachusetts Gen Hosp, Frontotemporal Dementia Unit, Boston, MA 02114 USA. [Dickerson, Bradford C.] Massachusetts Gen Hosp, Alzheimers Dis Res Ctr, Boston, MA 02114 USA. [Cole, Andrew J.] Massachusetts Gen Hosp, Dept Neurol, Epilepsy Serv, Boston, MA 02114 USA. [Chemali, Zeina N.] Massachusetts Gen Hosp, Dept Psychiat, Neuropsychiat Clin, Boston, MA 02114 USA. [Chemali, Zeina N.] Massachusetts Gen Hosp, Dept Neurol, Neuropsychiat Clin, Boston, MA 02114 USA. RP Sarkis, RA (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Edward B Bromfield Epilepsy Ctr, Boston, MA 02115 USA. EM rsarkis@partners.org NR 32 TC 2 Z9 2 U1 80 U2 149 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 EI 1545-7222 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD WIN PY 2016 VL 28 IS 1 BP 56 EP 61 DI 10.1176/appi.neuropsych.15060143 PG 6 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DM0PB UT WOS:000376046800020 PM 26404175 ER PT J AU Anderson, CA Woodcock, JH Filley, CM AF Anderson, C. Alan Woodcock, Jonathan H. Filley, Christopher M. TI Transient Prosopagnosia With Right Temporal Astrocytoma SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Letter ID FACE; SYNESTHESIA C1 [Anderson, C. Alan; Woodcock, Jonathan H.; Filley, Christopher M.] Univ Colorado, Sch Med, Dept Neurol, Behav Neurol Sect, Aurora, CO USA. [Anderson, C. Alan; Woodcock, Jonathan H.; Filley, Christopher M.] Univ Colorado, Sch Med, Dept Psychiat, Behav Neurol Sect, Aurora, CO USA. [Anderson, C. Alan; Filley, Christopher M.] Denver Vet Affairs Med Ctr, Denver, CO USA. RP Anderson, CA (reprint author), Univ Colorado, Sch Med, Dept Neurol, Behav Neurol Sect, Aurora, CO USA.; Anderson, CA (reprint author), Univ Colorado, Sch Med, Dept Psychiat, Behav Neurol Sect, Aurora, CO USA.; Anderson, CA (reprint author), Denver Vet Affairs Med Ctr, Denver, CO USA. EM al.anderson@ucdenver.edu NR 10 TC 0 Z9 0 U1 11 U2 13 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 EI 1545-7222 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD WIN PY 2016 VL 28 IS 1 BP E13 EP E14 DI 10.1176/appi.neuropsych.15070169 PG 2 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DM0PB UT WOS:000376046800006 PM 26844963 ER PT J AU Abers, MS Ghebremichael, MS Timmons, AK Warren, HS Poznansky, MC Vyas, JM AF Abers, Michael S. Ghebremichael, Musie S. Timmons, Allison K. Warren, H. Shaw Poznansky, Mark C. Vyas, Jatin M. TI A Critical Reappraisal of Prolonged Neutropenia as a Risk Factor for Invasive Pulmonary Aspergillosis SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE Aspergillus; immunosuppression; invasive aspergillosis; invasive fungal infection; neutropenia ID DISEASE AB Prolonged neutropenia is generally thought to be the major factor for invasive pulmonary aspergillosis (IPA). In the present study, we characterize the frequency, severity, and duration of neutropenia that immediately precedes IPA. Prolonged neutropenia was identified in only one third of all IPA cases and occurred exclusively in hematologic patients. C1 [Abers, Michael S.; Ghebremichael, Musie S.; Timmons, Allison K.; Warren, H. Shaw; Poznansky, Mark C.; Vyas, Jatin M.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Abers, Michael S.; Ghebremichael, Musie S.; Warren, H. Shaw; Poznansky, Mark C.; Vyas, Jatin M.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Ghebremichael, Musie S.] MGH MIT & Harvard, Ragon Inst, Cambridge, MA USA. [Poznansky, Mark C.] Massachusetts Gen Hosp, Vaccine & Immunotherapy Ctr, Boston, MA 02114 USA. RP Vyas, JM (reprint author), 55 Fruit St,GRJ-5-504, Boston, MA 02114 USA. EM jvyas@partners.org OI Lord, Allison/0000-0002-8412-315X NR 7 TC 1 Z9 1 U1 6 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD WIN PY 2016 VL 3 IS 1 DI 10.1093/ofid/ofw036 PG 3 WC Infectious Diseases SC Infectious Diseases GA DJ4QB UT WOS:000374190900076 ER PT J AU Reddy, KP Bajwa, EK Parker, RA Onderdonk, AB Walensky, RP AF Reddy, Krishna P. Bajwa, Ednan K. Parker, Robert A. Onderdonk, Andrew B. Walensky, Rochelle P. TI Relationship Between Upper Respiratory Tract Influenza Test Result and Clinical Outcomes Among Critically Ill Influenza Patients SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE critically ill; influenza diagnosis; lower respiratory tract; upper respiratory tract ID 2009 A(H1N1) INFLUENZA; CRITICAL ILLNESS; VIRUS; INFECTION AB Among critically ill patients with lower respiratory tract (LRT)-confirmed influenza, we retrospectively observed worse 28-day clinical outcomes in upper respiratory tract (URT)-negative versus URT-positive subjects. This finding may reflect disease progression and highlights the need for influenza testing of both URT and LRT specimens to improve diagnostic yield and possibly inform prognosis. C1 [Reddy, Krishna P.; Parker, Robert A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, 50 Staniford St,9th Floor, Boston, MA 02114 USA. [Reddy, Krishna P.; Bajwa, Ednan K.] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Parker, Robert A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Parker, Robert A.] Massachusetts Gen Hosp, Biostat Ctr, Boston, MA 02114 USA. [Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Reddy, Krishna P.] Brigham & Womens Hosp, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA. [Onderdonk, Andrew B.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. [Reddy, Krishna P.] Beth Israel Deaconess Med Ctr, Div Pulm & Crit Care Med, Boston, MA 02215 USA. [Reddy, Krishna P.; Bajwa, Ednan K.; Parker, Robert A.; Onderdonk, Andrew B.; Walensky, Rochelle P.] Harvard Univ, Sch Med, Boston, MA USA. RP Reddy, KP (reprint author), Massachusetts Gen Hosp, Med Practice Evaluat Ctr, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM kpreddy@partners.org NR 13 TC 1 Z9 1 U1 11 U2 21 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD WIN PY 2016 VL 3 IS 1 DI 10.1093/ofid/ofw023 PG 3 WC Infectious Diseases SC Infectious Diseases GA DJ4QB UT WOS:000374190900063 ER PT J AU Siedner, MJ AF Siedner, Mark J. TI START or SMART? Timing of Antiretroviral Therapy Initiation and Cardiovascular Risk for People With Human Immunodeficiency Virus Infection SO OPEN FORUM INFECTIOUS DISEASES LA English DT Review DE antiretroviral therapy; cardiovascular disease; epidemiology; HIV/AIDS; systematic review ID INTIMA-MEDIA THICKNESS; T-CELL COUNT; SUBCLINICAL CORONARY ATHEROSCLEROSIS; POPULATION-BASED COHORT; CHRONIC HIV-INFECTION; HEALTH-CARE-SYSTEM; MYOCARDIAL-INFARCTION; HEART-DISEASE; CAROTID ATHEROSCLEROSIS; IMMUNE ACTIVATION AB The Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection (START) study has reinforced the benefits of early initiation of antiretroviral therapy (ART). However, a notable secondary finding from that study was that immediate initiation of ART did not prevent cardiovascular disease (CVD) events (0.17 vs 0.20 events/1000 person-years, P = .65). This result appears to contradict a body of evidence, most notably from the Strategies for Management of Antiretroviral Therapy (SMART) study, which reported a 70% increased hazard of cardiovascular events for those deferring or interrupting treatment. Thus, an important unresolved question is whether the timing of ART impacts CVD risk. In this review, published data on relationships between timing of ART and CVD risk are reviewed. The data support a role for ART in mitigating CVD risk at lower CD4 counts, but data also suggests that, among those initiating therapy early, ART alone appears to suboptimally mitigate CVD risk. Additional interventions to address CVD risk among human immunodeficiency virus-infected populations are likely to be needed. C1 [Siedner, Mark J.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Siedner, Mark J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Siedner, MJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Global Hlth, 125 Nashua St,Suite 722, Boston, MA 02114 USA. EM msiedner@mgh.harvard.edu NR 71 TC 1 Z9 1 U1 29 U2 97 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD WIN PY 2016 VL 3 IS 1 DI 10.1093/ofid/ofw032 PG 8 WC Infectious Diseases SC Infectious Diseases GA DJ4QB UT WOS:000374190900072 ER PT J AU Thorner, AR Cao, B Jiang, T Warner, AJ Bonis, PA AF Thorner, Anna R. Cao, Bin Jiang, Terrence Warner, Amy J. Bonis, Peter A. TI Correlation Between UpToDate Searches and Reported Cases of Middle East Respiratory Syndrome During Outbreaks in Saudi Arabia SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE digital disease detection; epidemic intelligence; Middle East respiratory syndrome (MERS); Middle East respiratory syndrome coronavirus (MERS-CoV); UpToDate ID SURVEILLANCE AB Background. UpToDate is an online clinical decision support resource that is used extensively by clinicians around the world. Digital surveillance techniques have shown promise to aid with the detection and monitoring of infectious disease outbreaks. We sought to determine whether UpToDate searches for Middle East respiratory syndrome (MERS) could be used to detect and monitor MERS outbreaks in Saudi Arabia. Methods. We analyzed daily searches related to MERS in Jeddah and Riyadh, Saudi Arabia during 3 outbreaks in these cities in 2014 and 2015 and compared them with reported cases during the same periods. We also compared UpToDate MERS searches in the affected cities to those in a composite of 4 negative control cities for the 2 outbreaks in 2014. Results. UpToDate MERS searches during all 3 MERS outbreaks in Saudi Arabia showed a correlation to reported cases. In addition, UpToDate MERS search volume in Jeddah and Riyadh during the outbreak periods in 2014 was significantly higher than the concurrent search volume in the 4 negative control cities. In contrast, during the baseline periods, there was no difference between UpToDate searches for MERS in the affected cities compared with the negative control cities. Conclusions. UpToDate search activity seems to be useful for detecting and monitoring outbreaks of MERS in Saudi Arabia. C1 [Thorner, Anna R.; Cao, Bin; Jiang, Terrence; Warner, Amy J.; Bonis, Peter A.] Wolters Kluwer Hlth, UpToDate, 230 Third Ave, Waltham, MA 02451 USA. [Thorner, Anna R.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Thorner, Anna R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Thorner, Anna R.] Harvard Univ, Sch Med, Boston, MA USA. [Bonis, Peter A.] Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Thorner, AR (reprint author), Wolters Kluwer Hlth, UpToDate, 230 Third Ave, Waltham, MA 02451 USA. EM anna.thorner@wolterskluwer.com NR 17 TC 1 Z9 1 U1 12 U2 24 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD WIN PY 2016 VL 3 IS 1 DI 10.1093/ofid/ofw043 PG 5 WC Infectious Diseases SC Infectious Diseases GA DJ4QB UT WOS:000374190900082 ER PT J AU Wesolowski, LG Nasrullah, M Coombs, RW Rosenberg, E Ethridge, SF Hutchinson, AB Dragavon, J Rychert, J Nolte, FS Madory, JE Werner, BG AF Wesolowski, Laura G. Nasrullah, Muazzam Coombs, Robert W. Rosenberg, Eric Ethridge, Steven F. Hutchinson, Angela B. Dragavon, Joan Rychert, Jennifer Nolte, Frederick S. Madory, James E. Werner, Barbara G. TI Acute Infections, Cost per Infection and Turnaround Time in Three United States Hospital Laboratories Using Fourth-Generation Antigen-Antibody Human Immunodeficiency Virus Immunoassays SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE acute infection; cost; HIV; laboratory ID HIV-1 INFECTION; ANTIRETROVIRAL THERAPY; RAPID TEST; TRANSMISSION; PERFORMANCE; ASSAY; INDIVIDUALS; ALGORITHMS; PLASMA; TYPE-1 AB Background. To improve clinical and public health outcomes through early human immunodeficiency virus (HIV) detection, fourth-generation antigen/antibody immunoassay (4IA) and supplemental testing results must be returned rapidly. Methods. We examined HIV testing data at Harborview Medical Center (HMC), Massachusetts General Hospital (MGH), and the Medical University of South Carolina (MUSC), which used 4IA and supplemental antibody and nucleic acid tests (NATs). At MGH and MUSC, HIV-1 Western blot (WB) and HIV-2 testing were conducted at a reference laboratory. We compared time from specimen collection to laboratory result for established (positive WB) and acute infections (reactive 4IA, negative/indeterminate WB, detectable NAT), and we calculated testing cost per positive-test result. Results. From 3731 (MUSC) to 19 774 (MGH) tests were conducted; 0.01% (MGH) to 0.05% (HMC) were acute infections. Each laboratory had reactive 4IA, WB-negative, or indeterminate specimens without NAT (ie, potential acute infections). Time to result was 1.5 (HMC) to 5.2 days (MGH) for acute and 1.0 (HMC) to 5.2 days (MGH) for established infections. Costs were $1054 (MGH) to $1521 (MUSC). Conclusions. Conducting supplemental testing in-house lowered turnaround times, which may be further reduced with rapid HIV-1/HIV-2 differentiation tests. Hospitals may benefit from quantitative NATs not requiring physician orders, so all potential acute infections receive NAT. C1 [Wesolowski, Laura G.; Nasrullah, Muazzam; Ethridge, Steven F.; Hutchinson, Angela B.] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Natl Ctr HIV Hepatitis STD & TB Prevent, Atlanta, GA 30333 USA. [Coombs, Robert W.; Dragavon, Joan] Univ Washington, Harborview Med Ctr, Dept Lab Med, 325 9Th Ave, Seattle, WA 98104 USA. [Coombs, Robert W.] Univ Washington, Harborview Med Ctr, Dept Med, Seattle, WA 98104 USA. [Rosenberg, Eric] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Rosenberg, Eric; Rychert, Jennifer] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Nolte, Frederick S.; Madory, James E.] Med Univ S Carolina, Dept Pathol & Lab Med, Charleston, SC USA. [Werner, Barbara G.] Massachusetts Dept Publ Hlth, Bur Infect Dis, Boston, MA USA. [Rychert, Jennifer] ARUP Inst Clin & Expt Pathol, Salt Lake City, UT USA. RP Wesolowski, LG (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd NE,MS E46, Atlanta, GA 30333 USA. EM lig7@cdc.gov NR 31 TC 0 Z9 0 U1 18 U2 36 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD WIN PY 2016 VL 3 IS 1 DI 10.1093/ofid/ofv188 PG 8 WC Infectious Diseases SC Infectious Diseases GA DJ4QB UT WOS:000374190900010 ER PT J AU Kressin, NR Long, JA Glickman, ME Bokhour, BG Orner, MB Clark, C Rothendler, JA Berlowitz, DR AF Kressin, Nancy R. Long, Judith A. Glickman, Mark E. Bokhour, Barbara G. Orner, Michelle B. Clark, Christine Rothendler, James A. Berlowitz, Dan R. TI A BRIEF, MULTIFACETED, GENERIC INTERVENTION TO IMPROVE BLOOD PRESSURE CONTROL AND REDUCE DISPARITIES HAD LITTLE EFFECT SO ETHNICITY & DISEASE LA English DT Article DE Physician-Patient Relations; Hypertension; Patient Compliance ID WORCESTER-AREA TRIAL; HYPERTENSION MANAGEMENT; MEDICATION ADHERENCE; RACIAL DISPARITIES; ANTIHYPERTENSIVE THERAPY; HYPERLIPIDEMIA WATCH; DIABETES-MELLITUS; RANDOMIZED-TRIAL; UNITED-STATES; HEALTH-CARE AB Background: Poor blood pressure (BP) control and racial disparities therein may be a function of clinical inertia and ineffective communication about BP care. Methods: We compared two different interventions (electronic medical record reminder for BP care (Reminder only, [RO]), and clinician training on BP care-related communication skills plus the reminder (Reminder + Training, [R + T]) with usual care in three primary care clinics, examining BP outcomes among 8,866 patients, and provider-patient communication and medication adherence among a subsample of 793. Results: Clinician counseling improved most at R + T. BP improved overall; R + T had a small but significantly greater reduction in diastolic BP (DBP; -1.7 mm Hg). White patients at RO experienced greater overall improvements in BP control. Site and race disparities trends suggested that disparities decreased at R + T, either stayed the same or decreased at Control; and stayed the same or increased at RO. Conclusions: More substantial or racial/ethnically tailored interventions are needed. C1 [Kressin, Nancy R.] VA Boston Healthcare Syst, 150 S Huntington Ave,152c,Bldg 9,4th Floor, Boston, MA 02130 USA. [Kressin, Nancy R.; Glickman, Mark E.; Bokhour, Barbara G.; Orner, Michelle B.; Rothendler, James A.; Berlowitz, Dan R.] Boston Bedford VA Med Ctr, Ctr Healthcare Org & Implementat Res, Boston, MA USA. [Kressin, Nancy R.] Boston Univ, Sch Med, Sect Gen Internal Med, Boston, MA 02215 USA. [Kressin, Nancy R.] Health Care Dispar Res Program, Boston, MA USA. [Long, Judith A.] Philadelphia VAMC, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Long, Judith A.] Univ Penn, Sch Med, Dept Internal Med, Philadelphia, PA 19104 USA. [Glickman, Mark E.; Bokhour, Barbara G.; Rothendler, James A.; Berlowitz, Dan R.] Boston Univ, Sch Publ Hlth, Hlth Policy & Management Dept, Boston, MA 02215 USA. [Clark, Christine] Univ Illinois, Chicago, IL USA. RP Kressin, NR (reprint author), VA Boston Healthcare Syst, 150 S Huntington Ave,152c,Bldg 9,4th Floor, Boston, MA 02130 USA. EM Nkressin@bu.edu FU VA Health Services Research and Development Service [TRH01-038]; Senior Research Career Scientist Award, VA Health Services Research Development [RCS 02-066]; VA HSRD Service [00-023] FX This research was supported by funding from the VA Health Services Research and Development Service (TRH01-038, N. Kressin, P.I.). Dr. Kressin is supported by a Senior Research Career Scientist Award, VA Health Services Research & Development (RCS 02-066); Dr. Long was an Associate in the Career Development Award Program of the VA HSR&D Service when this work was performed (CDA # 00-023). We thank Surekha Reddy, MD, and Laura P. Kroupa, MD for their contributions to the study. NR 42 TC 0 Z9 0 U1 46 U2 121 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X EI 1945-0826 J9 ETHNIC DIS JI Ethn. Dis. PD WIN PY 2016 VL 26 IS 1 BP 27 EP 36 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DJ1EI UT WOS:000373945700004 PM 26843793 ER PT J AU Koven, S AF Koven, Suzanne TI Poor Historians Some Notes on the Medical Memoir SO VIRGINIA QUARTERLY REVIEW LA English DT Article C1 [Koven, Suzanne] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. RP Koven, S (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV VIRGINIA PI CHARLOTTESVILLE PA ONE WEST RANGE, BOX 400223 W RANGE, CHARLOTTESVILLE, VA 22904-4223 USA SN 0042-675X EI 2154-6932 J9 VA QUART REV JI VA. Q. Rev. PD WIN PY 2016 VL 92 IS 1 BP 172 EP 180 PG 9 WC Literary Reviews SC Literature GA DA5UY UT WOS:000367869300012 ER PT J AU Lee, HW Lee, JH Kim, JS Mun, JH Chung, JH Koo, H Kim, CH Yun, SH Hahn, SK AF Lee, Hwiwon Lee, Jung Ho Kim, Jeesu Mun, Jong Hwan Chung, Junho Koo, Heebeom Kim, Chulhong Yun, Seok Hyun Hahn, Sei Kwang TI Hyaluronate-Gold Nanorod/DR5 Antibody Complex for Noninvasive Theranosis of Skin Cancer SO ACS APPLIED MATERIALS & INTERFACES LA English DT Article DE gold nanorod; hyaluronate; antibody; transdermal delivery; skin cancer ID PHOTOTHERMAL THERAPY; MONOCLONAL-ANTIBODY; OPTICAL-PROPERTIES; PLASMON RESONANCE; CONTRAST AGENTS; IN-VITRO; DELIVERY; ACID; DEATH; NANOPARTICLES AB Noninvasive transdermal delivery is a promising method with distinct advantages including patient compliance over other delivery routes. Here, hyaluronate gold nanorod/death receptor 5 antibody (HA-AuNR/DR5 Ab) complex was developed for transdermal theranosis of skin cancer. The successful formation of the complex was corroborated by H-1 nuclear magnetic resonance, UV vis spectroscopy, dynamic light scattering, zeta potential, and transmission electron microscopy. In vitro biological activity of the complex was verified by ELISA and MTT assay using HCT116 cancer cells. In addition, in vivo photoacoustic imaging and two-photon microscopy clearly-visualized the transdermal delivery of HA-AuNR/DR5 Ab complex through the inevitable barrier of stratum corneum in the skin. Furthermore, in vivo antitumor effect on skin cancer model mice was confirmed from statistically significant decrease of tumor-reflecting luciferase expression levels and apoptotic signals in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Taken together, we could confirm the feasibility of HA-AuNR/DR5 Ab complex as a novel theranostic platform for noninvasive transdermal treatment of skin cancers. C1 [Lee, Hwiwon; Lee, Jung Ho; Mun, Jong Hwan; Hahn, Sei Kwang] Pohang Univ Sci & Technol POSTECH, Dept Mat Sci & Engn, 77 Cheongam Ro, Pohang 37673, Gyeongbuk, South Korea. [Kim, Jeesu; Kim, Chulhong] Pohang Univ Sci & Technol POSTECH, Dept Creat IT Engn, 77 Cheongam Ro, Pohang 37673, Gyeongbuk, South Korea. [Kim, Jeesu; Kim, Chulhong] Pohang Univ Sci & Technol POSTECH, Dept Elect Engn, 77 Cheongam Ro, Pohang 37673, Gyeongbuk, South Korea. [Chung, Junho] Seoul Natl Univ, Coll Med, Dept Biochem & Mol Biol, Seoul 151742, South Korea. [Chung, Junho] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 151742, South Korea. [Koo, Heebeom; Yun, Seok Hyun] Harvard Med Sch, Wellman Ctr Photomed, Cambridge, MA 02139 USA. [Koo, Heebeom; Yun, Seok Hyun] Massachusetts Gen Hosp, 65 Landsdowne St UP-5, Cambridge, MA 02139 USA. RP Hahn, SK (reprint author), Pohang Univ Sci & Technol POSTECH, Dept Mat Sci & Engn, 77 Cheongam Ro, Pohang 37673, Gyeongbuk, South Korea. EM skhanb@postech.ac.kr FU National Research Foundation (NRF) - Korean government (MEST) [2012M3A9C6049791, 2015R1A2A1A15053779]; Korea Health Technology R&D Project of the Ministry of Health and Welfare [HI15C1817] FX This research was supported by the Bio & Medical Technology Development Program (No. 2012M3A9C6049791) and Midcareer Researcher Program (No. 2015R1A2A1A15053779) of the National Research Foundation (NRF) funded by the Korean government (MEST). This work was supported by Korea Health Technology R&D Project (HI15C1817) of the Ministry of Health and Welfare. NR 40 TC 1 Z9 1 U1 13 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1944-8244 J9 ACS APPL MATER INTER JI ACS Appl. Mater. Interfaces PD NOV 30 PY 2016 VL 8 IS 47 BP 32202 EP 32210 DI 10.1021/acsami.6b11319 PG 9 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA ED9AF UT WOS:000389161600013 PM 27933820 ER PT J AU Engel, NW Neumann, JE Ahlfeld, J Wefers, AK Merk, DJ Ohli, J Schuller, U AF Engel, Nils W. Neumann, Julia E. Ahlfeld, Julia Wefers, Annika K. Merk, Daniel J. Ohli, Jasmin Schueller, Ulrich TI Canonical Wnt Signaling Drives Tumor-Like Lesions from Sox2-Positive Precursors of the Murine Olfactory Epithelium SO PLOS ONE LA English DT Article ID BETA-CATENIN GENE; CONSTITUTIVE ACTIVATION; SINONASAL HEMANGIOPERICYTOMA; PROGENITOR CELLS; SMALL-INTESTINE; STEM-CELLS; MUTATIONS; PROLIFERATION; EXPRESSION; CARCINOMA AB Canonical Wnt signaling is known to promote proliferation of olfactory stem cells. In order to investigate the effects of a constitutive activation of Wnt signaling in Sox2-positive precursor cells of the olfactory epithelium, we used transgenic mice that allowed an inducible deletion of exon 3 of the Ctnnb1 gene, which is responsible for the phosphorylation and degradation of Ctnnb1 protein. After induction of aberrant Wnt activation by Ctnnb1 deletion at embryonic day 14, such mice developed tumor-like lesions in upper parts of the nasal cavity. We still observed areas of epithelial hyperplasia within the olfactory epithelium following early postnatal Wnt activation, but the olfactory epithelial architecture remained unaffected in most parts when Wnt was activated at postnatal day 21 or later. In summary, our results suggest an age-dependent tumorigenic potential of aberrant Wnt signaling in the olfactory epithelium of mice. C1 [Engel, Nils W.; Neumann, Julia E.; Ahlfeld, Julia; Wefers, Annika K.; Merk, Daniel J.; Ohli, Jasmin; Schueller, Ulrich] Ludwig Maximilians Univ Munchen, Ctr Neuropathol, Munich, Germany. [Engel, Nils W.] Univ Med Ctr, Dept Internal Med 2, Hamburg, Germany. [Neumann, Julia E.; Schueller, Ulrich] Univ Med Ctr, Inst Neuropathol, Hamburg, Germany. [Schueller, Ulrich] Res Inst Childrens Canc Ctr, Hamburg, Germany. [Schueller, Ulrich] Univ Med Ctr, Dept Pediat Hematol & Oncol, Hamburg, Germany. [Ahlfeld, Julia] Ludwig Maximilians Univ Munchen, Dept Internal Med 4, Div Clin Pharmacol, Munich, Germany. [Wefers, Annika K.] Heidelberg Univ, Inst Pathol, Dept Neuropathol, D-69115 Heidelberg, Germany. [Merk, Daniel J.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Schuller, U (reprint author), Ludwig Maximilians Univ Munchen, Ctr Neuropathol, Munich, Germany.; Schuller, U (reprint author), Univ Med Ctr, Inst Neuropathol, Hamburg, Germany.; Schuller, U (reprint author), Res Inst Childrens Canc Ctr, Hamburg, Germany.; Schuller, U (reprint author), Univ Med Ctr, Dept Pediat Hematol & Oncol, Hamburg, Germany. EM u.schueller@uke.de FU Deutsche Krebshilfe [111630] FX This work was supported by Deutsche Krebshilfe, grant number 111630. NR 48 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 NOV 30 PY 2016 VL 11 IS 11 AR e0166690 DI 10.1371/journal.pone.0166690 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3FV UT WOS:000389474100033 PM 27902722 ER PT J AU Yang, JK Zhang, Q Li, PY Dong, TT Wu, MX AF Yang, Jingke Zhang, Qi Li, Peiyu Dong, Tingting Wu, Mei X. TI Low-level light treatment ameliorates immune thrombocytopenia SO SCIENTIFIC REPORTS LA English DT Article ID BIPHASIC DOSE-RESPONSE; LASER THERAPY; PROPLATELET FORMATION; PLATELET APOPTOSIS; PURPURA ITP; LONG-TERM; IN-VITRO; EFFICACY; SAFETY; MEGAKARYOCYTOPOIESIS AB Immune thrombocytopenia (ITP) is an immune-mediated acquired bleeding disorder characterized by abnormally low platelet counts. We reported here the ability of low-level light treatment (LLLT) to alleviate ITP in mice. The treatment is based on noninvasive whole body illumination 30 min a day for a few consecutive days by near infrared light (830 nm) transmitted by an array of light-emitting diodes (LEDs). LLLT significantly lifted the nadir of platelet counts and restored tail bleeding time when applied to two passive ITP models induced by anti-CD41 antibody. The anti-platelet antibody hindered megakaryocyte differentiation from the progenitors, impaired proplatelet and platelet formation, and induced apoptosis of platelets. These adverse effects of anti-CD41 antibody were all mitigated by LLLT to varying degrees, owing to its ability to enhance mitochondrial biogenesis and activity in megakaryocytes and preserve mitochondrial functions in platelets in the presence of the antibody. The observations argue not only for contribution of mitochondrial stress to the pathology of ITP, but also clinical potentials of LLLT as a safe, simple, and cost-effective modality of ITP. C1 [Yang, Jingke; Zhang, Qi; Li, Peiyu; Dong, Tingting; Wu, Mei X.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, Boston, MA 02114 USA. [Wu, Mei X.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02115 USA. [Yang, Jingke] Zhengzhou Univ, Affiliated Canc Hosp, Dept Hematol, Zhengzhou 450008, Henan, Peoples R China. RP Zhang, Q; Wu, MX (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, Boston, MA 02114 USA.; Wu, MX (reprint author), Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02115 USA. EM qzhang0@mgh.harvard.edu; mwu5@mgh.harvard.edu NR 36 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 30 PY 2016 VL 6 AR 38238 DI 10.1038/srep38238 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3ES UT WOS:000389471000001 PM 27901126 ER PT J AU Yu, BL Blaesi, AH Casey, N Raykhtsaum, G Zazzeron, L Jones, R Morrese, A Dobrynin, D Malhotra, R Bloch, DB Goldstein, LE Zapol, WM AF Yu, Binglan Blaesi, Aron H. Casey, Noel Raykhtsaum, Grigory Zazzeron, Luca Jones, Rosemary Morrese, Alexander Dobrynin, Danil Malhotra, Rajeev Bloch, Donald B. Goldstein, Lee E. Zapol, Warren M. TI Detection and removal of impurities in nitric oxide generated from air by pulsed electrical discharge SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE Nitric oxide; Pulsed electrical discharge; Metal particles; Iridium electrode ID PULMONARY-HYPERTENSION; EXPOSURE; PLASMAS; MICE AB Inhalation of nitric oxide (NO) produces selective pulmonary vasodilation without dilating the systemic circulation. However, the current NO/N-2 cylinder delivery system is cumbersome and expensive. We developed a lightweight, portable, and economical device to generate NO from air by pulsed electrical discharge. The objective of this study was to investigate and optimize the purity and safety of NO generated by this device. By using low temperature streamer discharges in the plasma generator, we produced therapeutic levels of NO with very low levels of nitrogen dioxide (NO2) and ozone. Despite the low temperature, spark generation eroded the surface of the electrodes, contaminating the gas stream with metal particles. During prolonged NO generation there was gradual loss of the iridium high-voltage tip (-90 mu g/day) and the platinum-nickel ground electrode (-55 mu g/day). Metal particles released from the electrodes were trapped by a high-efficiency particulate air (HEPA) filter. Quadrupole mass spectroscopy measurements of effluent gas during plasma NO generation showed that a single HEPA filter removed all of the metal particles. Mice were exposed to breathing 50 parts per million of electrically generated NO in air for 28 days with only a scavenger and no HEPA filter; the mice did not develop pulmonary inflammation or structural changes and iridium and platinum particles were not detected in the lungs of these mice. In conclusion, an electric plasma generator produced therapeutic levels of NO from air; scavenging and filtration effectively eliminated metallic impurities from the effluent gas. (C) 2016 Elsevier Inc. All rights reserved. C1 [Yu, Binglan; Blaesi, Aron H.; Zazzeron, Luca; Jones, Rosemary; Bloch, Donald B.; Zapol, Warren M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. [Casey, Noel; Goldstein, Lee E.] Boston Univ, Ctr Biomet & Metall, Sch Med, Coll Engn,Photon Ctr, Boston, MA 02118 USA. [Casey, Noel; Goldstein, Lee E.] Alzheimers Dis Ctr, Boston, MA 02118 USA. [Goldstein, Lee E.] Boston Univ, Sch Med, Coll Engn, Photon Ctr, Boston, MA 02118 USA. [Goldstein, Lee E.] Boston Univ, Alzheimers Dis Ctr, Boston, MA 02118 USA. [Raykhtsaum, Grigory] LeachGarner, Dept Met, Attleboro, MA 02703 USA. [Morrese, Alexander; Dobrynin, Danil] Drexel Univ, Appl Phys Lab, AJ Drexel Plasma Inst, Camden, NJ 08103 USA. [Malhotra, Rajeev] Harvard Med Sch, Div Cardiol, Boston, MA 02114 USA. [Malhotra, Rajeev] Harvard Med Sch, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Bloch, Donald B.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Zapol, WM (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,Thier 503, Boston, MA 02114 USA. EM wzapol@mgh.harvard.edu RI Dobrynin, Danil/A-2121-2009; OI Malhotra, Rajeev/0000-0003-0120-4630 FU NHLBI B-BIC/NCAI [U54HL119145]; Massachusetts General Hospital; NSF [0821304]; NIH [S10RR021131]; laboratory funds of the Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital FX This study was partially supported by grant from NHLBI B-BIC/NCAI (#U54HL119145) to W.M.Z. The portions of the study related to optical emission spectroscopy and plasma characterization were performed by a Drexel University team (D.D. and A. M.), and supported by funding from Massachusetts General Hospital. The ICP-MS study was supported by grants to L.E.G. for development of MIMS platform technology, NSF (0821304), and NIH (S10RR021131). Also, this study was supported by funding from laboratory funds of the Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital. NR 25 TC 0 Z9 0 U1 10 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 EI 1089-8611 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD NOV 30 PY 2016 VL 60 BP 16 EP 23 DI 10.1016/j.niox.2016.08.005 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EB2MR UT WOS:000387197000003 PM 27592386 ER PT J AU Chang, KAJ Kim, K Fava, M Mischoulon, D Hong, JP Kim, DJH Heb, JY Choi, H Jeon, HJ AF Chang, Kyung-Ah Judy Kim, Kiwon Fava, Maurizio Mischoulon, David Hong, Jin Pyo Kim, Daniel J. H. Heb, Jung-Yoon Choi, Hong Jeon, Hong Jin TI Cross-national differences in hypochondriasis symptoms between Korean and American outpatients with major depressive disorder SO PSYCHIATRY RESEARCH LA English DT Article DE Hamilton Rating Scale for Depression; Korean; American; Major depressive disorder; Hypochondriasis ID QUALITY-OF-LIFE; CULTURAL-DIFFERENCES; HEALTH ANXIETY; RATING-SCALE; SYMPTOMATOLOGY; SENSITIVITY; DIMENSIONS; SAMPLE; DSM-5 AB Hypochondriasis is defined as the tendency to worry excessively about having a serious illness. This study aimed to investigate cross-national differences in hypochondriasis symptoms between Korean and American patients with major depressive disorder (MDD). This study examined 1592 Korean and 3744 American MDD outpatients of age >= 18 years using the Hamilton Rating Scale for Depression (HAM-D) and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF). Korean MDD patients exhibited significantly higher scores for hypochondriasis than Americans after controlling for total HAM-D scores and demographic variables (p < 0.0001), even though Americans had significantly higher total HAM-D scores (p < 0.0001). Multivariate logistic regression analyses revealed that hypochondriasis was significantly associated with somatic and psychic anxiety, insomnia-middle, and suicide for both Korean and American MDD patients after adjusting for demographic covariates. Among all factors, somatic anxiety was the most strongly associated with hypochondriasis in both Korean (AOR=2.14, 95% CI 1.31-3.52) and American (AOR=1.98, 95% CI 1.69-2.31) MDD outpatients. Hypochondriasis symptoms are more prevalent among Korean than American MDD patients but appear to be associated with high levels of somatic anxiety regardless of culture. This suggests that cultural and personal factors play a shared role in the presentation of hypochondriasis symptoms. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Chang, Kyung-Ah Judy; Kim, Kiwon; Hong, Jin Pyo; Kim, Daniel J. H.; Heb, Jung-Yoon; Choi, Hong; Jeon, Hong Jin] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Psychiat,Depress Ctr, Seoul, South Korea. [Fava, Maurizio; Mischoulon, David; Jeon, Hong Jin] Harvard Med Sch, Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA USA. [Jeon, Hong Jin] Sungkyunkwan Univ, Dept Med Device Management & Res, Dept Hlth Sci & Technol, Seoul, South Korea. [Jeon, Hong Jin] Sungkyunkwan Univ, Samsung Adv Inst Hlth Sci & Technol, Dept Clin Res Design & Evaluat, Seoul, South Korea. RP Jeon, HJ (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Psychiat,Depress Ctr, Seoul, South Korea.; Jeon, HJ (reprint author), Sungkyunkwan Univ, Samsung Adv Inst Hlth Sci & Technol, Dept Clin Res Design & Evaluat, Seoul, South Korea.; Jeon, HJ (reprint author), Sungkyunkwan Univ, Samsung Adv Inst Hlth Sci & Technol, Dept Hlth Sci & Technol, Seoul, South Korea.; Jeon, HJ (reprint author), Sungkyunkwan Univ, Samsung Adv Inst Hlth Sci & Technol, Dept Med Device Management & Res, Seoul, South Korea. EM jeonhj@skku.edu FU National Institute of Mental Health (NIMH) [N01 MH-90003]; Pfizer Pharmaceuticals Korea Ltd.; Korean Mental Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [HM14C2567]; Institute for Information & communications Technology Promotion (IITP) - Korea Government (MSIP) [B0132-15-1003]; Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2011-0013064] FX The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study was supported by federal funds from the National Institute of Mental Health (NIMH) under contract N01 MH-90003 to the University of Texas - Southwestern Medical Center at Dallas (A.J. Rush, MD, Principal Investigator). Korean study was supported by Pfizer Pharmaceuticals Korea Ltd., by a grant of the Korean Mental Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (No. HM14C2567), by the Institute for Information & communications Technology Promotion (IITP) grant funded by the Korea Government (MSIP) (No. B0132-15-1003, the development of skin adhesive patches for the monitoring and prediction of mental disorders), and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2011-0013064). The authors thank the Samsung Statistical Support Team, Chief Dr. Seon-Woo Kim for statistical support. NR 25 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 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD NOV 30 PY 2016 VL 245 BP 127 EP 132 DI 10.1016/j.psychres.2016.08.019 PG 6 WC Psychiatry SC Psychiatry GA EA6LV UT WOS:000386741600019 PM 27541348 ER PT J AU Frankfurt, SB Armour, C Contractor, AA Elhai, JD AF Frankfurt, Sheila B. Armour, Cherie Contractor, Ateka A. Elhai, Jon D. TI Do gender and directness of trauma exposure moderate PTSD's latent structure? SO PSYCHIATRY RESEARCH LA English DT Article DE Posttraumatic stress disorder; Measurement invariance; Factor structure; Gender; Directness of trauma; PCL-5 ID POSTTRAUMATIC-STRESS-DISORDER; MEASUREMENT INVARIANCE; FACTORIAL INVARIANCE; FIT INDEXES; DSM-5; SYMPTOMS; SAMPLE; CHECKLIST; PREVALENCE; DIMENSIONS AB The PTSD diagnosis and latent structure were substantially revised in the transition from DSM-IV to DSM-5. However, three alternative models (i.e., anhedonia model, externalizing behavior model, and hybrid model) of PTSD fit the DSM-5 symptom criteria better than the DSM-5 factor model. Thus, the psychometric performance of the DSM-5 and alternative models' PTSD factor structure needs to be critically evaluated. The current study examined whether gender or trauma directness (i.e., direct or indirect trauma exposure) moderates the PTSD latent structure when using the DSM-5 or alternative models. Model performance was evaluated with measurement invariance testing procedures on a large undergraduate sample (n=455). Gender and trauma directness moderated the DSM-5 PTSD and externalizing behavior model and did not moderate the anhedonia and hybrid models' latent structure. Clinical implications and directions for future research are discussed. Published by Elsevier Ireland Ltd. C1 [Frankfurt, Sheila B.] Doris Miller VA Med Ctr, Dept Vet Affairs, VISN Ctr Excellence Res Returning War Vet 17, Waco, TX 76711 USA. [Armour, Cherie] Univ Ulster, Psychol Res Inst, Coleraine, Londonderry, North Ireland. [Contractor, Ateka A.] Univ North Texas, Dept Psychol, Denton, TX USA. [Elhai, Jon D.] Univ Toledo, Dept Psychol, Toledo, OH 43606 USA. [Elhai, Jon D.] Univ Toledo, Dept Psychiat, 2801 W Bancroft St, Toledo, OH 43606 USA. [Contractor, Ateka A.] Univ North Texas, Denton, TX USA. [Contractor, Ateka A.] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA USA. [Contractor, Ateka A.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. RP Frankfurt, SB (reprint author), Doris Miller VA Med Ctr, Dept Vet Affairs, VISN Ctr Excellence Res Returning War Vet 17, Waco, TX 76711 USA. EM Sheila.frankfurt@gmail.com FU Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment; Central Texas Veterans Health Care System; VISN 17 Center of Excellence for Research on Returning War Veterans FX This work is supported by the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment, the Central Texas Veterans Health Care System, and the VISN 17 Center of Excellence for Research on Returning War Veterans. 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 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD NOV 30 PY 2016 VL 245 BP 365 EP 370 DI 10.1016/j.psychres.2016.08.049 PG 6 WC Psychiatry SC Psychiatry GA EA6LV UT WOS:000386741600053 PM 27591411 ER PT J AU Logan, J Bohnert, A Spies, E Jannausch, M AF Logan, Joseph Bohnert, Amy Spies, Erica Jannausch, Mary TI Suicidal ideation among young Afghanistan/Iraq War Veterans and civilians: Individual, social, and environmental risk factors and perception of unmet mental healthcare needs, United States, 2013 SO PSYCHIATRY RESEARCH LA English DT Article DE Suicide; Veterans; Socio-ecological model; Health care needs; Surveillance ID SERVICEMEMBERS ARMY STARRS; POSTTRAUMATIC-STRESS-DISORDER; US ARMY; ACTIVE-DUTY; MILITARY PERSONNEL; PREVALENCE; SAMPLE; RESILIENCE; DEPRESSION; BEHAVIORS AB Suicidal Ideation among Afghanistan/Iraq War Veterans remains a health concern. As young Veterans adjust to civilian life, new risk factors might emerge and manifest differently in this group versus those in the general population. We explored these differences. With 2013 National Survey on Drug Use and Health data, we examined differences in risk of past-year suicidal ideation between Veterans of the Afghanistan/Iraq War periods aged 18-34 years (N=328) and age-comparable civilians (N=23,222). We compared groups based on individual and socio-environmental risk factors as well as perceptions of unmet mental healthcare needs. We report adjusted rate ratios (aRRs); interaction terms tested for between-group differences. PY suicidal ideation rates for Veterans and civilians did not differ (52 versus 59 per 1,000, p=0.60) and both groups shared many risk factors. However, drug problems and perceived unmet mental health care needs were vastly stronger risk factors among Veterans versus civilians (interaction terms indicated that the aRRs were 3.8-8.0 times higher for Veterans versus civilians). Other differences were discovered as well. Past-year suicidal ideation rates did not differ by Veteran status among young adults. However, different risk factors per group were detected, which can inform Veteran suicide prevention efforts. Published by Elsevier Ireland Ltd. C1 [Logan, Joseph; Spies, Erica] Ctr Dis Control & Prevent, Natl Ctr Injury Prevent & Control, Div Violence Prevent, 4770 Buford Highway,MS-F63, Atlanta, GA 30341 USA. [Bohnert, Amy; Jannausch, Mary] Univ Michigan, Ann Arbor, MI 48109 USA. [Bohnert, Amy; Jannausch, Mary] US Dept Vet Affairs, Ctr Clin Management Res, Ann Arbor, MI USA. RP Logan, J (reprint author), Ctr Dis Control & Prevent, Natl Ctr Injury Prevent & Control, Div Violence Prevent, 4770 Buford Highway,MS-F63, Atlanta, GA 30341 USA. EM ffa3@cdc.gov FU CDC; VA [CDA 09-204] FX All work for this manuscript was funded by CDC and the VA (CDA 09-204). NR 76 TC 0 Z9 0 U1 12 U2 12 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 NOV 30 PY 2016 VL 245 BP 398 EP 405 DI 10.1016/j.psychres.2016.08.054 PG 8 WC Psychiatry SC Psychiatry GA EA6LV UT WOS:000386741600058 PM 27611069 ER PT J AU Sinclair, SJ Roche, MJ Temes, C Massey, C Chung, WJ Stein, M Richardson, L Blais, M AF Sinclair, Samuel Justin Roche, Michael J. Temes, Christina Massey, Christina Chung, Wei-Jean Stein, Michelle Richardson, Laura Blais, Mark TI Evaluating chronic suicide risk with the Personality Assessment Inventory: Development and initial validation of the Chronic Suicide Risk Index (S_Chron) SO PSYCHIATRY RESEARCH LA English DT Article DE Suicide; S_Chron; Multiple suicide attempts; Chronic suicide risk; Personality; Assessment Inventory; PAI ID PSYCHIATRIC SAMPLE; MULTIPLE; VALIDITY; PSYCHOPATHOLOGY; HISTORY; SINGLE; PAI AB The current study sought to develop and validate a new measure of chronic suicide risk (the S_Chron) from the Personality Assessment Inventory in a mixed sample of psychiatric inpatients and outpatients. In an initial development sample (N=397), hierarchical logistic regression identified six PAI variables uniquely associated with multiple versus single/no prior suicide attempts after controlling for sample demographics: Negative Impression Management, Situational Stress, Mania Grandiosity, Borderline Negative Relationships, Borderline Self-Harm, and Antisocial Behaviors. These indicators were then aggregated into a single index (S_Chron) and evaluated in terms of validity in an independent clinical sample (N=398). Results indicated the S_Chron effectively differentiated between groups with multiple versus single/no prior suicide attempts, even after controlling for the effects of the PAI Suicidal Ideation (SUI) and Suicide Potential (SPI) indices, with moderate to large effect sizes observed (range of Cohen's d's=0.30-0.91). Further, the S_Chron incremented all other PAI indices and SUI in predicting multiple suicide attempts. The potential clinical application and ways in which the S_Chron may augment other existing measures of suicide risk are discussed. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Sinclair, Samuel Justin] William James Coll, Clin Psychol Program, One Wells Ave, Newton, MA 02459 USA. [Roche, Michael J.] Penn State Univ, Penn State Altoona, PA USA. [Temes, Christina; Massey, Christina; Chung, Wei-Jean; Stein, Michelle; Richardson, Laura; Blais, Mark] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Temes, Christina; Massey, Christina; Chung, Wei-Jean; Stein, Michelle; Richardson, Laura; Blais, Mark] Harvard Med Sch, Boston, MA USA. RP Sinclair, SJ (reprint author), William James Coll, One Wells Ave, Newton, MA 02459 USA. EM DrJustinSinclair@gmail.com NR 25 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 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD NOV 30 PY 2016 VL 245 BP 443 EP 450 DI 10.1016/j.psychres.2016.08.048 PG 8 WC Psychiatry SC Psychiatry GA EA6LV UT WOS:000386741600065 PM 27620327 ER PT J AU Roberts, AL Johnson, NJ Chen, JT Cudkowicz, ME Weisskopf, MG AF Roberts, Andrea L. Johnson, Norman J. Chen, Jarvis T. Cudkowicz, Merit E. Weisskopf, Marc G. TI Race/ethnicity, socioeconomic status, and ALS mortality in the United States SO NEUROLOGY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; MOTOR-NEURON DISEASE; MILITARY SERVICE; POPULATION; DEATH; RISK; METAANALYSIS; DISPARITIES; PREVALENCE; AMERICANS AB Objective: To determine whether race/ethnicity and socioeconomic status are associated with amyotrophic lateral sclerosis (ALS) mortality in the United States. Methods: The National Longitudinal Mortality Study (NLMS), a United States-representative, multistage sample, collected race/ethnicity and socioeconomic data prospectively. Mortality information was obtained by matching NLMS records to the National Death Index (1979-2011). More than 2 million persons (n 5 1,145,368 women, n 5 1,011,172 men) were included, with 33,024,881 person-years of follow-up (1,299 ALS deaths, response rate 96%). Race/ethnicity was by self-report in 4 categories. Hazard ratios (HRs) for ALS mortality were calculated for race/ethnicity and socioeconomic status separately and in mutually adjusted models. Results: Minority vs white race/ethnicity predicted lower ALS mortality in models adjusted for socioeconomic status, type of health insurance, and birthplace (non-Hispanic black, HR 0.61, 95% confidence interval [CI] 0.48-0.78; Hispanic, HR 0.64, 95% CI 0.46-0.88; other races, non-Hispanic, HR 0.52, 95% CI 0.31-0.86). Higher educational attainment compared with < high school was in general associated with higher rate of ALS (high school, HR 1.23, 95% CI 1.07-1.42; some college, HR 1.24, 95% CI 1.04-1.48; college, HR 1.10, 95% CI 0.90-1.36; postgraduate, HR 1.31, 95% CI 1.06-1.62). Income, household poverty, and home ownership were not associated with ALS after adjustment for race/ethnicity. Rates did not differ by sex. Conclusion: Higher rate of ALS among whites vs non-Hispanic blacks, Hispanics, and non-Hispanic other races was not accounted for by multiple measures of socioeconomic status, birthplace, or type of health insurance. Higher rate of ALS among whites likely reflects actual higher risk of ALS rather than ascertainment bias or effects of socioeconomic status on ALS risk. C1 [Roberts, Andrea L.; Chen, Jarvis T.] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Weisskopf, Marc G.] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Weisskopf, Marc G.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Johnson, Norman J.] US Bur Census, Washington, DC 20233 USA. [Cudkowicz, Merit E.] Harvard Med Sch, Boston, MA USA. [Cudkowicz, Merit E.] Massachusetts Gen Hosp, Dept Neurol, MGH Neurol Clin Res Inst, Boston, MA 02114 USA. RP Roberts, AL (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. EM aroberts@hsph.harvard.edu FU Muscular Dystrophy Association [MDA239243]; NIH [NS 082105]; Agency for Toxic Substances and Disease Registry's National ALS Registry program FX Funding was provided by Muscular Dystrophy Association grant MDA239243, NIH grant NS 082105, and the Agency for Toxic Substances and Disease Registry's National ALS Registry program. NR 40 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 NOV 29 PY 2016 VL 87 IS 22 BP 2300 EP 2308 DI 10.1212/WNL.0000000000003298 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA EI1MA UT WOS:000392240300011 PM 27742817 ER PT J AU Wang, LJ Xue, M Chung, DC AF Wang, Liangjing Xue, Meng Chung, Daniel C. TI c-Myc is regulated by HIF-2a in chronic hypoxia and influences sensitivity to 5-FU in colon cancer SO ONCOTARGET LA English DT Article DE c-Myc; HIF-2a; 5-FU; colon cancer ID TRANSCRIPTION FACTOR; CELL-PROLIFERATION; 5-FLUOROURACIL; AMPLIFICATION; CONTRIBUTES; REPRESSION; THERAPY; GLUCOSE; OXYGEN; TUMORS AB Colorectal cancers (CRCs) invariably become hypoxic as they enlarge, and this places unique metabolic demands upon the tumor cells. Hypoxic stress can enhance the invasiveness of cancer cells and induce chemoresistance. c-Myc, an oncogene regulated by hypoxia inducible factors (HIFs), plays a critical role in cell proliferation and metabolism. However, the interplay between c-Myc and HIFs and its clinical significance in hypoxic adaptation in CRCs are unknown. We demonstrate that c-Myc mRNA and protein levels in colon cancer cells are induced within 2 h of hypoxic stress (1% O-2) but are then significantly downregulated when exposed to prolonged hypoxia. In chronic hypoxia (over 8 h at 1% O2), HIF-2a but not HIF-1a gradually accumulated in colon cancer cells. Knockdown of HIF-2a increased levels of c-Myc and its downstream target cyclinD1 in chronic hypoxia, indicating that HIF-2a may function to downregulate c-Myc. Chronic hypoxia suppressed the expression of cyclinD1, CDK4, and CDK6, inducing G1 phase block and 5-flurouracil (5-FU) chemoresistance. Overexpression of c-Myc reversed the inhibition of cyclinD1, CDK4, and CDK6, which accelerated the G1/S phase transition under hypoxia and enhanced sensitivity to 5-FU. In contrast, knockdown of c-Myc impaired 5-FU chemosensitivity in colon cancer cells. In summary, HIF-2a plays an important role in regulating the expression of c-Myc in chronic hypoxia, and consequently controls the sensitivity of colon cancer cells to 5-FU treatment in this environment. C1 [Wang, Liangjing; Xue, Meng] Zhejiang Univ, Dept Gastroenterol, Affiliated Hosp 2, Sch Med, Hangzhou, Zhejiang, Peoples R China. [Wang, Liangjing; Xue, Meng] Zhejiang Univ, Inst Gastroenterol, Hangzhou, Zhejiang, Peoples R China. [Wang, Liangjing; Xue, Meng; Chung, Daniel C.] Harvard Med Sch, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02115 USA. [Wang, Liangjing; Xue, Meng; Chung, Daniel C.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02115 USA. RP Chung, DC (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02115 USA.; Chung, DC (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02115 USA. EM Chung.daniel@mgh.harvard.edu FU National Institutes of Health [CA92594]; National Natural Science Foundation of China [81472214, 81272678]; Science and Technology Innovation Team of Zhejiang Province in China [2013TD13] FX This work was supported by National Institutes of Health (CA92594), the National Natural Science Foundation of China (81472214, 81272678), Science and Technology Innovation Team of Zhejiang Province (2013TD13) in China. NR 27 TC 0 Z9 0 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 29 PY 2016 VL 7 IS 48 BP 78910 EP 78917 DI 10.18632/oncotarget.12911 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE5HH UT WOS:000389636000059 PM 27793037 ER PT J AU Zagorovskya, K Chou, LYT Chan, WCW AF Zagorovskya, Kyryl Chou, Leo Y. T. Chan, Warren C. W. TI Controlling DNA-nanoparticle serum interactions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE nanoparticle assembly; DNA nanostructures; serum stability; serum resistance; controlled cargo release ID GOLD NANOPARTICLES; PROTEIN ADSORPTION; BIOLOGICAL-SYSTEMS; SURFACE-CHEMISTRY; DELIVERY VEHICLES; MACROPHAGE UPTAKE; SULFANE SULFUR; STABILITY; OLIGONUCLEOTIDES; DEGRADATION AB Understanding the interaction of molecularly assembled nanoparticles with physiological fluids is critical to their use for in vivo delivery of drugs and contrast agents. Here, we systematically investigated the factors and mechanisms that govern the degradation of DNA on the nanoparticle surface in serum. We discovered that a higher DNA density, shorter oligonucleotides, and thicker PEG layer increased protection of DNA against serum degradation. Oligonucleotides on the surface of nanoparticles were highly resistant to DNase I endonucleases, and degradation was carried out exclusively by protein-mediated exonuclease cleavage and full-strand desorption. These results enabled the programming of the degradation rates of the DNA-assembled nanoparticle system from 0.1 to 0.7 h(-1) and the engineering of superstructures that can release two different preloaded dye molecules with distinct kinetics and half-lives ranging from 3.3 to 9.8 h. This study provides a general framework for investigating the serum stability of DNA-containing nanostructures. The results advance our understanding of engineering principles for designing nanoparticle assemblies with controlled in vivo behavior and present a strategy for storage and multistage release of drugs and contrast agents that can facilitate the diagnosis and treatment of cancer and other diseases. C1 [Zagorovskya, Kyryl; Chou, Leo Y. T.; Chan, Warren C. W.] Univ Toronto, Inst Biomat & Biomed Engn, Toronto, ON M5S 3G9, Canada. [Zagorovskya, Kyryl; Chan, Warren C. W.] Univ Toronto, Terrence Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada. [Chan, Warren C. W.] Univ Toronto, Dept Chem, Toronto, ON M5S 3H6, Canada. [Chan, Warren C. W.] Univ Toronto, Dept Mat Sci & Engn, Toronto, ON M5S 3E4, Canada. [Chan, Warren C. W.] Univ Toronto, Dept Chem Engn, Toronto, ON M5S 3E5, Canada. [Chou, Leo Y. T.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Chou, Leo Y. T.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Chan, WCW (reprint author), Univ Toronto, Inst Biomat & Biomed Engn, Toronto, ON M5S 3G9, Canada.; Chan, WCW (reprint author), Univ Toronto, Terrence Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada.; Chan, WCW (reprint author), Univ Toronto, Dept Chem, Toronto, ON M5S 3H6, Canada.; Chan, WCW (reprint author), Univ Toronto, Dept Mat Sci & Engn, Toronto, ON M5S 3E4, Canada.; Chan, WCW (reprint author), Univ Toronto, Dept Chem Engn, Toronto, ON M5S 3E5, Canada. EM warren.chan@utoronto.ca FU Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN288231]; Canadian Institute of Health Research [MOP 130143, GCS105653-1]; NSERC FX This work was supported by Natural Sciences and Engineering Research Council of Canada (NSERC, RGPIN288231) and Canadian Institute of Health Research (MOP 130143 and GCS105653-1). K.Z. and L.Y.T.C. acknowledge a fellowship from NSERC. L.Y.T.C. acknowledges a Banting Fellowship and a Canadian Breast Cancer Foundation Fellowship. NR 46 TC 0 Z9 0 U1 20 U2 20 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 NOV 29 PY 2016 VL 113 IS 48 BP 13600 EP 13605 DI 10.1073/pnas.1610028113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED4QR UT WOS:000388835700042 PM 27856755 ER PT J AU Wirtz, T Weber, T Kracker, S Sommermann, T Rajewsky, K Yasuda, T AF Wirtz, Tristan Weber, Timm Kracker, Sven Sommermann, Thomas Rajewsky, Klaus Yasuda, Tomoharu TI Mouse model for acute Epstein-Barr virus infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Epstein-Barr virus; LMP1; LMP2A; familial hemophagocytic lymphohistiocytosis; post-transplant lymphoproliferative disorder ID MEMBRANE-PROTEIN 2A; B-CELL SURVIVAL; IN-VIVO; LATENT MEMBRANE-PROTEIN-1; GERMINAL-CENTERS; MICE; RECEPTOR; TRANSFORMATION; DISEASES; MEMORY AB Epstein-Barr Virus (EBV) infects human B cells and drives them into continuous proliferation. Two key viral factors in this process are the latent membrane proteins LMP1 and LMP2A, which mimic constitutively activated CD40 receptor and B-cell receptor signaling, respectively. EBV-infected B cells elicit a powerful T-cell response that clears the infected B cells and leads to life-long immunity. Insufficient immune surveillance of EBV-infected B cells causes life-threatening lymphoproliferative disorders, including mostly germinal center (GC)-derived B-cell lymphomas. We have modeled acute EBV infection of naive and GC B cells in mice through timed expression of LMP1 and LMP2A. Although lethal when induced in all B cells, induction of LMP1 and LMP2A in just a small fraction of naive B cells initiated a phase of rapid B-cell expansion followed by a proliferative T-cell response, clearing the LMP-expressing B cells. Interfering with T-cell activity prevented clearance of LMP-expressing B cells. This was also true for perforin deficiency, which in the human causes a life-threatening EBV-related immunoproliferative syndrome. LMP expression in GC B cells impeded the GC reaction but, upon loss of T-cell surveillance, led to fatal B-cell expansion. Thus, timed expression of LMP1 together with LMP2A in subsets of mouse B cells allows one to study major clinically relevant features of human EBV infection in vivo, opening the way to new therapeutic approaches. C1 [Wirtz, Tristan; Weber, Timm; Sommermann, Thomas; Rajewsky, Klaus; Yasuda, Tomoharu] Max Delbrck Ctr Mol Med, Immune Regulat & Canc, D-13125 Berlin, Germany. [Kracker, Sven; Rajewsky, Klaus; Yasuda, Tomoharu] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Kracker, Sven; Rajewsky, Klaus; Yasuda, Tomoharu] Harvard Med Sch, Immune Dis Inst, Boston, MA 02115 USA. [Kracker, Sven] INSERM, UMR 1163, Human Lymphohematopoiesis Lab, F-75015 Paris, France. [Kracker, Sven] Univ Paris 05, Imagine Inst, Sorbonne Paris Cite, F-75015 Paris, France. RP Rajewsky, K; Yasuda, T (reprint author), Max Delbrck Ctr Mol Med, Immune Regulat & Canc, D-13125 Berlin, Germany.; Rajewsky, K; Yasuda, T (reprint author), Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Rajewsky, K; Yasuda, T (reprint author), Harvard Med Sch, Immune Dis Inst, Boston, MA 02115 USA. EM klaus.rajewsky@mdc-berlin.de; tomoharu.yasuda@mdc-berlin.de FU European Research Council [268921]; National Institutes of Health; Japan Society for the Promotion of Science; Astellas Foundation for Research on Metabolic Disorders; Preclinical Comprehensive Cancer Center grant FX We thank Dr. S. Cobbold for the anti-CD4, -CD8, and -Thy1 hybridomas; Dr. T. Blankenstein for providing Prf-/- mice; Dr. A. Franklin for critical reading of the manuscript; Dr. S. Sander for somatic mutation analysis; and A. Hesseling, M. Bamberg, C. Grosse, K. Petsch, J. Pempe, and J. Cernoch for technical assistance. This work was supported by grants from the National Institutes of Health and the European Research Council (Advanced Grant 268921 to K.R.). T.Y. was supported by the Japan Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad and by the Astellas Foundation for Research on Metabolic Disorders. T.S. is supported by a Preclinical Comprehensive Cancer Center grant. S.K. is a CNRS researcher. NR 37 TC 0 Z9 0 U1 4 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 29 PY 2016 VL 113 IS 48 BP 13821 EP 13826 DI 10.1073/pnas.1616574113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED4QR UT WOS:000388835700079 PM 27856754 ER PT J AU Kucyi, A Esterman, M Riley, CS Valera, EM AF Kucyi, Aaron Esterman, Michael Riley, Clay S. Valera, Eve M. TI Spontaneous default network activity reflects behavioral variability independent of mind-wandering SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE daydreaming; default mode network; sustained attention; spontaneous thought; resting state ID INTRINSIC FUNCTIONAL CONNECTIVITY; HUMAN POSTEROMEDIAL CORTEX; STREAM-OF-CONSCIOUSNESS; MODE NETWORK; SPONTANEOUS FLUCTUATIONS; CEREBRAL-CORTEX; ICA-AROMA; BRAIN; TASK; FMRI AB The brain's default mode network (DMN) is highly active during wakeful rest when people are not overtly engaged with a sensory stimulus or externally oriented task. In multiple contexts, increased spontaneous DMN activity has been associated with self-reported episodes of mind-wandering, or thoughts that are unrelated to the present sensory environment. Mind-wandering characterizes much of waking life and is often associated with error-prone, variable behavior. However, increased spontaneous DMN activity has also been reliably associated with stable, rather than variable, behavior. We aimed to address this seeming contradiction and to test the hypothesis that single measures of attentional states, either based on self-report or on behavior, are alone insufficient to account for DMN activity fluctuations. Thus, we simultaneously measured varying levels of self-reported mind-wandering, behavioral variability, and brain activity with fMRI during a unique continuous performance task optimized for detecting attentional fluctuations. We found that even though mind-wandering co-occurred with increased behavioral variability, highest DMN signal levels were best explained by intense mind-wandering combined with stable behavior simultaneously, compared with considering either single factor alone. These brain-behavior-experience relationships were highly consistent within known DMN subsystems and across DMN subregions. In contrast, such relationships were absent or in the opposite direction for other attention-relevant networks (salience, dorsal attention, and frontoparietal control networks). Our results suggest that the cognitive processes that spontaneous DMN activity specifically reflects are only partially related to mind-wandering and include also attentional state fluctuations that are not captured by self-report. C1 [Kucyi, Aaron] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Kucyi, Aaron; Valera, Eve M.] Harvard Med Sch, Dept Psychiat, Boston, MA 02129 USA. [Kucyi, Aaron; Riley, Clay S.; Valera, Eve M.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Esterman, Michael] Boston Healthcare Syst, Boston Attent & Learning Lab, Vet Adm, Boston, MA 02130 USA. [Esterman, Michael] Boston Healthcare Syst, Neuroimaging Res Vet Ctr NeRVe, Vet Adm, Boston, MA 02130 USA. [Esterman, Michael] Boston Univ, Dept Psychiat, Sch Med, Boston, MA 02130 USA. RP Valera, EM (reprint author), Harvard Med Sch, Dept Psychiat, Boston, MA 02129 USA.; Valera, EM (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. EM eve_valera@hms.harvard.edu FU Canadian Institutes of Health Research fellowship; NIH [R01 HD067744-01A1]; Athinoula A. Martinos Center for Biomedical Imaging; National Center for Research Resources [P41RR14075, P41 EB015896]; Veterans Affairs Clinical Science R&D Career Development Award [1IK2CX000706-01A2] FX We thank Jonathan Smallwood and Michael Hove for study design advising, Aya Hamadeh for data collection, and Francesca Fortenbaugh, David Rothlein, and Joke Durnez for analysis support. This work was performed at Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital. This work was supported by a Canadian Institutes of Health Research fellowship award (to A.K.), NIH Grant R01 HD067744-01A1 (to E.M.V.), the Athinoula A. Martinos Center for Biomedical Imaging, and National Center for Research Resources Grants P41RR14075 and P41 EB015896. M.E. was supported by a Veterans Affairs Clinical Science R&D Career Development Award 1IK2CX000706-01A2. NR 62 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 NOV 29 PY 2016 VL 113 IS 48 BP 13899 EP 13904 DI 10.1073/pnas.1611743113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED4QR UT WOS:000388835700092 PM 27856733 ER PT J AU Hill, SJ Mordes, DA Cameron, LA Neuberg, DS Landini, S Eggan, K Livingston, DM AF Hill, Sarah J. Mordes, Daniel A. Cameron, Lisa A. Neuberg, Donna S. Landini, Serena Eggan, Kevin Livingston, David M. TI Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DNA damage response; ALS; transcription; R loop ID DEPENDENT RECRUITMENT; PHASE-TRANSITION; GENOME INTEGRITY; PAUSE SITES; FUS BINDS; R LOOPS; REPAIR; STABILITY; CHROMATIN; MUTATION AB Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms. In support of this hypothesis, we find that FUS or TDP43 depletion leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. Thus, these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, both FUS and TDP43 colocalize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein, BRCA1, and FUS and TDP43 participate in the prevention or repair of R loop-associated DNA damage, a manifestation of aberrant transcription and/or RNA processing. Gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage could shed light on the mechanisms underlying ALS pathogenesis. C1 [Hill, Sarah J.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Hill, Sarah J.; Landini, Serena; Livingston, David M.] Harvard Med Sch, Dept Genet, Boston, MA 02215 USA. [Hill, Sarah J.; Landini, Serena; Livingston, David M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Mordes, Daniel A.; Eggan, Kevin] Harvard Univ, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Mordes, Daniel A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mordes, Daniel A.; Eggan, Kevin] Broad Inst Harvard & Massachusetts Inst Technol, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Cameron, Lisa A.] Dana Farber Canc Inst, Confocal & Light Microscopy Facil, Boston, MA 02215 USA. [Neuberg, Donna S.] Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02215 USA. [Landini, Serena; Livingston, David M.] Harvard Med Sch, Dept Med, Boston, MA 02215 USA. RP Hill, SJ (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA.; Hill, SJ; Livingston, DM (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02215 USA.; Hill, SJ; Livingston, DM (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.; Livingston, DM (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02215 USA. EM sarah_hill@dfci.harvard.edu; david_livingston@dfci.harvard.edu FU Target ALS; NIH [5T32CA009216]; US Department of Defense Breast Cancer Research Program Fellowship [W81XWH-08-1-0748]; National Cancer Institute Fellowship [1F30CA167895-01]; ALS Therapy Alliance; Harvard NeuroDiscovery Center Neurodegenerative Disease Pilot Study Grants Program; Murray Winston Foundation FX We thank Drs. Merit Cudkowicz and Matthew Frosch for valuable discussions and help. Confocal microscopy images for this study were acquired in the Confocal and Light Microscopy Core Facility at the Dana-Farber Cancer Institute with the assistance of L.A.C. Funding was provided by Target ALS (K.E. and D.A.M.) and NIH Training Grant 5T32CA009216 (to D.A.M.). S.J.H. was funded initially by US Department of Defense Breast Cancer Research Program Fellowship W81XWH-08-1-0748 and subsequently by National Cancer Institute Fellowship 1F30CA167895-01. S.J.H., S.L., and D.M.L. were funded by grants from the ALS Therapy Alliance, Harvard NeuroDiscovery Center Neurodegenerative Disease Pilot Study Grants Program, and the Murray Winston Foundation. NR 37 TC 3 Z9 3 U1 6 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 29 PY 2016 VL 113 IS 48 BP E7701 EP E7709 DI 10.1073/pnas.1611673113 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED4QR UT WOS:000388835700007 PM 27849576 ER PT J AU Toubai, T Mathewson, ND Magenau, J Reddy, P AF Toubai, Tomomi Mathewson, Nathan D. Magenau, John Reddy, Pavan TI Danger Signals and Graft-versus-host Disease: Current Understanding and Future Perspectives SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE allogeneic hematopoietic stem cell transplantation; graft-versus-host-disease; danger signals; pathogen-associated molecular patterns; damage-associated molecular patterns ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; GROUP BOX-1 PROTEIN; HEAT-SHOCK-PROTEIN; PATTERN-RECOGNITION RECEPTOR; INNATE ANTIVIRAL RESPONSES; NECROSIS-FACTOR-ALPHA; TOLL-LIKE RECEPTOR-5; SINGLE-STRANDED RNA; RIG-I AB Graft-versus-host response after allogeneic hematopoietic stem cell transplantation (allo-HCT) represents one of the most intense inflammatory responses observed in humans. Host conditioning facilitates engraftment of donor cells, but the tissue injury caused from it primes the critical first steps in the development of acute graft-versus-host disease (GVHD). Tissue injuries release pro-inflammatory cytokines (such as TNF-alpha, IL-1 beta, and IL-6) through widespread stimulation of pattern recognition receptors (PRRs) by the release of danger stimuli, such as damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). DAMPs and PAMPs function as potent stimulators for host and donor-derived antigen presenting cells (APCs) that in turn activate and amplify the responses of alloreactive donor T cells. Emerging data also point towards a role for suppression of DAMP induced inflammation by the APCs and donor T cells in mitigating GVHD severity. In this review, we summarize the current understanding on the role of danger stimuli, such as the DAMPs and PAMPs, in GVHD. C1 [Toubai, Tomomi; Magenau, John; Reddy, Pavan] Univ Michigan, Ctr Comprehens Canc, Dept Internal Med, Div Hematol & Oncol, Ann Arbor, MI 48109 USA. [Mathewson, Nathan D.] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA. RP Toubai, T; Reddy, P (reprint author), Univ Michigan, Ctr Comprehens Canc, Dept Internal Med, Div Hematol & Oncol, Ann Arbor, MI 48109 USA. EM tomomit@umich.edu; reddypr@med.umich.edu FU National Institutes of Health [HL-128046, HL-090775, CA-173878, CA-203542]; American Society of Blood and Marrow Transplantation New Investigator Award FX This work was supported by National Institutes of Health grants HL-128046 (PR), HL-090775 (PR), CA-173878(PR), and CA-203542 (PR), and American Society of Blood and Marrow Transplantation New Investigator Award (TT). NR 182 TC 0 Z9 0 U1 4 U2 4 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 NOV 29 PY 2016 VL 7 AR 539 DI 10.3389/fimmu.2016.00539 PG 15 WC Immunology SC Immunology GA ED3LJ UT WOS:000388750300002 PM 27965667 ER PT J AU Moye, ZD Valiuskyte, K Dewhirst, FE Nichols, FC Davey, ME AF Moye, Zachary D. Valiuskyte, Kornelija Dewhirst, Floyd E. Nichols, Frank C. Davey, Mary E. TI Synthesis of Sphingolipids Impacts Survival of Porphyromonas gingivalis and the Presentation of Surface Polysaccharides SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE sphingolipid biosynthesis; dihydroceramides; capsular polysaccharides; stress response; persistence ID LIPIDS; GENE; DIHYDROCERAMIDES; APOPTOSIS; PROTEASES; DELETION; SIGNALS; CELLS; W50 AB Bacteria alter the biophysical properties of their membrane lipids in response to environmental cues, such as shifts in pH or temperature. In essence, lipid composition determines membrane structure, which in turn influences many basic functions, such as transport, secretion, and signaling. Like other members of the phylum Bacteroidetes, the oral anaerobe Porphyromonas gingiyalis possesses the ability to synthesize a variety of novel membrane lipids, including species of dihydroceramides that are distinct, yet similar in structure to sphingolipids produced by the human host. The role of dihydroceramides in the physiology and pathogenic potential of the human microbiota is only beginning to be explored; yet there is increasing data indicating that these lipids play a role in human diseases, such as periodontitis and multiple sclerosis. Here, we report on the identification of a gene (PG1780) in the chromosome of P. gingivalis strain W83 encoding a putative serine palmitoyltransferase, the enzyme that catalyzes the first step in sphingolipid biosynthesis. While we were able to detect dihydroceramides in whole lipid extracts of P gingivalis cells as well as crude preparations of outer membrane vesicles, sphingolipids were absent in the PG1780 mutant strain. Moreover, we show that the synthesis of sphingolipids plays an essential role in the long-term survival of the organism as well as its resistance to oxidative stress. Further, a PG1780 mutant displayed much lower activity of cell-associated arginine and lysine gingipains, yet slightly higher activity in the corresponding culture supernates, which we hypothesize is due to altered membrane properties and anchoring of these proteases to the cell surface. In addition, we determined that sphingolipid production is critical to the presentation of surface polysaccharides, with the mutant strain displaying less K-antigen capsule and more anionic polysaccharide (APS). Overall, we have discovered that, in addition to their role in pathogenicity, the synthesis of sphingolipids is critical to the cellular homeostasis and persistence of this important dental pathogen. C1 [Moye, Zachary D.; Valiuskyte, Kornelija; Davey, Mary E.] Univ Florida, Coll Dent, Dept Oral Biol, Gainesville, FL 32610 USA. [Dewhirst, Floyd E.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Dewhirst, Floyd E.] Harvard Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA USA. [Nichols, Frank C.] Univ Connecticut, Sch Dent Med, Dept Oral Hlth & Diagnost Sci, Div Periodont, Farmington, CT 06032 USA. RP Davey, ME (reprint author), Univ Florida, Coll Dent, Dept Oral Biol, Gainesville, FL 32610 USA. EM mdavey@dental.ufl.edu FU National institute of Dental and Craniofacial Research of the National Institutes of Health [R01DE019117, RO1DE021055, R37DE016937]; [T90DE021990] FX Research reported in this publication was supported by The National institute of Dental and Craniofacial Research of the National Institutes of Health under award number R01DE019117 to MD, RO1DE021055 to UN, R37DE016937 to FD, and ZM was supported by T90DE021990. NR 37 TC 0 Z9 0 U1 5 U2 5 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD NOV 29 PY 2016 VL 7 AR 1919 DI 10.3389/fmicb.2016.01919 PG 13 WC Microbiology SC Microbiology GA ED3RD UT WOS:000388765300002 PM 27965646 ER PT J AU Henzler, C Li, YM Yang, RD McBride, T Ho, Y Sprenger, C Liu, G Coleman, I Lakely, B Li, R Ma, SH Landman, SR Kumar, V Hwang, TH Raj, GV Higano, CS Morrissey, C Nelson, PS Plymate, SR Dehm, SM AF Henzler, Christine Li, Yingming Yang, Rendong McBride, Terri Ho, Yeung Sprenger, Cynthia Liu, Gang Coleman, Ilsa Lakely, Bryce Li, Rui Ma, Shihong Landman, Sean R. Kumar, Vipin Hwang, Tae Hyun Raj, Ganesh V. Higano, Celestia S. Morrissey, Colm Nelson, Peter S. Plymate, Stephen R. Dehm, Scott M. TI Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer SO NATURE COMMUNICATIONS LA English DT Article ID STRUCTURAL VARIANT DISCOVERY; SPLICE VARIANTS; RNA-SEQ; SEQUENCING DATA; CELL-GROWTH; RESISTANCE; ENZALUTAMIDE; PROGRESSION; MUTATION; THERAPY AB Molecularly targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signalling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements (AR-GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumours. AR-GSRs occur in the context of copy-neutral and amplified AR and display heterogeneity in breakpoint location, rearrangement class and sub-clonal enrichment in tumours within and between patients. Despite this heterogeneity, one common outcome in tumours with high sub-clonal enrichment of AR-GSRs is outlier expression of diverse AR variant species lacking the ligand-binding domain and possessing ligand-independent transcriptional activity. Collectively, these findings reveal AR-GSRs as important drivers of persistent AR signalling in CRPC. C1 [Henzler, Christine; Yang, Rendong] Univ Minnesota, Minnesota Supercomp Inst, 117 Pleasant St Southeast, Minneapolis, MN 55455 USA. [Li, Yingming; McBride, Terri; Ho, Yeung; Dehm, Scott M.] Univ Minnesota, Masonic Canc Ctr, Mayo Mail Code 806,420 Delaware St Southeast, Minneapolis, MN 55455 USA. [McBride, Terri] Univ Minnesota, Med Scientist Training Program, Minneapolis, MN 55455 USA. [Sprenger, Cynthia; Liu, Gang; Plymate, Stephen R.] Univ Washington, Div Gerontol & Geriatr Med, Seattle, WA 98104 USA. [Coleman, Ilsa; Higano, Celestia S.; Nelson, Peter S.] Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave North, Seattle, WA 98109 USA. [Lakely, Bryce; Higano, Celestia S.; Morrissey, Colm; Plymate, Stephen R.] Univ Washington, Dept Urol, 1959 Northeast Pacific St,Box 356510, Seattle, WA 98195 USA. [Li, Rui; Ma, Shihong; Raj, Ganesh V.] Univ Texas Southwestern Med Ctr Dallas, Dept Urol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. [Landman, Sean R.; Kumar, Vipin] Univ Minnesota, Dept Comp Sci & Engn, 200 Union St Southeast, Minneapolis, MN 55455 USA. [Hwang, Tae Hyun] Univ Texas Southwestern Med Ctr Dallas, Quantitat Biomed Res Ctr, 2201 Inwood Rd, Dallas, TX 75390 USA. [Higano, Celestia S.] Univ Washington, Dept Med, 825 Eastlake Ave East, Seattle, WA 98109 USA. [Plymate, Stephen R.] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, 325 9th Ave,Box 359625, Seattle, WA 98104 USA. [Dehm, Scott M.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Dehm, Scott M.] Univ Minnesota, Dept Urol, Minneapolis, MN 55455 USA. RP Dehm, SM (reprint author), Univ Minnesota, Masonic Canc Ctr, Mayo Mail Code 806,420 Delaware St Southeast, Minneapolis, MN 55455 USA.; Dehm, SM (reprint author), Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA.; Dehm, SM (reprint author), Univ Minnesota, Dept Urol, Minneapolis, MN 55455 USA. EM dehm@umn.edu OI McBride, Terri/0000-0002-9305-8038 FU NIH [R01CA174777]; U.S. Department of Defense Prostate Cancer Research Program Transformative Impact Award [W81XWH-15-1-0430]; Pacific Northwest Prostate Cancer SPORE [P50CA97186]; PO1 NIH grants [PO1CA085859, PO1CA163227]; Richard M. Lucas Foundation; NIH Medical Scientist Training Program [T32GM008244] FX We thank the patients and their families who were willing to participate in the Prostate Cancer Donor Program. We acknowledge Drs Robert Vessella, Bruce Montgomery, Evan Yu, Elahe Mostaghel, Heather Cheng, Paul Lange, Martine Roudier and Lawrence True, and the tissue acquisition teams for their contributions to the University of Washington Prostate Cancer Donor Program. In addition, we thank Dr Eva Corey for access to LuCaP xenograft tissue and Belinda Nghiem for her technical expertise. This research was supported by funding from NIH grants R01CA174777 (to S.M.D.), U.S. Department of Defense Prostate Cancer Research Program Transformative Impact Award W81XWH-15-1-0430 (to S.R.P. and S.M.D.), the Pacific Northwest Prostate Cancer SPORE (P50CA97186 to P.S.N.), PO1 NIH grants (PO1CA085859 and PO1CA163227) and the Richard M. Lucas Foundation. T.M. was supported by NIH Medical Scientist Training Program grant T32GM008244. NR 55 TC 2 Z9 2 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD NOV 29 PY 2016 VL 7 AR 13668 DI 10.1038/ncomms13668 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED2GM UT WOS:000388662000001 PM 27897170 ER PT J AU Liu, YZ Lin, WJ Liu, C Luo, YJ Wu, JH Bayley, PJ Qin, SZ AF Liu, Yunzhe Lin, Wanjun Liu, Chao Luo, Yuejia Wu, Jianhui Bayley, Peter J. Qin, Shaozheng TI Memory consolidation reconfigures neural pathways involved in the suppression of emotional memories SO NATURE COMMUNICATIONS LA English DT Article ID UNWANTED MEMORIES; AUTOBIOGRAPHICAL MEMORIES; COMPETING MEMORIES; PATTERN SEPARATION; SLEEP; BRAIN; HIPPOCAMPAL; RETRIEVAL; MECHANISMS; NETWORK AB The ability to suppress unwanted emotional memories is crucial for human mental health. Through consolidation over time, emotional memories often become resistant to change. However, how consolidation impacts the effectiveness of emotional memory suppression is still unknown. Using event-related fMRI while concurrently recording skin conductance, we investigated the neurobiological processes underlying the suppression of aversive memories before and after overnight consolidation. Here we report that consolidated aversive memories retain their emotional reactivity and become more resistant to suppression. Suppression of consolidated memories involves higher prefrontal engagement, and less concomitant hippocampal and amygdala disengagement. In parallel, we show a shift away from hippocampal-dependent representational patterns to distributed neocortical representational patterns in the suppression of aversive memories after consolidation. These findings demonstrate rapid changes in emotional memory organization with overnight consolidation, and suggest possible neurobiological bases underlying the resistance to suppression of emotional memories in affective disorders. C1 [Liu, Yunzhe; Lin, Wanjun; Liu, Chao; Qin, Shaozheng] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing 100875, Peoples R China. [Liu, Yunzhe; Lin, Wanjun; Liu, Chao; Qin, Shaozheng] Beijing Normal Univ, IDG McGovern Inst Brain Res, Beijing 100875, Peoples R China. [Luo, Yuejia; Wu, Jianhui] Shenzhen Univ, Inst Affect & Social Neurosci, Shenzhen 518060, Peoples R China. [Luo, Yuejia; Wu, Jianhui] Shenzhen Univ, Coll Psychol & Sociol, Shenzhen 518060, Peoples R China. [Luo, Yuejia] Shenzhen Inst Neurosci, Shenzhen 518057, Peoples R China. [Bayley, Peter J.] US Dept Vet Affairs, War Related Illness & Injury Study Ctr, Palo Alto, CA 94304 USA. [Bayley, Peter J.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. RP Qin, SZ (reprint author), Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing 100875, Peoples R China.; Qin, SZ (reprint author), Beijing Normal Univ, IDG McGovern Inst Brain Res, Beijing 100875, Peoples R China.; Wu, JH (reprint author), Shenzhen Univ, Inst Affect & Social Neurosci, Shenzhen 518060, Peoples R China.; Wu, JH (reprint author), Shenzhen Univ, Coll Psychol & Sociol, Shenzhen 518060, Peoples R China. EM wujh8@szu.edu.cn; szqin@bnu.edu.cn RI Liu, Chao/E-9068-2017 OI Liu, Chao/0000-0003-1149-2314 FU National Natural Science Foundation of China [31530031, 31522028, 81371203, 81571056, 81471376, 2014NT15]; National Key Basic Research Program of China (973 Program) [2014CB744600]; Thousand (Young) Talents Program of China FX This work was supported by the National Natural Science Foundation of China (31530031, 31522028, 81371203, 81571056, 81471376, 2014NT15), the National Key Basic Research Program of China (973 Program, 2014CB744600), and the Thousand (Young) Talents Program of China. We thank Zhi Yang, Xueyi Shen, Xiaping Lu, Wanqing Li and Honghong Tang for their assistance in data collection, and we also thank all of the subjects who participated in this study. NR 70 TC 0 Z9 0 U1 19 U2 19 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 NOV 29 PY 2016 VL 7 AR 13375 DI 10.1038/ncomms13375 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED6TX UT WOS:000388990400001 PM 27898050 ER PT J AU Capodanno, D Gargiulo, G Buccheri, S Chieffo, A Meliga, E Latib, A Park, SJ Onuma, Y Capranzano, P Valgimigli, M Narbute, I Makkar, RR Palacios, IF Kim, YH Buszman, PE Chakravarty, T Sheiban, I Mehran, R Naber, C Margey, R Agnihotri, A Marra, S Leon, MB Moses, JW Fajadet, J Lefevre, T Morice, MC Erglis, A Alfieri, O Serruys, PW Colombo, A Tamburino, C AF Capodanno, Davide Gargiulo, Giuseppe Buccheri, Sergio Chieffo, Alaide Meliga, Emanuele Latib, Azeem Park, Seung-Jung Onuma, Yoshinobu Capranzano, Piera Valgimigli, Marco Narbute, Inga Makkar, Raj R. Palacios, Igor F. Kim, Young-Hak Buszman, Pawel E. Chakravarty, Tarun Sheiban, Imad Mehran, Roxana Naber, Christoph Margey, Ronan Agnihotri, Arvind Marra, Sebastiano Leon, Martin B. Moses, Jeffrey W. Fajadet, Jean Lefevre, Thierry Morice, Marie-Claude Erglis, Andrejs Alfieri, Ottavio Serruys, Patrick W. Colombo, Antonio Tamburino, Corrado CA DELTA Investigators TI Computing Methods for Composite Clinical Endpoints in Unprotected Left Main Coronary Artery Revascularization A Post Hoc Analysis of the DELTA Registry SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE Andersen-Gill; competing risk; left main; weighted composite event(s); win ratio ID DRUG-ELUTING STENTS; BYPASS GRAFT-SURGERY; SYNTAX SCORE-II; 5-YEAR OUTCOMES; COMPETING RISK; INTERVENTION; DISEASE; TRIAL; METAANALYSIS; STENOSIS AB OBJECTIVES The study sought to investigate the impact of different computing methods for composite endpoints other than time-to-event (TTE) statistics in a large, multicenter registry of unprotected left main coronary artery (ULMCA) disease. BACKGROUND TTE statistics for composite outcome measures used in ULMCA studies consider only the first event, and all the contributory outcomes are handled as if of equal importance. METHODS The TTE, Andersen-Gill, win ratio (WR), competing risk, and weighted composite endpoint (WCE) computing methods were applied to ULMCA patients revascularized by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) at 14 international centers. RESULTS At a median follow-up of 1,295 days (interquartile range: 928 to 1,713 days), all analyses showed no difference in combinations of death, myocardial infarction, and cerebrovascular accident between PCI and CABG. When target vessel revascularization was incorporated in the composite endpoint, the TTE (p = 0.03), Andersen-Gill (p = 0.04), WR (p = 0.025), and competing risk (p < 0.001) computing methods showed CABG to be significantly superior to PCI in the analysis of 1,204 propensity-matched patients, whereas incorporating the clinical relevance of the component endpoints using WCE resulted in marked attenuation of the treatment effect of CABG, with loss of significance for the difference between revascularization strategies (p = 0.10). CONCLUSIONS In a large study of ULMCA revascularization, incorporating the clinical relevance of the individual outcomes resulted in sensibly different findings as compared with the conventional TTE approach. In particular, using the WCE computing method, PCI and CABG were no longer significantly different with respect to the composite of death, myocardial infarction, cerebrovascular accident, or target vessel revascularization at a median of 3 years. (C) 2016 by the American College of Cardiology Foundation. C1 [Capodanno, Davide; Gargiulo, Giuseppe; Buccheri, Sergio; Capranzano, Piera; Tamburino, Corrado] Univ Catania, Ferrarotto Hosp, Cardiothoracic Vasc Dept, Catania, Italy. [Gargiulo, Giuseppe] Univ Naples Federico II, Dept Adv Biomed Sci, Naples, Italy. [Chieffo, Alaide; Latib, Azeem; Colombo, Antonio] Ist Sci San Raffaele, Dept Cardiothorac & Vasc Dis, Milan, Italy. [Meliga, Emanuele] AO Ordine Mauriziano Umberto I, Intervent Cardiol Unit, Turin, Italy. [Park, Seung-Jung; Kim, Young-Hak] Univ Ulsan, Coll Med, Asan Med Ctr, Depat Cardiol,Ctr Med Res & Informat, Seoul, South Korea. [Onuma, Yoshinobu; Serruys, Patrick W.] Erasmus MC, Thoraxctr, Rotterdam, Netherlands. [Valgimigli, Marco] Univ Hosp Bern, Bern, Switzerland. [Narbute, Inga; Erglis, Andrejs] Pauls Stradins Clin Univ Hosp, Latvian Ctr Cardiol, Riga, Latvia. [Narbute, Inga; Erglis, Andrejs] Univ Latvia, Inst Cardiol, Riga, Latvia. [Makkar, Raj R.; Chakravarty, Tarun; Margey, Ronan] Cedars Sinai Med Ctr, Cedars Sinai Heart Inst, Los Angeles, CA 90048 USA. [Palacios, Igor F.; Agnihotri, Arvind] Massachusetts Gen Hosp, Cardiac Catheterizat Lab, Boston, MA 02114 USA. [Palacios, Igor F.; Agnihotri, Arvind] Harvard Med Sch, Boston, MA USA. [Buszman, Pawel E.] Ctr Cardiovasc Res & Dev Amer Heart Poland, Katowice, Poland. [Sheiban, Imad; Marra, Sebastiano] Univ Turin, S Giovanni Battista Molinette Hosp, Div Cardiol, Intervent Cardiol, Turin, Italy. [Mehran, Roxana] Mt Sinai Med Ctr, New York, NY 10029 USA. [Naber, Christoph] Elisabeth Hosp, Klin Kardiol & Angiol, Essen, Germany. [Leon, Martin B.; Moses, Jeffrey W.] Columbia Univ, Med Ctr, New York, NY USA. [Leon, Martin B.; Moses, Jeffrey W.] Cardiovasc Res Fdn, New York, NY USA. [Fajadet, Jean] Clin Pasteur, Toulouse, France. [Lefevre, Thierry; Morice, Marie-Claude] Ramsay Gen Sante, Hop Prive Jacques Cartier, Massy, France. EM dcapodanno@gmail.com FU European Association of Percutaneous Cardiovascular Intervention; CardioPaTh PhD program at Federico II University of Naples; Abbott Vascular; Boston Scientific; Medtronic; Terumo FX Dr. Gargiulo has received research grant support from the European Association of Percutaneous Cardiovascular Intervention and from the CardioPaTh PhD program at Federico II University of Naples. Dr. Makkar has served as a consultant for Abbott Vascular, Cordis, and Medtronic. Dr. Fajadet has received educational grant support from Abbott Vascular, Boston Scientific, Medtronic, and Terumo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Capodanno and Gargiulo contributed equally to this work. NR 32 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 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD NOV 28 PY 2016 VL 9 IS 22 BP 2280 EP 2288 DI 10.1016/j.jcin.2016.08.025 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI6PO UT WOS:000392618100005 PM 27884354 ER PT J AU Salisbury, AC Li, HY Vilain, KR Jaff, MR Schneider, PA Laird, JR Cohen, DJ AF Salisbury, Adam C. Li, Haiyan Vilain, Katherine R. Jaff, Michael R. Schneider, Peter A. Laird, John R. Cohen, David J. TI Cost-Effectiveness of Endovascular Femoropopliteal Intervention Using Drug-Coated Balloons Versus Standard Percutaneous Transluminal Angioplasty SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE angioplasty; cost-effectiveness; drug-coated balloon; femoropopliteal artery; peripheral arterial disease ID PERIPHERAL ARTERY-DISEASE; UNITED-STATES; TRIAL; STENT; MANAGEMENT; IMPACT; MODEL; RATES; RISK; SFA AB OBJECTIVES The aim of this study was to evaluate the cost-effectiveness of drug-coated balloon (DCB) angioplasty versus standard percutaneous transluminal angioplasty (PTA). BACKGROUND Recent trials have reported lower rates of target lesion revascularization with DCB angioplasty versus standard PTA. However, the cost-effectiveness of DCB angioplasty is unknown. METHODS A prospective economic study was performed alongside the IN. PACT SFA II (IN. PACT Admiral Drug-Coated Balloon vs. Standard Balloon Angioplasty for the Treatment of Superficial Femoral Artery [SFA] and Proximal Popliteal Artery [PPA]) trial, which randomized 181 patients with femoropopliteal disease to the IN. PACT DCB versus standard PTA. Resource use data were collected over 2-year follow-up, and costs were assigned using resource-based accounting and billing data. Health utilities were assessed using the EuroQol 5-dimensions questionnaire. Cost-effectiveness was assessed as cost per quality-adjusted life-year (QALY) gained using a decision-analytic model on the basis of empirical data from the trial assuming identical long-term mortality. RESULTS Initial costs were $1,129 per patient higher with DCB angioplasty than standard PTA, driven by higher costs for the DCB itself. Between discharge and 24 months, target limb-related costs were $1,212 per patient lower with DCB angioplasty such that discounted 2-year costs were similar for the 2 groups ($11,277 vs. $11,359, p = 0.97), whereas QALYs tended to be greater among patients treated with DCBs (1.53 perpendicular to 0.44 vs. 1.47 perpendicular to 0.42, p = 0.40). The probability that DCB angioplasty is cost-effective compared with standard PTA was 70% using a threshold of $50,000 per QALY gained and 79% at a threshold of $150,000 per QALY gained. CONCLUSIONS For patients with femoropopliteal disease, DCB angioplasty is associated with better 2-year outcomes and similar target limb-related costs compared with standard PTA. Formal cost-effectiveness analysis on the basis of these results suggests that use of the DCB angioplasty is likely to be economically attractive. (C) 2016 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. C1 [Salisbury, Adam C.; Li, Haiyan; Vilain, Katherine R.; Cohen, David J.] St Lukes Mid Amer Heart Inst, Dept Cardiovasc Med, Kansas City, MO USA. [Salisbury, Adam C.; Cohen, David J.] Univ Missouri, Sch Med, Kansas City, MO 64108 USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Mass Gen Vasc Ctr, Boston, MA 02114 USA. [Schneider, Peter A.] Kaiser Permanente, Div Vasc Therapy, Dept Surg, Honolulu, HI USA. [Laird, John R.] Univ Calif Davis, Div Cardiovasc Med, Sacramento, CA 95817 USA. [Laird, John R.] Univ Calif Davis, Vasc Ctr, Dept Med, Sacramento, CA 95817 USA. EM dcohen@saint-lukes.org FU Medtronic; Boston Scientific; W.L. Gore; Abbott Vascular FX This research was sponsored by Medtronic. Dr. Salisbury has received research grant support from Boston Scientific and honoraria or speaking fees from Medtronic and and is a compensated advisor for Abiomed. Dr. Jaff is a noncompensated adviser to Abbott Vascular, Boston Scientific, Cordis, and Medtronic; is a compensated adviser to Cardinal Health and Volcano; has equity interest in PQ Bypass and Vascular Therapies; and is on the boards of VIVA Physicians (a501[c][3] not-for-profit education and research organization) and the Society for Cardiovascular Angiography and Interventions. Dr. Schnieder has received modest royalties for intellectual property from Cook; serves as a noncompensated adviser to Medtronic, Cardinal, Abbott Vascular; and is on the board of VIVA Physicians. Dr. Laird has received research grant support from W.L. Gore and has provided consulting services to Abbott Vascular, Bard Peripheral Vascular, Boston Scientific, Cordis and Medtronic. Dr. Cohen has received research grant support from Abbott Vascular, Boston Scientific, and Medtronic; and has provided consulting services to Abbott Vascular, Cardinal Health, and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 21 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 NOV 28 PY 2016 VL 9 IS 22 BP 2343 EP 2352 DI 10.1016/j.jcin.206.08.036 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI6PO UT WOS:000392618100015 PM 27884360 ER PT J AU Chan, MC Ziegler, O Liu, L Rowe, GC Das, S Otterbein, LE Arany, Z AF Chan, Mun Chun Ziegler, Olivia Liu, Laura Rowe, Glenn C. Das, Saumya Otterbein, Leo E. Arany, Zoltan TI Heme oxygenase and carbon monoxide protect from muscle dystrophy SO SKELETAL MUSCLE LA English DT Article DE PGC-1 alpha; mdx; Duchenne muscle dystrophy; Heme oxygenase; HO-1; Carbon monoxide ID DUCHENNE MUSCULAR-DYSTROPHY; TRANSCRIPTIONAL COACTIVATOR PGC-1-ALPHA; SKELETAL-MUSCLE; MITOCHONDRIAL BIOGENESIS; MOUSE MODEL; ANGIOGENESIS; GENE; EXPRESSION; PGC-1-BETA; INDUCTION AB Background: Duchenne muscle dystrophy (DMD) is one of the most common lethal genetic diseases of children worldwide and is 100% fatal. Steroids, the only therapy currently available, are marred by poor efficacy and a high side-effect profile. New therapeutic approaches are urgently needed. Methods: Here, we leverage PGC-1 alpha, a powerful transcriptional coactivator known to protect against dystrophy in the mdx murine model of DMD, to search for novel mechanisms of protection against dystrophy. Results: We identify heme oxygenase-1 (HO-1) as a potential novel target for the treatment of DMD. Expression of HO-1 is blunted in the muscles from the mdx murine model of DMD, and further reduction of HO-1 by genetic haploinsufficiency worsens muscle damage in mdx mice. Conversely, induction of HO-1 pharmacologically protects against muscle damage. Mechanistically, HO-1 degrades heme into biliverdin, releasing in the process ferrous iron and carbon monoxide (CO). We show that exposure to a safe low dose of CO protects against muscle damage in mdx mice, as does pharmacological treatment with CO-releasing molecules. Conclusions: These data identify HO-1 and CO as novel therapeutic agents for the treatment of DMD. Safety profiles and clinical testing of inhaled CO already exist, underscoring the translational potential of these observations. C1 [Chan, Mun Chun; Ziegler, Olivia; Liu, Laura; Rowe, Glenn C.; Das, Saumya] Beth Israel Deaconess Med Ctr, Cardiovasc Inst, Boston, MA 02215 USA. [Chan, Mun Chun; Ziegler, Olivia; Liu, Laura; Das, Saumya] Massachusetts Gen Hosp, Cardiovasc Inst, Boston, MA 02114 USA. [Rowe, Glenn C.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Otterbein, Leo E.] Beth Israel Deaconess Med Ctr, Dept Surg, 330 Brookline Ave, Boston, MA 02215 USA. [Arany, Zoltan] Univ Penn, Cardiovasc Inst, Perelman Sch Med, Smilow Ctr Translat Res, 11th Floor,3400 Civ Blvd, Philadelphia, PA 19104 USA. [Arany, Zoltan] Univ Penn, Inst Diabet Obes & Metab, Perelman Sch Med, Smilow Ctr Translat Res, 11th Floor,3400 Civ Blvd, Philadelphia, PA 19104 USA. RP Arany, Z (reprint author), Univ Penn, Cardiovasc Inst, Perelman Sch Med, Smilow Ctr Translat Res, 11th Floor,3400 Civ Blvd, Philadelphia, PA 19104 USA.; Arany, Z (reprint author), Univ Penn, Inst Diabet Obes & Metab, Perelman Sch Med, Smilow Ctr Translat Res, 11th Floor,3400 Civ Blvd, Philadelphia, PA 19104 USA. EM zarany@mail.med.upenn.edu OI Rowe, Glenn/0000-0002-8195-9605 FU NHLBI; Ellison Foundation; MDA; NRSA FX The NHLBI (ZA and GCR), the Ellison Foundation (ZA), the MDA (ZA), and the NRSA (SR) supported this work. NR 39 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 2044-5040 J9 SKELET MUSCLE JI Skeletal Muscle PD NOV 28 PY 2016 VL 6 AR 41 DI 10.1186/s13395-016-0114-6 PG 12 WC Cell Biology SC Cell Biology GA EG9TR UT WOS:000391402900001 PM 27906108 ER PT J AU Song, DL Wilson, B Zhao, LL Bhuyan, R Bandyopadhyay, M Lyubarsky, A Yu, C Li, YF Kanu, L Miwa, T Song, WC Finnemann, SC Rohrer, B Dunaief, JL AF Song, Delu Wilson, Brooks Zhao, Liangliang Bhuyan, Rupak Bandyopadhyay, Mausumi Lyubarsky, Arkady Yu, Chen Li, Yafeng Kanu, Levi Miwa, Takashi Song, Wen-Chao Finnemann, Silvia C. Rohrer, Barbel Dunaief, Joshua L. TI Retinal Pre-Conditioning by CD59a Knockout Protects against Light-Induced Photoreceptor Degeneration SO PLOS ONE LA English DT Article ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; PIGMENT EPITHELIAL-CELLS; COMPLEMENT REGULATORY PROTEINS; CHELATOR DEFERIPRONE PROTECTS; DECAY-ACCELERATING FACTOR; FACTOR-H DEFICIENCY; MACULAR DEGENERATION; CHOROIDAL NEOVASCULARIZATION; FUNCTIONAL-CHARACTERIZATION; OXIDATIVE STRESS AB Complement dysregulation plays a key role in the pathogenesis of age-related macular degeneration (AMD), but the specific mechanisms are incompletely understood. Complement also potentiates retinal degeneration in the murine light damage model. To test the retinal function of CD59a, a complement inhibitor, CD59a knockout (KO) mice were used for light damage (LD) experiments. Retinal degeneration and function were compared in WT versus KO mice following light damage. Gene expression changes, endoplasmic reticulum (ER) stress, and glial cell activation were also compared. At baseline, the ERG responses and rhodopsin levels were lower in CD59aKO compared to wild-type (WT) mice. Following LD, the ERG responses were better preserved in CD59aKO compared to WT mice. Correspondingly, the number of photoreceptors was higher in CD59aKO retinas than WT controls after LD. Under normal light conditions, CD59aKO mice had higher levels than WT for GFAP immunostaining in Muller cells, mRNA and protein levels of two ER-stress markers, and neurotrophic factors. The reduction in photon capture, together with the neurotrophic factor upregulation, may explain the structural and functional protection against LD in the CD59aKO. C1 [Song, Delu; Zhao, Liangliang; Bhuyan, Rupak; Lyubarsky, Arkady; Li, Yafeng; Kanu, Levi; Dunaief, Joshua L.] Univ Penn, Perelman Sch Med, Scheie Eye Inst, FM Kirby Ctr Mol Ophthalmol, Philadelphia, PA 19104 USA. [Wilson, Brooks; Bandyopadhyay, Mausumi; Rohrer, Barbel] Med Univ South Carolina, Dept Ophthalmol, 171 Ashley Ave, Charleston, SC 29425 USA. [Zhao, Liangliang] Jilin Univ, Hosp 2, Dept Ophthalmol, Changchun, Jilin, Peoples R China. [Yu, Chen; Finnemann, Silvia C.] Fordham Univ, Dept Biol Sci, Ctr Canc Genet Dis & Gene Regulat, Bronx, NY 10458 USA. [Miwa, Takashi; Song, Wen-Chao] Univ Penn, Perelman Sch Med, Dept Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA. [Rohrer, Barbel] Ralph H Johnson VA Med Ctr, Res Serv, Charleston, SC 29401 USA. RP Dunaief, JL (reprint author), Univ Penn, Perelman Sch Med, Scheie Eye Inst, FM Kirby Ctr Mol Ophthalmol, Philadelphia, PA 19104 USA.; Rohrer, B (reprint author), Med Univ South Carolina, Dept Ophthalmol, 171 Ashley Ave, Charleston, SC 29425 USA.; Rohrer, B (reprint author), Ralph H Johnson VA Med Ctr, Res Serv, Charleston, SC 29401 USA. EM rohrer@musc.edu; jdunaief@upenn.edu OI Song, Delu/0000-0002-9030-7211 FU NIH [EY015240, CO6RR015455]; Research to Prevent Blindness; FM Kirby Foundation; Paul and Evanina Bell Mackall Foundation Trust; National Center for Advancing Translational Sciences of the NIH [KL2TR001879]; National Institutes of Health [NIH R01EY019320, R01EY013295]; Department for Veteran Affairs merit award [RX000444]; Beckman Initiative for Macular Research; Research to Prevent Blindness (RPB), New York, NY FX This work was supported in the laboratory of J.D. by NIH EY015240, Research to Prevent Blindness, the FM Kirby Foundation, the Paul and Evanina Bell Mackall Foundation Trust, a gift in memory of Dr. Lee F. Mauger, and grant KL2TR001879 from the National Center for Advancing Translational Sciences of the NIH; in the laboratory of B.R. in part by the National Institutes of Health (NIH R01EY019320), a Department for Veteran Affairs merit award RX000444, the Beckman Initiative for Macular Research, an unrestricted grant to MUSC from Research to Prevent Blindness (RPB), New York, NY; and in the laboratory of S.C.F. by grants from the National Institutes of Health (R01EY013295) and the Beckman Initiative for Macular Research. B.R.'s animal studies were conducted in a facility constructed with support from the NIH CO6RR015455. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This work was supported in the laboratory of J.L.D. by NIH EY015240, Research to Prevent Blindness, the FM Kirby Foundation, the Paul and Evanina Bell Mackall Foundation Trust, a gift in memory of Dr. Lee F. Mauger, and grant KL2TR001879 from the National Center for Advancing Translational Sciences of the NIH; in the laboratory of B.R. in part by the National Institutes of Health (NIH R01EY019320), a Department for Veteran Affairs merit award RX000444, the Beckman Initiative for Macular Research, an unrestricted grant to MUSC from Research to Prevent Blindness (RPB), New York, NY; and in the laboratory of S.C.F. by grants from the National Institutes of Health (R01EY013295) and the Beckman Initiative for Macular Research. B.R.'s animal studies were conducted in a facility constructed with support from the NIH C06RR015455. NR 57 TC 0 Z9 0 U1 0 U2 0 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 NOV 28 PY 2016 VL 11 IS 11 AR e0166348 DI 10.1371/journal.pone.0166348 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3FE UT WOS:000389472400022 PM 27893831 ER PT J AU Wang, HQ Osseiran, S Igras, V Nichols, AJ Roider, EM Pruessner, J Tsao, H Fisher, DE Evans, CL AF Wang, Hequn Osseiran, Sam Igras, Vivien Nichols, Alexander J. Roider, Elisabeth M. Pruessner, Joachim Tsao, Hensin Fisher, David E. Evans, Conor L. TI In vivo coherent Raman imaging of the melanomagenesis-associated pigment pheomelanin SO SCIENTIFIC REPORTS LA English DT Article ID SCATTERING MICROSCOPY; ONE-LASER AB Melanoma is the most deadly form of skin cancer with a yearly global incidence over 232,000 patients. Individuals with fair skin and red hair exhibit the highest risk for developing melanoma, with evidence suggesting the red/blond pigment known as pheomelanin may elevate melanoma risk through both UV radiation-dependent and -independent mechanisms. Although the ability to identify, characterize, and monitor pheomelanin within skin is vital for improving our understanding of the underlying biology of these lesions, no tools exist for real-time, in vivo detection of the pigment. Here we show that the distribution of pheomelanin in cells and tissues can be visually characterized non-destructively and noninvasively in vivo with coherent anti-Stokes Raman scattering ( CARS) microscopy, a label-free vibrational imaging technique. We validated our CARS imaging strategy in vitro to in vivo with synthetic pheomelanin, isolated melanocytes, and the Mc1r(e/e), red-haired mouse model. Nests of pheomelanotic melanocytes were observed in the red-haired animals, but not in the genetically matched Mc1r(e/e); Tyr(c/c) ("albino-red-haired") mice. Importantly, samples from human amelanotic melanomas subjected to CARS imaging exhibited strong pheomelanotic signals. This is the first time, to our knowledge, that pheomelanin has been visualized and spatially localized in melanocytes, skin, and human amelanotic melanomas. C1 [Wang, Hequn; Osseiran, Sam; Nichols, Alexander J.; Pruessner, Joachim; Tsao, Hensin; Evans, Conor L.] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, 149 13th St, Charlestown, MA 02129 USA. [Osseiran, Sam; Nichols, Alexander J.] Harvard MIT, Div Hlth Sci & Technol, 77 Massachusetts Ave E25-519, Cambridge, MA 02139 USA. [Igras, Vivien; Roider, Elisabeth M.; Fisher, David E.] Harvard Med Sch, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, 149 13th St, Charlestown, MA 02129 USA. [Nichols, Alexander J.; Evans, Conor L.] Harvard Univ, Program Biophys, Bldg C2 Room 112,240 Longwood Ave, Boston, MA 02115 USA. [Evans, Conor L.] Harvard Med Sch, Ludwig Ctr Harvard, 200 Longwood Ave, Boston, MA 02115 USA. RP Evans, CL (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, 149 13th St, Charlestown, MA 02129 USA.; Fisher, DE (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, 149 13th St, Charlestown, MA 02129 USA.; Evans, CL (reprint author), Harvard Univ, Program Biophys, Bldg C2 Room 112,240 Longwood Ave, Boston, MA 02115 USA.; Evans, CL (reprint author), Harvard Med Sch, Ludwig Ctr Harvard, 200 Longwood Ave, Boston, MA 02115 USA. EM dfisher3@mgh.harvard.edu; evans.conor@mgh.harvard.edu FU Bridge Project Grant [222700]; Canadian Institute of Health Research; Henry C. and Frances Keany Rickard Fund Fellowship via MIT; NIH [5P01 CA163222-03, 5R01 AR043369-19]; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation FX We thank J. Hsiao for preparation of mouse ear samples. We also thank Y. Suita for help with melanoma cell preparation. We also thank the Wellman Photopathology Core, with special thanks to J. Zhao for processing all the staining. We gratefully acknowledge T. Kunisada for the K14-SCF transgenic mouse strain and L. Larue for the Tyr-CRE mouse strain. We also thank Tom Powell for assistance in manuscript editing. This work was supported by a Bridge Project Grant (222700) to D.E.F and C.L.E. H.W and S.O would like to acknowledge funding support from the Canadian Institute of Health Research and the Henry C. (1926) and Frances Keany Rickard Fund Fellowship via MIT, respectively. D.E.F was supported by grants from NIH (5P01 CA163222-03 and 5R01 AR043369-19), as well as from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. NR 22 TC 0 Z9 0 U1 14 U2 14 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 NOV 28 PY 2016 VL 6 AR 37986 DI 10.1038/srep37986 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED0XM UT WOS:000388567000001 PM 27892516 ER PT J AU Cheson, BD Ansell, S Schwartz, L Gordon, LI Advani, R Jacene, HA Hoos, A Barrington, SF Armand, P AF Cheson, Bruce D. Ansell, Stephen Schwartz, Larry Gordon, Leo I. Advani, Ranjana Jacene, Heather A. Hoos, Axel Barrington, Sally F. Armand, Philippe TI Refinement of the Lugano Classification lymphoma response criteria in the era of immunomodulatory therapy SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; MANTLE-CELL LYMPHOMA; SINGLE-AGENT LENALIDOMIDE; NON-HODGKINS-LYMPHOMA; TUMOR FLARE REACTION; PHASE-II; ADVANCED MELANOMA; WORKING GROUP; INTERNATIONAL WORKSHOP; TARGETING BTK AB Uniformly adopted response criteria are essential for assessment of therapies incorporating conventional chemotherapy and chemoimmunotherapy regimens. Recently, immunomodulatory agents, such as immune checkpoint inhibitors, have demonstrated impressive activity in a broad range of lymphoma histologies. However, these agents may be associated with clinical and imaging findings during treatment suggestive of progressive disease (PD) despite evidence of clinical benefit (eg, tumor flare or pseudoprogression). Considering this finding as PD could lead to patients being prematurely removed from a treatment from which they actually stand to benefit. This phenomenon has been well described with checkpoint blockade therapy in solid tumorsandanecdotally seeninlymphoma as well. To address this issue in the context of lymphoma immunomodulatory therapy, a workshop was convened to provide provisional recommendations to modify current response criteria in patients receiving these and future agents in clinical trials. The term "indeterminate response" was introduced to identify such lesions until confirmed as flare/pseudo-progression or true PD by either biopsy or subsequent imaging. C1 [Cheson, Bruce D.] Georgetown Univ Hosp, Dept Med, Lombardi Comprehens Canc Ctr, Dept Hematol Oncol, Washington, DC 20007 USA. [Ansell, Stephen] Mayo Clin, Div Hematol, Rochester, MN USA. [Schwartz, Larry] Columbia Univ Coll Phys & Surg, New York Presbyterian Hosp, Dept Radiol, 630 W 168th St, New York, NY 10032 USA. [Gordon, Leo I.] Northwestern Univ, Dept Med, Feinberg Sch Med, Div Hematol Oncol, Chicago, IL 60611 USA. [Gordon, Leo I.] Robert H Lurie Comprehens Canc Ctr, Chicago, IL USA. [Advani, Ranjana] Stanford Univ, Dept Med Oncol, Stanford, CA 94305 USA. [Jacene, Heather A.; Armand, Philippe] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. [Hoos, Axel] GlaxoSmithKline, Oncol R&D, Collegeville, PA USA. [Barrington, Sally F.] PET Imaging Ctr St Thomas, Dept Nucl Med, London, England. EM bdc4@georgetown.edu FU Lymphoma Research Foundation; Cancer Research Institute FX The authors thank Richard I. Fisher. T. Andrew Lister, and Emanuele Zucca for critical review of the manuscript and Fernanda C. Cabral and Annick D. Van Den Abbeele for provision of images. Most notably, we appreciate the Lymphoma Research Foundation and the Cancer Research Institute for their sponsoring of the workshop leading to these recommendations. NR 39 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 NOV 24 PY 2016 VL 128 IS 21 BP 2489 EP 2496 DI 10.1182/blood-2016-05-718528 PG 8 WC Hematology SC Hematology GA EI7AO UT WOS:000392649400007 PM 27574190 ER PT J AU Ujjani, CS Jung, SH Pitcher, B Martin, P Park, SI Blum, KA Smith, SM Czuczman, M Davids, MS Levine, E Lewis, LD Smith, SE Bartlett, NL Leonard, JP Cheson, BD AF Ujjani, Chaitra S. Jung, Sin-Ho Pitcher, Brandelyn Martin, Peter Park, Steven I. Blum, Kristie A. Smith, Sonali M. Czuczman, Myron Davids, Matthew S. Levine, Ellis Lewis, Lionel D. Smith, Scott E. Bartlett, Nancy L. Leonard, John P. Cheson, Bruce D. TI Phase 1 trial of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma: Alliance A051103 SO BLOOD LA English DT Article ID PLUS RITUXIMAB; 1ST-LINE TREATMENT; RANDOMIZED-TRIAL; OPEN-LABEL; INDOLENT; CHOP; CVP AB Chemoimmunotherapy in follicular lymphoma is associated with significant toxicity. Targeted therapies are being investigated as potentially more efficacious and tolerable alternatives for this multiply-relapsing disease. Based on promising activity with rituximab and lenalidomide in previously untreated follicular lymphoma (overall response rate [ORR] 90%-96%) and ibrutinib in relapsed disease (ORR 30%-55%), the Alliance for Clinical Trials in Oncology conducted a phase 1 trial of rituximab, lenalidomide, and ibrutinib. Previously untreated patients with follicular lymphoma received rituximab 375 mg/m(2) on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 4, 6, 8, and 10; lenalidomide as per cohort doseon days 1 to 21 of 28 for 18 cycles; and ibrutinib as per cohort dose daily until progression. Dose escalation used a 313 design from a starting dose level (DL) of lenalidomide 15 mg and ibrutinib 420 mg (DL0) to DL2 (lenalidomide 20 mg, ibrutinib 560 mg). Twenty-two patients were enrolled; DL2 was determined to be the recommended phase II dose. Although no protocol-defined dose-limiting toxicities were reported, a high incidence of rash was observed (all grades 82%, grade 3 36%). Eleven patients (50%) required dose reduction, 7 because of rash. The ORR for the entire cohort was 95%, and the 12-month progression-free survival was 80% (95% confidence interval, 57%-92%). Five patients developed new malignancies; 3 had known risk factors before enrollment. Given the increased toxicity and required dose modifications, as well as the apparent lack of additional clinical benefit to the rituximab-lenalidomide doublet, further investigation of the regimen in this setting seems unwarranted. C1 [Ujjani, Chaitra S.; Cheson, Bruce D.] Medstar Georgetown Univ Hosp, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Jung, Sin-Ho; Pitcher, Brandelyn] Duke Univ, Alliance Stat & Data Ctr, Durham, NC USA. [Martin, Peter; Leonard, John P.] Cornell Univ, Weill Med Coll, Meyer Canc Ctr, New York, NY 10021 USA. [Martin, Peter; Leonard, John P.] New York Presbyterian Hosp, New York, NY USA. [Park, Steven I.] Univ North Carolina Chapel Hill, UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Blum, Kristie A.] Ohio State Univ, Div Hematol, Columbus, OH 43210 USA. [Smith, Sonali M.] Univ Chicago, Univ Chicago Med Comprehens Canc Ctr, Chicago, IL 60637 USA. [Czuczman, Myron; Levine, Ellis] SUNY Buffalo, Roswell Pk Canc Inst, Buffalo, NY USA. [Davids, Matthew S.] Dana Farber Partners CancerCare, Boston, MA USA. [Lewis, Lionel D.] Geisel Sch Med Dartmouth, Norris Cotton Canc Ctr, Lebanon, NH USA. [Smith, Scott E.] Loyola Univ, Med Ctr, Cardinal Bernardin Canc Ctr, 2160 S 1st Ave, Maywood, IL 60153 USA. [Bartlett, Nancy L.] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO USA. EM csu@georgetown.edu FU National Cancer Institute (NCI) of the National Institutes of Health [U10CA180821, U10CA180882, U10CA180833, U10CA180836, U10CA180838, U10CA180850, U10CA180854, U10CA180866, U10CA180867]; NCI [U10CA180850, 5U10CA180867, 5U10CA180866, 5U10CA180838, 5U10CA180836] FX This study was supported by the National Cancer Institute (NCI) of the National Institutes of Health under award numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology); U10CA180833, U10CA180836, U10CA180838, U10CA180850, U10CA180854, U10CA180866, and U10CA180867. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; The following institutions participated in this study (principal investigators and NCI grants in parentheses): Dana-Farber/Partners CancerCare LAPS, Boston, MA (Harold Burstein; 5U10CA180867); MedStar Georgetown University Hospital, Washington, DC(B.D.C.); Ohio State University Comprehensive Cancer Center LAPS, Columbus, OH (Richard Goldberg; U10CA180850); Roswell Park Cancer Institute LAPS, Buffalo, NY (E.L.; 5U10CA180866); UNC Lineberger Comprehensive Cancer Center LAPS, Chapel Hill, NC (Thomas Shea; 5U10CA180838); University of Chicago Comprehensive Cancer Center LAPS, Chicago, IL (Hedy Kindler; 5U10CA180836); and Weill Medical College of Cornell University, New York, NY (Scott Tagawa). NR 17 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 NOV 24 PY 2016 VL 128 IS 21 BP 2510 EP 2516 DI 10.1182/blood-2016-06-718106 PG 7 WC Hematology SC Hematology GA EI7AO UT WOS:000392649400010 PM 27697771 ER PT J AU Jacobson, C Kopp, N Layer, JV Redd, RA Tschuri, S Haebe, S van Bodegom, D Bird, L Christie, AL Christodoulou, A Saur, A Tivey, T Zapf, S Bararia, D Zimber-Strobl, U Rodig, SJ Weigert, O Weinstock, DM AF Jacobson, Caron Kopp, Nadja Layer, Jacob V. Redd, Robert A. Tschuri, Sebastian Haebe, Sarah van Bodegom, Diederik Bird, Liat Christie, Amanda L. Christodoulou, Alexandra Saur, Amy Tivey, Trevor Zapf, Stefanie Bararia, Deepak Zimber-Strobl, Ursula Rodig, Scott J. Weigert, Oliver Weinstock, David M. TI HSP90 inhibition overcomes ibrutinib resistance in mantle cell lymphoma SO BLOOD LA English DT Article ID BRUTONS TYROSINE KINASE; CANCER; EXPRESSION; LEUKEMIA; MALIGNANCIES; PATHOGENESIS; ACTIVATION; GANETESPIB; MUTATION; OUTCOMES AB The Bruton tyrosine kinase (BTK) inhibitor ibrutinib induces responses in 70% of patients with relapsed and refractory mantle cell lymphoma (MCL). Intrinsic resistance can occur through activation of the nonclassical NF-kappa B pathway and acquired resistance may involve the BTKC481S mutation. Outcomes after ibrutinib failure are dismal, indicating an unmet medical need. We reasoned that newer heat shock protein 90 (HSP90) inhibitors could overcome ibrutinib resistance by targeting multiple oncogenic pathways in MCL. HSP90 inhibition induced the complete degradation of both BTK and I kappa B kinase a in MCL lines and CD40-dependent B cells, with downstream loss of MAPK and nonclassical NF-kappa B signaling. A proteome-wide analysis in MCL lines and an MCL patient-derived xenograft identified a restricted set of targets from HSP90 inhibition that were enriched for factors involved in B-cell receptor and JAK/STAT signaling, the nonclassical NF-kappa B pathway, cell-cycle regulation, and DNA repair. Finally, multiple HSP90 inhibitors potently killed MCL lines in vitro, and the clinical agent AUY922 was active in vivo against both patient-derived and cell-line xenografts. Together, these findings define the HSP90-dependent proteome in MCL. Considering the disappointing clinical activity of HSP90 inhibitors in other contexts, trials in patients with MCL will be essential for defining the efficacy of and mechanisms of resistance after ibrutinib failure. C1 [Jacobson, Caron; Kopp, Nadja; Layer, Jacob V.; van Bodegom, Diederik; Bird, Liat; Christie, Amanda L.; Christodoulou, Alexandra; Tivey, Trevor; Weinstock, David M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Redd, Robert A.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Tschuri, Sebastian; Haebe, Sarah; Bararia, Deepak; Weigert, Oliver] Ludwig Maximilians Univ Munchen, Dept Med 3, Lab Expt Leukemia & Lymphoma Res, Munich, Germany. [Tschuri, Sebastian; Haebe, Sarah; Bararia, Deepak; Weigert, Oliver] German Canc Consortium, Heidelberg, Germany. [Tschuri, Sebastian; Haebe, Sarah; Bararia, Deepak; Weigert, Oliver] German Canc Res Ctr, Heidelberg, Germany. [Christie, Amanda L.; Saur, Amy] Dana Farber Canc Inst, Lurie Family Imaging Ctr, Boston, MA 02115 USA. [Zapf, Stefanie; Zimber-Strobl, Ursula] Helmholtz Zentrum Munchen, German Res Ctr Environm & Hlth, Dept Gene Vectors, Munich, Germany. [Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Weinstock, David M.] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Weinstock, David M.] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM oliver.weigert@med.uni-muenchen.de; dweinstock@partners.org FU Max-Eder Program of the Deutsche Krebshilfe [110659]; German Research Foundation [SFB1243 TP-A11, TP-A13]; William Lawrence and Blanche Hughes Foundation; Leukemia & Lymphoma Society Translational Research Program award FX This work was supported by the Max-Eder Program of the Deutsche Krebshilfe (#110659 [O.W.]), the German Research Foundation (SFB1243 TP-A11 [O.W.] and TP-A13 [U.Z.-S.]), the William Lawrence and Blanche Hughes Foundation (D.M.W.), and a Leukemia & Lymphoma Society Translational Research Program award (D.M.W.). NR 43 TC 1 Z9 1 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 NOV 24 PY 2016 VL 128 IS 21 BP 2517 EP 2526 DI 10.1182/blood-2016-04-711176 PG 10 WC Hematology SC Hematology GA EI7AO UT WOS:000392649400011 PM 27742706 ER PT J AU Jhamb, M McNulty, ML Ingalsbe, G Childers, JW Schell, J Conroy, MB Forman, DE Hergenroeder, A Dew, MA AF Jhamb, Manisha McNulty, Mary L. Ingalsbe, Gerald Childers, Julie W. Schell, Jane Conroy, Molly B. Forman, Daniel E. Hergenroeder, Andrea Dew, Mary Amanda TI Knowledge, barriers and facilitators of exercise in dialysis patients: a qualitative study of patients, staff and nephrologists SO BMC Nephrology LA English DT Article DE Exercise; Dialysis patients; Qualitative study ID STAGE RENAL-DISEASE; CHRONIC KIDNEY-DISEASE; PHYSICAL-ACTIVITY; CHRONIC-HEMODIALYSIS; COMPREHENSIVE DIALYSIS; PROSPECTIVE COHORT; MORTALITY; ASSOCIATION; FRAILTY; ADULTS AB Background: Despite growing evidence on benefits of increased physical activity in hemodialysis (HD) patients and safety of intra-dialytic exercise, it is not part of standard clinical care, resulting in a missed opportunity to improve clinical outcomes in these patients. To develop a successful exercise program for HD patients, it is critical to understand patients', staff and nephrologists' knowledge, barriers, motivators and preferences for patient exercise. Methods: In-depth interviews were conducted with a purposive sample of HD patients, staff and nephrologists from 4 dialysis units. The data collection, analysis and interpretation followed Criteria for Reporting Qualitative Research guidelines. Using grounded theory, emergent themes were identified, discussed and organized into major themes and subthemes. Results: We interviewed 16 in-center HD patients (mean age 60 years, 50% females, 63% blacks), 14 dialysis staff members (6 nurses, 3 technicians, 2 dietitians, 1 social worker, 2 unit administrators) and 6 nephrologists (50% females, 50% in private practice). Although majority of the participants viewed exercise as beneficial for overall health, most patients failed to recognize potential mental health benefits. Most commonly reported barriers to exercise were dialysis-related fatigue, comorbid health conditions and lack of motivation. Specifically for intradialytic exercise, participants expressed concern over safety and type of exercise, impact on staff workload and resistance to changing dialysis routine. One of the most important motivators identified was support from friends, family and health care providers. Specific recommendations for an intra-dialytic exercise program included building a culture of exercise in the dialysis unit, and providing an individualized engaging program that incorporates education and incentives for exercising. Conclusion: Patients, staff and nephrologists perceive a number of barriers to exercise, some of which may be modifiable. Participants desired an individualized intra-dialytic exercise program which incorporates education and motivation, and they provided a number of recommendations that should be considered when implementing such a program. C1 [Jhamb, Manisha; Schell, Jane] Univ Pittsburgh, Sch Med, Renal Electrolyte Div, 200 Lothrop St,PUH C-1101, Pittsburgh, PA 15213 USA. [McNulty, Mary L.; Dew, Mary Amanda] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Ingalsbe, Gerald] Community Member Receiving Hemodialysis, Pittsburgh, PA USA. [Childers, Julie W.; Schell, Jane] Univ Pittsburgh, Div Gen Internal Med, Dept Med Hosp & Palliat Med, Pittsburgh, PA USA. [Conroy, Molly B.] Univ Pittsburgh, Div Gen Internal Med, Dept Med, Pittsburgh, PA USA. [Forman, Daniel E.] Univ Pittsburgh, Dept Med, Geriatr Cardiol Sect, Pittsburgh, PA USA. [Forman, Daniel E.] VA Pittsburgh Healthcare Syst, Ctr Clin, Geriatr Res, Educ, Pittsburgh, PA USA. [Hergenroeder, Andrea] Univ Pittsburgh, Dept Phys Therapy, Pittsburgh, PA USA. [Dew, Mary Amanda] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Dew, Mary Amanda] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Dew, Mary Amanda] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. RP Jhamb, M (reprint author), Univ Pittsburgh, Sch Med, Renal Electrolyte Div, 200 Lothrop St,PUH C-1101, Pittsburgh, PA 15213 USA. EM jhambm@upmc.edu FU American Heart Association [11FTF7520014]; Junior Scholar Award, University of Pittsburgh; NIA [P30 AG024827, 1R56AG051637-01A1]; PCORI [IH-1304678]; VA Office of Rehabilitation Research and Development grant [F0834-R] FX This work was supported by American Heart Association grant 11FTF7520014 (Jhamb) and Junior Scholar Award, University of Pittsburgh (Jhamb). In addition, Dr. Forman is supported in part by NIA grants P30 AG024827 and 1R56AG051637-01A1, PCORI grant IH-1304678, and VA Office of Rehabilitation Research and Development grant F0834-R. NR 33 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD NOV 24 PY 2016 VL 17 AR 192 DI 10.1186/s12882-016-0399-z PG 14 WC Urology & Nephrology SC Urology & Nephrology GA EE0OX UT WOS:000389279300004 PM 27881101 ER PT J AU Welch, JS Petti, AA Miller, CA Fronick, CC O'Laughlin, M Fulton, RS Wilson, RK Baty, JD Duncavage, EJ Tandon, B Lee, YS Wartman, LD Uy, GL Ghobadi, A Tomasson, MH Pusic, I Romee, R Fehniger, TA Stockerl-Goldstein, KE Vij, R Oh, ST Abboud, CN Cashen, AF Schroeder, MA Jacoby, MA Heath, SE Luber, K Janke, MR Hantel, A Khan, N Sukhanova, MJ Knoebel, RW Stock, W Graubert, TA Walter, MJ Westervelt, P Link, DC DiPersio, JF Ley, TJ AF Welch, J. S. Petti, A. A. Miller, C. A. Fronick, C. C. O'Laughlin, M. Fulton, R. S. Wilson, R. K. Baty, J. D. Duncavage, E. J. Tandon, B. Lee, Y-S Wartman, L. D. Uy, G. L. Ghobadi, A. Tomasson, M. H. Pusic, I. Romee, R. Fehniger, T. A. Stockerl-Goldstein, K. E. Vij, R. Oh, S. T. Abboud, C. N. Cashen, A. F. Schroeder, M. A. Jacoby, M. A. Heath, S. E. Luber, K. Janke, M. R. Hantel, A. Khan, N. Sukhanova, M. J. Knoebel, R. W. Stock, W. Graubert, T. A. Walter, M. J. Westervelt, P. Link, D. C. DiPersio, J. F. Ley, T. J. TI TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID INTERNATIONAL WORKING GROUP; HYPOMETHYLATING AGENTS; CLONAL HEMATOPOIESIS; COMPLEX KARYOTYPE; RESPONSE CRITERIA; DNA METHYLATION; TET2 MUTATIONS; OLDER PATIENTS; IN-VIVO; THERAPY AB BACKGROUND The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. METHODS We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols. RESULTS Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles. CONCLUSIONS Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400.) C1 [Welch, J. S.; Wartman, L. D.; Uy, G. L.; Ghobadi, A.; Tomasson, M. H.; Pusic, I.; Romee, R.; Fehniger, T. A.; Stockerl-Goldstein, K. E.; Vij, R.; Oh, S. T.; Abboud, C. N.; Cashen, A. F.; Schroeder, M. A.; Jacoby, M. A.; Heath, S. E.; Luber, K.; Janke, M. R.; Walter, M. J.; Westervelt, P.; Link, D. C.; DiPersio, J. F.; Ley, T. J.] Washington Univ, Sch Med, Dept Internal Med, Div Oncol, St Louis, MO 63110 USA. [Baty, J. D.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Duncavage, E. J.; Tandon, B.; Lee, Y-S] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Petti, A. A.; Miller, C. A.; Fronick, C. C.; O'Laughlin, M.; Fulton, R. S.; Wilson, R. K.; Wartman, L. D.; Ley, T. J.] Washington Univ, McDonnell Genome Inst, St Louis, MO USA. [Hantel, A.; Khan, N.; Sukhanova, M. J.; Stock, W.] Univ Chicago, Dept Internal Med, Chicago, IL 60637 USA. [Knoebel, R. W.] Univ Chicago, Dept Pharm, Chicago, IL 60637 USA. [Graubert, T. A.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. RP Ley, TJ (reprint author), Washington Univ, Sch Med, Dept Internal Med, 660 S Euclid Ave,Box 8007, St Louis, MO 63110 USA. EM timley@wustl.edu FU Specialized Program of Research Excellence in AML of the National Cancer Institute [P50 CA171963]; Genomics of AML Program Project [P01 CA101937]; Novartis; Quintiles; Agios FX Supported by grants from the Specialized Program of Research Excellence in AML of the National Cancer Institute (P50 CA171963, to Dr. Link) and the Genomics of AML Program Project (P01 CA101937, to Dr. Ley). Three patients received treatment in the LBH589 Plus Decitabine for Myelodysplastic Syndromes or Acute Myeloid Leukemia trial, which was supported by Novartis.; Dr. Uy reports receiving fees for serving on an advisory board and clinical-trial support from Novartis; Dr. Jacoby, receiving consulting fees and fees for end-point adjudication from Quintiles and clinical-trial support from Sunesis Pharmaceuticals; and Dr. Graubert, receiving consulting fees from Agios. No other potential conflict of interest relevant to this article was reported. NR 36 TC 9 Z9 9 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 NOV 24 PY 2016 VL 375 IS 21 BP 2023 EP 2036 DI 10.1056/NEJMoa1605949 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA EC9KU UT WOS:000388464300005 PM 27959731 ER PT J AU Friedman, LS Lee, SR Nelson, SB Masia, R AF Friedman, Lawrence S. Lee, Stephen R. Nelson, Sandra B. Masia, Ricard TI Case 36-2016: A 50-Year-Old Man with Acute Liver Injury SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HEPATITIS-E-VIRUS; TRANSPLANT RECIPIENTS; E INFECTION; FAILURE; DISEASE C1 [Friedman, Lawrence S.] Newton Wellesley Hosp, Dept Med, Newton, MA 02462 USA. [Friedman, Lawrence S.; Nelson, Sandra B.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Lee, Stephen R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Masia, Ricard] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Friedman, Lawrence S.] Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. [Friedman, Lawrence S.; Nelson, Sandra B.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Lee, Stephen R.] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Masia, Ricard] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Friedman, LS (reprint author), Newton Wellesley Hosp, Dept Med, Newton, MA 02462 USA.; Friedman, LS (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Friedman, LS (reprint author), Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA.; Friedman, LS (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA. NR 23 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 NOV 24 PY 2016 VL 375 IS 21 BP 2082 EP 2092 DI 10.1056/NEJMcpc1610099 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EC9KU UT WOS:000388464300012 PM 27959737 ER PT J AU Padilla, C Mendez, MF Jimenez, EE Teng, E AF Padilla, Claudia Mendez, Mario F. Jimenez, Elvira E. Teng, Edmond TI Bilingualism in older Mexican-American immigrants is associated with higher scores on cognitive screening SO BMC GERIATRICS LA English DT Article DE Bilingualism; Cognitive reserve; Cognitive decline; Aging; SALSA ID ALZHEIMERS-DISEASE; LIFELONG BILINGUALISM; EXECUTIVE CONTROL; DEMENTIA; ADULTS; ONSET; RESERVE; BRAIN; AGE; ACCULTURATION AB Background: Bilingualism may protect against cognitive aging and delay the onset of dementia. However, studies comparing monolinguals and bilinguals on such metrics have produced inconsistent results complicated by confounding variables and methodological concerns. Methods: We addressed this issue by comparing cognitive performance in a more culturally homogeneous cohort of older Spanish-speaking monolingual (n = 289) and Spanish-English bilingual (n = 339) Mexican-American immigrants from the Sacramento Longitudinal Study on Aging. Results: After adjusting for demographic differences and depressive symptoms, both groups performed similarly at baseline on verbal memory but the bilingual group performed significantly better than the monolingual group on a cognitive screening test, the Modified Mini-Mental State Examination (3MS; p < 0.001). Group differences on the 3MS were driven by language/executive and language/praxis factors. Within the bilingual group, neither language of testing nor degree of bilingualism was significantly associated with 3MS or verbal memory scores. Amongst individuals who performed in the normal or better range on both tests at baseline and were followed for an average of 6 years, both monolinguals and bilinguals exhibited similar rates of cognitive decline on both measures. Conclusions: These findings suggest that bilingualism is associated with modest benefits in cognitive screening performance in older individuals in cross-sectional analyses that persist across longitudinal analyses. The effects of bilingualism should be considered when cognitively screening is performed in aging immigrant populations. C1 [Padilla, Claudia; Mendez, Mario F.; Jimenez, Elvira E.; Teng, Edmond] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Mendez, Mario F.; Teng, Edmond] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90095 USA. [Padilla, Claudia; Mendez, Mario F.; Jimenez, Elvira E.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Teng, E (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA.; Teng, E (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90095 USA. EM eteng@mednet.ucla.edu FU NIA [P01 AG020166]; Sidell-Kagan Foundation FX Data used for this research was provided by the "Sacramento Area Latino Study on Aging," (SALSA), which is managed by the Institute on Aging, University of Wisconsin and supported by the NIA (P01 AG020166). Additional research support was provided by the Sidell-Kagan Foundation. NR 43 TC 0 Z9 0 U1 15 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2318 J9 BMC GERIATR JI BMC Geriatr. PD NOV 24 PY 2016 VL 16 AR 189 DI 10.1186/s12877-016-0368-1 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA ED0VH UT WOS:000388559900001 PM 27881073 ER PT J AU Bernasconi-Elias, P Hu, T Jenkins, D Firestone, B Gans, S Kurth, E Capodieci, P Deplazes-Lauber, J Petropoulos, K Thiel, P Ponsel, D Choi, SH LeMotte, P London, A Goetcshkes, M Nolin, E Jones, MD Slocum, K Kluk, MJ Weinstock, DM Christodoulou, A Weinberg, O Jaehrling, J Ettenberg, SA Buckler, A Blacklow, SC Aster, JC Fryer, CJ AF Bernasconi-Elias, P. Hu, T. Jenkins, D. Firestone, B. Gans, S. Kurth, E. Capodieci, P. Deplazes-Lauber, J. Petropoulos, K. Thiel, P. Ponsel, D. Choi, S. Hee LeMotte, P. London, A. Goetcshkes, M. Nolin, E. Jones, M. D. Slocum, K. Kluk, M. J. Weinstock, D. M. Christodoulou, A. Weinberg, O. Jaehrling, J. Ettenberg, S. A. Buckler, A. Blacklow, S. C. Aster, J. C. Fryer, C. J. TI Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies SO ONCOGENE LA English DT Article ID NEGATIVE REGULATORY REGION; ADENOID CYSTIC CARCINOMA; BREAST-CANCER; MICE; PATHWAY; RECEPTORS; INSIGHTS; ANGIOGENESIS; MATURATION AB Notch receptors have been implicated as oncogenic drivers in several cancers, the most notable example being NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL). To characterize the role of activated NOTCH3 in cancer, we generated an antibody that detects the neo-epitope created upon gamma-secretase cleavage of NOTCH3 to release its intracellular domain (ICD3), and sequenced the negative regulatory region (NRR) and PEST (proline, glutamate, serine, threonine) domain coding regions of NOTCH3 in a panel of cell lines. We also characterize NOTCH3 tumor-associated mutations that result in activation of signaling and report new inhibitory antibodies. We determined the structural basis for receptor inhibition by obtaining the first co-crystal structure of a NOTCH3 antibody with the NRR protein and defined two distinct epitopes for NRR antibodies. The antibodies exhibit potent anti-leukemic activity in cell lines and tumor xenografts harboring NOTCH3 activating mutations. Screening of primary T-ALL samples reveals that 2 of 40 tumors examined show active NOTCH3 signaling. We also identified evidence of NOTCH3 activation in 12 of 24 patient-derived orthotopic xenograft models, 2 of which exhibit activation of NOTCH3 without activation of NOTCH1. Our studies provide additional insights into NOTCH3 activation and offer a path forward for identification of cancers that are likely to respond to therapy with NOTCH3 selective inhibitory antibodies. C1 [Bernasconi-Elias, P.; Gans, S.; Capodieci, P.; Goetcshkes, M.; Nolin, E.; Buckler, A.; Fryer, C. J.] Novartis Inst Biomed Res, Dev & Mol Pathways, 250 Massachusetts Ave,Bldg 600-5B263, Cambridge, MA 02139 USA. [Hu, T.] Novartis Inst Biomed Res, Ctr Prote Chem, Cambridge, MA USA. [Jenkins, D.; Firestone, B.; Kurth, E.; Jones, M. D.; Slocum, K.; Ettenberg, S. A.] Novartis Inst Biomed Res, Dept Oncol, Cambridge, MA USA. [Deplazes-Lauber, J.; Petropoulos, K.; Thiel, P.; Ponsel, D.; Jaehrling, J.] MorphoSys AG, Discovery Alliances & Technol, Martinsried, Germany. [Choi, S. Hee; Weinstock, D. M.; Christodoulou, A.; Blacklow, S. C.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Choi, S. Hee; Blacklow, S. C.; Aster, J. C.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA. [LeMotte, P.; London, A.] Novartis Inst Biomed Res, Dept Biol, Cambridge, MA USA. [Kluk, M. J.; Blacklow, S. C.; Aster, J. C.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Weinberg, O.] Children Hosp Boston, Pathol, Boston, MA USA. [Jenkins, D.] Tesaro, Waltham, MA USA. [Thiel, P.] IstQ Deutschland GmbH & Co KG, Mannheim, Germany. [Ponsel, D.] Roche AG, Penzberg, Germany. [Goetcshkes, M.; Buckler, A.] Biogen, Cambridge, MA USA. [Kluk, M. J.] Cornell Weill Med Coll, New York, NY USA. [Ettenberg, S. A.] Unum Therapeut, Cambridge, MA USA. RP Fryer, CJ (reprint author), Novartis Inst Biomed Res, Dev & Mol Pathways, 250 Massachusetts Ave,Bldg 600-5B263, Cambridge, MA 02139 USA. EM christy.fryer@novartis.com FU Industrial Macromolecular Crystallography Association; Hauptman-Woodward Medical Research Institute; US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; Dana Farber-Novartis DDP; National Institutes of Health [P01 CA119070]; Leukemia and Lymphoma Society [7003-13] FX The JAGGED1 and DLL1 expressing cell lines were kindly provide by Dr Gerry Weinmaster (UCLA). HPB-ALL cells were kindly provided by Andreas Stasser (Walter and Eliza Hall Institute for Medical Research, Australia). We thank the Novartis Biologics Center including Thomas Pietzonka, Janine Shulok, Nadine Charara, Bill Tschantz and Tony Fleming. We also thank many senior Novartis leaders for supporting this project, including Jeff Porter and William Sellers. We thank Rajiv Chopra and Kirk Clark of Novartis Institutes for BioMedical Research for the instructive discussion on crystallography experiments. Use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman-Woodward Medical Research Institute. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. This work was financially supported in part by the Dana Farber-Novartis DDP, and grants from the National Institutes of Health (P01 CA119070) and the Leukemia and Lymphoma Society (7003-13). NR 45 TC 2 Z9 2 U1 3 U2 3 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 NOV 24 PY 2016 VL 35 IS 47 BP 6077 EP 6086 DI 10.1038/onc.2016.133 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ED0CE UT WOS:000388509800004 PM 27157619 ER PT J AU Tao, JF Wu, H Coronado, AA de Laittre, E Osterweil, EK Zhang, Y Bear, MF AF Tao, Jifang Wu, Hao Coronado, Amanda A. de Laittre, Elizabeth Osterweil, Emily K. Zhang, Yi Bear, Mark F. TI Negative Allosteric Modulation of mGluR5 Partially Corrects Pathophysiology in a Mouse Model of Rett Syndrome SO JOURNAL OF NEUROSCIENCE LA English DT Article DE autism; fragile X; intellectual disability; metabotropic glutamate receptor; Rett syndrome; synaptic protein synthesis ID MECP2 MUTANT MICE; TRANSLATIONAL PROFILING APPROACH; AUTISM SPECTRUM DISORDER; CPG-BINDING PROTEIN-2; LONG-TERM DEPRESSION; FRAGILE-X-SYNDROME; CNS CELL-TYPES; SYNAPTIC PLASTICITY; EXPRESSION PROFILES; METHYLATED DNA AB Rett syndrome (RTT) is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2), an epigenetic regulator of mRNA transcription. Here, we report a test of the hypothesis of shared pathophysiology of RTT and fragile X, another monogenic cause of autism and intellectual disability. In fragile X, the loss of the mRNA translational repressor FMRP leads to exaggerated protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5). We found that mGluR5- and protein-synthesis-dependent synaptic plasticity were similarly altered in area CA1 of Mecp2 KO mice. CA1 pyramidal cell-type-specific, genome-wide profiling of ribosome-bound mRNAs was performed in wild-type and Mecp2 KO hippocampal CA1 neurons to reveal the MeCP2-regulated "translatome." We found significant overlap between ribosome-bound transcripts overexpressed in the Mecp2 KO and FMRP mRNA targets. These tended to encode long genes that were functionally related to either cytoskeleton organization or the development of neuronal connectivity. In the Fmr1 KO mouse, chronic treatment with mGluR5-negative allosteric modulators (NAMs) has been shown to ameliorate many mutant phenotypes by correcting excessive protein synthesis. In Mecp2 KO mice, we found that mGluR5 NAM treatment significantly reduced the level of overexpressed ribosome-associated transcripts, particularly those that were also FMRP targets. Some Rett phenotypes were also ameliorated by treatment, most notably hippocampal cell size and lifespan. Together, these results suggest a potential mechanistic link between MeCP2-mediated transcription regulation and mGluR5/FMRP-mediated protein translation regulation through coregulation of a subset of genes relevant to synaptic functions. C1 [Tao, Jifang; Coronado, Amanda A.; de Laittre, Elizabeth; Bear, Mark F.] MIT, Picower Inst Learning & Memory, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Tao, Jifang; Coronado, Amanda A.; de Laittre, Elizabeth; Bear, Mark F.] MIT, Dept Brain & Cognit Sci, 77 Massachusetts Ave,46-3301, Cambridge, MA 02139 USA. [Wu, Hao; Zhang, Yi] Howard Hughes Med Inst, Boston, MA 02115 USA. [Wu, Hao; Zhang, Yi] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Wu, Hao; Zhang, Yi] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Osterweil, Emily K.] Univ Edinburgh, Ctr Integrat Physiol, Edinburgh EH8 9XD, Midlothian, Scotland. RP Bear, MF (reprint author), MIT, Dept Brain & Cognit Sci, 77 Massachusetts Ave,46-3301, Cambridge, MA 02139 USA. EM mbear@mit.edu OI Osterweil, Emily/0000-0003-0582-2284; Bear, Mark/0000-0002-9903-2541 FU Simons Foundation [SFARI 275050]; Rett Syndrome Research Trust; Jane Coffin Childs Memorial Fund for Medical Research; National Human Genome Research Institute [K99HG007982]; Howard Hughes Medical Institute FX This work was supported by the Howard Hughes Medical Institute, the Simons Foundation (Grant SFARI 275050 to M.F.B.). J.T. received a postdoctoral fellowship from Rett Syndrome Research Trust. H.W. received postdoctoral fellowships from the Jane Coffin Childs Memorial Fund for Medical Research, and the National Human Genome Research Institute (Grant K99HG007982). Y.Z. is an investigator of the Howard Hughes Medical Institute. We thank Nathaniel Heintz and Myriam Heiman for assistance with the TRAP experiments and Arnold Heynen, Robert Komorowski, Rujie Yao, Alana H. Peters, Tyrone Lee, Rodrigo Garcia, Erik Sklar, and Suzanne Meagher for technical and administrative assistance. NR 57 TC 0 Z9 0 U1 1 U2 1 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 NOV 23 PY 2016 VL 36 IS 47 BP 11946 EP 11958 DI 10.1523/JNEUROSCI.0672-16.2016 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EG6FI UT WOS:000391139500013 PM 27881780 ER PT J AU Ried, JS Jeff, JM Chu, AY Bragg-Gresham, JL van Dongen, J Huffman, JE Ahluwalia, TS Cadby, G Eklund, N Eriksson, J Esko, T Feitosa, MF Goel, A Gorski, M Hayward, C Heard-Costa, NL Jackson, AU Jokinen, E Kanoni, S Kristiansson, K Kutalik, Z Lahti, J Luan, JA Magi, R Mahajan, A Mangino, M Medina-Gomez, C Monda, KL Nolte, IM Perusse, L Prokopenko, I Qi, L Rose, LM Salvi, E Smith, MT Snieder, H Stancakova, A Sung, YJ Tachmazidou, I Teumer, A Thorleifsson, G van der Harst, P Walker, RW Wang, SR Wild, SH Willems, SM Wong, A Zhang, WH Albrecht, E Alves, AC Bakker, SJL Barlassina, C Bartz, TM Beilby, J Bellis, C Bergman, RN Bergmann, S Blangero, J Bluher, M Boerwinkle, E Bonnycastle, LL Bornstein, SR Bruinenberg, M Campbell, H Chen, YDI Chiang, CWK Chines, PS Collins, FS Cucca, F Cupples, LA D'Avila, F de Geus, EJC Dedoussis, G Dimitriou, M Doring, A Eriksson, JG Farmaki, AE Farrall, M Ferreira, T Fischer, K Forouhi, NG Friedrich, N Gjesing, AP Glorioso, N Graff, M Grallert, H Grarup, N Grassler, J Grewal, J Hamsten, A Harder, MN Hartman, CA Hassinen, M Hastie, N Hattersley, AT Havulinna, AS Heliovaara, M Hillege, H Hofman, A Holmen, O Homuth, G Hottenga, JJ Hui, JN Husemoen, LL Hysi, PG Isaacs, A Ittermann, T Jalilzadeh, S James, AL Jorgensen, T Jousilahti, P Jula, A Justesen, JM Justice, AE Kahonen, M Karaleftheri, M Khaw, KT Keinanen-Kiukaanniemi, SM Kinnunen, L Knekt, PB Koistinen, HA Kolcic, I Kooner, IK Koskinen, S Kovacs, P Kyriakou, T Laitinen, T Langenberg, C Lewin, AM Lichtner, P Lindgren, CM Lindstrom, J Linneberg, A Lorbeer, R Lorentzon, M Luben, R Lyssenko, V Mannisto, S Manunta, P Leach, IM McArdle, WL Mcknight, B Mohlke, KL Mihailov, E Milani, L Mills, R Montasser, ME Morris, AP Muller, G Musk, AW Narisu, N Ong, KK Oostra, BA Osmond, C Palotie, A Pankow, JS Paternoster, L Penninx, BW Pichler, I Pilia, MG Polasek, O Pramstaller, PP Raitakari, OT Rankinen, T Rao, DC Rayner, NW Ribel-Madsen, R Rice, TK Richards, M Ridker, PM Rivadeneira, F Ryan, KA Sanna, S Sarzynski, MA Scholtens, S Scott, RA Sebert, S Southam, L Sparso, TH Steinthorsdottir, V Stirrups, K Stolk, RP Strauch, K Stringham, HM Swertz, MA Swift, AJ Tonjes, A Tsafantakis, E van der Most, PJ Van Vliet-Ostaptchouk, JV Vandenput, L Vartiainen, E Venturini, C Verweij, N Viikari, JS Vitart, V Vohl, MC Vonk, JM Waeber, G Widen, E Willemsen, G Wilsgaard, T Winkler, TW Wright, AF Yerges-Armstrong, LM Zhao, JH Zillikens, MC Boomsma, DI Bouchard, C Chambers, JC Chasman, DI Cusi, D Gansevoort, RT Gieger, C Hansen, T Hicks, AA Hu, F Hveem, K Jarvelin, MR Kajantie, E Kooner, JS Kuh, D Kuusisto, J Laakso, M Lakka, TA Lehtimaki, T Metspalu, A Njolstad, I Ohlsson, C Oldehinkel, AJ Palmer, LJ Pedersen, O Perola, M Peters, A Psaty, BM Puolijoki, H Rauramaa, R Rudan, I Salomaa, V Schwarz, PEH Shudiner, AR Smit, JH Sorensen, TIA Spector, TD Stefansson, K Stumvoll, M Tremblay, A Tuomilehto, J Uitterlinden, AG Uusitupa, M Volker, U Vollenweider, P Wareham, NJ Watkins, H Wilson, JF Zeggini, E Abecasis, GR Boehnke, M Borecki, IB Deloukas, P van Duijn, CM Fox, C Groop, LC Heid, IM Hunter, DJ Kaplan, RC McCarthy, MI North, KE O'Connell, JR Schlessinger, D Thorsteinsdottir, U Strachan, DP Frayling, T Hirschhorn, JN Muller-Nurasyid, M Loos, RJF AF Ried, Janina S. Jeff, Janina M. Chu, Audrey Y. Bragg-Gresham, Jennifer L. van Dongen, Jenny Huffman, Jennifer E. Ahluwalia, Tarunveer S. Cadby, Gemma Eklund, Niina Eriksson, Joel Esko, Tonu Feitosa, Mary F. Goel, Anuj Gorski, Mathias Hayward, Caroline Heard-Costa, Nancy L. Jackson, Anne U. Jokinen, Eero Kanoni, Stavroula Kristiansson, Kati Kutalik, Zoltan Lahti, Jari Luan, Jian'an Maegi, Reedik Mahajan, Anubha Mangino, Massimo Medina-Gomez, Carolina Monda, Keri L. Nolte, Ilja M. Perusse, Louis Prokopenko, Inga Qi, Lu Rose, Lynda M. Salvi, Erika Smith, Megan T. Snieder, Harold Stancakova, Alena Sung, Yun Ju Tachmazidou, Ioanna Teumer, Alexander Thorleifsson, Gudmar van der Harst, Pim Walker, Ryan W. Wang, Sophie R. Wild, Sarah H. Willems, Sara M. Wong, Andrew Zhang, Weihua Albrecht, Eva Alves, Alexessander Couto Bakker, Stephan J. L. Barlassina, Cristina Bartz, Traci M. Beilby, John Bellis, Claire Bergman, Richard N. Bergmann, Sven Blangero, John Blueher, Matthias Boerwinkle, Eric Bonnycastle, Lori L. Bornstein, Stefan R. Bruinenberg, Marcel Campbell, Harry Chen, Yii-Der Ida Chiang, Charleston W. K. Chines, Peter S. Collins, Francis S. Cucca, Fracensco Cupples, L. Adrienne D'Avila, Francesca de Geus, Eco J. C. Dedoussis, George Dimitriou, Maria Doering, Angela Eriksson, Johan G. Farmaki, Aliki-Eleni Farrall, Martin Ferreira, Teresa Fischer, Krista Forouhi, Nita G. Friedrich, Nele Gjesing, Anette Prior Glorioso, Nicola Graff, Mariaelisa Grallert, Harald Grarup, Niels Graessler, Juergen Grewal, Jagvir Hamsten, Anders Harder, Marie Neergaard Hartman, Catharina A. Hassinen, Maija Hastie, Nicholas Hattersley, Andrew Tym Havulinna, Aki S. Heliovaara, Markku Hillege, Hans Hofman, Albert Holmen, Oddgeir Homuth, Georg Hottenga, Jouke-Jan Hui, Jennie Husemoen, Lise Lotte Hysi, Pirro G. Isaacs, Aaron Ittermann, Till Jalilzadeh, Shapour James, Alan L. Jorgensen, Torben Jousilahti, Pekka Jula, Antti Justesen, Johanne Marie Justice, Anne E. Kahonen, Mika Karaleftheri, Maria Khaw, Kay Tee Keinanen-Kiukaanniemi, Sirkka M. Kinnunen, Leena Knekt, Paul B. Koistinen, Heikki A. Kolcic, Ivana Kooner, Ishminder K. Koskinen, Seppo Kovacs, Peter Kyriakou, Theodosios Laitinen, Tomi Langenberg, Claudia Lewin, Alexandra M. Lichtner, Peter Lindgren, Cecilia M. Lindstrom, Jaana Linneberg, Allan Lorbeer, Roberto Lorentzon, Mattias Luben, Robert Lyssenko, Valeriya Mannisto, Satu Manunta, Paolo Leach, Irene Mateo McArdle, Wendy L. Mcknight, Barbara Mohlke, Karen L. Mihailov, Evelin Milani, Lili Mills, Rebecca Montasser, May E. Morris, Andrew P. Mueller, Gabriele Musk, Arthur W. Narisu, Narisu Ong, Ken K. Oostra, Ben A. Osmond, Clive Palotie, Aarno Pankow, James S. Paternoster, Lavinia Penninx, Brenda W. Pichler, Irene Pilia, Maria G. Polasek, Ozren Pramstaller, Peter P. Raitakari, Olli T. Rankinen, Tuomo Rao, D. C. Rayner, Nigel W. Ribel-Madsen, Rasmus Rice, Treva K. Richards, Marcus Ridker, Paul M. Rivadeneira, Fernando Ryan, Kathy A. Sanna, Serena Sarzynski, Mark A. Scholtens, Salome Scott, Robert A. Sebert, Sylvain Southam, Lorraine Sparso, Thomas Hempel Steinthorsdottir, Valgerdur Stirrups, Kathleen Stolk, Ronald P. Strauch, Konstantin Stringham, Heather M. Swertz, Morris A. Swift, Amy J. Toenjes, Anke Tsafantakis, Emmanouil van der Most, Peter J. Van Vliet-Ostaptchouk, Jana V. Vandenput, Liesbeth Vartiainen, Erkki Venturini, Cristina Verweij, Niek Viikari, Jorma S. Vitart, Veronique Vohl, Marie-Claude Vonk, Judith M. Waeber, Gerard Widen, Elisabeth Willemsen, Gonneke Wilsgaard, Tom Winkler, Thomas W. Wright, Alan F. Yerges-Armstrong, Laura M. Zhao, Jing Hua Zillikens, M. Carola Boomsma, Dorret I. Bouchard, Claude Chambers, John C. Chasman, Daniel I. Cusi, Daniele Gansevoort, Ron T. Gieger, Christian Hansen, Torben Hicks, Andrew A. Hu, Frank Hveem, Kristian Jarvelin, Marjo-Riitta Kajantie, Eero Kooner, Jaspal S. Kuh, Diana Kuusisto, Johanna Laakso, Markku Lakka, Timo A. Lehtimaeki, Terho Metspalu, Andres Njolstad, Inger Ohlsson, Claes Oldehinkel, Albertine J. Palmer, Lyle J. Pedersen, Oluf Perola, Markus Peters, Annette Psaty, Bruce M. Puolijoki, Hannu Rauramaa, Rainer Rudan, Igor Salomaa, Veikko Schwarz, Peter E. H. Shudiner, Alan R. Smit, Jan H. Sorensen, Thorkild I. A. Spector, Timothy D. Stefansson, Kari Stumvoll, Michael Tremblay, Angelo Tuomilehto, Jaakko Uitterlinden, Andre G. Uusitupa, Matti Voelker, Uwe Vollenweider, Peter Wareham, Nicholas J. Watkins, Hugh Wilson, James F. Zeggini, Eleftheria Abecasis, Goncalo R. Boehnke, Michael Borecki, Ingrid B. Deloukas, Panos van Duijn, Cornelia M. Fox, Caroline Groop, Leif C. Heid, Iris M. Hunter, David J. Kaplan, Robert C. McCarthy, Mark I. North, Kari E. O'Connell, Jeffrey R. Schlessinger, David Thorsteinsdottir, Unnur Strachan, David P. Frayling, Timothy Hirschhorn, Joel N. Mueller-Nurasyid, Martina Loos, Ruth J. F. TI A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; DIET-INDUCED OBESITY; MASS INDEX; DISEASE ASSOCIATIONS; FAT DISTRIBUTION; EARLY-ONSET; HIP RATIO; RESOURCE; BIOLOGY; HEIGHT AB Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways. C1 [Ried, Janina S.; Albrecht, Eva; Strauch, Konstantin; Gieger, Christian; Mueller-Nurasyid, Martina] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, D-85764 Neuherberg, Germany. [Jeff, Janina M.; Walker, Ryan W.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Chu, Audrey Y.; Rose, Lynda M.; Ridker, Paul M.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. 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[Bartz, Traci M.; Mcknight, Barbara; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Beilby, John; Hui, Jennie] Pathwest Lab Med Western Australia, Nedlands, WA 6009, Australia. [Beilby, John; Hui, Jennie] Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA 6009, Australia. [Bellis, Claire] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Genom Res Ctr, Brisbane, Qld 4001, Australia. [Bellis, Claire] Agcy Sci Technol & Res Singapore, Genome Inst Singapore, Human Genet, Singapore 138672, Singapore. [Bergman, Richard N.] Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA. [Blangero, John] Univ Texas Rio Grande Valley, South Texas Diabet & Obes Inst, Brownsville, TX 78520 USA. [Blueher, Matthias; Kovacs, Peter; Stumvoll, Michael] Univ Leipzig, IFB Adipos Dis, D-04103 Leipzig, Germany. [Blueher, Matthias; Toenjes, Anke; Stumvoll, Michael] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany. Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Bonnycastle, Lori L.; Chines, Peter S.; Collins, Francis S.; Narisu, Narisu; Swift, Amy J.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. [Bornstein, Stefan R.; Schwarz, Peter E. H.] Univ Dresden, Med Fac Carl Gustav Carus, Dept Med 3, D-01307 Dresden, Germany. [Bruinenberg, Marcel] Univ Groningen, Univ Med Ctr Groningen, Life Lines Cohort Study, NL-9700 RB Groningen, Netherlands. [Chen, Yii-Der Ida] Harbor UCLA Med Ctr, Los Angeles BioMed Resesarch Inst, Torrance, CA 90502 USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90095 USA. [Cucca, Fracensco] Univ Sassari, I-07100 Sassari, Italy. [de Geus, Eco J. C.] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, NL-1081 BT Amsterdam, Netherlands. [Dedoussis, George; Dimitriou, Maria; Farmaki, Aliki-Eleni] Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens 17671, Greece. [Doering, Angela] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 1, D-85764 Neuherberg, Germany. [Doering, Angela; Grallert, Harald; Gieger, Christian; Peters, Annette] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, D-85764 Neuherberg, Germany. [Eriksson, Johan G.; Kajantie, Eero] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, FI-00271 Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, FI-00014 Helsinki, Finland. [Friedrich, Nele] Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17475 Greifswald, Germany. [Glorioso, Nicola] AOU Univ Sassari, Hypertens & Related Dis Ctr, I-7100 Sassari, Italy. [Grallert, Harald] German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany. [Grallert, Harald; Gieger, Christian; Peters, Annette] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany. [Graessler, Juergen] Tech Univ, Dept Med 3, Pathobiochem, D-01307 Dresden, Germany. [Hamsten, Anders] Karolinska Inst, Dept Med, Stockholm, Sweden. [Hamsten, Anders] Karolinska Inst, Atherosclerosis Res Unit, Dept Med Solna, S-17176 Stockholm, Sweden. [Hamsten, Anders] Karolinska Univ Hosp, Ctr Mol Med, S-17176 Stockholm, Sweden. [Hartman, Catharina A.; Oldehinkel, Albertine J.] Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, NL-9700 RB Groningen, Netherlands. [Hassinen, Maija; Lakka, Timo A.; Rauramaa, Rainer] Kuopio Res Inst Exercise Med, Kuopio 70100, Finland. [Hattersley, Andrew Tym] Univ Exeter, Inst Biomed & Clin Sci, Barrack Rd, Exeter EX2 5DW, Devon, England. [Holmen, Oddgeir; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, N-7489 Trondheim, Norway. [Hui, Jennie] Univ Western Australia, Sch Populat Hlth, Nedlands, WA 6009, Australia. [Husemoen, Lise Lotte; Linneberg, Allan] Glostrup Cty Hosp, Res Ctr Prevent & Hlth, DK-2600 Glostrup, Denmark. [James, Alan L.] Sir Charles Gairdner Hosp, Dept Pulm Physiol & Sleep Med, Nedlands, WA 6009, Australia. [Jorgensen, Torben; Linneberg, Allan] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, DK-2200 Copenhagen, Denmark. [Jorgensen, Torben] Aalborg Univ, Fac Med, DK-9220 Aalborg, Denmark. [Jorgensen, Torben] Capital Region Denmark, Res Ctr Prevent & Hlth, DK-2600 Glostrup, Denmark. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, FI-33521 Tampere, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Dept Clin Physiol, FI-33014 Tampere, Finland. [Karaleftheri, Maria] Echinos Med Ctr, Echinos 67300, Greece. [Khaw, Kay Tee] Addenbrookes Hosp, Clin Gerontol Unit, Box 251,Hills Rd, Cambridge CB2 2QQ, England. [Keinanen-Kiukaanniemi, Sirkka M.] Univ Oulu, Fac Med, Inst Hlth Sci, FI-90014 Oulu, Finland. [Keinanen-Kiukaanniemi, Sirkka M.] Oulu Univ Hosp, Unit Gen Practice, FI-90029 Oulu, Finland. [Kinnunen, Leena; Koistinen, Heikki A.] Natl Inst Hlth & Welf, FI-00271 Helsinki, Finland. [Koistinen, Heikki A.] Univ Helsinki, Abdominal Ctr Endocrinol, Dept Med, Helsinki 00290, Finland. [Koistinen, Heikki A.] Minerva Fdn, Helsinki 00290, Finland. [Kolcic, Ivana; Polasek, Ozren] Univ Split, Fac Med, Dept Publ Hlth, Split 21000, Croatia. [Laitinen, Tomi] Kuopio Univ Hosp, Kuopio 70029, Finland. [Laitinen, Tomi] Univ Eastern Finland, Dept Clin Physiol & Nucl Med, FI-70211 Kuopio, Finland. [Langenberg, Claudia] UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England. [Lichtner, Peter] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, D-85764 Neuherberg, Germany. [Lindgren, Cecilia M.] Univ Oxford, Big Data Inst, Oxford OX3 7LJ, England. [Linneberg, Allan] Rigshosp, Dept Clin Expt Res, DK-2600 Glostrup, Denmark. [Luben, Robert] Strangeways Res Lab Worts Causeway, Cambridge CB1 8RN, England. [Lyssenko, Valeriya; Groop, Leif C.] Lund Univ, Diabet Ctr, S-22100 Malmo, Sweden. [Lyssenko, Valeriya; Groop, Leif C.] Lund Univ, Dept Clin Sci, Diabet & Endocrinol Unit, S-22100 Malmo, Sweden. [Manunta, Paolo] Univ Vita Salute San Raffaele, Chair Nephrol, I-20139 Milan, Italy. [Manunta, Paolo] IRCCS San Raffaele Sci Inst, Genom Renal Dis & Hypertens Unit, I-20139 Milan, Italy. [McArdle, Wendy L.] Univ Bristol, Sch Social & Community Med, Bristol BS82BN, Avon, England. [Mcknight, Barbara] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Biostat & Biomath, Seattle, WA 98109 USA. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Montasser, May E.; Ryan, Kathy A.; Yerges-Armstrong, Laura M.; Shudiner, Alan R.; O'Connell, Jeffrey R.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3GA, Merseyside, England. [Mueller, Gabriele] Univ Dresden, Med Fac Carl Gustav Carus, Ctr Evidence Based Healthcare, D-01307 Dresden, Germany. [Musk, Arthur W.] Sir Charles Gairdner Hosp, Dept Resp Med, Nedlands, WA 6009, Australia. [Ong, Ken K.] Univ Cambridge, Dept Paediat, Cambridge CB2 0QQ, England. [Osmond, Clive] Univ Southampton, Southampton Gen Hosp, MRC Lifecourse Epidemiol Unit, Southampton SO16 6YD, Hants, England. [Palotie, Aarno] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Pankow, James S.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Paternoster, Lavinia] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 1TH, Avon, England. [Penninx, Brenda W.; Smit, Jan H.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, AJ Ernstr 1887, NL-1081 HL Amsterdam, Netherlands. [Penninx, Brenda W.; Smit, Jan H.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, AJ Ernstr 1887, NL-1081 HL Amsterdam, Netherlands. [Pichler, Irene; Pramstaller, Peter P.; Hicks, Andrew A.] European Acad Bozen Bolzano EURAC, Ctr Biomed, I-39100 Bolzano, Italy. [Pichler, Irene; Pramstaller, Peter P.; Hicks, Andrew A.] Inst Univ Lubeck, D-23562 Lubeck, Germany. [Pilia, Maria G.; Sanna, Serena] CNR, Ist Ric Genet & Biomed, I-9042 Monserrato, Italy. [Pramstaller, Peter P.] Univ Lubeck, Dept Neurol, D-23562 Lubeck, Germany. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, I-39100 Bolzano, Italy. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FI-20521 Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FI-20520 Turku, Finland. [Rankinen, Tuomo; Sarzynski, Mark A.; Bouchard, Claude] Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70808 USA. [Rice, Treva K.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Rayner, Nigel W.; Deloukas, Panos] Wellcome Trust Sanger Inst, Human Genet, Hinxton CB10 1HH, England. [Ridker, Paul M.; Chasman, Daniel I.; Fox, Caroline] Harvard Med Sch, Boston, MA 02115 USA. [Sebert, Sylvain; Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, FI-90014 Oulu, Finland. [Sebert, Sylvain] Univ Oulu, Ctr Life Course Hlth Res, FI-90014 Oulu, Finland. [Strauch, Konstantin; Mueller-Nurasyid, Martina] Ludwig Maximilians Univ Munchen, Inst Med Informat Biometry & Epidemiol, Chair Genet Epidemiol, D-81377 Munich, Germany. [Tsafantakis, Emmanouil] Anogia Med Ctr, Anogia 74051, Greece. [Van Vliet-Ostaptchouk, Jana V.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, NL-9700 RB Groningen, Netherlands. [Venturini, Cristina] UCL, Inst Ophthalmol, London EC1V 9EL, England. [Viikari, Jorma S.] Univ Turku, Dept Med, FI 20521 Turku, FI-20521 Turku, Finland. [Viikari, Jorma S.] Turku Univ Hosp, Div Med, Turku, Finland. [Vohl, Marie-Claude] Univ Laval, Sch Nutr, Quebec City, PQ G1V 0A6, Canada. [Waeber, Gerard; Vollenweider, Peter] Univ Hosp Lausanne CHUV, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Waeber, Gerard; Vollenweider, Peter] Univ Lausanne, CH-1011 Lausanne, Switzerland. [Wilsgaard, Tom; Njolstad, Inger] Univ Tromso, Fac Hlth Sci, Dept Community Med, N-9037 Tromso, Norway. [Chambers, John C.; Kooner, Jaspal S.] Imperial Coll Healthcare NHS Trust, London W12 0HS, England. [Hansen, Torben] Univ Southern Denmark, Fac Hlth Sci, DK-5000 Odense, Denmark. Oulu Univ Hosp, Unit Primary Care, Oys Oulu 90029, Finland. [Jarvelin, Marjo-Riitta] Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W12 0NN, England. [Jarvelin, Marjo-Riitta] Univ Oulu, Ctr Life Course Epidemiol, Fac Med, POB 5000, FI-90014 Oulu, Finland. [Kajantie, Eero] Helsinki Univ Hosp, Childrens Hosp, FI-00029 Helsinki, Finland. [Kajantie, Eero] Univ Helsinki, FI-00029 Helsinki, Finland. [Kajantie, Eero] Oulu Univ Hosp, MRC Oulu, Dept Obstet & Gynecol, FI-90029 Oulu, Finland. [Kajantie, Eero] Univ Oulu, FI-90029 Oulu, Finland. [Kooner, Jaspal S.] Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England. [Lakka, Timo A.] Univ Eastern Finland, Inst Biomed, Dept Physiol, Kuopio Campus, Kuopio 70210, Finland. [Lehtimaeki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, FI-33014 Tampere, Finland. [Lehtimaeki, Terho] Univ Tampere, Fimlab Labs, Dept Clin Chem, FI-33520 Tampere, Finland. [Lehtimaeki, Terho] Univ Tampere, Sch Med, FI-33520 Tampere, Finland. [Njolstad, Inger] Univ Tromso, Fac Hlth Sci, Dept Clin Med, N-9037 Tromso, Norway. [Palmer, Lyle J.] Univ Adelaide, Sch Publ Hlth, Adelaide, SA 5005, Australia. [Palmer, Lyle J.] Univ Adelaide, Robinson Res Inst, Adelaide, SA 5005, Australia. [Peters, Annette; Mueller-Nurasyid, Martina] DZHK German Ctr Cardiovasc Res, Partnersite Munich Heart Alliance, D-80802 Munich, Germany. [Tuomilehto, Jaakko] Univ Washington, Dept Med, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Washington, DC 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Washington, DC 98101 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Washington, DC 98101 USA. [Puolijoki, Hannu] South Ostrobothnia Cent Hosp, FI-60220 Seinajoki, Finland. [Rauramaa, Rainer] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, Kuopio 70211, Finland. [Schwarz, Peter E. H.] German Ctr Diabet Res DZD, Paul Langerhans Inst Dresden, D-01307 Dresden, Germany. [Shudiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21042 USA. [Sorensen, Thorkild I. A.] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England. [Sorensen, Thorkild I. A.] Bispebjerg & Frederiksberg Hosp, Inst Prevent Med, DK-2000 Frederiksberg, Denmark. [Stefansson, Kari; Thorsteinsdottir, Unnur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Diabet Prevent Unit, FI-00271 Helsinki, Finland. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, A-3500 Krems, Austria. [Tuomilehto, Jaakko] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21589, Saudi Arabia. [Uusitupa, Matti] Univ Eastern Finland, Dept Publ Hlth & Clin Nutr, Kuopio 70211, Finland. [Uusitupa, Matti] Kuopio Univ Hosp, Res Unit, Kuopio 70029, Finland. [Voelker, Uwe] DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, D-17475 Greifswald, Germany. [Deloukas, Panos] King Abdulaziz Univ, PACER HD, Jeddah 21589, Saudi Arabia. [van Duijn, Cornelia M.] Ctr Med Syst Biol, NL-2300 Leiden, Netherlands. [Groop, Leif C.] Univ Helsinki, Finnish Inst Mol Med FIMM, Helsinki 00014, Finland. [Heid, Iris M.] Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany. [Hunter, David J.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Popualt Hlth, Bronx, NY 10461 USA. [McCarthy, Mark I.] Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [North, Kari E.] Univ North Carolina Chapel Hill, Dept Epidemiol, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Schlessinger, David] NIA, NIH, Bethesda, MD 20892 USA. [Strachan, David P.] St Georges Univ London, Populat Hlth Res Inst, London SW17 0RE, England. [Frayling, Timothy] Univ Exeter, Sch Med, Genet Complex Traits, Exeter EX1 2LU, Devon, England. [Hirschhorn, Joel N.] Broad Inst, Metab Initiat, Cambridge, MA 02142 USA. [Mueller-Nurasyid, Martina] Ludwig Maximilians Univ Munchen, Univ Hosp Grosshadern, Dept Med 1, D-81377 Munich, Germany. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. RP Muller-Nurasyid, M (reprint author), Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, D-85764 Neuherberg, Germany.; Loos, RJF (reprint author), Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.; Loos, RJF (reprint author), Univ Cambridge, Inst Metab Sci, Sch Clin Med, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge CB2 0QQ, England.; Loos, RJF (reprint author), Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA.; Muller-Nurasyid, M (reprint author), Ludwig Maximilians Univ Munchen, Inst Med Informat Biometry & Epidemiol, Chair Genet Epidemiol, D-81377 Munich, Germany.; Muller-Nurasyid, M (reprint author), DZHK German Ctr Cardiovasc Res, Partnersite Munich Heart Alliance, D-80802 Munich, Germany.; Muller-Nurasyid, M (reprint author), Ludwig Maximilians Univ Munchen, Univ Hosp Grosshadern, Dept Med 1, D-81377 Munich, Germany.; Loos, RJF (reprint author), Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.; Loos, RJF (reprint author), Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. EM ruth.loos@mssm.edu RI Hicks, Andrew/E-9518-2017; Sarzynski, Mark/A-9798-2014; Justesen, Johanne Marie/L-6023-2015; Wong, Andrew/M-8899-2016; Verweij, Niek/A-4499-2017; Colaus, PsyColaus/K-6607-2013; Grallert, Harald/B-3424-2013; Grarup, Niels/K-2807-2015; Bouchard, Claude/A-7637-2009; Palmer, Lyle/K-3196-2014; Polasek, Ozren/B-6002-2011; Kolcic, Ivana/E-2713-2017; Feitosa, Mary/K-8044-2012; OI Hicks, Andrew/0000-0001-6320-0411; Justesen, Johanne Marie/0000-0002-0484-8522; Wong, Andrew/0000-0003-2079-4779; Grarup, Niels/0000-0001-5526-1070; Palmer, Lyle/0000-0002-1628-3055; Polasek, Ozren/0000-0002-5765-1862; Kolcic, Ivana/0000-0001-7918-6052; Feitosa, Mary/0000-0002-0933-2410; Linneberg, Allan/0000-0002-0994-0184; Peters, Annette/0000-0001-6645-0985; Lahti, Jari/0000-0002-4310-5297; Havulinna, Aki/0000-0002-4787-8959; Forouhi, Nita/0000-0002-5041-248X; Salvi, Erika/0000-0002-2724-2291; Vandenput, Liesbeth/0000-0002-1712-6131; Jorgensen, Torben/0000-0001-9453-2830; Medina-Gomez, Carolina/0000-0001-7999-5538; Pankow, James/0000-0001-7076-483X; de Geus, Eco/0000-0001-6022-2666 FU Medical Research Council [MR/J012165/1, G0601261, MC_PC_U127561128, MC_UP_A620_1016, MC_UU_12011/3, MC_UU_12015/1, MC_UU_12019/1]; NCATS NIH HHS [UL1 TR000124]; NHLBI NIH HHS [R01 HL117626]; NICHD NIH HHS [P2C HD050924]; NIDDK NIH HHS [P30 DK020541, P30 DK063491, U01 DK062370] NR 48 TC 0 Z9 0 U1 9 U2 9 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 NOV 23 PY 2016 VL 7 AR 13357 DI 10.1038/ncomms13357 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC7LH UT WOS:000388319700001 PM 27876822 ER PT J AU Dey, D Bagarova, J Hatsell, SJ Armstrong, KA Huang, L Ermann, J Vonner, AJ Shen, Y Mohedas, AH Lee, A Eekhoff, EMW van Schie, A Demay, MB Keller, C Wagers, AJ Economides, AN Yu, PB AF Dey, Devaveena Bagarova, Jana Hatsell, Sarah J. Armstrong, Kelli A. Huang, Lily Ermann, Joerg Vonner, Ashley J. Shen, Yue Mohedas, Agustin H. Lee, Arthur Eekhoff, Elisabeth M. W. van Schie, Annelies Demay, Marie B. Keller, Charles Wagers, Amy J. Economides, Aris N. Yu, Paul B. TI Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification SO Science Translational Medicine LA English DT Article ID SMOOTH-MUSCLE-CELLS; SKELETAL-MUSCLE; I RECEPTOR; NATURAL-HISTORY; TRANSGENIC MICE; BONE-FORMATION; PROGRESSIVA; MOUSE; ALK2; CONTRIBUTE AB Fibrodysplasia ossificans progressiva (FOP), a congenital heterotopic ossification (HO) syndrome caused by gain-of-function mutations of bone morphogenetic protein (BMP) type I receptor ACVR1, manifests with progressive ossification of skeletal muscles, tendons, ligaments, and joints. In this disease, HO can occur in discrete flares, often triggered by injury or inflammation, or may progress incrementally without identified triggers. Mice harboring an Acvr1(R206H) knock-in allele recapitulate the phenotypic spectrum of FOP, including injury-responsive intramuscular HO and spontaneous articular, tendon, and ligament ossification. The cells that drive HO in these diverse tissues can be compartmentalized into two lineages: an Scx(+) tendon-derived progenitor that mediates endochondral HO of ligaments and joints without exogenous injury, and a muscle-resident interstitial Mx1(+) population that mediates intramuscular, injury-dependent endochondral HO. Expression of Acvr1(R206H) in either lineage confers aberrant gain of BMP signaling and chondrogenic differentiation in response to activin A and gives rise to mutation-expressing hypertrophic chondrocytes in HO lesions. Compared to Acvr1(R206H), expression of the man-made, ligand-independent ACVR1(Q207D) mutation accelerates and increases the penetrance of all observed phenotypes, but does not abrogate the need for antecedent injury in muscle HO, demonstrating the need for an injury factor in addition to enhanced BMP signaling. Both injury-dependent intramuscular and spontaneous ligament HO in Acvr(1R206H) knock-in mice were effectively controlled by the selective ACVR1 inhibitor LDN-212854. Thus, diverse phenotypes of HO found in FOP are rooted in cell-autonomous effects of dysregulated ACVR1 signaling in nonoverlapping tissue-resident progenitor pools that may be addressed by systemic therapy or by modulating injury-mediated factors involved in their local recruitment. C1 [Dey, Devaveena; Bagarova, Jana; Armstrong, Kelli A.; Vonner, Ashley J.; Shen, Yue; Mohedas, Agustin H.; Yu, Paul B.] Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc Med, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Hatsell, Sarah J.; Huang, Lily; Economides, Aris N.] Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA. [Ermann, Joerg] Harvard Med Sch, Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Dept Med, Boston, MA 02115 USA. [Lee, Arthur] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Eekhoff, Elisabeth M. W.; van Schie, Annelies] Vrije Univ Amsterdam, Med Ctr, Dept Internal Med, Endocrine Sect, POB 7057, NL-1007 MB Amsterdam, Netherlands. [Eekhoff, Elisabeth M. W.; van Schie, Annelies] Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, POB 7057, NL-1007 MB Amsterdam, Netherlands. [Demay, Marie B.] Harvard Med Sch, Massachusetts Gen Hosp, Endocrine Unit, 55 Fruit St, Boston, MA 02114 USA. [Keller, Charles] Childrens Canc Therapy Dev Inst, 12655 SW Beaverdam Road West, Beaverton, OR 97005 USA. [Wagers, Amy J.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Wagers, Amy J.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Wagers, Amy J.] Beth Israel Deaconess Med Ctr, Joslin Diabet Ctr, Boston, MA 02215 USA. [Economides, Aris N.] Regeneron Genet Ctr, Tarrytown, NY 10591 USA. RP Yu, PB (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc Med, Dept Med, 75 Francis St, Boston, MA 02115 USA. EM pbyu@partners.org OI Economides, Aris/0000-0002-6508-8942 FU US NIH [HL079943, AR057374, DK036836, HL100402]; Brigham and Women's Hospital Cardiovascular Division T32 [HL007604]; National Institute of Arthritis and Musculoskeletal and Skin Diseases P30 Center for Skeletal Research Core [AR066261]; Department of Defense [MR140072]; Harvard Stem Cell Institute Seed Award; International FOP Association Competitive Grant Award; Harvard Stem Cell Institute; Pulmonary Hypertension Association Clinician Scientist Career Development Award; Leducq Foundation Transatlantic Network of Excellence Award; Howard Hughes Medical Institute Early Career Physician-Scientist Award; Massachusetts Technology Transfer Award FX This work was supported by the US NIH [HL079943 (to P.B.Y.), AR057374 (to P.B.Y.), DK036836 (to A.J.W.), and HL100402 (to A.J.W.)], Brigham and Women's Hospital Cardiovascular Division T32 [HL007604 (to D.D.)], National Institute of Arthritis and Musculoskeletal and Skin Diseases P30 Center for Skeletal Research Core (AR066261), Department of Defense [MR140072 (to P.B.Y.)], Harvard Stem Cell Institute Seed Award (to P.B.Y.), International FOP Association Competitive Grant Award (to P.B.Y. and Y.S.), Harvard Stem Cell Institute funding for the Joslin Diabetes Center Flow Core Facility, Pulmonary Hypertension Association Clinician Scientist Career Development Award (to P.B.Y.), Leducq Foundation Transatlantic Network of Excellence Award (to P.B.Y.), Howard Hughes Medical Institute Early Career Physician-Scientist Award (to P.B.Y.), and Massachusetts Technology Transfer Award (to P.B.Y.). NR 60 TC 2 Z9 2 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 NOV 23 PY 2016 VL 8 IS 366 AR 366ra163 DI 10.1126/scitranslmed.aaf1090 PG 13 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EE2XQ UT WOS:000389449400004 PM 27881824 ER PT J AU O'Laughlin, KN Rabideau, DJ Kasozi, J Parker, RA Bustamante, ND Faustin, ZM Greenwald, KE Walensky, RP Bassett, IV AF O'Laughlin, Kelli N. Rabideau, Dustin J. Kasozi, Julius Parker, Robert A. Bustamante, Nirma D. Faustin, Zikama M. Greenwald, Kelsy E. Walensky, Rochelle P. Bassett, Ingrid V. TI Predictors of HIV infection: a prospective HIV screening study in a Ugandan refugee settlement SO BMC INFECTIOUS DISEASES LA English DT Article DE HIV; Refugee; HIV testing; HIV screening; sub-Saharan Africa ID PREVALENCE; KNOWLEDGE AB Background: The instability faced by refugees may place them at increased risk of exposure to HIV infection. Nakivale Refugee Settlement in southwestern Uganda hosts 68,000 refugees from 11 countries, many with high HIV prevalence. We implemented an HIV screening program in Nakivale and examined factors associated with new HIV diagnosis. Methods: From March 2013-November 2014, we offered free HIV screening to all clients in the Nakivale Health Center while they waited for their outpatient clinic visit. Clients included refugees and Ugandan nationals accessing services in the settlement. Prior to receiving the HIV test result, participants were surveyed to obtain demographic information including gender, marital status, travel time to reach clinic, refugee status, and history of prior HIV testing. We compared variables for HIV-infected and non-infected clients using Pearson's chi-square test, and used multivariable binomial regression models to identify predictors of HIV infection. Results: During the HIV screening intervention period, 330 (4%) of 7766 individuals tested were identified as HIV-infected. Refugees were one quarter as likely as Ugandan nationals to be HIV-infected (aRR 0.27 [0.21, 0.34], p < 0.0001). Additionally, being female (aRR 1.43 [1.14, 1.80], p = 0.002) and traveling more than 1 h to the clinic (aRR 1.39 [1.11, 1.74], p = 0.003) increased the likelihood of being HIV-infected. Compared to individuals who were married or in a stable relationship, being divorced/separated/widowed increased the risk of being HIV-infected (aRR 2.41 [1.88, 3.08], p < 0.0001), while being single reduced the risk (aRR 0.60 [0.41, 0.86], p < 0.0001). Having been previously tested for HIV (aRR 0.59 [0.47, 0.74], p < 0.0001) also lowered the likelihood of being HIV-infected. Conclusions: In an HIV screening program in a refugee settlement in Uganda, Ugandan nationals are at higher risk of having HIV than refugees. The high HIV prevalence among clients seeking outpatient care, including Ugandan nationals and refugees, warrants enhanced HIV screening services in Nakivale and in the surrounding region. Findings from this research may be relevant for other refugee settlements in Sub-Saharan Africa hosting populations with similar demographics, including the 9 other refugee settlements in Uganda. C1 [O'Laughlin, Kelli N.; Bustamante, Nirma D.] Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. [O'Laughlin, Kelli N.; Parker, Robert A.; Walensky, Rochelle P.; Bassett, Ingrid V.] Massachusetts Gen Hosp, Dept Med, Med Practice Evaluat Ctr, 50 Staniford St,9th Floor, Boston, MA 02114 USA. [O'Laughlin, Kelli N.; Parker, Robert A.; Greenwald, Kelsy E.; Walensky, Rochelle P.; Bassett, Ingrid V.] Harvard Med Sch, 25 Shattuck St, Boston, MA 02115 USA. [O'Laughlin, Kelli N.] Harvard Humanitarian Initiat, Cambridge, MA 02138 USA. [Rabideau, Dustin J.; Parker, Robert A.] Massachusetts Gen Hosp, MGH Biostat Ctr, Boston, MA 02114 USA. [Rabideau, Dustin J.; Parker, Robert A.; Walensky, Rochelle P.; Bassett, Ingrid V.] Harvard Univ, Ctr AIDS Res CFAR, Boston, MA USA. [Kasozi, Julius] United Nations High Commissioner Refugees, Representat Uganda, POB 3813, Kampala, Uganda. [Parker, Robert A.; Walensky, Rochelle P.; Bassett, Ingrid V.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Bustamante, Nirma D.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Faustin, Zikama M.] Bugema Univ, Kasese Campus,POB 6529, Kampala, Uganda. [Walensky, Rochelle P.; Bassett, Ingrid V.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. RP O'Laughlin, KN (reprint author), Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA.; O'Laughlin, KN (reprint author), Massachusetts Gen Hosp, Dept Med, Med Practice Evaluat Ctr, 50 Staniford St,9th Floor, Boston, MA 02114 USA.; O'Laughlin, KN (reprint author), Harvard Med Sch, 25 Shattuck St, Boston, MA 02115 USA.; O'Laughlin, KN (reprint author), Harvard Humanitarian Initiat, Cambridge, MA 02138 USA. EM kolaughlin@partners.org FU National Institute of Mental Health [K23 MH108440, R01 MH 090326, P30 AI060354]; Harvard University Center for AIDS Researh [NIH/NIAID 5P30AI060354]; Harvard Global Health Institute; National Institute of Allergy and Infectious Diseases [R01 AI058736] FX This work was supported by the National Institute of Mental Health (K23 MH108440) to KNO, the Harvard University Center for AIDS Researh (NIH/NIAID 5P30AI060354) to KNO, the Harvard Global Health Institute to KNO, the National Institute of Allergy and Infectious Diseases (R01 AI058736) to KNO, RAP, and RPW, the National Institute of Mental Health (R01 MH 090326) to IVB and (P30 AI060354) to DJR and RAP. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funders. Study data were collected and managed using REDCap (Research Electronic Data Capture) tools hosted at Harvard University. NR 24 TC 1 Z9 1 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD NOV 23 PY 2016 VL 16 AR 695 DI 10.1186/s12879-016-2021-1 PG 7 WC Infectious Diseases SC Infectious Diseases GA ED7VN UT WOS:000389079800001 PM 27881099 ER PT J AU Jayaraman, D Kodani, A Gonzalez, DM Mancias, JD Mochida, GH Vagnoni, C Johnson, J Krogan, N Harper, JW Reiter, JF Yu, TW Bae, BI Walsh, CA AF Jayaraman, Divya Kodani, Andrew Gonzalez, Dilenny M. Mancias, Joseph D. Mochida, Ganeshwaran H. Vagnoni, Cristiana Johnson, Jeffrey Krogan, Nevan Harper, J. Wade Reiter, Jeremy F. Yu, Timothy W. Bae, Byoung-il Walsh, Christopher A. TI Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate SO NEURON LA English DT Article ID CEREBRAL CORTICAL SIZE; MITOTIC PROGRESSION; BRAIN SIZE; CENTROSOME; MUTATIONS; CDK5RAP2; CYTOKINESIS; RECRUITMENT; PROGENITORS; ELEGANS AB Mutations in several genes encoding centrosomal proteins dramatically decrease the size of the human brain. We show that Aspm (abnormal spindle-like, microcephaly-associated) and Wdr62 (WD repeat-containing protein 62) interact genetically to control brain size, with mice lacking Wdr62, Aspm, or both showing gene dose-related centriole duplication defects that parallel the severity of the microcephaly and increased ectopic basal progenitors, suggesting premature delamination from the ventricular zone. Wdr62 and Aspm localize to the proximal end of the mother centriole and interact physically, with Wdr62 required for Aspm localization, and both proteins, as well as microcephaly protein Cep63, required to localize CENPJ/CPAP/Sas-4, a final common target. Unexpectedly, Aspm and Wdr62 are required for normal apical complex localization and apical epithelial structure, providing a plausible unifying mechanism for the premature delamination and precocious differentiation of progenitors. Together, our results reveal links among centrioles, apical proteins, and cell fate, and illuminate how alterations in these interactions can dynamically regulate brain size. C1 [Jayaraman, Divya; Gonzalez, Dilenny M.; Mochida, Ganeshwaran H.; Yu, Timothy W.; Bae, Byoung-il; Walsh, Christopher A.] Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA. [Jayaraman, Divya; Gonzalez, Dilenny M.; Mochida, Ganeshwaran H.; Bae, Byoung-il; Walsh, Christopher A.] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Jayaraman, Divya; Gonzalez, Dilenny M.; Bae, Byoung-il; Walsh, Christopher A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Jayaraman, Divya; Walsh, Christopher A.] Harvard Med Sch, Program Neurosci, Boston, MA 02115 USA. [Jayaraman, Divya] Harvard Med Sch, Harvard MIT MD PhD Program, Boston, MA 02115 USA. [Kodani, Andrew; Reiter, Jeremy F.] Univ Calif San Francisco, Cardiovasc Res Inst, Dept Biochem & Biophys, San Francisco, CA 94158 USA. [Mancias, Joseph D.; Harper, J. Wade] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. [Mancias, Joseph D.] Dana Farber Canc Inst, Dept Radiat Oncol, Div Genom Stabil & DNA Repair, Boston, MA 02215 USA. [Mochida, Ganeshwaran H.; Yu, Timothy W.; Walsh, Christopher A.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Mochida, Ganeshwaran H.] Massachusetts Gen Hosp, Dept Neurol, Pediat Neurol Unit, Boston, MA 02114 USA. [Vagnoni, Cristiana] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England. [Johnson, Jeffrey; Krogan, Nevan] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA. [Yu, Timothy W.; Walsh, Christopher A.] Broad Inst MIT & Harvard Univ, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Walsh, Christopher A.] Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. [Jayaraman, Divya; Bae, Byoung-il] Yale Univ, Sch Med, Dept Neurosurg, 333 Cedar St, New Haven, CT 06510 USA. RP Yu, TW; Bae, BI; Walsh, CA (reprint author), Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA.; Bae, BI; Walsh, CA (reprint author), Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA.; Bae, BI; Walsh, CA (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.; Walsh, CA (reprint author), Harvard Med Sch, Program Neurosci, Boston, MA 02115 USA.; Yu, TW; Walsh, CA (reprint author), Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA.; Yu, TW; Walsh, CA (reprint author), Broad Inst MIT & Harvard Univ, Program Med & Populat Genet, Cambridge, MA 02142 USA.; Walsh, CA (reprint author), Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA.; Bae, BI (reprint author), Yale Univ, Sch Med, Dept Neurosurg, 333 Cedar St, New Haven, CT 06510 USA. EM timothy.yu@childrens.harvard.edu; byoung-il.bae@yale.edu; christopher.walsh@childrens.harvard.edu FU NIH MSTP training grant NIGMS [T32GM007753]; NIH/NHLBI [T32HL007731]; UCSF Program for Breakthrough Biomedical Research; Sandler Foundation; NIH/NINDS [1 R21 NS091865-01]; American Society of Radiation Oncology [JF2013-2]; KL2/Catalyst Medical Research Investigator Training award [TR001100]; Burroughs-Wellcome Career Award for Medical Scientists; Nancy Lurie Marks Junior Faculty MeRIT Fellowship; Manton Center for Orphan Disease Research; F. Hoffman-La Roche Ltd.; NIH [GM070565, GM095567]; NIAMS [R01AR054396]; NIGMS [R01GM095941]; Burroughs Wellcome Fund; Packard Foundation; Sandler Family Supporting Foundation; NINDS [R01 NS035129, R01 NS32457] FX We thank Paul Chang for pointing out the maternal centriolar localization of ASPM, Victor Larionov for reagents, Kutay Atabay and Cameron Sadegh for technical expertise, and Garrett Kingman and Alberta Yen for help with MS and the Aspm mutant mouse. We thank the Boston Children's Hospital (BCH) Mouse Gene Manipulation Core and BCH Cellular Imaging Core (BCH IDDRC, P30 HD18655), the Beth Israel Deaconess Medical Center (BIDMC) Histology Core Facility, the Harvard Medical School Electron Microscopy Facility, and the BIDMC Confocal Imaging Core for technical support. This research was supported by the NIH MSTP training grant NIGMS T32GM007753 (to D.J.); NIH/NHLBI (T32HL007731), the UCSF Program for Breakthrough Biomedical Research, and the Sandler Foundation (to A.K.); NIH/NINDS 1 R21 NS091865-01 (to B.-i.B.); American Society of Radiation Oncology Junior Faculty Career Research Training Award (JF2013-2), KL2/Catalyst Medical Research Investigator Training award (TR001100), and Burroughs-Wellcome Career Award for Medical Scientists (to J.D.M.); Nancy Lurie Marks Junior Faculty MeRIT Fellowship (to T.W.Y.); Manton Center for Orphan Disease Research and F. Hoffman-La Roche Ltd. (G.H.M.); NIH GM070565 and GM095567 (to J.W.H.); NIAMS R01AR054396, NIGMS R01GM095941, the Burroughs Wellcome Fund, the Packard Foundation, and the Sandler Family Supporting Foundation (to J.F.R.); and NINDS (R01 NS035129 and R01 NS32457) and the Manton Center for Orphan Disease Research (to C.A.W.). C.A.W. is an Investigator of the Howard Hughes Medical Institute. NR 39 TC 0 Z9 0 U1 5 U2 5 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 NOV 23 PY 2016 VL 92 IS 4 BP 813 EP 828 DI 10.1016/j.neuron.2016.09.056 PG 16 WC Neurosciences SC Neurosciences & Neurology GA ED0ZH UT WOS:000388572700016 PM 27974163 ER PT J AU Pacheco, B Menendez-Arias, L Sodroski, J AF Pacheco, Beatriz Menendez-Arias, Luis Sodroski, Joseph TI Characterization of two distinct early post-entry blocks to HIV-1 in common marmoset lymphocytes SO SCIENTIFIC REPORTS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; SPECIES-SPECIFIC TROPISM; MURINE LEUKEMIA-VIRUS; NUCLEAR IMPORT; REVERSE TRANSCRIPTION; RESTRICTION FACTOR; SAMHD1 RESTRICTS; MONKEY CELLS; INFECTION; REPLICATION AB In nature, primate lentiviruses infect humans and several Old World monkeys and apes. However, to date, lentiviruses infecting New World monkeys have not been described. We studied the susceptibility of common marmoset cells to HIV-1 infection and observed the presence of post-entry blocks to the early phase of HIV-1 infection in peripheral blood lymphocytes (PBLs) and a B lymphocytic cell line (B-LCL). The blocks present in these cells are dominant and phenotypically different from each other. In PBLs, the block occurs at the level of reverse transcription, reducing the accumulation of early and late transcripts, similar to the block imposed by TRIM5 alpha. However, we have found that marmoset TRIM5a does not block HIV-1. In contrast, the restriction factor present in B-LCLs blocks HIV-1 replication at a later step, after nuclear entry, and inhibits integration. Additionally, we have identified an HIV-1 capsid mutant, N74D, that is able to escape the restriction in the marmoset B-LCLs. Our results suggest that the factors responsible for the blocks present in marmoset PBLs and B-LCLs are different. We propose the existence of at least two new restriction factors able to block HIV-1 infection in marmoset lymphocytes. C1 [Pacheco, Beatriz; Menendez-Arias, Luis] CSIC, Ctr Biol Mol Severo Ochoa, Madrid, Spain. [Pacheco, Beatriz; Menendez-Arias, Luis] Univ Autonoma Madrid, Madrid, Spain. [Pacheco, Beatriz; Sodroski, Joseph] Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA USA. [Pacheco, Beatriz; Sodroski, Joseph] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA USA. [Sodroski, Joseph] Harvard Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA. [Pacheco, Beatriz] CSIC, Ctr Nacl Biotecnol, Madrid, Spain. RP Pacheco, B (reprint author), CSIC, Ctr Biol Mol Severo Ochoa, Madrid, Spain.; Pacheco, B (reprint author), Univ Autonoma Madrid, Madrid, Spain.; Pacheco, B (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA USA.; Pacheco, B (reprint author), Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA USA.; Pacheco, B (reprint author), CSIC, Ctr Nacl Biotecnol, Madrid, Spain. EM b.pacheco.phd@hotmail.com FU National Institutes of Health [AI63987, AI67854]; Spanish Ministry of Economy and Competitiveness [BIO2013-48788-C2-1-R]; European Commission under the 7th Framework Programme through a Marie Curie Career Integration Grant [332623]; Harvard University Center for AIDS Research (CFAR); NIH [P30 AI060354]; Fundacion Ramon Areces; EUPRIM-NetII under the EU of the 7th Framework Programme [262443]; CSIC JAE-Doc contract; European Social Fund FX We thank Dr. Alan Engelman (Dana-Farber Cancer Institute) for the pUC19.2LTR plasmid. We thank the New England Primate Research Center, the Biomedical Primate Research Center and the German Primate Center for providing the common marmoset and rhesus macaque blood needed for this study. We thank the Transfusion Center of the Community of Madrid and all the volunteers that altruistically provided blood samples needed for this research. We acknowledge the personnel from the genomics facility at Centro de Biologia Molecular "Severo Ochoa" for their technical support. This research was supported by grants from the National Institutes of Health (AI63987 and AI67854) to J.S., the Spanish Ministry of Economy and Competitiveness (BIO2013-48788-C2-1-R) to L.M.-A., the European Commission under the 7th Framework Programme through a Marie Curie Career Integration Grant (332623) and a Scholar Award from the Harvard University Center for AIDS Research (CFAR), an NIH funded program (P30 AI060354), to B.P., and an institutional grant from the Fundacion Ramon Areces, to the Centro de Biologia Molecular "Severo Ochoa". Part of this work has been supported by EUPRIM-NetII under the EU grant 262443 of the 7th Framework Programme. B.P. has been a recipient of a CSIC JAE-Doc contract, a program co-financed by the European Social Fund. The funders had no role in study design, data collection and interpretation, decision to publish, or preparation of the manuscript. NR 60 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 NOV 23 PY 2016 VL 6 AR 37489 DI 10.1038/srep37489 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC7VF UT WOS:000388347700001 PM 27876849 ER PT J AU Gomez-Cabrero, D Menche, J Vargas, C Cano, I Maier, D Barabasi, AL Tegner, J Roca, J AF Gomez-Cabrero, David Menche, Jorg Vargas, Claudia Cano, Isaac Maier, Dieter Barabasi, Albert-Laszlo Tegner, Jesper Roca, Josep CA Synergy-COPD Consortia TI From comorbidities of chronic obstructive pulmonary disease to identification of shared molecular mechanisms by data integration SO BMC BIOINFORMATICS LA English DT Article ID COPD PATIENTS; TRANSLATIONAL MEDICINE; RHEUMATOID-ARTHRITIS; SYSTEMS BIOLOGY; GENE ONTOLOGY; RISK; CANCER; EXACERBATIONS; ENRICHMENT; EXERCISE AB Background: Deep mining of healthcare data has provided maps of comorbidity relationships between diseases. In parallel, integrative multi-omics investigations have generated high-resolution molecular maps of putative relevance for understanding disease initiation and progression. Yet, it is unclear how to advance an observation of comorbidity relations (one disease to others) to a molecular understanding of the driver processes and associated biomarkers. Results: Since Chronic Obstructive Pulmonary disease (COPD) has emerged as a central hub in temporal comorbidity networks, we developed a systematic integrative data-driven framework to identify shared disease-associated genes and pathways, as a proxy for the underlying generative mechanisms inducing comorbidity. We integrated records from approximately 13 M patients from the Medicare database with disease-gene maps that we derived from several resources including a semantic-derived knowledge-base. Using rank-based statistics we not only recovered known comorbidities but also discovered a novel association between COPD and digestive diseases. Furthermore, our analysis provides the first set of COPD co-morbidity candidate biomarkers, including IL15, TNF and JUP, and characterizes their association to aging and life-style conditions, such as smoking and physical activity. Conclusions: The developed framework provides novel insights in COPD and especially COPD co-morbidity associated mechanisms. The methodology could be used to discover and decipher the molecular underpinning of other comorbidity relationships and furthermore, allow the identification of candidate co-morbidity biomarkers. C1 [Gomez-Cabrero, David; Tegner, Jesper] Karolinska Inst, Dept Med, Unit Computat Med, S-17177 Stockholm, Sweden. [Gomez-Cabrero, David; Tegner, Jesper] Karolinska Inst, Ctr Mol Med, S-17177 Stockholm, Sweden. [Gomez-Cabrero, David; Tegner, Jesper] Karolinska Univ Hosp, Dept Med, Clin Epidemiol Unit, L8, S-17176 Solna, Sweden. [Gomez-Cabrero, David; Tegner, Jesper] Sci Life Lab, S-17121 Solna, Sweden. [Menche, Jorg; Barabasi, Albert-Laszlo] Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA. [Menche, Jorg; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Vargas, Claudia; Cano, Isaac; Roca, Josep] Univ Barcelona, Hosp Clin Barcelona, Inst Invest Biomed August Pi I Sunyer IDIBAPS, Barcelona, Spain. [Vargas, Claudia; Cano, Isaac; Roca, Josep] Ctr Biomed Network Res Resp Dis CIBERES, Madrid, Spain. [Maier, Dieter] Biomax Informat AG, Planegg, Germany. [Menche, Jorg; Barabasi, Albert-Laszlo] Dana Farber Canc Inst, CCSB, Boston, MA 02115 USA. [Menche, Jorg; Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Menche, Jorg; Barabasi, Albert-Laszlo] Cent European Univ, Ctr Network Sci, Budapest, Hungary. [Barabasi, Albert-Laszlo] Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA USA. [Gomez-Cabrero, David] Kings Coll London, Inst Dent, Mucosal & Salivary Biol Div, London, England. RP Gomez-Cabrero, D (reprint author), Karolinska Inst, Dept Med, Unit Computat Med, S-17177 Stockholm, Sweden.; Gomez-Cabrero, D (reprint author), Karolinska Inst, Ctr Mol Med, S-17177 Stockholm, Sweden.; Gomez-Cabrero, D (reprint author), Karolinska Univ Hosp, Dept Med, Clin Epidemiol Unit, L8, S-17176 Solna, Sweden.; Gomez-Cabrero, D (reprint author), Sci Life Lab, S-17121 Solna, Sweden.; Roca, J (reprint author), Univ Barcelona, Hosp Clin Barcelona, Inst Invest Biomed August Pi I Sunyer IDIBAPS, Barcelona, Spain.; Roca, J (reprint author), Ctr Biomed Network Res Resp Dis CIBERES, Madrid, Spain.; Gomez-Cabrero, D (reprint author), Kings Coll London, Inst Dent, Mucosal & Salivary Biol Div, London, England. EM david.gomezcabrero@ki.se; jroca@clinic.ub.es FU Synergy-COPD European project [FP7-ICT-270086] FX Publication of this article has been funded by the Synergy-COPD European project (FP7-ICT-270086). NR 85 TC 1 Z9 1 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD NOV 22 PY 2016 VL 17 SU 15 AR 441 DI 10.1186/s12859-016-1291-3 PG 13 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA EI4NM UT WOS:000392470500004 PM 28185567 ER PT J AU Muehlschlegel, S Ayturk, D Ahlawat, A Izzy, S Scalea, TM Stein, DM Emhoff, T Sheth, KN AF Muehlschlegel, Susanne Ayturk, Didem Ahlawat, Aditi Izzy, Saef Scalea, Thomas M. Stein, Deborah M. Emhoff, Timothy Sheth, Kevin N. TI Predicting survival after acute civilian penetrating brain injuries The SPIN score SO NEUROLOGY LA English DT Article ID GLASGOW COMA SCALE; GUNSHOT WOUNDS; HEAD; PROGESTERONE; IMPACT; WITHDRAWAL; TRAUMA; CARE AB Objective: To identify predictors associated with survival in civilian penetrating traumatic brain injury (pTBI) utilizing a contemporary, large, diverse 2-center cohort, and to develop a parsimonious survival prediction score for pTBI. Methods: Our cohort comprised 413 pTBI patients retrospectively identified from the local trauma registries at 2 US level 1 trauma centers, of which one was predominantly urban and the other predominantly rural. Predictors of in-hospital and 6-month survival identified in univariate and multivariable logistic regression were used to develop the simple Surviving Penetrating Injury to the Brain (SPIN) score. Results: The mean age was 33 6 16 years and patients were predominantly male (87%). Survival at hospital discharge as well as 6 months post pTBI was 42.4%. Higher motor Glasgow Coma Scale subscore, pupillary reactivity, lack of self-inflicted injury, transfer from other hospital, female sex, lower Injury Severity Score, and lower international normalized ratio were independently associated with survival (all p < 0.001; model area under the curve 0.962). Important radiologic factors associated with survival were also identified but their addition to the full multivariable would have resulted in model overfitting without much gain in the area under the curve. Conclusions: The SPIN score, a logistic regression-based clinical risk stratification scale estimating survival after pTBI, was developed in this large, diverse 2-center cohort. While this preliminary clinical survival prediction tool does not include radiologic factors, it may support clinical decision-making after civilian pTBI if external validation confirms the probability estimates. C1 [Muehlschlegel, Susanne; Ahlawat, Aditi] Univ Massachusetts, Sch Med, Dept Neurol Neurocrit Care, Worcester, MA 01655 USA. [Muehlschlegel, Susanne; Ayturk, Didem; Emhoff, Timothy] Univ Massachusetts, Sch Med, Dept Surg, Worcester, MA 01655 USA. [Muehlschlegel, Susanne] Univ Massachusetts, Sch Med, Dept Anesthesia Crit Care, Worcester, MA 01655 USA. [Izzy, Saef] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Div Neurocrit Care, Boston, MA USA. Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Scalea, Thomas M.; Stein, Deborah M.] Univ Maryland, R Adams Cowley Shock Trauma Ctr, Dept Surg, Baltimore, MD USA. [Sheth, Kevin N.] Yale Univ, Dept Neurol Neurocrit Care & Emergency Neurol, New Haven, CT USA. [Sheth, Kevin N.] Yale Univ, Dept Neurosurg, New Haven, CT USA. RP Muehlschlegel, S (reprint author), Univ Massachusetts, Sch Med, Dept Neurol Neurocrit Care, Worcester, MA 01655 USA.; Muehlschlegel, S (reprint author), Univ Massachusetts, Sch Med, Dept Surg, Worcester, MA 01655 USA.; Muehlschlegel, S (reprint author), Univ Massachusetts, Sch Med, Dept Anesthesia Crit Care, Worcester, MA 01655 USA. EM susanne.muehlschlegel@umassmemorial.org FU NICHD NIH HHS [K23 HD080971] NR 28 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 NOV 22 PY 2016 VL 87 IS 21 BP 2244 EP 2253 DI 10.1212/WNL.0000000000003355 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA EI1LE UT WOS:000392238000017 PM 27784772 ER PT J AU McGrath, ER Batra, A Lam, AD Rizzo, JF Cole, AJ AF McGrath, Emer R. Batra, Ayush Lam, Alice D. Rizzo, Joseph F., III Cole, Andrew J. TI Clinical Reasoning: A 64-year-old man with visual distortions SO NEUROLOGY LA English DT Editorial Material ID CREUTZFELDT-JAKOB-DISEASE; 14-3-3 PROTEIN; WONDERLAND; DIAGNOSIS; ALICE C1 [McGrath, Emer R.; Batra, Ayush; Lam, Alice D.; Cole, Andrew J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [McGrath, Emer R.; Batra, Ayush] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [McGrath, Emer R.; Batra, Ayush; Lam, Alice D.; Cole, Andrew J.] Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. [Rizzo, Joseph F., III] Harvard Med Sch, Dept Ophthalmol, Boston, MA USA. [Rizzo, Joseph F., III] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP McGrath, ER (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.; McGrath, ER (reprint author), Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA.; McGrath, ER (reprint author), Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. EM emcgrath2@partners.org OI McGrath, Emer/0000-0002-3589-2964 NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD NOV 22 PY 2016 VL 87 IS 21 BP E252 EP E256 DI 10.1212/WNL.0000000000003357 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA EI1LE UT WOS:000392238000003 PM 27872229 ER PT J AU Heath, RJ Goel, G Baxt, LA Rush, JS Mohanan, V Paulus, GLC Jani, V Lassen, KG Xavier, RJ AF Heath, Robert J. Goel, Gautam Baxt, Leigh A. Rush, Jason S. Mohanan, Vishnu Paulus, Geraldine L. C. Jani, Vijay Lassen, Kara G. Xavier, Ramnik J. TI RNF166 Determines Recruitment of Adaptor Proteins during Antibacterial Autophagy SO CELL REPORTS LA English DT Article ID E3 UBIQUITIN LIGASE; SELECTIVE AUTOPHAGY; SIRNA SCREEN; SALMONELLA-TYPHIMURIUM; BACTERIAL INVASION; VIRUS-INFECTION; DOMAIN; RECOGNITION; BINDING; CELLS AB Xenophagy is a form of selective autophagy that involves the targeting and elimination of intracellular pathogens through several recognition, recruitment, and ubiquitination events. E3 ubiquitin ligases control substrate selectivity in the ubiquitination cascade; however, systematic approaches to map the role of E3 ligases in antibacterial autophagy have been lacking. We screened more than 600 putative human E3 ligases, identifying E3 ligases that are required for adaptor protein recruitment and LC3-bacteria colocalization, critical steps in antibacterial autophagy. An unbiased informatics approach pin-pointed RNF166 as a key gene that interacts with the autophagy network and controls the recruitment of ubiquitin as well as the autophagy adaptors p62 and NDP52 to bacteria. Mechanistic studies demonstrated that RNF166 catalyzes K29- and K33-linked polyubiquitination of p62 at residues K91 and K189. Thus, our study expands the catalog of E3 ligases that mediate antibacterial autophagy and identifies a critical role for RNF166 in this process. C1 [Heath, Robert J.; Goel, Gautam; Baxt, Leigh A.; Mohanan, Vishnu; Paulus, Geraldine L. C.; Jani, Vijay; Lassen, Kara G.; Xavier, Ramnik J.] Harvard Med Sch, Gastrointestinal Unit, Boston, MA 02114 USA. [Heath, Robert J.; Goel, Gautam; Baxt, Leigh A.; Mohanan, Vishnu; Paulus, Geraldine L. C.; Jani, Vijay; Lassen, Kara G.; Xavier, Ramnik J.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Heath, Robert J.; Goel, Gautam; Baxt, Leigh A.; Mohanan, Vishnu; Paulus, Geraldine L. C.; Jani, Vijay; Lassen, Kara G.; Xavier, Ramnik J.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Heath, Robert J.; Goel, Gautam; Baxt, Leigh A.; Rush, Jason S.; Mohanan, Vishnu; Paulus, Geraldine L. C.; Jani, Vijay; Lassen, Kara G.; Xavier, Ramnik J.] Broad Inst & Harvard, Cambridge, MA 02142 USA. RP Heath, RJ; Lassen, KG; Xavier, RJ (reprint author), Harvard Med Sch, Gastrointestinal Unit, Boston, MA 02114 USA.; Heath, RJ; Lassen, KG; Xavier, RJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA.; Heath, RJ; Lassen, KG; Xavier, RJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA.; Heath, RJ; Lassen, KG; Xavier, RJ (reprint author), Broad Inst & Harvard, Cambridge, MA 02142 USA. EM rheath@broadinstitute.org; klassen@broadinstitute.org; xavier@molbio.mgh.harvard.edu FU Leona M. and Harry B. Helmsley Charitable Trust [2014PG-IBD016]; NIH [R01DK097485, U19AI109725, P30DK043351] FX We thank Natalia Nedelsky for editorial and graphics assistance. This work was supported by funding from The Leona M. and Harry B. Helmsley Charitable Trust (2014PG-IBD016) and NIH grants R01DK097485, U19AI109725, and P30DK043351 (to R.J.X.). NR 71 TC 0 Z9 0 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD NOV 22 PY 2016 VL 17 IS 9 BP 2183 EP 2194 DI 10.1016/j.celrep.2016.11.005 PG 12 WC Cell Biology SC Cell Biology GA EG2SE UT WOS:000390893600003 PM 27880896 ER PT J AU Johnson, SF Cruz, C Greifenberg, AK Dust, S Stover, DG Chi, D Primack, B Cao, SL Bernhardy, AJ Coulson, R Lazaro, JB Kochupurakkal, B Sun, H Unitt, C Moreau, LA Sarosiek, KA Scaltriti, M Juric, D Baselga, J Richardson, AL Rodig, SJ D'Andrea, AD Balmana, J Johnson, N Geyer, M Serra, V Lim, E Shapiro, GI AF Johnson, Shawn F. Cruz, Cristina Greifenberg, Ann Katrin Dust, Sofia Stover, Daniel G. Chi, David Primack, Benjamin Cao, Shiliang Bernhardy, Andrea J. Coulson, Rhiannon Lazaro, Jean-Bernard Kochupurakkal, Bose Sun, Heather Unitt, Christine Moreau, Lisa A. Sarosiek, Kristopher A. Scaltriti, Maurizio Juric, Dejan Baselga, Jose Richardson, Andrea L. Rodig, Scott J. D'Andrea, Alan D. Balmana, Judith Johnson, Neil Geyer, Matthias Serra, Violeta Lim, Elgene Shapiro, Geoffrey I. TI CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer SO CELL REPORTS LA English DT Article ID DEPENDENT KINASE INHIBITOR; HOMOLOGOUS RECOMBINATION; POLYMERASE INHIBITORS; MAMMARY-TUMORS; TRANSCRIPTION; SENSITIVITY; DINACICLIB; OVARIAN; CELLS; PHOSPHORYLATION AB Although poly (ADP-ribose) polymerase (PARP) inhibitors are active in homologous recombination (HR)-deficient cancers, their utility is limited by acquired resistance after restoration of HR. Here, we report that dinaciclib, an inhibitor of cyclin-dependent kinases (CDKs) 1, 2, 5, and 9, additionally has potent activity against CDK12, a transcriptional regulator of HR. In BRCA-mutated triple-negative breast cancer (TNBC) cells and patient-derived xenografts (PDXs), dinaciclib ablates restored HR and reverses PARP inhibitor resistance. Additionally, we show that de novo resistance to PARP inhibition in BRCA1-mutated cell lines and a PDX derived from a PARP-inhibitor-naive BRCA1 carrier is mediated by residual HR and is reversed by CDK12 inhibition. Finally, dinaciclib augments the degree of response in a PARP-inhibitor-sensitive model, converting tumor growth inhibition to durable regression. These results highlight the significance of HR disruption as a therapeutic strategy and support the broad use of combined CDK12 and PARP inhibition in TNBC. C1 [Johnson, Shawn F.; Stover, Daniel G.; Chi, David; Cao, Shiliang; Sarosiek, Kristopher A.; Lim, Elgene; Shapiro, Geoffrey I.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Cruz, Cristina; Serra, Violeta] Vall dHebron Inst Oncol, Expt Therapeut Grp, Barcelona 08035, Spain. [Cruz, Cristina; Balmana, Judith] Univ Autonoma Barcelona, Vall dHebron Inst Oncol, Hosp Vall dHebron, Med Oncol Dept, Barcelona 08035, Spain. [Greifenberg, Ann Katrin; Dust, Sofia; Geyer, Matthias] Univ Bonn, Inst Innate Immun, Dept Struct Immunol, D-53127 Bonn, Germany. [Greifenberg, Ann Katrin; Dust, Sofia; Geyer, Matthias] Ctr Adv European Studies & Res, Grp Phys Biochem, D-53175 Bonn, Germany. [Stover, Daniel G.] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. [Stover, Daniel G.; Shapiro, Geoffrey I.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Stover, Daniel G.; Primack, Benjamin; Lazaro, Jean-Bernard; Kochupurakkal, Bose; Sun, Heather; Unitt, Christine; Moreau, Lisa A.; Richardson, Andrea L.; Rodig, Scott J.; D'Andrea, Alan D.; Shapiro, Geoffrey I.] Harvard Med Sch, Boston, MA 02115 USA. [Primack, Benjamin; Lazaro, Jean-Bernard; Kochupurakkal, Bose; Moreau, Lisa A.; D'Andrea, Alan D.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. [Primack, Benjamin; Lazaro, Jean-Bernard; Kochupurakkal, Bose; Moreau, Lisa A.; D'Andrea, Alan D.] Dana Farber Canc Inst, Ctr DNA Damage & Repair, Boston, MA 02215 USA. [Primack, Benjamin; Moreau, Lisa A.; D'Andrea, Alan D.] Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Bernhardy, Andrea J.; Johnson, Neil] Fox Chase Canc Ctr, Dev Therapeut Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Coulson, Rhiannon; Lim, Elgene] St Vincents Hlth Network, Garvan Inst Med Res, Kinghorn Canc Ctr, Darlinghurst, NSW 2010, Australia. [Sun, Heather; Unitt, Christine; Richardson, Andrea L.; Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Scaltriti, Maurizio; Baselga, Jose] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Juric, Dejan] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Juric, Dejan] Harvard Med Sch, Dept Med, Boston, MA 02114 USA. [Richardson, Andrea L.] Johns Hopkins Med, Dept Pathol, Baltimore, MD 21287 USA. RP Lim, E; Shapiro, GI (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Shapiro, GI (reprint author), Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA.; Shapiro, GI (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Lim, E (reprint author), St Vincents Hlth Network, Garvan Inst Med Res, Kinghorn Canc Ctr, Darlinghurst, NSW 2010, Australia. EM e.lim@garvan.org.au; geoffrey_shapiro@dfci.harvard.edu FU NIH [R01 CA090687]; Dana-Farber Specialized Program of Research Excellence (SPORE) in Breast Cancer [P50 CA168504]; Susan G. Komen Investigator Initiated Research grant [IIR12223953]; Dana-Farber Claudia Adams Barr Award; National Health and Medical Research Council of Australia Fellowship; Instituto de Salud Carlos III grant [PI12/02606]; Asociacion Espanola Contra el Cancer; Deutsche Forschungsgemeinschaft grant [GE 976/9-1]; Merck Co.; AstraZeneca; Research Supplement to Promote Diversity in Health-Related Research [R01 CA090687]; SPORE Diversity Career Development Award [P50 CA168504] FX This work was supported by NIH grant R01 CA090687 (G.I.S.), an R01 CA090687 Research Supplement to Promote Diversity in Health-Related Research (S.F.J., G.I.S.), Dana-Farber Specialized Program of Research Excellence (SPORE) in Breast Cancer grant P50 CA168504 (G.I.S., A.D.D.), a P50 CA168504 SPORE Diversity Career Development Award (S.F.J. and G.I.S.), as well as Susan G. Komen Investigator Initiated Research grant IIR12223953 (G.I.S.). E.L. was supported by a Dana-Farber Claudia Adams Barr Award and a National Health and Medical Research Council of Australia Fellowship. Work at the Vall d'Hebron Institute of Oncology (VHIO) was supported by Instituto de Salud Carlos III grant PI12/02606 (J.B.) and the Asociacion Espanola Contra el Cancer (C.C.). M.G. is a member of the DFG excellence cluster ImmunoSensation and is supported by Deutsche Forschungsgemeinschaft grant GE 976/9-1. U2OS-pDR-GFP cells and Lenti-CRISP/Cas9 constructs were provided by Maria Jasin and Jean Zhao, respectively. We thank Donna Skinner of the DF/HCC Research Pathology Core, Pilar Anton of VHIO, and Lan Hu of the DFCI Center for Cancer Computational Biology for technical assistance, as well as Bjoern Chapuy and Margaret Shipp for sharing preliminary data. S.J.R. has consulted for AstraZeneca. J.B. has received speaking bureau and travel fees from AstraZeneca and has served in an advisory role for Clovis Oncology. V.S. has a non-commercial research agreement with AstraZeneca. G.I.S. has received research funding from Merck & Co. NR 31 TC 1 Z9 1 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 NOV 22 PY 2016 VL 17 IS 9 BP 2367 EP 2381 DI 10.1016/j.celrep.2016.10.077 PG 15 WC Cell Biology SC Cell Biology GA EG2SE UT WOS:000390893600017 PM 27880910 ER PT J AU Aguirre-Gamboa, R Joosten, I Urbano, PCM van der Molen, RG van Rijssen, E van Cranenbroek, B Oosting, M Smeekens, S Jaeger, M Zorro, M Withoff, S van Herwaarden, AE Sweep, FCGJ Netea, RT Swertz, MA Franke, L Xavier, RJ Joosten, LAB Netea, MG Wijmenga, C Kumar, V Li, Y Koenen, HJPM AF Aguirre-Gamboa, Raul Joosten, Irma Urbano, Paulo C. M. van der Molen, Renate G. van Rijssen, Esther van Cranenbroek, Bram Oosting, Marije Smeekens, Sanne Jaeger, Martin Zorro, Maria Withoff, Sebo van Herwaarden, Antonius E. Sweep, Fred C. G. J. Netea, Romana T. Swertz, Morris A. Franke, Lude Xavier, Ramnik J. Joosten, Leo A. B. Netea, Mihai G. Wijmenga, Cisca Kumar, Vinod Li, Yang Koenen, Hans J. P. M. TI Differential Effects of Environmental and Genetic Factors on T and B Cell Immune Traits SO CELL REPORTS LA English DT Article ID GENOME-WIDE ASSOCIATION; IMMUNOGLOBULIN PRODUCTION; EXPRESSION ANALYSIS; CYTOKINE PRODUCTION; INNATE IMMUNITY; SYSTEM; AGE; DISEASE; HUMANS; HERITABILITY AB Effective immunity requires a complex network of cellular and humoral components that interact with each other and are influenced by different environmental and host factors. We used a systems biology approach to comprehensively assess the impact of environmental and genetic factors on immune cell populations in peripheral blood, including associations with immunoglobulin concentrations, from similar to 500 healthy volunteers from the Human Functional Genomics Project. Genetic heritability estimation showed that variations in T cell numbers are more strongly driven by genetic factors, while B cell counts are more environmentally influenced. Quantitative trait loci (QTL) mapping identified eight independent genomic loci associated with leukocyte count variation, including four associations with T and B cell subtypes. The QTLs identified were enriched among genome-wide association study (GWAS) SNPs reported to increase susceptibility to immune-mediated diseases. Our systems approach provides insights into cellular and humoral immune trait variability in humans. C1 [Aguirre-Gamboa, Raul; Zorro, Maria; Withoff, Sebo; Swertz, Morris A.; Franke, Lude; Wijmenga, Cisca; Kumar, Vinod; Li, Yang] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands. [Joosten, Irma; Urbano, Paulo C. M.; van der Molen, Renate G.; van Rijssen, Esther; van Cranenbroek, Bram; Koenen, Hans J. P. M.] Radboud Univ Nijmegen, Med Ctr, Lab Med Immunol, Dept Lab Med, NL-6525 GA Nijmegen, Netherlands. [Oosting, Marije; Smeekens, Sanne; Jaeger, Martin; Netea, Romana T.; Joosten, Leo A. B.; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 GA Nijmegen, Netherlands. [Oosting, Marije; Smeekens, Sanne; Jaeger, Martin; Netea, Romana T.; Joosten, Leo A. B.; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis, NL-6525 GA Nijmegen, Netherlands. [van Herwaarden, Antonius E.; Sweep, Fred C. G. J.] Radboud Univ Nijmegen, Med Ctr, Clin Chem Lab, Dept Lab Med, NL-6525 GA Nijmegen, Netherlands. [Swertz, Morris A.] Univ Groningen, Univ Med Ctr Groningen, Genom Coordinat Ctr, NL-9713 AV Groningen, Netherlands. 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.] Harvard Sch Med, Boston, MA 02114 USA. [Xavier, Ramnik J.] MIT, Broad Inst, Cambridge, MA 02142 USA. [Xavier, Ramnik J.] Harvard Univ, Cambridge, MA 02142 USA. [Wijmenga, Cisca] Univ Oslo, Oslo Univ Hosp, Rikshosp, Dept Immunol, N-0372 Oslo, Norway. RP Li, Y (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands.; Koenen, HJPM (reprint author), Radboud Univ Nijmegen, Med Ctr, Lab Med Immunol, Dept Lab Med, NL-6525 GA Nijmegen, Netherlands. EM y.li01@umcg.nl; hans.koenen@radboudumc.nl RI Oosting, Marije/H-7437-2015; van der Molen, Renate/I-2398-2014; OI van der Molen, Renate/0000-0003-3113-6587; Urbano, Paulo/0000-0002-5769-1573 FU European Research Council (ERC) [3310372]; IN-CONTROL CVON grant [CVON2012-03]; ERC Advanced Grant (FP/ERC) [2012-322698]; Spinoza Prize (NWO) [SPI 92-266]; Dutch Digestive Diseases Foundation (MLDS) [WO11-30]; European Union Seventh Framework Program (EU FP7) grant (TANDEM) [HEALTH-F3-2012-305279]; Netherlands Organization for Scientific Research (NWO) VENI grant [863.13.011]; CONACYT-I2T2 scholarship [382117]; Brazil's Science Without Borders program [11920/13-0]; NWO [184021007] FX The authors thank all volunteers from the 500FG cohort of the HFGP for participation in the study. We thank Jackie Senior and Kate Mc Intyre for editorial assistance. The HFGP is supported by a European Research Council (ERC) Consolidator grant (3310372) and an IN-CONTROL CVON grant (CVON2012-03) to M.G.N., an ERC Advanced Grant (FP/2007-2013/ERC grant 2012-322698) and a Spinoza Prize (NWO SPI 92-266) to C.W., a Dutch Digestive Diseases Foundation (MLDS) grant (WO11-30) to C.W. and V.K., a European Union Seventh Framework Program (EU FP7) grant (TANDEM; HEALTH-F3-2012-305279) to C.W. and V.K., a Netherlands Organization for Scientific Research (NWO) VENI grant (863.13.011) to Y.L., a CONACYT-I2T2 scholarship (382117) to R.A.G., and a scholarship from Brazil's Science Without Borders program (11920/13-0) to P.C.M.U. This study made use of data generated by the Genome of the Netherlands project funded by NWO (grant no. 184021007), which was made available as a Rainbow Project of BBMRI-NL. NR 49 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 NOV 22 PY 2016 VL 17 IS 9 BP 2474 EP 2487 DI 10.1016/j.celrep.2016.10.053 PG 14 WC Cell Biology SC Cell Biology GA EG2SE UT WOS:000390893600025 PM 27818087 ER PT J AU Yan, J Herzog, JW Tsang, K Brennan, CA Bower, MA Garrett, WS Sartor, BR Aliprantis, AO Charles, JF AF Yan, Jing Herzog, Jeremy W. Tsang, Kelly Brennan, Caitlin A. Bower, Maureen A. Garrett, Wendy S. Sartor, Balfour R. Aliprantis, Antonios O. Charles, Julia F. TI Gut microbiota induce IGF-1 and promote bone formation and growth SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE microbiota; bone; IGF-1; SCFA ID CHAIN FATTY-ACIDS; INTESTINAL MICROBIOTA; LACTOBACILLUS-REUTERI; IMMUNE-SYSTEM; MICE; INSULIN; HEALTH; METABOLITES; EXPRESSION; SEROTONIN AB Appreciation of the role of the gut microbiome in regulating vertebrate metabolism has exploded recently. However, the effects of gut microbiota on skeletal growth and homeostasis have only recently begun to be explored. Here, we report that colonization of sexually mature germ-free (GF) mice with conventional specific pathogen-free (SPF) gut microbiota increases both bone formation and resorption, with the net effect of colonization varying with the duration of colonization. Although colonization of adult mice acutely reduces bone mass, in long-term colonized mice, an increase in bone formation and growth plate activity predominates, resulting in equalization of bone mass and increased longitudinal and radial bone growth. Serum levels of insulin-like growth factor 1 (IGF-1), a hormone with known actions on skeletal growth, are substantially increased in response to microbial colonization, with significant increases in liver and adipose tissue IGF-1 production. Antibiotic treatment of conventional mice, in contrast, decreases serum IGF-1 and inhibits bone formation. Supplementation of antibiotic-treated mice with short-chain fatty acids (SCFAs), products of microbial metabolism, restores IGF-1 and bone mass to levels seen in nonantibiotic-treated mice. Thus, SCFA production may be one mechanism by which microbiota increase serum IGF-1. Our study demonstrates that gut microbiota provide a net anabolic stimulus to the skeleton, which is likely mediated by IGF-1. Manipulation of the microbiome or its metabolites may afford opportunities to optimize bone health and growth. C1 [Yan, Jing; Tsang, Kelly; Aliprantis, Antonios O.; Charles, Julia F.] Brigham & Womens Hosp, Dept Med, Div Rheumatol Immunol & Allergy, 75 Francis St, Boston, MA 02115 USA. [Yan, Jing; Tsang, Kelly; Aliprantis, Antonios O.; Charles, Julia F.] Harvard Med Sch, Boston, MA 02115 USA. [Herzog, Jeremy W.; Bower, Maureen A.; Sartor, Balfour R.] Univ North Carolina Chapel Hill, Natl Gnotobiot Rodent Resource Ctr, Chapel Hill, NC 27599 USA. [Brennan, Caitlin A.; Garrett, Wendy S.] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Garrett, Wendy S.] Harvard TH Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Garrett, Wendy S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Garrett, Wendy S.] Broad Inst MIT & Harvard Univ, Cambridge, MA 02141 USA. [Aliprantis, Antonios O.] Merck Res Labs, 33 Ave Louis Pasteur, Boston, MA 02115 USA. RP Charles, JF (reprint author), Brigham & Womens Hosp, Dept Med, Div Rheumatol Immunol & Allergy, 75 Francis St, Boston, MA 02115 USA.; Charles, JF (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM JFCHARLES@partners.org FU NIH [K08 AR062590, R01 AG046257, R01 CA154426]; Rheumatology Research Foundation; Bettina Looram Fund; Hoffman-LaRoche research grant; National Gnotobiotic Rodent Resource Center at University of North Carolina at Chapel Hill [5-P30-DK034987, 5-P40-OD010995] FX We thank the Pathology Core Research Laboratory at the Department of Pathology, University of Alabama at Birmingham, for histomorphometric analysis, Wenhan Chang for helpful discussions, and Hank Kronenberg for comments on the manuscript. This work was supported by NIH grants K08 AR062590 (to J.F.C.), R01 AG046257 (to J.F.C. and A.O.A.), and R01 CA154426 (to W.S.G.). Additional support was provided by the Rheumatology Research Foundation (J.F.C.), the Bettina Looram Fund (J.F.C.), and a Hoffman-LaRoche research grant (W.S.G.). C.A.B. is the Dennis and Marsha Dammerman fellow of the Damon Runyon Cancer Research Foundation (DRG-2205-14). Gnotobiotic studies were performed at the National Gnotobiotic Rodent Resource Center at University of North Carolina at Chapel Hill (funding agencies 5-P30-DK034987 and 5-P40-OD010995 and Crohn's and Colitis Foundation of America). NR 64 TC 0 Z9 0 U1 7 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 22 PY 2016 VL 113 IS 47 BP E7554 EP E7563 DI 10.1073/pnas.1607235113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED4OY UT WOS:000388830700026 PM 27821775 ER PT J AU Bowlby, W Zelnick, LR Henry, C Himmelfarb, J Kahn, SE Kestenbaum, B Robinson-Cohen, C Utzschneider, KM de Boer, IH AF Bowlby, Wilson Zelnick, Leila R. Henry, Connor Himmelfarb, Jonathan Kahn, Steven E. Kestenbaum, Bryan Robinson-Cohen, Cassianne Utzschneider, Kristina M. de Boer, Ian H. TI Physical activity and metabolic health in chronic kidney disease: a cross-sectional study SO BMC Nephrology LA English DT Article DE Chronic kidney disease; Physical activity; Metabolism; Insulin resistance; Obesity; Triglycerides ID GLOMERULAR-FILTRATION-RATE; INSULIN-RESISTANCE; RENAL-INSUFFICIENCY; GENERAL-POPULATION; OBESITY PARADOX; ALL-CAUSE; CKD; MORTALITY; ASSOCIATION; EXERCISE AB Background: Patients with chronic kidney disease (CKD) are at high risk of progression to end stage renal disease and cardiovascular events. Physical activity may reduce these risks by improving metabolic health. We tested associations of physical activity with central components of metabolic health among people with moderate-severe non-diabetic CKD. Methods: We performed a cross-sectional study of 47 people with CKD (estimated GFR < 60 ml/min/1.73 m(2)) and 29 healthy control subjects. Accelerometry was used to measured physical activity over 7 days, the hyperinsulinemic-euglycemic clamp was used to measure insulin sensitivity, and DXA was used to measured fat mass. We tested associations of physical activity with insulin sensitivity, fat mass, blood pressure, serum lipid concentrations, and serum high sensitivity C-reactive protein concentration using multivariable linear regression, adjusting for possible confounding factors. Results: Participants with CKD were less active than participants without CKD (mean (SD) 468.1 (233.1) versus 662.3 (292.5) counts per minute) and had lower insulin sensitivity (4.1 (2.1) versus 5.2 (2.0 (mg/min)/(mu U/mL)), higher fat mass (32.0 (11.4) versus 29.4 (14.8) kg), and higher triglyceride concentrations (153.2 (91.6) versus 99.6 (66.8) mg/dL). With adjustment for demographics, comorbidity, medications, and estimated GFR, each two-fold higher level of physical activity was associated with a 0.9 (mg/min)/(mu U/mL) higher insulin sensitivity (95% CI 0.2, 1.5, p = 0.006), an 8.0 kg lower fat mass (-12.9, -3.1, p = 0.001), and a 37.9 mg/dL lower triglyceride concentration (-71.9, -3.9, p = 0.03). Associations of physical activity with insulin sensitivity and triglycerides did not differ significantly by CKD status (p-values for interaction > 0.3). Conclusions: Greater physical activity is associated with multiple manifestations of metabolic health among people with moderate-severe CKD. C1 [Bowlby, Wilson] Univ Washington, Sch Med, Seattle, WA USA. [Zelnick, Leila R.; Henry, Connor; Himmelfarb, Jonathan; Kestenbaum, Bryan; Robinson-Cohen, Cassianne; de Boer, Ian H.] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. [Zelnick, Leila R.; Henry, Connor; Himmelfarb, Jonathan; Kestenbaum, Bryan; Robinson-Cohen, Cassianne; de Boer, Ian H.] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA. [Kahn, Steven E.; Utzschneider, Kristina M.; de Boer, Ian H.] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Kahn, Steven E.; Utzschneider, Kristina M.] Univ Washington, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. RP de Boer, IH (reprint author), Univ Washington, Div Nephrol, Seattle, WA 98195 USA.; de Boer, IH (reprint author), Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA.; de Boer, IH (reprint author), VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. EM ideboer@Nephrology.washington.edu OI Robinson-Cohen, Cassianne/0000-0003-4783-7046; Kahn, Steven/0000-0001-7307-9002 FU National Institute of Diabetes and Digestive and Kidney Diseases [R01DK087726]; Department of Veterans Affairs; National Center for Advancing Translational Sciences, National Institutes of Health [TL1 TR000422]; [ULTR000423]; [P01DK017047]; [P30DK035816]; [R01DK088762]; [R01DK099199] FX SUGAR was funded by R01DK087726 from the National Institute of Diabetes and Digestive and Kidney Diseases with additional support from ULTR000423, P01DK017047, P30DK035816, R01DK088762, and R01DK099199. This project was supported in part by the Department of Veterans Affairs. This project was also made possible by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant TL1 TR000422. NR 37 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD NOV 22 PY 2016 VL 17 AR 187 DI 10.1186/s12882-016-0400-x PG 9 WC Urology & Nephrology SC Urology & Nephrology GA EE0OW UT WOS:000389279200003 PM 27876008 ER PT J AU Deeb, W Giordano, JJ Rossi, PJ Mogilner, AY Gunduz, A Judy, JW Klassen, BT Butson, CR Van Horne, C Deny, D Dougherty, DD Rowell, D Gerhardt, GA Smith, GS Ponce, FA Walker, HC Bronte-Stewart, HM Mayberg, HS Chizeck, HJ Langevin, JP Volkmann, J Ostrem, JL Shute, JB Jimenez-Shahed, J Foote, KD Shukla, AW Rossi, MA Oh, M Pourfar, M Rosenberg, PB Silburn, PA de Hemptine, C Starr, PA Denison, T Akbar, U Grill, WM Okun, MS AF Deeb, Wissam Giordano, James J. Rossi, Peter J. Mogilner, Alon Y. Gunduz, Aysegul Judy, Jack W. Klassen, Bryan T. Butson, Christopher R. Van Horne, Craig Deny, Damiaan Dougherty, Darin D. Rowell, David Gerhardt, Greg A. Smith, Gwenn S. Ponce, Francisco A. Walker, Harrison C. Bronte-Stewart, Helen M. Mayberg, Helen S. Chizeck, Howard J. Langevin, Jean-Philippe Volkmann, Jens Ostrem, Jill L. Shute, Jonathan B. Jimenez-Shahed, Joohi Foote, Kelly D. Shukla, Aparna Wagle Rossi, Marvin A. Oh, Michael Pourfar, Michael Rosenberg, Paul B. Silburn, Peter A. de Hemptine, Coralie Starr, Philip A. Denison, Timothy Akbar, Umer Grill, Warren M. Okun, Michael S. TI Proceedings of the Fourth Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies SO FRONTIERS IN INTEGRATIVE NEUROSCIENCE LA English DT Review DE deep brain stimulation; Parkinson's disease; Alzheimer's disease; closed-loop; depression; post-traumatic stress disorder; Tourette syndrome; DARPA ID TREATMENT-RESISTANT DEPRESSION; POSTTRAUMATIC-STRESS-DISORDER; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; TOURETTE-SYNDROME; MOVEMENT-DISORDERS; ADVERSE EVENTS; SUBTHALAMIC NUCLEUS; COST-EFFECTIVENESS; TRIAL AB This paper provides an overview of current progress in the technological advances and the use of deep brain stimulation (DBS) to treat neurological and neuropsychiatric disorders, as presented by participants of the Fourth Annual DBS Think Tank, which was convened in March 2016 in conjunction with the Center for Movement Disorders and Neurorestoration at the University of Florida, Gainesveille FL, USA. The Think Tank discussions first focused on policy and advocacy in DBS research and clinical practice, formation of registries, and issues involving the use of DBS in the treatment of Tourette Syndrome. Next, advances in the use of neuroimaging and electrochemical markers to enhance DBS specificity were addressed. Updates on ongoing use and developments of DBS for the treatment of Parkinson's disease, essential tremor, Alzheimer's disease, depression, post traumatic stress disorder, obesity, addiction were presented, and progress toward innovation(s) in closed-loop applications were discussed. Each section of these proceedings provides updates and highlights of new information as presented at this year's international Think Tank, with a view toward current and near future advancement of the field. C1 [Deeb, Wissam; Rossi, Peter J.; Gunduz, Aysegul; Judy, Jack W.; Foote, Kelly D.; Shukla, Aparna Wagle; Okun, Michael S.] Univ Florida, Ctr Movement Disorders & Neurorestorat, Dept Neurol, Gainesville, FL USA. [Giordano, James J.] Georgetown Univ, Med Ctr, Dept Neurol, Pellegrino Ctr Chhical Bioeth, Washington, DC 20007 USA. [Giordano, James J.] Georgetown Univ, Med Ctr, Neuroeth Studies Program, Pellegrino Ctr Chhical Bioeth, Washington, DC 20007 USA. [Mogilner, Alon Y.] NYU, Dept Neurosurg, Ctr Neuromodulat, Langone Med Ctr, 550 1St Ave, New York, NY 10016 USA. [Gunduz, Aysegul; Judy, Jack W.; Shute, Jonathan B.] Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL USA. [Klassen, Bryan T.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Butson, Christopher R.] Univ Utah, Dept Bioengn, Sci Comp & Imaging Inst, Salt Lake City, UT 84112 USA. [Van Horne, Craig] Univ Kentucky, Chandler Med Ctr, Dept Neurosurg, Lexington, KY USA. [Deny, Damiaan] Univ Amsterdam, Acad Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Dougherty, Darin D.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Rowell, David; Silburn, Peter A.] Univ Queensland, Queensland Brain Inst, Asia Pacific Ctr Neuromodulat, Brisbane, Qld, Australia. [Gerhardt, Greg A.] Univ Kentucky, Dept Anat & Neurobiol, Chandler Med Ctr, Lexington, KY 40536 USA. [Smith, Gwenn S.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Smith, Gwenn S.] Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD USA. [Ponce, Francisco A.] St Josephs Hosp & Med Ctr Phoenix, Barrow Neurol Inst, Div Neurol Surg, Phoenix, AZ USA. [Walker, Harrison C.] Univ Alabama Birmingham, Dept Neurol, UAB Stn, Birmingham, AL 35294 USA. [Walker, Harrison C.] Univ Alabama Birmingham, Dept Biomed Engn, Birmingham, AL 35294 USA. [Bronte-Stewart, Helen M.] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Bronte-Stewart, Helen M.] Stanford Univ, Dept Neurosurg, Stanford, CA 94305 USA. [Mayberg, Helen S.] Emory Univ, Sch Med, Dept Psychiat, Atlanta, GA 30322 USA. [Chizeck, Howard J.] Univ Washington, Dept Elect Engn, Seattle, WA 98195 USA. [Chizeck, Howard J.] NSF Engn Res Ctr Sensorimotor Neural Engn, Seattle, WA USA. [Langevin, Jean-Philippe] VA Greater Los Angeles Healthcare Syst, Dept Neurosurg, Los Angeles, CA USA. [Volkmann, Jens] Univ Clin Wurzburg, Dept Neurol, Wurzburg, Germany. [Ostrem, Jill L.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Jimenez-Shahed, Joohi] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Foote, Kelly D.] Univ Florida, Dept Neurol Sci, Gainesville, FL USA. [Rossi, Marvin A.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Rossi, Marvin A.] Rush Univ, Med Ctr, Dept Diagnost Radiol, Chicago, IL 60612 USA. [Rossi, Marvin A.] Rush Univ, Med Ctr, Dept Nucl Med, Chicago, IL 60612 USA. [Oh, Michael] Allegheny Gen Hosp, Dept Neurosurg, Div Funct Neurosurg, Pittsburgh, PA 15212 USA. [Pourfar, Michael] NYU, Dept Neurol, Langone Med Ctr, New York, NY 10016 USA. [Rosenberg, Paul B.] Johns Hopkins Sch Med, Johns Hopkins Bayview Med Ctr, Psychiat & Behav Sci, Baltimore, MD USA. [de Hemptine, Coralie; Starr, Philip A.] Univ Calif San Francisco, Grad Program Neurosci, Dept Neurol Surg, Kavli Inst Fundamental Neurosci, San Francisco, CA 94143 USA. [Denison, Timothy] Medtron Modulat, Minneapolis, MN USA. [Akbar, Umer] Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Movement Disorders Program,Dept Neurol, Providence, RI 02903 USA. [Grill, Warren M.] Duke Univ, Dept Biomed Engn, Durham, NC 27706 USA. RP Deeb, W (reprint author), Univ Florida, Ctr Movement Disorders & Neurorestorat, Dept Neurol, Gainesville, FL USA. EM wissam.deeb@neurology.ufl.edu OI Mogilner, Alon/0000-0003-1493-0463 FU National Institutes of Health; National Parkinson Foundation; Michael J. Fox Foundation for Parkinson's Research; Tourette Association of America FX National Institutes of Health, National Parkinson Foundation, Michael J. Fox Foundation for Parkinson's Research and the Tourette Association of America provided funding for the previous studies presented in this paper. NR 92 TC 2 Z9 2 U1 7 U2 7 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND EI 1662-5145 J9 FRONT INTEGR NEUROSC JI Front. Integr. Neurosci. PD NOV 22 PY 2016 VL 10 AR 38 DI 10.3389/fnint.2016.00038 PG 21 WC Neurosciences SC Neurosciences & Neurology GA EC8WO UT WOS:000388424000002 PM 27920671 ER PT J AU Mei, Y Bi, WL Greenwald, NF Du, ZM Agar, NYR Kaiser, UB Woodmansee, WW Reardon, DA Freeman, GJ Fecci, PE Laws, ER Santagata, S Dunn, GP Dunn, IF AF Mei, Yu Bi, Wenya Linda Greenwald, Noah F. Du, Ziming Agar, Nathalie Y. R. Kaiser, Ursula B. Woodmansee, Whitney W. Reardon, David A. Freeman, Gordon J. Fecci, Peter E. Laws, Edward R., Jr. Santagata, Sandro Dunn, Gavin P. Dunn, Ian F. TI Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors SO Oncotarget LA English DT Article DE pituitary adenoma; PD-L1; RNAscope; checkpoint inhibition; immunotherapy ID CELL LUNG-CANCER; UNTREATED MELANOMA; IMMUNE EVASION; T-CELLS; IMMUNOTHERAPY; ADENOMAS; ACTIVATION; NIVOLUMAB; SAFETY; B7-H1 AB Purpose: Subsets of pituitary tumors exhibit an aggressive clinical courses and recur despite surgery, radiation, and chemotherapy. Because modulation of the immune response through inhibition of T-cell checkpoints has led to durable clinical responses in multiple malignancies, we explored whether pituitary adenomas express immune-related biomarkers that could suggest suitability for immunotherapy. Specifically, programmed death ligand 1 (PD-L1) has emerged as a potential biomarker whose expression may portend more favorable responses to immune checkpoint blockade therapies. We thus investigated the expression of PD-L1 in pituitary adenomas. Methods: PD-L1 RNA and protein expression were evaluated in 48 pituitary tumors, including functioning and non-functioning adenomas as well as atypical and recurrent tumors. Tumor infiltrating lymphocyte populations were also assessed by immunohistochemistry. Results: Pituitary tumors express variable levels of PD-L1 transcript and protein. PD-L1 RNA and protein expression were significantly increased in functioning (growth hormone and prolactin-expressing) pituitary adenomas compared to non-functioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary adenomas harbored higher levels of PD-L1 mRNA compared to recurrent tumors. Tumor infiltrating lymphocytes were observed in all pituitary tumors and were positively correlated with increased PD-L1 expression, particularly in the functional subtypes. Conclusions: Human pituitary adenomas harbor PD-L1 across subtypes, with significantly higher expression in functioning adenomas compared to non-functioning adenomas. This expression is accompanied by the presence of tumor infiltrating lymphocytes. These findings suggest the existence of an immune response to pituitary tumors and raise the possibility of considering checkpoint blockade immunotherapy in cases refractory to conventional management. C1 [Mei, Yu; Bi, Wenya Linda; Greenwald, Noah F.; Agar, Nathalie Y. R.; Laws, Edward R., Jr.; Dunn, Ian F.] Harvard Med Sch, Dept Neurosurg, Brigham & Womens Hosp, Boston, MA 02115 USA. [Bi, Wenya Linda; Greenwald, Noah F.; Agar, Nathalie Y. R.; Santagata, Sandro] Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA USA. [Du, Ziming; Santagata, Sandro] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA. [Kaiser, Ursula B.; Woodmansee, Whitney W.] Harvard Med Sch, Brigham & Womens Hosp, Div Endocrinol, Boston, MA USA. [Reardon, David A.; Freeman, Gordon J.] Harvard Med Sch, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA USA. [Fecci, Peter E.] Duke Univ, Sch Med, Dept Neurosurg, Durham, NC USA. [Fecci, Peter E.] Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr, Durham, NC USA. [Dunn, Gavin P.] Washington Univ, Sch Med, Dept Neurol Surg, St Louis, MO USA. [Dunn, Gavin P.] Washington Univ, Sch Med, Ctr Human Immunol & Immunotherapy Programs, St Louis, MO USA. RP Dunn, IF (reprint author), Harvard Med Sch, Dept Neurosurg, Brigham & Womens Hosp, Boston, MA 02115 USA.; Dunn, GP (reprint author), Washington Univ, Sch Med, Dept Neurol Surg, St Louis, MO USA.; Dunn, GP (reprint author), Washington Univ, Sch Med, Ctr Human Immunol & Immunotherapy Programs, St Louis, MO USA. EM gpdunn@wustl.edu; idunn@partners.org OI Greenwald, Noah/0000-0002-7836-4379 NR 46 TC 0 Z9 0 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 22 PY 2016 VL 7 IS 47 BP 76565 EP 76576 DI 10.18632/oncotarget.12088 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE5GK UT WOS:000389633400018 PM 27655724 ER PT J AU Jakubikova, J Cholujova, D Hideshima, T Gronesova, P Soltysova, A Harada, T Joo, J Kong, SY Szalat, RE Richardson, PG Munshi, NC Dorfman, DM Anderson, KC AF Jakubikova, Jana Cholujova, Danka Hideshima, Teru Gronesova, Paulina Soltysova, Andrea Harada, Takeshi Joo, Jungnam Kong, Sun-Young Szalat, Raphael E. Richardson, Paul G. Munshi, Nikhil C. Dorfman, David M. Anderson, Kenneth C. TI A novel 3D mesenchymal stem cell model of the multiple myeloma bone marrow niche: biologic and clinical applications SO Oncotarget LA English DT Article DE multiple myeloma; tumor microenvironment; mesenchymal stem cells; 3D model; drug resistance ID MEDIATED DRUG-RESISTANCE; STROMAL CELLS; TUMOR MICROENVIRONMENT; 3-DIMENSIONAL CULTURES; APOPTOSIS; EXPRESSION; CANCER; TISSUE; DIFFERENTIATION; OPPORTUNITIES AB Specific niches within the tumor bone marrow (BM) microenvironment afford a sanctuary for multiple myeloma (MM) clones due to stromal cell-tumor cell interactions, which confer survival advantage and drug resistance. Defining the sequelae of tumor cell interactions within the MM niches on an individualized basis may provide the rationale for personalized therapies. To mimic the MM niche, we here describe a new 3D co-culture ex-vivo model in which primary MM patient BM cells are co-cultured with mesenchymal stem cells (MSC) in a hydrogel 3D system. In the 3D model, MSC with conserved phenotype (CD73+CD90+CD105+) formed compact clusters with active fibrous connections, and retained lineage differentiation capacity. Extracellular matrix molecules, integrins, and niche related molecules including N-cadherin and CXCL12 are expressed in 3D MSC model. Furthermore, activation of osteogenesis (MMP13, SPP1, ADAMTS4, and MGP genes) and osteoblastogenic differentiation was confirmed in 3D MSC model. Co-culture of patient-derived BM mononuclear cells with either autologous or allogeneic MSC in 3D model increased proliferation of MM cells, CXCR4 expression, and SP cells. We carried out immune profiling to show that distribution of immune cell subsets was similar in 3D and 2D MSC model systems. Importantly, resistance to novel agents (IMiDs, bortezomib, carfilzomib) and conventional agents (doxorubicin, dexamethasone, melphalan) was observed in 3D MSC system, reflective of clinical resistance. This 3D MSC model may therefore allow for studies of MM pathogenesis and drug resistance within the BM niche. Importantly, ongoing prospective trials are evaluating its utility to inform personalized targeted and immune therapy in MM. C1 [Jakubikova, Jana; Hideshima, Teru; Szalat, Raphael E.; Richardson, Paul G.; Munshi, Nikhil C.; Anderson, Kenneth C.] Dana Farber Canc Inst, Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Jakubikova, Jana; Hideshima, Teru; Harada, Takeshi; Szalat, Raphael E.; Richardson, Paul G.; Munshi, Nikhil C.; Dorfman, David M.; Anderson, Kenneth C.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Jakubikova, Jana; Cholujova, Danka; Gronesova, Paulina] SAS, Biomed Res Ctr, Canc Res Inst, Bratislava, Slovakia. [Soltysova, Andrea] Comenius Univ, Fac Nat Sci, Dept Mol Biol, Bratislava, Slovakia. [Joo, Jungnam] Natl Canc Ctr, Res Inst & Hosp, Div Canc Epidemiol & Prevent, Biometr Res Branch, Goyang Si, Gyeonggi Do, South Korea. [Kong, Sun-Young] Natl Canc Ctr, Res Inst & Hosp, Dept Lab Med, Goyang Si, Gyeonggi Do, South Korea. [Kong, Sun-Young] Natl Canc Ctr, Res Inst & Hosp, Translat Epidemiol Branch, Goyang Si, Gyeonggi Do, South Korea. [Dorfman, David M.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. RP Jakubikova, J; Anderson, KC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA.; Jakubikova, J; Anderson, KC (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA.; Jakubikova, J (reprint author), SAS, Biomed Res Ctr, Canc Res Inst, Bratislava, Slovakia. EM jana_jakubikova@dfci.harvard.edu; kenneth_anderson@dfci.harvard.edu FU MMRF Research Fellow Award; SASPRO [0064/01/02]; VEGA grant [2/0189/13] FX This study was supported by the MMRF 2012 Research Fellow Award; SASPRO 0064/01/02 and VEGA grant 2/0189/13. K.C.A. is an American Cancer Society Clinical Research Professor. NR 56 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 22 PY 2016 VL 7 IS 47 BP 77326 EP 77341 DI 10.18632/oncotarget.12643 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE5GK UT WOS:000389633400080 PM 27764795 ER PT J AU Ledermann, JA Harter, P Gourley, C Friedlander, M Vergote, I Rustin, G Scott, C Meier, W Shapira-Frommer, R Safra, T Matei, D Fielding, A Bennett, B Parry, D Spencer, S Mann, H Matulonis, U AF Ledermann, Jonathan A. Harter, Philipp Gourley, Charlie Friedlander, Michael Vergote, Ignace Rustin, Gordon Scott, Clare Meier, Werner Shapira-Frommer, Ronnie Safra, Tamar Matei, Daniela Fielding, Anitra Bennett, Bryan Parry, David Spencer, Stuart Mann, Helen Matulonis, Ursula TI Quality of life during olaparib maintenance therapy in platinum-sensitive relapsed serous ovarian cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE olaparib; quality of life; maintenance treatment; ovarian cancer; BRCA; FACT-O questionnaire ID PATIENT-REPORTED OUTCOMES; PHASE-III; OPEN-LABEL; CLINICAL-TRIALS; BREAST-CANCER; MULTICENTER; BEVACIZUMAB; AZD2281 AB Background: Maintenance monotherapy with the poly(ADP-ribose) polymerase inhibitor olaparib significantly prolongs progression-free survival over placebo in patients with platinum-sensitive relapsed serous ovarian cancer, with greatest benefit seen in patients with a BRCA1/2 mutation (BRCAm). Preservation of health-related quality of life (HRQoL) is important during maintenance therapy; we evaluated the effect of olaparib on HRQoL in this Phase II trial (NCT00753545, Study 19). Methods: Patients received olaparib 400mg b.i.d. (capsules) or placebo until progression. Patient-reported HRQoL and disease-related symptoms were evaluated using the FACT-Ovarian (FACT-O) questionnaire (completed at baseline and every 28 days until progression), the FACT/NCCN Ovarian Symptom Index (FOSI) and the Trial Outcome Index (TOI). TOI of the FACT-O was the primary measure. Results: Overall, 265 women were randomised to maintenance olaparib (n = 136) or placebo (n = 129). Compliance for HRQoL assessment was high (similar to 80% over time). Most patients in both arms reported a best response of 'no change' on TOI (81%) and other HRQoL measures. There were no statistically significant differences in time to worsening or improvement rates of TOI, FOSI and FACT-O scores in the overall, BRCAm and germline BRCAm populations. Conclusions: Maintenance treatment with olaparib was well tolerated and had no adverse impact on HRQoL in this study of patients with platinum-sensitive relapsed serous ovarian cancer who had responded to their most recent platinum-based therapy (partial or complete response). Interpretation of the HRQoL results in this population may differ from patients who have not responded to their most recent platinum-based therapy. C1 [Ledermann, Jonathan A.] UCL, Canc Res UK, 90 Tottenham Court Rd, London W1T 4TJ, England. [Ledermann, Jonathan A.] UCL Canc Trials Ctr, 90 Tottenham Court Rd, London W1T 4TJ, England. [Harter, Philipp] Kliniken Essen Mitte, Henricistr 95, D-45136 Essen, Germany. [Gourley, Charlie] Univ Edinburgh, Western Gen Hosp, MRC IGMM, Canc Res UK Ctr, Crewe Rd South, Edinburgh EH4 2XR, Midlothian, Scotland. [Friedlander, Michael] Prince Wales Hosp, UNSW Clin Sch, High St, Randwick, NSW 2031, Australia. [Vergote, Ignace] Univ Leuven, Herestr 49, B-3000 Leuven, Belgium. [Rustin, Gordon] Mt Vernon Hosp, Rickmansworth Rd, Northwood HA6 2RN, Middx, England. [Scott, Clare] Royal Melbourne Hosp, 300 Grattan St, Parkville, Vic 3050, Australia. [Meier, Werner] Evangel Krankenhaus, Kirchfeldstr 40, D-40217 Dusseldorf, Germany. [Shapira-Frommer, Ronnie] Chaim Sheba Med Ctr, Derech Sheba 2, IL-52621 Tel Hashomer, Israel. [Safra, Tamar] Tel Aviv Sourasky Med Ctr, 6 Weizmann St, IL-64239 Tel Aviv, Israel. [Matei, Daniela] Indiana Univ Sch Med, 980 West Walnut St, Indianapolis, IN 46202 USA. [Fielding, Anitra; Bennett, Bryan; Parry, David; Spencer, Stuart; Mann, Helen] AstraZeneca, Mereside, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England. [Matulonis, Ursula] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Bennett, Bryan] Adelphi Mill, Adelphi Values, Grimshaw Lane, Bollington SK10 5JB, England. RP Ledermann, JA (reprint author), UCL, Canc Res UK, 90 Tottenham Court Rd, London W1T 4TJ, England.; Ledermann, JA (reprint author), UCL Canc Trials Ctr, 90 Tottenham Court Rd, London W1T 4TJ, England. EM j.ledermann@ucl.ac.uk FU AstraZeneca FX Medical writing assistance during the development of this manuscript was provided by Rachel Patel from Mudskipper Business Ltd, funded by AstraZeneca. This work was supported by funding from AstraZeneca. NR 16 TC 1 Z9 1 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD NOV 22 PY 2016 VL 115 IS 11 BP 1313 EP 1320 DI 10.1038/bjc.2016.348 PG 8 WC Oncology SC Oncology GA ED2ZP UT WOS:000388719100007 PM 27824811 ER PT J AU Shafrir, AL Babic, A Tamimi, RM Rosner, BA Tworoger, SS Terry, KL AF Shafrir, Amy L. Babic, Ana Tamimi, Rulla M. Rosner, Bernard A. Tworoger, Shelley S. Terry, Kathryn L. TI Reproductive and hormonal factors in relation to survival and platinum resistance among ovarian cancer cases SO BRITISH JOURNAL OF CANCER LA English DT Article DE ovarian cancer; survival; endometriosis; platinum chemotherapy; hormone therapy ID REPLACEMENT THERAPY; RISK-FACTORS; RECEPTOR EXPRESSION; ENDOMETRIOSIS; PREDICTORS; DIAGNOSIS; PROGNOSIS; WOMEN AB Background: Ovarian cancer survival is poor, particularly for platinum-resistant cases. The previous literature on pre-diagnostic reproductive factors and ovarian cancer survival has been mixed. Therefore, we evaluated pre-diagnostic reproductive and hormonal factors with overall survival and, additionally, platinum-chemotherapy resistance. Methods: We followed 1649 invasive epithelial ovarian cancer cases who were enrolled between 1992 and 2008 for overall mortality within the New England Case-Control Study and abstracted chemotherapy data on a subset (n = 449). We assessed pre-diagnostic reproductive and hormonal factors during in-person interviews. We calculated hazard ratios (HRs) using Cox-proportional hazards models. Results: We observed 911 all-cause deaths among 1649 ovarian cancer cases. Self-reported endometriosis and longer duration of hormone therapy use were associated with improved survival (HR: 0.72; 95% confidence interval (CI): 0.54-0.94 and HR, >= 5 years vs never: 0.70; 95% CI: 0.55-0.90, respectively). Older age at menopause and menarche were associated with worse survival (HR, <= 50 vs >50 years: 1.23; 95% CI: 1.03-1.46 and HR, 13 vs <13 years: 1.24; 95% CI: 1.06-1.44, respectively). We observed no association between oral contraceptive use, parity and tubal ligation, and overall survival. No significant associations were observed for any of the reproductive and hormonal factors and platinum resistance. Conclusions: These results suggest that pre-diagnostic exposures such as endometriosis and HT use may influence overall survival among ovarian cancer patients. C1 [Shafrir, Amy L.; Tamimi, Rulla M.; Tworoger, Shelley S.; Terry, Kathryn L.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave,9th Floor, Boston, MA 02115 USA. [Shafrir, Amy L.; Tamimi, Rulla M.; Rosner, Bernard A.; Tworoger, Shelley S.] Brigham & Womens Hosp, Channing Div Network Med, Dept Med, 181 Longwood Ave, Boston, MA 02115 USA. [Shafrir, Amy L.; Tamimi, Rulla M.; Rosner, Bernard A.; Tworoger, Shelley S.] Harvard Med Sch, 181 Longwood Ave, Boston, MA 02115 USA. [Babic, Ana] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Babic, Ana] Harvard Med Sch, 450 Brookline Ave, Boston, MA 02215 USA. [Rosner, Bernard A.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, 677 Huntington Ave, Boston, MA 02115 USA. [Terry, Kathryn L.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Dept Obstet & Gynecol, 221 Longwood Ave, Boston, MA 02115 USA. [Terry, Kathryn L.] Harvard Med Sch, 221 Longwood Ave, Boston, MA 02115 USA. RP Shafrir, AL (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave,9th Floor, Boston, MA 02115 USA.; Shafrir, AL (reprint author), Brigham & Womens Hosp, Channing Div Network Med, Dept Med, 181 Longwood Ave, Boston, MA 02115 USA.; Shafrir, AL (reprint author), Harvard Med Sch, 181 Longwood Ave, Boston, MA 02115 USA. EM amy.shafrir@mail.harvard.edu FU National Institutes of Health [R01 CA054419]; Department of Defense [W81XWH-10-1-0280]; Training Grant in Reproductive, Perinatal and Pediatric Epidemiology from National Institute of Child Health and Human Development, National Institutes of Health [T32 HD060454]; Cancer Epidemiology Training Program [NIH T32CA09001] FX This project was supported by the National Institutes of Health (R01 CA054419) and the Department of Defense (W81XWH-10-1-0280). ALS was supported by Training Grant T32 HD060454 in Reproductive, Perinatal and Pediatric Epidemiology from the National Institute of Child Health and Human Development, National Institutes of Health. ALS and AB were supported by the Cancer Epidemiology Training Program (NIH T32CA09001). NR 36 TC 2 Z9 2 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD NOV 22 PY 2016 VL 115 IS 11 BP 1391 EP 1399 DI 10.1038/bjc.2016.316 PG 9 WC Oncology SC Oncology GA ED2ZP UT WOS:000388719100017 PM 27701384 ER PT J AU Gomez-Cabrero, D Almgren, M Sjoholm, LK Hensvold, AH Ringh, MV Tryggvadottir, R Kere, J Scheynius, A Acevedo, N Reinius, L Taub, MA Montano, C Aryee, MJ Feinberg, JI Feinberg, AP Tegner, J Klareskog, L Catrina, AI Ekstrom, TJ AF Gomez-Cabrero, David Almgren, Malin Sjoholm, Louise K. Hensvold, Aase H. Ringh, Mikael V. Tryggvadottir, Rakel Kere, Juha Scheynius, Annika Acevedo, Nathalie Reinius, Lovisa Taub, Margaret A. Montano, Carolina Aryee, Martin J. Feinberg, Jason I. Feinberg, Andrew P. Tegner, Jesper Klareskog, Lars Catrina, Anca I. Ekstrom, Tomas J. TI High-specificity bioinformatics framework for epigenomic profiling of discordant twins reveals specific and shared markers for ACPA and ACPA-positive rheumatoid arthritis SO GENOME MEDICINE LA English DT Article DE Rheumatoid arthritis; ACPA; DNA methylation; Epigenetics; Bioinformatics ID DNA METHYLATION; WIDE ASSOCIATION; HUMAN GENOME; ANTIBODIES; RISK; HERITABILITY; AUTOIMMUNITY; INDIVIDUALS; EPIGENETICS; MICROARRAY AB Background: Twin studies are powerful models to elucidate epigenetic modifications resulting from gene-environment interactions. Yet, commonly a limited number of clinical twin samples are available, leading to an underpowered situation afflicted with false positives and hampered by low sensitivity. We investigated genome-wide DNA methylation data from two small sets of monozygotic twins representing different phases during the progression of rheumatoid arthritis (RA) to find novel genes for further research. Methods: We implemented a robust statistical methodology aimed at investigating a small number of samples to identify differential methylation utilizing the comprehensive CHARM platform with whole blood cell DNA from two sets of twin pairs discordant either for ACPA (antibodies to citrullinated protein antigens)positive RA versus ACPA-negative healthy or for ACPA-positive healthy (a pre-RA stage) versus ACPA-negative healthy. To deconvolute cell type-dependent differential methylation, we assayed the methylation patterns of sorted cells and used computational algorithms to resolve the relative contributions of different cell types and used them as covariates. Results: To identify methylation biomarkers, five healthy twin pairs discordant for ACPAs were profiled, revealing a single differentially methylated region (DMR). Seven twin pairs discordant for ACPA-positive RA revealed six significant DMRs. After deconvolution of cell type proportions, profiling of the healthy ACPA discordant twin-set revealed 17 genome-wide significant DMRs. When methylation profiles of ACPA-positive RA twin pairs were adjusted for cell type, the analysis disclosed one significant DMR, associated with the EXOSC1 gene. Additionally, the results from our methodology suggest a temporal connection of the protocadherine beta-14 gene to ACPA-positivity with clinical RA. Conclusions: Our biostatistical methodology, optimized for a low-sample twin design, revealed non-genetically linked genes associated with two distinct phases of RA. Functional evidence is still lacking but the results reinforce further study of epigenetic modifications influencing the progression of RA. Our study design and methodology may prove generally useful in twin studies. C1 [Gomez-Cabrero, David; Almgren, Malin; Sjoholm, Louise K.; Hensvold, Aase H.; Ringh, Mikael V.; Tegner, Jesper; Klareskog, Lars; Catrina, Anca I.; Ekstrom, Tomas J.] Karolinska Inst, Ctr Mol Med, Stockholm, Sweden. [Gomez-Cabrero, David; Almgren, Malin; Sjoholm, Louise K.; Hensvold, Aase H.; Ringh, Mikael V.; Acevedo, Nathalie; Tegner, Jesper; Klareskog, Lars; Catrina, Anca I.; Ekstrom, Tomas J.] Karolinska Univ Hosp, Stockholm, Sweden. [Gomez-Cabrero, David; Tegner, Jesper] Dept Med, Unit Computat Med, Stockholm, Sweden. [Gomez-Cabrero, David] Bioinformat Infrastruct Life Sci, Stockholm, Sweden. [Almgren, Malin; Sjoholm, Louise K.; Ringh, Mikael V.; Ekstrom, Tomas J.] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Hensvold, Aase H.; Klareskog, Lars; Catrina, Anca I.] Karolinska Univ Hosp Solna, Dept Med, Rheumatol Unit, Stockholm, Sweden. [Kere, Juha; Reinius, Lovisa] Karolinska Inst, Dept Biosci & Nutr, Ctr Biosci, Stockholm, Sweden. [Acevedo, Nathalie] Karolinska Inst, Dept Med Solna, Translat Immunol Unit, Stockholm, Sweden. [Almgren, Malin; Tryggvadottir, Rakel; Taub, Margaret A.; Feinberg, Jason I.; Feinberg, Andrew P.] Johns Hopkins Univ, Ctr Epigen, Baltimore, MD USA. [Taub, Margaret A.; Feinberg, Andrew P.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Feinberg, Andrew P.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Feinberg, Jason I.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Montano, Carolina] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Med Scientist Training Program, Baltimore, MD USA. [Montano, Carolina] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Predoctoral Training Program Human Genet, Baltimore, MD USA. [Aryee, Martin J.] Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA USA. [Aryee, Martin J.] Harvard Med Sch, Boston, MD USA. [Aryee, Martin J.] Harvard TH Chan Sch Publ Hlth, Biostat, Boston, MA USA. [Aryee, Martin J.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Gomez-Cabrero, David] Kings Coll London, Inst Dent, Mucosal & Salivary Biol Div, London, England. [Scheynius, Annika] Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden. [Scheynius, Annika] Soder Sjukhuset, Sachs Children & Youth Hosp, Stockholm, Sweden. RP Ekstrom, TJ (reprint author), Karolinska Inst, Ctr Mol Med, Stockholm, Sweden.; Ekstrom, TJ (reprint author), Karolinska Univ Hosp, Stockholm, Sweden.; Ekstrom, TJ (reprint author), Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. EM Tomas.Ekstrom@ki.se RI Kere, Juha/A-9179-2008 OI Kere, Juha/0000-0003-1974-0271 FU AFA Insurance; Swedish Research Council; Swedish Rheumatism Association; Swedish Research Foundation of Strategic Research [RBc08-0027]; STATegra EU FP7 project [306000] FX This work was financed by AFA Insurance, the Swedish Research Council, the Swedish Rheumatism Association, and the Swedish Research Foundation of Strategic Research (RBc08-0027), and the STATegra EU FP7 project (306000). The funding bodies have no role in the design of the study, the collection, analysis, or interpretation of data, or in writing the manuscript. NR 50 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 1756-994X J9 GENOME MED JI Genome Med. PD NOV 22 PY 2016 VL 8 AR 124 DI 10.1186/s13073-016-0374-0 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA ED6ZY UT WOS:000389006700002 PM 27876072 ER PT J AU Bhattacharyya, R Fenn, RH Barren, C Tanzi, RE Kovacs, DM AF Bhattacharyya, Raja Fenn, Rebecca H. Barren, Cory Tanzi, Rudolph E. Kovacs, Dora M. TI Palmitoylated APP Forms Dimers, Cleaved by BACE1 SO PLOS ONE LA English DT Article ID AMYLOID PRECURSOR PROTEIN; HEPARIN-INDUCED DIMERIZATION; FACTOR-LIKE DOMAIN; A-BETA PRODUCTION; ALZHEIMERS-DISEASE; LIPID RAFTS; EXTRACELLULAR DOMAIN; GXXXG MOTIFS; IDENTIFICATION; SECRETASE AB A major rate-limiting step for A beta generation and deposition in Alzheimer's disease brains is BACE1-mediated cleavage (beta-cleavage) of the amyloid precursor protein (APP). We previously reported that APP undergoes palmitoylation at two cysteine residues (Cys(186) and Cys(187)) in the E1-ectodomain. 8-10% of total APP is palmitoylated in vitro and in vivo. Palmitoylated APP (palAPP) shows greater preference for beta-cleavage than total APP in detergent resistant lipid rafts. Protein palmitoylation is known to promote protein dimerization. Since dimerization of APP at its E1-ectodomain results in elevated BACE1-mediated cleavage of APP, we have now investigated whether palmitoylation of APP affects its dimerization and whether this leads to elevated beta-cleavage of the protein. Here we report that over 90% of palAPP is dimerized while only similar to 20% of total APP forms dimers. PalAPP-dimers are predominantly cis-oriented while total APP dimerizes in both cis- and trans-orientation. PalAPP forms dimers 4.5-times more efficiently than total APP. Overexpression of the palmitoylating enzymes DHHC7 and DHHC21 that increase palAPP levels and A beta release, also increased APP dimerization in cells. Conversely, inhibition of APP palmitoylation by pharmacological inhibitors reduced APP-dimerization in coimmunoprecipitation and FLIM/FRET assays. Finally, in vitro BACE1-activity assays demonstrate that palmitoylation-dependent dimerization of APP promotes beta-cleavage of APP in lipid-rich detergent resistant cell membranes (DRMs), when compared to total APP. Most importantly, generation of sAPP(beta)-sAPP(beta) dimers is dependent on APP-palmitoylation while total sAPP(beta) generation is not. Since BACE1 shows preference for palAPP dimers over total APP, palAPP dimers may serve as novel targets for effective beta-cleavage inhibitors of APP as opposed to BACE1 inhibitors. C1 [Bhattacharyya, Raja; Fenn, Rebecca H.; Barren, Cory; Tanzi, Rudolph E.; Kovacs, Dora M.] Harvard Med Sch, Massachusetts Gen Hosp, MassGeneral Inst Neurodegenerat Dis MIND, Genet & Aging Res Unit, Charlestown, MA 02129 USA. RP Kovacs, DM (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, MassGeneral Inst Neurodegenerat Dis MIND, Genet & Aging Res Unit, Charlestown, MA 02129 USA. EM dora_kovacs@hms.harvard.edu FU Cure Alzheimer's Fund; NIH/NINDS [R01NS45860] FX This work was funded by the Cure Alzheimer's Fund (grants to D.M.K. and R.E.T.) and the NIH/NINDS (R01NS45860 to D.M.K/R.E.T.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We thank our funding agencies the Cure Alzheimer's Fund (grants to D.M.K. and R.E.T.) and the NIH/NINDS (R01NS45860 to D.M.K/R.E.T.). We also thank Dr. Masaki Fukata (NIPS, Okazaki, Japan) for providing us with the DHHC-expression plasmids; Dr. Stephen Pasternak for providing us expression plasmid for HA-APPy; Dr. Stefan Kins for giving us the APP-dimerization deficient APP(H108/110A)-expression plasmid; Dr. Claus U. Pietrzik for the generous gifts of APP-split GFP plasmids; and Dr. Doo Yeon Kim (Massachusetts General Hospital, Charlestown, MA) for helpful advice on ReN cell maintenance and differentiation. We also thank Dr. Katarzyna Marta Zoltowska and Sarah Svirsky (Massachusetts General Hospital, Charlestown, MA) for FRET/FLIM analysis. NR 48 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 NOV 22 PY 2016 VL 11 IS 11 AR e0166400 DI 10.1371/journal.pone.0166400 PG 25 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED5IV UT WOS:000388886000013 PM 27875558 ER PT J AU Bang, A Patel, A Bellad, R Gisore, P Goudar, SS Esamai, F Liechty, EA Meleth, S Goco, N Niermeyer, S Keenan, W Kamath-Rayne, BD Little, GA Clarke, SB Flanagan, VA Bucher, S Jain, M Mujawar, N Jain, V Rukunga, J Mahantshetti, N Dhaded, S Bhandankar, M McClure, EM Carlo, WA Wright, LL Hibberd, PL AF Bang, Akash Patel, Archana Bellad, Roopa Gisore, Peter Goudar, Shivaprasad S. Esamai, Fabian Liechty, Edward A. Meleth, Sreelatha Goco, Norman Niermeyer, Susan Keenan, William Kamath-Rayne, Beena D. Little, George A. Clarke, Susan B. Flanagan, Victoria A. Bucher, Sherri Jain, Manish Mujawar, Nilofer Jain, Vinita Rukunga, Janet Mahantshetti, Niranjana Dhaded, Sangappa Bhandankar, Manisha McClure, Elizabeth M. Carlo, Waldemar A. Wright, Linda L. Hibberd, Patricia L. TI Helping Babies Breathe (HBB) training: What happens to knowledge and skills over time? SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article DE Helping Babies Breathe; Resuscitation; Bag and mask ventilation; Perinatal mortality; Asphyxia; Stillbirth; Training ID EMERGENCY CARDIOVASCULAR CARE; NEONATAL RESUSCITATION; CARDIOPULMONARY-RESUSCITATION; NEWBORN MORTALITY; SAVE LIVES; SCALE-UP; COUNTRIES; DEATHS; PERFORMANCE; STILLBIRTH AB Background: The first minutes after birth are critical to reducing neonatal mortality. Helping Babies Breathe (HBB) is a simulation-based neonatal resuscitation program for low resource settings. We studied the impact of initial HBB training followed by refresher training on the knowledge and skills of the birth attendants in facilities. Methods: We conducted HBB trainings in 71 facilities in the NICHD Global Network research sites (Nagpur and Belgaum, India and Eldoret, Kenya), with a 6: 1 ratio of facility trainees to Master Trainers (MT). Because of staff turnover, some birth attendants (BA) were trained as they joined the delivery room staff, after the initial training was completed (catch-up initial training). We compared pass rates for skills and knowledge pre- and post-initial HBB training and following refresher training among active BAs. An Objective Structured Clinical Examination (OSCE) B tested resuscitation skill retention by comparing post-initial training performance with pre-refresher training performance. We identified factors associated with loss of skills in pre-refresher training performance using multivariable logistic regression analysis. Daily bag and mask ventilation practice, equipment checks and supportive supervision were stressed as part of training. Results: One hundred five MT (1.6 MT per facility) conducted initial and refresher HBB trainings for 835 BAs; 76% had no prior resuscitation training. Initial training improved knowledge and skills: the pass percentage for knowledge tests improved from 74 to 99% (p < 0.001). Only 5% could ventilate a newborn mannequin correctly before initial training but 97% passed the post-initial ventilation training test (p < 0.0001) and 99% passed the OSCE B resuscitation evaluation. During pre-refresher training evaluation, a mean of 6.7 (SD 2.49) months after the initial training, 99% passed the knowledge test, but the successful completion rate fell to 81% for the OSCE B resuscitation skills test. Characteristics associated with deterioration of resuscitation skills were BAs from tertiary care facilities, no prior resuscitation training, and the timing of training (initial vs. catch-up training). Conclusions: HBB training significantly improved neonatal resuscitation knowledge and skills. However, skills declined more than knowledge over time. Ongoing skills practice and monitoring, more frequent retesting, and refresher trainings are needed to maintain neonatal resuscitation skills. C1 [Bang, Akash; Jain, Manish] Mahatma Gandhi Inst Med Sci, Sevagram, India. [Patel, Archana] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Bellad, Roopa; Goudar, Shivaprasad S.; Mahantshetti, Niranjana; Dhaded, Sangappa; Bhandankar, Manisha] KLE Univ, JN Med Coll, Belgaum, India. [Gisore, Peter; Esamai, Fabian; Rukunga, Janet] Moi Univ, Moi Teaching & Referral Hosp, Eldoret, Kenya. [Liechty, Edward A.; Bucher, Sherri] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Meleth, Sreelatha; Goco, Norman; McClure, Elizabeth M.] RTI Int, Durham, NC USA. [Niermeyer, Susan] Univ Colorado, Sch Med, Aurora, CO USA. [Keenan, William] St Louis Univ, St Louis, MO 63103 USA. [Kamath-Rayne, Beena D.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Little, George A.; Flanagan, Victoria A.] Geisel Sch Med Dartmouth, Lebanon, NH USA. [Clarke, Susan B.] Childrens Hosp Colorado, Aurora, CO USA. [Mujawar, Nilofer] NKP Salve Inst Med Sci, Nagpur, Maharashtra, India. [Jain, Vinita] Daga Mem Govt Womens Hosp, Nagpur, Maharashtra, India. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Wright, Linda L.] George Washington Univ, 5800 Nicholson Lane,1206, Rockville, MD 20852 USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Wright, LL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA.; Wright, LL (reprint author), George Washington Univ, 5800 Nicholson Lane,1206, Rockville, MD 20852 USA. EM lindawright.md@gmail.com FU Laerdal Foundation; Norwegian Agency for Development Cooperation (Norad); NICHD [U01 HD040636, U01 HD058322, U10 HD078439, HD U01058326, U01 HD058326-04S1, U10 HD076461, U01 HD042372, U10 HD076457] FX This study was funded with grants from the Laerdal Foundation, Norwegian Agency for Development Cooperation (Norad), and the NICHD (grant numbers U01 HD040636; U01 HD058322 and U10 HD078439; HD U01058326; U01 HD058326-04S1, U10 HD076461, U01 HD042372, U10 HD076457). NR 33 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD NOV 22 PY 2016 VL 16 AR 364 DI 10.1186/s12884-016-1141-3 PG 12 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EC8XU UT WOS:000388427200002 PM 27875999 ER PT J AU Bonaca, MP Wiviott, SD AF Bonaca, Marc P. Wiviott, Stephen D. TI Prasugrel Versus Ticagrelor Uncertainty Remains SO CIRCULATION LA English DT Editorial Material DE Editorials; acute coronary syndromes; antiplatelet; clinical trial; myocardial ischemia; P2Y12 inhibitor; stent ID ACUTE CORONARY SYNDROMES; CLOPIDOGREL C1 [Bonaca, Marc P.; Wiviott, Stephen D.] Brigham & Womens Hosp, Heart & Vasc Ctr, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. RP Wiviott, SD (reprint author), Brigham & Womens Hosp, Cardiovasc Div, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM swiviott@partners.org NR 5 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD NOV 22 PY 2016 VL 134 IS 21 BP 1613 EP 1616 DI 10.1161/CIRCULATIONAHA.116.025113 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EC9LQ UT WOS:000388466500010 PM 27881505 ER PT J AU El-Jawahri, A LeBlanc, T VanDusen, H Traeger, L Greer, JA Pirl, WF Jackson, VA Telles, J Rhodes, A Spitzer, TR McAfee, S Chen, YBA Lee, SJ Temel, JS AF El-Jawahri, Areej LeBlanc, Thomas VanDusen, Harry Traeger, Lara Greer, Joseph A. Pirl, William F. Jackson, Vicki A. Telles, Jason Rhodes, Alison Spitzer, Thomas R. McAfee, Steven Chen, Yi-Bin A. Lee, Stephanie J. Temel, Jennifer S. TI Effect of Inpatient Palliative Care on Quality of Life 2 Weeks After Hematopoietic Stem Cell Transplantation A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BONE-MARROW-TRANSPLANTATION; CANCER-TREATMENT; ONCOLOGY; PATIENT; INTERVENTION; SPECIALIST; CAREGIVERS; DISTRESS; RECOVERY; OUTCOMES AB IMPORTANCE During hospitalization for hematopoietic stem cell transplantation (HCT), patients receive high-dose chemotherapy before transplantation and experience significant physical and psychological symptoms and poor quality of life (QOL). OBJECTIVE To assess the effect of inpatient palliative care on patient-and caregiver-reported outcomes during hospitalization for HCT and 3 months after transplantation. DESIGN, SETTING, AND PARTICIPANTS Nonblinded randomized clinical trial among 160 adults with hematologic malignancies undergoing autologous/allogeneic HCT and their caregivers (n = 94). The study was conducted from August 2014 to January 2016 in a Boston hospital; follow-up was completed in May 2016. INTERVENTIONS Patients assigned to the intervention (n= 81) were seen by palliative care clinicians at least twice a week during HCT hospitalization; the palliative intervention was focused on management of physical and psychological symptoms. Patients assigned to standard transplant care (n= 79) could be seen by palliative care clinicians on request. MAIN OUTCOMES AND MEASURES Primary: change in patient QOL from baseline to week 2; secondary: patient-assessed mood, fatigue, and symptom burden scores at baseline, 2 weeks, and 3 months after HCT and caregiver-assessed QOL and mood at baseline and 2 weeks after HCT. RESULTS Among 160 patients (mean age, 60[SD, 13.3] years; 91 women[56.9%]; median hospital stay, 21 days) and 94 caregivers, 157(98.1%) and 89(94.7%), respectively, completed 2-week follow-up, and 149 patients(93.1%) completed 3-month follow-up. Intervention patients reported a smaller decrease in QOL from baseline to week 2 vs controls. Intervention patients had less increase in depression, lower anxiety, no difference in fatigue, and less increase in symptom burden. At 3 months, intervention patients had higher QOL and less depression but no significant differences in anxiety, fatigue, or symptom burden. From baseline to week 2 after HCT, caregivers of intervention patients vs controls reported no significant differences in QOL or anxiety but had a smaller increase in depression (mean, 0.25 vs 1.80; mean difference, 1.55; 95% CI, 0.14-2.96; P =.03). [GRAPHICS] CONCLUSIONS AND RELEVANCE Among adults at a single institution undergoing HCT for hematologic malignancy, the use of inpatient palliative care compared with standard transplant care resulted in a smaller decrease in QOL 2 weeks after transplantation. Further research is needed for replication and to assess longer-term outcomes and cost implications. C1 [El-Jawahri, Areej; VanDusen, Harry; Traeger, Lara; Greer, Joseph A.; Pirl, William F.; Jackson, Vicki A.; Telles, Jason; Rhodes, Alison; Spitzer, Thomas R.; McAfee, Steven; Chen, Yi-Bin A.; Temel, Jennifer S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [El-Jawahri, Areej; VanDusen, Harry; Traeger, Lara; Greer, Joseph A.; Pirl, William F.; Jackson, Vicki A.; Telles, Jason; Rhodes, Alison; Spitzer, Thomas R.; McAfee, Steven; Chen, Yi-Bin A.; Temel, Jennifer S.] Harvard Med Sch, Boston, MA USA. [LeBlanc, Thomas] Duke Univ, Sch Med, Durham, NC USA. [Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. RP El-Jawahri, A (reprint author), Dept Hematol Oncol, Bone Marrow Transplant Program, 55 Fruit St,Cox 120, Boston, MA 02114 USA. EM ael-jawahri@partners.org FU NCI NIH HHS [K12 CA087723, K24 CA181253] NR 29 TC 2 Z9 2 U1 11 U2 11 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 NOV 22 PY 2016 VL 316 IS 20 BP 2094 EP 2103 DI 10.1001/jama.2016.16786 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA ED1XD UT WOS:000388637300017 PM 27893130 ER PT J AU Kavousi, M Desai, CS Ayers, C Blumenthal, RS Budoff, MJ Mahabadi, AA Ikram, MA van der Lugt, A Hofman, A Erbel, R Khera, A Geisel, MH Jockel, KH Lehmann, N Hoffmann, U O'Donnell, CJ Massaro, JM Liu, K Mohlenkamp, S Ning, HY Franco, OH Greenland, P AF Kavousi, Maryam Desai, Chintan S. Ayers, Colby Blumenthal, Roger S. Budoff, Matthew J. Mahabadi, Amir-Abbas Ikram, M. Arfan van der Lugt, Aad Hofman, Albert Erbel, Raimund Khera, Amit Geisel, Marie H. Joeckel, Karl-Heinz Lehmann, Nils Hoffmann, Udo O'Donnell, Christopher J. Massaro, Joseph M. Liu, Kiang Moehlenkamp, Stefan Ning, Hongyan Franco, Oscar H. Greenland, Philip TI Prevalence and Prognostic Implications of Coronary Artery Calcification in Low-Risk Women A Meta-analysis SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HEART-DISEASE; CARDIOVASCULAR-DISEASE; STATIN THERAPY; CALCIUM SCORE; PREDICTION; DESIGN; CLASSIFICATION; INDIVIDUALS; PREVENTION; MARKERS AB IMPORTANCE The role of coronary artery calcium (CAC) testing for guiding preventive strategies among women at low cardiovascular disease (CVD) risk based on the American College of Cardiology and American Heart Association CVD prevention guidelines is unclear. OBJECTIVE To assess the potential utility of CAC testing for CVD risk estimation and stratification among low-risk women. DESIGN, SETTING, AND PARTICIPANTS Women with 10-year atherosclerotic CVD (ASCVD) risk lower than 7.5% from 5 large population-based cohorts: the Dallas Heart Study (United States), the Framingham Heart Study (United States), the Heinz Nixdorf Recall study (Germany), the Multi-Ethnic Study of Atherosclerosis (United States), and the Rotterdam Study (the Netherlands). The 5 cohorts were selected based on the availability of CAC data in a sizable group of low-risk women from the general population together with the long detailed follow-up data. Across the cohorts, events were assessed from the date of CAC scan (performed from 1998 through 2006) until January 1, 2012; January 1, 2014; or March 6, 2015. Fixed-effects meta-analysis was conducted to combine the results of the 5 studies. EXPOSURES CAC score by computed tomography. MAIN OUTCOMES AND MEASURES Main outcome was incident ASCVD, including nonfatal myocardial infarction, coronary heart disease (CHD) death, and stroke. Association of CAC with ASCVD was examined using Cox proportional hazards models. To assess whether CAC was associated with improved ASCVD risk predictions beyond the traditional risk factors, the C statistic and the continuous net reclassification improvement (cNRI) index were calculated. RESULTS Among 6739 women with low ASCVD risk from the 5 studies, mean age ranged from 44 to 63 years and CAC was present in 36.1%. Across the cohorts, median follow-up ranged from 7.0 to 11.6 years. A total of 165 ASCVD events occurred (64 nonfatal myocardial infarctions, 29 CHD deaths, and 72 strokes), with the ASCVD incidence rates ranging from 1.5 to 6.0 per 1000 person-years. Compared with the absence of CAC (CAC = 0), presence of CAC (CAC > 0) was associated with an increased risk of ASCVD (incidence rates per 1000 person-years, 1.41 for CAC absence vs 4.33 for CAC presence; difference, 2.92 [95% CI, 2.02-3.83]; multivariable-adjusted hazard ratio, 2.04 [95% CI, 1.44-2.90]). The addition of CAC to traditional risk factors improved the C statistic from 0.73 (95% CI, 0.69-0.77) to 0.77 (95% CI, 0.74-0.81) and provided a cNRI of 0.20 (95% CI, 0.09-0.31) for ASCVD prediction. CONCLUSIONS AND RELEVANCE Among women at low ASCVD risk, CAC was present in approximately one-third and was associated with an increased risk of ASCVD and modest improvement in prognostic accuracy compared with traditional risk factors. Further research is needed to assess the clinical utility and cost-effectiveness of this additional accuracy. C1 [Kavousi, Maryam; Ikram, M. Arfan; Hofman, Albert; Franco, Oscar H.] Erasmus Univ, Med Ctr, Dept Epidemiol, Off Na 2906,POB 2040, NL-3000 CA Rotterdam, Netherlands. [Desai, Chintan S.; Blumenthal, Roger S.] Johns Hopkins Med Inst, Div Cardiol, Ciccarone Ctr Prevent Heart Dis, Baltimore, MD 21205 USA. [Ayers, Colby] Univ Texas Southwestern Med Ctr Dallas, Div Clin Sci, Dallas, TX 75390 USA. [Budoff, Matthew J.] Harbor Univ Calif Los Angeles Med Ctr, Los Angeles Biomed Res Inst, Div Cardiol, Los Angeles, CA USA. [Mahabadi, Amir-Abbas] Univ Clin Essen, West German Heart & Vasc Ctr, Dept Cardiol, Essen, Germany. [Ikram, M. Arfan; van der Lugt, Aad] Erasmus Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands. [Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Neurol, Rotterdam, Netherlands. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Erbel, Raimund; Geisel, Marie H.; Joeckel, Karl-Heinz; Lehmann, Nils] Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Khera, Amit] Univ Texas Southwestern Med Ctr Dallas, Div Cardiol, Dallas, TX 75390 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Dept Radiol, Boston, MA 02114 USA. [Hoffmann, Udo] Harvard Med Sch, Boston, MA USA. [O'Donnell, Christopher J.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA USA. [O'Donnell, Christopher J.; Massaro, Joseph M.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Donnell, Christopher J.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Liu, Kiang; Ning, Hongyan; Greenland, Philip] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Moehlenkamp, Stefan] Krankenhaus Bethanien, Dept Cardiol, Moers, Germany. RP Kavousi, M (reprint author), Erasmus Univ, Med Ctr, Dept Epidemiol, Off Na 2906,POB 2040, NL-3000 CA Rotterdam, Netherlands. EM m.kavousi@erasmusmc.nl FU NCATS NIH HHS [UL1 TR000040, UL1 TR001105]; NHLBI NIH HHS [R01 HL076784, N01 HC025195, R01 HL060040, R01 HL070100, R01 HL071039, R01 HL077447, R01 HL080124, R01 HL107385]; NIA NIH HHS [R01 AG028321] NR 34 TC 1 Z9 1 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 NOV 22 PY 2016 VL 316 IS 20 BP 2126 EP 2134 DI 10.1001/jama.2016.17020 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA ED1XD UT WOS:000388637300020 PM 27846641 ER PT J AU Killian, NJ Vurro, M Keith, SB Kyada, MJ Pezaris, JS AF Killian, Nathaniel J. Vurro, Milena Keith, Sarah B. Kyada, Margee J. Pezaris, John S. TI Perceptual learning in a non-human primate model of artificial vision SO SCIENTIFIC REPORTS LA English DT Article ID LATERAL GENICULATE-NUCLEUS; VISUAL CORTICAL AREAS; PROSTHETIC VISION; VIRTUAL-REALITY; CORTEX; SIMULATION; ATTENTION; ACUITY; CONNECTIONS; MONKEYS AB Visual perceptual grouping, the process of forming global percepts from discrete elements, is experience-dependent. Here we show that the learning time course in an animal model of artificial vision is predicted primarily from the density of visual elements. Three naive adult non-human primates were tasked with recognizing the letters of the Roman alphabet presented at variable size and visualized through patterns of discrete visual elements, specifically, simulated phosphenes mimicking a thalamic visual prosthesis. The animals viewed a spatially static letter using a gaze-contingent pattern and then chose, by gaze fixation, between a matching letter and a non-matching distractor. Months of learning were required for the animals to recognize letters using simulated phosphene vision. Learning rates increased in proportion to the mean density of the phosphenes in each pattern. Furthermore, skill acquisition transferred from trained to untrained patterns, not depending on the precise retinal layout of the simulated phosphenes. Taken together, the findings suggest that learning of perceptual grouping in a gaze-contingent visual prosthesis can be described simply by the density of visual activation. C1 [Killian, Nathaniel J.; Vurro, Milena; Keith, Sarah B.; Kyada, Margee J.; Pezaris, John S.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Killian, Nathaniel J.; Vurro, Milena; Keith, Sarah B.; Kyada, Margee J.; Pezaris, John S.] Harvard Med Sch, Dept Neurosurg, Boston, MA 02115 USA. RP Killian, NJ; Pezaris, JS (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA.; Killian, NJ; Pezaris, JS (reprint author), Harvard Med Sch, Dept Neurosurg, Boston, MA 02115 USA. EM nkillian@mgh.harvard.edu; john@pezlab.org FU National Eye Institute of National Institutes of Health [R01EY019679, F32EY025542] FX Research reported in this publication was supported by the National Eye Institute of the National Institutes of Health under Awards R01EY019679 to JP and F32EY025542 to NK. The Rappaport Foundation, The NIMA Foundation, Peter D. Pezaris, and William and Lori Goldenthal. The content is solely the responsibility of the authors and does not necessarily represent official views of the sponsors. NR 55 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 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 22 PY 2016 VL 6 AR 36329 DI 10.1038/srep36329 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC6BP UT WOS:000388221500001 PM 27874058 ER PT J AU Januzzi, JL AF Januzzi, James L. TI Troponins in equipoise SO EUROPEAN HEART JOURNAL LA English DT Editorial Material ID MYOCARDIAL-INFARCTION; DIAGNOSIS C1 [Januzzi, James L.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Januzzi, James L.] Harvard Clin Res Inst, Boston, MA USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. EM jjanuzzi@partners.org FU Hutter Family Professorship at Harvard Medical School FX This work was supported in part by the Hutter Family Professorship at Harvard Medical School. NR 7 TC 0 Z9 0 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 NOV 21 PY 2016 VL 37 IS 44 BP 3333 EP 3334 DI 10.1093/eurheartj/ehw355 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EK5RQ UT WOS:000393983900012 PM 27581970 ER PT J AU Fast, EM Zon, LI AF Fast, Eva Maria Zon, Leonard Ira TI Aging Hematopoietic Stem Cells Make Their History SO DEVELOPMENTAL CELL LA English DT Editorial Material ID HOMEOSTASIS C1 [Fast, Eva Maria; Zon, Leonard Ira] Harvard Med Sch, Dana Farber Canc Inst, Howard Hughes Med Inst, Stem Cell Program,Boston Childrens Hosp, Boston, MA 02115 USA. [Fast, Eva Maria; Zon, Leonard Ira] Harvard Med Sch, Dana Farber Canc Inst, Div Pediat Hematol Oncol, Boston Childrens Hosp, Boston, MA 02115 USA. [Fast, Eva Maria; Zon, Leonard Ira] Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Zon, LI (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Howard Hughes Med Inst, Stem Cell Program,Boston Childrens Hosp, Boston, MA 02115 USA.; Zon, LI (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Div Pediat Hematol Oncol, Boston Childrens Hosp, Boston, MA 02115 USA.; Zon, LI (reprint author), Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. EM zon@enders.tch.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 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD NOV 21 PY 2016 VL 39 IS 4 BP 390 EP 391 DI 10.1016/j.devce1.2016.11.005 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA ED9AQ UT WOS:000389162800004 PM 27875682 ER PT J AU Kim, H AF Kim, Hwijin TI The transcription cofactor CRTC1 protects from aberrant hepatic lipid accumulation SO SCIENTIFIC REPORTS LA English DT Article ID FATTY LIVER-DISEASE; FARNESOID X RECEPTOR; INSULIN-RESISTANCE; NONALCOHOLIC STEATOHEPATITIS; OBETICHOLIC ACID; ENERGY-BALANCE; SIRTUIN 1; METABOLISM; STEATOSIS; MICE AB Nonalcoholic fatty liver disease (NAFLD) is a rapidly emerging global health-problem. NAFLD encompasses a range of conditions associated with hepatic steatosis, aberrant accumulation of fat in hepatocytes. Although obesity and metabolic syndrome are considered to have a strong association with NAFLD, genetic factors that predispose liver to NAFLD and molecular mechanisms by which excess hepatic lipid develops remain largely unknown. We report that the transcription cofactor CRTC1 confers broad spectrum protection against hepatic steatosis development. CRTC1 directly interferes with the expression of genes regulated by lipogenic transcription factors, most prominently liver x receptor alpha (LXR alpha). Accordingly, Crtc1 deficient mice develop spontaneous hepatic steatosis in young age. As a cyclic AMP effector, CRTC1 mediates anti-steatotic effects of calorie restriction (CR). Notably, CRTC1 also mediates anti-lipogenic effects of bile acid signaling, whereas it is negatively regulated by miR-34a, a pathogenic microRNA upregulated in a broad spectrum of NAFLD. These patterns of gene function and regulation of CRTC1 are distinct from other CR-responsive proteins, highlighting critical protective roles that CRTC1 selectively plays against NAFLD development, which in turn provides novel opportunities for selectively targeting beneficial therapeutic effects of CR. C1 [Kim, Hwijin] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Kim, Hwijin] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. RP Kim, H (reprint author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA.; Kim, H (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. EM hwijinkim@gmail.com FU Brian Seed FX We thank Brian Seed for financial supports, and Rasma Niedra, Parimal Korgaonkar and Naifang Lu for experimental assistance. NR 45 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 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 21 PY 2016 VL 6 AR 37280 DI 10.1038/srep37280 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC5HH UT WOS:000388163500001 PM 27869139 ER PT J AU Alam, S Elwyn, G Percac-Lima, S Grande, S Durand, MA AF Alam, Shama Elwyn, Glyn Percac-Lima, Sanja Grande, Stuart Durand, Marie-Anne TI Assessing the acceptability and feasibility of encounter decision aids for early stage breast cancer targeted at underserved patients SO BMC MEDICAL INFORMATICS AND DECISION MAKING LA English DT Article DE Decision aids; Encounter decision aids; Health disparities; Breast cancer; Low socioeconomic status; Acceptability; Feasibility ID CHOICE RANDOMIZED-TRIAL; DIABETES-MELLITUS; TREATMENT OPTIONS; DISPARITIES; COMMUNICATION; INFORMATION; SURGERY; WOMEN; COMPREHENSION; OUTCOMES AB Background: Women of low socioeconomic status (SES) diagnosed with early stage breast cancer are less likely to be involved in treatment decisions. They tend to report higher decisional regret and poorer communication. Evidence suggests that well-designed encounter decision aids (DAs) could improve outcomes and potentially reduce healthcare disparities. Our goal was to evaluate the acceptability and feasibility of encounter decision aids (Option Grid, Comic Option Grid, and Picture Option Grid) adapted for a low-SES and low-literacy population. Methods: We used a multi-phase, mixed-methods approach. In phase 1, we conducted a focus group with rural community stakeholders. In phase 2, we developed and administered a web-based questionnaire with patients of low and high SES. In phase 3, we interviewed patients of low SES and relevant healthcare professionals. Results: Data from phase 1 (n = 5) highlighted the importance of addressing treatment costs for patients. Data from phase 2 (n = 268) and phase 3 (n = 15) indicated that using both visual displays and numbers are helpful for understanding statistical information. Data from all three phases suggested that using plain language and simple images (Picture Option Grid) was most acceptable and feasible. The Comic Option Grid was deemed least acceptable. Conclusion: Option Grid and Picture Option Grid appeared acceptable and feasible in facilitating patient involvement and improving perceived understanding among patients of high and low SES. Picture Option Grid was considered most acceptable, accessible and feasible in the clinic visit. However, given the small sample sizes used, those findings need to be interpreted with caution. Further research is needed to determine the impact of pictorial and text-based encounter decision aids in underserved patients and across socioeconomic strata. C1 [Alam, Shama; Elwyn, Glyn; Grande, Stuart; Durand, Marie-Anne] Dartmouth Inst Hlth Policy & Clin Practice, Level 5,Williamson Translat Res Bldg, Lebanon, NH 03756 USA. [Percac-Lima, Sanja] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Percac-Lima, Sanja] Harvard Med Sch, Boston, MA USA. RP Durand, MA (reprint author), Dartmouth Inst Hlth Policy & Clin Practice, Level 5,Williamson Translat Res Bldg, Lebanon, NH 03756 USA. EM marie-anne.durand@dartmouth.edu NR 37 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 1472-6947 J9 BMC MED INFORM DECIS JI BMC Med. Inform. Decis. Mak. PD NOV 21 PY 2016 VL 16 AR 147 DI 10.1186/s12911-016-0384-2 PG 13 WC Medical Informatics SC Medical Informatics GA EC4RF UT WOS:000388120400001 PM 27871271 ER PT J AU Doolan, PJ Collins-Fekete, CA Dias, MF Ruggieri, TA D'Souza, D Seco, J AF Doolan, P. J. Collins-Fekete, Charles-Antoine Dias, Marta F. Ruggieri, Thomas A. D'Souza, Derek Seco, Joao TI Inter-comparison of relative stopping power estimation models for proton therapy SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE proton therapy; relative stopping power; range uncertainty ID MONTE-CARLO SIMULATIONS; CT-HOUNSFIELD UNITS; COMPUTED-TOMOGRAPHY; STOICHIOMETRIC CALIBRATION; RANGE UNCERTAINTIES; BONE MODELS; RADIOGRAPHY; WATER; TISSUE; BEAMS AB Theoretical stopping power values were inter-compared for the Bichsel, Janni, ICRU and Schneider relative stopping power ( RSP) estimation models, for a variety of tissues and tissue substitute materials taken from the literature. The RSPs of eleven plastic tissue substitutes were measured using Bragg peak shift measurements in water in order to establish a gold standard of RSP values specific to our centre's proton beam characteristics. The theoretical tissue substitute RSP values were computed based on literature compositions to assess the four different computation approaches. The Bichsel/Janni/ICRU approaches led to mean errors in the RSP of -0.1/+0.7/-0.8%, respectively. Errors when using the Schneider approach, with I-values from the Bichsel, Janni and ICRU sources, followed the same pattern but were generally larger. Following this, the mean elemental ionisation energies were optimized until the differences between theoretical RSP values matched measurements. Failing to use optimized I-values when applying the Schneider technique to 72 human tissues could introduce errors in the RSP of up to -1.7/+ 1.1/-0.4% when using Bichsel/Janni/ICRU I-values, respectively. As such, it may be necessary to introduce an additional step in the current stoichiometric calibration procedure in which tissue insert RSPs are measured in a proton beam. Elemental I-values can then optimized to match these measurements, reducing the uncertainty when calculating human tissue RSPs. C1 [Doolan, P. J.; D'Souza, Derek] Univ Coll London Hosp, Dept Radiotherapy Phys, London, England. [Collins-Fekete, Charles-Antoine; Dias, Marta F.; Ruggieri, Thomas A.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Collins-Fekete, Charles-Antoine] Univ Laval, Dept Phys Genie Phys & Opt, Quebec City, PQ, Canada. [Collins-Fekete, Charles-Antoine] Univ Laval, Ctr Rech Canc, Quebec City, PQ, Canada. [Dias, Marta F.] Politecn Milan, DEIB, Milan, Italy. [Seco, Joao] Heidelberg Univ, DKFZ German Canc Res Ctr, Dept Med Phys Radiooncol, Heidelberg, Germany. [Seco, Joao] Heidelberg Univ, Dept Phys & Astron, Heidelberg, Germany. RP Doolan, PJ (reprint author), Univ Coll London Hosp, Dept Radiotherapy Phys, London, England. EM paul.doolan@uclh.nhs.uk FU Engineering and Physical Sciences Research Council (UK); Ion Beam Applications (Louvain-La-Neuve, Belgium) FX This project was funded equally by the Engineering and Physical Sciences Research Council (UK) and Ion Beam Applications (Louvain-La-Neuve, Belgium). We would like to acknowledge the support of Dr Hsiao-Ming Lu of Massachusetts General Hospital, for his help in facilitating the project. We would also like to acknowledge Paige Taylor from IROC Houston, who provided information of the current use of the stoichiometric calibration. NR 47 TC 0 Z9 0 U1 3 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD NOV 21 PY 2016 VL 61 IS 22 DI 10.1088/0031-9155/61/22/8085 PG 20 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA EB3AI UT WOS:000387233300001 PM 27781999 ER PT J AU Lee, J Gursoy-Ozdemir, Y Fu, BY Boas, DA Dalkara, T AF Lee, Jonghwan Gursoy-Ozdemir, Yasemin Fu, Buyin Boas, David A. Dalkara, Turgay TI Optical coherence tomography imaging of capillary reperfusion after ischemic stroke SO APPLIED OPTICS LA English DT Article ID CEREBRAL-BLOOD-FLOW; ENDOVASCULAR REPERFUSION; POOLED ANALYSIS; RAT; THERAPY; NETWORK; EPITHET; REFLOW; ARTERY; TIME AB Although progress has been made for recanalization therapies after ischemic stroke, post-treatment imaging studies show that tissue reperfusion cannot be attained despite satisfactory recanalization in a significant percentage of patients. Hence, investigation of microcirculatory changes in both surface and deep cortical levels after ischemia reperfusion is important for understanding the post-stroke blood flow dynamics. In this study, we applied optical coherence tomography (OCT) imaging of cerebral blood flow for the quantification of the microcirculatory changes. We obtained OCT microangiogram of the brain cortex in a mouse stroke model and analyzed the data to trace changes in the capillary perfusion level (CPL) before, during, and after the stroke. The CPL changes were estimated in 1 and 2 h ischemia groups as well as in a non-ischemic sham-operated group. For the estimation of CPL, a decorrelation amplitude-based algorithm was implemented and used. As a result, the CPL considerably decreased during ischemia but recovered to the baseline when recanalization was performed 1 h after ischemia; however, the CPL was significantly reduced when recanalization was delayed to 2 h after ischemia. These data demonstrate that ischemia causes microcirculation dysfunction, leading to a decreased capillary reperfusion after recanalization. Microcirculatory no-reflow warrants more rigorous assessment in clinical trials, whereas advanced optical imaging techniques may provide mechanistic insight and solutions in experimental studies. (C) 2016 Optical Society of America C1 [Lee, Jonghwan] Brown Univ, Inst Brain Sci, Sch Engn, Providence, RI 02912 USA. [Gursoy-Ozdemir, Yasemin] Koc Univ, Dept Neurol, Sch Med, Istanbul, Turkey. [Gursoy-Ozdemir, Yasemin; Dalkara, Turgay] Hacettepe Univ, Inst Neurol Sci & Psychiat, Fac Med, Ankara, Turkey. [Gursoy-Ozdemir, Yasemin; Dalkara, Turgay] Hacettepe Univ, Fac Med, Dept Neurol, Ankara, Turkey. [Fu, Buyin; Boas, David A.] Harvard Med Sch, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Lee, J (reprint author), Brown Univ, Inst Brain Sci, Sch Engn, Providence, RI 02912 USA. EM jonghwan_lee@brown.edu; ygursoy@ku.edu.tr FU National Institute of Biomedical Imaging and Bioengineering (NIBIB) [R00-EB014879, R01-EB000790]; National Institute of Neurological Disorders and Stroke (NINDS) [P01-NS055104]; Air Force Office of Scientific Research (AFOSR) [MFEL FA9550-07-1-0101] FX National Institute of Biomedical Imaging and Bioengineering (NIBIB) (R00-EB014879, R01-EB000790); National Institute of Neurological Disorders and Stroke (NINDS) (P01-NS055104); Air Force Office of Scientific Research (AFOSR) (MFEL FA9550-07-1-0101). NR 22 TC 0 Z9 0 U1 2 U2 2 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1559-128X EI 2155-3165 J9 APPL OPTICS JI Appl. Optics PD NOV 20 PY 2016 VL 55 IS 33 BP 9526 EP 9531 DI 10.1364/AO.55.009526 PG 6 WC Optics SC Optics GA ED6AQ UT WOS:000388936300026 PM 27869849 ER PT J AU Rose, BS Winer, EP Mamon, HJ AF Rose, Brent S. Winer, Eric P. Mamon, Harvey J. TI Perils of the Pathologic Complete Response SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID OPERABLE BREAST-CANCER; DOSE-INTENSIFIED CHEMOTHERAPY; SURGICAL ADJUVANT BREAST; ADVANCED RECTAL-CANCER; NEOADJUVANT CHEMOTHERAPY; PREOPERATIVE CHEMOTHERAPY; DARBEPOETIN ALPHA; ANTICANCER DRUGS; RANDOMIZED-TRIAL; PREPARE TRIAL C1 [Rose, Brent S.] Harvard Radiat Oncol Program, Boston, MA 02115 USA. [Winer, Eric P.; Mamon, Harvey J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Mamon, Harvey J.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Rose, BS (reprint author), Harvard Radiat Oncol Program, Boston, MA 02115 USA. NR 43 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 20 PY 2016 VL 34 IS 33 BP 3959 EP U40 DI 10.1200/JCO.2016.68.1718 PG 5 WC Oncology SC Oncology GA ED5XU UT WOS:000388927700003 PM 27551115 ER PT J AU Raldow, AC Sher, D Chen, AB Recht, A Punglia, RS AF Raldow, Ann C. Sher, David Chen, Aileen B. Recht, Abram Punglia, Rinaa S. TI Cost Effectiveness of the Oncotype DX DCIS Score for Guiding Treatment of PatientsWith Ductal Carcinoma In Situ SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BREAST-CONSERVING TREATMENT; RECEIVE RADIATION-THERAPY; GENE-EXPRESSION; RECURRENCE RISK; CANCER; RADIOTHERAPY; POPULATION; WOMEN; TAMOXIFEN; SURGERY AB Purpose The Oncotype DX DCIS Score short form (DCIS Score) estimates the risk of an ipsilateral breast event (IBE) in patients with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery without adjuvant radiation therapy (RT). We determined the cost effectiveness of strategies using this test. Materials and Methods We developed a Markov model simulating 10-year outcomes for 60-year-old women eligible for the Eastern Cooperative Oncology Group E5194 study (cohort 1: low/intermediate-grade DCIS, # 2.5 cm; cohort 2: high-grade DCIS,# 1 cm) with each of five strategies: (1) no testing, no RT; (2) no testing, RT only for cohort 2; (3) no RT for low-grade DCIS, test for intermediate-and high-grade DCIS, RT for intermediate-or high-risk scores; (4) test all, RT for intermediate-or high-risk scores; and (5) no testing, RT for all. We used utilities and costs extracted from the literature and Medicare claims to determine incremental cost-effectiveness ratios and examined the number of women needed to irradiate per IBE prevented. Results No strategy using the DCIS Score was cost effective. The most cost-effective strategy (RT for none or RT for all) was sensitive to small differences between the utilities of receiving or not receiving RT and remaining without recurrence. The numbers needed to irradiate per IBE prevented were 10.5, 9.1, 7.5, and 13.1 for strategies 2 to 5, respectively, relative to strategy 1. Conclusion Strategies using the DCIS Score lowered the proportion of women undergoing RT per IBE prevented. However, no strategy incorporating the DCIS Score was cost effective. The cost effectiveness of RT was exquisitely utility sensitive, highlighting the importance of engaging patient preferences in this decision. Physicians should discuss trade-offs associated with omitting or adding adjuvant RT with each patient to maximize quality-of-life outcomes. (C) 2016 by American Society of Clinical Oncology C1 [Raldow, Ann C.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Chen, Aileen B.; Punglia, Rinaa S.] Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. [Recht, Abram] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Sher, David] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. RP Punglia, RS (reprint author), Dana Farber Canc Inst, Ctr Outcomes & Policy Res, 450 Brookline Ave, Boston, MA 02115 USA. EM rpunglia@partners.org NR 26 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 20 PY 2016 VL 34 IS 33 BP 3963 EP U49 DI 10.1200/JCO.2016.67.8532 PG 9 WC Oncology SC Oncology GA ED5XU UT WOS:000388927700004 ER PT J AU Sullivan, DR Forsberg, CW Ganzini, L Au, DH Gould, MK Provenzale, D Slatore, CG AF Sullivan, Donald R. Forsberg, Christopher W. Ganzini, Linda Au, David H. Gould, Michael K. Provenzale, Dawn Slatore, Christopher G. TI Longitudinal Changes in Depression Symptoms and Survival Among Patients With Lung Cancer: A National Cohort Assessment SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; INTEGRATED COLLABORATIVE CARE; MAJOR DEPRESSION; OLDER-ADULTS; PSYCHOLOGICAL DISTRESS; OUTCOMES RESEARCH; SUPPORTIVE CARE; BREAST-CANCER; PREVALENCE; ANXIETY AB Purpose Depression symptoms are common among patients with lung cancer patients; however, longitudinal changes and their impact on survival are understudied. Methods This was a prospective, observational study from the Cancer Care Outcomes Research and Surveillance Consortium from five US geographically defined regions from September 2003 through December 2005. Patients enrolled within 3 months of their lung cancer diagnosis were eligible. The eight-item Center for Epidemiologic Studies Depression scale was administered at diagnosis and 12 months' follow-up. The main outcome was survival, which was evaluated using Kaplan-Meyer curves and adjusted Cox proportional hazards modeling. Results Among 1,790 participants, 681 (38%) had depression symptoms at baseline and an additional 105 (14%) developed new-onset depression symptoms during treatment. At baseline, depression symptomswere associated with increased mortality (hazard ratio [HR], 1.17; 95% CI, 1.03 to 1.32; P =.01). Participants were classified into the following four groups based on longitudinal changes in depression symptoms from baseline to follow-up: never depression symptoms (n = 640), new-onset depression symptoms (n = 105), depression symptom remission (n = 156), and persistent depression symptoms (n = 254) and HRs were calculated. Using the never-depression symptoms group as a reference group, HRs were as follows: new-onset depression symptoms, 1.50 (95% CI, 1.12 to 2.01; P =.006); depression symptom remission, 1.02 (95% CI, 0.79 to 1.31; P =.89), and persistent depression symptoms, 1.42 (95% CI, 1.15 to 1.75; P =.001). At baseline, depression symptoms were associated with increased mortality among participants with early-stage disease (stages I and II; HR, 1.61; 95% CI, 1.26 to 2.04), but not late-stage disease (stages III and IV; HR, 1.05; 95% CI, 0.91 to 1.22). At follow-up, depression symptoms were associated with increasedmortality among participants with early-stage disease (HR, 1.71; 95% CI, 1.27 to 2.31) and those with late-stage disease (HR, 1.32; 95% CI, 1.04 to 1.69). Conclusion Among patients with lung cancer, longitudinal changes in depression symptoms are associated with differences in mortality, particularly among patients with early-stage disease. Symptom remission is associated with a similar mortality rate as never having had depression. (C) 2016 by American Society of Clinical Oncology C1 [Sullivan, Donald R.; Ganzini, Linda; Slatore, Christopher G.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Sullivan, Donald R.; Forsberg, Christopher W.; Ganzini, Linda; Slatore, Christopher G.] Vet Affairs Portland Hlth Care Syst, Portland, OR USA. [Au, David H.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Au, David H.] Univ Washington, Seattle, WA 98195 USA. [Gould, Michael K.] Kaiser Permanente Southern Calif, Pasadena, CA USA. [Gould, Michael K.] Univ Southern Calif, Los Angeles, CA USA. [Provenzale, Dawn] Durham VA Med Ctr, Durham, NC USA. [Provenzale, Dawn] Duke Univ, Durham, NC USA. RP Sullivan, DR (reprint author), Oregon Hlth & Sci Univ, Div Pulm & Crit Care Med, UHN67, Portland, OR 97239 USA. EM sullivad@ohsu.edu OI Sullivan, Donald/0000-0003-3266-3389 FU American Lung Association [SB-164388-N]; National Center for Advancing Translational Sciences of the National Institutes of Health [5KL2TR000152-08]; National Center for Research Resources through the Oregon Health & Science University Oregon Clinical & Translational Research Institute [UL1TR000128, 1K07CA190706-01A1]; Veterans Affairs (VA) Health Services Research and Development Career Development [CDA 09-025, CDP 11-227]; Portland VA Portland Health Care System, Oregon; National Cancer Institute [U01 CA093344, U01 CA093332]; Harvard Medical School/Northern California Cancer Center [U01 CA093324]; RAND/UCLA [U01 CA093348]; University of Alabama at Birmingham [U01 CA093329]; University of Iowa [U01 CA093339]; University of North Carolina [U01 CA 093326]; Department of Veteran's Affairs [HSRD CRS-02-164] FX This work was supported by Grant No. SB-164388-N from the American Lung Association (C.G.S.). D.R.S. was supported by Grant No. 5KL2TR000152-08 funded through the National Center for Advancing Translational Sciences of the National Institutes of Health and National Center for Research Resources through the Oregon Health & Science University Oregon Clinical & Translational Research Institute Grants No. UL1TR000128 and 1K07CA190706-01A1. C.G.S. was supported by Veterans Affairs (VA) Health Services Research and Development Career Development Awards No. CDA 09-025 and CDP 11-227. D.R.S., L.G., and C.G.S. are supported by resources from the Portland VA Portland Health Care System, Oregon. The work of the CanCORS consortium was supported by Grant No. U01 CA093344 from the National Cancer Institute to the Statistical Coordinating Center and the National Cancer Institute- supported Primary Data Collection and Research Centers (Dana-Farber Cancer Institute/Cancer Research Network, Grant No. U01 CA093332; Harvard Medical School/Northern California Cancer Center, Grant No. U01 CA093324; RAND/UCLA, Grant No. U01 CA093348; University of Alabama at Birmingham, Grant No. U01 CA093329; University of Iowa, Grant No. U01 CA093339; and University of North Carolina, Grant No. U01 CA 093326) and by Department of Veteran's Affairs Grant No. HSRD CRS-02-164 to the Durham VA Medical Center. The Department of Veterans Affairs did not have a role in the conduct of the study, in the collection, management, analysis, interpretation of data, or in the preparation of the manuscript. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the US Government. NR 58 TC 0 Z9 0 U1 7 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 20 PY 2016 VL 34 IS 33 BP 3984 EP U80 DI 10.1200/JCO.2016.66.8459 PG 10 WC Oncology SC Oncology GA ED5XU UT WOS:000388927700007 PM 27996350 ER PT J AU Pang, HH Wang, XF Stinchcombe, TE Wong, ML Cheng, P Ganti, AK Sargent, DJ Zhang, Y Hu, C Mandrekar, SJ Redman, MW Manola, JB Schilsky, RL Cohen, HJ Bradley, JD Adjei, AA Gandara, D Ramalingam, SS Vokes, EE AF Pang, Herbert H. Wang, Xiaofei Stinchcombe, Thomas E. Wong, Melisa L. Cheng, Perry Ganti, Apar Kishor Sargent, Daniel J. Zhang, Ying Hu, Chen Mandrekar, Sumithra J. Redman, Mary W. Manola, Judith B. Schilsky, Richard L. Cohen, Harvey J. Bradley, Jeffrey D. Adjei, Alex A. Gandara, David Ramalingam, Suresh S. Vokes, Everett E. TI Enrollment Trends and Disparity Among Patients With Lung Cancer in National Clinical Trials, 1990 to 2012 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ENHANCING MINORITY PARTICIPATION; UNDERREPRESENTED POPULATIONS; BARRIERS; OLDER; AGE; RECRUITMENT; STRATEGIES; EMPACT; BREAST AB Purpose Under-representation of elderly, women, and racial/ethnic minority patients with cancer in clinical trials is of national concern. The goal of this study was to characterize enrollment trends and disparities by age, sex, and race/ethnicity in lung cancer trials. Methods We analyzed data for 23,006 National Cancer Institute cooperative group lung cancer trial participants and 578,476 patients with lung cancer from the SEER registry from 1990 to 2012. The enrollment disparity difference (EDD) and enrollment disparity ratio (EDR) were calculated on the basis of the proportion of each subgroup in the trial population and the US lung cancer population. Annual percentage changes (APCs) in the subgroup proportions in each population were compared over time. Results Enrollment disparity for patients $ 70 years of age with non-small-cell lung cancer improved from 1990 to 2012 (test of parallelism, P =.020), with a remaining EDD of 0.22 (95% CI, 0.19 to 0.25) and EDR of 1.65 (95% CI, 1.51 to 1.82) in 2010 to 2012. No improvement was seen for elderly patients with small-cell lung cancer (SCLC), with an APC of 0.20 (P =.714) among trial participants, despite a rising proportion of elderly patients with SCLC in the US population (APC, 0.32; P =.020). Enrollment disparity for women with lung cancer improved overall, with the gap closing by 2012 (EDD, 0.03 [95% CI, 0.00 to 0.06]; EDR, 1.07 [95% CI, 1.00 to 1.16]). Enrollment disparities persisted without significant improvement for elderly women, blacks, Asians/Pacific Islanders, and Hispanics. Conclusion Under-representation in lung cancer trials improved significantly from 1990 to 2012 for elderly patients with non-small-cell lung cancer and for women, but ongoing efforts to improve the enrollment of elderly patients with SCLC and minorities are needed. Our study highlights the importance of addressing enrollment disparities by demographic and disease subgroups to better target under-represented groups of patients with lung cancer. (C) 2016 by American Society of Clinical Oncology C1 [Pang, Herbert H.; Cheng, Perry] Li Ka Shing Fac Med, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China. [Pang, Herbert H.; Wang, Xiaofei; Stinchcombe, Thomas E.; Zhang, Ying; Cohen, Harvey J.] Duke Univ, Sch Med, Durham, NC USA. [Wong, Melisa L.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Gandara, David] Univ Calif Davis, Ctr Comprehens Canc, Sacramento, CA USA. [Ganti, Apar Kishor] Vet Affairs Nebraska Western Iowa Hlth Care Syst, Omaha, NE USA. [Ganti, Apar Kishor] Univ Nebraska Med Ctr, Omaha, NE USA. [Sargent, Daniel J.; Mandrekar, Sumithra J.] Mayo Clin, Rochester, MN USA. [Hu, Chen] NRG Oncol Stat & Data Management Ctr, Philadelphia, PA USA. [Hu, Chen] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Redman, Mary W.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Manola, Judith B.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Schilsky, Richard L.] ASCO, Alexandria, VA USA. [Bradley, Jeffrey D.] Washington Univ, Sch Med, St Louis, MO USA. [Adjei, Alex A.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Ramalingam, Suresh S.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Vokes, Everett E.] Univ Chicago, Chicago, IL 60637 USA. RP Wang, XF (reprint author), Duke Univ, Sch Med, Dept Biostat & Bioinformat, 2424 Erwin Rd, Durham, NC 27705 USA. EM xiaofei.wang@duke.edu OI Cheng, Kit Man/0000-0002-5797-4274 FU National Institutes of Health National Institute on Aging and the Health and Medical Research Fund of Hong Kong [R21-AG042894]; National Institute on Aging [T32-AG000212] FX Supported by Grant No. R21-AG042894 from the National Institutes of Health National Institute on Aging and the Health and Medical Research Fund of Hong Kong, and by the National Institute on Aging (Grant No. T32-AG000212 to M.L.W.). NR 27 TC 0 Z9 0 U1 2 U2 2 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 NOV 20 PY 2016 VL 34 IS 33 BP 3992 EP U90 DI 10.1200/JCO.2016.67.7088 PG 10 WC Oncology SC Oncology GA ED5XU UT WOS:000388927700008 ER PT J AU Mack, JW Cronin, AM Kang, TI AF Mack, Jennifer W. Cronin, Angel M. Kang, Tammy I. TI Decisional Regret Among Parents of Children With Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SCALE; COMMUNICATION; PROGNOSIS; PATIENT; CARE; PARTICIPATION; ONCOLOGISTS; PREFERENCES; INFORMATION; VALIDATION AB Purpose Decision making is one of the ways in which parents serve as stewards of their children with cancer, but barriers to informed decision making among parents of children with cancer have been identified. We sought to evaluate the extent to which parents feel satisfied with, or regretful of, decisions made for their child's cancer treatment and to identify factors associated with heightened regret. Methods We surveyed 346 parents of children with cancer within 12 weeks of their initial cancer treatment decision and the children's physicians at Dana-Farber Cancer Institute/Boston Children's Hospital and the Children's Hospital of Philadelphia. Our main outcome measure was heightened regret as measured by the Decisional Regret Scale. Results Sixteen percent of parents (N = 54) met our definition of heightened decisional regret. In a multi-variable logistic regression model, race/ethnicity was associated with regret, with black (odds ratio [OR], 6.55; 95% CI, 2.30 to 18.7), Hispanic (OR, 2.15; 95% CI, .69 to 6.65), and other race parents (OR, 4.68; 95% CI, 1.58 to 13.8) at increased risk for regret relative to whites (P = .001 across all categories). In contrast, parents who reported receiving high-quality information (OR, .45; 95% CI, .23 to .91; P = .03) and detailed prognostic information (OR, .48; 95% CI, .24 to.96; P = .04), who trusted the oncologist completely (OR, .32; 95% CI, .17 to.63; P = .001), and who held their ideal role in decision making (OR, .49; 95% CI, .25 to.95; P = .04) were less likely to experience regret. Conclusion Although many parents are satisfied with decisions made for their children with cancer, racial and ethnic minority parents are at heightened risk for regret. Clinicians may be able to reduce this risk by providing high- quality information, including prognostic information, involving parents in decision making in the ways they wish, and serving as trusted providers. (C) 2016 by American Society of Clinical Oncology C1 [Mack, Jennifer W.; Cronin, Angel M.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Mack, Jennifer W.] Boston Childrens Hosp, Boston, MA USA. [Kang, Tammy I.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Mack, JW (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM Jennifer_mack@dfci.harvard.edu FU American Cancer Society Mentored Research Scholar Grant [MRSG-08-010-01-CPPB]; American Society of Clinical Oncology Career Development Award FX Supported by an American Cancer Society Mentored Research Scholar Grant MRSG-08-010-01-CPPB (J.W.M.) and a 2007 American Society of Clinical Oncology Career Development Award (J.W.M.). NR 29 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 20 PY 2016 VL 34 IS 33 BP 4023 EP U136 DI 10.1200/JCO.2016.69.1634 PG 8 WC Oncology SC Oncology GA ED5XU UT WOS:000388927700012 ER PT J AU Nipp, RD Abel, GA AF Nipp, Ryan D. Abel, Gregory A. TI Small Step for Geriatric Oncology That Could Have Been a Giant Leap SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID CELL LUNG-CANCER; ELDERLY-PATIENTS C1 [Nipp, Ryan D.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Nipp, Ryan D.; Abel, Gregory A.] Harvard Med Sch, Boston, MA 02115 USA. [Abel, Gregory A.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Nipp, RD (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA.; Nipp, RD (reprint author), Harvard Med Sch, Boston, MA 02115 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 20 PY 2016 VL 34 IS 33 BP 4048 EP U172 DI 10.1200/JCO.2016.69.0446 PG 3 WC Oncology SC Oncology GA ED5XU UT WOS:000388927700016 ER PT J AU Lee, JH Kim, HH Ko, JY Jang, JH Kim, GH Lee, JS Nah, JW Jeon, YJ AF Lee, Ji-Hyeok Kim, Hyung-Ho Ko, Ju-Young Jang, Jun-Ho Kim, Gwang-Hoon Lee, Jung-Suck Nah, Jae-Woon Jeon, You-Jin TI Rapid preparation of functional polysaccharides from Pyropia yezoensis by microwave-assistant rapid enzyme digest system SO CARBOHYDRATE POLYMERS LA English DT Article DE Pyropia yezoensis; Microwave-assisted rapid enzyme digest system; Low molecular weight polysaccharides; Antioxidative effect ID PORPHYRA-YEZOENSIS; ANTIOXIDANT ACTIVITY; SULFATED POLYSACCHARIDES; MASS-SPECTROMETRY; RED ALGAE; IN-VITRO; EXTRACTION; PROTEIN; DEGRADATION; HYDROLYSIS AB This study describes a simple preparation of functional polysaccharides from Pyropia yezoensis using a microwave-assistant rapid enzyme digest system (MAREDS) with various carbohydrases, and evaluates their antioxidative effects. Polysaccharide hydrolysates were prepared using MAREDS under different hydrolytic conditions of the carbohydrases and microwave powers. Polysaccharides less than 10 kDa (Low molecular weight polysaccharides, LMWP, <= 10 kDa) were efficiently obtained using an ultrafiltration (molecular weight cut-off of 10 kDa). MAREDS increases AMG activation via an increased degree of hydrolysis; the best AMG hydrolysate was prepared using a 10:1 ratio of substrate to enzyme for 2 h in MAREDS with 400W. LMWP consisted of galactose (27.3%), glucose (64.5%), and mannose (8.3%) from the AMG hydrolysate had stronger antioxidant effects than the high molecular weight polysaccharides (>10 kDa). We rapidly prepared functional LMWPs by using MAREDS with carbohydrases, and suggest that LMWP might be potentially a valuable algal polysaccharide antioxidant. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Lee, Ji-Hyeok; Kim, Hyung-Ho; Ko, Ju-Young; Jeon, You-Jin] Jeju Natl Univ, Dept Marine Life Sci, Jeju 690756, South Korea. [Jang, Jun-Ho] Univ Pittsburgh, Dept Internal Med, Div Pulm Crit Care & Sleep Med, Pittsburgh, PA 15260 USA. [Jang, Jun-Ho] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15260 USA. [Kim, Gwang-Hoon] Kongju Natl Univ, Coll Nat Sci, Dept Biol, Kong Ju 314701, South Korea. [Lee, Jung-Suck] Jeju Natl Univ, Ind Acad Cooperat Fdn, Jeju 690756, South Korea. [Nah, Jae-Woon] Sunchon Natl Univ, Dept High Polymer Engn, Sunchon, Jeollanam Do, South Korea. RP Jeon, YJ (reprint author), Jeju Natl Univ, Dept Marine Life Sci, Jeju 690756, South Korea.; Nah, JW (reprint author), Sunchon Natl Univ, Dept High Polymer Engn, Sunchon, Jeollanam Do, South Korea. EM jwnah@sunchon.ac.kr; youjin2014@gmail.com FU Ministry of Agriculture, Food and Rural Affairs (MAFRA); Ministry of Oceans and Fisheries (MOF); Korea Forest Service (KFS) [213004-04-4-SBA30] FX This research was supported by Ministry of Agriculture, Food and Rural Affairs (MAFRA), Ministry of Oceans and Fisheries (MOF), Rural Development Administration (RDA) and Korea Forest Service (KFS) (213004-04-4-SBA30). NR 31 TC 0 Z9 0 U1 27 U2 27 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0144-8617 EI 1879-1344 J9 CARBOHYD POLYM JI Carbohydr. Polym. PD NOV 20 PY 2016 VL 153 BP 512 EP 517 DI 10.1016/j.carbpol.2016.07.122 PG 6 WC Chemistry, Applied; Chemistry, Organic; Polymer Science SC Chemistry; Polymer Science GA DU6IF UT WOS:000382317200059 PM 27561523 ER PT J AU Barrett, LF Quigley, KS Hamilton, P AF Barrett, Lisa Feldman Quigley, Karen S. Hamilton, Paul TI An active inference theory of allostasis and interoception in depression SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE interoception; visceromotor; major depressive disorder; fMRI; prediction ID ANTERIOR CINGULATE CORTEX; TREATMENT-RESISTANT DEPRESSION; NEURAL DEVELOPMENT DEPRIVATION; SUBGENUAL PREFRONTAL CORTEX; THALAMIC RETICULAR NUCLEUS; DEEP BRAIN-STIMULATION; DEFAULT-MODE NETWORK; LONG-TERM REGULATION; MAJOR DEPRESSION; FUNCTIONAL CONNECTIVITY AB In this paper, we integrate recent theoretical and empirical developments in predictive coding and active inference accounts of interoception (including the Embodied Predictive Interoception Coding model) with working hypotheses from the theory of constructed emotion to propose a biologically plausible unified theory of the mind that places metabolism and energy regulation (i.e. allostasis), as well as the sensory consequences of that regulation (i.e. interoception), at its core. We then consider the implications of this approach for understanding depression. We speculate that depression is a disorder of allostasis, whose myriad symptoms result from a 'locked in' brain that is relatively insensitive to its sensory context. We conclude with a brief discussion of the ways our approach might reveal new insights for the treatment of depression. This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. C1 [Barrett, Lisa Feldman; Quigley, Karen S.] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Barrett, Lisa Feldman] Harvard Med Sch, Charlestown, MA 02129 USA. [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Barrett, Lisa Feldman] Harvard Med Sch, Boston, MA 02115 USA. [Hamilton, Paul] Linkoping Univ, Dept Clin & Expt Med, Ctr Social & Affect Neurosci, Linkoping, Sweden. RP Barrett, LF (reprint author), Northeastern Univ, Dept Psychol, Boston, MA 02115 USA.; Barrett, LF (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA.; Barrett, LF (reprint author), Harvard Med Sch, Charlestown, MA 02129 USA.; Barrett, LF (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.; Barrett, LF (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM l.barrett@neu.edu OI Barrett, Lisa/0000-0003-4478-2051 FU National Institutes on Aging [R01 AG030311]; National Cancer Institute [U01 CA193632]; National Science Foundation [1638234]; US Army Research Institute for the Behavioral and Social Sciences [W911NF-15-1-0647, W911NF-16-1-0191] FX This paper was prepared with support from the National Institutes on Aging (R01 AG030311), the National Cancer Institute (U01 CA193632), the National Science Foundation (1638234) and the US Army Research Institute for the Behavioral and Social Sciences (W911NF-15-1-0647 and W911NF-16-1-0191). NR 240 TC 6 Z9 6 U1 8 U2 8 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD NOV 19 PY 2016 VL 371 IS 1708 AR 20160011 DI 10.1098/rstb.2016.0011 PG 17 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EC0CU UT WOS:000387766300009 ER PT J AU Strigo, IA Craig, AD AF Strigo, Irina A. Craig, Arthur D. (Bud) TI Interoception, homeostatic emotions and sympathovagal balance SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE anterior cingulate; insula; vagus; asymmetry; respiration ID VAGUS NERVE-STIMULATION; TREATMENT-RESISTANT DEPRESSION; CEREBRAL-BLOOD-FLOW; MACAQUE MONKEY; INSULAR CORTEX; PARASYMPATHETIC CONTROL; PARAFASCICULAR NUCLEUS; CHEMOREFLEX RESPONSE; HEMISPHERE ASYMMETRY; PARABRACHIAL NUCLEUS AB We briefly review the evidence for distinct neuroanatomical substrates that underlie interoception in humans, and we explain how they substantialize feelings from the body (in the insular cortex) that are conjoined with homeostatic motivations that guide adaptive behaviours (in the cingulate cortex). This hierarchical sensorimotor architecture coincides with the limbic cortical architecture that underlies emotions, and thus we regard interoceptive feelings and their conjoint motivations as homeostatic emotions. We describe how bivalent feelings, emotions and sympathovagal balance can be organized and regulated efficiently in the bicameral forebrain as asymmetric positive/negative, approach/avoidance and parasympathetic/sympathetic components. We provide original evidence supporting this organization from studies of cardiorespiratory vagal activity in monkeys and functional imaging studies in healthy humans showing activation modulated by paced breathing and passively viewed emotional images. The neuroanatomical architecture of interoception provides deep insight into the functional organization of all emotional feelings and behaviours in humans. This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. C1 [Strigo, Irina A.] San Francisco VA Med Ctr, Res Serv, San Francisco, CA 94121 USA. [Strigo, Irina A.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. [Craig, Arthur D. (Bud)] Barrow Neurol Inst, Neurosurg Res, Phoenix, AZ 85013 USA. RP Strigo, IA (reprint author), San Francisco VA Med Ctr, Res Serv, San Francisco, CA 94121 USA.; Strigo, IA (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA.; Craig, AD (reprint author), Barrow Neurol Inst, Neurosurg Res, Phoenix, AZ 85013 USA. EM irina.strigo@ucsf.edu; arthur.craig@dignityhealth.org OI Strigo, Irina/0000-0002-8799-716X FU U.S. Department of Veterans Affairs CS RD Service [I01-CX-000816]; Barrow Neurological Foundation; National Chimpanzee Brain Resource (NINDS) [NS092988, AG014308] FX This work was supported in part by I01-CX-000816 from the U.S. Department of Veterans Affairs CS R&D Service and by the Barrow Neurological Foundation, with contributions by the National Chimpanzee Brain Resource (NINDS grant NS092988 to C. C. Sherwood et al.) and grant no. AG014308 (to J. M. Erwin for support of primate histological archives). NR 86 TC 1 Z9 1 U1 7 U2 7 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD NOV 19 PY 2016 VL 371 IS 1708 AR 20160010 DI 10.1098/rstb.2016.0010 PG 9 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EC0CU UT WOS:000387766300008 ER PT J AU Lambert-Kerzner, A Lucatorto, M McCreight, M Williams, KM Fehling, KB Peterson, J Hess, E Plumley, R Ladebue, A Battaglia, C AF Lambert-Kerzner, Anne Lucatorto, Michelle McCreight, Marina Williams, Katherine M. Fehling, Kelty B. Peterson, Jamie Hess, Edward Plumley, Robert Ladebue, Amy Battaglia, Catherine TI The Veterans Health Administration's proposal for APRN full-practice authority SO NURSE PRACTITIONER LA English DT Article DE advanced practice registered nurses; APRNs; full-practice authority; US Department of Veterans Affairs; Veterans Health Administration ID NURSE-PRACTITIONERS; VIRGINIA MASON; CARE; OUTCOMES; COSTS AB The Veterans Health Administration (VHA) is proposing full-practice authority for advanced practice registered nurses (APRNs) to improve access, care delivery, and patient choice, as well as reduce costs. The authors performed a mixed-methods assessment to obtain the perspectives of administrators and APRNs on the characterization of the APRN workforce and their present practice in the VHA. C1 [Lambert-Kerzner, Anne] Denver VA Med Ctr, Denver, CO 80220 USA. [Lucatorto, Michelle; Fehling, Kelty B.] Vet Hlth Adm, Washington, DC USA. [McCreight, Marina; Williams, Katherine M.; Peterson, Jamie; Ladebue, Amy; Battaglia, Catherine] Eastern Colorado Hlth Care Syst, Denver, CO USA. [Hess, Edward] Univ Colorado, Aurora, CO USA. [Plumley, Robert] Hlth Serv Res & Dev Ctr, Seattle, WA USA. RP Lambert-Kerzner, A (reprint author), Denver VA Med Ctr, Denver, CO 80220 USA. NR 23 TC 0 Z9 0 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0361-1817 EI 1538-8662 J9 NURSE PRACT JI Nurse Pract. PD NOV 19 PY 2016 VL 41 IS 11 BP 16 EP 23 DI 10.1097/01.NPR.0000502792.43113.73 PG 8 WC Nursing SC Nursing GA EB0NU UT WOS:000387041500006 PM 27764064 ER PT J AU Segev, E Wyche, TP Kim, KH Petersen, J Ellebrandt, C Vlamakis, H Barteneva, N Paulson, JN Chai, L Clardy, J Kolter, R AF Segev, Einat Wyche, Thomas P. Kim, Ki Hyun Petersen, Joern Ellebrandt, Claire Vlamakis, Hera Barteneva, Natasha Paulson, Joseph N. Chai, Liraz Clardy, Jon Kolter, Roberto TI Dynamic metabolic exchange governs a marine algal-bacterial interaction SO ELIFE LA English DT Article ID PROGRAMMED CELL-DEATH; EMILIANIA-HUXLEYI; PHAEOBACTER-GALLAECIENSIS; DSM 17395; INDOLE-3-ACETIC-ACID SYNTHESIS; OCEANIC PHYTOPLANKTON; ATMOSPHERIC SULFUR; INDOLEACETIC-ACID; BIOFILM FORMATION; GENETIC-ANALYSIS AB Emiliania huxleyi is a model coccolithophore micro-alga that generates vast blooms in the ocean. Bacteria are not considered among the major factors influencing coccolithophore physiology. Here we show through a laboratory model system that the bacterium Phaeobacter inhibens, a well-studied member of the Roseobacter group, intimately interacts with E. huxleyi. While attached to the algal cell, bacteria initially promote algal growth but ultimately kill their algal host. Both algal growth enhancement and algal death are driven by the bacterially-produced phytohormone indole-3-acetic acid. Bacterial production of indole-3-acetic acid and attachment to algae are significantly increased by tryptophan, which is exuded from the algal cell. Algal death triggered by bacteria involves activation of pathways unique to oxidative stress response and programmed cell death. Our observations suggest that bacteria greatly influence the physiology and metabolism of E. huxleyi. Coccolithophore-bacteria interactions should be further studied in the environment to determine whether they impact micro-algal population dynamics on a global scale. C1 [Segev, Einat; Vlamakis, Hera; Chai, Liraz; Kolter, Roberto] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Wyche, Thomas P.; Kim, Ki Hyun; Clardy, Jon] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA. [Petersen, Joern; Ellebrandt, Claire] Leibniz Inst DSMZ Deutsch Sammlung Mikroorganisme, Braunschweig, Germany. [Barteneva, Natasha] Harvard Med Sch, Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Paulson, Joseph N.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Kim, Ki Hyun] Sungkyunkwan Univ, Sch Pharm, Suwon, South Korea. [Vlamakis, Hera] Broad Inst, Cambridge, MA USA. [Chai, Liraz] Hebrew Univ Jerusalem, Inst Chem, Jerusalem, Israel. RP Segev, E; Kolter, R (reprint author), Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. EM Einat_Segev@hms.harvard.edu; roberto_kolter@hms.harvard.edu OI Kim, Ki Hyun/0000-0002-5285-9138 FU European Molecular Biology Organization [LTF 649-2012]; Human Frontier Science Program [LT000061/2013-L]; Deutsche Forschungsgemeinschaft [Transregio TRR-51]; Program in Cellular and Molecular Medicine, Boston Children's Hospital; National Institutes of Health [RR023459, GM086258, GM58213, GM82137] FX European Molecular Biology Organization LTF 649-2012 Einat Segevr Human Frontier Science Program LT000061/2013-L Einat Segevr Deutsche Forschungsgemeinschaft Transregio TRR-51 Roseobacter Jorn Petersenr Program in Cellular and Molecular Medicine, Boston Children's Hospital Natasha Bartenevar National Institutes of Health RR023459 Natasha Bartenevar National Institutes of Health GM086258 Jon Clardyr National Institutes of Health GM58213 Roberto Kolterr National Institutes of Health GM82137 Roberto Kolterr The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 83 TC 1 Z9 1 U1 15 U2 15 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD NOV 18 PY 2016 VL 5 AR e17473 DI 10.7554/eLife.17473 PG 28 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EF9MU UT WOS:000390655100001 ER PT J AU Davis, MI Pragani, R Fox, JT Shen, M Parmar, K Gaudiano, EF Liu, L Tanega, C Mcgee, L Hall, MD McKnight, C Shinn, P Nelson, H Chattopadhyay, D D'Andrea, AD Auld, DS DeLucas, LJ Li, ZY Boxer, MB Sinneonov, A AF Davis, Mindy I. Pragani, Rajan Fox, Jennifer T. Shen, Min Parmar, Kalindi Gaudiano, Emily F. Liu, Li Tanega, Cordelle McGee, Lauren Hall, Matthew D. McKnight, Crystal Shinn, Paul Nelson, Henrike Chattopadhyay, Debasish D'Andrea, Alan D. Auld, Douglas S. DeLucas, Larry J. Li, Zhuyin Boxer, Matthew B. Sinneonov, Anton TI Small Molecule Inhibition of the Ubiquitin-specific Protease USP2 Accelerates cyclin D1 Degradation and Leads to Cell Cycle Arrest in Colorectal Cancer and Mantle Cell Lymphoma Models SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FATTY-ACID SYNTHASE; PROSTATE-CANCER; DNA-DAMAGE; MAMMALIAN-CELLS; STABILITY; REPAIR; TARGET AB Deubiquitinases are important components of the protein degradation regulatory network. We report the discovery of ML364, a small molecule inhibitor of the deubiquitinase USP2 and its use to interrogate the biology of USP2 and its putative substrate cyclin DL ML364 has an IC50 of 1.1 mu M in a biochemical assay using an internally quenched fluorescent di-ubiquitin substrate. Direct binding of ML364 to USP2 was demonstrated using microscale thermophoresis. ML364 induced an increase in cellular cyclin D1 degradation and caused cell cycle arrest as shown in Western blottings and flow cytometry assays utilizing both Mino and HCT116 cancer cell lines. ML364, and not the inactive analog 2, was antiproliferative in cancer cell lines. Consistent with the role of cyclin D1 in DNA damage response, ML364 also caused a decrease in homologous recombination mediated DNA repair. These effects by a small molecule inhibitor support a key role for USP2 as a regulator of cell cycle, DNA repair, and tumor cell growth. C1 [Davis, Mindy I.; Pragani, Rajan; Fox, Jennifer T.; Shen, Min; Liu, Li; Tanega, Cordelle; McGee, Lauren; Hall, Matthew D.; McKnight, Crystal; Shinn, Paul; Nelson, Henrike; Auld, Douglas S.; Li, Zhuyin; Boxer, Matthew B.; Sinneonov, Anton] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Parmar, Kalindi; Gaudiano, Emily F.; D'Andrea, Alan D.] Harvard Med Sch, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. [Chattopadhyay, Debasish; DeLucas, Larry J.] Univ Alabama Birmingham, Struct Biol Ctr, Birmingham, AL 35294 USA. [Auld, Douglas S.] Novartis Inst Biomed Res, Ctr Proteorn Chem, Cambridge, MA 02139 USA. RP Boxer, MB; Sinneonov, A (reprint author), NIH, NCATS, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM boxerrn@mail.nih.gov; asimeono@mail.nih.gov FU NCATS Intramural Research Program; Molecular Libraries Initiative of the National Institutes of Health Common Fund; National Institutes of Health [U54 MH 084681]; Alabama Drug Discovery Alliance; National Institutes of Health/NCI Grant [5P30CA13148-37]; Translational Research Grant from the Leukemia & Lymphoma Society [6237-13] FX This work was supported by the NCATS Intramural Research Program, Molecular Libraries Initiative of the National Institutes of Health Common Fund, National Institutes of Health Grant U54 MH 084681, Alabama Drug Discovery Alliance, National Institutes of Health/NCI Grant 5P30CA13148-37, and Translational Research Grant from the Leukemia & Lymphoma Society Grant 6237-13. 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 36 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 NOV 18 PY 2016 VL 291 IS 47 BP 24628 EP 24640 DI 10.1074/jbc.M116.738567 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ED5EX UT WOS:000388875500024 PM 27681596 ER PT J AU Ricq, EL Hooker, JM Haggarty, SJ AF Ricq, Emily L. Hooker, Jacob M. Haggarty, Stephen J. TI Activity-dependent Regulation of Histone Lysine Demethylase KDM1 A by a Putative Thiol/Disulfide Switch SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MONOAMINE-OXIDASE-A; STRUCTURAL BASIS; MOLECULAR-MECHANISMS; DNA OXIDATION; LSD1; INACTIVATION; INHIBITION; ASSAY; TRANSCRIPTION; METHYLATION AB Lysine demethylation of proteins such as histones is catalyzed by several classes of enzymes, including the FAD-dependent amine oxidases KDM1A/B. The KDM1 family is homologous to the mitochondrial monoamine oxidases MAO-A/B and produces hydrogen peroxide in the nucleus as a byproduct of demethylation. Here, we show KDM1A is highly thiol-reactive in vitro and in cellular models. Enzyme activity is potently and reversibly inhibited by the drug disulfiram and by hydrogen peroxide. Hydrogen peroxide produced by KDM1A catalysis reduces thiol labeling and inactivates demethylase activity over time. MALDI-TOF mass spectrometry indicates that hydrogen peroxide blocks labeling of cysteine 600, which we propose forms an intramolecular disulfide with cysteine 618 to negatively regulate the catalytic activity of KDM1A. This activity dependent regulation is unique among histone-modifying enzymes but consistent with redox sensitivity of epigenetic regulators. C1 [Ricq, Emily L.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Ricq, Emily L.; Hooker, Jacob M.] Harvard Med Sch, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Ricq, Emily L.; Haggarty, Stephen J.] Harvard Med Sch, Massachusetts Gen Hosp, Chem Neurobiol Lab, Ctr Human Genet Res,Dept Neurol, Boston, MA 02114 USA. [Ricq, Emily L.; Haggarty, Stephen J.] Harvard Med Sch, Massachusetts Gen Hosp, Chem Neurobiol Lab, Ctr Human Genet Res,Dept Psychiat, Boston, MA 02114 USA. RP Haggarty, SJ (reprint author), Massachusetts Gen Hosp, Chem Neurobiol Lab, Ctr Human Genet Res, 185 Cambridge St, Boston, MA 02114 USA. EM shaggarty@mgh.harvard.edu OI Haggarty, Stephen J./0000-0002-7872-168X FU National Institute of Mental Health [R01MH095088]; National Institutes of Health [2T90DA022759-06] FX This project was supported by National Institute of Mental Health Grant R01MH095088. 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.; Supported by National Institutes of Health Training Grant 2T90DA022759-06. NR 42 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 NOV 18 PY 2016 VL 291 IS 47 BP 24756 EP 24767 DI 10.1074/jbc.M116.734426 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ED5EX UT WOS:000388875500033 PM 27634040 ER PT J AU Senbabaoglu, Y Gejman, RS Winer, AG Liu, M Van Allen, EM de Velasco, G Miao, D Ostrovnaya, I Drill, E Luna, A Weinhold, N Lee, W Manley, BJ Khalil, DN Kaffenberger, SD Chen, YB Danilova, L Voss, MH Coleman, JA Russo, P Reuter, VE Chan, TA Cheng, EH Scheinberg, DA Li, MO Choueiri, TK Hsieh, JJ Sander, C Hakimi, AA AF Senbabaoglu, Yasin Gejman, Ron S. Winer, Andrew G. Liu, Ming Van Allen, Eliezer M. de Velasco, Guillermo Miao, Diana Ostrovnaya, Irina Drill, Esther Luna, Augustin Weinhold, Nils Lee, William Manley, Brandon J. Khalil, Danny N. Kaffenberger, Samuel D. Chen, Yingbei Danilova, Ludmila Voss, Martin H. Coleman, Jonathan A. Russo, Paul Reuter, Victor E. Chan, Timothy A. Cheng, Emily H. Scheinberg, David A. Li, Ming O. Choueiri, Toni K. Hsieh, James J. Sander, Chris Hakimi, A. Ari TI Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures SO GENOME BIOLOGY LA English DT Article DE Tumor immune microenvironment; Checkpoint blockade; Clear cell renal cell carcinoma (ccRCC); Computational deconvolution; Cancer immunotherapy ID EXOME ANALYSIS REVEALS; MHC CLASS-I; SEQ DATA; T-CELLS; CANCER-IMMUNOTHERAPY; CHECKPOINT BLOCKADE; COLORECTAL-CANCER; PATIENT SURVIVAL; EXPRESSION DATA; PD-1 BLOCKADE AB Background: Tumor-infiltrating immune cells have been linked to prognosis and response to immunotherapy; however, the levels of distinct immune cell subsets and the signals that draw them into a tumor, such as the expression of antigen presenting machinery genes, remain poorly characterized. Here, we employ a gene expression-based computational method to profile the infiltration levels of 24 immune cell populations in 19 cancer types. Results: We compare cancer types using an immune infiltration score and a T cell infiltration score and find that clear cell renal cell carcinoma (ccRCC) is among the highest for both scores. Using immune infiltration profiles as well as transcriptomic and proteomic datasets, we characterize three groups of ccRCC tumors: T cell enriched, heterogeneously infiltrated, and non-infiltrated. We observe that the immunogenicity of ccRCC tumors cannot be explained by mutation load or neo-antigen load, but is highly correlated with MHC class I antigen presenting machinery expression (APM). We explore the prognostic value of distinct T cell subsets and show in two cohorts that Th17 cells and CD8(+) T/Treg ratio are associated with improved survival, whereas Th2 cells and Tregs are associated with negative outcomes. Investigation of the association of immune infiltration patterns with the subclonal architecture of tumors shows that both APM and T cell levels are negatively associated with subclone number. Conclusions: Our analysis sheds light on the immune infiltration patterns of 19 human cancers and unravels mRNA signatures with prognostic utility and immunotherapeutic biomarker potential in ccRCC. C1 [Senbabaoglu, Yasin; Luna, Augustin; Weinhold, Nils; Lee, William; Sander, Chris; Hakimi, A. Ari] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, 1275 York Ave, New York, NY 10021 USA. [Gejman, Ron S.; Scheinberg, David A.] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, 1275 York Ave, New York, NY 10021 USA. [Winer, Andrew G.; Manley, Brandon J.; Kaffenberger, Samuel D.; Coleman, Jonathan A.; Russo, Paul; Hakimi, A. Ari] Mem Sloan Kettering Canc Ctr, Dept Surg, Urol Serv, New York, NY 10021 USA. [Liu, Ming; Li, Ming O.] Mem Sloan Kettering Canc Ctr, Program Immunol, 1275 York Ave, New York, NY 10021 USA. [Van Allen, Eliezer M.; de Velasco, Guillermo; Miao, Diana; Choueiri, Toni K.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ostrovnaya, Irina; Drill, Esther] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Lee, William; Chan, Timothy A.] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10021 USA. [Chen, Yingbei; Reuter, Victor E.; Cheng, Emily H.] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. [Danilova, Ludmila] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Danilova, Ludmila] Russian Acad Sci, Vavilov Inst Gen Genet, Moscow, Russia. [Voss, Martin H.; Hsieh, James J.] Mem Sloan Kettering Canc Ctr, Dept Med, Genitourinary Oncol Serv, 1275 York Ave, New York, NY 10021 USA. [Chan, Timothy A.; Cheng, Emily H.; Hsieh, James J.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA. [Khalil, Danny N.; Scheinberg, David A.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Gejman, Ron S.; Chan, Timothy A.; Scheinberg, David A.] Weill Cornell Med Coll, New York, NY USA. [Senbabaoglu, Yasin] Mem Sloan Kettering Canc Ctr, Dept Med, Swim Amer Ludwig Collaborat Lab, 1275 York Ave, New York, NY 10021 USA. RP Senbabaoglu, Y (reprint author), Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, 1275 York Ave, New York, NY 10021 USA. EM shenbaba@gmail.com; hakimia@mskcc.org OI Gejman, Ron/0000-0001-5138-2772 FU MSKCC Department of Surgery Faculty Research Award; Stephen P. Hanson Family Fund Fellowship in Kidney Cancer; Sidney Kimmel Center for Prostate and Urologic Cancers; Ruth L. Kirschstein F30 individual fellowship from NCI [F30 CA200327-02]; Medical Scientist Training Program grant from National Institute of General Medical Sciences of the National Institutes of Health [T32GM007739]; Cycle for Survival of MSKCC; RBRF [13-04-40279-H]; MSK Translational Kidney Cancer Research Program; Geoffrey Beene Cancer Research Center; NRNB [P41GM103504]; GDAC [U24CA143840]; [P30 CA008748]; [RO1CA55349]; [P01CA23766]; [T32CA082088-15] FX AAH was supported by the MSKCC Department of Surgery Faculty Research Award. AGW was supported by the Stephen P. Hanson Family Fund Fellowship in Kidney Cancer. AAH, AGW, SDK, PR, and JAC were supported by the Sidney Kimmel Center for Prostate and Urologic Cancers. RSG was supported by a Ruth L. Kirschstein F30 individual fellowship from the NCI (F30 CA200327-02) and a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the National Institutes of Health under award number: T32GM007739 to the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program. IO was supported in part by the Core Grant P30 CA008748. YBC was supported by Cycle for Survival of MSKCC. LD was supported by RBRF (13-04-40279-H). DAS was supported by RO1CA55349 and P01CA23766. SDK was supported by T32CA082088-15. MOL was supported by MSK Translational Kidney Cancer Research Program and Geoffrey Beene Cancer Research Center. CS and YS were supported by NRNB P41GM103504 and GDAC U24CA143840. NR 85 TC 3 Z9 3 U1 4 U2 4 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 NOV 17 PY 2016 VL 17 AR 231 DI 10.1186/s13059-016-1092-z PG 25 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EE1WU UT WOS:000389375300001 PM 27855702 ER PT J AU Sholl, LM Do, K Shivdasani, P Cerami, E Dubuc, AM Kuo, FC Garcia, EP Jia, YH Davineni, P Abo, RP Pugh, TJ van Hummelen, P Thorner, AR Ducar, M Berger, AH Nishino, M Janeway, KA Church, A Harris, M Ritterhouse, LL Campbell, JD Rojas-Rudilla, V Ligon, AH Ramkissoon, S Cleary, JM Matulonis, U Oxnard, GR Chao, R Tassell, V Christensen, J Hahn, WC Kantoff, PW Kwiatkowski, DJ Johnson, BE Meyerson, M Garraway, LA Shapiro, GI Rollins, BJ Lindeman, NI MacConaill, LE AF Sholl, Lynette M. Do, Khanh Shivdasani, Priyanka Cerami, Ethan Dubuc, Adrian M. Kuo, Frank C. Garcia, Elizabeth P. Jia, Yonghui Davineni, Phani Abo, Ryan P. Pugh, Trevor J. van Hummelen, Paul Thorner, Aaron R. Ducar, Matthew Berger, Alice H. Nishino, Mizuki Janeway, Katherine A. Church, Alanna Harris, Marian Ritterhouse, Lauren L. Campbell, Joshua D. Rojas-Rudilla, Vanesa Ligon, Azra H. Ramkissoon, Shakti Cleary, James M. Matulonis, Ursula Oxnard, Geoffrey R. Chao, Richard Tassell, Vanessa Christensen, James Hahn, William C. Kantoff, Philip W. Kwiatkowski, David J. Johnson, Bruce E. Meyerson, Matthew Garraway, Levi A. Shapiro, Geoffrey I. Rollins, Barrett J. Lindeman, Neal I. MacConaill, Laura E. TI Institutional implementation of clinical tumor profiling on an unselected cancer population SO JCI INSIGHT LA English DT Article ID ACTIONABLE GENOMIC ALTERATIONS; METASTATIC BREAST-CANCER; FIND POTENTIAL TARGETS; CELL LUNG-CANCER; PERSONALIZED MEDICINE; KINASE INHIBITORS; TYROSINE KINASE; MUTATIONS; THERAPY; EFFICACY AB BACKGROUND. Comprehensive genomic profiling of a patient's cancer can be used to diagnose, monitor, and recommend treatment. Clinical implementation of tumor profiling in an enterprise-wide, unselected cancer patient population has yet to be reported. METHODS. We deployed a hybrid-capture and massively parallel sequencing assay (OncoPanel) for all adult and pediatric patients at our combined cancer centers. Results were categorized by pathologists based on actionability. We report the results for the first 3,727 patients tested. RESULTS. Our cohort consists of cancer patients unrestricted by disease site or stage. Across all consented patients, half had sufficient and available (>20% tumor) material for profiling; once specimens were received in the laboratory for pathology review, 73% were scored as adequate for genomic testing. When sufficient DNA was obtained, OncoPanel yielded a result in 96% of cases. 73% of patients harbored an actionable or informative alteration; only 19% of these represented a current standard of care for therapeutic stratification. The findings recapitulate those of previous studies of common cancers but also identify alterations, including in AXL and EGFR, associated with response to targeted therapies. In rare cancers, potentially actionable alterations suggest the utility of a "cancer-agnostic" approach in genomic profiling. Retrospective analyses uncovered contextual genomic features that may inform therapeutic response and examples where diagnoses revised by genomic profiling markedly changed clinical management. CONCLUSIONS. Broad sequencing-based testing deployed across an unselected cancer cohort is feasible. Genomic results may alter management in diverse scenarios; however, additional barriers must be overcome to enable precision cancer medicine on a large scale. C1 [Sholl, Lynette M.; Shivdasani, Priyanka; Dubuc, Adrian M.; Kuo, Frank C.; Garcia, Elizabeth P.; Jia, Yonghui; Davineni, Phani; Abo, Ryan P.; Ducar, Matthew; Ritterhouse, Lauren L.; Rojas-Rudilla, Vanesa; Ligon, Azra H.; Ramkissoon, Shakti; Meyerson, Matthew; Lindeman, Neal I.; MacConaill, Laura E.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Do, Khanh; Berger, Alice H.; Campbell, Joshua D.; Rojas-Rudilla, Vanesa; Cleary, James M.; Matulonis, Ursula; Oxnard, Geoffrey R.; Hahn, William C.; Kwiatkowski, David J.; Johnson, Bruce E.; Meyerson, Matthew; Garraway, Levi A.; Shapiro, Geoffrey I.; Rollins, Barrett J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Do, Khanh; Berger, Alice H.; Campbell, Joshua D.; Rojas-Rudilla, Vanesa; Cleary, James M.; Matulonis, Ursula; Oxnard, Geoffrey R.; Hahn, William C.; Kwiatkowski, David J.; Johnson, Bruce E.; Meyerson, Matthew; Garraway, Levi A.; Shapiro, Geoffrey I.; Rollins, Barrett J.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Do, Khanh; Cleary, James M.; Shapiro, Geoffrey I.] DFCI, Early Drug Discovery Ctr, Boston, MA USA. [Cerami, Ethan; van Hummelen, Paul] DFCI, Dept Biostat & Computat Biol, Boston, MA USA. [Abo, Ryan P.; Thorner, Aaron R.; Ducar, Matthew; Meyerson, Matthew; MacConaill, Laura E.] DFCI, Ctr Canc Genome Discovery, Boston, MA USA. [Pugh, Trevor J.] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Pugh, Trevor J.] Univ Toronto, Dept Med Biophys, Toronto, ON M5S 1A1, Canada. [Berger, Alice H.; Meyerson, Matthew] Broad Inst Harvard & MIT, Cambridge, MA USA. [Nishino, Mizuki] DFCI, Dept Radiol, Boston, MA USA. [Nishino, Mizuki] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Janeway, Katherine A.] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. [Church, Alanna; Harris, Marian] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Chao, Richard; Tassell, Vanessa; Christensen, James] Mirati Therapeut, San Diego, CA USA. [Hahn, William C.; Kantoff, Philip W.] DFCI, Lank Ctr Genitourinary Oncol, Boston, MA USA. [Garraway, Levi A.] DFCI, Ctr Canc Precis Med, Boston, MA USA. RP MacConaill, LE (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana 1539, Boston, MA 02215 USA. EM Laura_macconaill@dfci.harvard.edu NR 54 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD NOV 17 PY 2016 VL 1 IS 19 AR e87062 DI 10.1172/jci.insight.87062 PG 19 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EE7LI UT WOS:000389797700003 PM 27882345 ER PT J AU Hanley, A Walsh, KA Joyce, C McLellan, MA Clauss, S Hagen, A Shea, MA Tucker, NR Lin, HH Fahy, GJ Ellinor, PT AF Hanley, Alan Walsh, Katie A. Joyce, Caroline McLellan, Michael A. Clauss, Sebastian Hagen, Amaya Shea, Marisa A. Tucker, Nathan R. Lin, Honghuang Fahy, Gerard J. Ellinor, Patrick T. TI Mutation of a common amino acid in NKX2.5 results in dilated cardiomyopathy in two large families SO BMC Medical Genetics LA English DT Article DE Sudden cardiac death; Cardiomyopathy; Arrhythmia; Next generation sequencing ID CONGENITAL HEART-DISEASE; HYPERTROPHIC CARDIOMYOPATHY; FRAMEWORK; PROTEIN; UPDATE; GENES; MICE AB Background: The genetic basis for dilated cardiomyopathy (DCM) can be difficult to determine, particularly in familial cases with complex phenotypes. Next generation sequencing may be useful in the management of such cases. Methods: We report two large families with pleiotropic inherited cardiomyopathy. In addition to DCM, the phenotypes included atrial and ventricular septal defects, cardiac arrhythmia and sudden death. Probands underwent whole exome sequencing to identify potentially causative variants. Results: Each whole exome sequence yielded over 18,000 variants. We identified distinct mutations affecting a common amino acid in NKX2.5. Segregation analysis of the families support the pathogenic role of these variants. Conclusion: Our study emphasizes the utility of next generation sequencing in identifying causative mutations in complex inherited cardiac disease. We also report a novel pathogenic NKX2.5 mutation. C1 [Hanley, Alan; McLellan, Michael A.; Clauss, Sebastian; Hagen, Amaya; Shea, Marisa A.; Tucker, Nathan R.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Walsh, Katie A.; Joyce, Caroline; Fahy, Gerard J.] Cork Univ Hosp, Cork, Wilton, Ireland. [Hanley, Alan; Tucker, Nathan R.; Ellinor, Patrick T.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Lin, Honghuang] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. RP Ellinor, PT (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.; Ellinor, PT (reprint author), Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. EM ellinor@mgh.harvard.edu FU Irish Cardiac Society; T32 award [T32HL007208, 2R01HL092577, R01HL104156, K24HL105780]; American Heart Association Established Investigator Award [13EIA14220013]; Fondation Leducq [14CVD01] FX This study was supported by fellowship support from the Irish Cardiac Society (Hanley), an institutional T32 award, T32HL007208 (Tucker), 2R01HL092577, R01HL104156, and K24HL105780 (Ellinor), an American Heart Association Established Investigator Award 13EIA14220013 (Ellinor), and from the Fondation Leducq (14CVD01). NR 20 TC 1 Z9 1 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD NOV 17 PY 2016 VL 17 AR 83 DI 10.1186/s12881-016-0347-6 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA EE0OK UT WOS:000389277400001 PM 27855642 ER PT J AU Hu, BL Wang, QH Wang, YA Hua, SJ Sauve, CEG Ong, D Lan, ZD Chang, Q Ho, YW Monasterio, MM Lu, X Zhong, Y Zhang, JH Deng, PN Tan, Z Wang, GC Liao, WT Corley, LJ Yan, HY Zhang, JX You, YP Liu, N Cai, LB Finocchiaro, G Phillips, JJ Berger, MS Spring, DJ Hu, J Sulman, EP Fuller, GN Chin, L Verhaak, RGW DePinho, RA AF Hu, Baoli Wang, Qianghu Wang, Y. Alan Hua, Sujun Sauve, Charles-Etienne Gabriel Ong, Derrick Lan, Zheng D. Chang, Qing Ho, Yan Wing Monasterio, Marta Moreno Lu, Xin Zhong, Yi Zhang, Jianhua Deng, Pingna Tan, Zhi Wang, Guocan Liao, Wen-Ting Corley, Lynda J. Yan, Haiyan Zhang, Junxia You, Yongping Liu, Ning Cai, Linbo Finocchiaro, Gaetano Phillips, Joanna J. Berger, Mitchel S. Spring, Denise J. Hu, Jian Sulman, Erik P. Fuller, Gregory N. Chin, Lynda Verhaak, Roeland G. W. DePinho, Ronald A. TI Epigenetic Activation of WNT5A Drives Glioblastoma Stem Cell Differentiation and Invasive Growth SO CELL LA English DT Article ID ENDOTHELIAL-CELLS; SELF-RENEWAL; MALIGNANT GLIOMAS; PAX6 SUPPRESSES; IN-VITRO; CANCER; EXPRESSION; PROLIFERATION; DYNAMICS; NEUROGENESIS AB Glioblastoma stem cells (GSCs) are implicated in tumor neovascularization, invasiveness, and therapeutic resistance. To illuminate mechanisms governing these hallmark features, we developed a de novo glioblastoma multiforme (GBM) model derived from immortalized human neural stem/progenitor cells (hNSCs) to enable precise system-level comparisons of pre-malignant and oncogene-induced malignant states of NSCs. Integrated transcriptomic and epigenomic analyses uncovered a PAX6/DLX5 transcriptional program driving WNT5A-mediated GSC differentiation into endothelial-like cells (GdECs). GdECs recruit existing endothelial cells to promote peritumoral satellite lesions, which serve as a niche supporting the growth of invasive glioma cells away from the primary tumor. Clinical data reveal higher WNT5A and GdECs expression in peritumoral and recurrent GBMs relative to matched intratumoral and primary GBMs, respectively, supporting WNT5A-mediated GSC differentiation and invasive growth in disease recurrence. Thus, the PAX6/DLX5-WNT5A axis governs the diffuse spread of glioma cells throughout the brain parenchyma, contributing to the lethality of GBM. C1 [Hu, Baoli; Wang, Y. Alan; Hua, Sujun; Sauve, Charles-Etienne Gabriel; Ong, Derrick; Lan, Zheng D.; Ho, Yan Wing; Monasterio, Marta Moreno; Lu, Xin; Deng, Pingna; Wang, Guocan; Liao, Wen-Ting; Spring, Denise J.; Hu, Jian; DePinho, Ronald A.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Wang, Qianghu; Verhaak, Roeland G. W.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Wang, Qianghu; Chang, Qing; Zhang, Jianhua; Chin, Lynda; Verhaak, Roeland G. W.] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. [Zhong, Yi] Univ Texas MD Anderson Canc Ctr, Dept Epigenet & Mol Carcinogenesis, Houston, TX 77030 USA. [Tan, Zhi] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. [Corley, Lynda J.; Fuller, Gregory N.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Sulman, Erik P.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Sulman, Erik P.] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA. [Chang, Qing; Zhang, Jianhua] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 USA. [Yan, Haiyan] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Zhang, Junxia; You, Yongping; Liu, Ning] Nanjing Med Univ, Dept Neurosurg, Affiliated Hosp 1, Nanjing 210029, Jiangsu, Peoples R China. [Cai, Linbo] Guangdong 999 Brain Hosp, Dept Oncol, Guangzhou 510510, Guangdong, Peoples R China. [Finocchiaro, Gaetano] Fdn IRCCS Ist Neurol C Besta, Unit Mol Neurooncol, I-20133 Milan, Italy. [Phillips, Joanna J.] Univ Calif San Francisco, Dept Neurol Surg & Pathol, San Francisco, CA 94143 USA. [Berger, Mitchel S.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. RP Wang, YA; DePinho, RA (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. EM yalanwang@mdanderson.org; rdepinho@mdanderson.org RI Tan, Zhi/B-9065-2017 OI Tan, Zhi/0000-0003-1895-0285 FU UCSF Brain Tumor SPORE Tissue Bank [P50 CA097257]; NIH [2P50CA127001, 5P01CA095616]; Ben and Catherine Ivy Foundation Research Award; Clayton Foundation; [P30CA16672] FX The authors thank Dr. Raghu Kalluri for critical reading and comments; Dr. Keith L. Ligon for initial assistance with histopathological analysis and providing GSCs lines; Drs. Colin Watts, Andrea Sottoriva, and Sara G.M. Piccirillo for providing detailed information about their published datasets of gene expression profile; Verlene K. Henry and her staff for their help in mouse brain implantation; Keith A. Michel and Charles V. Kingsley for assistance with MRI imaging and analysis; Shan Jiang for excellent mouse husbandry and care; Dr. Jared K. Burks for assistance with confocal image and PE Vectra system; Dr. Karen C. Dwyer and her staff for assistance with flow cytometer; Sequencing & Non-Coding RNA program and Sequencing and Microarray Facility at MDACC provided sequencing service. This research is supported by UCSF Brain Tumor SPORE Tissue Bank P50 CA097257 (J.J.P.), NIH 2P50CA127001 (YAW), 5P01CA095616 (R.A.D. and L.C.), the Ben and Catherine Ivy Foundation Research Award (2009, R.A.D. and L.C.), and Clayton Foundation (RAD). The core facilities are supported by P30CA16672. NR 50 TC 1 Z9 1 U1 11 U2 11 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 NOV 17 PY 2016 VL 167 IS 5 BP 1281 EP + DI 10.1016/j.cell.2016.10.039 PG 32 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE3EK UT WOS:000389470100019 PM 27863244 ER PT J AU Yu, VWC Yusuf, RZ Oki, T Wu, J Saez, B Wang, X Cook, C Baryawno, N Ziller, MJ Lee, E Gu, HC Meissner, A Lin, CP Kharchenko, PV Scadden, DT AF Yu, Vionnie W. C. Yusuf, Rushdia Z. Oki, Toshihiko Wu, Juwell Saez, Borja Wang, Xin Cook, Colleen Baryawno, Ninib Ziller, Michael J. Lee, Eunjung Gu, Hongcang Meissner, Alexander Lin, Charles P. Kharchenko, Peter V. Scadden, David T. TI Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells SO CELL LA English DT Article ID IN-VIVO; EXPRESSION ANALYSIS; CLONAL DYNAMICS; SELF-RENEWAL; DIFFERENTIATION; LINEAGE; EVOLUTION; QUIESCENT; ALIGNMENT; PROTEINS AB Stem cells determine homeostasis and repair of many tissues and are increasingly recognized as functionally heterogeneous. To define the extent of-and molecular basis for-heterogeneity, we overlaid functional, transcriptional, and epigenetic attributes of hematopoietic stem cells (HSCs) at a clonal level using endogenous fluorescent tagging. Endogenous HSC had clone-specific functional attributes over time in vivo. The intra-clonal behaviors were highly stereotypic, conserved under the stress of transplantation, inflammation, and genotoxic injury, and associated with distinctive transcriptional, DNA methylation, and chromatin accessibility patterns. Further, HSC function corresponded to epigenetic configuration but not always to transcriptional state. Therefore, hematopoiesis under homeostatic and stress conditions represents the integrated action of highly heterogeneous clones of HSC with epigenetically scripted behaviors. This high degree of epigenetically driven cell autonomy among HSCs implies that refinement of the concepts of stem cell plasticity and of the stem cell niche is warranted. C1 [Yu, Vionnie W. C.; Yusuf, Rushdia Z.; Oki, Toshihiko; Saez, Borja; Cook, Colleen; Baryawno, Ninib; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Yu, Vionnie W. C.; Yusuf, Rushdia Z.; Oki, Toshihiko; Saez, Borja; Cook, Colleen; Baryawno, Ninib; Ziller, Michael J.; Meissner, Alexander; Lin, Charles P.; Kharchenko, Peter V.; Scadden, David T.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Yu, Vionnie W. C.; Yusuf, Rushdia Z.; Oki, Toshihiko; Saez, Borja; Cook, Colleen; Baryawno, Ninib; Ziller, Michael J.; Meissner, Alexander; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Wu, Juwell; Ziller, Michael J.; Gu, Hongcang; Meissner, Alexander] Broad Inst Harvard & MIT, Cambridge, MA 02138 USA. [Wang, Xin; Lee, Eunjung; Kharchenko, Peter V.] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA. [Lee, Eunjung] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Lin, Charles P.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Scadden, DT (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA.; Kharchenko, PV; Scadden, DT (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA.; Scadden, DT (reprint author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.; Kharchenko, PV (reprint author), Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA. EM peter.kharchenko@post.harvard.edu; david_scadden@harvard.edu FU Science for Life Laboratory; Knut and Alice Wallenberg Foundation; National Genomics Infrastructure - Swedish Research Council; NIH [1R21HL126070-01A1, DK103074, CA193461]; Gerald and Darlene Jordan Chair; Ellison Medical Foundation [AG-NS-0965-12]; NIA [5K25AG037596] FX We are grateful to Drs. Jeff W. Lichtman, Jean Livet, and Joshua R. Sanes for their kind gifts of the Brainbow fluorescent vectors. We also thank Laura Prickett, Kathryn E. Folz-Donahue, and Meredith Weglarz at the Flow Cytometry Core Facility of the Harvard Stem Cell Institute for their technical assistance. We are grateful for support from Science for Life Laboratory, the Knut and Alice Wallenberg Foundation, and the National Genomics Infrastructure, funded by the Swedish Research Council, for assistance with single-cell RNA-seq measurements. This work was supported by NIH grants 1R21HL126070-01A1 to V.W.C.Y., DK103074 and CA193461 and the Gerald and Darlene Jordan Chair to D.T.S, and the Ellison Medical Foundation AG-NS-0965-12 and NIA 5K25AG037596 to P.V.K. NR 38 TC 2 Z9 2 U1 10 U2 10 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 NOV 17 PY 2016 VL 167 IS 5 BP 1310 EP + DI 10.1016/j.cell.2016.10.045 PG 29 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE3EK UT WOS:000389470100021 PM 27863245 ER PT J AU Kottakis, F Nicolay, BN Roumane, A Karnik, R Gu, HC Nagle, JM Boukhali, M Hayward, MC Li, YY Chen, T Liesa, M Hammerman, PS Wong, KK Hayes, DN Shirihai, OS Dyson, NJ Haas, W Meissner, A Bardeesy, N AF Kottakis, Filippos Nicolay, Brandon N. Roumane, Ahlima Karnik, Rahul Gu, Hongcang Nagle, Julia M. Boukhali, Myriam Hayward, Michele C. Li, Yvonne Y. Chen, Ting Liesa, Marc Hammerman, Peter S. Wong, Kwok Kin Hayes, D. Neil Shirihai, Orian S. Dyson, Nicholas J. Haas, Wilhelm Meissner, Alexander Bardeesy, Nabeel TI LKB1 loss links serine metabolism to DNA methylation and tumorigenesis SO NATURE LA English DT Article ID PEUTZ-JEGHERS-SYNDROME; CELL LUNG-CANCER; PANCREATIC-CANCER; HISTONE METHYLATION; PATHWAY; PROGRESSION; GROWTH; L-2-HYDROXYGLUTARATE; DIFFERENTIATION; BIOSYNTHESIS AB Intermediary metabolism generates substrates for chromatin modification, enabling the potential coupling of metabolic and epigenetic states. Here we identify a network linking metabolic and epigenetic alterations that is central to oncogenic transformation downstream of the liver kinase B1 (LKB1, also known as STK11) tumour suppressor, an integrator of nutrient availability, metabolism and growth. By developing genetically engineered mouse models and primary pancreatic epithelial cells, and employing transcriptional, proteomics, and metabolic analyses, we find that oncogenic cooperation between LKB1 loss and KRAS activation is fuelled by pronounced mTOR-dependent induction of the serine-glycine-one-carbon pathway coupled to S-adenosylmethionine generation. At the same time, DNA methyltransferases are upregulated, leading to elevation in DNA methylation with particular enrichment at retrotransposon elements associated with their transcriptional silencing. Correspondingly, LKB1 deficiency sensitizes cells and tumours to inhibition of serine biosynthesis and DNA methylation. Thus, we define a hypermetabolic state that incites changes in the epigenetic landscape to support tumorigenic growth of LKB1-mutant cells, while resulting in potential therapeutic vulnerabilities. C1 [Kottakis, Filippos; Nicolay, Brandon N.; Roumane, Ahlima; Nagle, Julia M.; Boukhali, Myriam; Dyson, Nicholas J.; Haas, Wilhelm; Bardeesy, Nabeel] Massachusetts Gen Hosp, Ctr Canc, 185 Cambridge St, Boston, MA 02114 USA. [Kottakis, Filippos; Roumane, Ahlima; Nagle, Julia M.; Bardeesy, Nabeel] Massachusetts Gen Hosp, Ctr Regenerat Med, 185 Cambridge St, Boston, MA 02114 USA. [Kottakis, Filippos; Nicolay, Brandon N.; Roumane, Ahlima; Nagle, Julia M.; Boukhali, Myriam; Dyson, Nicholas J.; Haas, Wilhelm; Bardeesy, Nabeel] Harvard Med Sch, Dept Med, Boston, MA 02114 USA. [Karnik, Rahul; Gu, Hongcang; Meissner, Alexander] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Karnik, Rahul; Gu, Hongcang; Meissner, Alexander] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Karnik, Rahul; Gu, Hongcang; Meissner, Alexander] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Hayward, Michele C.; Hayes, D. Neil] UNC, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Li, Yvonne Y.; Chen, Ting; Hammerman, Peter S.; Wong, Kwok Kin] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Li, Yvonne Y.; Chen, Ting; Hammerman, Peter S.; Wong, Kwok Kin] Harvard Med Sch, Boston, MA 02115 USA. [Li, Yvonne Y.; Chen, Ting; Hammerman, Peter S.; Wong, Kwok Kin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Chen, Ting; Wong, Kwok Kin] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02215 USA. [Liesa, Marc; Shirihai, Orian S.] Boston Univ, Sch Med, Mitochondria ARC, Evans Ctr Interdisciplinary Res,Dept Med, Boston, MA 02118 USA. [Liesa, Marc; Shirihai, Orian S.] Univ Calif Los Angeles, David Geffen Sch Med, Div Endocrinol Diabet & Hypertens, Dept Med, Los Angeles, CA 90095 USA. [Hammerman, Peter S.] Broad Inst Harvard & MIT, Canc Program, Cambridge, MA 02142 USA. RP Bardeesy, N (reprint author), Massachusetts Gen Hosp, Ctr Canc, 185 Cambridge St, Boston, MA 02114 USA.; Bardeesy, N (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, 185 Cambridge St, Boston, MA 02114 USA.; Bardeesy, N (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02114 USA. EM bardeesy.nabeel@mgh.harvard.edu FU Granara-Skerry Trust; Linda J. Verville Foundation; Begg Family; NIH [P01 CA117969-07, R01 CA133557-05, P50CA1270003]; Hirshberg Foundation FX We thank A. Kimmelman, K. Patra, L. J. Etchegaray, and R. Mostoslaysky for comments on the manuscript, and P. Foltopoulou, B. Martinez and Bardeesy laboratory members for advice. N.B. holds the Gallagher Endowed Chair in Gastrointestinal Cancer Research and received support from the Granara-Skerry Trust, the Linda J. Verville Foundation and the Begg Family, and grants from the NIH (P01 CA117969-07, R01 CA133557-05). F.K. is supported by a Hirshberg Foundation Career Development Award. F.K and N.B. were supported by NIH grant P50CA1270003 and are members of the Andrew Warshaw Institute. NR 39 TC 3 Z9 3 U1 25 U2 25 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 NOV 17 PY 2016 VL 539 IS 7629 BP 390 EP 395 DI 10.1038/nature20132 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC5GP UT WOS:000388161700046 PM 27799657 ER PT J AU Geno, KA Kennedy, RE Sawyer, P Brown, CJ Nahm, MH AF Geno, Kimball Aaron Kennedy, Richard E. Sawyer, Patricia Brown, Cynthia J. Nahm, Moon H. TI Ficolin-2 inhibitors are present in sera after prolonged storage at-80 degrees C SO PEERJ LA English DT Article DE Ficolins; Lectins; Storage artifacts; Lectin pathway; Complement ID MANNAN-BINDING LECTIN; COMPLEMENT ACTIVATION; IN-VITRO; ACETYLSALICYLIC-ACID; HUMAN COLLECTIN; H-FICOLIN; PATHWAY; RECOGNITION; VIVO; INTERLEUKIN-6 AB Ficolins can activate the lectin pathway of the complement system that provides innate immune protection against pathogens, marks host cellular debris for clearance, and promotes inflammation. Baseline inflammation increases with aging in a phenomenon known as "inflammaging,." Although IL-6 and C-reacrive protein are known to increase with age, contributions of many complement factors, including ficolins, to inflammaging have been little studied. Ficolin-2 is abundant in human serum and can recognize many target structures; therefore, ficolin-2 has potential to contribute to inflammaging. We hypothesized that inflammaging would alter ficolin-2 levels among older adults and examined 360 archived sera collected from older individuals. We found that these sera had apparently reduced ficolin-2 levels and that 84.2% of archived sera exhibited ficolin-2 inhibitors, which suppressed apparent amounts of ficolin-2 detected by enzyme linked immunosorbent assay. Fresh serum samples were obtained from donors whose archived sera showed inhibitors, but the fresh sera did not have ficolin-2 inhibitors. Ficolin-2 inhibitors were present in other long-stored sera from younger persons. Furthermore, noninhibiting samples and fresh sera from older adults had apparently normal amounts of ficolin-2. Thus, ficolin-2 inhibitors may arise as an artifact of long-term storage of serum at -80 degrees C. C1 [Geno, Kimball Aaron; Nahm, Moon H.] Univ Alabama Birmingham, Div Pulm Allergy & Crit Care Med, Birmingham, AL 35294 USA. [Kennedy, Richard E.; Sawyer, Patricia; Brown, Cynthia J.] Univ Alabama Birmingham, Div Gerontol Geriatr & Palliat Care, Birmingham, AL USA. [Kennedy, Richard E.; Sawyer, Patricia] Univ Alabama Birmingham, Comprehens Ctr Hlth Aging, Birmingham, AL USA. [Brown, Cynthia J.] Birmingham Vet Affairs Med Ctr, Birmingham Atlanta Geriatr Res Educ & Clin Ctr, Birmingham, AL USA. [Nahm, Moon H.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. RP Nahm, MH (reprint author), Univ Alabama Birmingham, Div Pulm Allergy & Crit Care Med, Birmingham, AL 35294 USA.; Nahm, MH (reprint author), Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. EM mnahm@uabmc.edu FU NIH [HL105346, AG0500607, AG015062] FX This work was funded by NIH grants HL105346 (KAG) and AG0500607 (MHN). The UAB Study of Aging was funded by NIH grant AG015062. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 0 Z9 0 U1 0 U2 0 PU PEERJ INC PI LONDON PA 341-345 OLD ST, THIRD FLR, LONDON, EC1V 9LL, ENGLAND SN 2167-8359 J9 PEERJ JI PeerJ PD NOV 17 PY 2016 VL 4 AR e2705 DI 10.7717/peerj.2705 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC8XE UT WOS:000388425600005 PM 27896034 ER PT J AU Bhatraju, PK Mukherjee, P Robinson-Cohen, C O'Keefe, GE Frank, AJ Christie, JD Meyer, NJ Liu, KD Matthay, MA Calfee, CS Christiani, DC Himmelfarb, J Wurfel, MM AF Bhatraju, Pavan K. Mukherjee, Paramita Robinson-Cohen, Cassianne O'Keefe, Grant E. Frank, Angela J. Christie, Jason D. Meyer, Nuala J. Liu, Kathleen D. Matthay, Michael A. Calfee, Carolyn S. Christiani, David C. Himmelfarb, Jonathan Wurfel, Mark M. TI Acute kidney injury subphenotypes based on creatinine trajectory identifies patients at increased risk of death SO CRITICAL CARE LA English DT Article DE Critical care; Acute kidney injury; Mortality; Subphenotypes; Trajectory; Intensive care unit ID CRITICALLY-ILL PATIENTS; GELATINASE-ASSOCIATED LIPOCALIN; RESPIRATORY-DISTRESS-SYNDROME; PHENOTYPES; MULTICENTER; EPIDEMIOLOGY; MORTALITY; TRANSIENT; PREDICTS; SURVIVAL AB Background: Acute kidney injury (AKI) is common among intensive care unit (ICU) patients. AKI is highly heterogeneous, with variable links to poor outcomes. Current approaches to classify AKI severity and identify patients at highest risk for poor outcomes focus on the maximum change in serum creatinine (SCr) values. However, these scores are hampered by the need for a reliable baseline SCr value and the absence of a component differentiating transient from persistent rises in SCr. We hypothesized that identification of resolving or nonresolving AKI subphenotypes based on the early trajectory of SCr values in the ICU would better differentiate patients at risk of hospital mortality. Methods: We performed a secondary analysis of two prospective studies of ICU patients admitted to a trauma ICU (group 1; n = 1914) or general medical-surgical ICUs (group 2; n = 1867). In group 1, we tested definitions for resolving and nonresolving AKI subphenotypes and selected the definitions resulting in subphenotypes with the greatest separation in risk of death relative to non-AKI controls. We applied this definition to group 2 and tested whether the subphenotypes were independently associated with hospital mortality after adjustment for AKI severity. Results: AKI occurred in 46% and 69% of patients in groups 1 and 2, respectively. In group 1, a resolving AKI subphenotype (defined as a decrease in SCr of 0.3 mg/dl or 25% from maximum in the first 72 h of study enrollment) was associated with a low risk of death. A nonresolving AKI subphenotype (defined as all AKI cases not meeting the "resolving" definition) was associated with a high risk of death. In group 2, the resolving AKI subphenotype was not associated with increased mortality (relative risk [RR] 0.86, 95% CI 0.63-1.17), whereas the nonresolving AKI subphenotype was associated with higher mortality (RR 1.68, 95% CI 1.15-2.44) even after adjustment for AKI severity stage. Conclusions: The trajectory of SCr levels identifies AKI subphenotypes with different risks for death, even among AKI cases of similar severity. These AKI subphenotypes might better define the patients at risk for poor outcomes who might benefit from novel interventions. C1 [Bhatraju, Pavan K.; Wurfel, Mark M.] Univ Washington, Harborview Med Ctr, Div Pulm & Crit Care Med, 325 9th Ave, Seattle, WA 98104 USA. [Mukherjee, Paramita; Robinson-Cohen, Cassianne; Himmelfarb, Jonathan] Univ Washington, Kidney Res Inst, Seattle, WA 98104 USA. [Mukherjee, Paramita; Robinson-Cohen, Cassianne; Himmelfarb, Jonathan] Univ Washington, Div Nephrol, Seattle, WA 98104 USA. [O'Keefe, Grant E.] Univ Washington, Dept Surg, Seattle, WA 98104 USA. [Frank, Angela J.; Christiani, David C.] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Frank, Angela J.; Christiani, David C.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Frank, Angela J.; Christiani, David C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Pulm & Crit Care Div, Boston, MA USA. [Christie, Jason D.; Meyer, Nuala J.] Univ Penn, Div Pulm Allergy & Crit Care, Perelman Sch Med, Philadelphia, PA 19104 USA. [Christie, Jason D.; Meyer, Nuala J.] Univ Penn, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Liu, Kathleen D.; Matthay, Michael A.; Calfee, Carolyn S.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Liu, Kathleen D.; Matthay, Michael A.; Calfee, Carolyn S.] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco, CA 94143 USA. [Liu, Kathleen D.; Matthay, Michael A.; Calfee, Carolyn S.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA USA. RP Bhatraju, PK (reprint author), Univ Washington, Harborview Med Ctr, Div Pulm & Crit Care Med, 325 9th Ave, Seattle, WA 98104 USA. EM bhatraju@uw.edu FU Pulmonary and Critical Care Medicine Research Training Grant (University of Washington) [T32 HL007287]; NIH [RC2 HL101779, R01 HL060710, R01 GM066946] FX This work was supported by Pulmonary and Critical Care Medicine Research Training Grant T32 HL007287 (University of Washington) and by NIH grants RC2 HL101779 (Identification of SNPs Predisposing to Altered ALI Risk), R01 HL060710 (MEA; Massachusetts General Hospital), and R01 GM066946 (Gene Polymorphisms, Inflammation and Outcomes from Trauma). NR 35 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 1466-609X EI 1364-8535 J9 CRIT CARE JI Crit. Care PD NOV 17 PY 2016 VL 20 AR 372 DI 10.1186/s13054-016-1546-4 PG 10 WC Critical Care Medicine SC General & Internal Medicine GA EC1VO UT WOS:000387896500001 PM 27852290 ER PT J AU Zanchi, D Brody, A Borgwardt, S Haller, S AF Zanchi, Davide Brody, Arthur Borgwardt, Stefan Haller, Sven TI Sex Effects on Smoking Cue Perception in Non-Smokers, Smokers, and Ex-Smokers: A Pilot Study SO FRONTIERS IN PSYCHIATRY LA English DT Article DE nicotine; tobacco; fMRI; sex; females; males ID PATHOLOGICAL GAMBLERS; NICOTINE ABSTINENCE; CIGARETTE SMOKERS; BRAIN ACTIVITY; FMRI; WOMEN; DEPENDENCE; RESPONSES; HEALTH; ROBUST AB Introduction: Recent neuroimaging research suggests sex-related brain differences in smoking addiction, In the present pilot study, we assessed gender-related differences in brain activation in response to cigarette-related video cues, investigating non-smokers, smokers, and ex-smokers. Methods: First, we compared 29 females (28.6 +/- 5.3) vs. 23 males (31.5 +/- 6.4), regardless of current smoking status to assess global gender-related effects. Second, we performed a post hoc analysis of non-smokers (9 females and 7 males). Participants performed a block-design functional magnetic resonance imaging paradigm contrasting smoking with control cue video exposures. Data analyses included task-related general linear model, voxel-based morphometry of gray matter (GM), and tract-based spatial statistics of white matter (WM). Results: First, the global effect regardless of current smoking status revealed higher activation in the bilateral superior frontal gyrus and anterior cingulate cortex (ACC) for females compared to males. Second, the analysis according to current smoking status demonstrated higher activation in female vs. male smokers vs. non-smokers in the superior frontal gyrus, anterior and posterior cingulate cortex, and precuneus, and higher activationi in female vs. male ex-smokers vs. non-smokers in the right precentral gyrus, in the right insula and ACC. No structural differences were found in GM or WM. Conclusion: The current study identifies gender-related brain functional differences in smokers and ex-smokers compared to non-smokers. The current work can be considered as a starting point for future investigations into gender differences in brain responses to cigarette-related cues C1 [Zanchi, Davide; Borgwardt, Stefan] Univ Basel, Dept Psychiat UPK, Basel, Switzerland. [Brody, Arthur] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Brody, Arthur] VA Greater Los Angeles Healthcare Syst, Dept Res, Los Angeles, CA USA. [Haller, Sven] Affidea Ctr Diagnost Radiol Carouge CDRC, Geneva, Switzerland. [Haller, Sven] Univ Geneva, Fac Med, Geneva, Switzerland. [Haller, Sven] Uppsala Univ, Radiol, Dept Surg Sci, Uppsala, Sweden. [Haller, Sven] Univ Hosp Freiburg, Dept Neuroradiol, Freiburg, Germany. RP Zanchi, D (reprint author), Univ Basel, Dept Psychiat UPK, Basel, Switzerland. EM davide.zanchi@upkbs.ch NR 25 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 1664-0640 J9 FRONT PSYCHIATRY JI Front. Psychiatry PD NOV 17 PY 2016 VL 7 AR 187 DI 10.3389/fpsyt.2016.00187 PG 7 WC Psychiatry SC Psychiatry GA EC1DZ UT WOS:000387845100001 PM 27909413 ER PT J AU Kwak, EL Hong, TS Forcione, DG Kambadakone, A Lennerz, JK AF Kwak, Eunice L. Hong, Theodore S. Forcione, David G. Kambadakone, Avinash Lennerz, Jochen K. TI Case 35-2016: A 62-Year-Old Man with Dysphagia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PHASE-III TRIAL; ESOPHAGEAL CANCER; ESOPHAGOGASTRIC CANCER; PIK3CA MUTATIONS; IN-VIVO; ADENOCARCINOMA; MET; CHEMORADIOTHERAPY; PLUS; AMPLIFICATION C1 [Kwak, Eunice L.; Forcione, David G.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hong, Theodore S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Kambadakone, Avinash] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Lennerz, Jochen K.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kwak, Eunice L.; Forcione, David G.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Hong, Theodore S.] Harvard Med Sch, Dept Radiat Oncol, Boston, MA USA. [Kambadakone, Avinash] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Lennerz, Jochen K.] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Kwak, EL (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Kwak, EL (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA. NR 27 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 NOV 17 PY 2016 VL 375 IS 20 BP 1983 EP 1991 DI 10.1056/NEJMcpc1610714 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EC1HS UT WOS:000387856100012 PM 27959609 ER PT J AU Bazari, H AF Bazari, Hasan TI Case 24-2016: A Man with Malaise, Weakness, and Hypercalcemia REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Bazari, Hasan] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Bazari, H (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD NOV 17 PY 2016 VL 375 IS 20 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EC1HS UT WOS:000387856100030 ER PT J AU Reyes, LF Restrepo, MI Hinojosa, CA Soni, NJ Shenoy, AT Gilley, RP Gonzalez-Juarbe, N Noda, JR Winter, VT de la Garza, MA Shade, RE Coalson, JJ Giavedoni, LD Anzueto, A Orihuela, CJ AF Reyes, Luis F. Restrepo, Marcos I. Hinojosa, Cecilia A. Soni, Nilam J. Shenoy, Anukul T. Gilley, Ryan P. Gonzalez-Juarbe, Norberto Noda, Julio R. Winter, Vicki T. de la Garza, Melissa A. Shade, Robert E. Coalson, Jacqueline J. Giavedoni, Luis D. Anzueto, Antonio Orihuela, Carlos J. TI A Non-Human Primate Model of Severe Pneumococcal Pneumonia SO PLOS ONE LA English DT Article ID COMMUNITY-ACQUIRED PNEUMONIA; STREPTOCOCCUS-PNEUMONIAE; CARDIOVASCULAR-DISEASE; INFLAMMATORY RESPONSE; LUNG ULTRASOUND; CRITICALLY-ILL; BLUE-PROTOCOL; HOSPITALIZATION; DIAGNOSIS; MOUSE AB Rationale Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and infectious death in adults worldwide. A non-human primate model is needed to study the molecular mechanisms that underlie the development of severe pneumonia, identify diagnostic tools, explore potential therapeutic targets, and test clinical interventions during pneumococcal pneumonia. Objective To develop a non-human primate model of pneumococcal pneumonia. Methods Seven adult baboons (Papio cynocephalus) were surgically tethered to a continuous monitoring system that recorded heart rate, temperature, and electrocardiography. Animals were inoculated with 10(9) colony-forming units of S. pneumoniae using bronchoscopy. Three baboons were rescued with intravenous ampicillin therapy. Pneumonia was diagnosed using lung ultrasonography and ex vivo confirmation by histopathology and immunodetection of pneumococcal capsule. Organ failure, using serum biomarkers and quantification of bacteremia, was assessed daily. Results Challenged animals developed signs and symptoms of pneumonia 4 days after infection. Infection was characterized by the presence of cough, tachypnea, dyspnea, tachycardia and fever. All animals developed leukocytosis and bacteremia 24 hours after infection. A severe inflammatory reaction was detected by elevation of serum cytokines, including Interleukin (IL)1Ra, IL-6, and IL-8, after infection. Lung ultrasonography precisely detected the lobes with pneumonia that were later confirmed by pathological analysis. Lung pathology positively correlated with disease severity. Antimicrobial therapy rapidly reversed symptomology and reduced serum cytokines. Conclusions We have developed a novel animal model for severe pneumococcal pneumonia that mimics the clinical presentation, inflammatory response, and infection kinetics seen in humans. This is a novel model to test vaccines and treatments, measure biomarkers to diagnose pneumonia, and predict outcomes. C1 [Reyes, Luis F.; Restrepo, Marcos I.; Hinojosa, Cecilia A.; Soni, Nilam J.; Noda, Julio R.; Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, Div Pulm Dis & Crit Care Med, San Antonio, TX 78229 USA. [Reyes, Luis F.; Restrepo, Marcos I.; Hinojosa, Cecilia A.; Soni, Nilam J.; Noda, Julio R.; Anzueto, Antonio] South Texas Vet Hlth Care Syst, Div Pulm Dis & Crit Care Med, San Antonio, TX USA. [Gilley, Ryan P.; Orihuela, Carlos J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. [Shenoy, Anukul T.; Gonzalez-Juarbe, Norberto; Orihuela, Carlos J.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Winter, Vicki T.; Coalson, Jacqueline J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [de la Garza, Melissa A.; Shade, Robert E.; Giavedoni, Luis D.] Texas Biomed Res Inst, San Antonio, TX USA. RP Restrepo, MI (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Pulm Dis & Crit Care Med, San Antonio, TX 78229 USA.; Restrepo, MI (reprint author), South Texas Vet Hlth Care Syst, Div Pulm Dis & Crit Care Med, San Antonio, TX USA. EM restrepom@uthscsa.edu FU National Heart, Lung, and Blood Institute [K23HL096054]; NIH [AI114800]; Southwest National Primate Research Center grant from the Office of Research Infrastructure Programs, NIH [P51 OD011133] FX MIR's time is partially protected by Award Number K23HL096054 from the National Heart, Lung, and Blood Institute. CJO receives support from NIH grant AI114800. This investigation used resources that were supported by the Southwest National Primate Research Center grant P51 0D011133 from the Office of Research Infrastructure Programs, NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding agencies or sources of support received during this specific study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 0 Z9 0 U1 0 U2 0 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 NOV 17 PY 2016 VL 11 IS 11 AR e0166092 DI 10.1371/journal.pone.0166092 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC2AC UT WOS:000387910200018 PM 27855182 ER PT J AU Healy, WL AF Healy, William L. TI Overlapping Surgery: Do the Right Thing SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Editorial Material C1 [Healy, William L.] Newton Wellesley Hosp, Dept Orthopaed Surg, Newton, MA 02462 USA. [Healy, William L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Healy, WL (reprint author), Newton Wellesley Hosp, Dept Orthopaed Surg, Newton, MA 02462 USA.; Healy, WL (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 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 NOV 16 PY 2016 VL 98 IS 22 AR e101 DI 10.2106/JBJS.16.00879 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA EN4AH UT WOS:000395949000003 PM 27852917 ER PT J AU Hussey, DK Madanat, R Donahue, GS Rolfson, O Bragdon, CR Muratoglu, OK Malchau, H AF Hussey, Daniel K. Madanat, Rami Donahue, Gabrielle S. Rolfson, Ola Bragdon, Charles R. Muratoglu, Orhun K. Malchau, Henrik TI Scoring the Current Risk Stratification Guidelines in Follow-up Evaluation of Patients After Metal-on-Metal Hip Arthroplasty A Proposal for a Metal-on-Metal Risk Score Supporting Clinical Decision-Making SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID REPLACEMENT; JOINT; FRACTURES; IMPLANTS; DEVICES; ASR AB Background: In the follow-up evaluation of patients with metal-on-metal (MoM) hip replacements, current evidence suggests that orthopaedic surgeons should avoid reliance on any single investigative tool. Current risk stratification guidelines can be difficult to interpret because they do not provide guidance when there are several risk factors in different groups (high and low risk). To improve the clinical utility of risk stratification guidelines, we designed a scoring system to assess the risk of revision. Methods: The study population consisted of 1,709 patients (1,912 hips) enrolled in a multicenter follow-up study of a recalled MoM hip replacement. Eleven scoring criteria were determined on the basis of existing follow-up algorithm recommendations and consisted of patient-related factors, symptoms, clinical status, implant type, metal ion levels, and radiographic imaging results. Forward stepwise logistic regression was conducted to determine the minimum set of predictive variables for the risk of revision and to assign variable weights. The MoM risk score for each hip was then created by averaging the weighted values of each predictive variable. Results: Receiver operating characteristic curve analysis yielded good discrimination between all revised and unrevised hips, with an area under the curve of 0.82 (p < 0.001). The odds of revision for the group with a high MoM risk score were increased by 5.8-fold (95% confidence interval [CI], 3.1 to 11.0) relative to the moderate risk group and by 21.8-fold (95% CI, 9.9 to 48.0) compared with the low risk group. Conclusions: Although the use of MoM hip arthroplasty has been limited since 2010, we continue to be faced with the follow-up and risk assessment of thousands of patients who have not had a revision. As more knowledge about risk stratification is gained, the complexity of the algorithms is expected to increase. We propose the use of the MoM risk score as a tool to aid in the clinical decision-making process. C1 [Hussey, Daniel K.; Madanat, Rami; Donahue, Gabrielle S.; Rolfson, Ola; Bragdon, Charles R.; Muratoglu, Orhun K.; Malchau, Henrik] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. [Madanat, Rami; Rolfson, Ola; Bragdon, Charles R.; Muratoglu, Orhun K.; Malchau, Henrik] Harvard Med Sch, Dept Orthopaed Surg, Boston, MA 02115 USA. [Rolfson, Ola] Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Orthopaed, Gothenburg, Sweden. RP Malchau, H (reprint author), Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA.; Malchau, H (reprint author), Harvard Med Sch, Dept Orthopaed Surg, Boston, MA 02115 USA. EM hmalchau@mgh.harvard.edu FU Harris Orthopaedic Laboratory, Massachusetts General Hospital, Boston, Massachusetts; DePuy Orthopaedics, Warsaw, Indiana FX This study was supported by the Harris Orthopaedic Laboratory, Massachusetts General Hospital, Boston, Massachusetts, and DePuy Orthopaedics, Warsaw, Indiana. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article. NR 27 TC 0 Z9 0 U1 1 U2 1 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 NOV 16 PY 2016 VL 98 IS 22 DI 10.2106/JBJS.15.00685 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA EN4AH UT WOS:000395949000011 PM 27852907 ER PT J AU Avery, RK Albadawi, H Akbari, M Zhang, YS Duggan, MJ Sahani, DV Olsen, BD Khademhosseini, A Oklu, R AF Avery, Reginald K. Albadawi, Hassan Akbari, Mohsen Zhang, Yu Shrike Duggan, Michael J. Sahani, Dushyant V. Olsen, Bradley D. Khademhosseini, Ali Oklu, Rahmi TI An injectable shear-thinning biomaterial for endovascular embolization SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID INTRACRANIAL ANEURYSMS; ARTERIOVENOUS-MALFORMATIONS; INDUCED ANGIOGENESIS; VASCULAR OCCLUSION; PLATINUM COILS; EMBOLIC AGENT; ONYX; HYDROGELS; EXPERIENCE; SURGERY AB Improved endovascular embolization of vascular conditions can generate better patient outcomes and minimize the need for repeat procedures. However, many embolic materials, such as metallic coils or liquid embolic agents, are associated with limitations and complications such as breakthrough bleeding, coil migration, coil compaction, recanalization, adhesion of the catheter to the embolic agent, or toxicity. Here, we engineered a shear-thinning biomaterial (STB), a nanocomposite hydrogel containing gelatin and silicate nanoplatelets, to function as an embolic agent for endovascular embolization procedures. STBs are injectable through clinical catheters and needles and have hemostatic activity comparable to metallic coils, the current gold standard. In addition, STBs withstand physiological pressures without fragmentation or displacement in elastomeric channels in vitro and in explant vessels ex vivo. In vitro experiments also indicated that STB embolization did not rely on intrinsic thrombosis as coils did for occlusion, suggesting that the biomaterial may be suitable for use in patients on anticoagulation therapy or those with coagulopathy. Using computed tomography imaging, the biomaterial was shown to fully occlude murine and porcine vasculature in vivo and remain at the site of injection without fragmentation or nontarget embolization. Given the advantages of rapid delivery, in vivo stability, and independent occlusion that does not rely on intrinsic thrombosis, STBs offer an alternative gel-based embolic agent with translational potential for endovascular embolization. C1 [Avery, Reginald K.; Akbari, Mohsen; Zhang, Yu Shrike; Khademhosseini, Ali; Oklu, Rahmi] Brigham & Womens Hosp, Biomat Innovat Res Ctr, Harvard Med Sch, Dept Med,Div Engn Med, Boston, MA 02139 USA. [Avery, Reginald K.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Avery, Reginald K.; Akbari, Mohsen; Zhang, Yu Shrike; Khademhosseini, Ali] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Albadawi, Hassan] Massachusetts Gen Hosp, Harvard Med Sch, Dept Surg, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. [Akbari, Mohsen; Zhang, Yu Shrike; Khademhosseini, Ali] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Duggan, Michael J.] Massachusetts Gen Hosp, Harvard Med Sch, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02144 USA. [Sahani, Dushyant V.] Massachusetts Gen Hosp, Harvard Med Sch, Dept Radiol, Boston, MA 02144 USA. [Olsen, Bradley D.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Khademhosseini, Ali] King Abdulaziz Univ, Dept Phys, Jeddah, Saudi Arabia. [Oklu, Rahmi] Massachusetts Gen Hosp, Harvard Med Sch, Divi Vasc & Intervent Radiol, Boston, MA 02114 USA. [Albadawi, Hassan; Oklu, Rahmi] Mayo Clin, Div Vasc & Intervent Radiol, Phoenix, AZ 85054 USA. [Akbari, Mohsen] Univ Victoria, Dept Mech Engn, Victoria, BC V8W 2Y2, Canada. RP Khademhosseini, A (reprint author), Brigham & Womens Hosp, Biomat Innovat Res Ctr, Harvard Med Sch, Dept Med,Div Engn Med, Boston, MA 02139 USA. EM alik@bwh.harvard.edu; oklu.rahmi@mayo.edu FU NIH Interdepartmental Biotechnology Training Program (NIH/NIGMS) [5T32GM008334]; U.S. Army Research Office [W911NF-13-D-0001]; National Cancer Institute of the NIH Pathway to Independence Award [1K99CA201603-01A1]; NSF [EFRI-1240443]; IMMODGEL [602694]; NIH [EB012597, AR057837, DE021468, HL099073, AI105024, AR063745, EB021148, CA172738]; Mayo Clinic FX R.K.A. was supported by the NIH Interdepartmental Biotechnology Training Program (NIH/NIGMS 5T32GM008334). This research was supported by the U.S. Army Research Office under contract W911NF-13-D-0001. Y.S.Z. acknowledges the National Cancer Institute of the NIH Pathway to Independence Award (1K99CA201603-01A1). A.K. acknowledges funding from the NSF (EFRI-1240443), IMMODGEL (602694), and the NIH (EB012597, AR057837, DE021468, HL099073, AI105024, and AR063745). R.O. acknowledges funding from the NIH (EB021148 and CA172738) and the Mayo Clinic. NR 60 TC 0 Z9 0 U1 9 U2 9 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 NOV 16 PY 2016 VL 8 IS 365 AR 365ra156 DI 10.1126/scitranslmed.aah5533 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EE2XJ UT WOS:000389448500001 ER PT J AU Bellinger, AM Jafari, M Grant, TM Zhang, SY Slater, HC Wenger, EA Mo, S Lee, YAL Mazdiyasni, H Kogan, L Barman, R Cleveland, C Booth, L Bensel, T Minahan, D Hurowitz, HM Tai, T Daily, J Nikolic, B Wood, L Eckhoff, PA Langer, R Traverso, G AF Bellinger, Andrew M. Jafari, Mousa Grant, Tyler M. Zhang, Shiyi Slater, Hannah C. Wenger, Edward A. Mo, Stacy Lee, Young-Ah Lucy Mazdiyasni, Hormoz Kogan, Lawrence Barman, Ross Cleveland, Cody Booth, Lucas Bensel, Taylor Minahan, Daniel Hurowitz, Haley M. Tai, Tammy Daily, Johanna Nikolic, Boris Wood, Lowell Eckhoff, Philip A. Langer, Robert Traverso, Giovanni TI Oral, ultra-long-lasting drug delivery: Application toward malaria elimination goals SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID PLASMODIUM-FALCIPARUM MALARIA; GASTRIC RESIDENCE TIMES; ANOPHELES-GAMBIAE; LYMPHATIC FILARIASIS; RESEARCH AGENDA; BEAGLE DOGS; IVERMECTIN; TRANSMISSION; DISEASE; AFRICA AB Efforts at elimination of scourges, such as malaria, are limited by the logistic challenges of reaching large rural populations and ensuring patient adherence to adequate pharmacologic treatment. We have developed an oral, ultra-long-acting capsule that dissolves in the stomach and deploys a star-shaped dosage form that releases drug while assuming a geometry that prevents passage through the pylorus yet allows passage of food, enabling prolonged gastric residence. This gastric-resident, drug delivery dosage form releases small-molecule drugs for days to weeks and potentially longer. Upon dissolution of the macrostructure, the components can safely pass through the gastrointestinal tract. Clinical, radiographic, and endoscopic evaluation of a swine large-animal model that received these dosage forms showed no evidence of gastrointestinal obstruction or mucosal injury. We generated long-acting formulations for controlled release of ivermectin, a drug that targets malaria-transmitting mosquitoes, in the gastric environment and incorporated these into our dosage form, which then delivered a sustained therapeutic dose of ivermectin for up to 14 days in our swine model. Further, by using mathematical models of malaria transmission that incorporate the lethal effect of ivermectin against malaria-transmitting mosquitoes, we demonstrated that this system will boost the efficacy of mass drug administration toward malaria elimination goals. Encapsulated, gastric-resident dosage forms for ultra-long-acting drug delivery have the potential to revolutionize treatment options for malaria and other diseases that affect large populations around the globe for which treatment adherence is essential for efficacy. C1 [Bellinger, Andrew M.; Jafari, Mousa; Grant, Tyler M.; Zhang, Shiyi; Mo, Stacy; Lee, Young-Ah Lucy; Mazdiyasni, Hormoz; Kogan, Lawrence; Barman, Ross; Cleveland, Cody; Booth, Lucas; Bensel, Taylor; Minahan, Daniel; Hurowitz, Haley M.; Tai, Tammy; Langer, Robert; Traverso, Giovanni] MIT, Dept Chem Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Bellinger, Andrew M.; Jafari, Mousa; Grant, Tyler M.; Zhang, Shiyi; Mo, Stacy; Lee, Young-Ah Lucy; Mazdiyasni, Hormoz; Kogan, Lawrence; Barman, Ross; Cleveland, Cody; Booth, Lucas; Bensel, Taylor; Minahan, Daniel; Hurowitz, Haley M.; Tai, Tammy; Langer, Robert; Traverso, Giovanni] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Bellinger, Andrew M.] Brigham & Womens Hosp, Harvard Med Sch, Dept Med, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. [Bellinger, Andrew M.; Grant, Tyler M.] Lyndra Inc, Watertown, MA 02472 USA. [Slater, Hannah C.] Imperial Coll London, MRC Ctr Outbreak Anal & Modelling, Dept Infect Dis Epidemiol, London, England. [Wenger, Edward A.; Eckhoff, Philip A.] Inst Dis Modeling, Bellevue, WA 98005 USA. [Cleveland, Cody; Traverso, Giovanni] Brigham & Womens Hosp, Harvard Med Sch, Div Gastroenterol, 75 Francis St, Boston, MA 02115 USA. [Daily, Johanna] Albert Einstein Coll Med, Div Infect Dis, Bronx, NY 10461 USA. [Nikolic, Boris] Biomat Capital, 1107 1st Ave,Apartment 1305, Seattle, WA 98101 USA. [Langer, Robert] MIT, Media Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Langer, Robert] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Traverso, Giovanni] Massachusetts Gen Hosp, Harvard Med Sch, Div Gastroenterol, Boston, MA 02114 USA. [Zhang, Shiyi] Shanghai Jiao Tong Univ, Sch Biomed Engn, Shanghai, Peoples R China. RP Langer, R (reprint author), MIT, Dept Chem Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Langer, R (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM rlanger@mit.edu; ctraverso@partners.org FU Bill and Melinda Gates Foundation [OPP1096734, OPP1139921, OPP1068440]; NIH [EB-000244, T32 5T32HL007604-29]; Alexander von Humboldt-Stiftung Foundation (Max Planck Research Award); National Sciences and Engineering Research Council of Canada postdoctoral fellowship; Bill and Melinda Gates through Global Good Fund; Divisions of Gastroenterology at the Massachusetts General Hospital; Brigham and Women's Hospital FX This work was funded, in part, by the Bill and Melinda Gates Foundation (grant nos. OPP1096734 and OPP1139921), by NIH (grant no. EB-000244), and by the Alexander von Humboldt-Stiftung Foundation (Max Planck Research Award, Award Ltr Dtd. 2/11/08) (to R.L.). A.M.B. was supported in part by the NIH (T32 5T32HL007604-29), and M.J. was supported in part by the National Sciences and Engineering Research Council of Canada postdoctoral fellowship. H.C.S. was supported by the Bill and Melinda Gates Foundation (grant no. OPP1068440). E.A.W. and P.A.E. were supported by the Bill and Melinda Gates through the Global Good Fund. G.T. was supported in part by the Divisions of Gastroenterology at the Massachusetts General Hospital and Brigham and Women's Hospital. NR 47 TC 1 Z9 1 U1 9 U2 9 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 NOV 16 PY 2016 VL 8 IS 365 AR 365ra157 DI 10.1126/scitranslmed.aag2374 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EE2XJ UT WOS:000389448500002 PM 27856796 ER PT J AU Maus, MV Plotkin, J Jakka, G Stewart-Jones, G Riviere, I Merghoub, T Wolchok, J Renner, C Sadelain, M AF Maus, Marcela V. Plotkin, Jason Jakka, Gopinadh Stewart-Jones, Guillaume Riviere, Isabelle Merghoub, Taha Wolchok, Jedd Renner, Christoph Sadelain, Michel TI An MHC-restricted antibody-based chimeric antigen receptor requires TCR-like affinity to maintain antigen specificity SO Molecular Therapy-Oncolytics LA English DT Article ID T-CELL-RECEPTORS; TUMOR REJECTION; PHAGE DISPLAY; THERAPY; MICE; PROLIFERATION; LYMPHOCYTES; MOLECULES; RECOGNIZE; SURVIVAL AB Chimeric antigen receptors (CARs) are synthetic receptors that usually redirect T cells to surface antigens independent of human leukocyte antigen (HLA). Here, we investigated a T cell receptor-like CAR based on an antibody that recognizes HLA-A*0201 presenting a peptide epitope derived from the cancer-testis antigen NY-ESO-1. We hypothesized that this CAR would efficiently redirect transduced T cells in an HLA-restricted, antigen-specific manner. However, we found that despite the specificity of the soluble Fab, the same antibody in the form of a CAR caused moderate lysis of HLA-A2 expressing targets independent of antigen owing to T cell avidity. We hypothesized that lowering the affinity of the CAR for HLA-A2 would improve its specificity. We undertook a rational approach of mutating residues that, in the crystal structure, were predicted to stabilize binding to HLA-A2. We found that one mutation (DN) lowered the affinity of the Fab to T cell receptor-range and restored the epitope specificity of the CAR. DN CAR T cells lysed native tumor targets in vitro, and, in a xenogeneic mouse model implanted with two human melanoma lines (A2+/NYESO+ and A2+/NYESO-), DN CAR T cells specifically migrated to, and delayed progression of, only the HLA-A2+/NY-ESO-1+ melanoma. Thus, although maintaining MHC-restricted antigen specificity required T cell receptor-like affinity that decreased potency, there is exciting potential for CARs to expand their repertoire to include a broad range of intracellular antigens. C1 [Maus, Marcela V.; Plotkin, Jason; Riviere, Isabelle; Sadelain, Michel] Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, 1275 York Ave, New York, NY 10021 USA. [Maus, Marcela V.] Harvard Med Sch, Ctr Canc, Massachusetts Gen Hosp, Cellular Immunotherapy Program, Boston, MA USA. [Stewart-Jones, Guillaume] Univ Oxford, Welcome Trust Ctr Human Genet, Div Struct Biol, Oxford, England. [Merghoub, Taha; Wolchok, Jedd] MSKCC, Swim Amer Lab, Ludwig Ctr Canc Immunotherapy, New York, NY USA. [Jakka, Gopinadh; Renner, Christoph] Univ Zurich Hosp, Dept Oncol, Zurich, Switzerland. [Renner, Christoph] Univ Basel Hosp, Dept Oncol, Basel, Switzerland. [Sadelain, Michel] Weill Cornell Med Coll, York, NY 10065 USA. RP Sadelain, M (reprint author), Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, 1275 York Ave, New York, NY 10021 USA.; Sadelain, M (reprint author), Weill Cornell Med Coll, York, NY 10065 USA. EM m-sadelain@ski.mskcc.org FU Cancer Research Institute; Lake Road Foundation NIH grant [T32CA009512]; Ludwig Trust; MSK core grant [NIH P30-CA008748]; Swim Across America (SDW) FX The authors thank the MSKCC antitumor assessment and cytology cores at MSKCC. This research was in part supported by the Cancer Research Institute (MS), the Lake Road Foundation (MS) NIH grant T32CA009512 (MVM), the Ludwig Trust and Swim Across America (SDW) and the MSK core grant NIH P30-CA008748. MS thanks Loyd Old for interesting discussion to initiate this project. NR 46 TC 0 Z9 0 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2372-7705 J9 Mol Ther-Oncolytics JI Mol. Ther.-Oncolytics PD NOV 16 PY 2016 VL 3 AR UNSP 16023 DI 10.1038/mto.2016.23 PG 9 WC Oncology; Medicine, Research & Experimental SC Oncology; Research & Experimental Medicine GA EE2WK UT WOS:000389445700001 ER PT J AU Krishnan, GP Chauvette, S Shamie, I Soltani, S Timofeev, I Cash, SS Halgren, E Bazhenov, M AF Krishnan, Giri P. Chauvette, Sylvain Shamie, Isaac Soltani, Sara Timofeev, Igor Cash, Sydney S. Halgren, Eric Bazhenov, Maxim TI Cellular and neurochemical basis of sleep stages in the thalamocortical network SO ELIFE LA English DT Article ID FREELY MOVING RATS; EYE-MOVEMENT SLEEP; SLOW OSCILLATIONS; ACETYLCHOLINE-RELEASE; BASAL FOREBRAIN; CEREBRAL-CORTEX; DELTA-WAVES; WAKE CYCLE; K-COMPLEX; IN-VIVO AB The link between the combined action of neuromodulators in the brain and global brain states remains a mystery. In this study, using biophysically realistic models of the thalamocortical network, we identified the critical intrinsic and synaptic mechanisms, associated with the putative action of acetylcholine (ACh), GABA and monoamines, which lead to transitions between primary brain vigilance states (waking, non-rapid eye movement sleep [NREM] and REM sleep) within an ultradian cycle. Using ECoG recordings from humans and LFP recordings from cats and mice, we found that during NREM sleep the power of spindle and delta oscillations is negatively correlated in humans and positively correlated in animal recordings. We explained this discrepancy by the differences in the relative level of ACh. Overall, our study revealed the critical intrinsic and synaptic mechanisms through which different neuromodulators acting in combination result in characteristic brain EEG rhythms and transitions between sleep stages. C1 [Krishnan, Giri P.; Bazhenov, Maxim] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Chauvette, Sylvain; Soltani, Sara; Timofeev, Igor] Univ Laval, Dept Psychiat & Neurosci, Quebec City, PQ, Canada. [Chauvette, Sylvain; Soltani, Sara; Timofeev, Igor] Univ Laval, Ctr Rech, Inst Univ Sante Mentale Quebec, Quebec City, PQ, Canada. [Shamie, Isaac; Halgren, Eric] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Shamie, Isaac; Halgren, Eric] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Cash, Sydney S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Cash, Sydney S.] Harvard Med Sch, Boston, MA USA. RP Krishnan, GP (reprint author), Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. EM gkrishnan@ucsd.edu FU Canadian Institutes of Health Research [MOP-136969, MOP-136967]; Office of Naval Research [MURI: N000141310672]; National Institutes of Health [MH099645]; National Sciences and Engineering Research Council of Canada [298475] FX Canadian Institutes of Health Research MOP-136969 lgor Timofeev; Canadian Institutes of Health Research MOP-136967 lgor Timofeev; Office of Naval Research MURI: N000141310672 Sydney S Cash Eric Halgren Maxim Bazhenov; National Institutes of Health MH099645 Eric Halgren Maxim Bazhenov; National Sciences and Engineering Research Council of Canada 298475 Igor Timofeev NR 94 TC 1 Z9 1 U1 5 U2 5 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD NOV 16 PY 2016 VL 5 AR e18607 DI 10.7554/eLife.18607 PG 29 WC Biology SC Life Sciences & Biomedicine - Other Topics GA ED2LU UT WOS:000388677500001 ER PT J AU Agha, G Hajj, H Rifas-Shiman, SL Just, AC Hivert, MF Burris, HH Lin, XH Litonjua, AA Oken, E DeMeo, DL Gillman, MW Baccarelli, AA AF Agha, Golareh Hajj, Hanine Rifas-Shiman, Sheryl L. Just, Allan C. Hivert, Marie-France Burris, Heather H. Lin, Xihong Litonjua, Augusto A. Oken, Emily DeMeo, Dawn L. Gillman, Matthew W. Baccarelli, Andrea A. TI Birth weight-for-gestational age is associated with DNA methylation at birth and in childhood SO CLINICAL EPIGENETICS LA English DT Article DE Epigenetics; DNA methylation; Birth weight ID RED-BLOOD-CELLS; RHO-ASSOCIATED KINASE; DEVELOPMENTAL ORIGINS; MATERNAL SMOKING; FETAL-GROWTH; HUMAN GENOME; CPG SITES; MICROARRAY; NEWBORNS; EXPRESSION AB Background: Both higher and lower fetal growth are associated with cardio-metabolic health later in life, suggesting that prenatal developmental programming determines long-term cardiovascular disease risk. Epigenetic mechanisms, which orchestrate fetal growth and development, may offer insight on the early programming of health and disease. We investigated whether birth weight-for-gestational is associated with DNA methylation at birth and mid-childhood, measured via the Infinium 450K array. Methods/results: Participants were from Project Viva, a pre-birth cohort of pregnant women and their children in Eastern Massachusetts. After exclusion of participants with maternal type 1 or 2 diabetes and gestational age <34 weeks, we used DNA methylation assays from 476 venous umbilical cord blood samples and a subset of 235 who additionally had peripheral blood samples available in mid-childhood (age 7-10 years). Among 392,918 CpG sites analyzed, birth weight-for-gestational age z-score was associated with cord blood DNA methylation at 34 CpGs (false discovery rate P < 0.05), after adjusting for maternal age, race/ethnicity, education, smoking, parity, delivery mode, pre-pregnancy BMI, gestational diabetes status, child sex, and estimated cord blood cell proportions based on a cord blood reference panel. Two of these CpGs were previously reported in epigenome-wide analyses of birth weight, and several other CpGs map to genes relevant to fetal growth and development. Namely, higher birth weight-for-gestational age was associated with higher methylation at four CpGs at the PBX1 locus (e.g., beta (95% CI) for lead signal at cg06750897 = 1.9 (1.2, 2.6)), which encodes a transcription factor that regulates embryonic development. Birth weight-for-gestational age was also associated with mid-childhood blood DNA methylation at four of the 34 CpGs identified in cord blood analyses, including sites at the PBX1 locus described. Conclusions: We identified CpG sites where birth weight-for-gestational age was associated with DNA methylation at birth, and for a subset of these sites, birth weight-for-gestational age was also associated with DNA methylation at mid-childhood. C1 [Agha, Golareh; Baccarelli, Andrea A.] Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, 722 West 168th St, New York, NY 10032 USA. [Hajj, Hanine] Boston Childrens Hosp, Div Newborn Med, Boston, MA USA. [Rifas-Shiman, Sheryl L.; Hivert, Marie-France; Oken, Emily; Gillman, Matthew W.] Harvard Med Sch, Dept Populat Med, Obes Prevent Program, Boston, MA USA. [Rifas-Shiman, Sheryl L.; Hivert, Marie-France; Oken, Emily; Gillman, Matthew W.] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Just, Allan C.] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. [Hivert, Marie-France] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Burris, Heather H.] Harvard Med Sch, Dept Neonatol, Dept Pediat, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Burris, Heather H.] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Lin, Xihong] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Litonjua, Augusto A.] Brigham & Womens Hosp, Channing Lab, 75 Francis St, Boston, MA 02115 USA. [DeMeo, Dawn L.] Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA USA. [Gillman, Matthew W.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. RP Agha, G (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, 722 West 168th St, New York, NY 10032 USA. EM Golareh.agha@columbia.edu OI Just, Allan/0000-0003-4312-5957 FU National Institutes of Health [R01 NR013945, R01 HL111108, R01 HD034568, K24 HD069408, K23 ES022242] FX This study was supported by grants from the National Institutes of Health (R01 NR013945, R01 HL111108, R01 HD 034568, K24 HD069408, K23 ES022242 NR 59 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 1868-7083 J9 CLIN EPIGENETICS JI Clin. Epigenetics PD NOV 16 PY 2016 VL 8 AR 118 DI 10.1186/s13148-016-0285-3 PG 12 WC Oncology SC Oncology GA EC0YK UT WOS:000387828700003 PM 27891191 ER PT J AU Evans, WS Quimby, M Dickey, MW Dickerson, BC AF Evans, William S. Quimby, Megan Dickey, Michael Walsh Dickerson, Bradford C. TI Relearning and Retaining Personally-Relevant Words using Computer-Based Flashcard Software in Primary Progressive Aphasia SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE primary progressiveaphasia; rehabilitation; computer-basedtreatment; distributed practice; aphasia; spaced retrieval ID SEMANTIC DEMENTIA; VERBAL LABELS; THERAPY; ANOMIA; MODELS AB Although anomia treatments have often focused on training small sets of words in the hopes of promoting generalization to untrained items, an alternative is to directly train a larger set of words more efficiently. The current case study reports on a novel treatment for a patient with semantic variant Primary Progressive Aphasia (svPPA), in which the patient was taught to make and practice flashcards for personally-relevant words using an open-source computer program (Anki). Results show that the patient was able to relearn and retain a large subset of her studied words for up to 20 months, the full duration of the study period. At the end of treatment, she showed good retention for 139 words. While only a subset of the 591 studied overall, this is still far more words than is typically targeted in svPPA interventions. Furthermore, she showed evidence of generalization to perceptually distinct stimuli during confrontation naming and temporary gains in semantic fluency, suggesting limited gains in semantic knowledge as a result of training. This case represents a successful example of patient-centered treatment, where the patient used a computer-based intervention independently at home. It also illustrates how data captured from computer-based treatments during routine clinical care can provide valuable practice-based evidence for motivating further treatment research C1 [Evans, William S.; Dickey, Michael Walsh] VA Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15261 USA. [Quimby, Megan; Dickerson, Bradford C.] Massachusetts Gen Hosp, Dept Neurol, Frontotemporal Disorders Unit, Boston, MA 02114 USA. RP Evans, WS (reprint author), VA Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15261 USA. EM william.evans5@va.gov FU VA Rehabilitation Research and Development [I01 RX000832]; National Institutes of Health [R21 NS077059]; VA Pittsburgh Healthcare System Geriatric Research Education and Clinical Center FX This research was supported by VA Rehabilitation Research and Development grant I01 RX000832 (MWD), National Institutes of Health grant R21 NS077059 (BCD), and the VA Pittsburgh Healthcare System Geriatric Research Education and Clinical Center (WSE and MWD). The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government. NR 27 TC 0 Z9 0 U1 6 U2 6 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 NOV 16 PY 2016 VL 10 AR 561 DI 10.3389/fnhum.2016.00561 PG 8 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA EC0XL UT WOS:000387824900001 PM 27899886 ER PT J AU Baez-Mendoza, R Schultz, W AF Baez-Mendoza, Raymundo Schultz, Wolfram TI Performance error-related activity in monkey striatum during social interactions SO SCIENTIFIC REPORTS LA English DT Article ID PRIMATE STRIATUM; CINGULATE CORTEX; NEURAL SYSTEM; REWARD; NEURONS; PREDICTION; BEHAVIOR; COMPENSATION; DOPAMINE; VALUES AB Monitoring our performance is fundamental to motor control while monitoring other's performance is fundamental to social coordination. The striatum is hypothesized to play a role in action selection, action initiation, and action parsing, but we know little of its role in performance monitoring. Furthermore, the striatum contains neurons that respond to own and other's actions. Therefore, we asked if striatal neurons signal own and conspecific's performance errors. Two macaque monkeys sitting across a touch-sensitive table in plain view of each other took turns performing a simple motor task to obtain juice rewards while we recorded single striatal neurons from one monkey at a time. Both monkeys made more errors after individually making an error but made fewer errors after a conspecific error. Thus, monkeys' behavior was influenced by their own and their conspecific's past behavior. A population of striatal neurons responded to own and conspecific's performance errors independently of a negative reward prediction error signal. Overall, these data suggest that monkeys are influenced by social errors and that striatal neurons signal performance errors. These signals might be important for social coordination, observational learning and adjusting to an ever-changing social landscape. C1 [Baez-Mendoza, Raymundo; Schultz, Wolfram] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England. [Baez-Mendoza, Raymundo] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Baez-Mendoza, Raymundo] Harvard Med Sch, Boston, MA 02114 USA. RP Baez-Mendoza, R (reprint author), Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England.; Baez-Mendoza, R (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA.; Baez-Mendoza, R (reprint author), Harvard Med Sch, Boston, MA 02114 USA. EM raymundobaez@gmail.com OI Baez-Mendoza, Raymundo/0000-0002-5989-7647 FU Wellcome Trust (Principal Research Fellowship) [095495]; European Research Council (ERC Advanced Grant) [293549]; NIH Caltech Conte Center [P50MH094258]; Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health) [UL1 TR001102]; Harvard University FX We thank Kelly MJ Diederen, Fabian Grabenhorst, and William R Stauffer for discussions, Armin Lak for advice on TD modelling and discussions, and Aled David for technical support. This work was supported by the Wellcome Trust (Principal Research Fellowship and Programme Grant 095495), European Research Council (ERC Advanced Grant 293549), and NIH Caltech Conte Center (P50MH094258). This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic healthcare centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. NR 30 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 16 PY 2016 VL 6 AR 37199 DI 10.1038/srep37199 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC1UZ UT WOS:000387894800001 PM 27849004 ER PT J AU Yu, ZW Zeng, ZW Zhang, J Pan, YX Chen, MJ Guo, YH Yu, N Chodosh, J Fu, N Che, XY Zhang, QW AF Yu, Zhiwu Zeng, Zhiwei Zhang, Jing Pan, Yuxian Chen, Manjun Guo, Yonghui Yu, Nan Chodosh, James Fu, Ning Che, Xiaoyan Zhang, Qiwei TI Fatal Community-acquired Pneumonia in Children Caused by Re-emergent Human Adenovirus 7d Associated with Higher Severity of Illness and Fatality Rate SO SCIENTIFIC REPORTS LA English DT Article ID ACUTE RESPIRATORY-DISEASE; L1 52/55-KILODALTON PROTEIN; MOLECULAR EPIDEMIOLOGY; CHILDHOOD DEATHS; TRACT INFECTIONS; GENOME SEQUENCE; SOUTHERN CHINA; OUTBREAK; TYPE-7; IMMUNOCOMPETENT AB Human adenoviruses (HAdVs) are highly contagious pathogens causing acute respiratory disease (ARD), such as community-acquired pneumonia. HAdV-7d, a re-emergent genomic variant, has been recently reported in Asia and the United States after a several-decade absence. However, whether HAdV-7d is associated with higher severity than other types is currently unclear. In this study, the clinical and epidemiological investigation showed that fever, cough, and sore throat were the three most common respiratory symptoms of HAdV infections. HAdV-7 caused longer duration of fever, higher morbidity of tachypnea/dyspnea, pleural effusion, diarrhea, hepatosplenomegaly, consciousness alteration, as well as higher rates of pneumonia, mechanical ventilation and higher fatality rate (28.6%) than other types, particularly HAdV-3 and HAdV-2. The genomes of seven HAdV-7d isolates from mild, severe, and fatal cases were sequenced and highly similar with each other. Surprisingly, two isolates (2011, 2012) had 100% identical genomes with an earlier strain from a fatal ARD outbreak in China (2009), which elucidates the virus origin and confirms the unexpected HAdV genomic conservation and stability. Phylogenetic analysis indicated that L1 52/55-kDa DNA packaging protein may be associated with the higher severity of illness and fatality rate of HAdV-7. Clinicians need to be aware of HAdVs in children with ARD. C1 [Yu, Zhiwu; Pan, Yuxian; Chen, Manjun; Guo, Yonghui; Yu, Nan; Fu, Ning; Che, Xiaoyan] Southern Med Univ, Zhujiang Hosp, Lab Emerging Infect Dis, Guangzhou 510282, Guangdong, Peoples R China. [Yu, Zhiwu; Pan, Yuxian; Chen, Manjun; Guo, Yonghui; Yu, Nan; Fu, Ning; Che, Xiaoyan] Southern Med Univ, Zhujiang Hosp, Div Lab Med, Guangzhou 510282, Guangdong, Peoples R China. [Zeng, Zhiwei; Zhang, Jing; Zhang, Qiwei] Southern Med Univ, Guangdong Prov Key Lab Trop Dis Res, Sch Publ Hlth, Biosafety Level Lab 3, Guangzhou 510515, Guangdong, Peoples R China. [Chodosh, James; Zhang, Qiwei] Harvard Med Sch, Dept Ophthalmol, Howe Lab, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Zhang, QW (reprint author), Southern Med Univ, Guangdong Prov Key Lab Trop Dis Res, Sch Publ Hlth, Biosafety Level Lab 3, Guangzhou 510515, Guangdong, Peoples R China.; Zhang, QW (reprint author), Harvard Med Sch, Dept Ophthalmol, Howe Lab, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. EM zhang.qiwei@yahoo.com FU National Projects of Major Infectious Disease Control and Prevention [2012ZX10004213, 2013ZX10004805]; National High Technology Research and Development Program of China [863 Program] [2011AA02A116]; Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme; National Natural Science Foundation of China [31370199, 31570155]; Guangzhou Healthcare Collaborative Innovation Major Project [201400000002]; Excellent Young Teacher Training Plan of Guangdong Province [Yq2013039]; China Scholarship Council (CSC) [201508440056]; Young Top-notch Talents of Guangdong Provincial Special Support Program FX This work was supported by grants from the National Projects of Major Infectious Disease Control and Prevention [2012ZX10004213 and 2013ZX10004805], National High Technology Research and Development Program of China [863 Program 2011AA02A116], Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme as well as the National Natural Science Foundation of China [31370199 and 31570155], Guangzhou Healthcare Collaborative Innovation Major Project (201400000002), and the Excellent Young Teacher Training Plan of Guangdong Province [Yq2013039]. Q.Z. was funded by the China Scholarship Council (CSC No. 201508440056) as a Visiting Scholar (2015-2016) and Young Top-notch Talents of Guangdong Provincial Special Support Program (2014). The Funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors dedicate this work to their friend, colleague, and collaborator Professor Xiaoyan Che (1962-2013). NR 60 TC 1 Z9 1 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 NOV 16 PY 2016 VL 6 AR 37216 DI 10.1038/srep37216 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC2DN UT WOS:000387919900001 PM 27848998 ER PT J AU Lesenfants, D Habbal, D Chatelle, C Schnakers, C Laureys, S Noirhomme, Q AF Lesenfants, Damien Habbal, Dina Chatelle, Camille Schnakers, Caroline Laureys, Steven Noirhomme, Quentin TI Electromyographic decoding of response to command in disorders of consciousness SO NEUROLOGY LA English DT Article ID BRAIN-COMPUTER INTERFACE; LOCKED-IN SYNDROME; UNRESPONSIVE WAKEFULNESS; DIFFERENTIAL-DIAGNOSIS; VEGETATIVE STATE; COMA; AWARENESS; PARADIGM AB Objective: To propose a new methodology based on single-trial analysis for detecting residual response to command with EMG in patients with disorders of consciousness (DOC), overcoming the issue of trial dependency and decreasing the influence of a patient's fluctuation of vigilance or arousal over time on diagnostic accuracy. Methods: Forty-five patients with DOC (18 with vegetative/unresponsive wakefulness syndrome [VS/UWS], 22 in a minimally conscious state [MCS], 3 who emerged from MCS [EMCS], and 2 with locked-in syndrome [LIS]) and 20 healthy controls were included in the study. Patients were randomly instructed to either move their left or right hand or listen to a control command ("It is a sunny day") while EMG activity was recorded on both arms. Results: Differential EMG activity was detected in all MCS cases displaying reproducible response to command at bedside on multiple assessments, even though only 6 of the 14 individuals presented a behavioral response to command on the day of the EMG assessment. An EMG response was also detected in all EMCS and LIS patients, and 2 MCS patients showing nonreflexive movements without command following at the bedside. None of the VS/UWS presented a response to command with this method. Conclusions: This method allowed us to reliably distinguish between different levels of consciousness and could potentially help decrease diagnostic errors in patients with motor impairment but presenting residual motor activity. C1 [Lesenfants, Damien] Brown Univ, Sch Engn, Providence, RI 02912 USA. [Lesenfants, Damien] Brown Univ, Inst Brain Sci, Providence, RI 02912 USA. [Habbal, Dina; Laureys, Steven] CHU Univ Hosp Liege, GIGA Res, Coma Sci Grp, Liege, Belgium. [Chatelle, Camille] Massachusetts Gen Hosp, Lab NeuroImaging Coma & Consciousness, Boston, MA 02114 USA. [Schnakers, Caroline] Univ Calif Los Angeles, Dept Neurosurg, Los Angeles, CA USA. [Noirhomme, Quentin] Brain Innovat BV, Maastricht, Netherlands. [Noirhomme, Quentin] Maastricht Univ, Maastricht, Netherlands. RP Lesenfants, D (reprint author), Brown Univ, Sch Engn, Providence, RI 02912 USA.; Lesenfants, D (reprint author), Brown Univ, Inst Brain Sci, Providence, RI 02912 USA. EM damien_lesenfants@brown.edu FU National Funds for Scientific Research (FNRS); European ICT Programme Projects [FP7-247919 DECODER]; James McDonnell Foundation; French Speaking Community Concerted Research Action; University of Liege FX Supported by the National Funds for Scientific Research (FNRS), European ICT Programme Projects FP7-247919 DECODER, James McDonnell Foundation, French Speaking Community Concerted Research Action, and University of Liege. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. D.L., D.H., C.C., C.S., S.L., and Q.N. had full access to all the data in the study, and the corresponding author had final responsibility for the decision to submit for publication. NR 36 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD NOV 15 PY 2016 VL 87 IS 20 BP 2099 EP 2107 DI 10.1212/WNL.0000000000003333 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA EI1KM UT WOS:000392236100010 PM 27770069 ER PT J AU Degrauwe, N Suva, ML Janiszewska, M Riggi, N Stamenkovic, I AF Degrauwe, Nils Suva, Mario-Luca Janiszewska, Michalina Riggi, Nicolo Stamenkovic, Ivan TI IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer SO GENES & DEVELOPMENT LA English DT Review DE cancer; IGF2BP; IMP; RNA binding proteins; let-7; stem cells ID ACTIN MESSENGER-RNA; LONG NONCODING RNA; PREDICTS EARLY RECURRENCE; GENOME-WIDE ASSOCIATION; NEGATIVE BREAST-CANCER; LINDAU GENE-PRODUCT; CODING REGION; HEPATOCELLULAR-CARCINOMA; MICRORNA BIOGENESIS; CRD-BP AB IMPs, also known as insulin-like growth factor 2 (IGF2) messenger RNA (mRNA)-binding proteins (IGF2BPs), are highly conserved oncofetal RNA-binding proteins (RBPs) that regulate RNA processing at several levels, including localization, translation, and stability. Three mammalian IMP paralogs (IMPI-3) have been identified that are expressed in most organs during embryogenesis, where they are believed to play an important role in cell migration, metabolism, and stem cell renewal. Whereas some IMP2 expression is retained in several adult mouse organs, IMP1 and IMP3 are either absent or expressed at very low levels in most tissues after birth. However, all three paralogs can be re-expressed upon malignant transformation and are found in a broad range of cancer types where their expression often correlates with poor prognosis. IMPs appear to resume their physiological functions in malignant cells, which not only. contribute to tumor progression but participate in the establishment and maintenance of tumor cell hierarchies. This review summarizes our current understanding of the functions of IMPs during normal development and focuses on a series of recent observations that have provided new insight into how their physiological functions enable IMPs to play a potentially key role in cancer stem cell maintenance and tumor growth. C1 [Degrauwe, Nils] Univ Lausanne, CHU Vaudois, Dept Med, CH-1011 Lausanne, Switzerland. [Suva, Mario-Luca] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Mol Pathol Unit, Boston, MA 02129 USA. [Janiszewska, Michalina] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02215 USA. [Riggi, Nicolo; Stamenkovic, Ivan] Univ Lausanne, CHU Vaudois, Expt Pathol Serv, CH-1011 Lausanne, Switzerland. RP Stamenkovic, I (reprint author), Univ Lausanne, CHU Vaudois, Expt Pathol Serv, CH-1011 Lausanne, Switzerland. EM ivan.stamenkovic@chuv.ch FU Swiss National Foundation (FNS) [310030_150024]; Swiss Institute for Experimental Cancer Research (ISREC) grant FX Work on IMPs was supported by the Swiss National Foundation (FNS) grant 310030_150024 and a Swiss Institute for Experimental Cancer Research (ISREC) grant. NR 147 TC 0 Z9 0 U1 9 U2 9 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 NOV 15 PY 2016 VL 30 IS 22 BP 2459 EP 2474 DI 10.1101/gad.287540.116 PG 16 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA EF8XQ UT WOS:000390615700001 PM 27940961 ER PT J AU Wada, S Neinast, M Jang, C Ibrahim, YH Lee, G Babu, A Li, J Hoshino, A Rowe, GC Rhee, J Martina, JA Puertollano, R Blenis, J Morley, M Baur, JA Seale, P Arany, Z AF Wada, Shogo Neinast, Michael Jang, Cholsoon Ibrahim, Yasir H. Lee, Gina Babu, Apoorva Li, Jian Hoshino, Atsushi Rowe, Glenn C. Rhee, James Martina, Jose A. Puertollano, Rosa Blenis, John Morley, Michael Baur, Joseph A. Seale, Patrick Arany, Zoltan TI The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue SO GENES & DEVELOPMENT LA English DT Article DE adipose tissue; beige fat; mitochondria; FLCN; mTOR; TFE3 ID TRANSCRIPTION FACTOR TFE3; LYSOSOMAL BIOGENESIS; OXIDATIVE-METABOLISM; SIGNAL INTEGRATION; RAG GTPASES; BEIGE FAT; ACTIVATION; FOLLICULIN; AUTOPHAGY; MUSCLE AB Noncanonical mechanistic target of rapamycin (mTOR) pathways remain poorly understood. Mutations in the tumor suppressor folliculin (FLCN) cause Birt-Hogg-Dube syndrome, a hamartomatous disease marked by mitochondria-rich kidney tumors. FLCN functionally interacts with mTOR and is expressed in most tissues, but its role in fat has not been explored. We show here that FLCN regulates adipose tissue browning via mTOR and the transcription factor TFE3. Adipose-specific deletion of FLCN relieves mTOR-dependent cytoplasmic retention of TFE3, leading to direct induction of the PGC-1 transcriptional coactivators, drivers of mitochondrial biogenesis and the browning program. Cytoplasmic retention of TFE3 by mTOR is sensitive to ambient amino acids, is independent of growth factor and tuberous sclerosis complex (TSC) signaling, is driven by RagC/D, and is separable from canonical mTOR signaling to S6K. Codeletion of TFE3 in adipose-specific FLCN knockout animals rescues adipose tissue browning, as does codeletion of PGC-1 beta. Conversely, inducible expression of PGC-1 beta in white adipose tissue is sufficient to induce beige fat gene expression in vivo. These data thus unveil a novel FLCN mTOR TFE3 PGC-1 beta pathway separate from the canonical TSC-mTOR-S6K pathway-that regulates browning of adipose tissue. C1 [Wada, Shogo; Neinast, Michael; Jang, Cholsoon; Babu, Apoorva; Li, Jian; Hoshino, Atsushi; Morley, Michael; Baur, Joseph A.; Seale, Patrick; Arany, Zoltan] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Wada, Shogo; Neinast, Michael; Jang, Cholsoon; Babu, Apoorva; Li, Jian; Hoshino, Atsushi; Morley, Michael; Baur, Joseph A.; Seale, Patrick; Arany, Zoltan] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Jang, Cholsoon] Princeton Univ, Chem & Integrat Genom, Princeton, NJ 08544 USA. [Ibrahim, Yasir H.; Lee, Gina; Blenis, John] Weill Cornell Med, Meyer Canc Ctr, Dept Pharmacol, New York, NY USA. [Rowe, Glenn C.] Univ Alabama Birmingham, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Rhee, James] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Martina, Jose A.; Puertollano, Rosa] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20814 USA. RP Arany, Z (reprint author), Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA.; Arany, Z (reprint author), Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. EM zarany@mail.med.upenn.edu OI Rowe, Glenn/0000-0002-8195-9605 FU American Diabetes Association [1-16-PDF-117]; Toyobo Biotechnology Foundation; University of Pennsylvania [T32 GM-07229]; LAM Foundation; Tuberous Sclerosis Alliance; National Research Foundation of Korea; National Institutes of Health [T32GM007592, GM51405, HL121266]; Foundation for Anesthesia Education and Research; Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases [DK098656, DK107667]; National Institute on Aging [AG043483]; National Heart, Lung, and Blood Institute [HL094499] FX We thank Bridget Gosis for technical support and critical discussion; Dr. Antonio Davila Jr. for expert advice; Dr. Eleftheria Maratos-Flier in Beth Israel Deaconess Medical Center/Harvard Medical School for CLAMS and DEXA analyses; Dr. Rexford Ahima, Dr. Frederick Anokye-Danso, and the Diabetes Research Center (DRC) Mouse Phenotyping Core at the University of Pennsylvania for in vivo respiration assay (P30-DK19525); Andrea Stout and Jasmine Zhao from the Cell and Developmental Biology Microscopy Core at the University of Pennsylvania for confocal microscopy imaging; Raymond Meade from the Electron Microscopy Resource laboratory at the Perelman School of Medicine, University of Pennsylvania, for TEM imaging; and Lan Cheng from the Histology and Gene Expression Core at the University of Pennsylvania Cardiovascular Institute for histology sample processing. S.W. is supported by an American Diabetes Association Postdoctoral Fellowship Award (1-16-PDF-117) and was supported by the Toyobo Biotechnology Foundation. M.N. is supported by a University of Pennsylvania Cell and Molecular Biology training grant (T32 GM-07229). G.L. is supported by the LAM Foundation, the Tuberous Sclerosis Alliance, and the National Research Foundation of Korea. J.R. was supported by grants from the National Institutes of Health [T32GM007592] and a Mentored Research Training Grant from the Foundation for Anesthesia Education and Research. J.A.M. and R.P. were supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health. J.B. is supported by the National Institutes of Health (GM51405 and HL121266). J.A.B. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (DK098656) and National Institute on Aging (AG043483). Z.A. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (DK107667) and National Heart, Lung, and Blood Institute (HL094499). S.W. designed and conducted the experiments, analyzed/interpreted the data, and wrote the manuscript. C.J. and M.N. conducted experiments and analyzed data. Y.H.I., G.L., and J.A.B conducted the in vitro kinase assay and gave intellectual input on mTOR signaling. A.B. and M.M. performed bioinformatics analysis on RNA-seq data. J.L. and A.H. generated critical reagents. J.A.M. and R.P. generated the phospho-TFE3 (Ser320)-specific antibody and gave intellectual input on TFE3 biology. G.C.R., J.R., JAB., and P.S. assisted in critical discussion and study design. Z.A. designed the study, interpreted the data, and wrote the manuscript. NR 47 TC 0 Z9 0 U1 1 U2 1 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 NOV 15 PY 2016 VL 30 IS 22 BP 2551 EP 2564 DI 10.1101/gad.287953.116 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA EF8XQ UT WOS:000390615700008 PM 27913603 ER PT J AU Ding, J Bai, X Wang, XL Wang, YF Shi, HN Rosenthal, B Boireau, P Wu, XP Liu, MY Liu, XL AF Ding, J. Bai, X. Wang, X. L. Wang, Y. F. Shi, H. N. Rosenthal, B. Boireau, P. Wu, X. P. Liu, M. Y. Liu, X. L. TI Developmental profile of select immune cells in mice infected with Trichinella spiralis during the intestinal phase SO VETERINARY PARASITOLOGY LA English DT Article; Proceedings Paper CT 14th International Conference on Trichinellosis (ICT) CY SEP 14-18, 2015 CL Berlin, GERMANY SP Fed Inst Risk Assessment, Free Univ Berlin, Fac Vet Med, German Soc Vet Med, Sect Parasitol, Fed Minist Food & Agr DE Trichinella spiralis; Immune response; T cells; B cells; CD41+/CD8+ratio; Macrophages ID IN-VITRO; WORM EXPULSION; T-CELLS; APOPTOSIS; MACROPHAGES; SUPPRESSION; MECHANISM; STAGE AB Trichinella spiralis can cause immunosuppression during the intestinal phase of early infection. However, changes in the peripheral blood during T. spiralis early infection remain unclear. Here, select immune cells in mice infected with 500 muscle larvae (ML) of T. spiralis during the intestinal phase of infection were studied. First, the recovery rates of the intestinal worms and female fecundity were determined, and the results showed that the intestinal worms were completely eliminated at 17 days post-infection (dpi) and that large numbers of new-born larvae (NBL) were generated from 5 to 9 dpi. Using flow cytometry, it was shown that the number of CD4+ T cells and CD8+ T cells increased over the entire intestinal phase, except on 7 dpi when CD4+ T cells decreased significantly compared to the control groups. Although both CD4+ and CD8+ T cells increased, CD8+ T cells increased more than CD4+ T cells, leading to a lower CD4+/CD8+ ratio compared to the control group. Subsequently, a depression of the proliferative response of T cells to concanavalin A (Con A) was noticed at 7 and 11 dpi. Although the proliferative response of B cells to LPS was enhanced, the number of B cells from mouse peripheral blood stimulated by T. spiralis antigens showed no differences with the control group prior to 11 dpi. The expression of CD14 on monocytemacrophages decreased during the same period, which meant that the antigen-presenting response was reduced in the immune system of the infected mice. Moreover, the alternatively activated macrophages were induced in T. spiralis early infection. These data provide a better understanding of the development of the intestinal immune response in mice infected with T. spiralis. (C) 2016 Elsevier B.V. All rights reserved. C1 [Ding, J.; Bai, X.; Wang, X. L.; Wang, Y. F.; Wu, X. P.; Liu, M. Y.; Liu, X. L.] Jilin Univ, Natl Inst Parasit Dis, Chinese Ctr Dis Control & Prevent, Shanghai Key Lab Zoonoses Res,Minist Educ,Inst Zo, Changchun, Peoples R China. [Shi, H. N.] Massachusetts Gen Hosp East, Mucosal Immunol Lab, Pediat Gastroenterol Unit, Boston, MA USA. [Rosenthal, B.] USDA, Anim Parasit Dis Lab, Bldg 1180, Beltsville, MD 20705 USA. [Boireau, P.] Hlth Anim Lab, ANSES, Maisons Alfort, France. [Liu, M. Y.] Jiangsu Coinnovat Ctr Prevent & Control Important, Yangzhou, Jiangsu, Peoples R China. RP Wu, XP; Liu, MY; Liu, XL (reprint author), Jilin Univ, Natl Inst Parasit Dis, Chinese Ctr Dis Control & Prevent, Shanghai Key Lab Zoonoses Res,Minist Educ,Inst Zo, Changchun, Peoples R China. EM lvy.2001@163.com; liumy@jlu.edu.cn; liuxlei@163.com NR 30 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4017 EI 1873-2550 J9 VET PARASITOL JI Vet. Parasitol. PD NOV 15 PY 2016 VL 231 SI SI BP 77 EP 82 DI 10.1016/j.vetpar.2016.07.019 PG 6 WC Parasitology; Veterinary Sciences SC Parasitology; Veterinary Sciences GA EG0LK UT WOS:000390724100013 PM 27501987 ER PT J AU Bai, X Wang, XL Tang, B Shi, HN Boireau, P Rosenthal, B Wu, XP Liu, MY Liu, XL AF Bai, X. Wang, X. L. Tang, B. Shi, H. N. Boireau, P. Rosenthal, B. Wu, X. P. Liu, M. Y. Liu, X. L. TI The roles of supernatant of macrophage treated by excretory-secretory products from muscle larvae of Trichinella spiralis on the differentiation of C2C12 myoblasts SO VETERINARY PARASITOLOGY LA English DT Article; Proceedings Paper CT 14th International Conference on Trichinellosis (ICT) CY SEP 14-18, 2015 CL Berlin, GERMANY SP Fed Inst Risk Assessment, Free Univ Berlin, Fac Vet Med, German Soc Vet Med, Sect Parasitol, Fed Minist Food & Agr DE Trichinella spiralis; Excretory-secretory products; J774A.1 macrophage; C2C12 myoblast ID NURSE CELL-FORMATION; SKELETAL-MUSCLE; IN-VITRO; MYOGENIC DIFFERENTIATION; SATELLITE CELLS; EXPRESSION; PROTEIN; REGENERATION; PROLIFERATION; TRICHINOSIS AB The excretory-secretory products (ESPs) released by the muscle-larvae (ML) stage of Trichinella spiralis have been suggested to be involved in nurse cell formation. However, the molecular mechanisms by which ML-ESPs modulate nurse cell formation remain unclear. Macrophages exert either beneficial or deleterious effects on tissue repair, depending on their activation/polarization state. They are crucial for skeletal muscle repair, notably, via their actions on myogenic precursor cells. However, these interactions during T. spiralis infection have not been characterized. In the present study, the ability of conditioned medium (CM) from J774A.1 macrophages treated with ML-ESPs to influence the differentiation of murine myoblasts, and the mechanisms of this influence, were investigated in vitro. The results showed that the expression of Myogenic Regulatory Factors (MRFs) MyoD and myogenin, myosin heavy chain (MyHC), and the p21 cyclin-dependent kinase inhibitor were reduced in CM treated cells compared to their expression in the control group. These findings indicated that CM inhibited myoblast differentiation. Conversely, CM promoted myoblast proliferation and increased cyclin D1 levels. Taken together, results of our study suggested that CM can indirectly influence myoblast differentiation and proliferation, which provides a new method for the elucidation of the complex mechanisms involved in cell-parasite and cell-cell interactions during T. spiralis infection. (C) 2016 Elsevier B.V. All rights reserved. C1 [Bai, X.; Wang, X. L.; Tang, B.; Wu, X. P.; Liu, M. Y.; Liu, X. L.] Jilin Univ, Natl Inst Parasit Dis, Chinese Ctr Dis Control & Prevent, Shanghai Key Lab Zoonoses Res,Minist Educ,Inst Zo, Changchun, Peoples R China. [Shi, H. N.] Massachusetts Gen Hosp East, Pediat Gastroenterol Unit, Mucosal Immunol Lab, Boston, MA USA. [Boireau, P.] Hlth Anim Lab, ANSES, Maisons Alfort, France. [Rosenthal, B.] USDA, Anim Parasit Dis Lab, Bldg 1180, Beltsville, MD 20705 USA. [Liu, M. Y.] Jiangsu Coinnovat Ctr Prevent & Control Important, Yangzhou, Jiangsu, Peoples R China. RP Wu, XP; Liu, MY; Liu, XL (reprint author), Jilin Univ, Natl Inst Parasit Dis, Chinese Ctr Dis Control & Prevent, Shanghai Key Lab Zoonoses Res,Minist Educ,Inst Zo, Changchun, Peoples R China. EM lvy.2001@163.com; liumy@jlu.edu.cn; liuxlei@163.com OI Rosenthal, Benjamin/0000-0002-0224-3773 NR 42 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4017 EI 1873-2550 J9 VET PARASITOL JI Vet. Parasitol. PD NOV 15 PY 2016 VL 231 SI SI BP 83 EP 91 DI 10.1016/j.vetpar.2016.07.033 PG 9 WC Parasitology; Veterinary Sciences SC Parasitology; Veterinary Sciences GA EG0LK UT WOS:000390724100014 PM 27501988 ER PT J AU Goto, K Kato, N Chung, RT AF Goto, Kaku Kato, Naoya Chung, Raymond T. TI Anti-hepatocellular carcinoma properties of the anti-alcoholism drug disulfiram discovered to enzymatically inhibit the AMPK-related kinase SNARK in vitro SO ONCOTARGET LA English DT Article DE disulfiram; Antabuse; SNARK; NUAK2; HCC ID C VIRUS-REPLICATION; HUMAN-MELANOMA; BREAST-CANCER; TUMOR-GROWTH; CELLS; PROTEIN; APOPTOSIS; MOLECULE; PATHWAY AB We recently described that the anti-apoptotic AMPK-related kinase, SNARK, promotes transforming growth factor (TGF)-beta signaling in hepatocellular carcinoma (HCC) cells, as a potentially new therapeutic target. Here we explored FDA-approved drugs inhibiting the enzymatic activity of SNARK, using an in vitro luminescence kinase assay system. Interestingly, the long-used anti-alcoholism drug disulfiram (DSF), also known as Antabuse, emerged as the top hit. Enzymatic kinetics analyses revealed that DSF inhibited SNARK kinase activity in a noncompetitive manner to ATP or phosphosubstrates. Comparative in vitro analyses of DSF analogs indicated the significance of the disulfide bond-based molecular integrity for the kinase inhibition. DSF suppressed SNARK-promoted TGF-beta signaling and demonstrated anti-HCC effects. The chemical and enzymatic findings herein reveal novel pharmacological effects of and use for DSF and its derivatives, and could be conducive to prevention and inhibition of liver fibrosis and HCC. C1 [Goto, Kaku; Kato, Naoya] Univ Tokyo, Inst Med Sci, Adv Clin Res Ctr, Tokyo 1088639, Japan. [Chung, Raymond T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Liver Ctr, Boston, MA 02114 USA. [Chung, Raymond T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Gastrointestinal Div, Boston, MA 02114 USA. RP Kato, N (reprint author), Univ Tokyo, Inst Med Sci, Adv Clin Res Ctr, Tokyo 1088639, Japan.; Chung, RT (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Liver Ctr, Boston, MA 02114 USA.; Chung, RT (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Gastrointestinal Div, Boston, MA 02114 USA. EM Chung.Raymond@mgh.harvard.edu FU Ministry of Education, Culture, Sports, Science and Technology in Japan [24390184]; Japan Agency for Medical Research and Development [15fk0310009h0004]; Japan Society for the Promotion of Science [15K19106] FX N.K. is supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan (24390184) and Japan Agency for Medical Research and Development (15fk0310009h0004). K.G. is supported by a Grant-in-Aid for Young Scientist (15K19106) from the Japan Society for the Promotion of Science. NR 41 TC 0 Z9 0 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 15 PY 2016 VL 7 IS 46 BP 74987 EP 74999 DI 10.18632/oncotarget.11820 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE5GF UT WOS:000389632800044 PM 27602492 ER PT J AU Park, JO Ryoo, BY Yen, CJ Kudo, M Yang, L Abada, PB Cheng, R Orlando, M Zhu, AX Okusaka, T AF Park, Joon Oh Ryoo, Baek-Yeol Yen, Chia-Jui Kudo, Masatoshi Yang, Ling Abada, Paolo B. Cheng, Rebecca Orlando, Mauro Zhu, Andrew X. Okusaka, Takuji TI Second-line ramucirumab therapy for advanced hepatocellular carcinoma (REACH): an East Asian and non-East Asian subgroup analysis SO ONCOTARGET LA English DT Article DE Asians; alpha-fetoprotein; clinical trial; liver neoplasms; vascular endothelial growth factor receptor-2 ID ENDOTHELIAL GROWTH-FACTOR; PHASE-3 TRIAL; 1ST-LINE THERAPY; DOUBLE-BLIND; SORAFENIB; PLACEBO; CANCER; ANGIOGENESIS; MULTICENTER; BRIVANIB AB Purpose: REACH investigated second-line ramucirumab therapy for advanced hepatocellular carcinoma. Results: Median overall survival was 8.2 months for ramucirumab and 6.9 months for placebo (HR, 0.835; 95% CI, 0.634-1.100; p = 0.2046) for East Asians, and 10.1 months for ramucirumab and 8.0 months for placebo (HR, 0.895; 95% CI, 0.690-1.161; p = 0.4023) for non-East Asians. Median overall survival in patients with baseline alpha-fetoprotein >= 400 ng/mL was 7.8 months for ramucirumab and 4.2 months for placebo (HR, 0.749; 95% CI, 0.519-1.082; p = 0.1213) for East Asians (n = 139), and 8.2 months for ramucirumab and 4.5 months for placebo (HR, 0.579; 95% CI, 0.371-0.904; p = 0.0149) for non-East Asians (n = 111). The most common grade >= 3 treatment-emergent adverse events in East Asians and non-East Asians included hypertension and malignant neoplasm progression. Materials and methods: A post-hoc analysis of East Asians (N = 252) and non-East Asians (N = 313) in the intent-to-treat population was performed. Conclusions: In East Asians and non-East Asians, ramucirumab did not significantly prolong overall survival. In patients with baseline alpha-fetoprotein >= 400 ng/mL, a potentially larger survival benefit was observed in both subgroups. Safety for East Asians was similar to non-East Asians. C1 [Park, Joon Oh] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea. [Ryoo, Baek-Yeol] Univ Ulsan, Coll Med, Asan Med Ctr, Seoul, South Korea. [Yen, Chia-Jui] Natl Cheng Kung Univ Hosp, Tainan, Taiwan. [Kudo, Masatoshi] Kinki Univ, Sch Med, Osaka, Osaka, Japan. [Yang, Ling] Eli Lilly & Co, Bridgewater, NJ USA. [Abada, Paolo B.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Cheng, Rebecca] Eli Lilly & Co, Taipei, Taiwan. [Orlando, Mauro] Eli Lilly & Co, Buenos Aires, DF, Argentina. [Zhu, Andrew X.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Okusaka, Takuji] Natl Canc Ctr, Tokyo, Japan. RP Park, JO (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea. EM oncopark@skku.edu FU Eli Lilly and Company FX This study was sponsored by Eli Lilly and Company. NR 20 TC 0 Z9 0 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 15 PY 2016 VL 7 IS 46 BP 75482 EP 75491 DI 10.18632/oncotarget.12780 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE5GF UT WOS:000389632800082 PM 27776351 ER PT J AU Kanzaki, H Makihira, S Suzuki, M Ishii, T Movila, A Hirschfeld, J Mawardi, H Lin, XP Han, XZ Taubman, MA Kawai, T AF Kanzaki, Hiroyuki Makihira, Seicho Suzuki, Maiko Ishii, Takenobu Movila, Alexandru Hirschfeld, Josefine Mawardi, Hani Lin, Xiaoping Han, Xiaozhe Taubman, Martin A. Kawai, Toshihisa TI Soluble RANKL Cleaved from Activated Lymphocytes by TNF-alpha-Converting Enzyme Contributes to Osteoclastogenesis in Periodontitis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; KAPPA-B LIGAND; GINGIVAL CREVICULAR FLUID; RECEPTOR ACTIVATOR; PORPHYROMONAS-GINGIVALIS; DIFFERENTIATION FACTOR; BONE-RESORPTION; T-CELLS; MATRIX METALLOPROTEINASE-7; OSTEOPROTEGERIN LIGAND AB Host immune responses play a key role in promoting bone resorption in periodontitis via receptor activator of NF-kappa B ligand (RANKL)-dependent osteoclastogenesis. Both membrane-bound RANKL (mRANKL) expressed on lymphocytes and soluble RANKL (sRANKL) are found in periodontal lesions. However, the underlying mechanism and cellular source of sRANKL release and its biological role in periodontitis are unclear. TNF-alpha-converting enzyme (TACE) is reported to cleave the following: 1) precursor TNF-alpha with release of mature, soluble TNF-alpha and 2) mRANKL with release of sRANKL. Both soluble TNF-alpha and sRANKL are found in the periodontitis lesion, leading to the hypothesis that TACE expressed on lymphocytes is engaged in RANKL shedding and that the resulting sRANKL induces osteoclastogenesis. In the current study, upon stimulating PBLs with mitogens in vitro, RANKL expression, sRANKL secretion, and TACE expression were all upregulated. Among the four putative mRANKL sheddases examined in neutralization assays, TACE was the only functional sheddase able to cleave mRANKL expressed on PBL. Moreover, PBL culture supernatant stimulated with mitogens in the presence of anti-TACE Ab or anti-RANKL Ab showed a marked reduction of osteoclastogenesis from osteoclast precursors, indicating that TACE-mediated sRANKL may possess sufficient osteoclastogenic activity. According to double-color confocal microscopy, B cells expressed a more pronounced level of RANKL and TACE expression than T cells or monocytes in periodontally diseased gingiva. Conditioned medium of patients' gingival lymphocyte culture increased in vitro osteoclastogenic activity, which was suppressed by the addition of anti-TACE Ab and anti-RANKL Ab. Therefore, TACE-mediated cleavage of sRANKL from activated lymphocytes, especially B cells, can promote osteoclastogenesis in periodontitis. C1 [Kanzaki, Hiroyuki] Tsurumi Univ, Sch Dent Med, Dept Orthodont, Yokohama, Kanagawa 2308501, Japan. [Makihira, Seicho] Kyushu Univ, Fac Dent Sci, Div Oral Rehabil, Dept Dent Sci, Fukuoka 8128582, Japan. [Suzuki, Maiko] Ohio State Univ, Coll Dent Biosci, Columbus, OH 43210 USA. [Ishii, Takenobu] Tokyo Dent Coll, Dept Orthodont, Tokyo 1010061, Japan. [Movila, Alexandru; Han, Xiaozhe; Taubman, Martin A.; Kawai, Toshihisa] Forsyth Inst, Dept Immunol & Infect Dis, 245 First St, Cambridge, MA 02142 USA. [Hirschfeld, Josefine] Birmingham Dent Sch & Hosp, Birmingham B5 7EG, W Midlands, England. [Mawardi, Hani] King Abdulaziz Univ, Dept Oral Basic & Clin Sci, Fac Dent, Jeddah 21481, Saudi Arabia. [Lin, Xiaoping] China Med Univ, Shengjing Hosp, Dept Stomatol, Shenyang 110004, Liaoning, Peoples R China. RP Kawai, T (reprint author), Forsyth Inst, Dept Immunol & Infect Dis, 245 First St, Cambridge, MA 02142 USA. EM tkawai@forsyth.org FU National Institutes of Health [RO1 DE-03420, RO1 DE-018499, RO1 DE-019917, R56 DE 023807, RO1 DE025255]; National Institute of Dental and Craniofacial Research [T32 DE 7327-12]; Japan Society for the Promotion of Science [23689081, 25670841, 15K11376]; German Society of Periodontology [2-RST-2013] FX This work was supported by National Institutes of Health Grants RO1 DE-03420, RO1 DE-018499, RO1 DE-019917, R56 DE 023807, and RO1 DE025255; National Institute of Dental and Craniofacial Research Grant T32 DE 7327-12; Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (23689081, 25670841, and 15K11376); and German Society of Periodontology Grant 2-RST-2013. NR 67 TC 0 Z9 0 U1 1 U2 1 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 NOV 15 PY 2016 VL 197 IS 10 BP 3871 EP 3883 DI 10.4049/jimmunol.1601114 PG 13 WC Immunology SC Immunology GA EE5GW UT WOS:000389634600013 PM 27815441 ER PT J AU Abbott, RK Thayer, M Labuda, J Silva, M Philbrook, P Cain, DW Kojima, H Hatfield, S Sethumadhavan, S Ohta, A Reinherz, EL Kelsoe, G Sitkovsky, M AF Abbott, Robert K. Thayer, Molly Labuda, Jasmine Silva, Murillo Philbrook, Phaethon Cain, Derek W. Kojima, Hidefumi Hatfield, Stephen Sethumadhavan, Shalini Ohta, Akio Reinherz, Ellis L. Kelsoe, Garnett Sitkovsky, Michail TI Germinal Center Hypoxia Potentiates Immunoglobulin Class Switch Recombination SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CENTER B-CELLS; T-CELL; AID; MICE; PHOSPHORYLATION; ACTIVATION; AUTOIMMUNITY; INFLAMMATION; RESPONSES; SELECTION AB Germinal centers (GCs) are anatomic sites where B cells undergo secondary diversification to produce high-affinity, class-switched Abs. We hypothesized that proliferating B cells in GCs create a hypoxic microenvironment that governs their further differentiation. Using molecular markers, we found GCs to be predominantly hypoxic. Compared to normoxia (21% O-2), hypoxic culture conditions (1% O-2) in vitro accelerated class switching and plasma cell formation and enhanced expression of GL-7 on B and CD4(+) T cells. Reversal of GC hypoxia in vivo by breathing 60% O-2 during immunization resulted in reduced frequencies of GC B cells, T follicular helper cells, and plasmacytes, as well as lower expression of ICOS on T follicular helper cells. Importantly, this reversal of GC hypoxia decreased Ag-specific serum IgG1 and reduced the frequency of IgG1(+) B cells within the Ag-specific GC. Taken together, these observations reveal a critical role for hypoxia in GC B cell differentiation. C1 [Abbott, Robert K.; Thayer, Molly; Labuda, Jasmine; Silva, Murillo; Philbrook, Phaethon; Hatfield, Stephen; Sethumadhavan, Shalini; Ohta, Akio; Sitkovsky, Michail] Northeastern Univ, New England Inflammat & Tissue Protect Inst, Boston, MA 02115 USA. [Cain, Derek W.; Kelsoe, Garnett] Duke Univ, Dept Immunol, Durham, NC 27710 USA. [Cain, Derek W.; Kelsoe, Garnett] Duke Univ, Human Vaccine Inst, Durham, NC 27710 USA. [Kojima, Hidefumi] Dokkyo Med Univ, Dept Immunol, Sch Med, Mibu, Tochigi 3210293, Japan. [Reinherz, Ellis L.] Dana Farber Canc Inst, Dept Med Oncol, Lab Immunobiol, Boston, MA 02115 USA. [Reinherz, Ellis L.] Harvard Med Sch, Boston, MA 02115 USA. RP Abbott, RK (reprint author), Northeastern Univ, Dept Biol, 360 Huntington Ave,Mugar Bldg Room 031, Boston, MA 02115 USA. EM robertkabbott@gmail.com FU National Institutes of Health [U19 AI 091693] FX This work was supported by National Institutes of Health Grant U19 AI 091693 (to E.L.R., M. Sitkovsky, and G.K.). NR 33 TC 2 Z9 2 U1 0 U2 0 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 NOV 15 PY 2016 VL 197 IS 10 BP 4014 EP 4020 DI 10.4049/jimmunol.1601401 PG 7 WC Immunology SC Immunology GA EE5GW UT WOS:000389634600025 PM 27798169 ER PT J AU Chen, SB Wu, JY Lu, Y Ma, YB Lee, BH Yu, Z Ouyang, Q Finley, DJ Kirschner, MW Mao, YD AF Chen, Shuobing Wu, Jiayi Lu, Ying Ma, Yong-Bei Lee, Byung-Hoon Yu, Zhou Ouyang, Qi Finley, Daniel J. Kirschner, Marc W. Mao, Youdong TI Structural basis for dynamic regulation of the human 26S proteasome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ubiquitin-proteasome system; AAA-ATPase; cyroelectron microscopy ID 20S PROTEASOME; CRYSTAL-STRUCTURE; METHANOCALDOCOCCUS-JANNASCHII; MOLECULAR ARCHITECTURE; FUNCTIONAL ASYMMETRIES; CONFORMATIONAL STATES; ANGSTROM RESOLUTION; PARTICLE; SUBSTRATE; REVEALS AB The proteasome is the major engine of protein degradation in all eukaryotic cells. At the heart of this machine is a heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitylated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides. Using cryoelectron microscopy, we determined a near-atomic-resolution structure of the 2.5-MDa human proteasome in its ground state, as well as subnanometer-resolution structures of the holoenzyme in three alternative conformational states. The substrate-unfolding AAA-ATPase channel is narrowed by 10 inward-facing pore loops arranged into two helices that run in parallel with each other, one hydrophobic in character and the other highly charged. The gate of the core particle was unexpectedly found closed in the ground state and open in only one of the alternative states. Coordinated, stepwise conformational changes of the regulatory particle couple ATP hydrolysis to substrate translocation and regulate gating of the core particle, leading to processive degradation. C1 [Chen, Shuobing; Ouyang, Qi; Mao, Youdong] Peking Univ, Ctr Quantitat Biol, Beijing 100871, Peoples R China. [Chen, Shuobing; Wu, Jiayi; Ouyang, Qi; Mao, Youdong] Peking Univ, Sch Phys, Inst Condensed Matter Phys, State Key Lab Artificial Microstruct & Mesoscop P, Beijing 100871, Peoples R China. [Chen, Shuobing; Ma, Yong-Bei; Mao, Youdong] Dana Farber Canc Inst, Intel Parallel Comp Ctr Struct Biol, Boston, MA 02215 USA. [Lu, Ying; Kirschner, Marc W.] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA. [Lee, Byung-Hoon; Finley, Daniel J.] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. [Yu, Zhou] Harvard Univ, Grad Sch Arts & Sci, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Ouyang, Qi] Peking Univ, Peking Tsinghua Joint Ctr Life Sci, Beijing 100871, Peoples R China. [Mao, Youdong] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA. [Mao, Youdong] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. RP Mao, YD (reprint author), Peking Univ, Ctr Quantitat Biol, Beijing 100871, Peoples R China.; Mao, YD (reprint author), Peking Univ, Sch Phys, Inst Condensed Matter Phys, State Key Lab Artificial Microstruct & Mesoscop P, Beijing 100871, Peoples R China.; Mao, YD (reprint author), Dana Farber Canc Inst, Intel Parallel Comp Ctr Struct Biol, Boston, MA 02215 USA.; Kirschner, MW (reprint author), Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA.; Mao, YD (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA.; Mao, YD (reprint author), Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. EM marc@hms.harvard.edu; youdong_mao@dfci.harvard.edu FU NIGMS [GM026875]; Thousand Talents Plan of China; Intel academic grant; National Natural Science Foundation of China [91530321, 1541959]; NIH [GM43601, AI100645]; Center for HIV/AIDS Vaccine Immunology and Immunogen Design FX This work was funded in part by a grant from the NIGMS (GM026875; to M.W.K.), a grant of the Thousand Talents Plan of China (to Y.M.), an Intel academic grant (to Y.M.), a grant from the National Natural Science Foundation of China (91530321; to Y.M. and Q.O.), and an NIH grant (GM43601; to D.J.F.). The cryo-EM experiments were performed in part at the Center for Nanoscale Systems at Harvard University, which is supported by the National Science Foundation under NSF Award 1541959. The cryo-EM facility was funded through NIH Grant AI100645 and the Center for HIV/AIDS Vaccine Immunology and Immunogen Design. NR 50 TC 0 Z9 0 U1 2 U2 2 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 NOV 15 PY 2016 VL 113 IS 46 BP 12991 EP 12996 DI 10.1073/pnas.1614614113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED6MQ UT WOS:000388970100048 ER PT J AU Mathew, G Hannan, A Hertzler-Schaefer, K Wang, F Feng, GS Zhong, J Zhao, JJ Downward, J Zhang, X AF Mathew, Grinu Hannan, Abdul Hertzler-Schaefer, Kristina Wang, Fen Feng, Gen-Sheng Zhong, Jian Zhao, Jean J. Downward, Julian Zhang, Xin TI Targeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE FGF; skin; Ras; Pten; Erk ID B-RAF; PHOSPHOINOSITIDE 3-KINASE; GROWTH-FACTOR; KINASE; MICE; DIFFERENTIATION; TUMORIGENESIS; MUTATIONS; PATHWAY; CANCER AB Deficiency in PTEN (phosphatase and tensin homolog deleted on chromosome 10) is the underlying cause of PTEN hamartoma tumor syndrome and a wide variety of human cancers. In skin epidermis, we have previously identified an autocrine FGF signaling induced by loss of Pten in keratinocytes. In this study, we demonstrate that skin hyperplasia requires FGF receptor adaptor protein Frs2 alpha and tyrosine phosphatase Shp2, two upstream regulators of Ras signaling. Although the PI3-kinase regulatory sub-units p85 alpha and p85 beta are dispensable, the PI3-kinase catalytic subunit p110 alpha requires interaction with Ras to promote hyperplasia in Pten-deficient skin, thus demonstrating an important crosstalk between Ras and PI3K pathways. Furthermore, genetic and pharmacological inhibition of Ras-MAPK pathway impeded epidermal hyperplasia in Pten animals. These results reveal a positive feedback loop connecting Pten and Ras pathways and suggest that FGF-activated Ras-MAPK pathway is an effective therapeutic target for preventing skin tumor induced by aberrant Pten signaling. C1 [Mathew, Grinu; Hannan, Abdul; Zhang, Xin] Columbia Univ, Dept Ophthalmol, New York, NY 10032 USA. [Mathew, Grinu; Hannan, Abdul; Zhang, Xin] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Hertzler-Schaefer, Kristina] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Wang, Fen] Texas A&M, Inst Biosci & Technol, Ctr Canc Biol & Nutr, Houston, TX 77030 USA. [Feng, Gen-Sheng] Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA. [Feng, Gen-Sheng] Univ Calif San Diego, Div Biol Sci, Sect Mol Biol, La Jolla, CA 92093 USA. [Zhong, Jian] Weill Cornell Med, Feil Family Brain & Mind Res Inst, Burke Med Res Inst, White Plains, NY 10605 USA. [Zhao, Jean J.] Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Zhao, Jean J.] Harvard Med Sch, Dept Biochem & Mol Pharmacol, Boston, MA 02115 USA. [Downward, Julian] Francis Crick Inst, Oncogene Biol Lab, London WC2A 3LY, England. [Zhao, Jean J.] Cold Spring Harbor Lab, Canc Biol, Cold Spring Harbor, NY 11724 USA. RP Zhang, X (reprint author), Columbia Univ, Dept Ophthalmol, New York, NY 10032 USA.; Zhang, X (reprint author), Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA. EM xz2369@columbia.edu FU Columbia Skin Diseases Research Center; NIH [EY017061, EY018868, EY025933, EY022409, 5P30AR044535, 5P30EY019007]; Research to Prevent Blindness; Jules and Doris Stein Research to Prevent Blindness Professorship FX The authors thank Drs. Lewis Cantley and Ruth Ashery-Padan for mice, and the Columbia Dermatology Core Facility for technical support. The work was supported by a pilot grant from Columbia Skin Diseases Research Center, and NIH Grants EY017061, EY018868, and EY025933 (to X.Z.), and EY022409 (to J.J.Z.). The Columbia Dermatology Core Facility is supported by NIH Core Grant 5P30AR044535. The Columbia Ophthalmology Core Facility is supported by NIH Core Grant 5P30EY019007 and unrestricted funds from Research to Prevent Blindness. X.Z. is supported by the Jules and Doris Stein Research to Prevent Blindness Professorship. NR 49 TC 0 Z9 0 U1 2 U2 2 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 NOV 15 PY 2016 VL 113 IS 46 BP 13156 EP 13161 DI 10.1073/pnas.1604450113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED6MQ UT WOS:000388970100076 PM 27799550 ER PT J AU Hideshima, T Qi, J Paranal, RM Tang, WP Greenberg, E West, N Colling, ME Estiu, G Mazitschek, R Perry, JA Ohguchi, H Cottini, F Mimura, N Gorgun, G Tai, YT Richardson, PG Carrasco, RD Wiest, O Schreiber, SL Anderson, KC Bradner, JE AF Hideshima, Teru Qi, Jun Paranal, Ronald M. Tang, Weiping Greenberg, Edward West, Nathan Colling, Meaghan E. Estiu, Guillermina Mazitschek, Ralph Perry, Jennifer A. Ohguchi, Hiroto Cottini, Francesca Mimura, Naoya Goerguen, Guellue Tai, Yu-Tzu Richardson, Paul G. Carrasco, Ruben D. Wiest, Olaf Schreiber, Stuart L. Anderson, Kenneth C. Bradner, James E. TI Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE histone deacetylase 6; proteasome inhibitor; multiple myeloma; bortezomib-resistance; WT161 ID HISTONE DEACETYLASE INHIBITORS; ER STRESS; PRECLINICAL ACTIVITY; ANTITUMOR-ACTIVITY; CANCER-CELLS; BORTEZOMIB; APOPTOSIS; KINASE; DEXAMETHASONE; MULTICENTER AB Multiple myeloma (MM) has proven clinically susceptible to modulation of pathways of protein homeostasis. Blockade of proteasomal degradation of polyubiquitinated misfolded proteins by the proteasome inhibitor bortezomib (BTZ) achieves responses and prolongs survival in MM, but long-term treatment with BTZ leads to drug-resistant relapse in most patients. In a proof-of-concept study, we previously demonstrated that blocking aggresomal breakdown of polyubiquitinated misfolded proteins with the histone deacetylase 6 (HDAC6) inhibitor tubacin enhances BTZ-induced cytotoxicity in MM cells in vitro. However, these foundational studies were limited by the pharmacologic liabilities of tubacin as a chemical probe with only in vitro utility. Emerging from a focused library synthesis, a potent, selective, and bioavailable HDAC6 inhibitor, WT161, was created to study the mechanism of action of HDAC6 inhibition in MM alone and in combination with BTZ. WT161 in combination with BTZ triggers significant accumulation of polyubiquitinated proteins and cell stress, followed by caspase activation and apoptosis. More importantly, this combination treatment was effective in BTZ-resistant cells and in the presence of bone marrow stromal cells, which have been shown to mediate MM cell drug resistance. The activity of WT161 was confirmed in our human MM cell xenograft mouse model and established the framework for clinical trials of the combination treatment to improve patient outcomes in MM. C1 [Hideshima, Teru; Qi, Jun; Paranal, Ronald M.; Greenberg, Edward; West, Nathan; Colling, Meaghan E.; Perry, Jennifer A.; Ohguchi, Hiroto; Cottini, Francesca; Mimura, Naoya; Goerguen, Guellue; Tai, Yu-Tzu; Richardson, Paul G.; Carrasco, Ruben D.; Anderson, Kenneth C.; Bradner, James E.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Tang, Weiping] Univ Wisconsin, Sch Pharmacol, Madison, WI 53705 USA. [Tang, Weiping; Schreiber, Stuart L.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Estiu, Guillermina; Wiest, Olaf] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. [Mazitschek, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02142 USA. [Wiest, Olaf] Peking Univ, Shenzhen Grad Sch, Lab Chem Genom, Lab Computat Chem & Drug Discovery, Shenzhen 518055, Peoples R China. RP Anderson, KC; Bradner, JE (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM kenneth_anderson@dfci.harvard.edu; james_bradner@dfci.harvard.edu FU NIH [SPORE CA10070, P01 78378, R01 CA50947, R01 CA178264, R01 GM38627, K08 CA128972, T32 HL07623-18, R01 CA152314]; Burroughs-Wellcome Foundation Career Award for Medical Scientists; Doris Duke Charitable Foundation; National Science Foundation [TG-CHE090124] FX This study was supported by NIH Grants SPORE CA10070, P01 78378, and R01 CA50947 (to K.C.A.), R01 CA178264 (to T.H. and K.C.A.), R01 GM38627 (to S.L.S.), K08 CA128972 (to J.E.B.), T32 HL07623-18 (to J.E.B.), and R01 CA152314 (to J.E.B. and O.W.); a Burroughs-Wellcome Foundation Career Award for Medical Scientists (to J.E.B.); the Doris Duke Charitable Foundation (J.E.B.); and National Science Foundation Grant TG-CHE090124 (to O.W.). K.C.A. is an American Cancer Society Clinical Research Professor. NR 36 TC 0 Z9 0 U1 5 U2 5 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 NOV 15 PY 2016 VL 113 IS 46 BP 13162 EP 13167 DI 10.1073/pnas.1608067113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED6MQ UT WOS:000388970100077 PM 27799547 ER PT J AU Kirschbaum, K Sonner, JK Zeller, MW Deumelandt, K Bode, J Sharma, R Kruwel, T Fischer, M Hoffmann, A da Silva, MC Muckenthaler, MU Wick, W Tews, B Chen, JW Heiland, S Bendszus, M Platten, M Breckwoldt, MO AF Kirschbaum, Klara Sonner, Jana K. Zeller, Matthias W. Deumelandt, Katrin Bode, Julia Sharma, Rakesh Kruewel, Thomas Fischer, Manuel Hoffmann, Angelika da Silva, Milene Costa Muckenthaler, Martina U. Wick, Wolfgang Tews, Bjoern Chen, John W. Heiland, Sabine Bendszus, Martin Platten, Michael Breckwoldt, Michael O. TI In vivo nanoparticle imaging of innate immune cells can serve as a marker of disease severity in a model of multiple sclerosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE MRI; nanoparticle imaging; USPIO; multiple sclerosis; EAE ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; SUPERPARAMAGNETIC IRON-OXIDE; TUMOR-ASSOCIATED MACROPHAGES; HIGH-RESOLUTION; BRAIN; MRI; LESIONS; MYELOPEROXIDASE; GADOLINIUM; NEUROINFLAMMATION AB Innate immune cells play a key role in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Current clinical imaging is restricted to visualizing secondary effects of inflammation, such as gliosis and blood-brain barrier disruption. Advanced molecular imaging, such as iron oxide nanoparticle imaging, can allow direct imaging of cellular and molecular activity, but the exact cell types that phagocytose nano-particles in vivo and how phagocytic activity relates to disease severity is not well understood. In this study we used MRI to map inflammatory infiltrates using high-field MRI and fluores-cently labeled cross-linked iron oxide nanoparticles for cell tracking. We confirmed nanoparticle uptake and MR detectability ex vivo. Using in vivo MRI, we identified extensive nanoparticle signal in the cerebellar white matter and circumscribed cortical gray matter lesions that developed during the disease course (4.6-fold increase of nanoparticle accumulation in EAE compared with healthy controls, P < 0.001). Nanoparticles showed good cellular specificity for innate immune cells in vivo, labeling activated microglia, infiltrating macrophages, and neutrophils, whereas there was only sparse uptake by adaptive immune cells. Importantly, nanoparticle signal correlated better with clinical disease than conventional gadolinium (Gd) imaging (r, 0.83 for nanoparticles vs. 0.71 for Gd-imaging, P < 0.001). We validated our approach using the Food and Drug Administration-approved iron oxide nanoparticle ferumoxytol. Our results show that noninvasive molecular imaging of innate immune responses can serve as an imaging biomarker of disease activity in autoimmune-mediated neuroinflammation with potential clinical applications in a wide range of inflammatory diseases. C1 [Kirschbaum, Klara; Sonner, Jana K.; Deumelandt, Katrin; Platten, Michael; Breckwoldt, Michael O.] German Canc Res Ctr, Clin Cooperat Unit Neuroimmunol & Brain Tumor Imm, German Canc Consortium, D-69120 Heidelberg, Germany. [Kirschbaum, Klara; Fischer, Manuel; Hoffmann, Angelika; Heiland, Sabine; Bendszus, Martin; Breckwoldt, Michael O.] Univ Heidelberg Hosp, Dept Neuroradiol, D-69120 Heidelberg, Germany. [Zeller, Matthias W.; Chen, John W.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02115 USA. [Zeller, Matthias W.; Chen, John W.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Div Neuroradiol, Boston, MA 02115 USA. [Bode, Julia; Sharma, Rakesh; Kruewel, Thomas; Tews, Bjoern] Heidelberg Univ, Schaller Res Grp, D-69120 Heidelberg, Germany. [Bode, Julia; Sharma, Rakesh; Kruewel, Thomas; Tews, Bjoern] DKFZ, D-69120 Heidelberg, Germany. [Bode, Julia; Sharma, Rakesh; Kruewel, Thomas; Tews, Bjoern] DKFZ, Mol Mech Tumor Invas, D-69120 Heidelberg, Germany. [da Silva, Milene Costa; Muckenthaler, Martina U.] Heidelberg Univ, Dept Pediat Hematol Oncol & Immunol, D-69120 Heidelberg, Germany. [da Silva, Milene Costa; Muckenthaler, Martina U.] Univ Heidelberg Hosp, Mol Med Partnership Unit, D-69120 Heidelberg, Germany. [da Silva, Milene Costa] Univ Porto, Abel Salazar Biomed Sci Inst, Grad Program Areas Basic & Appl Biol, P-4050313 Oporto, Portugal. [Wick, Wolfgang; Platten, Michael] Univ Heidelberg Hosp, Dept Neurol, D-69120 Heidelberg, Germany. [Wick, Wolfgang; Platten, Michael] Univ Heidelberg Hosp, Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany. [Wick, Wolfgang] DKFZ, German Canc Consortium, Clin Cooperat Unit Neurooncol, D-69120 Heidelberg, Germany. RP Breckwoldt, MO (reprint author), German Canc Res Ctr, Clin Cooperat Unit Neuroimmunol & Brain Tumor Imm, German Canc Consortium, D-69120 Heidelberg, Germany.; Breckwoldt, MO (reprint author), Univ Heidelberg Hosp, Dept Neuroradiol, D-69120 Heidelberg, Germany. EM michael.breckwoldt@med.uni-heidelberg.de FU Heidelberg University Innovation Fund FRONTIER; Deutsche Forschungsgemeinschaft [FOR2289: PL315/3-1]; Physician-Scientist Fellowship of the Medical Faculty, University of Heidelberg; Hoffmann-Klose Foundation (University of Heidelberg); Novartis Foundation; Neurowind e.V.; Helmholtz International Graduate School for Cancer Research at DKFZ; German Federal Ministry of Education and Research; Medical Faculty, University of Heidelberg FX We thank Simon Becker for excellent technical assistance; Ralph Weissleder of the Massachusetts General Hospital, Harvard Medical School for providing CLIO nanoparticles and for helpful discussion of the manuscript; E. Neuwelt of the Oregon Health and Science University for the kind gift of ferumoxytol; and D. Krunic of the DKFZ Light Microscopy Facility for experimental support. This work was funded by grants from the Heidelberg University Innovation Fund FRONTIER (to M.P.) and by Deutsche Forschungsgemeinschaft Grant FOR2289: PL315/3-1 (to M.P). M.O.B. and A.H. were supported by a Physician-Scientist Fellowship of the Medical Faculty, University of Heidelberg. M.O.B. received funding from the Hoffmann-Klose Foundation (University of Heidelberg), the Novartis Foundation, and Neurowind e.V. J.K.S. was supported by the Helmholtz International Graduate School for Cancer Research at DKFZ, and K.D. was supported by the German Federal Ministry of Education and Research. NR 48 TC 0 Z9 0 U1 24 U2 24 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 NOV 15 PY 2016 VL 113 IS 46 BP 13227 EP 13232 DI 10.1073/pnas.1609397113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED6MQ UT WOS:000388970100088 PM 27799546 ER PT J AU Choo, SP Tan, WL Goh, BKP Tai, WM Zhu, AX AF Choo, Su Pin Tan, Wan Ling Goh, Brian K. P. Tai, Wai Meng Zhu, Andrew X. TI Comparison of hepatocellular carcinoma in Eastern versus Western populations SO CANCER LA English DT Review DE Asian versus non-Asian; East versus West; hepatocellular carcinoma; liver cancer; regional differences ID RANDOMIZED PHASE-III; GLOBAL CANCER STATISTICS; FATTY LIVER-DISEASE; CHRONIC HEPATITIS-C; 7 STAGING SYSTEMS; TERM-FOLLOW-UP; TRANSARTERIAL CHEMOEMBOLIZATION; UNITED-STATES; PROGNOSTIC CLASSIFICATION; COMBINATION CHEMOTHERAPY AB Hepatocellular carcinoma (HCC) is a heterogeneous disease that remains highly prevalent in many Asian countries and is the second most common cause of cancer-related mortality worldwide. Significant differences exist between Eastern and Western populations on many key aspects of HCC, contributing to the potential different treatment outcomes and challenges of clinical trial design and data interpretation. In this review, the authors compare HCC in Asia versus the West and highlight 1) differences in terms of epidemiology and trends and their correlation with etiology, 2) differences in genetics and how they relate to underlying etiology, 3) differences in treatment approaches based on existing guidelines and consensus statements, and 4) differences in clinical outcomes for Asian versus non-Asian patients with HCC in clinical trials and the implications for future clinical trial design. Cancer 2016;122:3430-3446. (c) 2016 American Cancer Society C1 [Choo, Su Pin; Tan, Wan Ling; Tai, Wai Meng] Natl Canc Ctr, Dept Med Oncol, Singapore, Singapore. [Goh, Brian K. P.] Singapore Gen Hosp, Dept Hepatopancreaticobiliary Surg, Singapore, Singapore. [Zhu, Andrew X.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Choo, SP (reprint author), Natl Canc Ctr Singapore, Med Oncol, 11 Hosp Dr, Singapore 169610, Singapore. EM choo.su.pin@singhealth.com.sg NR 122 TC 0 Z9 0 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 NOV 15 PY 2016 VL 122 IS 22 BP 3430 EP 3446 DI 10.1002/cncr.30237 PG 17 WC Oncology SC Oncology GA EB5IJ UT WOS:000387407200006 ER PT J AU Lampson, BL Nishino, M Dahlberg, SE Paul, D Santos, AA Janne, PA Oxnard, GR AF Lampson, Benjamin L. Nishino, Mizuki Dahlberg, Suzanne E. Paul, Danie Santos, Abigail A. Jaenne, Pasi A. Oxnard, Geoffrey R. TI Activity of erlotinib when dosed below the maximum tolerated dose for EGFR-mutant lung cancer: Implications for targeted therapy development SO CANCER LA English DT Article DE epidermal growth factor receptor (EGFR) gene; erlotinib; molecular-targeted therapy; nonsmall cell lung carcinoma; pharmacokinetics ID TYROSINE KINASE INHIBITORS; NERVOUS-SYSTEM METASTASES; FACTOR RECEPTOR MUTATION; OPEN-LABEL; 1ST-LINE TREATMENT; CELL; CHEMOTHERAPY; PHASE-3; ADENOCARCINOMA; MULTICENTER AB BACKGROUNDErlotinib is a standard first-line therapy for patients who have metastatic nonsmall cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The recommended dose of 150mg daily is the maximum tolerated dose (MTD). Few clinical data are available regarding its efficacy at doses less than the MTD. METHODSAn institutional database was queried for patients with advanced NSCLC who were positive for EGFR L858R mutations or exon 19 deletions and had received treatment with erlotinib. The treatment course, including the erlotinib dose at initiation of treatment, at 4 months into therapy, and at disease progression, was retrospectively studied. Progression-free survival (PFS) was compared between patients who received the MTD (150mg) and those who received reduced-dose erlotinib (100mg). RESULTSIn total, 198 eligible patients were identified. Thirty-one patients (16%) were initiated on reduced-dose erlotinib; they were older (P=.001) and had lower performance status (P=.01) compared with those who were initiated on erlotinib at the MTD. The response rate to reduced-dose erlotinib was 77%. The median PFS of patients initiated on reduced-dose erlotinib was 9.6 months versus 11.4 months for those initiated at the MTD, a difference that was not statistically significant (hazard ratio, 0.81; 95% confidence interval, 0.54-1.21; P=.30). There was a nonsignificant trend toward higher rates of progression within the central nervous system with reduced-dose erlotinib. CONCLUSIONSAt doses below the MTD, erlotinib treatment results in a high response rate and a prolonged median PFS. Review of the literature indicates that 15 of 30 small-molecule inhibitors that are approved or in late-stage development for cancer therapy have recommended doses below the MTD. When the toxicities of MTD dosing are a concern, an investigation of small-molecule inhibitors at doses below the MTD is warranted. Cancer 2016;122:3456-63. (c) 2016 American Cancer Society. At doses below the maximum tolerated dose, erlotinib treatment still results in a high response rate and prolonged median progression-free survival. A review of small-molecule inhibitors demonstrates that many are developed at the maximum tolerated dose, suggesting the need for additional studies to determine whether lower doses can have similar efficacy. See also pages 3424-7. C1 [Lampson, Benjamin L.; Jaenne, Pasi A.; Oxnard, Geoffrey R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Nishino, Mizuki] Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. [Nishino, Mizuki] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Dahlberg, Suzanne E.; Paul, Danie] 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. [Santos, Abigail A.; Jaenne, Pasi A.; Oxnard, Geoffrey R.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. RP Oxnard, GR (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,D1234, Boston, MA 02215 USA. EM geoffrey_oxnard@dfci.harvard.edu FU National Institutes of Health [5R01CA114465-09] FX This work was supported by grant 5R01CA114465-09 from the National Institutes of Health. NR 28 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD NOV 15 PY 2016 VL 122 IS 22 BP 3456 EP 3463 DI 10.1002/cncr.30270 PG 8 WC Oncology SC Oncology GA EB5IJ UT WOS:000387407200008 ER PT J AU Makker, V Recio, FO Ma, L Matulonis, UA Lauchle, JO Parmar, H Gilbert, HN Ware, JA Zhu, R Lu, S Huw, LY Wang, YL Koeppen, H Spoerke, JM Lackner, MR Aghajanian, CA AF Makker, Vicky Recio, Fernando O. Ma, Ling Matulonis, Ursula A. Lauchle, Jennifer O. Parmar, Hema Gilbert, Houston N. Ware, Joseph A. Zhu, Rui Lu, Shan Huw, Ling-Yuh Wang, Yulei Koeppen, Hartmut Spoerke, Jill M. Lackner, Mark R. Aghajanian, Carol A. TI A multicenter, single-arm, open-label, phase 2 study of apitolisib (GDC-0980) for the treatment of recurrent or persistent endometrial carcinoma (MAGGIE study) SO CANCER LA English DT Article DE apitolisib; endometrial cancer; GDC-0980; MAGGIE ID GYNECOLOGIC-ONCOLOGY-GROUP; MAMMALIAN TARGET; PHOSPHOINOSITIDE 3-KINASE; KINASE INHIBITOR; PI3K PATHWAY; SOLID TUMORS; CANCER; RAPAMYCIN; TRIAL; RIDAFOROLIMUS AB BACKGROUNDThe current single-arm, open-label trial was designed to evaluate the activity of apitolisib (GDC-0980), a dual phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor, in patients with advanced endometrial cancer (EC). METHODSPatients with recurrent or persistent EC who were treated with 1 to 2 prior lines of chemotherapy but no prior PI3K/mTOR inhibitor received oral apitolisib at a dose of 40mg daily during 28-day cycles until disease progression or intolerable toxicity occurred. Patients with type I/II diabetes who required insulin were excluded. The primary endpoints were progression-free survival (PFS) at 6 months and objective response rate. RESULTSA total of 56 women were enrolled, including 13 (23%) with well-controlled diabetes. Reasons for discontinuation were disease progression (24 patients; 43%), adverse events (13 patients; 23%), and withdrawal by subject (12 patients; 21%). Grade 3/4 apitolisib-related adverse events were hyperglycemia (46%), rash (30%), colitis (5%), and pneumonitis (4%) (toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The PFS rate at 6 months was 20% (Kaplan-Meier estimate; 95% confidence interval [95% CI], 7%-33%). The objective response rate was 6% (confirmed). The median PFS was 3.5 months (95% CI, 2.7-3.7 months) and the median overall survival was 15.7 months (95% CI, 9.2-17.0 months). Nineteen patients discontinued the study before the first tumor assessment. Dose reductions were required for 4 diabetic (31%) and 18 nondiabetic (42%) patients. Comprehensive molecular profiling of 46 evaluable archival tumor samples demonstrated that 57% of patients had at least 1 alteration in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), or AKT1. All 3 patients with a confirmed response had at least 1 alteration in a PI3K pathway gene. CONCLUSIONSThe antitumor activity noted with the use of a dose of 40mg of apitolisib daily was limited by tolerability, especially in diabetic patients. Patients with PI3K pathway mutations may have derived enhanced benefit from apitolisib. Cancer 2016;122:3519-28. (c) 2016 American Cancer Society. C1 [Makker, Vicky; Aghajanian, Carol A.] Mem Sloan Kettering Canc Ctr, Gynecol Med Oncol Serv, 1275 York Ave, New York, NY 10065 USA. [Makker, Vicky; Aghajanian, Carol A.] Weill Cornell Med Coll, New York, NY USA. [Recio, Fernando O.] South Florida Ctr Gynecol Oncol, Boca Raton, FL USA. [Ma, Ling] Rocky Mt Canc Ctr, Lakewood, CO USA. [Matulonis, Ursula A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lauchle, Jennifer O.; Parmar, Hema; Gilbert, Houston N.; Ware, Joseph A.; Zhu, Rui; Lu, Shan; Huw, Ling-Yuh; Wang, Yulei; Koeppen, Hartmut; Spoerke, Jill M.; Lackner, Mark R.] Genentech Inc, San Francisco, CA 94080 USA. RP Makker, V (reprint author), Mem Sloan Kettering Canc Ctr, Gynecol Med Oncol Serv, 1275 York Ave, New York, NY 10065 USA. EM makkerv@mskcc.org FU Genentech Inc. FX Funded by Genentech Inc. NR 26 TC 1 Z9 1 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD NOV 15 PY 2016 VL 122 IS 22 BP 3519 EP 3528 DI 10.1002/cncr.30286 PG 10 WC Oncology SC Oncology GA EB5IJ UT WOS:000387407200015 ER PT J AU Ruddy, KJ Guo, H Baker, EL Goldstein, MJ Mullaney, EE Shulman, LN Partridge, AH AF Ruddy, Kathryn J. Guo, Hao Baker, Emily L. Goldstein, Matthew J. Mullaney, Erin E. Shulman, Lawrence N. Partridge, Ann H. TI Randomized phase 2 trial of a coordinated breast cancer follow-up care program SO CANCER LA English DT Article DE breast neoplasms; continuity of patient care; delivery of health care; patient care planning; program effectiveness ID CLINICAL-TRIAL; YOUNG-WOMEN; SURVIVORSHIP; PLANS; NEEDS; OUTCOMES; THERAPY AB BACKGROUNDPrevious research has demonstrated that cancer survivors often fail to receive recommended care and also undergo unnecessary care; this reduces care quality and increases costs. METHODSThis phase 2 trial randomized 100 stage 0 to IIIa breast cancer patients who had primary care providers within a large Massachusetts-based hospital network (with accessible online records) to either coordinated follow-up care (CC), which entailed a tailored survivorship care plan (SCP) and patient navigator calls every 3 months, or standard care (SC), which did not include an SCP or patient navigation, for 1 year after the completion of their last chemotherapy, surgery, or radiation treatment. The primary endpoint was the frequency of redundant examinations (>1 breast/chest wall examination per patient within any 30-day period in the absence of a new breast or chest wall complaint) over the year of follow-up. The total number of non-plastic surgery visits in the year of follow-up was a secondary endpoint. RESULTSTwo patients (both on CC) were ineligible, and 2 patients (1 per arm) had a recurrence or died during follow-up; this left 96 for analysis (47 in the CC arm and 49 in the SC arm). Twenty-two of the 47 CC patients (47%; 95% confidence interval, 32%-62%) and 19 of the 49 SC patients (39%; 95% confidence interval, 25%-54%) had 1 or more redundant breast/chest wall examinations during the year. The median number of non-plastic surgery visits was 12 for CC patients and 8 for SC patients. CONCLUSIONSEarly-stage breast cancer patients visit health care providers very frequently during their first year of follow-up and often receive unnecessary breast/chest wall examinations. An SCP and patient navigator calls did not reduce this surrogate for redundant care. Cancer 2016;122:3546-3554. (c) 2016 American Cancer Society C1 [Ruddy, Kathryn J.] Mayo Clin, Dept Oncol, Rochester, MN USA. [Guo, Hao] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Baker, Emily L.; Mullaney, Erin E.; Partridge, Ann H.] Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02115 USA. [Goldstein, Matthew J.; Partridge, Ann H.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Shulman, Lawrence N.] Univ Penn, Div Hematol Oncol, Philadelphia, PA 19104 USA. RP Ruddy, KJ (reprint author), Mayo Clin, 200 First St Southwest, Rochester, MN 55905 USA. EM ruddy.kathryn@mayo.edu FU Dana-Farber Cancer Institute; National Center for Advancing Translational Sciences, a component of the National Institutes of Health [KL2TR000136-09] FX This study was funded by institutional funds at the Dana-Farber Cancer Institute. Kathryn J. Ruddy's effort was partially supported by KL2TR000136-09 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health. NR 30 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD NOV 15 PY 2016 VL 122 IS 22 BP 3546 EP 3554 DI 10.1002/cncr.30206 PG 9 WC Oncology SC Oncology GA EB5IJ UT WOS:000387407200018 ER PT J AU Lee, JJ Yin, XY Hoffmann, U Fox, CS Benjamin, EJ AF Lee, Jane J. Yin, Xiaoyan Hoffmann, Udo Fox, Caroline S. Benjamin, Emelia J. TI Relation of Pericardial Fat, Intrathoracic Fat, and Abdominal Visceral Fat With Incident Atrial Fibrillation (from the Framingham Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID EPICARDIAL ADIPOSE-TISSUE; INFLAMMATORY CYTOKINES; CARDIOVASCULAR-DISEASE; RISK-FACTORS; VOLUME; ASSOCIATION; ABLATION AB Obesity is associated with increased risk of developing atrial fibrillation (AF). Different fat depots may have differential associations with cardiac pathology. We examined the longitudinal associations between pericardial, intrathoracic, and visceral fat with incident AF. We studied Framingham Heart Study Offspring and Third-Generation Cohorts who participated in the multidetector computed tomography substudy examination 1. We constructed multivariable-adjusted Cox proportional hazard models for risk of incident AF. Body mass index was included in the multivariable-adjusted model as a secondary adjustment. We included 2,135 participants (53.3% women; mean age 58.8 years). During a median follow-up of 9.7 years, we identified 162 cases of incident AF. Across the increasing tertiles of pericardial fat volume, age- and gender-adjusted incident AF rate per 1,000 person-years of follow-up were 8.4, 7.5, and 10.2. Based on an age- and gender-adjusted model, greater pericardial fat (hazard ratio [BR] 1.17, 95% confidence interval [CI] 1.03 to 1.34) and intrathoracic fat (HR 1.24, 95% CI 1.06 to 1.45) were associated with an increased risk of incident AF. The BRs (95% CI) for incident AF were 1.13 (0.99 to 1.30) for pericardial fat, 1.19 (1.01 to 1.40) for intrathoracic fat, and 1.09 (0.93 to 1.28) for abdominal visceral fat after multivariable adjustment. After additional adjustment of body mass index, none of the associations remained significant (all p >0.05). Our findings suggest that cardiac ectopic fat depots may share common risk factors with AF, which may have led to a lack of independence in the association between pericardial fat with incident AF. (C) 2016 Elsevier Inc. All rights reserved. C1 [Lee, Jane J.; Yin, Xiaoyan; Fox, Caroline S.; Benjamin, Emelia J.] NHLBI, Populat Sci Branch, Div Intramural Res, Framingham, MA 01702 USA. [Yin, Xiaoyan; Benjamin, Emelia J.] Boston Univ Framingham Heart Study, Framingham, MA 01702 USA. [Hoffmann, Udo] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Fox, Caroline S.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Benjamin, Emelia J.] Harvard Med Sch, Brigham & Womens Hosp, Div Endocrinol, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Benjamin, EJ (reprint author), NHLBI, Populat Sci Branch, Div Intramural Res, Framingham, MA 01702 USA.; Benjamin, EJ (reprint author), Boston Univ Framingham Heart Study, Framingham, MA 01702 USA.; Benjamin, EJ (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Endocrinol, Boston, MA USA. EM emelia@bu.edu OI Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung and Blood Institute's Framingham Heart Study (Framingham, Massachusetts) [N01-HC-25195]; National Institutes of Health [HHSN268201500001I, 2R01HL092577, 1R01 HL128914, 1R01 HL102214, 1RC1HL101056] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Framingham, Massachusetts) (contract N01-HC-25195). Dr. Emelia Benjamin is supported by grants HHSN268201500001I, 2R01HL092577, 1R01 HL128914, 1R01 HL102214, 1RC1HL101056 from the National Institutes of Health. NR 30 TC 1 Z9 1 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 NOV 15 PY 2016 VL 118 IS 10 BP 1486 EP 1492 DI 10.1016/j.amjcard.2016.08.011 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ED7DM UT WOS:000389015900009 PM 27666172 ER PT J AU Ko, D Riles, EM Marcos, EG Magnani, JW Lubitz, SA Lin, HH Long, MT Schnabel, RB McManus, DD Ellinor, PT Ramachandran, VS Wang, TJ Gerszten, RE Benjamin, EJ Yin, XY Rienstra, M AF Ko, Darae Riles, Eric M. Marcos, Ernaldo G. Magnani, Jared W. Lubitz, Steven A. Lin, Honghuang Long, Michelle T. Schnabel, Renate B. McManus, David D. Ellinor, Patrick T. Ramachandran, Vasan S. Wang, Thomas J. Gerszten, Robert E. Benjamin, Emelia J. Yin, Xiaoyan Rienstra, Michiel TI Metabolomic Profiling in Relation to New-Onset Atrial Fibrillation (from the Framingham Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID SERUM URIC-ACID; OXIDATIVE STRESS; RISK; BIOMARKER; FAILURE AB Previous studies have shown several metabolic biomarkers to be associated with prevalent and incident atrial fibrillation (AF), but the results have not been replicated.. We investigated metabolite profiles of 2,458 European ancestry participants from the Framingham Heart Study without AF at the index examination and followed them for 10 years for new onset AF. Amino acids, organic acids, lipids, and other plasma metabolites were profiled by liquid chromatography tandem mass spectrometry using fasting plasma samples. We conducted Cox proportional hazard analyses for association between metabolites and new onset AF. We performed hypothesis-generating analysis to identify novel metabolites and hypothesis-testing analysis to confirm the previously reported associations between metabolites and AF. Mean age was 55.1 +/- 9.9 years, and 53% were women. Incident AF developed in 156 participants (6.3%) in 10 years of follow-up. A total of 217 metabolites were examined, consisting of 54 positively charged metabolites, 59 negatively charged metabolites, and 104 lipids. None of the 217 metabolites met our a priori specified Bonferroni corrected level of significance in the multivariate analyses. We were unable to replicate previous results demonstrating associations between metabolites that we had measured and AF. In conclusion, in our metabolomics approach, none of the metabolites we tested were significantly associated with the risk of future AF. (C) 2016 Elsevier Inc. All rights reserved. C1 [Ko, Darae] Boston Univ, Sch Med, Boston Med Ctr, Dept Internal Med,Gen Internal Med Sect, Boston, MA 02118 USA. [Riles, Eric M.; Magnani, Jared W.; Ramachandran, Vasan S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Boston Med Ctr, Dept Internal Med,Sect Cardiovasc Med, Boston, MA 02118 USA. [Long, Michelle T.] Boston Univ, Sch Med, Boston Med Ctr, Dept Internal Med,Gastroenterol Sect, Boston, MA 02118 USA. [Ramachandran, Vasan S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Boston Med Ctr, Dept Internal Med,Sect Prevent Med, Boston, MA 02118 USA. [Ko, Darae; Ramachandran, Vasan S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Ko, Darae] Boston Univ, Sch Med, Clin & Translat Sci Inst, Boston, MA 02118 USA. [Marcos, Ernaldo G.; Rienstra, Michiel] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Lubitz, Steven A.; Ellinor, Patrick T.; Gerszten, Robert E.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA USA. [Ramachandran, Vasan S.; Benjamin, Emelia J.] Boston Univ, Framingham, MA USA. [Ramachandran, Vasan S.; Benjamin, Emelia J.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Schnabel, Renate B.] Univ Hamburg, Heart Ctr Hamburg Eppendorf, Dept Gen & Intervent Cardiol, Hamburg, Germany. [McManus, David D.] Univ Massachusetts, Sch Med, Div Cardiovasc Med, Worcester, MA USA. [Ramachandran, Vasan S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Wang, Thomas J.] Vanderbilt Univ, Div Cardiovasc Med, 221 Kirkland Hall, Nashville, TN 37235 USA. [Yin, Xiaoyan] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Rienstra, M (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. EM m.rienstra@umcg.nl OI Rienstra, Michiel/0000-0002-2581-070X FU NIH/NHLBI [HHSN268201500001I, N01-HC25195, 2R01HL092577, 1R01 HL102214, 1R01HL128914, 1RC1HL101056]; National Institutes of Health [2R01HL092577, 1K24HL105780]; Established Investigator Award from the American Heart Association [13EIA14220013]; Fondation Leducq [14CVD01]; NIH Career Development Award [K23HL114724]; Doris Duke Charitable Foundation Clinical Scientist Development Award [2014105, 2015084]; European Research Council under the European Union's Horizon research and innovation program [648131]; German Ministry of Research and Education [BMBF 01ZX1408A]; German Research Foundation Emmy Noether Program [SCHN 1149/3-1]; Netherlands Organization for Scientific Research [616.136.055]; NIH [R01-DK-HL081572]; [5T32HL007224-38]; [UL1-TR000157] FX Dr. Ko is supported by 5T32HL007224-38 and UL1-TR000157. Dr. Benjamin is supported in part through NIH/NHLBI HHSN268201500001I; N01-HC25195, 2R01HL092577, 1R01 HL102214, 1R01HL128914, and 1RC1HL101056. Dr. Ellinor is supported by grants from the National Institutes of Health (2R01HL092577, 1K24HL105780), an Established Investigator Award from the American Heart Association (13EIA14220013), and the Fondation Leducq (14CVD01). Dr. Lubitz is supported by an NIH Career Development Award (K23HL114724) and Doris Duke Charitable Foundation Clinical Scientist Development Award (2014105). Dr. Magnani is supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award (2015084). Dr. R. Schnabel has received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement No 648131), German Ministry of Research and Education (BMBF 01ZX1408A), German Research Foundation Emmy Noether Program SCHN 1149/3-1. Dr. Rienstra is supported by a grant from the Netherlands Organization for Scientific Research (Veni grant 616.136.055). The project was funded by NIH R01-DK-HL081572. NR 25 TC 0 Z9 0 U1 2 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD NOV 15 PY 2016 VL 118 IS 10 BP 1493 EP 1496 DI 10.1016/j.amjcard.2016.08.010 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ED7DM UT WOS:000389015900010 PM 27666170 ER PT J AU Sachdeva, R Douglas, PS Kelleman, MS McCracken, CE Lopez, L Stern, KWD Eidem, BW Benavidez, OJ Weiner, RB Welch, E Campbell, RM Lai, WW AF Sachdeva, Ritu Douglas, Pamela S. Kelleman, Michael S. McCracken, Courtney E. Lopez, Leo Stern, Kenan W. D. Eidem, Benjamin W. Benavidez, Oscar J. Weiner, Rory B. Welch, Elizabeth Campbell, Robert M. Lai, Wyman W. TI Effect of Release of the First Pediatric Appropriate Use Criteria on Transthoracic Echocardiogram Ordering Practice SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID QUALITY IMPROVEMENT INTERVENTIONS; AMERICAN-SOCIETY; EDUCATIONAL INTERVENTION; COMPUTED-TOMOGRAPHY; HEART-DISEASE; TASK-FORCE; MULTICENTER; IMPACT; ANGIOGRAPHY; PERFORMANCE AB Pediatric appropriate use criteria (AUC) were recently published for initial outpatient transthoracic echocardiography (TTE). The purpose of this study was to determine the effect of AUC publication on TTE ordering patterns of pediatric cardiologists. Data were prospectiVely collected on patients who had initial outpatient TTE ordered before (phase I, April to September 2014) and 3 months after (phase II, January to April 2015) AUC document publication at 6 centers. Site investigators assessed each study's indication and assigned AUC appropriateness as "appropriate" (A), "may be appropriate" (M), "rarely appropriate" (R), or "unclassifiable." One hundred three physicians ordered 4,562 TTEs (2,655 phase I and 1,907 phase II). Overall, there was no statistically significant change in the proportion of A, M, or unclassifiable, but R decreased (12.0% to 9.6%, p = 0.01). There was significant variability among the centers in the percentage of studies for indications rated R (4.9% to 34.8%). There was no significant change in any of the appropriateness ratings at 4 centers, a decrease in R and an increase in A at 1 and a decrease in R and increase in unclassifiable at another. The first pediatric AUC document had only a small impact on physician ordering behavior for initial TTEs, including a small decrease in R. There was a significant variability in appropriateness of studies among centers. These data suggest that active educational interventions are required to substantially improve the appropriate use of pediatric TTE in the outpatient setting. (C) 2016 Elsevier Inc. All rights reserved. C1 [Sachdeva, Ritu; Campbell, Robert M.] Emory Univ, Sch Med, Dept Pediat, Div Pediat Cardiol, Atlanta, GA 30322 USA. [Sachdeva, Ritu; Campbell, Robert M.] Childrens Healthcare Atlanta Sibley Heart Ctr Car, Atlanta, GA 30341 USA. [Douglas, Pamela S.] Duke Univ, Dept Med, Duke Clin Res Inst, Durham, NC USA. [Kelleman, Michael S.; McCracken, Courtney E.] Emory Univ, Sch Med, Dept Pediat Biostat Core, Atlanta, GA USA. [Lopez, Leo; Welch, Elizabeth] Nicklaus Childrens Hosp, Dept Pediat, Div Cardiol, Miami, FL USA. [Stern, Kenan W. D.] Childrens Hosp Montefiore, Dept Pediat, Div Pediat Cardiol, New York, NY USA. [Eidem, Benjamin W.] Mayo Clin Rochester, Dept Pediat, Div Pediat Cardiol, Rochester, MN USA. [Benavidez, Oscar J.; Weiner, Rory B.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Lai, Wyman W.] Morgan Stanley Childrens Hosp, NewYork Presbyterian, Div Pediat Cardiol, New York, NY USA. RP Sachdeva, R (reprint author), Emory Univ, Sch Med, Dept Pediat, Div Pediat Cardiol, Atlanta, GA 30322 USA.; Sachdeva, R (reprint author), Childrens Healthcare Atlanta Sibley Heart Ctr Car, Atlanta, GA 30341 USA. EM sachdevar@kidsheart.com NR 25 TC 1 Z9 1 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 NOV 15 PY 2016 VL 118 IS 10 BP 1545 EP 1551 DI 10.1016/j.amjcard.2016.08.019 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ED7DM UT WOS:000389015900018 PM 27639687 ER PT J AU Hariharan, P Dudzinski, DM Rosovsky, R Haddad, F MacMahon, P Parry, B Chang, YC Kabrhel, C AF Hariharan, Praveen Dudzinski, David M. Rosovsky, Rachel Haddad, Farris MacMahon, Peter Parry, Blair Chang, Yuchiao Kabrhel, Christopher TI Relation Among Clot Burden, Right-Sided Heart Strain, and Adverse Events After Acute Pulmonary Embolism SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID RIGHT-VENTRICULAR DYSFUNCTION; DEEP-VEIN THROMBOSIS; COMPUTED-TOMOGRAPHY; LOAD SCORES; HELICAL CT; FOLLOW-UP; MORTALITY; ECHOCARDIOGRAPHY; ANGIOGRAPHY; SEVERITY AB Computed tomography pulmonary angiogram (CTPA) provides a volumetric assessment of clot burden in acute pulmonary embolism (PE). However, it is unclear if clot burden is associated with right-sided heart strain (RHS) or adverse clinical events (ACE). We prospectively enrolled Emergency Department patients with PE (in CTPA) from 2008 to 2011. We assigned 1 to 9 points as clot burden score, based on whether emboli were saddle, central, lobar, segmental, and subsegmental. We evaluated a novel score (the "CT-PASS") based on the sum (in millimeters) of the largest filling defects in the right and left pulmonary vasculature. Our primary outcome was RHS, defined by imaging (echocardiography or CTPA) or cardiac biomarkers. Our secondary outcomes included 5 -day ACE. We included 271 patients (50% women), with a mean age of 59 +/- 17 years. Based on CTPA, 131 patients (48%) had central PE (clot burden score >= 5 points). The median CT -PASS was 9.1 mm (interquartile range 4.9 to 16.4). In univariate analysis, higher clot burden (highest quartile CT -PASS) was associated with RHS (p = 0.003). In multivariate analysis, after adjusting for RHS, age, and gender, central PE (odds ratio [OR] 2.92, 95% confidence interval [CI] 1.10 to 7.81) and CT PASS >20 mm (OR 3.54, 95% CI 1.39 to 8.97) were significantly associated with ACE. However, this association of central PE with ACE was not statistically significant after excluding patients with shock index >1 (OR 2.56, 95% CI 0.62 to 10.64). In conclusion, highest quartile CT -PASS was' associated with RHS and central PE and ACE, but this association was not statistically significant in hemodynamically stable PE. (C) 2016 Elsevier Inc. All rights reserved. C1 [Hariharan, Praveen; Dudzinski, David M.; Rosovsky, Rachel; Parry, Blair; Kabrhel, Christopher] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Vasc Emergencies, Dept Emergency Med, Boston, MA 02115 USA. [Dudzinski, David M.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA USA. [Rosovsky, Rachel] Harvard Med Sch, Massachusetts Gen Hosp, Div Hematol & Oncol, Dept Med, Boston, MA USA. [Chang, Yuchiao] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Haddad, Farris] Inova Fairfax Hosp, Dept Radiol, Falls River, VA USA. [MacMahon, Peter] Mater Misericordiae Univ Hosp, Dept Radiol, Dublin, Ireland. RP Kabrhel, C (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Vasc Emergencies, Dept Emergency Med, Boston, MA 02115 USA. EM ckabrhel@partners.org NR 30 TC 1 Z9 1 U1 1 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD NOV 15 PY 2016 VL 118 IS 10 BP 1568 EP 1573 DI 10.1016/j.amjcard.2016.08.025 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ED7DM UT WOS:000389015900022 PM 27742425 ER PT J AU Marusyk, A Tabassum, DP Janiszewska, M Place, AE Trinh, A Rozhok, AI Pyne, S Guerriero, JL Shu, S Ekram, M Ishkin, A Cahill, DP Nikolsky, Y Chan, TA Rimawi, MF Hilsenbeck, S Schiff, R Osborne, KC Letai, A Polyak, K AF Marusyk, Andriy Tabassum, Doris P. Janiszewska, Michalina Place, Andrew E. Trinh, Anne Rozhok, Andrii I. Pyne, Saumyadipta Guerriero, Jennifer L. Shu, Shaokun Ekram, Muhammad Ishkin, Alexander Cahill, Daniel P. Nikolsky, Yuri Chan, Timothy A. Rimawi, Mothaffar F. Hilsenbeck, Susan Schiff, Rachel Osborne, Kent C. Letai, Antony Polyak, Kornelia TI Spatial Proximity to Fibroblasts Impacts Molecular Features and Therapeutic Sensitivity of Breast Cancer Cells Influencing Clinical Outcomes SO CANCER RESEARCH LA English DT Article ID MEDIATED DRUG-RESISTANCE; TUMOR MICROENVIRONMENT; GENE-EXPRESSION; PANCREAS CANCER; IN-SITU; LAPATINIB; HETEROGENEITY; CHEMOTHERAPY; HYALURONAN; EVOLUTION AB Using a three-dimensional coculture model, we identified significant subtype-specific changes in gene expression, metabolic, and therapeutic sensitivity profiles of breast cancer cells in contact with cancer-associated fibroblasts (CAF). CAF-induced gene expression signatures predicted clinical outcome and immune-related differences in the microenvironment. We found that fibroblasts strongly protect carcinoma cells from lapatinib, attributable to its reduced accumulation in carcinoma cells and an elevated apoptotic threshold. Fibroblasts from normal breast tissues and stromal cultures of brain metastases of breast cancer had similar effects as CAFs. Using synthetic lethality approaches, we identified molecular pathways whose inhibition sensitizes HER2(+) breast cancer cells to lapatinib both in vitro and in vivo, including JAK2/STAT3 and hyaluronic acid. Neoadjuvant lapatinib therapy in HER2(+) breast tumors lead to a significant increase of phospho-STAT3(+) cancer cells and a decrease in the spatial proximity of proliferating (Ki67(+)) cells to CAFs impacting therapeutic responses. Our studies identify CAF-induced physiologically and clinically relevant changes in cancer cells and offer novel approaches for overcoming microenvironment-mediated therapeutic resistance. (C) 2016 AACR. C1 [Marusyk, Andriy; Tabassum, Doris P.; Janiszewska, Michalina; Trinh, Anne; Pyne, Saumyadipta; Guerriero, Jennifer L.; Shu, Shaokun; Ekram, Muhammad; Letai, Antony; Polyak, Kornelia] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Marusyk, Andriy; Janiszewska, Michalina; Trinh, Anne; Guerriero, Jennifer L.; Shu, Shaokun; Ekram, Muhammad; Letai, Antony; Polyak, Kornelia] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Marusyk, Andriy; Janiszewska, Michalina; Trinh, Anne; Guerriero, Jennifer L.; Shu, Shaokun; Ekram, Muhammad; Letai, Antony; Polyak, Kornelia] Harvard Med Sch, Dept Med, Boston, MA USA. [Tabassum, Doris P.; Polyak, Kornelia] Harvard Med Sch, BBS Program, Boston, MA USA. [Place, Andrew E.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Place, Andrew E.] Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. [Rozhok, Andrii I.] Univ Colorado, Dept Biochem & Mol Genet, Aurora, CO USA. [Ishkin, Alexander; Nikolsky, Yuri] Thomson Reuters Healthcare & Sci, Encinitas, CA USA. [Cahill, Daniel P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cahill, Daniel P.] Harvard Med Sch, Dept Neurosurg, Boston, MA USA. [Chan, Timothy A.] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10021 USA. [Rimawi, Mothaffar F.; Hilsenbeck, Susan; Schiff, Rachel; Osborne, Kent C.] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. [Rimawi, Mothaffar F.; Hilsenbeck, Susan; Schiff, Rachel; Osborne, Kent C.] Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Polyak, Kornelia] Broad Inst, Cambridge, MA USA. RP Polyak, K (reprint author), Harvard Med Sch, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA.; Marusyk, A (reprint author), H Lee Moffitt Canc Ctr & Res Inst, 12901 Magnolia Dr, Tampa, FL 33612 USA. EM andriy.marusyk@moffitt.org; Kornelia_polyak@dfci.harvard.edu FU DBT-Ramalingaswami Fellowship; CDRMP [W81XWH-09-1-0561]; Shula fund; NIH [CA116235]; Breast Cancer Alliance; Breast Cancer Research Foundation FX This work was supported by the DBT-Ramalingaswami Fellowship (S. Pyne), CDRMP W81XWH-09-1-0561 and Shula fund (A. Marusyk), NIH CA116235, Breast Cancer Alliance, and Breast Cancer Research Foundation (K. Polyak). NR 40 TC 0 Z9 0 U1 5 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD NOV 15 PY 2016 VL 76 IS 22 BP 6495 EP 6506 DI 10.1158/0008-5472.CAN-16-1457 PG 12 WC Oncology SC Oncology GA ED3IF UT WOS:000388742100009 PM 27671678 ER PT J AU Anderson, KC AF Anderson, Kenneth C. TI Progress and Paradigms in Multiple Myeloma SO CLINICAL CANCER RESEARCH LA English DT Article ID PROTEASOME INHIBITOR PS-341; LENALIDOMIDE PLUS DEXAMETHASONE; OVERCOMES BORTEZOMIB RESISTANCE; MINIMAL RESIDUAL DISEASE; SMALL-MOLECULE INHIBITOR; IN-VIVO MODEL; BONE-MARROW; T-CELLS; HEMATOLOGIC MALIGNANCIES; DARATUMUMAB MONOTHERAPY AB Remarkable progress has been achieved in multiple myeloma, and patientmedian survival has been extended 3- to 4-fold. Specifically, there have been 18 newly approved treatments for multiple myeloma in the past 12 years, including seven in 2015, and the treatment paradigm and patient outcome have been transformed. The definition of patients benefitting from these therapies has been broadened. Response criteria now include minimal residual disease (MRD), assessed in bone marrow by multicolor flow cytometry or sequencing, and by imaging for extramedullary disease. Initial therapy for transplant candidates is a triplet incorporating novel therapies-that is, lenalidomide, bortezomib, and dexamethasone or cyclophosphamide, bortezomib, and dexamethasone. Lenalidomide maintenance until progression can prolong progression-free and overall survival in standard-risk multiple myeloma, with incorporation of proteasome inhibitor for high-risk disease. Studies are evaluating the value of early versus late transplant and MRD as a therapeutic goal to inform therapy. In nontransplant patients, triplet therapies are also preferred, with doublet therapy reserved for frail patients, and maintenance as described above. The availability of second-generation proteasome inhibitors (carfilzomib and ixazomib), immunomodulatory drugs (pomalidomide), histone deacetylase inhibitors (panobinostat), and monoclonal antibodies (elotuzumab and daratumumab) allows for effective combination therapies of relapsed disease as well. Finally, novel therapies targeting protein degradation, restoring autologous memory anti-multiple myeloma immunity, and exploiting genetic vulnerabilities show promise to improve patient outcome even further. C1 [Anderson, Kenneth C.] Harvard Med Sch, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Dept Med Oncol,Div Hematol Malignancy, Boston, MA USA. RP Anderson, KC (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM kenneth_anderson@dfci.harvard.edu FU NIH/NCI [RO-1 CA207237, RO-1 CA050947, RO-1 CA178264, P50 CA100707, PO-1 CA155258, P30 CA006516] FX This work is supported by NIH/NCI grants RO-1 CA207237, RO-1 CA050947, RO-1 CA178264, P50 CA100707, PO-1 CA155258, and P30 CA006516 (to K.C. Anderson). K.C. Anderson is an American Cancer Society Clinical Research Professor. NR 93 TC 0 Z9 0 U1 8 U2 8 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 NOV 15 PY 2016 VL 22 IS 22 BP 5419 EP 5427 DI 10.1158/1078-0432.CCR-16-0625 PG 9 WC Oncology SC Oncology GA ED3IU UT WOS:000388743600006 PM 28151709 ER PT J AU Szalat, R Avet-Loiseau, H Munshi, NC AF Szalat, Raphael Avet-Loiseau, Herve Munshi, Nikhil C. TI Gene Expression Profiles in Myeloma: Ready for the Real World? SO CLINICAL CANCER RESEARCH LA English DT Article ID DIAGNOSED MULTIPLE-MYELOMA; SINGLE-AGENT BORTEZOMIB; HIGH-RISK PATIENTS; MOLECULAR CLASSIFICATION; INTRACLONAL HETEROGENEITY; THERAPEUTIC AGENT; COMPLETE RESPONSE; TARGETED THERAPY; DEXAMETHASONE; PROGRESSION AB Multiple myeloma is a plasma cell malignancy characterized by molecular and clinical heterogeneity. The outcome of the disease has been dramatically improved with the advent of new drugs in the past few years. However, even in this context of increasing therapeutic options, important challenges remain, such as accurately evaluating patients' prognosis and predicting sensitivity to specific treatments and drug combinations. Transcriptomic studies have largely contributed to help decipher multiple myeloma complexity, characterizing multiple myeloma subgroups distinguished by different outcomes. Microarrays and, more recently, RNA sequencing allow evaluation of expression of coding and noncoding genes, alternate splicing events, mutations, and novel transcriptome modifiers, providing new information regarding myeloma biology, prognostication, and therapy. In this review, we discuss the role and impact of gene expression profiling studies in myeloma. C1 [Szalat, Raphael; Munshi, Nikhil C.] Harvard Med Sch, Dana Farber Canc Inst, Med Oncol, Boston, MA USA. [Avet-Loiseau, Herve] Ctr Rech Cancerol Toulouse, Inst Natl Sante & Rech Med, Toulouse, France. [Munshi, Nikhil C.] Boston Vet Adm Healthcare Syst, Boston, MA USA. RP Munshi, NC (reprint author), Harvard Med Sch, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA.; Avet-Loiseau, H (reprint author), Ctr Rech Cancerol Toulouse, Inst Natl Sante & Rech Med, U1037, 1 Ave Irene Joliot Curie, F-31059 Toulouse 9, France. EM avet-loiseau.h@chu-toulouse.fr; nikhil_munshi@dfci.harvard.edu FU NIH [PO1-155258, P50-100707]; U.S. Department of Veterans Affairs Merit Review Award I [I01BX001584-01]; Leukemia & Lymphoma Society Translational Research Program Award FX This work was supported by NIH grants PO1-155258 and P50-100707 (to H. Avet-Loiseau and N.C. Munshi), U.S. Department of Veterans Affairs Merit Review Award I I01BX001584-01 (to N.C. Munshi), and a Leukemia & Lymphoma Society Translational Research Program Award (to N.C. Munshi). NR 81 TC 4 Z9 4 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 15 PY 2016 VL 22 IS 22 BP 5434 EP 5442 DI 10.1158/1078-0432.CCR-16-0867 PG 9 WC Oncology SC Oncology GA ED3IU UT WOS:000388743600008 PM 28151711 ER PT J AU Kumar, SK Anderson, KC AF Kumar, Shaji K. Anderson, Kenneth C. TI Immune Therapies in Multiple Myeloma SO CLINICAL CANCER RESEARCH LA English DT Article ID MONOCLONAL-ANTIBODY DARATUMUMAB; RHAMM-R3 PEPTIDE VACCINATION; STEM-CELL TRANSPLANTATION; NATURAL-KILLER-CELLS; T-CELLS; IDIOTYPE VACCINATION; ANTITUMOR-ACTIVITY; DENDRITIC CELLS; HUMAN CD38; MYELODYSPLASTIC SYNDROME AB Treatment paradigms have changed rapidly for multiple myeloma, and immune therapies have taken center stage. Advances in therapies for myeloma have led to a dramatic improvement in the survival of patients with this incurable malignancy. The immune system is significantly impaired in patients with myeloma as a result of the disease leading to suppression of normal plasma cells as well the negative effects on cellular immunity. Given this scenario, immune approaches have not been successful until recently. Monoclonal antibodies directed against CD38 (daratumumab) and SLAMF7 (elotuzumab) are already in the clinic, and several other antibodies directed against different plasma cell antigens are under evaluation. Although immune checkpoint inhibition with PD-1 inhibitors had no clinical efficacy when the inhibitors were used as single agents, it has led to some dramatic results when the inhibitors are combined with immunomodulatory drugs such as lenalidomide and pomalidomide. Vaccination strategies have shown in vivo immune responses but no clear clinical efficacy. Newer approaches to vaccination with multiple antigens, used in combinations with immunomodulatory drugs and in the setting of minimal residual disease, have all increased possibility of this approach succeeding. Ex vivo effector cell expansion also appears to be promising and is in clinical trials. Finally, a chimeric antigen receptor T-cell approach appears to have some promise based on isolated reports of success and remains an area of intense investigation. Immune-based approaches can potentially augment or even supplant some of the current approaches and, given the low toxicity profile, may hold great potential in the early treatment of precursor-stage diseases. C1 [Kumar, Shaji K.] Mayo Clin, Div Hematol, Rochester, MN USA. [Anderson, Kenneth C.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Kumar, SK (reprint author), Mayo Clin, 200 First St SW, Rochester, MN 55905 USA. EM kumar.shaji@mayo.edu NR 59 TC 3 Z9 3 U1 6 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 15 PY 2016 VL 22 IS 22 BP 5453 EP 5460 DI 10.1158/1078-0432.CCR-16-0868 PG 8 WC Oncology SC Oncology GA ED3IU UT WOS:000388743600010 PM 28151713 ER PT J AU Choueiri, TK Fishman, MN Escudier, B McDermott, DF Drake, CG Kluger, H Stadler, WM Perez-Gracia, JL McNeel, DG Curti, B Harrison, MR Plimack, ER Appleman, L Fong, L Albiges, L Cohen, L Young, TC Chasalow, SD Ross-Macdonald, P Srivastava, S Jure-Kunkel, M Kurland, JF Simon, JS Sznol, M AF Choueiri, Toni K. Fishman, Mayer N. Escudier, Bernard McDermott, David F. Drake, Charles G. Kluger, Harriet Stadler, Walter M. Perez-Gracia, Jose Luis McNeel, Douglas G. Curti, Brendan Harrison, Michael R. Plimack, Elizabeth R. Appleman, Leonard Fong, Lawrence Albiges, Laurence Cohen, Lewis Young, Tina C. Chasalow, Scott D. Ross-Macdonald, Petra Srivastava, Shivani Jure-Kunkel, Maria Kurland, John F. Simon, Jason S. Sznol, Mario TI Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID RANDOMIZED PHASE-3 TRIAL; LONG-TERM SAFETY; PD-1 BLOCKADE; RECEIVING NIVOLUMAB; IMMUNE-RESPONSE; EXPRESSION; SURVIVAL; THERAPY; CHEMOKINES; SORAFENIB AB Purpose: Nivolumab, an anti-PD-1 immune checkpoint inhibitor, improved overall survival versus everolimus in a phase 3 trial of previously treated patients with metastatic renal cell carcinoma (mRCC). We investigated immunomodulatory activity of nivolumab in a hypothesis-generating prospective mRCC trial. Experimental Design: Nivolumab was administered intravenously every 3 weeks at 0.3, 2, or 10 mg/kg to previously treated patients and 10 mg/kg to treatment-naive patients with mRCC. Baseline and on-treatment biopsies and blood were obtained. Clinical activity, tumor-associated lymphocytes, PD-L1 expression (Dako immunohistochemistry; >= 5% vs. <5% tumor membrane staining), tumor gene expression (Affymetrix U219), serum chemokines, and safety were assessed. Results: In 91 treated patients, median overall survival [95% confidence interval (CI)] was 16.4 months [10.1 to not reached (NR)] for nivolumab 0.3 mg/kg, NR for 2 mg/kg, 25.2 months (12.0 to NR) for 10 mg/kg, and NR for treatment-naive patients. Median percent change from baseline in tumor-associated lymphocytes was 69% (CD3(+)), 180% (CD4(+)), and 117% (CD8(+)). Of 56 baseline biopsies, 32% had >= 5% PD-L1 expression, and there was no consistent change from baseline to on-treatment biopsies. Transcriptional changes in tumors on treatment included upregulation of IFN gamma-stimulated genes (e.g., CXCL9). Median increases in chemokine levels from baseline to C2D8 were 101% (CXCL9) and 37% (CXCL10) in peripheral blood. No new safety signals were identified. Conclusions: Immunomodulatory effects of PD-1 inhibition were demonstrated through multiple lines of evidence across nivolumab doses. Biomarker changes from baseline reflect nivolumab pharmacodynamics in the tumor microenvironment. These data may inform potential combinations. (C)2016 AACR. C1 [Choueiri, Toni K.] Brigham & Womens Hosp, Dana Farber Canc Inst, Kidney Canc Ctr, 75 Francis St, Boston, MA 02115 USA. [Choueiri, Toni K.] Harvard Med Sch, Boston, MA USA. [Fishman, Mayer N.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Escudier, Bernard] Inst Gustave Roussy, Villejuif, France. [McDermott, David F.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Drake, Charles G.] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Drake, Charles G.] Brady Urol Inst, Baltimore, MD USA. [Kluger, Harriet; Sznol, Mario] Yale Univ, Sch Med, New Haven, CT USA. [Kluger, Harriet; Sznol, Mario] Yale Canc Ctr, New Haven, CT USA. [Stadler, Walter M.] Univ Chicago, Sch Med, Chicago, IL 60637 USA. [Perez-Gracia, Jose Luis] Univ Navarra Clin, Pamplona, Navarra, Spain. [McNeel, Douglas G.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Curti, Brendan] Earle A Chiles Res Inst, Portland, OR USA. [Harrison, Michael R.] Duke Univ, Med Ctr, Durham, NC USA. [Plimack, Elizabeth R.] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Appleman, Leonard] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Fong, Lawrence] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Albiges, Laurence] Dana Farber Canc Inst, Kidney Canc Ctr, Boston, MA 02115 USA. [Albiges, Laurence] Inst Gustave Roussy, Villejuif, France. [Cohen, Lewis; Young, Tina C.; Chasalow, Scott D.; Ross-Macdonald, Petra; Srivastava, Shivani; Jure-Kunkel, Maria; Kurland, John F.; Simon, Jason S.] Bristol Myers Squibb Co, Princeton, NJ USA. RP Choueiri, TK (reprint author), Dana Farber Canc Inst, 450 Brookline Ave DANA 1230, Boston, MA 02115 USA. EM Toni_Choueiri@dfci.harvard.edu FU Bristol-Myers Squibb/Ono Pharmaceutical Company Limited FX The analyses and studies described in this report were funded by Bristol-Myers Squibb/Ono Pharmaceutical Company Limited. NR 41 TC 4 Z9 4 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 NOV 15 PY 2016 VL 22 IS 22 BP 5461 EP 5471 DI 10.1158/1078-0432.CCR-15-2839 PG 11 WC Oncology SC Oncology GA ED3IU UT WOS:000388743600011 PM 27169994 ER PT J AU Zhao, S Chen, C Chang, K Karnad, A Jagirdar, J Kumar, AP Freeman, JW AF Zhao, Shujie Chen, Chen Chang, Katherine Karnad, Anand Jagirdar, Jaishree Kumar, Addanki P. Freeman, James W. TI CD44 Expression Level and Isoform Contributes to Pancreatic Cancer Cell Plasticity, Invasiveness, and Response to Therapy SO CLINICAL CANCER RESEARCH LA English DT Article ID STEM-CELLS; ADHESION MOLECULES; BREAST-CANCER; COLON-CANCER; METASTASIS; ADENOCARCINOMA; PROGRESSION; GROWTH; EMT; PROLIFERATION AB Purpose: A subpopulation of pancreatic ductal adenocarcinoma (PDAC) cells is thought to be inherently resistant to chemotherapy or to give rise to tumor cells that become resistant during treatment. Here we determined the role of CD44 expression and its isoforms as a marker and potential target for tumor cells that give rise to invasive and gemcitabineresistant tumors. Experimental Design: RT-PCR, Western blotting, and DNA sequencing was used to determine CD44 isoform and expression levels. Flow cytometry was used to sort cells on the basis of their CD44 expression level. CD44 expression was knocked down using shRNA. Tumorigenic properties were determined by clonogenic and Matrigel assays, IHC, tumor growth in vivo using luciferase imaging and by tumor weight. Results: Weidentified an invasive cell population that gives rise to gemcitabine-resistant tumors. These cancer cells express a high level of CD44 standard isoform and have an EMT phenotype (CD44s/EMT). In vivo, CD44s/EMT engraft and expand rapidly and give rise to tumors that express high levels of CD44 isoforms that contain multiple exon variants. CD44low-expressing cells show continued sensitivity to gemcitabine in vivo and knockdown of CD44 in CD44s/EMT cells increases sensitivity to gemcitabine and decreases invasiveness. Conclusions: PDAC cells expressing high levels of CD44s with a mesenchymal-like phenotype were highly invasive and developed gemcitabine resistance in vivo. Thus, initial targeting CD44 or reversing the CD44high phenotype may improve therapeutic response. (C) 2016 AACR. C1 [Zhao, Shujie; Chen, Chen; Chang, Katherine; Karnad, Anand; Freeman, James W.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Med Oncol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. [Chang, Katherine; Karnad, Anand; Freeman, James W.] Canc Therapy & Res Ctr S Texas, Expt & Dev Therapeut Program, 4450 Med Dr, San Antonio, TX 78229 USA. [Jagirdar, Jaishree] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Kumar, Addanki P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. [Kumar, Addanki P.; Freeman, James W.] Audie L Murphy Mem Vet Adm Med Ctr, Res & Dev, San Antonio, TX USA. RP Freeman, JW (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Med Oncol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM freemanjw@uthscsa.edu FU William and Ella Owens Medical Research Foundation; VA Merit Award; Cancer Center Grant [NIH-P30CA054174]; CPRIT training grant FX This work was supported by grants from the William and Ella Owens Medical Research Foundation, VA Merit Award, Cancer Center Grant to CTRC and NIH-P30CA054174 (to J. W. Freeman), and CPRIT training grant (to K. Chang). NR 41 TC 0 Z9 0 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 NOV 15 PY 2016 VL 22 IS 22 BP 5592 EP 5604 DI 10.1158/1078-0432.CCR-15-3115 PG 13 WC Oncology SC Oncology GA ED3IU UT WOS:000388743600024 PM 27267855 ER PT J AU Van Hise, NW Manian, FA AF Van Hise, Nicholas W. Manian, Farrin A. TI Efficacy of Oral Vancomycin in Preventing Recurrent Clostridium difficile Infection in Patients Treated With Systemic Antimicrobial Agents Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID DIARRHEA C1 [Van Hise, Nicholas W.] Edward Elmhurst Hosp, Dept Pharm, Naperville, IL USA. [Manian, Farrin A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. RP Van Hise, NW (reprint author), 2304 Modaff Rd, Naperville, IL 60565 USA. EM nicholas.vanhise@gmail.com NR 9 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD NOV 15 PY 2016 VL 63 IS 10 BP 1392 EP U142 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA ED0TI UT WOS:000388554500027 PM 27567121 ER PT J AU Muller, L Piantoni, G Koller, D Cash, SS Halgren, E Sejnowski, TJ AF Muller, Lyle Piantoni, Giovanni Koller, Dominik Cash, Sydney S. Halgren, Eric Sejnowski, Terrence J. TI Rotating waves during human sleep spindles organize global patterns of activity that repeat precisely through the night SO ELIFE LA English DT Article ID LOCAL-FIELD POTENTIALS; SURFACE-BASED ANALYSIS; VISUAL-CORTEX; CORTICOTHALAMIC FEEDBACK; SOMATOSENSORY CORTEX; MEMORY; OSCILLATIONS; PLASTICITY; COHERENCE; DENSITY AB During sleep, the thalamus generates a characteristic pattern of transient, 11-15 Hz sleep spindle oscillations, which synchronize the cortex through large-scale thalamocortical loops. Spindles have been increasingly demonstrated to be critical for sleep-dependent consolidation of memory, but the specific neural mechanism for this process remains unclear. We show here that cortical spindles are spatiotemporally organized into circular wave-like patterns, organizing neuronal activity over tens of milliseconds, within the timescale for storing memories in large-scale networks across the cortex via spike-time dependent plasticity. These circular patterns repeat over hours of sleep with millisecond temporal precision, allowing reinforcement of the activity patterns through hundreds of reverberations. These results provide a novel mechanistic account for how global sleep oscillations and synaptic plasticity could strengthen networks distributed across the cortex to store coherent and integrated memories. C1 [Muller, Lyle; Koller, Dominik; Sejnowski, Terrence J.] Salk Inst Biol Studies, Computat Neurobiol Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. [Piantoni, Giovanni; Cash, Sydney S.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Halgren, Eric] Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA. [Halgren, Eric] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. RP Sejnowski, TJ (reprint author), Salk Inst Biol Studies, Computat Neurobiol Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM terry@salk.edu OI Muller, Lyle/0000-0001-5165-9890 FU Swartz Foundation; Howard Hughes Medical Institute; Office of Naval Research [MURI N000141310672, N000141210299]; National Institutes of Health [R01EB009282, 5T32EY20503-5]; Bial Foundation [BIAL 220/12] FX Swartz Foundation Terrence J Sejnowski; Howard Hughes Medical Institute Terrence J Sejnowski; Office of Naval Research MURI N000141310672 Sydney S Cash Eric Halgren Terrence J Sejnowski; National Institutes of Health R01EB009282 Terrence J Sejnowski; National Institutes of Health 5T32EY20503-5 Lyle Muller; Bial Foundation BIAL 220/12 Giovanni Piantoni; Office of Naval Research N000141210299 Terrence J Sejnowski; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 53 TC 1 Z9 1 U1 1 U2 1 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD NOV 15 PY 2016 VL 5 AR e17267 DI 10.7554/eLife.17267 PG 16 WC Biology SC Life Sciences & Biomedicine - Other Topics GA ED2NN UT WOS:000388683900001 ER PT J AU Ibrahim, NE Rabideau, DJ Gaggin, HK Belcher, AM Conrad, MJ Jarolim, P Januzzi, JL AF Ibrahim, Nasrien E. Rabideau, Dustin J. Gaggin, Hanna K. Belcher, Arianna M. Conrad, Michael J. Jarolim, Petr Januzzi, James L. TI Circulating Concentrations of Orexin A Predict Left Ventricular Myocardial Remodeling SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter ID HEART-FAILURE C1 [Ibrahim, Nasrien E.; Rabideau, Dustin J.; Gaggin, Hanna K.; Belcher, Arianna M.; Conrad, Michael J.; Jarolim, Petr; Januzzi, James L.] Massachusetts Gen Hosp, Div Cardiol, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. EM jjanuzzi@partners.org NR 4 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD NOV 15 PY 2016 VL 68 IS 20 BP 2238 EP 2240 DI 10.1016/j.jacc.2016.08.049 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ED5PB UT WOS:000388903100016 PM 27855816 ER PT J AU Gao, L Smielewski, P Czosnyka, M Ercole, A AF Gao, Lei Smielewski, Peter Czosnyka, Marek Ercole, Ari TI Cerebrovascular Signal Complexity Six Hours after Intensive Care Unit Admission Correlates with Outcome after Severe Traumatic Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE approximate entropy; autoregulation; complexity; ICP; traumatic brain injury ID CEREBRAL PERFUSION-PRESSURE; RATE MULTISCALE ENTROPY; APPROXIMATE ENTROPY; INTRACRANIAL-PRESSURE; HEART-RATE; PHYSIOLOGICAL-COMPLEXITY; CRITICAL ILLNESS; VARIABILITY; HYPERTENSION; DISEASE AB Disease states are associated with a breakdown in healthy interactions and are often characterized by reduced signal complexity. We applied approximate entropy (ApEn) analysis to investigate the correlation between the complexity of heart rate (ApEn-HR), mean arterial pressure (ApEn-MAP), intracranial pressure (ApEn-ICP), and a combined ApEn-product (product of the three individual ApEns) and outcome after traumatic brain injury. In 174 severe traumatic brain injured patients, we found significant differences across groups classified by the Glasgow Outcome Score in ApEn-HR (p = 0.007), ApEn-MAP (p = 0.02), ApEn-ICP (p = 0.01), ApEn-product (p = 0.001), and pressure reactivity index (PRx) (p = 0.004) in the first 6 h. This relationship strengthened in a 24 h and 72 h analysis (ApEn-MAP continued to correlate with death but was not correlated with favorable outcome). Outcome was dichotomized as survival versus death, and favorable versus unfavorable; the ApEn-product achieved the strongest statistical significance at 6 h (F = 11.0; p = 0.001 and F = 10.5; p = 0.001, respectively) and was a significant independent predictor of mortality and favorable outcome (p < 0.001). Patients in the lowest quartile for ApEn-product were over four times more likely to die (39.5% vs. 9.3%, p < 0.001) than those in the highest quartile. ApEn-ICP was inversely correlated with PRx (r=-0.39, p < 0.000001) indicating unique information related to impaired cerebral autoregulation. Our results demonstrate that as early as 6 h into monitoring, complexity measures from easily attainable vital signs, such as HR and MAP, in addition to ICP, can help triage those who require more intensive neurological management at an early stage. C1 [Gao, Lei] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. [Smielewski, Peter; Czosnyka, Marek] Univ Cambridge, Dept Anesthesia, Div Neurosurg, Cambridge, England. [Ercole, Ari] Univ Cambridge, Dept Anesthesia, Neurosci Crit Care Unit, Cambridge, England. RP Gao, L (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM lgao4@partners.org OI Gao, Lei/0000-0003-1476-1460 FU Medical Research Council [G0600986, G9439390] NR 35 TC 1 Z9 1 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 NOV 15 PY 2016 VL 33 IS 22 BP 2011 EP 2018 DI 10.1089/neu.2015.4228 PG 8 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA EC4OL UT WOS:000388112300004 PM 26916703 ER PT J AU Hou, SS Bacskai, BJ Kumar, ATN AF Hou, Steven S. Bacskai, Brian J. Kumar, Anand T. N. TI Comparison of tomographic fluorescence spectral and lifetime multiplexing SO OPTICS LETTERS LA English DT Article ID DIFFUSE OPTICAL TOMOGRAPHY; VIVO; REGULARIZATION; MICROSCOPY; CONTRAST AB Multispectral and lifetime imaging in turbid media can be mathematically described in two steps, involving spectral or temporal mixing of the fluorophores and the diffuse light transport in the turbid medium. We show that the order of fluorophore mixing and diffuse propagation is reversed in spectral and lifetime multiplexing, resulting in a fundamental difference in their multiplexing capabilities, regardless of the measurement conditions. Using the resolution matrix to define a quantitative measure for inter-fluorophore crosstalk, we show that lifetime multiplexing, using the asymptotic time domain approach, provides zero cross-talk, while spectral multiplexing can achieve zero cross-talk under special conditions. We also compare the performance of spectral and lifetime multiplexing for tomographic inversion of two overlapping fluorophores in a heterogeneous digital mouse atlas. (C) 2016 Optical Society of America. C1 [Hou, Steven S.; Kumar, Anand T. N.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Hou, Steven S.; Bacskai, Brian J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. RP Kumar, ATN (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM ankumar@nmr.mgh.harvard.edu FU National Institute of Biomedical Imaging and Bioengineering (NIBIB) [R01 EB000768, R01 EB015325] FX National Institute of Biomedical Imaging and Bioengineering (NIBIB) (R01 EB000768, R01 EB015325). NR 16 TC 0 Z9 0 U1 3 U2 3 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 EI 1539-4794 J9 OPT LETT JI Opt. Lett. PD NOV 15 PY 2016 VL 41 IS 22 BP 5337 EP 5340 DI 10.1364/OL.41.005337 PG 4 WC Optics SC Optics GA EC0AV UT WOS:000387760700051 PM 27842127 ER PT J AU Stanford, FC Butsch, WS AF Stanford, Fatima Cody Butsch, W. Scott TI Metabolically Healthy Obesity and Development of Chronic Kidney Disease SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID BODY-MASS INDEX; COHORT C1 [Stanford, Fatima Cody] Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Stanford, FC (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 5 TC 0 Z9 0 U1 1 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD NOV 15 PY 2016 VL 165 IS 10 BP 742 EP 743 DI 10.7326/L16-0408 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EC2RB UT WOS:000387970500025 PM 27842408 ER PT J AU Maess, B Mamashli, F Obleser, J Helle, L Friederici, AD AF Maess, Burkhard Mamashli, Fahimeh Obleser, Jonas Helle, Liisa Friederici, Angela D. TI Prediction Signatures in the Brain: Semantic Pre-Activation during Language Comprehension SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE semantics; prediction; language; MEG; N400 ID EVENT-RELATED POTENTIALS; TOP-DOWN; WORD RECOGNITION; TIME-COURSE; EEG-DATA; SENTENCE COMPREHENSION; MENTAL REPRESENTATION; LEXICAL PREACTIVATION; PREFRONTAL CORTEX; SPEECH-PERCEPTION AB There is broad agreement that context-based predictions facilitate lexical-semantic processing. A robust index of semantic prediction during language comprehension is an evoked response, known as the N400, whose amplitude is modulated as a function of semantic context. However, the underlying neural mechanisms that utilize relations of the prior context and the embedded word within it are largely unknown. We measured magnetoencephalography (MEG) data while participants were listening to simple German sentences in which the verbs were either highly predictive for the occurrence of a particular noun (i.e., provided context) or not. The identical set of nouns was presented in both conditions. Hence, differences for the evoked responses of the nouns can only be due to differences in the earlier context. We observed a reduction of the N400 response for highly predicted nouns. Interestingly, the opposite pattern was observed for the preceding verbs: highly predictive (that is more informative) verbs yielded stronger neural magnitude compared to less predictive verbs. A negative correlation between the N400 effect of the verb and that of the noun was found in a distributed brain network, indicating an integral relation between the predictive power of the verb and the processing of the subsequent noun. This network consisted of left hemispheric superior and middle temporal areas and a subcortical area; the parahippocampus. Enhanced activity for highly predictive relative to less predictive verbs, likely reflects establishing semantic features associated with the expected nouns, that is a pre-activation of the expected nouns. C1 [Maess, Burkhard; Mamashli, Fahimeh] Max Planck Inst Human Cognit & Brain Sci, MEG & Cort Networks Grp, Leipzig, Germany. [Mamashli, Fahimeh; Friederici, Angela D.] Max Planck Inst Human Cognit & Brain Sci, Dept Neuropsychol, Leipzig, Germany. [Mamashli, Fahimeh] Harvard Med Sch, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA. [Obleser, Jonas] Max Planck Inst Human Cognit & Brain Sci, Max Planck Res Grp Auditory Cognit, Leipzig, Germany. [Obleser, Jonas] Univ Lubeck, Dept Psychol, Lubeck, Germany. [Helle, Liisa] Elekta Oy, Helsinki, Finland. [Helle, Liisa] Aalto Univ, Sch Sci, Dept Neurosci & Biomed Engn, Espoo, Finland. RP Maess, B; Mamashli, F (reprint author), Max Planck Inst Human Cognit & Brain Sci, MEG & Cort Networks Grp, Leipzig, Germany.; Mamashli, F (reprint author), Max Planck Inst Human Cognit & Brain Sci, Dept Neuropsychol, Leipzig, Germany.; Mamashli, F (reprint author), Harvard Med Sch, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA. EM maess@cbs.mpg.de; fmamashli@mgh.harvard.edu FU Max Planck Society, Munich, Germany; International Max Planck Research School on neuroscience of communication, Leipzig, Germany; Elekta Oy, Helsinki, Finland FX This research was supported by the Max Planck Society (ADF, JO, BM, FM), Munich, Germany, the International Max Planck Research School on neuroscience of communication (FM), Leipzig, Germany, and Elekta Oy, Helsinki, Finland. Yvonne Wolff acquired the data. We would like to thank Jane Neumann and Helga Smallwood for valuable comments on manuscript preparation, Samu Taulu and Antti Ahonen for providing us with the advanced sensor noise suppression method for MEG data. analysis. NR 92 TC 0 Z9 0 U1 5 U2 5 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 NOV 15 PY 2016 VL 10 AR 591 DI 10.3389/fnhum.2016.00591 PG 11 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA EB7UC UT WOS:000387595100001 PM 27895573 ER PT J AU Song, ZR Blumenthal, DM AF Song, Zirui Blumenthal, Daniel M. TI Expanding Payment Reform in Medicare The Cardiology Episode-Based Payment Model SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID PERCUTANEOUS CORONARY INTERVENTION; UNITED-STATES C1 [Song, Zirui; Blumenthal, Daniel M.] Massachusetts Gen Hosp, Dept Med, 55 Fruit St,Bigelow 730, Boston, MA 02114 USA. [Song, Zirui; Blumenthal, Daniel M.] Harvard Med Sch, Boston, MA USA. RP Song, ZR (reprint author), Massachusetts Gen Hosp, Dept Med, 55 Fruit St,Bigelow 730, Boston, MA 02114 USA. EM zirui_song@post.harvard.edu FU NIA NIH HHS [F30 AG039175] NR 7 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 NOV 15 PY 2016 VL 316 IS 19 BP 1973 EP 1974 DI 10.1001/jama.2016.16146 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EB8XC UT WOS:000387673800011 PM 27838725 ER PT J AU Raff, AB Kroshinsky, D AF Raff, Adam B. Kroshinsky, Daniela TI Therapy for Cellulitis Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Raff, Adam B.; Kroshinsky, Daniela] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kroshinsky, D (reprint author), 50 Staniford St,200, Boston, MA 02199 USA. EM dkroshinsky@partners.org NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD NOV 15 PY 2016 VL 316 IS 19 BP 2047 EP 2047 DI 10.1001/jama.2016.15613 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EB8XC UT WOS:000387673800030 PM 27838716 ER PT J AU Swan, M Doan, N Ortega, RA Barrett, M Nichols, W Ozelius, L Soto-Valencia, J Boschung, S Deik, A Sarva, H Cabassa, J Johannes, B Raymond, D Marder, K Giladi, N Miravite, J Severt, W Sachdev, R Shanker, V Bressman, S Saunders-Pullman, R AF Swan, Matthew Doan, Nancy Ortega, Robert A. Barrett, Matthew Nichols, William Ozelius, Laurie Soto-Valencia, Jeannie Boschung, Sarah Deik, Andres Sarva, Harini Cabassa, Jose Johannes, Brooke Raymond, Deborah Marder, Karen Giladi, Nir Miravite, Joan Severt, William Sachdev, Rivka Shanker, Vicki Bressman, Susan Saunders-Pullman, Rachel TI Neuropsychiatric characteristics of GBA-associated Parkinson disease SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Parkinson disease; Glucocerebrosidase; GBA1; Depression; Anxiety ID LEWY BODY DISEASE; GLUCOCEREBROSIDASE MUTATIONS; COGNITIVE IMPAIRMENT; ANXIETY DISORDERS; NONMOTOR SYMPTOMS; ASHKENAZI JEWS; LRRK2 G2019S; ALZHEIMER-DISEASE; RATING-SCALES; DEPRESSION AB Mutations in GBA1 are a well-established risk factor for Parkinson disease (PD). GBA-associated PD (GBA-PD) may have a higher burden of nonmotor symptoms than idiopathic PD (IPD). We sought to characterize the relationship between GBA-PD and neuropsychiatric symptoms. Subjects were screened for common GBA1 mutations. GBA-PD (n = 31) and non-carrier (IPD; n = 55) scores were compared on the Unified Parkinson Disease Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA), Beck Depression Inventory (BDI), and the State-Trait Anxiety Index (STAI). In univariate comparisons, GBA-PD had a greater prevalence of depression (33.3%) versus IPD (132%) (p < 0.05). In regression models controlling for age, sex, disease duration, motor disability, and MoCA score, GBA-PD had an increased odds of depression (OR 3.66, 95% CI 1.13-11.8) (p = 0.03). Post-hoc analysis stratified by sex showed that, among men, GBA-PD had a higher burden of trait anxiety and depression than IPD; this finding was sustained in multivariate models. Among women, GBA-PD did not confer greater psychiatric morbidity than IPD. These results suggest that GBA1 mutations confer greater risk of neuropsychiatric morbidity in PD, and that sex may affect this association. (C) 2016 Elsevier B.V. All rights reserved. C1 [Swan, Matthew; Doan, Nancy; Ortega, Robert A.; Soto-Valencia, Jeannie; Boschung, Sarah; Deik, Andres; Sarva, Harini; Cabassa, Jose; Johannes, Brooke; Raymond, Deborah; Miravite, Joan; Severt, William; Sachdev, Rivka; Shanker, Vicki; Bressman, Susan; Saunders-Pullman, Rachel] Icahn Sch Med Mt Sinai, Mt Sinai Beth Israel, Dept Neurol, New York, NY 10029 USA. [Swan, Matthew; Doan, Nancy; Ortega, Robert A.; Soto-Valencia, Jeannie; Boschung, Sarah; Deik, Andres; Sarva, Harini; Cabassa, Jose; Johannes, Brooke; Raymond, Deborah; Miravite, Joan; Severt, William; Sachdev, Rivka; Shanker, Vicki; Bressman, Susan; Saunders-Pullman, Rachel] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Swan, Matthew] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10467 USA. [Barrett, Matthew] Univ Virginia Hlth Syst, Dept Neurol, Charlottesville, VA USA. [Nichols, William] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH USA. [Nichols, William] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA. [Ozelius, Laurie] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Marder, Karen] Columbia Univ, Coll Phys & Surg, Taub Inst, Dept Neurol & Psychiat, New York, NY USA. [Marder, Karen] Columbia Univ, Coll Phys & Surg, Sergievsky Ctr, New York, NY USA. [Giladi, Nir] Tel Aviv Univ, Tel Aviv Med Ctr, Sackler Sch Med, Sagol Sch Neurosci,Neurol Inst,Movement Disorders, Tel Aviv, Israel. [Swan, Matthew] Albert Einstein Coll Med, Montefiore Med Ctr, 111 E 210th St,NW1 Blue Zone,Suite 002, Bronx, NY 10467 USA. [Doan, Nancy; Ortega, Robert A.; Soto-Valencia, Jeannie; Boschung, Sarah; Johannes, Brooke; Raymond, Deborah; Miravite, Joan; Severt, William; Sachdev, Rivka; Shanker, Vicki; Bressman, Susan; Saunders-Pullman, Rachel] Mt Sinai Beth Israel Med Ctr, 10 Union Sq East,Suite 51, New York, NY 10003 USA. [Barrett, Matthew] POB 800394, Charlottesville, VA 22908 USA. [Nichols, William] 3333 Burnet Ave ML7016, Cincinnati, OH 45229 USA. [Ozelius, Laurie] Collaborat Ctr X Linked Dystonia Parkinsonism, 16th St,Biding 114,Rm3200, Charlestown, MA 02129 USA. RP Swan, M (reprint author), Montefiore Med Ctr, Dept Neurol, 111 E 210th St,NW1 Blue Zone,Ste 002, Bronx, NY 10467 USA. EM matthew.c.swan@gmail.com; MJB5T@hscmail.mcc.virginia.edu; bill.nichols@cchmc.org; lozelius@partners.org; Andres.DeikAcostaMadiedo@uphs.upenn.edu; sarvaharini@gmail.com; jose.c.cabassa@gmail.com; ksm1@columbia.edu; nirg@tlvmc.gov.il; RSaunder@chpnet.org FU Bigglesworth Foundation; NINDS [K02-NS073836, U01-094148]; Empire Clinical Research Investigator Program (ECRIP) from the New York State Department of Health FX This project was funded by the Bigglesworth Foundation, the NINDS (grant numbers K02-NS073836, and U01-094148), and the Empire Clinical Research Investigator Program (ECRIP) from the New York State Department of Health. The funding sources had no involvement in collection, analysis or interpretation of data, or in the writing or submission of this article. NR 72 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X EI 1878-5883 J9 J NEUROL SCI JI J. Neurol. Sci. PD NOV 15 PY 2016 VL 370 BP 63 EP 69 DI 10.1016/j.jns.2016.08.059 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EB8FV UT WOS:000387627800016 PM 27772789 ER PT J AU Ascierto, PA Agarwala, S Botti, G Cesano, A Ciliberto, G Davies, MA Demaria, S Dummer, R Eggermont, AM Ferrone, S Fu, YX Gajewski, TF Garbe, C Huber, V Khleif, S Krauthammer, M Lo, RS Masucci, G Palmieri, G Postow, M Puzanov, I Silk, A Spranger, S Stroncek, DF Tarhini, A Taube, JM Testori, A Wang, E Wargo, JA Yee, C Zarour, H Zitvogel, L Fox, BA Mozzillo, N Marincola, FM Thurin, M AF Ascierto, Paolo A. Agarwala, Sanjiv Botti, Gerardo Cesano, Alessandra Ciliberto, Gennaro Davies, Michael A. Demaria, Sandra Dummer, Reinhard Eggermont, Alexander M. Ferrone, Soldano Fu, Yang Xin Gajewski, Thomas F. Garbe, Claus Huber, Veronica Khleif, Samir Krauthammer, Michael Lo, Roger S. Masucci, Giuseppe Palmieri, Giuseppe Postow, Michael Puzanov, Igor Silk, Ann Spranger, Stefani Stroncek, David F. Tarhini, Ahmad Taube, Janis M. Testori, Alessandro Wang, Ena Wargo, Jennifer A. Yee, Cassian Zarour, Hassane Zitvogel, Laurence Fox, Bernard A. Mozzillo, Nicola Marincola, Francesco M. Thurin, Magdalena TI Future perspectives in melanoma research SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID HERPES-SIMPLEX-VIRUS; STAGE-III MELANOMA; CD8(+) T-CELLS; METASTATIC MELANOMA; UNTREATED MELANOMA; ADJUVANT THERAPY; TUMOR MICROENVIRONMENT; ANTITUMOR IMMUNITY; BRAF INHIBITION; CTLA-4 BLOCKADE AB The sixth "Melanoma Bridge Meeting" took place in Naples, Italy, December 1st-4th, 2015. The four sessions at this meeting were focused on: (1) molecular and immune advances; (2) combination therapies; (3) news in immunotherapy; and 4) tumor microenvironment and biomarkers. Recent advances in tumor biology and immunology has led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS) of cancer patients. Immunotherapies in particular have emerged as highly successful approaches to treat patients with cancer including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkin's disease. Specifically, many clinical successes have been using checkpoint receptor blockade, including T cell inhibitory receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death-1 (PD-1) and its ligand PD-L1. Despite demonstrated successes, responses to immunotherapy interventions occur only in a minority of patients. Attempts are being made to improve responses to immunotherapy by developing biomarkers. Optimizing biomarkers for immunotherapy could help properly select patients for treatment and help to monitor response, progression and resistance that are critical challenges for the immuno-oncology (IO) field. Importantly, biomarkers could help to design rational combination therapies. In addition, biomarkers may help to define mechanism of action of different agents, dose selection and to sequence drug combinations. However, biomarkers and assays development to guide cancer immunotherapy is highly challenging for several reasons: (i) multiplicity of immunotherapy agents with different mechanisms of action including immunotherapies that target activating and inhibitory T cell receptors (e.g., CTLA-4, PD-1, etc.); adoptive T cell therapies that include tissue infiltrating lymphocytes (TILs), chimeric antigen receptors (CARs), and T cell receptor (TCR) modified T cells; (ii) tumor heterogeneity including changes in antigenic profiles over time and location in individual patient; and (iii) a variety of immune-suppressive mechanisms in the tumor microenvironment (TME) including T regulatory cells (Treg), myeloid derived suppressor cells (MDSC) and immunosuppressive cytokines. In addition, complex interaction of tumor-immune system further increases the level of difficulties in the process of biomarkers development and their validation for clinical use. Recent clinical trial results have highlighted the potential for combination therapies that include immunomodulating agents such as anti-PD-1 and anti-CTLA-4. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors on T cells and other approaches such as adoptive cell transfer are tested for clinical efficacy in melanoma as well. These agents are also being tested in combination with targeted therapies to improve upon shorter-term responses thus far seen with targeted therapy. Various locoregional interventions that demonstrate promising results in treatment of advanced melanoma are also integrated with immunotherapy agents and the combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for melanoma patients' population. This meeting's specific focus was on advances in immunotherapy and combination therapy for melanoma. The importance of understanding of melanoma genomic background for development of novel therapies and biomarkers for clinical application to predict the treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into personalized-medicine approach for treatment of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma. We also discussed the requirements for pre-analytical and analytical as well as clinical validation process as applied to biomarkers for cancer immunotherapy. The concept of the fit-for-purpose marker validation has been introduced to address the challenges and strategies for analytical and clinical validation design for specific assays. C1 [Ascierto, Paolo A.; Botti, Gerardo; Ciliberto, Gennaro; Mozzillo, Nicola] Fdn G Pascale, IRCCS Ist Nazl Tumori, Naples, Italy. [Agarwala, Sanjiv] St Lukes Univ Hosp, Dept Hematol & Oncol, Bethlehem, PA USA. [Agarwala, Sanjiv] Temple Univ, Bethlehem, PA USA. [Cesano, Alessandra] Nanostring Inc, 500 Fairview Ave N, Seattle, WA 98109 USA. [Davies, Michael A.] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Melanoma Med Oncol, Houston, TX 77030 USA. [Demaria, Sandra] Weill Cornell Med Coll, Dept Radiat Oncol, New York, NY USA. [Demaria, Sandra] Weill Cornell Med Coll, Dept Pathol, New York, NY USA. [Dummer, Reinhard] Univ Hosp Zurich, Skin Canc Unit, Dept Dermatol, CH-8091 Zurich, Switzerland. [Eggermont, Alexander M.] Gustave Roussy Canc Campus Grand Paris, Villejuif, France. [Ferrone, Soldano] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Fu, Yang Xin] UT Southwestern Med Ctr, Dept Pathol, Dallas, TX USA. [Gajewski, Thomas F.] Univ Chicago Med, Dept Med, Immunol & Canc Program, Chicago, IL USA. [Gajewski, Thomas F.] Univ Chicago Med, Dept Pathol, Immunol & Canc Program, Chicago, IL USA. [Garbe, Claus] Univ Tubingen, Dept Dermatol, Ctr Dermato Oncol, Tubingen, Germany. [Huber, Veronica] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Khleif, Samir] Georgia Regents Univ, Ctr Canc, Augusta, GA USA. [Krauthammer, Michael] Yale Univ, Sch Med, New Haven, CT USA. [Lo, Roger S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Lo, Roger S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Lo, Roger S.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Masucci, Giuseppe] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Palmieri, Giuseppe] CNR, Inst Biomol Chem, Unit Canc Genet, Sassari, Italy. [Postow, Michael] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Postow, Michael] Weill Cornell Med Coll, New York, NY USA. [Puzanov, Igor] Roswell Pk Canc Inst, Dept Med, Early Phase Clin Trials Program, New York, NY USA. [Silk, Ann] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Spranger, Stefani] Univ Chicago, Chicago, IL 60637 USA. [Stroncek, David F.] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Tarhini, Ahmad; Zarour, Hassane] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Tarhini, Ahmad; Zarour, Hassane] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA USA. [Tarhini, Ahmad; Zarour, Hassane] Univ Pittsburgh, Dept Dermatol, Pittsburgh, PA 15260 USA. [Taube, Janis M.] Johns Hopkins Univ SOM, Dept Dermatol, Baltimore, MD USA. [Testori, Alessandro] Ist Europeo Oncol, Milan, Italy. [Wang, Ena] Sidra Med & Res Ctr, Div Translat Med, Doha, Qatar. [Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Genom Med & Surg Oncol, Houston, TX 77030 USA. [Yee, Cassian; Marincola, Francesco M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Zitvogel, Laurence] Gustave Roussy Canc Ctr, INSERM, U1015, Villejuif, France. [Zitvogel, Laurence] Univ Paris 11, Le Kremlin Bicetre, France. [Fox, Bernard A.] Providence Portland Med Ctr, Robert W Franz Canc Res Ctr, Earle A Chiles Res Inst, Providence Canc Ctr, Portland, OR USA. [Fox, Bernard A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. [Thurin, Magdalena] NCI, Canc Diag Program, NIH, Bethesda, MD 20892 USA. [Ascierto, Paolo A.] Fdn G Pascale, Unit Med Oncol & Innovat Therapy, Ist Nazl Studio & Cura Tumori, Via Mariano Semmola, I-80131 Naples, Italy. RP Thurin, M (reprint author), NCI, Canc Diag Program, NIH, Bethesda, MD 20892 USA.; Ascierto, PA (reprint author), Fdn G Pascale, Unit Med Oncol & Innovat Therapy, Ist Nazl Studio & Cura Tumori, Via Mariano Semmola, I-80131 Naples, Italy. EM paolo.ascierto@gmail.com; thurinm@mail.nih.gov FU Fondazione Melanoma Onlus; Society of ImmunoTherapy of Cancer (SITC); 3P Solution of Napoli FX The meeting was supported by Fondazione Melanoma Onlus and the Society of ImmunoTherapy of Cancer (SITC). A special thanks to 3P Solution of Napoli for their support and cooperation in organizing the meeting and especially to Lucia Politi. NR 145 TC 0 Z9 0 U1 26 U2 26 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD NOV 15 PY 2016 VL 14 AR 313 DI 10.1186/s12967-016-1070-y PG 25 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB9QX UT WOS:000387732200001 PM 27846884 ER PT J AU Ge, T Reuter, M Winkler, AM Holmes, AJ Lee, PH Tirrell, LS Roffman, JL Buckner, RL Smoller, JW Sabuncu, MR AF Ge, Tian Reuter, Martin Winkler, Anderson M. Holmes, Avram J. Lee, Phil H. Tirrell, Lee S. Roffman, Joshua L. Buckner, Randy L. Smoller, Jordan W. Sabuncu, Mert R. TI Multidimensional heritability analysis of neuroanatomical shape SO NATURE COMMUNICATIONS LA English DT Article ID MILD COGNITIVE IMPAIRMENT; HUMAN CONNECTOME PROJECT; ALZHEIMERS-DISEASE; QUANTITATIVE-TRAIT; PSYCHIATRIC-DISORDERS; MISSING HERITABILITY; HIPPOCAMPAL SHAPE; BIPOLAR DISORDER; CORPUS-CALLOSUM; COMMON VARIANTS AB In the dawning era of large-scale biomedical data, multidimensional phenotype vectors will play an increasing role in examining the genetic underpinnings of brain features, behaviour and disease. For example, shape measurements derived from brain MRI scans are multi-dimensional geometric descriptions of brain structure and provide an alternate class of phenotypes that remains largely unexplored in genetic studies. Here we extend the concept of heritability to multidimensional traits, and present the first comprehensive analysis of the heritability of neuroanatomical shape measurements across an ensemble of brain structures based on genome-wide SNP and MRI data from 1,320 unrelated, young and healthy individuals. We replicate our findings in an extended twin sample from the Human Connectome Project (HCP). Our results demonstrate that neuroanatomical shape can be significantly heritable, above and beyond volume, and can serve as a complementary phenotype to study the genetic determinants and clinical relevance of brain structure. C1 [Ge, Tian; Reuter, Martin; Holmes, Avram J.; Tirrell, Lee S.; Buckner, Randy L.; Sabuncu, Mert R.] Harvard Med Sch, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Ge, Tian; Lee, Phil H.; Smoller, Jordan W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Ge, Tian; Lee, Phil H.; Smoller, Jordan W.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02138 USA. [Reuter, Martin; Sabuncu, Mert R.] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Winkler, Anderson M.] Univ Oxford, Ctr Funct MRI Brain FMRIB, Oxford OX3 9DU, England. [Holmes, Avram J.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Holmes, Avram J.; Roffman, Joshua L.; Buckner, Randy L.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Buckner, Randy L.] Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA. [Buckner, Randy L.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. RP Ge, T; Sabuncu, MR (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA.; Ge, T (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.; Ge, T (reprint author), Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02138 USA.; Sabuncu, MR (reprint author), MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM tge1@mgh.harvard.edu; msabuncu@nmr.mgh.harvard.edu FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); NIH Shared Instrumentation Grant Program [S10RR023043, S10RR023401]; Center for Brain Science Neuroinformatics Research Group; Athinoula A. Martinos Center for Biomedical Imaging; Center for Human Genetic Research; Stanley Center for Psychiatric Research; 16 NIH Institutes and Centers - NIH Blueprint for Neuroscience Research; McDonnell Center for Systems Neuroscience at Washington University; NIBIB, NIH; NIH [K25CA181632, K01MH099232, K99MH101367, R21AG050122-01A1, R41AG052246-01, 1K25EB013649-01, K24MH094614, R01MH101486]; MGH ECOR Tosteson Postdoctoral Fellowship Award; Brazilian National Research Council (CNPq) [211534/2013-7]; BrightFocus Foundation [AHAF-A2012333] FX This research was carried out in whole at the Athinoula A. Martinos Center for Biomedical Imaging at the MGH, 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 (NIH). This work also involved the use of instrumentation supported by the NIH Shared Instrumentation Grant Program; specifically, grant numbers S10RR023043 and S10RR023401. Data were provided in part by the Brain GSP of Harvard University and MGH, with support from the Center for Brain Science Neuroinformatics Research Group, Athinoula A. Martinos Center for Biomedical Imaging, Center for Human Genetic Research and Stanley Center for Psychiatric Research. Twenty individual investigators at Harvard and MGH generously contributed data to the overall project. Data were also provided in part by the HCP, WU-Minn Consortium (principal investigators: David Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University. This research was carried out in whole or in part at the Athinoula A. Martinos Center for Biomedical Imaging at the MGH, using resources provided by the Center for Functional Neuroimaging Technologies, P41EB015896, a P41 Biotechnology Resource Grant supported by the NIBIB, NIH. This research was also funded in part by NIH grants K25CA181632 (to M.R.); K01MH099232 (to A.J.H.); K99MH101367 (to P.H.L.); R21AG050122-01A1, R41AG052246-01 and 1K25EB013649-01 (to M.R.S.); K24MH094614 and R01MH101486 (to J.W.S.); an MGH ECOR Tosteson Postdoctoral Fellowship Award (to T.G.); the Brazilian National Research Council (CNPq), grant number 211534/2013-7 (to A.M.W.); and a BrightFocus Foundation grant AHAF-A2012333 (to M.R.S.). J.W.S. is a Tepper Family MGH Research Scholar. NR 69 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD NOV 15 PY 2016 VL 7 AR 13291 DI 10.1038/ncomms13291 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC2RK UT WOS:000387971400001 PM 27845344 ER PT J AU Ning, LP Setsompop, K Michailovich, O Makris, N Shenton, ME Westin, CF Rathi, Y AF Ning, Lipeng Setsompop, Kawin Michailovich, Oleg Makris, Nikos Shenton, Martha E. Westin, Carl-Fredrik Rathi, Yogesh TI A joint compressed-sensing and super-resolution approach for very high-resolution diffusion imaging (vol 125, pg 386, 2016) SO NEUROIMAGE LA English DT Correction C1 [Ning, Lipeng; Shenton, Martha E.; Westin, Carl-Fredrik; Rathi, Yogesh] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA. [Setsompop, Kawin; Makris, Nikos] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Michailovich, Oleg] Univ Waterloo, Elect & Comp Engn, Waterloo, ON N2L 3G1, Canada. RP Ning, LP (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA. EM lning@bwh.harvard.edu NR 1 TC 0 Z9 0 U1 4 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD NOV 15 PY 2016 VL 142 BP 696 EP 696 DI 10.1016/j.neuroimage.2016.07.053 PG 1 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EC2WW UT WOS:000387986000060 PM 27490271 ER PT J AU Sakata, K Araki, K Nakano, H Nishina, T Komazawa-Sakon, S Murai, S Lee, GE Hashimoto, D Suzuki, C Uchiyama, Y Notohara, K Gukovskaya, AS Gukovsky, I Yamamura, K Baba, H Ohmuraya, M AF Sakata, Kazuya Araki, Kimi Nakano, Hiroyasu Nishina, Takashi Komazawa-Sakon, Sachiko Murai, Shin Lee, Grace E. Hashimoto, Daisuke Suzuki, Chigure Uchiyama, Yasuo Notohara, Kenji Gukovskaya, Anna S. Gukovsky, Ilya Yamamura, Ken-ichi Baba, Hideo Ohmuraya, Masaki TI Novel method to rescue a lethal phenotype through integration of target gene onto the X-chromosome SO SCIENTIFIC REPORTS LA English DT Article ID PANCREATIC ACINAR-CELLS; TRYPSINOGEN ACTIVATION; MICE; AUTOPHAGY; PATHOGENESIS; CANCER; EXPRESSION; DEFICIENT; ALPHA AB The loss-of-function mutations of serine protease inhibitor, Kazal type 1 (SPINK1) gene are associated with human chronic pancreatitis, but the underlying mechanisms remain unknown. We previously reported that mice lacking Spink3, the murine homologue of human SPINK1, die perinatally due to massive pancreatic acinar cell death, precluding investigation of the effects of SPINK1 deficiency. To circumvent perinatal lethality, we have developed a novel method to integrate human SPINK1 gene on the X chromosome using Cre-loxP technology and thus generated transgenic mice termed "X-SPINK1". Consistent with the fact that one of the two X chromosomes is randomly inactivated, X-SPINK1 mice exhibit mosaic pattern of SPINK1 expression. Crossing of X-SPINK1 mice with Spink3(-/-) mice rescued perinatal lethality, but the resulting Spink3(-/-); XXSPINK1 mice developed spontaneous pancreatitis characterized by chronic inflammation and fibrosis. The results show that mice lacking a gene essential for cell survival can be rescued by expressing this gene on the X chromosome. The Spink3(-/-); XXSPINK1 mice, in which this method has been applied to partially restore SPINK1 function, present a novel genetic model of chronic pancreatitis. C1 [Sakata, Kazuya; Araki, Kimi; Yamamura, Ken-ichi; Ohmuraya, Masaki] Kumamoto Univ, Inst Resource Dev & Anal, Chuo Ku, 2-2-1 Honjo, Kumamoto 8600811, Japan. [Sakata, Kazuya; Hashimoto, Daisuke; Baba, Hideo] Kumamoto Univ, Dept Surg Gastroenterol, Chuo Ku, 1-1-1 Honjo, Kumamoto 8600811, Japan. [Nakano, Hiroyasu; Nishina, Takashi; Komazawa-Sakon, Sachiko; Murai, Shin] Toho Univ, Dept Biochem, Sch Med, Ota Ku, 5-21-16 Omori Nishi, Tokyo 1438540, Japan. [Lee, Grace E.; Gukovskaya, Anna S.; Gukovsky, Ilya] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Lee, Grace E.; Gukovskaya, Anna S.; Gukovsky, Ilya] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Suzuki, Chigure; Uchiyama, Yasuo] Juntendo Univ, Dept Cellular & Mol Neuropathol, Grad Sch Med, Bunkyo Ku, 2-1-1 Hongo, Tokyo 1138421, Japan. [Notohara, Kenji] Kurashiki Cent Hosp, Dept Pathol, 1-1-1 Miwa, Kurashiki, Okayama 7108602, Japan. RP Ohmuraya, M (reprint author), Kumamoto Univ, Inst Resource Dev & Anal, Chuo Ku, 2-2-1 Honjo, Kumamoto 8600811, Japan. EM ohmuraya@kumamoto-u.ac.jp FU MEXT (Ministry of Education, Culture, Sports, Science and Technology) [26111516, 26110003]; KAKENHI Scientific Research from Japan Society for the Promotion of Science (JSPS); Challenging Exploratory Research from Japan Society for the Promotion of Science (JSPS); Takeda Science Foundation; Naito Science Foundation; Uehara Science Foundation; Novartis Science Foundation; American Pancreatic Association FX We thank Y. Fukuchi and M. Nakata for technical assistance. This work was supported by MEXT (Ministry of Education, Culture, Sports, Science and Technology) grants (#26111516 and 26110003), KAKENHI Scientific Research (B and C) and Challenging Exploratory Research from Japan Society for the Promotion of Science (JSPS), and the Takeda Science Foundation, the Naito Science Foundation, the Uehara Science Foundation, and Novartis Science Foundation. M.O. is especially grateful to the American Pancreatic Association for a mini-sabbatical award that made possible for him to spend several months at the Gukovskaya laboratory in Los Angeles. NR 31 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 15 PY 2016 VL 6 AR 37200 DI 10.1038/srep37200 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB9WZ UT WOS:000387749700001 PM 27845447 ER PT J AU Karimi, M Mirshekari, H Basri, SMM Bahrami, S Moghoofei, M Hamblin, MR AF Karimi, Mahdi Mirshekari, Hamed Basri, Seyed Masoud Moosavi Bahrami, Sajad Moghoofei, Mohsen Hamblin, Michael R. TI Bacteriophages and phage-inspired nanocarriers for targeted delivery of therapeutic cargos SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE Bacteriophage; Bioinspired drug delivery; Nanocarriers; Phage; Display; Virus-like particles; Targeting ID ENGINEERED M13 BACTERIOPHAGE; MEDIATED GENE-TRANSFER; VIRUS-LIKE PARTICLES; BREAST-CANCER CELLS; HEPATITIS-B-VIRUS; IN-VIVO; MAMMALIAN-CELLS; FILAMENTOUS BACTERIOPHAGE; DRUG-DELIVERY; ANTITUMOR-ACTIVITY AB The main goal of drug delivery systems is to target therapeutic cargoes to desired cells and to ensure their efficient uptake. Recently a number of studies have focused on designing bio-inspired nanocarriers, such as bacteriophages, and synthetic carriers based on the bacteriophage structure. Bacteriophages are viruses that specifically recognize their bacterial hosts. They can replicate only inside their host cell and can act as natural gene carriers. Each type of phage has a particular shape, a different capacity for loading cargo, a specific production time, and their own mechanisms of supramolecular assembly, that have enabled them to act as tunable carriers. New phage-based technologies have led to the construction of different peptide libraries, and recognition abilities provided by novel targeting ligands. Phage hybridization with non-organic compounds introduces new properties to phages and could be a suitable strategy for construction of bio-inorganic carriers. In this review we try to cover the major phage species that have been used in drug and gene delivery systems, and the biological application of phages as novel targeting ligands and targeted therapeutics. (C) 2016 Elsevier B.V. All rights reserved. C1 [Karimi, Mahdi; Bahrami, Sajad] Iran Univ Med Sci, Fac Adv Technol Med, Dept Med Nanotechnol, Tehran, Iran. [Mirshekari, Hamed] Iran Univ Med Sci, ANNRG, Tehran, Iran. [Basri, Seyed Masoud Moosavi] Pasteur Inst Iran, Biotechnol Res Ctr, Med Biotechnol Dept, Drug Design & Bioinformat Unit, Tehran, Iran. [Basri, Seyed Masoud Moosavi] Shahid Beheshti Univ, Civil & Environm Engn Dept, Tehran, Iran. [Bahrami, Sajad; Moghoofei, Mohsen] Iran Univ Med Sci, Student Res Comm, Tehran, Iran. [Moghoofei, Mohsen] Iran Univ Med Sci, Fac Med, Dept Virol, Tehran, Iran. [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), 40 Blossom St, Boston, MA 02114 USA. EM Hamblin@helix.mgh.harvard.edu FU US NIH grant [R01AI050875] FX Michael R Hamblin was supported by the US NIH grant R01AI050875. NR 215 TC 4 Z9 4 U1 42 U2 42 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X EI 1872-8294 J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD NOV 15 PY 2016 VL 106 BP 45 EP 62 DI 10.1016/j.addr.2016.03.003 PN A PG 18 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EB6WE UT WOS:000387525500004 PM 26994592 ER PT J AU Wang, LX Bi, YY Cao, MH Ma, RS Wu, XM Zhang, Y Ding, WB Liu, Y Yu, Q Zhang, YQ Jiang, H Sun, YC Tong, DX Guo, L Dong, ZX Tian, Y Kou, JJ Shi, JL AF Wang, Lixiu Bi, Yayan Cao, Muhua Ma, Ruishuang Wu, Xiaoming Zhang, Yan Ding, Wenbo Liu, Yan Yu, Qian Zhang, Yingqian Jiang, Hua Sun, Yingchun Tong, Dongxia Guo, Li Dong, Zengxiang Tian, Ye Kou, Junjie Shi, Jialan TI Microparticles and blood cells induce procoagulant activity via phosphatidylserine exposure in NSTEMI patients following stent implantation SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Non-ST-elevated myocardial infarction; Stent; Procoagulant activity; Phosphatidylserine; Microparticles ID ACUTE CORONARY SYNDROMES; ACUTE MYOCARDIAL-INFARCTION; CIRCULATING MICROPARTICLES; CLINICAL PRESENTATION; THROMBUS COMPOSITION; UNSTABLE ANGINA; STABLE ANGINA; TISSUE FACTOR; ST-SEGMENT; ACTIVATION AB Background: Relatively little is known about the role of phosphatidylserine (PS) in procoagulant activity (PCA) in patients with non-ST-elevated myocardial infarction (NSTEMI) after stent implantation. This study was designed to evaluate whether exposed PS on microparticles (MPs) and blood cells were involved in the hypercoagulable state in NSTEMI patients with stent implantation. Methods: NSTEMI patients (n = 90) and healthy controls (n = 20) were included in our study. PS exposure on MPs and blood cells was analyzed with flow cytometer and confocal microscope. PCA was evaluated by clotting time, purified coagulation complex assays and fibrin production assays. Results: Baseline levels of MPs and PS+ blood cells were significantly higher (P < 0.001) in the patients than in controls. After stent implantation, a remarkable increase was observed in both MPs and PS+ blood cells. Specifically, PS+ MPs, PS+ platelets and erythrocytes peaked at 18 h following stent implantation, while PS+ leukocytes peaked on day 2. In addition, circulating MPs (mostly derived from platelets, leukocytes, erythrocytes and endothelial cells) cooperating with PS+ blood cells, contributed to markedly shortened coagulation time and markedly increased FXa/thrombin/fibrin (all P < 0.01) generation in patient group. Moreover, blockade of exposed PS on MPs and cells with lactadherin inhibited PCA by approximately 70%. Conclusions: Our results suggest that PS+ MPs and blood cells play a procoagulant role in NSTEMI patients following stent implantation. Blockade of PS could become a novel therapeutic modality for the prevention of thrombosis in these patients. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Wang, Lixiu; Bi, Yayan; Yu, Qian; Dong, Zengxiang; Tian, Ye] Harbin Med Univ, Hosp 1, Dept Cardiol, 23 Youzheng St, Harbin 150001, Peoples R China. [Cao, Muhua; Ma, Ruishuang; Wu, Xiaoming; Zhang, Yan; Liu, Yan; Tong, Dongxia; Guo, Li; Shi, Jialan] Harbin Med Univ, Hosp 1, Dept Hematol, Harbin, Peoples R China. [Ding, Wenbo; Zhang, Yingqian; Jiang, Hua; Kou, Junjie] Harbin Med Univ, Hosp 2, Dept Cardiol, 246 Xuefu Rd, Harbin 150001, Peoples R China. [Sun, Yingchun] Harbin Med Univ, Hosp 1, Dept Nephropathy, Harbin, Peoples R China. [Shi, Jialan] Harvard Med Sch, VA Boston Healthcare Syst, Brigham & Womens Hosp, Div Cardiothorac Surg, Boston, MA USA. RP Bi, YY (reprint author), Harbin Med Univ, Hosp 1, Dept Cardiol, 23 Youzheng St, Harbin 150001, Peoples R China.; Shi, JL (reprint author), Harbin Med Univ, Hosp 1, Dept Hematol, Harbin, Peoples R China.; Kou, JJ (reprint author), Harbin Med Univ, Hosp 2, Dept Cardiol, 246 Xuefu Rd, Harbin 150001, Peoples R China. EM biyayan@163.com; junjiekou@163.com; jialan_shi73661@gmail.com FU National Natural Science Foundation of China [81270588, 81470301]; Natural Science Foundation of Heilongjiang Province [H201347, ZD2015020] FX This work was supported by grants from the National Natural Science Foundation of China (81270588, 81470301), and the Natural Science Foundation of Heilongjiang Province (H201347, ZD2015020). NR 34 TC 2 Z9 2 U1 5 U2 5 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 NOV 15 PY 2016 VL 223 BP 121 EP 128 DI 10.1016/j.ijcard.2016.07.260 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EB0LV UT WOS:000387036200045 PM 27537737 ER PT J AU Duan, Q Mao, XX Liao, CN Zhou, HY Sun, ZL Deng, X Hu, QN Qi, J Zhang, GG Huang, H Plutzky, J Yang, TL AF Duan, Qiong Mao, Xiaoxiao Liao, Chaonan Zhou, Haoyang Sun, Zelin Deng, Xu Hu, Qiuning Qi, Jun Zhang, Guogang Huang, He Plutzky, Jorge Yang, Tianlun TI Inhibition of BET bromodomain attenuates angiotensin II induced abdominal aortic aneurysm in ApoE(-/-) mice SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE BET bromodomain; Aneurysm; Metalloproteinases; JQ1 ID MATRIX METALLOPROTEINASES; INFLAMMATION; ACTIVATION; RESPONSES; PROBES AB Background: Excessive degradation of extracellular matrix by matrix metalloproteinases (MMP) is the major pathological feature of abdominal aortic aneurysm (AAA). Suppression of extracellular matrix degradation attenuates AAA initiation and progression in preclinical models. In the present study, we wanted to test the effect of JQ1, a small chemical molecule that selectively targets bromodomain and extra-terminal domain (BET), on AngII induced AAA formation in ApoE(-/-) mice. Methods and results: To study the role of BET bromodomain in AAA pathogenesis, male ApoE-/- mice were infused with angiotensin II (AngII, 1000 ng/kg/min) for 21 days and cotreated with JQ1 (50 mg/kg daily) or vehicle control (DMSO). In the in vitro study, we determined the mRNA expression of MMP genes by qPCR and their activity both by the kit and gelatin zymography assay. BET bromodomain inhibition resulted in decreased abdominal aortic diameter (P < 0.05) measured by in vivo vascular ultrasound and ex vivo pathologic assessment of aortas. In pursuit of mechanisms for this effect on AAA, we observed that JQ1 treatment led to a downregulation of metalloproteinase gene expression and enzymatic activity both in vitro and in vivo. Conclusions: BET bromodomain inhibition improved AAA pathological sequelae, and this effect might be achieved though suppression of MMP genes expression and their activity. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Duan, Qiong; Mao, Xiaoxiao; Zhou, Haoyang; Sun, Zelin; Deng, Xu; Hu, Qiuning; Zhang, Guogang; Yang, Tianlun] Cent S Univ, Div Cardiovasc, Xiangya Hosp, 87 Xiangya Rd, Changsha 410078, Hunan, Peoples R China. [Mao, Xiaoxiao; Huang, He; Plutzky, Jorge] Brigham & Womens Hosp, Div Cardiovasc, 77 Ave Louis Pasteur,NRB 742, Boston, MA 02115 USA. [Liao, Chaonan; Huang, He; Plutzky, Jorge] Cent S Univ, Xiangya Sch Med, Dept Histol & Embryol, 172 Tongzipo Rd, Changsha 410013, Hunan, Peoples R China. [Qi, Jun] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. RP Yang, TL (reprint author), Cent S Univ, Div Cardiovasc, Xiangya Hosp, 87 Xiangya Rd, Changsha 410078, Hunan, Peoples R China.; Huang, H; Plutzky, J (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 77 Ave Louis Pasteur,NRB 742, Boston, MA 02115 USA.; Plutzky, J (reprint author), Cent S Univ, Xiangya Sch Med, Dept Histol & Embryol, 172 Tongzipo Rd, Changsha 410013, Hunan, Peoples R China. EM huanghe@csu.edu.cn; jplutzky@rics.bwh.harvard.edu; tianluny@163.com FU National Natural Science Foundation of China [81370320, 81570334, 81141068, 31571241]; Zijing Foundation [2014-0016] FX We thank Jingxuan He for performing in vivo fluorescence assay and Xiong Xiao for the assistance with picture editing. This work was supported by the National Natural Science Foundation of China 81370320, 81570334 (TL Yang), 81141068, 31571241 (H Huang), Zijing Foundation (Q Duan) (2014-0016). NR 17 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 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD NOV 15 PY 2016 VL 223 BP 428 EP 432 DI 10.1016/j.ijcard.2016.08.238 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EB0LV UT WOS:000387036200124 PM 27544600 ER PT J AU Kudaravalli, M Althouse, AD Marroquin, OC Khandhar, SJ Sharbaugh, MS Toma, C Smith, AJC Schindler, JT Lee, JS Mulukutla, SR AF Kudaravalli, Mrudula Althouse, Andrew D. Marroquin, Oscar C. Khandhar, Sameer J. Sharbaugh, Michael S. Toma, Catalin Smith, A. J. Conrad Schindler, John T. Lee, Joon S. Mulukutla, Suresh R. TI Assessment of P2Y12 inhibitor usage and switching in acute coronary syndrome patients undergoing percutaneous coronary revascularization SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Thienopyridine; P2Y12 inhibitor; Percutaneous coronary intervention; Coronary disease ID ACUTE MYOCARDIAL-INFARCTION; PLATO PLATELET INHIBITION; INTERVENTION INSIGHTS; CONTEMPORARY PRACTICE; ANTIPLATELET AGENTS; ARTERY-DISEASE; CLOPIDOGREL; PRASUGREL; TICAGRELOR; ASPIRIN AB Background: Dual antiplatelet therapy is recommended for patients with acute coronary syndrome (ACS) that undergo percutaneous coronary intervention (PCI). However, the effect of switching P2Y12 inhibitors between the loading dose and therapy after discharge is not well described. Methods: This post-hoc analysis of a prospectively collected registry included 3219 consecutive ACS patients who underwent PCI. Patients were categorized into four groups: clopidogrel at load and discharge (C-C), loading dose of clopidogrel and discharged on prasugrel/ticagrelor (C-PT), loading dose of prasugrel/ticagrelor and discharged on clopidogrel (PT-C), and prasugrel/ticagrelor at load and discharge (PT-PT). Results: While 77.6% of patients received the C-C treatment regimen and 13.6% received the PT-PT strategy, the strategy of P2Y12 switching was fairly common with 6.2% in the PT-C group and 2.6% in the C-PT group. While C-C was the most common treatment regimen, PT-C and PT-PT were more commonly used in STEMI patients than in NSTEMI or unstable angina patients. A significantly lower unadjusted incidence of the composite outcome (death, MI, and repeat revascularization) was appreciated in both the PT-C (1.0%) and PT-PT (2.3%) groups than the C-C group (4.0%). Propensity-score matched analysis still showed significantly reduced risk (HR = 0.22, 95% CI 0.05-0.93, p = 0.04) in the PT-C group vs. a matched group of C-C controls. Conclusions: The strategy of utilizing a newer P2Y12 inhibitor and then switching to clopidogrel in ACS patients following PCI is used with some frequency in routine clinical practice and further studies should evaluate the safety and efficacy of such a strategy. Published by Elsevier Ireland Ltd. C1 [Althouse, Andrew D.; Marroquin, Oscar C.; Sharbaugh, Michael S.; Toma, Catalin; Smith, A. J. Conrad; Schindler, John T.; Lee, Joon S.; Mulukutla, Suresh R.] Univ Pittsburgh, Dept Med, Inst Heart & Vasc, Pittsburgh, PA USA. [Mulukutla, Suresh R.] Vet Affairs Hosp, Div Cardiol, Pittsburgh, PA USA. [Khandhar, Sameer J.] Univ Penn, Div Cardiol, Philadelphia, PA 19104 USA. [Kudaravalli, Mrudula] Allegheny Gen Hosp, Dept Med, Pittsburgh, PA 15212 USA. RP Mulukutla, SR (reprint author), Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Div Cardiol, Univ Dr C,Cardiol Cath Lab 111C-U, Pittsburgh, PA 15240 USA. EM mulukutlasr@upmc.edu FU Abbott Vascular grant; St. Jude Medical; University of Pittsburgh Medical Center FX This research was funded, in part, by funds from an Abbott Vascular grant and from St. Jude Medical. The remaining funding was from the University of Pittsburgh Medical Center. NR 24 TC 0 Z9 0 U1 1 U2 1 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 NOV 15 PY 2016 VL 223 BP 854 EP 859 DI 10.1016/j.ijcard.2016.08.144 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EB0LV UT WOS:000387036200225 PM 27592042 ER PT J AU Arambula-Garza, E Castillo-Martinez, L Gonzalez-Islas, D Orea-Tejeda, A Santellano-Juarez, B Keirns-Davies, C Pelaez-Hernandez, V Sanchez-Santillan, R Pineda-Juarez, J Cintora-Martinez, C Pablo-Santiago, R AF Arambula-Garza, Estefana Castillo-Martinez, Lilia Gonzalez-Islas, Dulce Orea-Tejeda, Arturo Santellano-Juarez, Brenda Keirns-Davies, Candace Pelaez-Hernandez, Viridiana Sanchez-Santillan, Roco Pineda-Juarez, Juan Cintora-Martinez, Carlos Pablo-Santiago, Ruth TI Association of cardiac cachexia and atrial fibrillation in heart failure patients SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Heart failure; Cardiac cachexia; Atrial fibrillation ID VENTRICULAR SYSTOLIC DYSFUNCTION; MORBIDITY CHARM PROGRAM; ORAL ANTICOAGULANTS; BIOIMPEDANCE ANALYSIS; BETA-BLOCKERS; RISK-FACTORS; POPULATION; MORTALITY; PREVENTION; EPIDEMIOLOGY AB Background: Cachexia is a common complication in patients with advanced heart failure (HF) associated with inflammatory response activation. Atrial fibrillation (AF) is the most frequent arrhythmia (26%), probably both exacerbate the cardiac cachexia (CC). Objectives: Evaluate the association of cardiac cachexia and atrial fibrillation in heart failure patients. Material and methods: In a case control study, CC was diagnosed by electrical bioimpedance with vectorial analysis (BIVA). Subjects with congenital heart disease, cancer, HIV, drug use and other causes than HF were excluded. Results: Of the 359 subjects analyzed (men: 52.9%) median age 65 years (55-74). Those with CC were older [72 (61-67)] vs. without [62 (52-70) years old, p < 0.01]. During follow-up 47.8% of subjects developed CC and 17.27% AF, this was significantly more frequent in cachectic patients CC (23% vs 12.11%, OR: 2.17, 95% CI: 1.19-4.01, p = 0.006). Subjects, with AF had lower left ventricular ejection fraction (25.49 +/- 12.96 vs. 32.01 +/- 15.02, p = 0.08), lower posterior wall thickness (10.03 +/- 2.12 vs. 11.00 +/- 2.47, p = 0.007), larger diameter of the left atrium (49.87 +/- 9.84 vs. 42.66 +/- 7.56, p < 0.001), and a higher prevalence of CC (85.42% vs. 69.77%, p = 0.028). The 50.58% of was in NYHA class I. In NYHA III, 22.95% were in AF vs. 12.10% with not AF (p = 0.027). Conclusion: The frequent coexistence of CC and AF as HF complications indicate greater severity of HF, regardless of its type of HF. (C) 2016 Published by Elsevier Ireland Ltd. C1 [Arambula-Garza, Estefana; Gonzalez-Islas, Dulce; Orea-Tejeda, Arturo; Santellano-Juarez, Brenda; Pelaez-Hernandez, Viridiana; Sanchez-Santillan, Roco; Pineda-Juarez, Juan; Cintora-Martinez, Carlos; Pablo-Santiago, Ruth] Inst Nacl Enfermedades Resp Ismael Cosio Villegas, Dept Cardiol, Heart Failure & Resp Distress Clin, Mexico City, DF, Mexico. [Arambula-Garza, Estefana; Castillo-Martinez, Lilia] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mexico City, DF, Mexico. [Keirns-Davies, Candace] Massachusetts Gen Hosp, Interpreter Serv, Boston, MA 02114 USA. RP Orea-Tejeda, A (reprint author), Inst Nacl Enfermedades Resp Ismael Cosio Villegas, Calzada Tlalpan 4502 Col Sec 16, Mexico City 14080, DF, Mexico. RI Castillo-Martinez, Lilia/H-3750-2013 NR 46 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 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD NOV 15 PY 2016 VL 223 BP 863 EP 866 DI 10.1016/j.ijcard.2016.08.318 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EB0LV UT WOS:000387036200227 PM 27580222 ER PT J AU Demissei, BG Postmus, D Liu, LCY Cleland, JG O'Connor, CM Metra, M Ponikowski, P Teerlink, JR Cotter, G Davison, BA Edwards, C Givertz, MM Bloomfield, DM Dittrich, HC Voors, AA Hillege, HL AF Demissei, Biniyam G. Postmus, Douwe Liu, Licette C. Y. Cleland, John G. O'Connor, Christopher M. Metra, Marco Ponikowski, Piotr Teerlink, John R. Cotter, Gad Davison, Beth A. Edwards, Christopher Givertz, Michael M. Bloomfield, Daniel M. Dittrich, Howard C. Voors, Adriaan A. Hillege, Hans L. TI Risk-based evaluation of efficacy of rolofylline in patients hospitalized with acute heart failure - Post-hoc analysis of the PROTECT trial SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Acute heart failure; Rolofylline; Multivariable risk; Heterogeneity of treatment effect; Subgroup analysis; STEPP ID RECEPTOR ANTAGONIST ROLOFYLLINE; DIURETIC RESPONSE; CLINICAL-TRIALS; INDIVIDUAL PATIENTS; VOLUME OVERLOAD; RENAL-FUNCTION; RELAX-AHF; THERAPY; HETEROGENEITY; PREDICTORS AB Background: The selective adenosine A1 receptor antagonist rolofylline showed a neutral overall result on clinical outcomes in the PROTECT trial. However, we hypothesized that response to rolofylline treatment could be influenced by underlying clinical risk. Methods: We performed a post-hoc analysis of the PROTECT trial -a large, double-blind, randomized, placebo-controlled trial that enrolled 2033 patients. Baseline risk of 180-day all-cause mortality was estimated using a previously published 8-item model. Evaluation of efficacy of rolofylline across subpopulations defined based on estimated risk of mortality was performed using subpopulation treatment effect pattern plot (STEPP) analysis. Findings were validated in an independent cohort of acute heart failure patients. Results: Median estimated risk of mortality was 13.0%, IQR [8.0%-23.0%] and was comparable between the rolofylline and placebo arms. In low to intermediate risk subgroups of patients, rolofylline was associated with a higher rate of 180-day all-cause mortality (11.9% in the rolofylline versus 8.4% in the placebo arms, p = 0.050). In the high risk subgroup of patients, particularly those with estimated risk of mortality between 20% and 30%, 180-day all-cause mortality rate was markedly lower in the rolofylline arm(18.4% in the rolofylline versus 34.0% in the placebo arms, p = 0.003). The trend towards potential harm with rolofylline treatment in the low to intermediate risk subpopulations and significant benefit in high risk patients was also observed in the validation cohort. Conclusion: Our findings suggest that selective adenosine A1 receptor antagonism could be harmful in low risk acute heart failure patients, while it might significantly benefit higher risk patients. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Demissei, Biniyam G.; Liu, Licette C. Y.; Voors, Adriaan A.; Hillege, Hans L.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Demissei, Biniyam G.; Postmus, Douwe; Hillege, Hans L.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Cleland, John G.] Imperial Coll, London, England. [O'Connor, Christopher M.] Inova Heart & Vasc Inst, Falls Church, VA USA. [Metra, Marco] Univ Brescia, Brescia, Italy. [Ponikowski, Piotr] Med Univ, Clin Mil Hosp, Wroclaw, Poland. [Teerlink, John R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Teerlink, John R.] San Francisco VA Med Ctr, San Francisco, CA USA. [Cotter, Gad; Davison, Beth A.; Edwards, Christopher] Momentum Res, Durham, NC USA. [Givertz, Michael M.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Bloomfield, Daniel M.] Merck Res Labs, Rahway, NJ USA. [Dittrich, Howard C.] Univ Iowa, Carver Coll Med, Abboud Cardiovasc Res Ctr, Iowa City, IA 52242 USA. RP Voors, AA (reprint author), Univ Med Ctr Groningen, Hanzepl 1, NL-9713 GZ Groningen, Netherlands. EM a.a.voors@umcg.nl RI Ponikowski, Piotr/O-6454-2015 OI Ponikowski, Piotr/0000-0002-3391-7064 FU NovaCardia, a subsidiary of Merck FX The PROTECT trial was supported by NovaCardia, a subsidiary of Merck. NR 33 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD NOV 15 PY 2016 VL 223 BP 967 EP 975 DI 10.1016/j.ijcard.2016.08.271 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EB0LV UT WOS:000387036200247 PM 27589047 ER PT J AU Raskind, MA Millard, SP Petrie, EC Peterson, K Williams, T Hoff, DJ Hart, K Holmes, H Hill, J Daniels, C Hendrickson, R Peskind, ER AF Raskind, Murray A. Millard, Steven P. Petrie, Eric C. Peterson, Kris Williams, Tammy Hoff, David J. Hart, Kimberly Holmes, Hollie Hill, Jeffrey Daniels, Colin Hendrickson, Rebecca Peskind, Elaine R. TI Higher Pretreatment Blood Pressure Is Associated With Greater Posttraumatic Stress Disorder Symptom Reduction in Soldiers Treated With Prazosin SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Biomarker; Blood pressure; Military; Noradrenergic; Posttraumatic stress disorder (PTSD); Prazosin; Treatment response ID COMBAT VETERANS; SLEEP QUALITY; PTSD; TRAUMA; METHOXAMINE; NIGHTMARES; BRAIN; CYCLE; RAT AB BACKGROUND: In a previously reported positive randomized controlled trial of the alpha(1)-adrenoreceptor (alpha(1)AR) antagonist prazosin for combat posttraumatic stress disorder (PTSD) in 67 active duty soldiers, baseline symptoms did not predict therapeutic response. If increased brain alpha(1)AR activation in PTSD is the target of prazosin treatment action, higher brain alpha(1)AR activation should predict greater prazosin efficacy. Although brain alpha(1)AR activation is not measurable, coregulated peripheral alpha(1)AR activation could provide an estimate of brain alpha(1)AR activation. Standing blood pressure (BP) is an accessible biological parameter regulated by norepinephrine activation of alpha(1)ARs on peripheral arterioles. METHODS: Effects of baseline standing systolic and other BP parameters on PTSD outcome measures from the previously reported randomized controlled trial were analyzed using linear mixed-effects models. Prazosin participants (n = 32) and placebo participants (n = 35) were analyzed separately. RESULTS: In prazosin participants, each 10-mm Hg higher baseline standing systolic BP increment resulted in an additional 14-point reduction (improvement) of Clinician-Administered PTSD Scale total score at end point (p = .002). All other combinations of baseline BP parameters and PTSD outcome measures were similarly significant or demonstrated trends in the predicted direction. In placebo participants, there was no signal for a baseline BP effect on PTSD outcome measures. CONCLUSIONS: These findings suggest that higher standing BP is a biomarker that helps identify persons with combat PTSD who are likely to benefit from prazosin. These results also are consistent with alpha(1)AR activation contributing to PTSD pathophysiology in a subgroup of patients. C1 [Raskind, Murray A.; Millard, Steven P.; Petrie, Eric C.; Hoff, David J.; Hart, Kimberly; Holmes, Hollie; Hendrickson, Rebecca; Peskind, Elaine R.] Northwest Network Vet Integrated Serv, Network Mental Illness Res Educ & Clin Ctr 20, Seattle, WA USA. [Raskind, Murray A.; Holmes, Hollie; Peskind, Elaine R.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Peterson, Kris; Williams, Tammy; Hill, Jeffrey; Daniels, Colin] Madigan Army Med Ctr, Tacoma, WA 98431 USA. RP Raskind, MA (reprint author), VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,S116 MIRECC, Seattle, WA 98108 USA. EM murray.raskind@va.gov FU Department of Veterans Affairs; US Army Medical Research and Materiel Command, Fort Detrick, MD; Pfizer; Merck; Takeda Pharmaceuticals; Eli Lilly and Company; INSYS Therapeutics; Avanir Pharmaceuticals FX This work was supported by the Department of Veterans Affairs and the US Army Medical Research and Materiel Command, Fort Detrick, MD.; MAR is a paid advisory board member for Pfizer, Merck, and Takeda Pharmaceuticals. ERP is a paid advisory board member for Eli Lilly and Company, Takeda Pharmaceuticals, INSYS Therapeutics, and Avanir Pharmaceuticals. The other authors report no biomedical financial interests or potential conflicts of interest. NR 33 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 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD NOV 15 PY 2016 VL 80 IS 10 BP 736 EP 742 DI 10.1016/j.biopsych.2016.03.2108 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DZ0FS UT WOS:000385513500004 PM 27320368 ER PT J AU Peter, CJ Fischer, LK Kundakovic, M Garg, P Jakovcevski, M Dincer, A Amaral, AC Ginns, EI Galdzicka, M Bryce, CP Ratner, C Waber, DP Mokler, D Medford, G Champagne, FA Rosene, DL McGaughy, JA Sharp, AJ Galler, JR Akbarian, S AF Peter, Cyril J. Fischer, Laura K. Kundakovic, Marija Garg, Paras Jakovcevski, Mira Dincer, Aslihan Amaral, Ana C. Ginns, Edward I. Galdzicka, Marzena Bryce, Cyralene P. Ratner, Chana Waber, Deborah P. Mokler, David Medford, Gayle Champagne, Frances A. Rosene, Douglas L. McGaughy, Jill A. Sharp, Andrew J. Galler, Janina R. Akbarian, Schahram TI DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Attention deficits; Childhood malnutrition; Cognition; DNA methylation; Epigenetics; Prefrontal cortex ID PLURIPOTENT STEM-CELLS; CPG ISLAND SHORES; PREFRONTAL CORTEX; DIFFERENTIAL METHYLATION; IMPRINTED GENES; 1ST YEAR; GENOME; LIFE; EXPRESSION; HUMANS AB BACKGROUND: Early childhood malnutrition affects 113 million children worldwide, impacting health and increasing vulnerability for cognitive and behavioral disorders later in life. Molecular signatures after childhood malnutrition, including the potential for intergenerational transmission, remain unexplored. METHODS: We surveyed blood DNA methylomes (similar to 483,000 individual CpG sites) in 168 subjects across two generations, including 50 generation 1 individuals hospitalized during the first year of life for moderate to severe protein-energy malnutrition, then followed up to 48 years in the Barbados Nutrition Study. Attention deficits and cognitive performance were evaluated with the Connors Adult Attention Rating Scale and Wechsler Abbreviated Scale of Intelligence. Expression of nutrition-sensitive genes was explored by quantitative reverse transcriptase polymerase chain reaction in rat prefrontal cortex. RESULTS: We identified 134 nutrition-sensitive, differentially methylated genomic regions, with most (87%) specific for generation 1. Multiple neuropsychiatric risk genes, including COMT, IFNG, MIR200B, SYNGAP1, and VIPR2 showed associations of specific methyl-CpGs with attention and IQ. IFNG expression was decreased in prefrontal cortex of rats showing attention deficits after developmental malnutrition. CONCLUSIONS: Early childhood malnutrition entails long-lasting epigenetic signatures associated with liability for attention and cognition, and limited potential for intergenerational transmission. C1 [Peter, Cyril J.; Kundakovic, Marija; Jakovcevski, Mira; Dincer, Aslihan; Ratner, Chana; Akbarian, Schahram] Icahn Sch Med Mt Sinai, Dept Psychiat, 1470 Madison Ave,Hess CSM Room 9-105, New York, NY 10029 USA. [Garg, Paras; Dincer, Aslihan; Sharp, Andrew J.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Fischer, Laura K.; Galler, Janina R.] Harvard Med Sch, Massachusetts Gen Hosp, Chester M Pierce MD Div Global Psychiat, Charlestown, MA USA. [Amaral, Ana C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Jakovcevski, Mira] Max Planck Inst Psychiat, Munich, Germany. [Ginns, Edward I.] Univ Massachusetts, Sch Med, Dept Psychiat, Shrewsbury, MA USA. [Ginns, Edward I.] Univ Massachusetts, Sch Med, Dept Neurol, Shrewsbury, MA USA. [Ginns, Edward I.] Univ Massachusetts, Sch Med, Dept Clin Pathol, Shrewsbury, MA USA. [Galdzicka, Marzena] Univ Massachusetts, Sch Med, Dept Pathol, Shrewsbury, MA USA. [Bryce, Cyralene P.; Medford, Gayle] Barbados Nutr Study, Bridgetown, Barbados. [Mokler, David] Univ New England, Dept Biomed Sci, Coll Osteopath Med, Biddeford, ME USA. [Champagne, Frances A.] Columbia Univ, Dept Psychol, New York, NY 10027 USA. [Rosene, Douglas L.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [McGaughy, Jill A.] Univ New Hampshire, Dept Psychol, Durham, NH 03824 USA. [Waber, Deborah P.] Boston Childrens Hosp, Dept Psychiat, Boston, MA USA. [Waber, Deborah P.] Harvard Med Sch, Boston, MA USA. RP Akbarian, S (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, 1470 Madison Ave,Hess CSM Room 9-105, New York, NY 10029 USA. EM schahram.akbarian@mssm.edu OI Peter, Cyril/0000-0001-9190-8724; Kundakovic, Marija/0000-0002-6734-4217 FU National Institutes of Health [HD060986, MH074811, NS076958, MH086509, DA033660, HG006696, HD073731, MH097018]; Brain and Behavior Research Foundation National Alliance for Research on Schizophrenia and Depression Distinguished Investigator Grant; National Alliance for Research on Schizophrenia and Depression Young Investigator Grant; March of Dimes Research Grant [6-FY13-92] FX This work was supported by the National Institutes of Health Grant Nos. HD060986 and MH074811 (to JRG), NS076958 and MH086509 (to SA), and DA033660, HG006696, HD073731, and MH097018 (to AJS); Brain and Behavior Research Foundation National Alliance for Research on Schizophrenia and Depression Distinguished Investigator Grant (to SA) and National Alliance for Research on Schizophrenia and Depression Young Investigator Grant (to MK); and March of Dimes Research Grant No. 6-FY13-92 (to AJS). NR 57 TC 2 Z9 2 U1 17 U2 17 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 NOV 15 PY 2016 VL 80 IS 10 BP 765 EP 774 DI 10.1016/j.biopsych.2016.03.2100 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DZ0FS UT WOS:000385513500007 PM 27184921 ER PT J AU Roberts, HJ Zietman, AL Efstathiou, JA AF Roberts, Hannah J. Zietman, Anthony L. Efstathiou, Jason A. TI Painting Dose: The ART of Radiation SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Review ID AGE AB The discovery of X rays in 1895 captivated society like no other scientific advance. Radiation instantly became the subject not only of numerous scientific papers but also of circus bazaars, poetry, fiction, costume design, comics, and marketing for household items. Its spread was "viral." What is not well known, however, is its incorporation into visual art, despite the long tradition of medicine and surgery as a subject in art. Using several contemporary search methods, we identified 5 examples of paintings or sculpture that thematically feature radiation therapy. All were by artists with exhibited careers in art: Georges Chicotot, Marcel Duchamp, David Alfaro Siqueiros, Robert Pope, and Cookie Kerxton. Each artist portrays radiation differently, ranging from traditional healer, to mysterious danger, to futuristic propaganda, to the emotional challenges of undergoing cancer therapy. This range captures the complex role of radiation as both a therapy and a hazard. Whereas some of these artists are now world famous, none of these artworks are as well known as their surgical counterparts. The penetration of radiation into popular culture was rapid and pervasive; yet, its role as a thematic subject in art never fully caught on, perhaps because of a lack of understanding of the technology, radiation's intangibility, or even a suppressive effect of society's ambivalent relationship with it. These 5 artists have established a rich foundation upon which pop culture and art can further develop with time to reflect the extraordinary progress of modern radiation therapy. (C) 2016 Elsevier Inc. All rights reserved. C1 [Roberts, Hannah J.; Zietman, Anthony L.; Efstathiou, Jason A.] Columbia Univ Coll Phys & Surg, 630 W 168th St, New York, NY 10032 USA. [Roberts, Hannah J.; Zietman, Anthony L.; Efstathiou, Jason A.] Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. [Zietman, Anthony L.; Efstathiou, Jason A.] Harvard Med Sch, Boston, MA 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 25 TC 0 Z9 0 U1 10 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 15 PY 2016 VL 96 IS 4 BP 722 EP 728 DI 10.1016/j.ijrobp.2016.08.010 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DZ0JG UT WOS:000385524000003 PM 27788945 ER PT J AU Lee, JY Daignault-Newton, S Heath, G Scarlett, S Sanda, MG Chang, P Regan, MM Michalski, JM Sandler, HM Feng, FY Kuban, DA Zietman, AL Ciezki, JP Kaplan, ID Crociani, C McLaughlin, WP Mantz, CA Finkelstein, SE Suy, S Collins, SP Garin, O Ferrer, M Hamstra, DA Spratt, DE AF Lee, Jae Y. Daignault-Newton, Stephanie Heath, Gerard Scarlett, Sarah Sanda, Martin G. Chang, Peter Regan, Meredith M. Michalski, Jeff M. Sandler, Howard M. Feng, Felix Y. Kuban, Deborah A. Zietman, Anthony L. Ciezki, Jay P. Kaplan, Irving D. Crociani, Catrina McLaughlin, William P. Mantz, Constantine A. Finkelstein, Steven E. Suy, Simeng Collins, Sean P. Garin, Olatz Ferrer, Montserrat Hamstra, Daniel A. Spratt, Daniel E. TI Multinational Prospective Study of Patient-Reported Outcomes After Prostate Radiation Therapy: Detailed Assessment of Rectal Bleeding SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID QUALITY-OF-LIFE; INDEX COMPOSITE; CONFORMAL RADIOTHERAPY; CLINICAL-PRACTICE; CANCER SURVIVORS; RADICAL PROSTATECTOMY; ONCOLOGY-GROUP; BRACHYTHERAPY; VALIDATION; TOXICITY AB Purpose: The new short Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) patient-reported health-related quality of life (HRQOL) tool has removed the rectal bleeding question from the previous much longer version, EPIC-26. Herein, we assess the impact of losing the dedicated rectal bleeding question in 2 independent prospective multicenter cohorts. Methods and Materials: In a prospective multicenter test cohort (n=865), EPIC-26 patient-reported HRQOL data were collected for 2 years after treatment from patients treated with prostate radiation therapy from 2003 to 2011. A second prospective multicenter cohort (n=442) was used for independent validation. A repeated-effects model was used to predict the change from baseline in bowel summary scores from longer EPIC instruments using the change in EPIC-CP bowel summary scores with and without rectal bleeding scores. Results: Two years after radiation therapy, 91% of patients were free of bleeding, and only 2.6% reported bothersome bleeding problems. Correlations between EPIC-26 and EPIC-CP bowel scores were very high (r(2) =0.90-0.96) and were statistically improved with the addition of rectal bleeding information (r(2) =0.94-0.98). Considering all patients, only 0.2% of patients in the test cohort and 0.7% in the validation cohort reported bothersome bleeding and had clinically relevant HRQOL changes missed with EPIC-CP. However, of the 2.6% (n=17) of men with bothersome rectal bleeding in the test cohort, EPIC-CP failed to capture 1 patient (6%) as experiencing meaningful declines in bowel HRQOL. Conclusions: Modern prostate radiation therapy results in exceptionally low rates of bothersome rectal bleeding, and <1% of patients experience bothersome bleeding and are not captured by EPIC-CP as having meaningful HRQOL declines after radiation therapy. However, in the small subset of patients with bothersome rectal bleeding, the longer EPIC-26 should strongly be considered, given its superior performance in this patient subset. (C) 2016 Elsevier Inc. All rights reserved. C1 [Feng, Felix Y.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hamstra, Daniel A.] Texas Ctr Proton Therapy, Irving, TX USA. [Lee, Jae Y.; Daignault-Newton, Stephanie; Heath, Gerard; Scarlett, Sarah; Feng, Felix Y.; McLaughlin, William P.; Hamstra, Daniel A.; Spratt, Daniel E.] Univ Michigan, Ann Arbor, MI 48109 USA. [Sanda, Martin G.] Emory Univ, Dept Urol, Atlanta, GA 30322 USA. [Chang, Peter; Kaplan, Irving D.; Crociani, Catrina] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Regan, Meredith M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Michalski, Jeff M.] Washington Univ, Sch Med, St Louis, MO USA. [Sandler, Howard M.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Kuban, Deborah A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Zietman, Anthony L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ciezki, Jay P.] Cleveland Clin, Cleveland, OH 44106 USA. [Mantz, Constantine A.] 21st Century Oncol, Ft Myers, FL USA. [Finkelstein, Steven E.] 21st Century Oncol, Scottsdale, AZ USA. [Suy, Simeng] Georgetown Univ, Med Ctr, Washington, DC USA. [Garin, Olatz; Ferrer, Montserrat] Hosp del Mar, Med Res Inst, Hlth Serv Res Grp, Barcelona, Spain. [Garin, Olatz; Ferrer, Montserrat] CIBER Epidemiol & Salud Publ, Barcelona, Spain. RP Spratt, DE (reprint author), 1500 E Med Ctr Dr,SPC 5010,B2C490, Ann Arbor, MI 48109 USA. EM sprattda@med.umich.edu FU National Institutes of Health [R01 CA95662, RC1 CA146596, RC1 EB011001]; Prostate Cancer Foundation Young Investigator Award FX The PROSTQA Consortium is funded by National Institutes of Health Grants R01 CA95662, RC1 CA146596, and RC1 EB011001. The study sponsors played no role in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. D. E. Spratt is supported by the Prostate Cancer Foundation Young Investigator Award. NR 30 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 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 15 PY 2016 VL 96 IS 4 BP 770 EP 777 DI 10.1016/j.ijrobp.2016.07.038 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DZ0JG UT WOS:000385524000009 PM 27663760 ER PT J AU Rose, BS Chen, MH Wu, J Braccioforte, MH Moran, BJ Doseretz, DE Katin, MJ Ross, RH Salenius, SA D'Amico, AV AF Rose, Brent S. Chen, Ming-Hui Wu, Jing Braccioforte, Michelle H. Moran, Brian J. Doseretz, Daniel E. Katin, Michael J. Ross, Rudolf H. Salenius, Sharon A. D'Amico, Anthony V. TI Androgen Deprivation Therapy Use in the Setting of High-dose Radiation Therapy and the Risk of Prostate Cancer-Specific Mortality Stratified by the Extent of Competing Mortality SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID SHORT-TERM; RANDOMIZED-TRIAL; FOLLOW-UP; RADIOTHERAPY; BRACHYTHERAPY; COMORBIDITY; SUPPRESSION; SURVIVAL; DURATION; FAILURE AB Purpose: The addition of androgen deprivation therapy (ADT) to radiation therapy (RT) is the standard of care for men with intermediate- and high-risk prostate cancer (PC). However, whether competing mortality (CM) affects the ability of ADT to improve, survival remains unanswered. Methods and Materials: We calculated a CM risk score using a Fine-Gray semiparametric model that included age and cardiometabolic comorbidities from a cohort of 17,669 men treated with high-dose RT with or without supplemental ADT for nonmetastatic PC. Fine and Gray competing risk regression analysis was used to assess whether ADT reduced the risk of PC-specific mortality for men with a low versus a high risk of CM among the 4550 patients within the intermediate- and high-risk cohort after adjustment for established PC prognostic factors, year of treatment, site, and ADT propensity score. Results: After a median follow-up of 8.4 years, 1065 men had died, 89 (8.36%) of PC. Among the men with a low CM score, ADT use was associated with a significant reduction in the risk of PC-specific mortality (adjusted hazard ratio 0.35, 95% confidence interval 0.14-0.87, P=.02) but was not for men with high CM (adjusted hazard ratio 1.33, 95% confidence interval 0.77-2.30, P=.30). Conclusions: Adding ADT to high-dose RT appears to be associated with decreased PC-specific mortality risk in men with a low but not a high CM score. These data should serve to heighten awareness about the importance of considering competing risks when determining whether to add ADT to RT for older men with intermediateor high-risk PC. (C) 2016 Published by Elsevier Inc. C1 [Rose, Brent S.] Brigham & Womens Hosp, Dana Farber Canc Inst, Harvard Radiat Oncol Program, 75 Francis St, Boston, MA 92093 USA. [Chen, Ming-Hui; Wu, Jing] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Braccioforte, Michelle H.; Moran, Brian J.] Prostate Canc Fdn Chicago, Westmont, IL USA. [Doseretz, Daniel E.; Katin, Michael J.; Ross, Rudolf H.; Salenius, Sharon A.] 21st Century Oncol Inc, Ft Myers, FL USA. [D'Amico, Anthony V.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. RP Rose, BS (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Harvard Radiat Oncol Program, 75 Francis St, Boston, MA 92093 USA. EM brose44@gmail.com NR 22 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 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 15 PY 2016 VL 96 IS 4 BP 778 EP 784 DI 10.1016/j.ijrobp.2016.08.014 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DZ0JG UT WOS:000385524000010 PM 27788950 ER PT J AU Craft, D Khan, F Young, M Bortfeld, T AF Craft, David Khan, Fazal Young, Michael Bortfeld, Thomas TI The Price of Target Dose Uniformity SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article C1 [Craft, David] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Craft, David] Harvard Med Sch, Boston, MA 02114 USA. RP Craft, D (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA.; Craft, D (reprint author), Harvard Med Sch, Boston, MA 02114 USA. EM dcraft@partners.org NR 2 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 NOV 15 PY 2016 VL 96 IS 4 BP 913 EP 914 DI 10.1016/j.ijrobp.2016.07.033 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DZ0JG UT WOS:000385524000025 PM 27788961 ER PT J AU Hodgkin, D Merrick, EL O'Brien, PL McGuire, TG Lee, S Deckersbach, T Nierenberg, AA AF Hodgkin, Dominic Merrick, Elizabeth L. O'Brien, Peggy L. McGuire, Thomas G. Lee, Sue Deckersbach, Thilo Nierenberg, Andrew A. TI Testing for clinical inertia in medication treatment of bipolar disorder SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder; Pharmaceuticals; Prescribing decisions; Clinical inertia ID COMORBIDITY SURVEY REPLICATION; MOOD DISORDERS; UNITED-STATES; STEP-BD; PREVALENCE; DISABILITY; BURDEN AB Background: Clinical inertia has been defined as lack of change in medication treatment at visits where a medication adjustment appears to be indicated. This paper seeks to identify the extent of clinical inertia in medication treatment of bipolar disorder. A second goal is to identify patient characteristics that predict this treatment pattern. Method: Data describe 23,406 visits made by 1815 patients treated for bipolar disorder during the STEP BD practical clinical trial. Visits were classified in terms of whether a medication adjustment appears to be indicated, and also whether or not one occurred. Multivariable regression analyses were conducted to find which patient characteristics were predictive of whether adjustment occurred. Results: 36% of visits showed at least 1 indication for adjustment. The most common indications were non-response to medication, side effects, and start of a new illness episode. Among visits with an indication for adjustment, no adjustment occurred 19% of the time, which may be suggestive of clinical inertia. In multivariable models, presence of any indication for medication adjustment was a predictor of receiving one (OR=1.125, 95% CI=1.015, 1.246), although not as strong as clinical status measures. Limitations: The associations observed are not necessarily causal, given the study design. The data also lack information about physician-patient communication. Conclusions: Many patients remained on the same medication regimen despite indications of side effects or non-response to treatment. Although lack of adjustment does not necessarily reflect clinical inertia in all cases, the reasons for this treatment pattern merit further examination. (C) 2016 Elsevier B.V. All rights reserved. C1 [Hodgkin, Dominic; Merrick, Elizabeth L.; Lee, Sue] Brandeis Univ, Inst Behav Hlth, Heller Sch Social Policy & Management, Waltham, MA 02254 USA. [O'Brien, Peggy L.] Truven Hlth Analyt, Sacramento, CA USA. [McGuire, Thomas G.] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. [Deckersbach, Thilo; Nierenberg, Andrew A.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Deckersbach, Thilo; Nierenberg, Andrew A.] Massachusetts Gen Hosp, Bipolar Clin, Boston, MA 02114 USA. [Deckersbach, Thilo; Nierenberg, Andrew A.] Massachusetts Gen Hosp, Res Program, Boston, MA 02114 USA. RP Hodgkin, D (reprint author), Brandeis Univ, Heller Sch, MS 035,415 South St, Waltham, MA 02454 USA. EM hodgkin@brandeis.edu FU National Institute of Mental Health [R01 MH 96809] FX This research was supported by the National Institute of Mental Health, grant R01 MH 96809. NR 26 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 NOV 15 PY 2016 VL 205 BP 13 EP 19 DI 10.1016/j.jad.2016.03.073 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DY9GC UT WOS:000385440900002 PM 27391267 ER PT J AU Rush, G O'Donovan, A Nagle, L Conway, C McCrohan, A O'Farrelly, C Lucey, JV Malone, KM AF Rush, Gavin O'Donovan, Aoife Nagle, Laura Conway, Catherine McCrohan, AnnMaria O'Farrelly, Cliona Lucey, James V. Malone, Kevin M. TI Alteration of immune markers in a group of melancholic depressed patients and their response to electroconvulsive therapy SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Depression; Melancholic subtype; Psychoneuroimmunology; Cytokines; Electroconvulsive therapy ID C-REACTIVE PROTEIN; GROWTH-FACTOR-BETA; CORONARY-HEART-DISEASE; NECROSIS-FACTOR-ALPHA; NONMELANCHOLIC MAJOR DEPRESSION; TREATMENT-RESISTANT DEPRESSION; NEUROTROPHIC FACTOR; PROINFLAMMATORY CYTOKINES; PLASMA NORADRENALINE; ANXIETY DISORDERS AB Background: Immune system dysfunction is implicated in the pathophysiology of major depression, and is hypothesized to normalize with successful treatment. We aimed to investigate immune dysfunction in melancholic depression and its response to ECT. Methods: 55 melancholic depressed patients and 26 controls participated. 33 patients (60%) were referred for ECT. Blood samples were taken at baseline, one hour after the first ECT session, and 48 h after ECT series completion. Results: At baseline, melancholic depressed patients had significantly higher levels of the pro-inflammatory cytokine IL-6, and lower levels of the regulatory cytokine TGF-beta than controls. A significant surge in IL-6 levels was observed one hour after the first ECT session, but neither IL-6 nor TGF-beta levels normalized after completion of ECT series. Seventy per cent (n=23) of ECT recipients showed clinical response and 42% (n=10) reached remission. Neither IL-6 nor TGF-beta changes correlated with clinical improvement following ECT. No significant changes in IL-10, TNF-alpha and CRP levels were found in relation to melancholia or response to ECT. Limitations: As a naturalistic study, some potential confounders could not be eliminated or controlled, including medication use. Conclusions: Melancholic depressed patients demonstrated a peripheral increase in IL-6 and reduction in TGF-beta, which did not normalize despite clinical response to ECT. These findings may be consistent with emerging hypotheses of the role of inflammation in mediating neurotrophin expression. The implications of chronic inflammation in the melancholic depressed population for future medical health, particularly cardiovascular risk, are largely unknown and warrant further investigation. (C) 2016 Elsevier B.V. All rights reserved. C1 [Rush, Gavin; Nagle, Laura; Conway, Catherine; Lucey, James V.] St Patricks Univ Hosp, Dublin, Ireland. [O'Donovan, Aoife; McCrohan, AnnMaria; Malone, Kevin M.] Univ Coll Dublin, Sch Med & Med Sci, Dublin, Ireland. [O'Donovan, Aoife; McCrohan, AnnMaria; Malone, Kevin M.] St Vincents Univ Hosp, Dept Psychiat Psychotherapy & Mental Hlth Res, Dublin, Ireland. [O'Donovan, Aoife] San Francisco VA Med Ctr, Stress & Hlth Res Program, San Francisco, CA USA. [O'Donovan, Aoife] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [O'Farrelly, Cliona] Univ Dublin Trinity Coll, Sch Biochem & Immunol, Dublin, Ireland. RP Rush, G (reprint author), St Patricks Univ Hosp, Dublin, Ireland. EM grush@stpatsmail.com OI Malone, Kevin M/0000-0001-5665-4706 FU NIMH NIH HHS [K01 MH109871] NR 97 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 NOV 15 PY 2016 VL 205 BP 60 EP 68 DI 10.1016/j.jad.2016.06.035 PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DY9GC UT WOS:000385440900007 PM 27414954 ER PT J AU Reilly-Harrington, NA Sylvia, LG Rabideau, DJ Gold, AK Deckersbach, T Bowden, CL Bobo, WV Singh, V Calabrese, JR Shelton, RC Friedman, ES Thase, ME Kamali, M Tohen, M McInnis, MG McElroy, SL Ketter, TA Kocsis, JH Kinrys, G Nierenberg, AA AF Reilly-Harrington, Noreen A. Sylvia, Louisa G. Rabideau, Dustin J. Gold, Alexandra K. Deckersbach, Thilo Bowden, Charles L. Bobo, William V. Singh, Vivek Calabrese, Joseph R. Shelton, Richard C. Friedman, Edward S. Thase, Michael E. Kamali, Masoud Tohen, Mauricio McInnis, Melvin G. McElroy, Susan L. Ketter, Terence A. Kocsis, James H. Kinrys, Gustavo Nierenberg, Andrew A. TI Tracking medication changes to assess outcomes in comparative effectiveness research: A bipolar CHOICE study SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder; Medication; Comparative effectiveness; Big data; Electronic medical record ID COMORBID ANXIETY DISORDERS; CLINICAL DECISION-MAKING; I-DISORDER; SCALE; OUTPATIENTS; TRIAL; MANIA AB Background: Comparative effectiveness research uses multiple tools, but lacks outcome measures to assess large electronic medical records and claims data. Aggregate changes in medications in response to clinical need may serve as a surrogate outcome measure. We developed the Medication Recommendation Tracking Form (MRTF) to record the frequency, types, and reasons for medication adjustments in order to calculate Necessary Clinical Adjustments (NCAs), medication adjustments to reduce symptoms, maximize treatment response, or address problematic side effects. Methods: The MRTF was completed at every visit for 482 adult patients in Bipolar CHOICE, a 6-month randomized comparative effectiveness trial. Results: Responders had significantly fewer NCAs compared to non-responders. NCAs predicted subsequent response status such that every additional NCA during the previous visit decreased a patient's odds of response by approximately 30%. Patients with more severe symptoms had a greater number of NCAs at the subsequent visit. Patients with a comorbid anxiety disorder demonstrated a significantly higher rate of NCAs per month than those without a comorbid anxiety disorder. Patients with greater frequency, intensity, and interference of side effects had higher rates of NCAs. Participants with fewer NCAs reported a higher quality of life and decreased functional impairment. Limitations: The MRTF has not been examined in community clinic settings and did not predict response more efficiently than the Clinical Global Impression-Bipolar Version (CGI-BP). Conclusions: The MRTF is a feasible proxy of clinical outcome, with implications for clinical training and decision-making. Analyses of big data could use changes in medications as a surrogate outcome measure. (C) 2016 Elsevier B.V. All rights reserved. C1 [Reilly-Harrington, Noreen A.; Sylvia, Louisa G.; Gold, Alexandra K.; Deckersbach, Thilo; Kinrys, Gustavo; Nierenberg, Andrew A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Reilly-Harrington, Noreen A.; Sylvia, Louisa G.; Deckersbach, Thilo; Kinrys, Gustavo; Nierenberg, Andrew A.] Harvard Med Sch, Boston, MA USA. [Rabideau, Dustin J.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Bowden, Charles L.; Singh, Vivek] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Bobo, William V.] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA. [Calabrese, Joseph R.] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Bipolar Disorders Res Ctr, Cleveland, OH 44106 USA. [Shelton, Richard C.] Univ Alabama Birmingham, Dept Psychiat, Birmingham, AL USA. [Friedman, Edward S.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Thase, Michael E.] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Kamali, Masoud; McInnis, Melvin G.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Tohen, Mauricio] Univ New Mexico, Hlth Sci Ctr, Dept Psychiat, Albuquerque, NM 87131 USA. [McElroy, Susan L.] Lindner Ctr HOPE, Mason, OH USA. [McElroy, Susan L.] Univ Cincinnati, Coll Med, Dept Psychiat, Cincinnati, OH 45221 USA. [Ketter, Terence A.] Stanford Univ, Dept Psychiat & Behav Sci, Sch Med, Stanford, CA 94305 USA. [Kocsis, James H.] Cornell Univ, Weill Cornell Med Coll, Dept Psychiat, New York, NY 10021 USA. RP Reilly-Harrington, NA (reprint author), Massachusetts Gen Hosp, Bipolar Clin & Res Program, 50 Staniford St,Suite 580, Boston, MA 02114 USA. EM nhartington11@mgh.harvard.edu NR 22 TC 0 Z9 0 U1 6 U2 6 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 NOV 15 PY 2016 VL 205 BP 159 EP 164 DI 10.1016/j.jad.2016.07.007 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DY9GC UT WOS:000385440900021 PM 27449548 ER PT J AU Liu, J Fang, JL Wang, ZJ Rong, PJ Hong, Y Fan, YY Wang, XL Park, J Jin, Y Liu, CH Zhu, B Kong, J AF Liu, Jun Fang, Jiliang Wang, Zengjian Rong, Peijing Hong, Yang Fan, Yangyang Wang, Xiaoling Park, Joel Jin, Yu Liu, Chunhong Zhu, Bing Kong, Jian TI Transcutaneous vagus nerve stimulation modulates amygdala functional connectivity in patients with depression SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Transcutaneous vagus nerve stimulation; Resting-state functional connectivity; Amygdala; Depression; Emotion ID TREATMENT-RESISTANT DEPRESSION; DORSOLATERAL PREFRONTAL CORTEX; TEMPORAL-LOBE EPILEPSY; MAJOR DEPRESSION; EMOTION REGULATION; ANTIDEPRESSANT TREATMENT; AFFECTIVE STYLE; DISORDER; FMRI; TRIAL AB Background: The amygdala is a key region in emotion processing, and studies have suggested that amygdala-frontal functional connectivity deficits could be modulated by antidepressants in major depressive disorder (MDD). Transcutaneous vagus nerve stimulation (tVNS), a non-invasive, peripheral neuromodulation method at the ear, has shown promising results in treating major depressive disorder (MDD) in several pilot studies. However, the neural mechanism underlying tVNS treatment of depression has not been fully investigated. In this study, we investigated how tVNS can modulate the amygdalalateral prefrontal network resting state functional connectivity (rsFC) in mild or moderate major depressive disorder (MDD) patients. Methods: Forty-nine MDD patients were recruited and received tVNS or sham tVNS (stVNS) treatments for four weeks. Resting state fMRI scans were applied before and after treatments. Results: After 1 month of tVNS treatment, the 24-item Hamilton Depression Rating Scale (HAMD) scores were reduced significantly in the tVNS group as compared with the sham tVNS group. The rsFC in the tVNS group between the right amygdala and left dorsolateral prefrontal cortex was increased compared with sham tVNS. All the rsFC increases were also associated with HAMD reduction as well as reductions in the anxiety and retardation HAMD subscales. Conclusions: tVNS can significantly modulate the amygdala-lateral prefrontal rsFC of MDD patients; our results provide insights into the brain mechanism of tVNS treatment for MDD patients. (C) 2016 Elsevier B.V. All rights reserved. C1 [Liu, Jun; Fang, Jiliang; Hong, Yang; Fan, Yangyang; Wang, Xiaoling] China Acad Chinese Med Sci, Guanganmen Hosp, Beijing 100053, Peoples R China. [Liu, Jun; Wang, Zengjian; Park, Joel; Jin, Yu; Kong, Jian] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Rong, Peijing; Zhu, Bing] China Acad Chinese Med Sci, Inst Acupuncture & Moxibust, Beijing 100700, Peoples R China. [Liu, Chunhong] Capital Med Univ, Beijing Anding Hosp, Dept Radiol & Psychiat, Beijing Key Lab Mental Disorders, Beijing 100088, Peoples R China. [Wang, Zengjian] South China Normal Univ, Ctr Study Appl Psychol, Key Lab Mental Hlth & Cognit Sci Guangdong Prov, Sch Psychol, Guangzhou, Guangdong, Peoples R China. RP Kong, J (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA.; Rong, PJ (reprint author), China Acad Chinese Med Sci, Inst Acupuncture & Moxibust, Beijing 100700, Peoples R China. EM rongpj@hotmail.com; kongj@mnr.mgh.harvard.edu FU Special Program of Chinese Medicine of the National Basic Research Program of China (973 Program) [2012CB518503]; "Twelfth Five-year Plan" National Science and Technology Support Program of China [2012BAF14B10]; National Natural Science Foundation of China [81273674, 81471389, 81473780]; Beijing Natural Science Foundation of China [7111007]; NIH/NCCIH [R01AT006364, R01 AT008563, R21AT008707, P01 AT006663] FX The work is supported by the Special Program of Chinese Medicine of the National Basic Research Program of China (973 Program 2012CB518503), the "Twelfth Five-year Plan" National Science and Technology Support Program of China (2012BAF14B10), the National Natural Science Foundation of China (81273674, 81471389, 81473780), and the Beijing Natural Science Foundation of China (7111007). Jian Kong is supported by R01AT006364, R01 AT008563, R21AT008707, and P01 AT006663 from NIH/NCCIH. NR 81 TC 4 Z9 4 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 NOV 15 PY 2016 VL 205 BP 319 EP 326 DI 10.1016/j.jad.2016.08.003 PG 8 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DY9GC UT WOS:000385440900041 PM 27559632 ER PT J AU Zhang, XH Keum, N Wu, K Smith-Warner, SA Ogino, S Chan, AT Fuchs, CS Giovannucci, EL AF Zhang, Xuehong Keum, NaNa Wu, Kana Smith-Warner, Stephanie A. Ogino, Shuji Chan, Andrew T. Fuchs, Charles S. Giovannucci, Edward L. TI Calcium intake and colorectal cancer risk: Results from the nurses' health study and health professionals follow-up study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE calcium; colorectal cancer; distal colon cancer; calcium supplement; latency; prospective cohort; repeated assessments ID FOOD FREQUENCY QUESTIONNAIRE; COLON-CANCER; VITAMIN-D; REGRESSION-MODELS; PREVENTION; ADENOMA; WOMEN; TRIAL; MEN; SUPPLEMENTATION AB The relationship between calcium intake and colorectal cancer (CRC) risk remains inconclusive. We conducted this study to evaluate whether the association between calcium intake and CRC risk differs by anatomic subsite and determine the dose-response relationship for this association, as well as assess when in carcinogenesis calcium may play a role. We assessed calcium intake every 4 years and followed 88,509 women (1980-2012) in the Nurses' Health Study and 47,740 men (1986-2012) in the Health Professionals Follow-Up Study. We documented 3,078 incident CRC cases. Total calcium intake (>= 1,400 vs. <600 mg/d) was associated with a statistically significant lower risk of colon cancer (multivariable relative risk: 0.78, 95% CI: 0.65-0.95). Similar results were observed by different sources of calcium (from all foods or dairy products only). The inverse association was linear and suggestively stronger for distal colon cancer (0.65, 0.43-0.99) than for proximal colon cancer (0.94, 0.72-1.22, p-(common) (effects)=0.14). Additionally, when comparing different latencies, the overall pattern suggested that the inverse association appeared to be stronger with increasing latency and was strongest for intakes 12-16 years before diagnosis. Comparing total calcium intakes of >= 1,400 vs. <600 mg/d for intake 12-16 y before diagnosis, the pooled RR (95% CIs) of CRC was 0.76 (0.64-0.91). Higher calcium intake was associated with a lower risk of developing colon cancer, especially for distal colon cancer. Overall inverse association was linear and did not differ by intake source. Additionally, calcium intake approximately 10 years before diagnosis appeared to be associated with a lower risk of CRC. C1 [Zhang, Xuehong; Chan, Andrew T.; Fuchs, Charles S.; Giovannucci, Edward L.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 181 Longwood Ave,Room 453, Boston, MA 02115 USA. [Zhang, Xuehong; Ogino, Shuji; Chan, Andrew T.; Fuchs, Charles S.; Giovannucci, Edward L.] Harvard Med Sch, 181 Longwood Ave,Room 453, Boston, MA 02115 USA. [Keum, NaNa; Wu, Kana; Smith-Warner, Stephanie A.; Giovannucci, Edward L.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Smith-Warner, Stephanie A.; Ogino, Shuji; Giovannucci, Edward L.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Ogino, Shuji; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Div MPE Mol Pathol Epidemiol, 181 Longwood Ave,Room 453, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA. [Chan, Andrew T.] Broad Inst MIT & Harvard, Cambridge, MA USA. RP Zhang, XH (reprint author), Harvard Med Sch, 181 Longwood Ave,Room 453, Boston, MA 02115 USA.; Zhang, XH (reprint author), Brigham & Womens Hosp, 181 Longwood Ave,Room 453, Boston, MA 02115 USA. EM xuehong.zhang@channing.harvard.edu FU National Institutes of Health (NIH) [UM1CA186107, P50CA127003, P01CA87969, R01 CA137178, K24DK098311, R01CA151993, R35CA197735, R03CA176717, K07CA188126] FX This work was supported by a grant from the National Institutes of Health (NIH) grants UM1CA186107, P50CA127003, P01CA87969, R01 CA137178, K24DK098311, R01CA151993, R35CA197735, R03CA176717 and K07CA188126. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We would like to thank the participants and staff of the Nurses' Health Study and Health Professionals Follow-up Study, for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA and WY. All authors declare that they have no conflicts of interest. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. NR 46 TC 1 Z9 1 U1 18 U2 18 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 NOV 15 PY 2016 VL 139 IS 10 BP 2232 EP 2242 DI 10.1002/ijc.30293 PG 11 WC Oncology SC Oncology GA DX8NP UT WOS:000384646100008 PM 27466215 ER PT J AU Kim, SB Wildiers, H Krop, IE Smitt, M Yu, R de Haas, SL Gonzalez-Martin, A AF Kim, Sung-Bae Wildiers, Hans Krop, Ian E. Smitt, Melanie Yu, Ron de Haas, Sanne Lysbet Gonzalez-Martin, Antonio TI Relationship between tumor biomarkers and efficacy in TH3RESA, a phase III study of trastuzumab emtansine (T-DM1) vs. treatment of physician's choice in previously treated HER2-positive advanced breast cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE ado-trastuzumab emtansine; T-DM1; biomarkers; metastatic breast cancer; HER2 ID PTEN; PERTUZUMAB; RESISTANCE; AKT; INHIBITION; EXPRESSION; LAPATINIB; PATHWAY; TAXANE; PIK3CA AB In the phase III TH3RESA study (NCT01419197), 602 patients with HER2-positive advanced breast cancer who received prior taxane therapy and >= 2 HER2-directed regimens, including trastuzumab and lapatinib (advanced setting), were randomized to trastuzumab emtansine (T-DM1) or treatment of physician's choice (TPC). A statistically significant progression-free survival (PFS) benefit favoring T-DM1 was demonstrated. Here, we examine the relationship between HER2-related biomarkers and PFS in an exploratory analysis. Biomarkers assessed included HER2 (n=505) and HER3 (n=505) mRNA expression, PIK3CA mutation status (n=410) and PTEN protein expression (n=358). For biomarkers with continuous data (HER2, HER3, PTEN), subgroups were defined using median values (>median and <= median). For all biomarker subgroups, median PFS was longer with T-DM1 vs. TPC. The PFS benefit favoring T-DM1 vs. TPC was numerically greater in the HER2 mRNA >median subgroup (7.2 vs. 3.4 months; unstratified hazard ratio [HR], 0.40; 95% CI, 0.28-0.59; p < 0.0001) vs. <= median subgroup (5.5 vs. 3.9 months; HR, 0.68; 95% CI, 0.49-0.92; p=0.0131). The PFS benefit with T-DM1 was similar among HER3, PIK3CA and PTEN subgroups. Consistent with other reports, benefit was seen with T-DM1 regardless of PIK3CA mutation status. In a multivariate analysis including an interaction term (treatment group by log2-transformed HER2 mRNA), patients with higher HER2 mRNA levels benefited more from receiving T-DM1 (HR, 0.84; 95% CI, 0.75-0.94; interaction p value=0.0027). In summary, T-DM1 prolonged median PFS in all biomarker subgroups analyzed, including activating PIK3CA mutations, with numerically greater benefit in patients with tumors expressing HER2 mRNA > median vs. <= median. C1 [Kim, Sung-Bae] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Oncol, Seoul, South Korea. [Wildiers, Hans] Univ Hosp Leuven, Dept Gen Med Oncol, Leuven, Belgium. [Krop, Ian E.] Harvard Med Sch, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA USA. [Smitt, Melanie] Genentech Inc, Dept Prod Dev Oncol, San Francisco, CA 94080 USA. [Yu, Ron] Genentech Inc, Dept Biostat, San Francisco, CA 94080 USA. [de Haas, Sanne Lysbet] F Hoffmann La Roche Ltd, Dept Oncol Biomarker Dev, Basel, Switzerland. [Gonzalez-Martin, Antonio] MD Anderson Canc Ctr, Dept Med Oncol, Madrid, Spain. RP Kim, SB (reprint author), Univ Ulsan, Coll Med, Asan Med Ctr, Dept Oncol, Seoul, South Korea. EM sbkim3@amc.seoul.kr FU Novartis; Genentech, Inc. FX Sung-Bae Kim has received research funding from Novartis. Hans Wildiers has received honoraria from and has served as a consultant for F. Hoffmann-La Roche, Ltd. These financial compensations only served for scientific-and work-related costs. Ian E. Krop has received research support from Genentech, Inc. Melanie Smitt is an employee of Genentech, Inc. and owns stock in F. Hoffmann-La Roche, Ltd. Ron Yu was an employee of Genentech, Inc. at the time this work was conducted and owns stock in F. Hoffmann-La Roche, Ltd. Sanne Lysbet de Haas is an employee of F. Hoffmann-La Roche, Ltd. Antonio Gonzalez-Martin has served as a consultant for F. Hoffmann-La Roche, Ltd. NR 23 TC 2 Z9 2 U1 10 U2 10 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 NOV 15 PY 2016 VL 139 IS 10 BP 2336 EP 2342 DI 10.1002/ijc.30276 PG 7 WC Oncology SC Oncology GA DX8NP UT WOS:000384646100018 PM 27428671 ER PT J AU Abraham, G Havulinna, AS Bhalala, OG Byars, SG De Livera, AM Yetukuri, L Tikkanen, E Perola, M Schunkert, H Sijbrands, EJ Palotie, A Samani, NJ Salomaa, V Ripatti, S Inouye, M AF Abraham, Gad Havulinna, Aki S. Bhalala, Oneil G. Byars, Sean G. De Livera, Alysha M. Yetukuri, Laxman Tikkanen, Emmi Perola, Markus Schunkert, Heribert Sijbrands, Eric J. Palotie, Aarno Samani, Nilesh J. Salomaa, Veikko Ripatti, Samuli Inouye, Michael TI Genomic prediction of coronary heart disease SO EUROPEAN HEART JOURNAL LA English DT Review DE Genomic risk score; Coronary heart disease; Myocardial infarction; Framingham risk score; Primary prevention ID GENETIC RISK SCORE; CARDIOVASCULAR-DISEASE; EVENTS; FRAMINGHAM; POLYMORPHISMS; ASSOCIATION AB Aims Genetics plays an important role in coronary heart disease (CHD) but the clinical utility of genomic risk scores (GRSs) relative to clinical risk scores, such as the Framingham Risk Score (FRS), is unclear. Our aim was to construct and externally validate a CHD GRS, in terms of lifetime CHD risk and relative to traditional clinical risk scores. Methods and results We generated a GRS of 49 310 SNPs based on a CARDIoGRAMplusC4D Consortium meta-analysis of CHD, then independently tested it using five prospective population cohorts (three FINRISK cohorts, combined n = 12 676, 757 incident CHD events; two Framingham Heart Study cohorts (FHS), combined n = 3406, 587 incident CHD events). The GRS was associated with incident CHD (FINRISK HR = 1.74, 95% confidence interval (CI) 1.61-1.86 per S.D. of GRS; Framingham HR = 1.28, 95% CI 1.18-1.38), and was largely unchanged by adjustment for known risk factors, including family history. Integration of the GRS with the FRS or ACC/AHA13 scores improved the 10 years risk prediction (meta-analysis C-index: +1.5-1.6%, P < 0.001), particularly for individuals >= 60 years old (meta-analysis C-index: +4.6-5.1%, P < 0.001). Importantly, the GRS captured substantially different trajectories of absolute risk, with men in the top 20% of attaining 10% cumulative CHD risk 12-18 y earlier than those in the bottom 20%. High genomic risk was partially compensated for by low systolic blood pressure, low cholesterol level, and non-smoking. Conclusions A GRS based on a large number of SNPs improves CHD risk prediction and encodes different trajectories of lifetime risk not captured by traditional clinical risk scores. C1 [Abraham, Gad; Bhalala, Oneil G.; Byars, Sean G.; De Livera, Alysha M.; Inouye, Michael] Univ Melbourne, Sch BioSci, Ctr Syst Genom, Parkville, Vic 3010, Australia. [Abraham, Gad; Bhalala, Oneil G.; Byars, Sean G.; De Livera, Alysha M.; Inouye, Michael] Univ Melbourne, Dept Pathol, Parkville, Vic 3010, Australia. [Havulinna, Aki S.; Perola, Markus; Salomaa, Veikko] Natl Inst Hlth & Welf, FI-00271 Helsinki, Finland. [De Livera, Alysha M.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Parkville, Vic 3010, Australia. [Yetukuri, Laxman; Tikkanen, Emmi; Perola, Markus; Palotie, Aarno; Ripatti, Samuli; Inouye, Michael] Univ Helsinki, FIMM, FI-00014 Helsinki, Finland. [Schunkert, Heribert] Deutsch Herzzentrum Munich, D-80636 Munich, Germany. [Schunkert, Heribert] Tech Univ Munich, D-80636 Munich, Germany. [Schunkert, Heribert] DZHK, Partner Site Munich Heart Alliance, D-81377 Munich, Germany. [Sijbrands, Eric J.] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Palotie, Aarno] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Palotie, Aarno] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Palotie, Aarno] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, BHF Cardiovasc Res Ctr, Dept Cardiovasc Sci, Groby Rd, Leicester LE3 9QP, Leics, England. [Samani, Nilesh J.] Glenfield Hosp, Leicester Cardiovasc Biomed Res Unit, Natl Inst Hlth Res, Groby Rd, Leicester LE3 9QP, Leics, England. [Ripatti, Samuli] Wellcome Trust Res Labs, Wellcome Trust Sanger Inst, Genome Campus, Cambridge CB10 1SA, England. [Ripatti, Samuli] Univ Helsinki, Dept Publ Hlth, FI-00014 Helsinki, Finland. RP Inouye, M (reprint author), Univ Melbourne, Sch BioSci, Ctr Syst Genom, Parkville, Vic 3010, Australia.; Inouye, M (reprint author), Univ Melbourne, Dept Pathol, Parkville, Vic 3010, Australia.; Salomaa, V (reprint author), Natl Inst Hlth & Welf, FI-00271 Helsinki, Finland.; Ripatti, S; Inouye, M (reprint author), Univ Helsinki, FIMM, FI-00014 Helsinki, Finland.; Samani, NJ (reprint author), Univ Leicester, Glenfield Hosp, BHF Cardiovasc Res Ctr, Dept Cardiovasc Sci, Groby Rd, Leicester LE3 9QP, Leics, England.; Samani, NJ (reprint author), Glenfield Hosp, Leicester Cardiovasc Biomed Res Unit, Natl Inst Hlth Res, Groby Rd, Leicester LE3 9QP, Leics, England.; Ripatti, S (reprint author), Wellcome Trust Res Labs, Wellcome Trust Sanger Inst, Genome Campus, Cambridge CB10 1SA, England.; Ripatti, S (reprint author), Univ Helsinki, Dept Publ Hlth, FI-00014 Helsinki, Finland. EM njs@leicester.ac.uk; veikko.salomaa@thl.fi; samuli.ripatti@helsinki.fi; minouye@unimelb.edu.au FU National Health and Medical Research Council [1090462]; National Heart Foundation of Australia [1061435, 1062227]; Finnish Foundation for Cardiovascular Research; British Heart Foundation; NIHR; Academy of Finland [251704, 286500, 293404, 251217, 285380]; Juselius Foundation; NordForsk e-Science NIASC [62721]; Biocentrum Helsinki; National Heart, Lung, and Blood Institute of the United States National Institutes of Health [R01 HL087676]; Broad Institute Center for Genotyping and Analysis - National Center for Research Resources [U54 RR02027]; Wellcome Trust [076113, 085475]; European Union [261433] FX National Health and Medical Research Council Early Career Fellowship (1090462 to G.A.); National Health and Medical Research Council and the National Heart Foundation of Australia (1061435 and 1062227 to M.I.); Finnish Foundation for Cardiovascular Research to V.S; British Heart Foundation and NIHR to N.J.S.; AP and SR are supported by the Academy of Finland (grant no. 251704, 286500, 293404 to AP, and 251217, 285380 to SR), Juselius Foundation, Finnish Foundation for Cardiovascular Research, NordForsk e-Science NIASC (grant no 62721) and Biocentrum Helsinki (to SR). The MI Genetics (MIGen) Consortium Study was funded by the National Heart, Lung, and Blood Institute of the United States National Institutes of Health (R01 HL087676). Genotyping was partially funded by The Broad Institute Center for Genotyping and Analysis, which was supported by grant U54 RR02027 from the National Center for Research Resources. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113 and 085475. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 261433 (Biobank Standardisation and Harmonisation for Research Excellence in the European Union-BioSHaRE-EU). We are grateful to the CARDIoGRAMplusC4D consortium for making their large-scale genetic data available. A list of members of the consortium and the contributing studies is available at www.cardiogramplusc4d.org. NR 34 TC 2 Z9 2 U1 2 U2 2 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 NOV 14 PY 2016 VL 37 IS 43 BP 3267 EP 3278 DI 10.1093/eurheartj/ehw450 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EK5PY UT WOS:000393979500007 PM 27655226 ER PT J AU Banerjee, S Jeon-Slaughter, H Tsai, S Mohammad, A Foteh, M Abu-Fadel, M Gigliotti, OS Cawich, I Rodriguez, G Kumbhani, D Addo, T Luna, M Das, TS Prasad, A Armstrong, EJ Shammas, NW Brilakis, ES AF Banerjee, Subhash Jeon-Slaughter, Haekyung Tsai, Shirling Mohammad, Atif Foteh, Mazin Abu-Fadel, Mazen Gigliotti, Osvaldo S. Cawich, Ian Rodriguez, Gerardo Kumbhani, Dharam Addo, Tayo Luna, Michael Das, Tony S. Prasad, Anand Armstrong, Ehrin J. Shammas, Nicolas W. Brilakis, Emmanouil S. TI Comparative Assessment of Procedure Cost and Outcomes Between Guidewire and Crossing Device Strategies to Cross Peripheral Artery Chronic Total Occlusions SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE chronic total occlusion; cost-benefit analysis; peripheral artery disease ID VASCULAR INTERVENTION; CARE AB OBJECTIVES The aim of this study was to assess actual procedural costs and outcomes comparing wire-catheter and dedicated chronic total occlusion (CTO) device strategies to cross peripheral artery CTOs. BACKGROUND Peripheral artery CTO interventions are frequently performed, but there are limited data on actual procedural costs and outcomes comparing wire-catheter and dedicated CTO devices. METHODS The XLPAD (Excellence in Peripheral Artery Disease Intervention) registry (NCT01904851) was accessed to retrospectively compare cost and 30-day and 12-month outcomes of wire-catheter and crossing device strategies for treatment of infrainguinal peripheral artery CTO. RESULTS Of all 3,234 treated lesions, 42% (n = 1,362) were CTOs in 1,006 unique patients. Wire-catheter approaches were used in 82% of CTOs, whereas dedicated CTO devices were used in 18% (p < 0.0001). CTO crossing device use was associated with significantly higher technical success (74% vs. 65%; p < 0.0001) and mean procedure cost($7,800.09 vs. $4,973.24; p < 0.0001). Because 12-month repeat revascularization (11.3% vs. 17.2%; p = 0.02) and amputation rates (2.8% vs. 8.5%; p = 0.002) in the CTO crossing device arm were lower compared with the wire-catheter group, the net cost for an initial CTO crossing device strategy was $423.80 per procedure. CONCLUSIONS An initial wire-catheter approach to cross a peripheral artery CTO is most frequently adopted. The use of dedicated CTO crossing devices provides significantly higher technical success and lower reintervention and amputation rates, at a net cost of $423.80 per procedure at 12 months. (C) 2016 by the American College of Cardiology Foundation. C1 [Banerjee, Subhash; Jeon-Slaughter, Haekyung; Tsai, Shirling; Mohammad, Atif; Kumbhani, Dharam; Addo, Tayo; Luna, Michael; Brilakis, Emmanouil S.] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Banerjee, Subhash; Jeon-Slaughter, Haekyung; Tsai, Shirling; Brilakis, Emmanouil S.] VA North Texas Hlth Care Syst, 4500 S Lancaster Rd,111a, Dallas, TX 75216 USA. [Foteh, Mazin] Cardiothorac & Vasc Surg, Austin, TX USA. [Abu-Fadel, Mazen] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Gigliotti, Osvaldo S.] Seton Med Ctr, Austin, TX USA. [Cawich, Ian; Rodriguez, Gerardo] Arkansas Heart Hosp, Little Rock, AR USA. [Das, Tony S.] Walnut Hill Med Ctr, Dallas, TX USA. [Prasad, Anand] Univ Texas San Antonio, San Antonio, TX USA. [Armstrong, Ehrin J.] Denver VA Med Ctr, Denver, CO USA. [Shammas, Nicolas W.] Midwest Cardiovasc Res Fdn, Davenport, IA USA. EM subhash.banerjee@utsouthwestern.edu FU Academic Information Systems National Institutes of Health [UL1-RR024982] FX The authors acknowledge the contributions of M. Ishti Ali, MD, to the XLPAD registry. We also acknowledge the support of the University of Texas Southwestern Medical Center in establishing and managing the RedCap database software used in the XLPAD registry (Academic Information Systems National Institutes of Health grant UL1-RR024982). NR 12 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 NOV 14 PY 2016 VL 9 IS 21 BP 2243 EP 2252 DI 10.1016/j.jcin.2016.08.010 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI6PG UT WOS:000392617300013 PM 27832850 ER PT J AU Drain, PK Losina, E Coleman, SM Giddy, J Ross, D Katz, JN Bassett, IV AF Drain, Paul K. Losina, Elena Coleman, Sharon M. Giddy, Janet Ross, Douglas Katz, Jeffrey N. Bassett, Ingrid V. TI Rapid urine lipoarabinomannan assay as a clinic-based screening test for active tuberculosis at HIV diagnosis SO BMC PULMONARY MEDICINE LA English DT Article DE Tuberculosis; HIV/AIDS; Lipoarabinomannan (LAM); Urine; Diagnostic screening; South Africa ID ANTIRETROVIRAL THERAPY; PULMONARY TUBERCULOSIS; CARE; ACCURACY AB Background: World Health Organization (WHO) recommends tuberculosis (TB) screening at HIV diagnosis. We evaluated the inclusion of rapid urine lipoarabinomannan (LAM) testing in TB screening algorithms. Methods: We enrolled ART-naive adults who screened HIV-infected in KwaZulu-Natal, assessed TB-related symptoms (cough, fever, night sweats, weight loss), and obtained sputum specimens for mycobacterial culture. Trained nurses performed clinic-based urine LAM testing using a rapid assay. We used diagnostic accuracy, negative predictive value (NPV), and negative likelihood ratio, stratified by CD4 count, to evaluate screening for culture-positive TB. Results: Among 675 HIV-infected adults with median CD4 of 213/mm(3) (interquartile range 85-360/mm(3)), 123 (18%) had culture-confirmed pulmonary TB. The WHO-recommended algorithm of any TB-related symptom had a sensitivity of 77% [95% confidence interval (CI) 69-84%] and NPV of 89% (95% CI 84-92%) for identifying active pulmonary TB. Including the LAM assay improved sensitivity (83%; 95% CI 75-89%) and NPV (91%; 95% CI 86-94%), while decreasing the negative likelihood ratio (0.45 versus 0.57). Among participants with CD4 < 100/mm(3), including urine LAM testing improved the negative predictive value of symptom based screening from 83% to 87%. All screening algorithms with urine LAM performed better among participants with CD4 < 100/mm(3), compared to those with CD4 >= 100/mm(3). Conclusion: Clinic-based urine LAM screening increased the sensitivity of symptom-based screening by 6% among ART-naive HIV-infected adults in a TB-endemic setting, thereby providing marginal benefit. C1 [Drain, Paul K.] Univ Washington, Dept Global Hlth, 325 Ninth Ave,UW Box 359927, Seattle, WA 98104 USA. [Drain, Paul K.] Univ Washington, Dept Med, Seattle, WA 98105 USA. [Drain, Paul K.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Losina, Elena; Bassett, Ingrid V.] Harvard Med Sch, Med Practice Evaluat Ctr, Boston, MA USA. [Bassett, Ingrid V.] Harvard Med Sch, Div Infect Dis, Boston, MA USA. [Losina, Elena; Bassett, Ingrid V.] Harvard Med Sch, Div Gen Internal Med, Boston, MA USA. [Drain, Paul K.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02115 USA. [Losina, Elena; Katz, Jeffrey N.] Harvard Med Sch, Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA USA. [Coleman, Sharon M.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Giddy, Janet] McCord Hosp, Dept Med, Durban, South Africa. [Ross, Douglas] St Marys Hosp, Dept Med, Durban, South Africa. RP Drain, PK (reprint author), Univ Washington, Dept Global Hlth, 325 Ninth Ave,UW Box 359927, Seattle, WA 98104 USA.; Drain, PK (reprint author), Univ Washington, Dept Med, Seattle, WA 98105 USA.; Drain, PK (reprint author), Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.; Drain, PK (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02115 USA. EM pkdrain@uw.edu FU Harvard Global Health Institute; Fogarty International Clinical Research Scholars and Fellows Program at Vanderbilt University [R24 TW007988]; Infectious Disease Society of America Education & Research Foundation; National Foundation for Infectious Diseases; Massachusetts General Hospital Executive Committee on Research; Program in AIDS Clinical Research Training Grant [T32 AI007433]; National Institute of Mental Health [R01 MH090326]; National Institute of Allergy and Infectious Diseases [K23 AI108293]; Harvard University Center for AIDS Research [P30 AI060354]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [K24 AR057827]; National Center for Research Resources [UL1 RR 025758] FX This work was supported by the Harvard Global Health Institute (PKD); the Fogarty International Clinical Research Scholars and Fellows Program at Vanderbilt University [R24 TW007988] (PKD); the Infectious Disease Society of America Education & Research Foundation and National Foundation for Infectious Diseases (PKD); Massachusetts General Hospital Executive Committee on Research (PKD); the Program in AIDS Clinical Research Training Grant [T32 AI007433] (PKD); the National Institute of Mental Health [R01 MH090326] (IVB); the National Institute of Allergy and Infectious Diseases [K23 AI108293] (PKD); the Harvard University Center for AIDS Research [P30 AI060354] (PKD); the National Institute of Arthritis and Musculoskeletal and Skin Diseases [K24 AR057827] (EL); and the National Center for Research Resources [Harvard Catalyst UL1 RR 025758]. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health or other funding agencies. NR 27 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2466 J9 BMC PULM MED JI BMC Pulm. Med. PD NOV 14 PY 2016 VL 16 AR 147 DI 10.1186/s12890-016-0316-z PG 7 WC Respiratory System SC Respiratory System GA EC3OQ UT WOS:000388035900001 PM 27842535 ER PT J AU Wang, LL Brooks, AN Fan, J Wan, YZ Gambe, R Li, SQ Hergert, S Yin, SY Freeman, SS Levin, JZ Fan, L Seiler, M Buonamici, S Smith, PG Chau, KF Cibulskis, CL Zhang, WD Rassenti, LZ Ghia, EM Kipps, TJ Fernandes, S Bloch, DB Kotliar, D Landau, DA Shukla, SA Aster, JC Reed, R DeLuca, DS Brown, JR Neuberg, D Getz, G Livak, KJ Meyerson, MM Kharchenko, PV Wu, CJ AF Wang, Lili Brooks, Angela N. Fan, Jean Wan, Youzhong Gambe, Rutendo Li, Shuqiang Hergert, Sarah Yin, Shanye Freeman, Samuel S. Levin, Joshua Z. Fan, Lin Seiler, Michael Buonamici, Silvia Smith, Peter G. Chau, Kevin F. Cibulskis, Carrie L. Zhang, Wandi Rassenti, Laura Z. Ghia, Emanuela M. Kipps, Thomas J. Fernandes, Stacey Bloch, Donald B. Kotliar, Dylan Landau, Dan A. Shukla, Sachet A. Aster, Jon C. Reed, Robin DeLuca, David S. Brown, Jennifer R. Neuberg, Donna Getz, Gad Livak, Kenneth J. Meyerson, Matthew M. Kharchenko, Peter V. Wu, Catherine J. TI Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia SO CANCER CELL LA English DT Article ID RNA SEQUENCING METHODS; RECURRENT MUTATIONS; IN-VIVO; CLL; MALIGNANCIES; MECHANISMS; TRANSFORMATION; HEMATOPOIESIS; BRANCHPOINTS; RECOGNITION AB Mutations in SF3B1, which encodes a spliceosome component, are associated with poor outcome in chronic lymphocytic leukemia (CLL), but how these contribute to CLL progression remains poorly understood. We undertook a transcriptomic characterization of primary human CLL cells to identify transcripts and pathways affecied by SF3B1 mutation. Splicing alterations, identified in the analysis of bulk cells, were confirmed in single SF3B1-mutated CLL cells and also found in cell lines ectopically expressing mutant SF3B1. SF3B1 mutation was found to dysregulate multiple cellular functions including DNA damage response, telomere maintenance, and Notch signaling (mediated through KLF8 upregulation, increased TERC and TERT expression, or altered splicing of DVL2 transcript, respectively). SF3B1 mutation leads to diverse changes in CLL-related pathways. C1 [Wang, Lili; Brooks, Angela N.; Wan, Youzhong; Gambe, Rutendo; Hergert, Sarah; Zhang, Wandi; Fernandes, Stacey; Landau, Dan A.; Shukla, Sachet A.; Brown, Jennifer R.; Meyerson, Matthew M.; Wu, Catherine J.] Dana Farber Canc Inst, Dept Med Oncol, Dana 540,44 Binney St, Boston, MA 02115 USA. [Brooks, Angela N.; Freeman, Samuel S.; Levin, Joshua Z.; Fan, Lin; Cibulskis, Carrie L.; DeLuca, David S.; Getz, Gad; Wu, Catherine J.] Broad Inst MIT & Harvard, Cambridge, MA 02141 USA. [Brooks, Angela N.] Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA. [Fan, Jean; Kharchenko, Peter V.] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA. [Neuberg, Donna] Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02115 USA. [Rassenti, Laura Z.; Ghia, Emanuela M.; Kipps, Thomas J.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Li, Shuqiang; Livak, Kenneth J.] Fluidigm Corp, San Francisco, CA 94080 USA. [Aster, Jon C.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Brown, Jennifer R.; Wu, Catherine J.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Bloch, Donald B.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02115 USA. [Wang, Lili; Chau, Kevin F.; Kotliar, Dylan; Landau, Dan A.; Wu, Catherine J.] Harvard Med Sch, Boston, MA 02115 USA. [Yin, Shanye; Reed, Robin] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. [Wan, Youzhong] Jilin Univ, Sch Life Sci, Natl Engn Lab AIDS Vaccine, Changchun, Jilin, Peoples R China. [Seiler, Michael; Buonamici, Silvia; Smith, Peter G.] H3 Biomed, Cambridge, MA 02141 USA. RP Wu, CJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Dana 540,44 Binney St, Boston, MA 02115 USA.; Wu, CJ (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02141 USA.; Wu, CJ (reprint author), Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA.; Wu, CJ (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM cwu@partners.org FU NIH [P01-CA81534]; Lymphoma Research Foundation (LRF); National Science Foundation [DGE1144152]; Leukemia and Lymphoma Society (LLS); Blavatnik Family Foundation; LRF; NHLBI [1R01HL103532-01, 1R01HL116452-01]; NCI [1R01CA155010-01A1, 1U10CA180861-01]; LLS; AACR SU2C Innovative Research Grant FX The authors thank A. D'Andrea, G. Gould, and C. Burge for critical discussions, and J. Wong, G. Harris, and B.Z. Tong for excellent technical support. We thank J. Daley, S. Lazo-Kallanian, K. Cowens, and S. Paula of the DFCI Flow Cytometry facility for their assistance in single-cell sorting. We further thank M. Imielinksi, S. Lee, and K. Slowikowski for assistance with sequence analysis. This work was in part supported by funding from the NIH to the CLL Research Consortium (P01-CA81534). L.W. was supported by the Lymphoma Research Foundation (LRF) postdoctoral fellowship. A.N.B. was a Merck Fellow of the Damon Runyon Cancer Research Foundation (DRG-2138-12). J.F. was supported by the National Science Foundation Graduate Research Fellowship (DGE1144152). Y.W. was supported by a fellowship from the Leukemia and Lymphoma Society (LLS). C.J.W. acknowledges support from the Blavatnik Family Foundation, the LRF, NHLBI (1R01HL103532-01; 1R01HL116452-01) and NCI (1R01CA155010-01A1; 1U10CA180861-01), and is a recipient of an LLS Translational Research Program and Scholar Award and of an AACR SU2C Innovative Research Grant. M.S., S.B., and P.G.S. are employees and shareholders of H3 Biomedicine. C.J.W. is co-founder and scientific advisory board member of Neon Therapeutics, Inc. NR 43 TC 1 Z9 1 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 NOV 14 PY 2016 VL 30 IS 5 BP 750 EP 763 DI 10.1016/j.ccell.2016.10.005 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EC3ZE UT WOS:000388064800014 PM 27818134 ER PT J AU Chou, YY Krupp, A Kaynor, C Gaudin, R Ma, MH Cahir-McFarland, E Kirchhausen, T AF Chou, Yi-ying Krupp, Annabel Kaynor, Campbell Gaudin, Raphael Ma, Minghe Cahir-McFarland, Ellen Kirchhausen, Tom TI Inhibition of JCPyV infection mediated by targeted viral genome editing using CRISPR/Cas9 SO SCIENTIFIC REPORTS LA English DT Article ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; HEPATITIS-B-VIRUS; PERIPHERAL-BLOOD LEUKOCYTES; JC-VIRUS; HUMAN-CELLS; SYSTEM; DNA; POLYOMAVIRUSES; DISEASE; AAV AB Progressive multifocal leukoencephalopathy (PML) is a debilitating disease resulting from infection of oligodendrocytes by the JC polyomavirus (JCPyV). Currently, there is no anti-viral therapeutic available against JCPyV infection. The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPRassociated protein 9 (Cas9) system (CRISPR/Cas9) is a genome editing tool capable of introducing sequence specific breaks in double stranded DNA. Here we show that the CRISPR/Cas9 system can restrict the JCPyV life cycle in cultured cells. We utilized CRISPR/Cas9 to target the noncoding control region and the late gene open reading frame of the JCPyV genome. We found significant inhibition of virus replication and viral protein expression in cells recipient of Cas9 together with JCPyV-specific single-guide RNA delivered prior to or after JCPyV infection. C1 [Chou, Yi-ying; Gaudin, Raphael; Ma, Minghe; Kirchhausen, Tom] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. [Chou, Yi-ying; Gaudin, Raphael; Ma, Minghe; Kirchhausen, Tom] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Krupp, Annabel; Kaynor, Campbell; Cahir-McFarland, Ellen] Biogen, Dept Neuroimmunol, Cambridge, MA 02142 USA. [Kirchhausen, Tom] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Gaudin, Raphael] Inst Viral & Liver Dis, INSERM U1110, F-67000 Strasbourg, France. RP Chou, YY; Kirchhausen, T (reprint author), Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.; Chou, YY; Kirchhausen, T (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Kirchhausen, T (reprint author), Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. EM yi-ying.chou@childrens.harvard.edu; kirchhausen@crystal.harvard.edu FU Biogen; NIH CETR [U19-Al109740] FX We thank Walter J. Atwood for providing the SVG-A cells and we thank Wayne Marasco for collaborating to generate the HuK(i) G10 cell line. This work was supported in part by grants to T.K. from Biogen and NIH CETR U19-Al109740. NR 48 TC 0 Z9 0 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 NOV 14 PY 2016 VL 6 AR 36921 DI 10.1038/srep36921 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB7JD UT WOS:000387562100001 PM 27841295 ER PT J AU Rebbeck, TR Friebel, TM Mitra, N Wan, F Chen, S Andrulis, IL Apostolou, P Arnold, N Arun, BK Barrowdale, D Benitez, J Berger, R Berthet, P Borg, A Buys, SS Caldes, T Carter, J Chiquette, J Claes, KBM Couch, FJ Cybulski, C Daly, MB de la Hoya, M Diez, O Domchek, SM Nathanson, KL Durda, K Ellis, S Evans, DG Foretova, L Friedman, E Frost, D Ganz, PA Garber, J Glendon, G Godwin, AK Greene, MH Gronwald, J Hahnen, E Hallberg, E Hamann, U Hansen, TVO Imyanitov, EN Isaacs, C Jakubowska, A Janavicius, R Jaworska-Bieniek, K John, EM Karlan, BY Kaufman, B Kwong, A Laitman, Y Lasset, C Lazaro, C Lester, J Loman, N Lubinski, J Manoukian, S Mitchell, G Montagna, M Neuhausen, SL Nevanlinna, H Niederacher, D Nussbaum, RL Offit, K Olah, E Olopade, OI Park, SK Piedmonte, M Radice, P Rappaport-Fuerhauser, C Rookus, MA Seynaeve, C Simard, J Singer, CF Soucy, P Southey, M Stoppa-Lyonnet, D Sukiennicki, G Szabo, CI Tancredi, M Teixeira, MR Teo, SH Terry, MB Thomassen, M Tihomirova, L Tischkowitz, M Toland, AE Toloczko-Grabarek, A Tung, N van Rensburg, EJ Villano, D Wang-Gohrke, S Wappenschmidt, B Weitzel, JN Zidan, J Zorn, KK McGuffog, L Easton, D Chenevix-Trench, G Antoniou, AC Ramus, SJ AF Rebbeck, Timothy R. Friebel, Tara M. Mitra, Nandita Wan, Fei Chen, Stephanie Andrulis, Irene L. Apostolou, Paraskevi Arnold, Norbert Arun, Banu K. Barrowdale, Daniel Benitez, Javier Berger, Raanan Berthet, Pascaline Borg, Ake Buys, Saundra S. Caldes, Trinidad Carter, Jonathan Chiquette, Jocelyne Claes, Kathleen B. M. Couch, Fergus J. Cybulski, Cezary Daly, Mary B. de la Hoya, Miguel Diez, Orland Domchek, Susan M. Nathanson, Katherine L. Durda, Katarzyna Ellis, Steve Evans, D. Gareth Foretova, Lenka Friedman, Eitan Frost, Debra Ganz, Patricia A. Garber, Judy Glendon, Gord Godwin, Andrew K. Greene, Mark H. Gronwald, Jacek Hahnen, Eric Hallberg, Emily Hamann, Ute Hansen, Thomas V. O. Imyanitov, Evgeny N. Isaacs, Claudine Jakubowska, Anna Janavicius, Ramunas Jaworska-Bieniek, Katarzyna John, Esther M. Karlan, Beth Y. Kaufman, Bella Kwong, Ava Laitman, Yael Lasset, Christine Lazaro, Conxi Lester, Jenny Loman, Niklas Lubinski, Jan Manoukian, Siranoush Mitchell, Gillian Montagna, Marco Neuhausen, Susan L. Nevanlinna, Heli Niederacher, Dieter Nussbaum, Robert L. Offit, Kenneth Olah, Edith Olopade, Olufunmilayo I. Park, Sue Kyung Piedmonte, Marion Radice, Paolo Rappaport-Fuerhauser, Christine Rookus, Matti A. Seynaeve, Caroline Simard, Jacques Singer, Christian F. Soucy, Penny Southey, Melissa Stoppa-Lyonnet, Dominique Sukiennicki, Grzegorz Szabo, Csilla I. Tancredi, Mariella Teixeira, Manuel R. Teo, Soo-Hwang Terry, Mary Beth Thomassen, Mads Tihomirova, Laima Tischkowitz, Marc Toland, Amanda Ewart Toloczko-Grabarek, Aleksandra Tung, Nadine van Rensburg, Elizabeth J. Villano, Danylo Wang-Gohrke, Shan Wappenschmidt, Barbara Weitzel, Jeffrey N. Zidan, Jamal Zorn, Kristin K. McGuffog, Lesley Easton, Douglas Chenevix-Trench, Georgia Antoniou, Antonis C. Ramus, Susan J. CA EMBRACE HEBON KConFab Investigators TI Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women SO BREAST CANCER RESEARCH LA English DT Article DE Hereditary breast and ovarian cancer; Transheterozygosity; BRCA1; BRCA2 ID UNKNOWN CLINICAL-SIGNIFICANCE; CANCER SUSCEPTIBILITY GENE; SPORADIC BREAST-CANCER; DNA-SEQUENCE VARIANTS; WILD-TYPE CHROMOSOME; OVARIAN-CANCER; FANCONI-ANEMIA; DOUBLE HETEROZYGOSITY; GERMLINE MUTATIONS; HETEROGENIC LOSS AB Background: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2. C1 [Rebbeck, Timothy R.; Friebel, Tara M.; Garber, Judy] Dana Farber Canc Inst, Dept Epidemiol, 1101 Dana Bldg,450 Brookline Ave, Boston, MA 02115 USA. [Rebbeck, Timothy R.; Friebel, Tara M.; Garber, Judy] Harvard TH Chan Sch Publ Hlth, 1101 Dana Bldg,450 Brookline Ave, Boston, MA USA. [Mitra, Nandita] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Wan, Fei] Grp Hlth, Biostat Unit, Res Inst, Seattle, WA USA. [Chen, Stephanie; Ramus, Susan J.] Univ So Calif, Keck Sch Med, USC Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Barrowdale, Daniel; Chenevix-Trench, Georgia] QIMR Berghofer Inst Med Res, Dept Genet & Computat Biol, Brisbane, Qld, Australia. [McGuffog, Lesley; Easton, Douglas; Antoniou, Antonis C.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet & Lab Med, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Pathobiol, Toronto, ON, Canada. [Apostolou, Paraskevi] Natl Ctr Sci Res Demokritos, INRASTES Inst Nucl & Radiol Sci & Technol, Mol Diagnost Lab, Patriarchou Gregoriou & Neapoleos Str Aghia Paras, Athens, Greece. [Arnold, Norbert] Univ Kiel, Univ Hosp Schleswig Holstein, Dept Obstet & Gynaecol, Campus Kiel, Kiel, Germany. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, 1515 Pressler St,CBP 5, Houston, TX USA. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Clin Canc Genet Program, 1515 Pressler St,CBP 5, Houston, TX USA. [Benitez, Javier] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain. [Benitez, Javier] Biomed Network Rare Dis CIBERER, Madrid, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid, Spain. [Berger, Raanan; Kaufman, Bella] Chaim Sheba Med Ctr, Inst Oncol, IL-52621 Ramat Gan 52621, Israel. [Berthet, Pascaline] Ctr Francois Baclesse, 3 Ave General Harris, Caen, France. [Borg, Ake] Lund Univ, Dept Oncol Clin Sci, Lund, Sweden. [Borg, Ake] Skane Univ Hosp, Lund, Sweden. [Buys, Saundra S.] Huntsman Canc Inst, Dept Med, 2000 Circle Hope, Salt Lake City, UT 84112 USA. [Caldes, Trinidad; de la Hoya, Miguel] Hosp Clin San Carlos, IdISSC El Inst Invest Sanit Hosp Clin San Carlos, Mol Oncol Lab, Martin Lagos S N, Madrid, Spain. [Carter, Jonathan] Univ Sydney, Ctr Canc, Royal Prince Alfred Hosp, Gynaecol Oncol, Sydney, NSW, Australia. [Chiquette, Jocelyne] Hop St Sacrement, Ctr Malad Sein Deschenes Fabia, Unite Rech SantePopulat, 1050 Chemin Sainte Foy, Quebec City, PQ, Canada. [Claes, Kathleen B. M.] Univ Ghent, Ctr Med Genet, Pintelaan 185, B-9000 Ghent, Belgium. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, 200 First St SW, Rochester, MN USA. [Cybulski, Cezary; Durda, Katarzyna; Gronwald, Jacek; Jakubowska, Anna; Jaworska-Bieniek, Katarzyna; Lubinski, Jan; Sukiennicki, Grzegorz; Toloczko-Grabarek, Aleksandra] Pomeranian Med Univ, Dept Genet & Pathol, Polabska 4, Szczecin, Poland. [Daly, Mary B.] Fox Chase Canc Ctr, Div Populat Sci, 333 Cottman Ave, Philadelphia, PA 19111 USA. [Diez, Orland] Vall dHebron Univ Hosp, Vall dHebron Inst Oncol VHIO, Oncogenet Grp, Clinical & Mol Genet Area, Barcelona 11929, Spain. [Domchek, Susan M.; Nathanson, Katherine L.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Dept Med, Philadelphia, PA USA. [Ellis, Steve; Frost, Debra; EMBRACE] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Ctr Canc Genet Epidemiol, Worts Causeway, Cambridge, England. [Evans, D. Gareth] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Inst Human Dev, Genom Med, Manchester, Lancs, England. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Zluty Kopec 7, Brno 65653, Czech Republic. [Friedman, Eitan; Laitman, Yael] Chaim Sheba Med Ctr, Inst Human Genet, Susanne Levy Gertner Oncogenet Unit, IL-52621 Ramat Gan, Israel. [Friedman, Eitan; Laitman, Yael] Tel Aviv Univ, Sackler Fac Med, IL-69978 Ramat Aviv, Israel. [Ganz, Patricia A.] Univ Calif Los Angeles, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Sch Med, 650 Charles Young Dr South,Room A2-125 HS, Los Angeles, CA 90095 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Sch Publ Hlth, 650 Charles Young Dr South,Room A2-125 HS, Los Angeles, CA 90095 USA. [Glendon, Gord] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Ontario Canc Genet Network, Toronto, ON M5G 1X5, Canada. [Godwin, Andrew K.] Dept Pathol & Lab Med, 3901 Rainbow Blvd,4019 Wahl Hall EastMS 3040, Kansas City, KS USA. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Greene, Mark H.] NIH, NCI, DCEG, Clin Genet Branch, 9609 Med Ctr Dr,Room 6E-454, Bethesda, MD USA. [Hahnen, Eric; Wappenschmidt, Barbara] Univ Cologne, Ctr Hereditary Breast & Ovarian Canc CIO, Cologne, Germany. [Hahnen, Eric; Wappenschmidt, Barbara] Univ Cologne, Fac Med, Ctr Mol Med Cologne CMMC, Cologne, Germany. [Hahnen, Eric; Wappenschmidt, Barbara] Univ Hosp Cologne, Cologne, Germany. [Hallberg, Emily] Mayo Clin, Dept Hlth Sci Res, 13400 E Scottsdale Blvd, Scottsdale, AZ USA. [Hamann, Ute] German Canc Res Ctr, Mol Genet Breast Canc, Neuenheimer Feld 580, D-69120 Heidelberg, Germany. [Hansen, Thomas V. O.] Univ Copenhagen Hosp, Rigshosp, Ctr Genom Med, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Hereditary Breast & Ovarian Canc Res Grp Netherla, Amsterdam, Netherlands. [HEBON] Netherlands Canc Inst, Amsterdam, Netherlands. [Imyanitov, Evgeny N.] NN Petrov Inst Oncol, St Petersburg 197758, Russia. [Isaacs, Claudine] Georgetown Univ, Lombardi Comprehens Canc Ctr, 3800 Reservoir Rd NW, Washington, DC USA. [Janavicius, Ramunas] Vilnius Univ Hosp Santariskiu Clin, Hematol Oncol & Transfus Med Ctr, Dept Mol & Regenerat Med, Santariskiu St, Vilnius, Lithuania. [Janavicius, Ramunas] State Res Inst Ctr Innovat Med, Zygymantu St 9, Vilnius, Lithuania. [John, Esther M.] Canc Prevent Inst Calif, Dept Epidemiol, 2201 Walnut Ave,Suite 300, Fremont, CA 94538 USA. [Karlan, Beth Y.; Lester, Jenny] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, 8700 Beverly Blvd,Suite 290W, Los Angeles, CA USA. [KConFab Investigators] Peter MacCallum Canc Ctr, Kathleen Cuningham Consortium Res Familial Breast, Melbourne, Vic, Australia. [Kwong, Ava] Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China. [Kwong, Ava] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong, Hong Kong, Peoples R China. [Kwong, Ava] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Lasset, Christine] Ctr Leon Berard, Unite Prevent & Epidemiol Genet, 28 Rue Laennec, Lyon, France. [Lazaro, Conxi] IDIBELL Bellvitge Biomed Res Inst, Hereditary Canc Program, Catalan Inst Oncol, Mol Diagnost Unit,LHosp Barcelona, Gran Via Hosp 199-203, Barcelona 08908, Spain. [Loman, Niklas] Univ Lund Hosp, Dept Oncol, Lund, Sweden. [Manoukian, Siranoush] Fdn IRCCS, Dept Prevent & Predict Med, Ist Nazl Tumori, Unit Med Genet, Via Giacomo Venezian 1, I-20133 Milan, Italy. [Mitchell, Gillian] Peter MacCallum Canc Ctr, Familial Canc Ctr, Locked Bag 1,ABeckett St, Melbourne, Vic 8006, Australia. [Mitchell, Gillian] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia. [Montagna, Marco] IRCCS, Veneto Inst Oncol IOC, Immunol & Mol Oncol Unit, Via Gattamelata 64, Padua, Italy. [Neuhausen, Susan L.] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA. [Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynecol, POB 700,Haartmaninkatu 8, Helsinki 00029, Finland. [Nevanlinna, Heli] HUS, Helsinki Univ Hosp, Biomed Helsinki, POB 700,Haartmaninkatu 8, Helsinki 00029, Finland. [Niederacher, Dieter] Univ Dusseldorf, Univ Hosp Dusseldorf, Dept Obstet & Gynaecol, Dusseldorf, Germany. [Nussbaum, Robert L.] 62513 Parnassus Ave,HSE 901E, San Francisco, CA 94143 USA. [Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Dept Med Canc Biol & Genet, Clin Genet Res Lab, 1275 York Ave, New York, NY 10044 USA. [Olah, Edith] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary. [Olopade, Olufunmilayo I.] 5841 South Maryland Ave, Chicago, IL USA. [Park, Sue Kyung] Seoul Natl Univ, Coll Med, Dept Prevent Med, 103 Daehak Ro, Seoul 110799, South Korea. [Piedmonte, Marion] Roswell Pk Canc Inst, NRG Oncol Stat & Data Management Ctr, Elm St & Carlton St, Buffalo, NY 14263 USA. [Radice, Paolo] Fdn IRCCS, Dept Prevent & Predicted Med, Ist Nazl Tumori, Unit Mol Bases Genet Risk & Genet Testing, Amaedeolab Via GA Amadeo 42, I-20133 Milan, Italy. [Rappaport-Fuerhauser, Christine] Med Univ Vienna, Dept OB GYN, Waehringer Guertel 18-20, A-1090 Vienna, Austria. [Rookus, Matti A.] Netherlands Canc Inst, Dept Epidemiol, POB 902031000, Amsterdam, Netherlands. [Seynaeve, Caroline] Erasmus MC, Inst Canc, Family Canc Clin, Dept Med Oncol, POB 52013008, Rotterdam, Netherlands. [Simard, Jacques; Soucy, Penny] Univ Quebec, Res Ctr, Ctr Hosp, Genom Ctr, 2705 Laurier Blvd, Quebec City, PQ, Canada. [Simard, Jacques; Soucy, Penny] Univ Laval, 2705 Laurier Blvd, Quebec City, PQ, Canada. [Singer, Christian F.] Med Univ Vienna, Dept OB GYN, Waehringer Guertel 18-20, A-1090 Vienna, Austria. [Singer, Christian F.] Med Univ Vienna, Ctr Comprehens Canc, Waehringer Guertel 18-20, A-1090 Vienna, Austria. [Southey, Melissa] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic, Australia. [Stoppa-Lyonnet, Dominique] Inst Curie, Serv Genet Oncol, 26 Rue dUlm, Paris 05, France. [Szabo, Csilla I.] Natl Inst Hlth, NHGRI, Bldg 50,Room 5312,50 South Dr,MSC 004, Bethesda, MD 20892 USA. [Tancredi, Mariella] Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy. [Tancredi, Mariella] Univ Hosp Pisa, Pisa, Italy. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, Rua Dr Antonio Bernardino Almeida, P-4200072 Oporto, Portugal. [Teo, Soo-Hwang] Sime Darby Med Ctr, Canc Res Initiat Fdn, 1 Jalan SS12-1A, Subang Jaya 47500, Malaysia. [Teo, Soo-Hwang] Univ Malaya, Canc Res Inst, Kuala Lumpur 50603, Malaysia. [Terry, Mary Beth] Columbia Univ, Dept Epidemiol, New York, NY USA. [Thomassen, Mads] Odense Univ Hosp, Dept Clin Genet, Sonder Blvd 29, Odense C, Denmark. [Tihomirova, Laima] Latvian Biomed Res & Study Ctr, Ratsupites Str 1, Riga, Latvia. [Tischkowitz, Marc] McGill Univ, Dept Human Genet & Oncol, Program Canc Genet, Montreal, PQ, Canada. [Toland, Amanda Ewart] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med & Mol Virol, Div Human Canc Genet, 998 Biomed Res Tower, Columbus, OH USA. [Toland, Amanda Ewart] Ohio State Univ, Ctr Comprehens Canc, Dept Immunol & Med Genet, Div Human Canc Genet, 998 Biomed Res Tower, Columbus, OH USA. [Tung, Nadine] Beth Israel Deaconess Med Ctr, Dept Med Oncol, 330 Brookline Ave, Boston, MA 02215 USA. [van Rensburg, Elizabeth J.] Univ Pretoria, Dept Genet, Canc Genet Lab, Private Bag X323, ZA-0007 Arcadia, South Africa. [Villano, Danylo] Mem Sloan Kettering Canc Ctr, Clin Canc Genet Lab, New York, NY USA. [Wang-Gohrke, Shan] Univ Hosp Ulm, Dept Obstet & Gynaecol, Ulm, Germany. [Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Clin Canc Genet, 1500 East Duarte Rd, Duarte, CA 91010 USA. [Zidan, Jamal] Inst Oncol, Rivka Ziv Med Ctr, IL-13000 Safed, Israel. [Zidan, Jamal] Bar Ilan Univ, Fac Med, Safed, Israel. [Zorn, Kristin K.] 934301 West Markham St,Slot 793, Little Rock, AR 72205 USA. [Ramus, Susan J.] Univ New South Wales, Sch Womens & Childrens Hlth, 384 Victoria St, Darlinghurst, NSW 2010, Australia. [Ramus, Susan J.] Garvan Inst Med Res, Kinghorn Canc Ctr, 384 Victoria St, Darlinghurst, NSW 2010, Australia. RP Rebbeck, TR (reprint author), Dana Farber Canc Inst, Dept Epidemiol, 1101 Dana Bldg,450 Brookline Ave, Boston, MA 02115 USA.; Rebbeck, TR (reprint author), Harvard TH Chan Sch Publ Hlth, 1101 Dana Bldg,450 Brookline Ave, Boston, MA USA. EM Timothy_Rebbeck@dfci.harvard.edu RI Gronwald, Jacek/A-4576-2017; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Arnold, Norbert/E-3012-2010; manoukian, siranoush/E-7132-2017; montagna, marco/E-2225-2012 OI Gronwald, Jacek/0000-0002-3643-2871; Arnold, Norbert/0000-0003-4523-8808; manoukian, siranoush/0000-0002-6034-7562; montagna, marco/0000-0002-4929-2150 FU National Cancer Institute [UM1 CA164920, RC4CA153828]; Lithuania (BFBOCC-LT): Research Council of Lithuania grant [SEN-18/2015]; Breast Cancer Research Foundation; Cancer Association of South Africa (CANSA); Morris and Horowitz Families Endowed Professorship; Spanish Association against Cancer [AECC08, RTICC 06/0020/1060, FISPI08/1120]; Mutua Madrilena Foundation (FMMA); Office of the Director, National Institutes of Health; Italian citizens of the Fondazione IRCCS Istituto Nazionale Tumori; Cancer Research UK [C12292/A20861, C1287/A11990C5047/A8385C1287/A10118 C1287/A 10710 C12292/A11174 C1281/A12014 C5047/A8384 C5047/A15007 C5047/A10692 C8197/A16565]; European Union (European Social Fund - ESF); Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research Technology [SYN11_10_19 NBCA]; DKFZ; NIHR; University of Kansas Cancer Center [P30 CA168524]; Kansas Bioscience Authority Eminent Scholar Program; Chancellors Distinguished Chair in Biomedical Sciences Professorship; German Cancer Aid [110837]; Center for Molecular Medicine Cologne (CMMC); Ligue Nationale Contre le Cancer; Association "Le cancer du sein, parlons-en!" Award; Canadian Institutes of Health Research; French National Institute of Cancer (INCa); Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant) [P30-CA051008]; Fisher Center for Familial Cancer Research; Swing Fore the Cure; ISCIII (Spain) [RD12/0036/0006, 15/00059]; European Regional Development FEDER funds; Helsinki University Hospital Research Fund; Academy of Finland [266528]; Finnish Cancer Society; Sigrid Juselius Foundation; Dutch Cancer Society [NKI1998-1854, NKI2004-3088, NKI2007-3756]; Netherlands Organization of Scientific Research grant [NWO 91109024]; Pink Ribbon grant [110005]; BBMRI grant [NWO 184.021.007/CP46]; Hong Kong Hereditary Breast Cancer Family Registry; Dr. Ellen Li Charitable Foundation, Hong Kong; Hungarian Research Grants [KTIA-OTKA CK-80745, OTKA K-112228]; Norwegian EEA Financial Mechanism [Hu0115/NA/2008-3/OP-9]; Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia [ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290, 2014SGR364]; Canadian Breast Cancer Research Alliance-grant [019511]; Ministry of Economic Development, Innovation and Export Trade - grant [PSR-SIIRI-701]; Ministero della Salute and "5x1000" Istituto Oncologico Veneto grant; Liga Portuguesa Contra o Cancro; National Breast Cancer Foundation; Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia; NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201, CA125183, R01 CA142996, 1U01CA161032]; NIH [CA116167, CA128978, CA176785]; MH CZ - DRO (MMCI) [00209805]; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; Charles University in Prague project [UNCE204024]; Robert and Kate Niehaus Clinical Cancer Genetics Initiative; Andrew Sabin Research Fund; Intramural Research Program of the US National Cancer Institute, NIH; Westat, Inc, Rockville, MD [NO2-CP-11019-50, N02-CP-65504]; Russian Federation for Basic Research [14-04-93959, 15-04-01744]; NRG Oncology Operations grant [U10 CA180868]; NRG SDMC grant [U10 CA180822]; Gynecologic Oncology Group (GOG) Administrative Office; GOG Tissue Bank [CA 27469]; GOG Statistical and Data Center [CA 37517]; Intramural Research Program, NCI; Ohio State University Comprehensive Cancer Center; ITT (Istituto Toscano Tumori) grants; Ministry of Science, Technology and Innovation, Ministry of Higher Education [UM.C/HlR/MOHE/06)]; Cancer Research Initiatives Foundation; Israel cancer association; funding for the Israeli Inherited breast cancer consortium; Swedish Cancer Society; Ralph and Marion Falk Medical Research Trust; Entertainment Industry Fund National Women's Cancer Research Alliance; Jonsson Comprehensive Cancer Center Foundation; UCSF Cancer Risk Program; Helen Diller Family Comprehensive Cancer Center; CRUK; National Institutes of Health (NIH) [R01-CA102776, R01-CA083855]; Susan G. Komen Foundation for the cure; Basser Research Center for BRCA; Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program; Hackers for Hope Pittsburgh; Victorian Cancer Agency; Cancer Australia; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; National Center for Advancing Translational Sciences (NCATS) [UL1TR000124]; European Community [223175]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Komen Foundation for the Cure; Ovarian Cancer Research Fund; [SAF2010-20493]; [5U01CA113916]; [R01CA140323]; [PBZ_KBN_122/P05/2004] FX This work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR.; BFBOCC is partly supported by: Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015; BIDMC is supported by the Breast Cancer Research Foundation; BRCA gene mutations and breast cancer in South African women (BMBSA) was supported by grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg; SLN was partially supported by the Morris and Horowitz Families Endowed Professorship.; This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrilena Foundation (FMMA) and SAF2010-20493; City of Hope Clinical Cancer Genetics Community Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health; Funds from Italian citizens who allocated the 5x1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects `5x1000') to SM.; The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861, C12292/A11174. ACA is a Cancer Research UK Senior Cancer Research Fellow. GCT is an NHMRC Senior Principal Research Fellow.; This research has been co-financed by the European Union (European Social Fund - ESF) and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund.; The DKFZ study was supported by the DKFZ.; EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust; The authors acknowledge support from The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship.; The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 110837), Rita K. Schmutzler) and by the Center for Molecular Medicine Cologne (CMMC); The study was supported by the Ligue Nationale Contre le Cancer; the Association "Le cancer du sein, parlons-en!" Award; the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and the French National Institute of Cancer (INCa).; CI received support from the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Familial Cancer Research, and Swing Fore the Cure.; Was supported by a grant RD12/0036/0006 and 15/00059 from ISCIII (Spain), partially supported by European Regional Development FEDER funds; The HEBCS was financially supported by the Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation.; The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grant 110005 and the BBMRI grant NWO 184.021.007/CP46. HEBON thanks the registration teams of the Comprehensive Cancer Centre Netherlands and Comprehensive Centre South (together the Netherlands Cancer Registry) and PALGA (Dutch Pathology Registry) for part of the data collection.; HRBCP is supported by The Hong Kong Hereditary Breast Cancer Family Registry and the Dr. Ellen Li Charitable Foundation, Hong Kong; Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grants KTIA-OTKA CK-80745, OTKA K-112228 and the Norwegian EEA Financial Mechanism Hu0115/NA/2008-3/OP-9; ICO: Contract grant sponsor: Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract grant numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290 and 2014SGR364.; The IHCC was supported by Grant PBZ_KBN_122/P05/2004; This work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program, the Canadian Breast Cancer Research Alliance-grant #019511 and the Ministry of Economic Development, Innovation and Export Trade - grant # PSR-SIIRI-701.; IOCHBOCS is supported by Ministero della Salute and "5x1000" Istituto Oncologico Veneto grant.; This study was in part supported by Liga Portuguesa Contra o Cancro.; kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia;; MAYO is supported by NIH grants CA116167, CA128978 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, and a generous gift from the David F. and Margaret T. Grohne Family Foundation.; MODSQUAD was supported by MH CZ - DRO (MMCI, 00209805) and by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) to LF, and by Charles University in Prague project UNCE204024 (MZ).; MSKCC is supported by grants from the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, and the Andrew Sabin Research Fund.; The research of Drs. MH Greene and PL Mai was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD. For CIMBA PRS paper: The research of Drs. MH Greene and JT Loud was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD.; This work has been supported by the Russian Federation for Basic Research (grants 14-04-93959 and 15-04-01744).; This study was supported by NRG Oncology Operations grant number U10 CA180868 as well as NRG SDMC grant U10 CA180822, Gynecologic Oncology Group (GOG) Administrative Office and the GOG Tissue Bank (CA 27469) and the GOG Statistical and Data Center (CA 37517). Drs. Greene, Mai and Savage were supported by funding from the Intramural Research Program, NCI.; OSUCCG is supported by the Ohio State University Comprehensive Cancer Center.; This work was supported by the ITT (Istituto Toscano Tumori) grants 2011-2013.; Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; This project was partially funded through a grant by the Israel cancer association and the funding for the Israeli Inherited breast cancer consortium; SWE-BRCA collaborators are supported by the Swedish Cancer Society; UCHICAGO is supported by NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance and the Breast Cancer research Foundation. OIO is an ACS Clinical Research Professor.; Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation; UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center; UKFOCR was supported by a project grant from CRUK to Paul Pharoah.; National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA; Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program; Hackers for Hope Pittsburgh; Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation; Dr Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124; Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME- ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund NR 39 TC 1 Z9 1 U1 10 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD NOV 11 PY 2016 VL 18 AR 112 DI 10.1186/s13058-016-0768-3 PG 19 WC Oncology SC Oncology GA EG2UM UT WOS:000390899600001 PM 27836010 ER PT J AU Singh, JA AF Singh, Jasvinder A. TI Gout: will the "King of Diseases" be the first rheumatic disease to be cured? SO BMC MEDICINE LA English DT Editorial Material DE Gout; Urate-lowering therapy; Serum urate; Lesinurad; Allopurinol ID US GENERAL-POPULATION; URIC-ACID CRYSTALS; AMERICAN-COLLEGE; SERUM URATE; ALLOPURINOL; HYPERURICEMIA; PREVALENCE; MANAGEMENT; ARTHRITIS; THERAPY AB Gout is the most common inflammatory arthritis in adults in the Western world. Characterized by hyperuricemia and the effects of acute and chronic inflammation in joints and bursa, gout leads to an agonizing, chronically painful arthritis. Arthritis can also be accompanied by urate nephropathy and subcutaneous urate deposits (tophi). Exciting new developments in the last decade have brought back the focus on this interesting, crystal-induced chronic inflammatory condition. New insights include the role of NALP3 inflammasome-induced inflammation in acute gout, the characterization of diagnostic signs on ultrasound and dual-energy computed tomography imaging modalities, the recognition of target serum urate less than 6 mg/day as the goal for urate-lowering therapies, and evidence-based treatment guidelines. A better understanding of disease mechanisms has enabled drug discovery - three new urate-lowering drugs have been approved in the last decade, with several more in the pipeline. We now recognize the important role that environment and genetics play in the causation of gout. A focus on the cardiac, renal, and metabolic comorbidities of gout will help translational research and discovery over the next decade. C1 [Singh, Jasvinder A.] Birmingham VA Med Ctr, Birmingham, AL 35233 USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Sch Med, Dept Med, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Sch Publ Hlth, Div Epidemiol, Birmingham, AL 35294 USA. RP Singh, JA (reprint author), Birmingham VA Med Ctr, Birmingham, AL 35233 USA.; Singh, JA (reprint author), Univ Alabama Birmingham, Sch Med, Dept Med, Birmingham, AL 35294 USA.; Singh, JA (reprint author), Univ Alabama Birmingham, Sch Publ Hlth, Div Epidemiol, Birmingham, AL 35294 USA. EM jasvinder.md@gmail.com NR 42 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 1741-7015 J9 BMC MED JI BMC Med. PD NOV 11 PY 2016 VL 14 AR 180 DI 10.1186/s12916-016-0732-1 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA EB9QH UT WOS:000387729600001 PM 27832792 ER PT J AU Bischoff, J Casanovas, G Wylie-Sears, J Kim, DH Bartko, PE Guerrero, JL Dal-Bianco, JP Beaudoin, J Garcia, ML Sullivan, SM Seybolt, MM Morris, BA Keegan, J Irvin, WS Aikawa, E Levine, RA AF Bischoff, Joyce Casanovas, Guillem Wylie-Sears, Jill Kim, Dae-Hee Bartko, Philipp E. Guerrero, J. Luis Dal-Bianco, Jacob P. Beaudoin, Jonathan Garcia, Michael L. Sullivan, Suzanne M. Seybolt, Margo M. Morris, Brittan A. Keegan, Joshua Irvin, Whitney S. Aikawa, Elena Levine, Robert A. TI CD45 Expression in Mitral Valve Endothelial Cells After Myocardial Infarction SO CIRCULATION RESEARCH LA English DT Article DE CD45 antigen; endothelial cell; endothelial cell differentiation; flow cytometry; mitral valve; myocardial infarction ID GROWTH-FACTOR-BETA; MESENCHYMAL TRANSITION; EXTRACELLULAR-MATRIX; VENTRICULAR VOLUME; INTERSTITIAL-CELLS; PROGENITOR CELLS; HEART-FAILURE; TGF-BETA; DISEASE; REGURGITATION AB Rationale: Ischemic mitral regurgitation, a complication after myocardial infarction (MI), induces adaptive mitral valve (MV) responses that may be initially beneficial but eventually lead to leaflet fibrosis and MV dysfunction. We sought to examine the MV endothelial response and its potential contribution to ischemic mitral regurgitation. Objective: Endothelial, interstitial, and hematopoietic cells in MVs from post-MI sheep were quantified. MV endothelial CD45, found post MI, was analyzed in vitro. Methods and Results: Ovine MVs, harvested 6 months after inferior MI, showed CD45, a protein tyrosine phosphatase, colocalized with von Willebrand factor, an endothelial marker. Flow cytometry of MV cells revealed significant increases in CD45+ endothelial cells (VE-cadherin(+)/CD45(+)/alpha-smooth muscle actin [SMA](+) and VE-cadherin(+)/CD45(+)/alpha SMA-cells) and possible fibrocytes (VE-cadherin(-)/CD45(+)/alpha SMA(+)) in inferior MI compared with sham-operated and normal sheep. CD45+ cells correlated with MV fibrosis and mitral regurgitation severity. VE-cadherin+/CD45+/alpha SMA+ cells suggested that CD45 may be linked to endothelial-to-mesenchymal transition (EndMT). MV endothelial cells treated with transforming growth factor-beta 1 to induce EndMT expressed CD45 and fibrosis markers collagen 1 and 3 and transforming growth factor-beta 1 to 3, not observed in transforming growth factor-beta 1-treated arterial endothelial cells. A CD45 protein tyrosine phosphatase inhibitor blocked induction of EndMT and fibrosis markers and inhibited EndMT-associated migration of MV endothelial cells. Conclusions: MV endothelial cells express CD45, both in vivo post MI and in vitro in response to transforming growth factor-beta 1. A CD45 phosphatase inhibitor blocked hallmarks of EndMT in MV endothelial cells. These results point to a novel, functional requirement for CD45 phosphatase activity in EndMT. The contribution of CD45(+) endothelial cells to MV adaptation and fibrosis post MI warrants investigation. C1 [Bischoff, Joyce; Casanovas, Guillem; Wylie-Sears, Jill] Harvard Med Sch, Boston Childrens Hosp, Vasc Biol Program, Boston, MA USA. [Bischoff, Joyce; Casanovas, Guillem; Wylie-Sears, Jill] Harvard Med Sch, Boston Childrens Hosp, Dept Surg, Boston, MA USA. [Kim, Dae-Hee; Bartko, Philipp E.; Guerrero, J. Luis; Dal-Bianco, Jacob P.; Beaudoin, Jonathan; Garcia, Michael L.; Sullivan, Suzanne M.; Seybolt, Margo M.; Morris, Brittan A.; Levine, Robert A.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA USA. [Kim, Dae-Hee] Univ Ulsan, Coll Med, Asan Med Ctr, Div Cardiol, Seoul, South Korea. [Keegan, Joshua; Irvin, Whitney S.; Aikawa, Elena] Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc Med, Ctr Excellence Vasc Biol, Boston, MA USA. RP Bischoff, J (reprint author), Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA. EM joyce.bischoff@childrens.harvard.edu FU NHLBI of the National Institutes of Health [R01HL109506-01A1]; Fondation Leducq Transatlantic Network [07CVD04] FX Research reported in this article was supported by the NHLBI of the National Institutes of Health under award number R01HL109506-01A1 to E. Aikawa, J. Bischoff, and R.A. Levine. The study was also supported initially by the Fondation Leducq Transatlantic Network grant number 07CVD04 (J. Bischoff, E. Aikawa, and R.A. Levine). NR 49 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 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD NOV 11 PY 2016 VL 119 IS 11 BP 1215 EP + DI 10.1161/CIRCRESAHA.116.309598 PG 19 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA EC4NN UT WOS:000388108900016 PM 27750208 ER PT J AU Pugh, MJ Van Cott, AC Amuan, M Baca, C Rutecki, P Zack, MM Kobau, R AF Pugh, Mary Jo Van Cott, Anne C. Amuan, Megan Baca, Christine Rutecki, Paul Zack, Matthew M. Kobau, Rosemarie TI Epilepsy Among Iraq and Afghanistan War Veterans - United States, 2002-2015 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Editorial Material ID MORTALITY; PEOPLE C1 [Pugh, Mary Jo] South Texas Vet Hlth Care Syst, US Dept Vet Affairs, Epilepsy Ctr Excellence, San Antonio, TX 78229 USA. [Pugh, Mary Jo] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Van Cott, Anne C.] VA Pittsburgh Hlth Care Syst, US Dept Vet Affairs, Pittsburgh, PA USA. [Van Cott, Anne C.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Amuan, Megan] Edith Nourse Rogers Mem Vet Hosp, Bedford, MA USA. [Baca, Christine] Univ Colorado, Sch Med, Aurora, CO USA. [Rutecki, Paul] Univ Wisconsin, US Dept Vet Affairs, Epilepsy Ctr Excellence, Middleton Mem Vet Hosp,Dept Neurol, Madison, WI 53706 USA. [Zack, Matthew M.; Kobau, Rosemarie] CDC, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Populat Hlth, Atlanta, GA 30333 USA. RP Pugh, MJ (reprint author), South Texas Vet Hlth Care Syst, US Dept Vet Affairs, Epilepsy Ctr Excellence, San Antonio, TX 78229 USA.; Pugh, MJ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. EM pughm@uthscsa.edu NR 10 TC 0 Z9 0 U1 1 U2 1 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD NOV 11 PY 2016 VL 65 IS 44 BP 1224 EP 1227 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EC3XJ UT WOS:000388060100005 PM 27832054 ER PT J AU Maguire, EM Bokhour, BG Wagner, TH Asch, SM Gifford, AL Gallagher, TH Durfee, JM Martinello, RA Elwy, AR AF Maguire, Elizabeth M. Bokhour, Barbara G. Wagner, Todd H. Asch, Steven M. Gifford, Allen L. Gallagher, Thomas H. Durfee, Janet M. Martinello, Richard A. Elwy, A. Rani TI Evaluating the implementation of a national disclosure policy for large-scale adverse events in an integrated health care system: identification of gaps and successes SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Adverse events; Veterans; Qualitative; Communication ID MEDICAL ERRORS; MANAGEMENT; SETTINGS AB Background: Many healthcare organizations have developed disclosure policies for large-scale adverse events, including the Veterans Health Administration (VA). This study evaluated VA's national large-scale disclosure policy and identifies gaps and successes in its implementation. Methods: Semi-structured qualitative interviews were conducted with leaders, hospital employees, and patients at nine sites to elicit their perceptions of recent large-scale adverse events notifications and the national disclosure policy. Data were coded using the constructs of the Consolidated Framework for Implementation Research (CFIR). Results: We conducted 97 interviews. Insights included how to handle the communication of large-scale disclosures through multiple levels of a large healthcare organization and manage ongoing communications about the event with employees. Of the 5 CFIR constructs and 26 sub-constructs assessed, seven were prominent in interviews. Leaders and employees specifically mentioned key problem areas involving 1) networks and communications during disclosure, 2) organizational culture, 3) engagement of external change agents during disclosure, and 4) a need for reflecting on and evaluating the policy implementation and disclosure itself. Patients shared 5) preferences for personal outreach by phone in place of the current use of certified letters. All interviewees discussed 6) issues with execution and 7) costs of the disclosure. Conclusions: CFIR analysis reveals key problem areas that need to be addresses during disclosure, including: timely communication patterns throughout the organization, establishing a supportive culture prior to implementation, using patient-approved, effective communications strategies during disclosures; providing follow-up support for employees and patients, and sharing lessons learned. C1 [Maguire, Elizabeth M.; Bokhour, Barbara G.; Gifford, Allen L.] Edith Nourse Rogers Mem Vet Hosp, Ctr Healthcare Org & Implementat Res, Bedford, MA 01730 USA. [Bokhour, Barbara G.; Gifford, Allen L.; Elwy, A. Rani] Boston Univ, Sch Publ Hlth, Dept Hlth Law Policy & Management, Boston, MA USA. [Wagner, Todd H.] VA Palo Alto Healthcare Syst, Hlth Econ Resource Ctr, Menlo Pk, CA USA. [Wagner, Todd H.; Asch, Steven M.] VA Palo Alto Healthcare Syst, Ctr Innovat Implementat, Menlo Pk, CA USA. [Wagner, Todd H.; Asch, Steven M.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Gallagher, Thomas H.] Univ Washington, Sch Med, Seattle, WA USA. [Durfee, Janet M.] Vet Hlth Adm, Dept Vet Affairs, Patient Care Serv, Washington, DC USA. [Durfee, Janet M.] Yale Sch Med, New Haven, CT USA. [Elwy, A. Rani] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, 150 S Huntington Ave, Jamaica Plain, MA USA. [Maguire, Elizabeth M.] Ctr Healthcare Org & Implementat Res, 200 Springs Rd,Mailstop152, Bedford, MA 01730 USA. RP Maguire, EM (reprint author), Edith Nourse Rogers Mem Vet Hosp, Ctr Healthcare Org & Implementat Res, Bedford, MA 01730 USA.; Maguire, EM (reprint author), Ctr Healthcare Org & Implementat Res, 200 Springs Rd,Mailstop152, Bedford, MA 01730 USA. EM Elizabeth.maguire@va.gov FU Department of Veterans Affairs, Health Services Research and Development Service [SDR 11-440] FX This study was supported by the Department of Veterans Affairs, Health Services Research and Development Service, SDR 11-440. NR 24 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD NOV 11 PY 2016 VL 16 AR 648 DI 10.1186/s12913-016-1903-7 PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EB7BJ UT WOS:000387540000003 PM 27835983 ER PT J AU Chow, LQM Haddad, R Gupta, S Mahipal, A Mehra, R Tahara, M Berger, R Eder, JP Burtness, B Lee, SH Keam, B Kang, H Muro, K Weiss, J Geva, R Lin, CC Chung, HC Meister, A Dolled-Filhart, M Pathiraja, K Cheng, JD Seiwert, TY AF Chow, Laura Q. M. Haddad, Robert Gupta, Shilpa Mahipal, Amit Mehra, Ranee Tahara, Makoto Berger, Raanan Eder, Joseph Paul Burtness, Barbara Lee, Se-Hoon Keam, Bhumsuk Kang, Hyunseok Muro, Kei Weiss, Jared Geva, Ravit Lin, Chia-Chi Chung, Hyun Cheol Meister, Amy Dolled-Filhart, Marisa Pathiraja, Kumudu Cheng, Jonathan D. Seiwert, Tanguy Y. TI Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PLATINUM-BASED THERAPY; HPV-NEGATIVE HEAD; OPEN-LABEL; HUMAN-PAPILLOMAVIRUS; ADVANCED MELANOMA; PD-1 BLOCKADE; CANCER; IMMUNOTHERAPY; ACTIVATION; TRIAL AB Purpose Treatment with pembrolizumab, an anti-programmed death-1 antibody, at 10 mg/kg administered once every 2 weeks, displayed durable antitumor activity in programmed death-ligand 1 (PD-L1)-positive recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 trial. Results from the expansion cohort, in which patients with HNSCC, irrespective of biomarker status, received a fixed dose of pembrolizumab at a less frequent dosing schedule, are reported. Patients and Methods Patients with R/M HNSCC, irrespective of PD-L1 or human papillomavirus status, received pembrolizumab 200 mg intravenously once every 3 weeks. Imaging was performed every 8 weeks. Primary end points were overall response rate (ORR) per central imaging vendor (Response Evaluation Criteria in Solid Tumors v1.1) and safety. Secondary end points included progression-free survival, overall survival, and association of response and PD-L1 expression. Patients who received one or more doses of pembrolizumab were included in analyses. Results Of 132 patients enrolled, median age was 60 years (range, 25 to 84 years), 83% were male, and 57% received two or more lines of therapy for R/M disease. ORR was 18% (95% CI, 12 to 26) by central imaging vendor and 20% (95% CI, 13 to 28) by investigator review. Median duration of response was not reached (range, >= 2 to >= 11 months). Six-month progression-free survival and overall survival rates were 23% and 59%, respectively. By using tumor and immune cells, a statistically significant increase in ORR was observed for PD-L1-positive versus-negative patients (22% v 4%; P =.021). Treatment-related adverse events of any grade and grade >= 3 events occurred in 62% and 9% of patients, respectively. Conclusion Fixed-dose pembrolizumab 200 mg administered once every 3 weeks was well tolerated and yielded a clinically meaningful ORR with evidence of durable responses, which supports further development of this regimen in patients with advanced HNSCC. (C) 2016 by American Society of Clinical Oncology C1 [Chow, Laura Q. M.] Univ Washington, Seattle Canc Care Alliance, Seattle, WA 98195 USA. [Haddad, Robert] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gupta, Shilpa; Mahipal, Amit] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Mehra, Ranee] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Eder, Joseph Paul; Burtness, Barbara] Yale Univ, Ctr Canc, New Haven, CT USA. [Kang, Hyunseok] Johns Hopkins Univ, Baltimore, MD USA. [Weiss, Jared] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Meister, Amy; Dolled-Filhart, Marisa; Pathiraja, Kumudu; Cheng, Jonathan D.] Merck, Kenilworth, NJ USA. [Seiwert, Tanguy Y.] Univ Chicago, Chicago, IL 60637 USA. [Tahara, Makoto] Natl Canc Ctr Hosp East, Kashiwa, Chiba, Japan. [Muro, Kei] Aichi Canc Ctr Hosp, Nagoya, Aichi, Japan. [Berger, Raanan] Sheba Med Ctr, Tel Hashomer, Israel. [Geva, Ravit] Sourasky Med Ctr, Tel Aviv, Israel. [Lee, Se-Hoon; Keam, Bhumsuk] Seoul Natl Univ Hosp, Seoul, South Korea. [Chung, Hyun Cheol] Yonsei Univ, Coll Med, Seoul, South Korea. [Lin, Chia-Chi] Natl Taiwan Univ Hosp, Taipei, Taiwan. RP Chow, LQM (reprint author), Univ Washington, Dept Med Oncol, Box 358081,825 E Eastlake Ave,MS CE2-109, Seattle, WA 98109 USA. EM lchow@seattlecca.org FU Merck FX Supported by Merck. NR 32 TC 0 Z9 0 U1 6 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 10 PY 2016 VL 34 IS 32 BP 3838 EP + DI 10.1200/JCO.2016.68.1478 PG 10 WC Oncology SC Oncology GA ED5XO UT WOS:000388926900005 ER PT J AU Meyer, LA Cronin, AM Sun, CC Bixel, K Bookman, MA Cristea, MC Griggs, JJ Levenback, CF Burger, RA Mantia-Smaldone, G Matulonis, UA Niland, JC O'Malley, DM Wright, AA AF Meyer, Larissa A. Cronin, Angel M. Sun, Charlotte C. Bixel, Kristin Bookman, Michael A. Cristea, Mihaela C. Griggs, Jennifer J. Levenback, Charles F. Burger, Robert A. Mantia-Smaldone, Gina Matulonis, Ursula A. Niland, Joyce C. O'Malley, David M. Wright, Alexi A. TI Use and Effectiveness of Neoadjuvant Chemotherapy for Treatment of Ovarian Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID IIIC EPITHELIAL OVARIAN; CYTOREDUCTIVE SURGERY; SURGICAL-TREATMENT; IMPROVED SURVIVAL; PROPENSITY SCORE; DISEASE; CARCINOMA; METAANALYSIS; EVOLUTION; IMPACT AB Purpose In 2010, a randomized clinical trial demonstrated noninferior survival for patients with advanced ovarian cancer who were treated with neoadjuvant chemotherapy (NACT) compared with primary cytoreductive surgery (PCS). We examined the use and effectiveness of NACT in clinical practice. Patients and Methods A multi-institutional observational study of 1,538 women with stages IIIC to IV ovarian cancer who were treated at six National Cancer Institute-designated cancer centers. We examined NACT use in patients who were diagnosed between 2003 and 2012 (N = 1,538) and compared overall survival (OS), morbidity, and postoperative residual disease in a propensity-score matched sample of patients (N = 594). Results NACT use increased from 16% during 2003 to 2010 to 34% during 2011 to 2012 in stage IIIC disease (P-trend < .001), and from 41% to 62% in stage IV disease (P-trend < .001). Adoption of NACT varied by institution, from 8% to 30% for stage IIIC disease (P < .001) and from 27% to 61% (P = .007) for stage IV disease during this time period. In the matched sample, NACT was associated with shorter OS in stage IIIC disease (median OS: 33 v 43 months; hazard ratio [HR], 1.40; 95% CI, 1.11 to 1.77) compared with PCS, but not stage IV disease (median OS: 31 v 36 months; HR, 1.16; 95% CI, 0.89 to 1.52). Patients with stages IIIC and IV disease who received NACT were less likely to have >= 1 cm postoperative residual disease, an intensive care unit admission, or a rehospitalization (all P <= .04) compared with those who received PCS treatment. However, among women with stage IIIC disease who achieved microscopic or <= 1 cm postoperative residual disease, NACT was associated with decreased OS (HR, 1.49; 95% CI, 1.01 to 2.18; P = .04). Conclusion Use of NACT increased significantly between 2003 and 2012. In this observational study, PCS was associated with increased survival in stage IIIC, but not stage IV disease. Future studies should prospectively consider the efficacy of NACT by extent of residual disease in unselected patients. (C) 2016 by American Society of Clinical Oncology C1 [Meyer, Larissa A.; Sun, Charlotte C.; Levenback, Charles F.] Univ Texas MD Anderson Canc Ctr, 1155 Herman Pressler,Unit 1362, Houston, TX 77030 USA. [Cronin, Angel M.; Matulonis, Ursula A.; Wright, Alexi A.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Bixel, Kristin; O'Malley, David M.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Bookman, Michael A.] US Oncol Res, Tucson, AZ USA. [Bookman, Michael A.] Arizona Oncol, Tucson, AZ USA. [Cristea, Mihaela C.; Niland, Joyce C.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Griggs, Jennifer J.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Burger, Robert A.] Univ Penn, Philadelphia, PA 19104 USA. [Mantia-Smaldone, Gina] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. RP Meyer, LA (reprint author), Univ Texas MD Anderson Canc Ctr, 1155 Herman Pressler,Unit 1362, Houston, TX 77030 USA. EM lmeyer@mdanderson.org FU National Cancer Institute [K07 CA166210, K07 CA201013]; Cancer Prevention and Research Institute of Texas [RP140020] FX Supported by National Cancer Institute Grants No. K07 CA166210 (A.A.W.) and K07 CA201013 (L.A.M.) and Cancer Prevention and Research Institute of Texas Grant No. RP140020 (L.A.M.). NR 29 TC 4 Z9 4 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 10 PY 2016 VL 34 IS 32 BP 3854 EP + DI 10.1200/JCO.2016.68.1239 PG 16 WC Oncology SC Oncology GA ED5XO UT WOS:000388926900007 ER PT J AU Ryan, CW Merimsky, O Agulnik, M Blay, JY Schuetze, SM Van Tine, BA Jones, RL Elias, AD Choy, E Alcindor, T Keedy, VL Reed, DR Taub, RN Italiano, A del Muro, XG Judson, IR Buck, JY Lebel, F Lewis, JJ Maki, RG Schoffski, P AF Ryan, Christopher W. Merimsky, Ofer Agulnik, Mark Blay, Jean-Yves Schuetze, Scott M. Van Tine, Brian A. Jones, Robin L. Elias, Anthony D. Choy, Edwin Alcindor, Thierry Keedy, Vicki L. Reed, Damon R. Taub, Robert N. Italiano, Antoine Garcia del Muro, Xavier Judson, Ian R. Buck, Jill Y. Lebel, Francois Lewis, Jonathan J. Maki, Robert G. Schoffski, Patrick TI PICASSO III: A Phase III, Placebo-Controlled Study of Doxorubicin With or Without Palifosfamide in Patients With Metastatic Soft Tissue Sarcoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID STANDARD-DOSE DOXORUBICIN; EUROPEAN-ORGANIZATION; PLUS IFOSFAMIDE; 1ST-LINE TREATMENT; ADRIAMYCIN; TRIAL; MESNA; DACARBAZINE; EPIRUBICIN AB Purpose Palifosfamide is the active metabolite of ifosfamide and does not require prodrug activation, thereby avoiding the generation of toxic metabolites. The PICASSO III trial compared doxorubicin plus palifosfamide with doxorubicin plus placebo in patients who had received no prior systemic therapy for metastatic soft tissue sarcoma. Patients and Methods Patients were randomly assigned 1: 1 to receive doxorubicin 75 mg/m(2) intravenously day 1 plus palifosfamide 150 mg/m(2)/d intravenously days 1 to 3 or doxorubicin plus placebo once every 21 days for up to six cycles. The primary end point was progression-free survival (PFS) by independent radiologic review. Results In all, 447 patients were randomly assigned to receive doxorubicin plus palifosfamide (n = 226) or doxorubicin plus placebo (n = 221). Median PFS was 6.0 months for doxorubicin plus palifosfamide and 5.2 months for doxorubicin plus placebo (hazard ratio, 0.86; 95% CI, 0.68 to 1.08; P = .19). Median overall survival was 15.9 months for doxorubicin plus palifosfamide and 16.9 months for doxorubicin plus placebo (hazard ratio, 1.05; 95% CI, 0.79 to 1.39; P = .74). There was a higher incidence of grade 3 to 4 adverse events in the doxorubicin plus palifosfamide arm (63.6% v 50.9%) including a higher rate of febrile neutropenia (21.4% v 12.6%). Conclusion No significant difference in PFS was observed in patients receiving doxorubicin plus palifosfamide compared with those receiving doxorubicin plus placebo. The observed median PFS and overall survival in this large, international study can serve as a benchmark for future studies of doxorubicin in metastatic soft tissue sarcoma. (C) 2016 by American Society of Clinical Oncology C1 [Ryan, Christopher W.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Merimsky, Ofer] Sackler Sch Med, Tel Aviv, Israel. [Agulnik, Mark] Northwestern Univ, Chicago, IL 60611 USA. [Blay, Jean-Yves] Ctr Leon Berard, Lyon, France. [Italiano, Antoine] Inst Bergonie, Bordeaux, France. [Schuetze, Scott M.] Univ Michigan, Ann Arbor, MI 48109 USA. [Van Tine, Brian A.] Washington Univ, St Louis, MO USA. [Jones, Robin L.; Judson, Ian R.] Royal Marsden Hosp, London, England. [Elias, Anthony D.] Univ Colorado Denver, Aurora, CO USA. [Choy, Edwin] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Buck, Jill Y.; Lebel, Francois] ZIOPHARM Oncol, Boston, MA USA. [Alcindor, Thierry] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Keedy, Vicki L.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Reed, Damon R.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Taub, Robert N.] Columbia Univ, Med Ctr, New York, NY 10027 USA. [Lewis, Jonathan J.] Samus Therapeut, New York, NY USA. [Lewis, Jonathan J.] Mol Ninja Grp, New York, NY USA. [Maki, Robert G.] Mt Sinai Sch Med, New York, NY USA. [Garcia del Muro, Xavier] Inst Catala Oncol Lhospitalet, Barcelona, Spain. [Schoffski, Patrick] Univ Hosp Leuven, Leuven, Belgium. RP Ryan, CW (reprint author), Oregon Hlth & Sci Univ, Knight Canc Inst, 3303 SW Bond Ave,CH14R, Portland, OR 97212 USA. EM ryanc@ohsu.edu FU ZIOPHARM Oncology FX Supported by ZIOPHARM Oncology. NR 18 TC 2 Z9 2 U1 2 U2 2 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 NOV 10 PY 2016 VL 34 IS 32 BP 3898 EP + DI 10.1200/JCO.2016.67.6684 PG 14 WC Oncology SC Oncology GA ED5XO UT WOS:000388926900013 ER PT J AU Sgroi, DC Brufsky, A AF Sgroi, Dennis C. Brufsky, Adam TI Biomarkers for Early-Stage Breast Cancer: Clinical Utility for Extended Adjuvant Treatment Decisions SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID LATE-DISTANT RECURRENCE; PRACTICE GUIDELINE; AMERICAN SOCIETY; RANDOMIZED-TRIAL; THERAPY; TAMOXIFEN; WOMEN C1 [Sgroi, Dennis C.] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Sgroi, Dennis C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Brufsky, Adam] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. RP Sgroi, DC (reprint author), Massachusetts Gen Hosp, Charlestown, MA 02129 USA.; Sgroi, DC (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 8 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 10 PY 2016 VL 34 IS 32 BP 3941 EP + DI 10.1200/JCO.2016.67.2949 PG 3 WC Oncology SC Oncology GA ED5XO UT WOS:000388926900020 ER PT J AU Zhao, FM AF Zhao, Fengmin TI Surrogate End Points in Soft Tissue Sarcoma: Methodologic Challenges Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID PROGRESSION-FREE SURVIVAL; METASTATIC BREAST-CANCER; CLINICAL-TRIALS; TIME C1 [Zhao, Fengmin] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Zhao, FM (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 10 PY 2016 VL 34 IS 32 BP 3951 EP + DI 10.1200/JCO.2016.69.1063 PG 2 WC Oncology SC Oncology GA ED5XO UT WOS:000388926900027 ER PT J AU Smith, EC Luc, S Croney, DM Woodworth, MB Greig, LC Fujiwara, Y Nguyen, M Sher, F Macklis, JD Bauer, DE Orkin, SH AF Smith, Elenoe C. Luc, Sidinh Croney, Donyell M. Woodworth, Mollie B. Greig, Luciano C. Fujiwara, Yuko Minh Nguyen Sher, Falak Macklis, Jeffrey D. Bauer, Daniel E. Orkin, Stuart H. TI Strict in vivo specificity of the Bcl11a erythroid enhancer SO BLOOD LA English DT Article ID SICKLE-CELL-DISEASE; FETAL-HEMOGLOBIN; GLOBIN; GENE; STEM; EXPRESSION; PHENOTYPE; DEFECTS; PROTEIN; EKLF AB BCL11A, a repressor of human fetal (gamma-) globin expression, is required for immune and hematopoietic stem cell functions and brain development. Regulatory sequences within the gene, which are subject to genetic variation affecting fetal globin expression, display hallmarks of an erythroid enhancer in cell lines and transgenic mice. As such, this enhancer is a novel, attractive target for therapeutic gene editing. To explore the roles of such sequences in vivo, we generated mice in which the orthologous 10-kb intronic sequences were removed. Bcl11a enhancer-deleted mice, Bcl11a(Delta enh), phenocopy the BCL11A-null state with respect to alterations of globin expression, yet are viable and exhibit no observable blood, brain, or other abnormalities. These preclinical findings provide strong in vivo support for genetic modification of the enhancer for therapy of hemoglobin disorders. C1 [Smith, Elenoe C.; Luc, Sidinh; Croney, Donyell M.; Fujiwara, Yuko; Minh Nguyen; Sher, Falak; Bauer, Daniel E.; Orkin, Stuart H.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Smith, Elenoe C.; Luc, Sidinh; Croney, Donyell M.; Fujiwara, Yuko; Minh Nguyen; Sher, Falak; Bauer, Daniel E.; Orkin, Stuart H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Smith, Elenoe C.; Luc, Sidinh; Croney, Donyell M.; Woodworth, Mollie B.; Greig, Luciano C.; Fujiwara, Yuko; Minh Nguyen; Sher, Falak; Macklis, Jeffrey D.; Bauer, Daniel E.; Orkin, Stuart H.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Smith, Elenoe C.; Luc, Sidinh; Croney, Donyell M.; Fujiwara, Yuko; Minh Nguyen; Sher, Falak; Bauer, Daniel E.; Orkin, Stuart H.] Harvard Med Sch, Dept Pediat, Boston, MA USA. [Woodworth, Mollie B.; Greig, Luciano C.; Macklis, Jeffrey D.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Woodworth, Mollie B.; Greig, Luciano C.; Macklis, Jeffrey D.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Fujiwara, Yuko; Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Orkin, SH (reprint author), 44 Binney St, Boston, MA 02115 USA. EM stuart_orkin@dfci.harvard.edu FU Jane Coffin Childs Memorial Fund for Medical Research Fellowship; Burroughs Wellcome Fund Postdoctoral Enrichment Program Award; Leukemia & Lymphoma Society Fellow Award; National Institute of Neurological Disorders and Stroke; National Institutes of Health individual National Research Service Awards [NS064730, NS080343]; National Institute of Neurological Disorders and Stroke, National Institutes of Health [NS075672, NS045523, NS041590, NS093376]; DEARS Foundation; Harvard Medical Scientist Training Program; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [K08DK093705, R03DK109232]; Charles H. Hood Foundation; American Society of Hematology; Burroughs Wellcome Fund; Cooley's Anemia Foundation; National Heart, Lung, and Blood Institute, National Institutes of Health [P01HL032262]; National Institute of Diabetes and Digestive and Kidney Diseases (Center of Excellence in Molecular Hematology) [P30DK049216] FX E.C.S. was supported by a Jane Coffin Childs Memorial Fund for Medical Research Fellowship and a Burroughs Wellcome Fund Postdoctoral Enrichment Program Award. S.L. is supported by a Leukemia & Lymphoma Society Fellow Award. M.B.W. and L.C.G. were supported by National Institute of Neurological Disorders and Stroke, National Institutes of Health individual National Research Service Awards (grants NS064730 and NS080343); the National Institute of Neurological Disorders and Stroke, National Institutes of Health (grant NS075672) (J.D.M.); and the DEARS Foundation (J.D.M.), with additional infrastructure support by the National Institute of Neurological Disorders and Stroke, National Institutes of Health (grants NS045523, NS041590, and NS093376) (J.D.M.). J.D.M. is an Allen Distinguished Investigator of the Paul G. Allen Frontiers Group. L.C.G. is also supported by the Harvard Medical Scientist Training Program. D.E.B. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (grants K08DK093705 and R03DK109232); the Charles H. Hood Foundation; the American Society of Hematology; the Burroughs Wellcome Fund; and Cooley's Anemia Foundation. S.H.O. is supported by the National Heart, Lung, and Blood Institute, National Institutes of Health (grant P01HL032262) and National Institute of Diabetes and Digestive and Kidney Diseases (grant P30DK049216) (Center of Excellence in Molecular Hematology). NR 22 TC 0 Z9 0 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 NOV 10 PY 2016 VL 128 IS 19 BP 2338 EP 2342 DI 10.1182/blood-2016-08-736249 PG 5 WC Hematology SC Hematology GA EC4LI UT WOS:000388100700010 ER PT J AU Holtan, SG Khera, N Levine, JE Chai, XY Storer, B Liu, HD Inamoto, Y Chen, GL Mayer, S Arora, M Palmer, J Flowers, MED Cutler, CS Lukez, A Arai, S Lazaryan, A Newell, LF Krupski, C Jagasia, MH Pusic, I Wood, W Renteria, AS Yanik, G Hogan, WJ Hexner, E Ayuk, F Holler, E Watanaboonyongcharoen, P Efebera, YA Ferrara, JLM Panoskaltsis-Mortari, A Weisdorf, D Lee, SJ Pidala, J AF Holtan, Shernan G. Khera, Nandita Levine, John E. Chai, Xiaoyu Storer, Barry Liu, Hien D. Inamoto, Yoshihiro Chen, George L. Mayer, Sebastian Arora, Mukta Palmer, Jeanne Flowers, Mary E. D. Cutler, Corey S. Lukez, Alexander Arai, Sally Lazaryan, Aleksandr Newell, Laura F. Krupski, Christa Jagasia, Madan H. Pusic, Iskra Wood, William Renteria, Anne S. Yanik, Gregory Hogan, William J. Hexner, Elizabeth Ayuk, Francis Holler, Ernst Watanaboonyongcharoen, Phandee Efebera, Yvonne A. Ferrara, James L. M. Panoskaltsis-Mortari, Angela Weisdorf, Daniel Lee, Stephanie J. Pidala, Joseph TI Late acute graft-versus-host disease: a prospective analysis of clinical outcomes and circulating angiogenic factors SO BLOOD LA English DT Article ID HEMATOPOIETIC-CELL TRANSPLANTATION; NIH CONSENSUS CRITERIA; FAILURE-FREE SURVIVAL; EPIDERMAL-GROWTH-FACTOR; WORKING GROUP-REPORT; REDUCED INTENSITY; DEVELOPMENT PROJECT; SYSTEMIC TREATMENT; TISSUE-REPAIR; CHRONIC GVHD AB Late acute (LA) graft-versus-host disease (GVHD) is persistent, recurrent, or new-onset acute GVHD symptoms occurring > 100 days after allogeneic hematopoietic cell transplantation (HCT). The aim of this analysis is to describe the onset, course, morbidity, and mortality of and examine angiogenic factors associated with LA GVHD. A prospective cohort of patients (n 5 909) was enrolled as part of an observational study within the Chronic GVHD Consortium. Eighty-three patients (11%) developed LA GVHD at a median of 160 (interquartile range, 128-204) days after HCT. Although 51 out of 83 (61%) achieved complete or partial response to initial therapy by 28 days, median failure-free survival was only 7.1 months (95% confidence interval, 3.4-19.1 months), and estimated overall survival (OS) at 2 years was 56%. Given recently described alterations of circulating angiogenic factors in classic acute GVHD, we examined whether alterations in such factors could be identified in LA GVHD. We first tested cases (n=55) and controls (n=50) from the Chronic GVHD Consortium and then validated the findings in 37 cases from Mount Sinai Acute GVHD International Consortium. Plasma amphiregulin (AREG; an epidermal growth factor [EGF] receptor ligand) was elevated, and an AREG/EGF ratio at or above the median was associated with inferior OS and increased nonrelapse mortality in both cohorts. Elevation of AREG was detected in classic acute GVHD, but not chronic GVHD. These prospective data characterize the clinical course of LA GVHD and demonstrate alterations in angiogenic factors that make LA GVHD biologically distinct from chronic GVHD. C1 [Holtan, Shernan G.; Arora, Mukta; Lazaryan, Aleksandr; Panoskaltsis-Mortari, Angela; Weisdorf, Daniel] Univ Minnesota, Hematol Oncol & Transplant, Minneapolis, MN USA. [Khera, Nandita; Palmer, Jeanne] Mayo Clin, Phoenix, AZ USA. [Levine, John E.; Renteria, Anne S.; Ferrara, James L. M.] Icahn Sch Med Mt Sinai, Blood & Marrow Transplantat Program, New York, NY 10029 USA. [Chai, Xiaoyu; Storer, Barry; Flowers, Mary E. D.; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Liu, Hien D.] Cleveland Clin, Blood & Marrow Transplant Program, Cleveland, OH 44106 USA. [Inamoto, Yoshihiro] Natl Canc Ctr, Stem Cell Transplantat Div, Tokyo, Japan. [Chen, George L.] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Mayer, Sebastian] Weill Cornell Med Ctr, Dept Med, New York, NY USA. [Cutler, Corey S.; Lukez, Alexander] Harvard Med Sch, Dana Farber Canc Inst, Hematol Malignancies, Boston, MA USA. [Arai, Sally] Stanford Univ, Med Ctr, Div Blood & Marrow Transplantat, Stanford, CA 94305 USA. [Newell, Laura F.] Oregon Hlth & Sci Univ, Ctr Hematol Malignancies, Portland, OR 97201 USA. [Krupski, Christa; Jagasia, Madan H.] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol,Stem Cell Transplantat, Nashville, TN USA. [Pusic, Iskra] Washington Univ, Med Ctr, Med Oncol, St Louis, MO USA. [Wood, William] Univ North Carolina Healthcare, Hematol Oncol, Chapel Hill, NC USA. [Yanik, Gregory] Univ Michigan, Blood & Marrow Transplantat Program, Ann Arbor, MI 48109 USA. [Hogan, William J.] Mayo Clin, Blood & Marrow Transplantat Program, Rochester, MN USA. [Hexner, Elizabeth] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Ayuk, Francis] Univ Med Ctr, Dept Stem Cell Transplantat, Hamburg, Germany. [Holler, Ernst] Univ Regensburg, Blood & Marrow Transplantat Program, Regensburg, Germany. [Watanaboonyongcharoen, Phandee] Chulalongkorn Univ, Blood & Marrow Transplantat Program, Bangkok, Thailand. [Efebera, Yvonne A.] Ohio State Univ, Blood & Marrow Transplantat Program, Columbus, OH 43210 USA. [Pidala, Joseph] H Lee Moffitt Canc Ctr & Res Inst, Blood & Marrow Transplantat, Tampa, FL USA. RP Holtan, SG (reprint author), Univ Minnesota, Mayo Mail Code 480,420 Delaware St SE, Minneapolis, MN 55455 USA. EM sgholtan@umn.edu FU National Institutes of Health, National Cancer Institute [CA163438, CA118953]; Office of Rare Disease Research (ORDR), NCATS FX This study was funded by National Institutes of Health, National Cancer Institute grants CA163438 and CA118953. The Chronic GVHD Consortium (U54 CA163438) is part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Disease Research (ORDR), NCATS, funded through collaboration between NCATS and the National Cancer Institute. The angiogenic factor studies were made possible by the Masonic Cancer Center, University of Minnesota. NR 32 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 NOV 10 PY 2016 VL 128 IS 19 BP 2350 EP 2358 DI 10.1182/blood-2015-09-669846 PG 9 WC Hematology SC Hematology GA EC4LI UT WOS:000388100700012 ER PT J AU Dong, L Yu, WM Zheng, H Loh, ML Bunting, ST Pauly, M Huang, G Zhou, MX Broxmeyer, HE Scadden, DT Qu, CK AF Dong, Lei Yu, Wen-Mei Zheng, Hong Loh, Mignon L. Bunting, Silvia T. Pauly, Melinda Huang, Gang Zhou, Muxiang Broxmeyer, Hal E. Scadden, David T. Qu, Cheng-Kui TI Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment SO NATURE LA English DT Article ID BONE-MARROW NICHE; CHRONIC MYELOGENOUS LEUKEMIA; HEMATOPOIETIC STEM; NOONAN-SYNDROME; RECEPTOR GENE; SHP2 PTPN11; MOUSE MODEL; MAINTENANCE; PROGENITORS; REGENERATION AB Germline activating mutations of the protein tyrosine phosphatase SHP2 (encoded by PTPN11), a positive regulator of the RAS signalling pathway(1), are found in 50% of patients with Noonan syndrome(2). These patients have an increased risk of developing leukaemia(3), especially juvenile myelomonocytic leukaemia (JMML), a childhood myeloproliferative neoplasm (MPN). Previous studies have demonstrated that mutations in Ptpn11 induce a JMML-like MPN through cell-autonomous mechanisms that are dependent on Shp2 catalytic activity(4-7). However, the effect of these mutations in the bone marrow microenvironment remains unclear. Here we report that Ptpn11 activating mutations in the mouse bone marrow microenvironment promote the development and progression of MPN through profound detrimental effects on haematopoietic stem cells (HSCs). Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, cause excessive production of the CC chemokine CCL3 (also known as MIP-1 alpha), which recruits monocytes to the area in which HSCs also reside. Consequently, HSCs are hyperactivated by interleukin-1 beta and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor-cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reverses MPN development induced by the Ptpn11-mutated bone marrow microenvironment. This study reveals the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukaemogenesis and identifies CCL3 as a potential therapeutic target for controlling leukaemic progression in Noonan syndrome and for improving stem cell transplantation therapy in Noonansyndrome-associated leukaemias. C1 [Dong, Lei; Yu, Wen-Mei; Zheng, Hong; Pauly, Melinda; Zhou, Muxiang; Qu, Cheng-Kui] Emory Univ, Sch Med, Div Hematol Oncol,Dept Pediat, Aflac Canc & Blood Disorders Ctr,Childrens Health, Atlanta, GA 30322 USA. [Loh, Mignon L.] Univ Calif San Francisco, Div Pediat Hematol Oncol, Dept Pediat, San Francisco, CA 94122 USA. [Bunting, Silvia T.] Emory Univ, Childrens Healthcare Atlanta, Dept Pathol, Atlanta, GA 30322 USA. [Huang, Gang] Univ Cincinnati, Cincinnati Childrens Hosp, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. [Broxmeyer, Hal E.] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. [Scadden, David T.] Harvard Univ, Ctr Regenerat Med, Boston, MA 02114 USA. [Scadden, David T.] Harvard Univ, MGH Canc Ctr, Massachusetts Gen Hosp, Dept Stem Cell & Regenerat Biol, Boston, MA 02114 USA. [Scadden, David T.] Harvard Univ, Harvard Stem Cell Inst, Boston, MA 02114 USA. RP Qu, CK (reprint author), Emory Univ, Sch Med, Div Hematol Oncol,Dept Pediat, Aflac Canc & Blood Disorders Ctr,Childrens Health, Atlanta, GA 30322 USA. EM cheng-kui.qu@emory.edu FU National Institutes of Health [HL130995, DK092722] FX This work was supported by The National Institutes of Health grants HL130995 and DK092722 (to C.K.Q.). NR 39 TC 5 Z9 5 U1 6 U2 6 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 NOV 10 PY 2016 VL 539 IS 7628 BP 304 EP + DI 10.1038/nature20131 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB4CZ UT WOS:000387318500048 PM 27783593 ER PT J AU Tirosh, I Venteicher, AS Hebert, C Escalante, LE Patel, AP Yizhak, K Fisher, JM Rodman, C Mount, C Filbin, MG Neftel, C Desai, N Nyman, J Izar, B Luo, CC Francis, JM Patel, AA Onozato, ML Riggi, N Livak, KJ Gennert, D Satija, R Nahed, BV Curry, WT Martuza, RL Mylvaganam, R Iafrate, AJ Frosch, MP Golub, TR Rivera, MN Getz, G Rozenblatt-Rosen, O Cahill, DP Monje, M Bernstein, BE Louis, DN Regev, A Suva, ML AF Tirosh, Itay Venteicher, Andrew S. Hebert, Christine Escalante, Leah E. . Patel, Anoop P. Yizhak, Keren Fisher, Jonathan M. . Rodman, Christopher Mount, Christopher Filbin, Mariella G. Neftel, Cyril Desai, Niyati Nyman, Jackson Izar, Benjamin Luo, Christina C. Francis, Joshua M. . Patel, Aanand A. Onozato, Maristela L. Riggi, Nicolo Livak, Kenneth J. Gennert, Dave Satija, Rahul Nahed, Brian V. . Curry, William T. Martuza, Robert L. Mylvaganam, Ravindra Iafrate, A. John Frosch, Matthew P. Golub, Todd R. Rivera, Miguel N. . Getz, Gad Rozenblatt-Rosen, Orit Cahill, Daniel P. Monje, Michelle Bernstein, Bradley E. . Louis, David N. Regev, Aviv Suva, Mario L. TI Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma SO NATURE LA English DT Article ID HEMATOPOIETIC STEM-CELLS; SEQUENCING DATA; ADULT NEUROGENESIS; HUMAN BRAIN; CANCER; GLIOBLASTOMA; EXPRESSION; GLIOMA; MUTATIONS; GENOME AB Although human tumours are shaped by the genetic evolution of cancer cells, evidence also suggests that they display hierarchies related to developmental pathways and epigenetic programs in which cancer stem cells (CSCs) can drive tumour growth and give rise to differentiated progeny(1). Yet, unbiased evidence for CSCs in solid human malignancies remains elusive. Here we profile 4,347 single cells from six IDH1 or IDH2 mutant human oligodendrogliomas by RNA sequencing (RNA-seq) and reconstruct their developmental programs from genome-wide expression signatures. We infer that most cancer cells are differentiated along two specialized glial programs, whereas a rare subpopulation of cells is undifferentiated and associated with a neural stem cell expression program. Cells with expression signatures for proliferation are highly enriched in this rare subpopulation, consistent with a model in which CSCs are primarily responsible for fuelling the growth of oligodendroglioma in humans. Analysis of copy number variation (CNV) shows that distinct CNV sub-clones within tumours display similar cellular hierarchies, suggesting that the architecture of oligodendroglioma is primarily dictated by developmental programs. Subclonal point mutation analysis supports a similar model, although a full phylogenetic tree would be required to definitively determine the effect of genetic evolution on the inferred hierarchies. Our single-cell analyses provide insight into the cellular architecture of oligodendrogliomas at single-cell resolution and support the cancer stem cell model, with substantial implications for disease management. C1 [Tirosh, Itay; Venteicher, Andrew S.; Hebert, Christine; Escalante, Leah E. .; Yizhak, Keren; Fisher, Jonathan M. .; Rodman, Christopher; Filbin, Mariella G.; Neftel, Cyril; Nyman, Jackson; Izar, Benjamin; Francis, Joshua M. .; Livak, Kenneth J.; Gennert, Dave; Satija, Rahul; Golub, Todd R.; Rivera, Miguel N. .; Getz, Gad; Rozenblatt-Rosen, Orit; Bernstein, Bradley E. .; Regev, Aviv; Suva, Mario L.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Venteicher, Andrew S.; Hebert, Christine; Escalante, Leah E. .; Yizhak, Keren; Filbin, Mariella G.; Neftel, Cyril; Desai, Niyati; Luo, Christina C.; Patel, Aanand A.; Onozato, Maristela L.; Riggi, Nicolo; Mylvaganam, Ravindra; Iafrate, A. John; Frosch, Matthew P.; Rivera, Miguel N. .; Getz, Gad; Bernstein, Bradley E. .; Louis, David N.; Suva, Mario L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Venteicher, Andrew S.; Hebert, Christine; Escalante, Leah E. .; Yizhak, Keren; Filbin, Mariella G.; Neftel, Cyril; Desai, Niyati; Luo, Christina C.; Patel, Aanand A.; Onozato, Maristela L.; Riggi, Nicolo; Mylvaganam, Ravindra; Iafrate, A. John; Frosch, Matthew P.; Rivera, Miguel N. .; Getz, Gad; Bernstein, Bradley E. .; Louis, David N.; Suva, Mario L.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Venteicher, Andrew S.; Hebert, Christine; Escalante, Leah E. .; Patel, Anoop P.; Yizhak, Keren; Filbin, Mariella G.; Neftel, Cyril; Desai, Niyati; Luo, Christina C.; Patel, Aanand A.; Onozato, Maristela L.; Riggi, Nicolo; Nahed, Brian V. .; Curry, William T.; Martuza, Robert L.; Mylvaganam, Ravindra; Iafrate, A. John; Frosch, Matthew P.; Rivera, Miguel N. .; Getz, Gad; Cahill, Daniel P.; Bernstein, Bradley E. .; Louis, David N.; Suva, Mario L.] Harvard Med Sch, Boston, MA 02114 USA. [Venteicher, Andrew S.; Patel, Anoop P.; Nahed, Brian V. .; Curry, William T.; Martuza, Robert L.; Cahill, Daniel P.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Mount, Christopher; Monje, Michelle] Stanford Univ, Sch Med, Dept Neurol, Stanford, CA 94305 USA. [Mount, Christopher; Monje, Michelle] Stanford Univ, Sch Med, Dept Neurosurg, Stanford, CA 94305 USA. [Mount, Christopher; Monje, Michelle] Stanford Univ, Sch Med, Dept Pediat & Pathol, Stanford, CA 94305 USA. [Filbin, Mariella G.; Golub, Todd R.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Filbin, Mariella G.; Golub, Todd R.] Childrens Hosp, Ctr Canc, Boston, MA 02215 USA. [Francis, Joshua M. .] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Golub, Todd R.; Regev, Aviv] MIT, Koch Inst, Dept Biol, Howard Hughes Med Inst, Cambridge, MA 02139 USA. RP Regev, A; Suva, ML (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.; Suva, ML (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.; Suva, ML (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA.; Suva, ML (reprint author), Harvard Med Sch, Boston, MA 02114 USA.; Regev, A (reprint author), MIT, Koch Inst, Dept Biol, Howard Hughes Med Inst, Cambridge, MA 02139 USA. EM aregev@broadinstitute.org; suva.mario@mgh.harvard.edu FU National Brain Tumor Society; Smith Family Foundation; NIH-NCI SPORE on brain cancer Career Enhancement Project and Developmental Research Project; Broad Institute Broadnext10 program; American Cancer Society; MGH department of Pathology; NIH [NS065743]; American Brain Tumor Association and Neurosurgery Research and Education Foundation; Human Frontier Science Program fellowship; Rothschild fellowship; Howard Hughes Medicine Institute; Klarman Cell Observatory, STARR cancer consortium, NCI [1U24CA180922]; Koch Institute Support from the National Cancer Institute [P30-CA14051]; Ludwig Center and the Broad Institute; California Institute of Regenerative Medicine (CIRM) [RB4-06093, RN3-06510]; Virginia and D.K. Ludwig Fund for Cancer Research; [1S10RR023440-01A1] FX We thank L. Gaffney for graphic support. This work was supported by grants from the National Brain Tumor Society (to M.L.S. and D.N.L.), the Smith Family Foundation (to M.L.S.), NIH-NCI SPORE on brain cancer Career Enhancement Project and Developmental Research Project (to M.L.S.), the Broad Institute Broadnext10 program (to M.L.S. and O.R.R.), the American Cancer Society (to M.L.S.) and start-up funds from the MGH department of Pathology. A.S.V. was supported by the NIH R25 fellowship (NS065743) and research grants from the American Brain Tumor Association and Neurosurgery Research and Education Foundation. I.T. was supported by a Human Frontier Science Program fellowship and a Rothschild fellowship. A.R. was supported by funds from the Howard Hughes Medicine Institute, the Klarman Cell Observatory, STARR cancer consortium, NCI grant 1U24CA180922, by the Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute, the Ludwig Center and the Broad Institute. A.R. is a scientific advisory board member for ThermoFisher Scientific and Syros Pharmaceuticals and a consultant for Driver Group. Flow cytometry and sorting services were supported by shared instrumentation grant 1S10RR023440-01A1. M.M. was supported by the California Institute of Regenerative Medicine (CIRM) grants RB4-06093 and RN3-06510 and the Virginia and D.K. Ludwig Fund for Cancer Research. NR 40 TC 5 Z9 5 U1 20 U2 20 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 NOV 10 PY 2016 VL 539 IS 7628 BP 309 EP + DI 10.1038/nature20123 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB4CZ UT WOS:000387318500049 PM 27806376 ER PT J AU Buckley, RF Laming, G Chen, LPE Crole, A Hester, R AF Buckley, Rachel F. Laming, Gemma Chen, Li Peng Evelyn Crole, Alice Hester, Robert TI Assessing Error Awareness as a Mediator of the Relationship between Subjective Concerns and Cognitive Performance in Older Adults SO PLOS ONE LA English DT Article ID MEMORY COMPLAINTS; AGE; IMPAIRMENT; DEPRESSION; TASK; METAANALYSIS; BIOMARKERS; DOPAMINE; DEMENTIA; SPEED AB Objectives Subjective concerns of cognitive decline (SCD) often manifest in older adults who exhibit objectively normal cognitive functioning. This subjective-objective discrepancy is counterintuitive when mounting evidence suggests that subjective concerns relate to future clinical progression to Alzheimer's disease, and so possess the potential to be a sensitive early behavioural marker of disease. In the current study, we aimed to determine whether individual variability in conscious awareness of errors in daily life might mediate this subjective objective relationship. Methods 67 cognitively-normal older adults underwent cognitive, SCD and mood tests, and an error awareness task. Results Poorer error awareness was not found to mediate a relationship between SCD and objective performance. Furthermore, non-clinical levels of depressive symptomatology were a primary driving factor of SCD and error awareness, and significantly mediated a relationship between the two. Discussion We were unable to show that poorer error awareness mediates SCD and cognitive performance in older adults. Our study does suggest, however, that underlying depressive symptoms influence both poorer error awareness and greater SCD severity. Error awareness is thus not recommended as a proxy for SCD, as reduced levels of error awareness do not seem to be reflected by greater SCD. C1 [Buckley, Rachel F.] Florey Inst Neurosci & Mental Hlth, Melbourne, Vic, Australia. [Buckley, Rachel F.; Laming, Gemma; Chen, Li Peng Evelyn; Crole, Alice; Hester, Robert] Univ Melbourne, Melbourne Sch Psychol Sci, Melbourne, Vic, Australia. [Buckley, Rachel F.] Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. [Buckley, Rachel F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Buckley, RF (reprint author), Florey Inst Neurosci & Mental Hlth, Melbourne, Vic, Australia.; Buckley, RF (reprint author), Univ Melbourne, Melbourne Sch Psychol Sci, Melbourne, Vic, Australia.; Buckley, RF (reprint author), Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA.; Buckley, RF (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM rbuckley@mgh.harvard.edu FU National Health and Medical Research Council of Australia [1008044]; NHMRC/ARC Dementia Research Fellowship [APP1105576]; Australian Research Council [FT110100088.] FX This work was supported by the National Health and Medical Research Council of Australia (grant number 1008044). Dr Buckley is funded by the NHMRC/ARC Dementia Research Fellowship (APP1105576), and A/Prof Hester is funded by Australian Research Council FT110100088. NR 31 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 NOV 10 PY 2016 VL 11 IS 11 AR e0166315 DI 10.1371/journal.pone.0166315 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB9ON UT WOS:000387725000094 PM 27832173 ER PT J AU Eggermont, AMM Chiarion-Sileni, V Grob, JJ Dummer, R Wolchok, JD Schmidt, H Hamid, O Robert, C Ascierto, PA Richards, JM Lebbe, C Ferraresi, V Smylie, M Weber, JS Maio, M Bastholt, L Mortier, L Thomas, L Tahir, S Hauschild, A Hassel, JC Hodi, FS Taitt, C de Pril, V de Schaetzen, G Suciu, S Testori, A AF Eggermont, A. M. M. Chiarion-Sileni, V. Grob, J. -J. Dummer, R. Wolchok, J. D. Schmidt, H. Hamid, O. Robert, C. Ascierto, P. A. Richards, J. M. Lebbe, C. Ferraresi, V. Smylie, M. Weber, J. S. Maio, M. Bastholt, L. Mortier, L. Thomas, L. Tahir, S. Hauschild, A. Hassel, J. C. Hodi, F. S. Taitt, C. de Pril, V. de Schaetzen, G. Suciu, S. Testori, A. TI Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID NODE-POSITIVE MELANOMA; HIGH-RISK MELANOMA; CUTANEOUS MELANOMA; METASTATIC MELANOMA; INTERFERON-ALPHA; TUMOR BURDEN; TRIAL; METAANALYSIS; MULTICENTER; ULCERATION AB BACKGROUND On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma. METHODS After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis-free survival, and safety. RESULTS At a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001). The rate of distant metastasis-free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P=0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immunerelated adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events. CONCLUSIONS As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. C1 [Eggermont, A. M. M.; Robert, C.] Gustave Roussy Canc Campus Grand Paris, 114 Rue Edouard Vaillant, F-94805 Villejuif, France. [Grob, J. -J.] Aix Marseille Univ, Hop La Timone, Marseille, France. [Lebbe, C.] Hop St Louis, AP HP, Paris, France. [Mortier, L.] Univ Lille, Ctr Hosp Univ CHU Lille, INSERM, Unite 1189,Serv Dermatol, Lille, France. [Thomas, L.] CHU Lyon, Lyon, France. [Chiarion-Sileni, V.] Oncol Inst Veneto, Ist Ricovero & Cura Carattere Sci, Padua, Italy. [Ascierto, P. A.] Fdn G Pascale, Ist Nazl Tumori, Naples, Italy. [Ferraresi, V.] Ist Fisioterap Ospitalieri, Rome, Italy. [Maio, M.] Univ Hosp Siena, Ist Toscano Tumori, Siena, Italy. [Testori, A.] European Inst Oncol, Milan, Italy. [Dummer, R.] Univ Zurich Hosp, Zurich, Switzerland. [Wolchok, J. D.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Schmidt, H.] Aarhus Univ Hosp, Aarhus, Denmark. [Bastholt, L.] Odense Univ Hosp, Odense, Denmark. [Hamid, O.] Angeles Clin & Res Inst, Los Angeles, CA USA. [Richards, J. M.] Oncol Specialists, Park Ridge, IL USA. [Smylie, M.] Cross Canc Inst, Edmonton, AB, Canada. [Weber, J. S.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Tahir, S.] Broomfield Hosp, Chelmsford, England. [Hauschild, A.] Univ Klinikum Schleswig Holstein, Kiel, Germany. [Hassel, J. C.] Univ Heidelberg Hosp, Heidelberg, Germany. [Hodi, F. S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Taitt, C.; de Pril, V.] Bristol Myers Squibb Co, Princeton, NJ USA. [de Schaetzen, G.; Suciu, S.] European Org Res Treatment Canc, Brussels, Belgium. RP Eggermont, AMM (reprint author), Gustave Roussy Canc Campus Grand Paris, 114 Rue Edouard Vaillant, F-94805 Villejuif, France.; Eggermont, AMM (reprint author), Univ Paris Sud, 114 Rue Edouard Vaillant, F-94805 Villejuif, France. EM alexander.eggermont@gustaveroussy.fr FU Actelion Pharmaceuticals; Agenus; Bristol-Myers Squibb; GlaxoSmithKline; HalioDx; Incyte; Merck Sharp Dohme; Novartis; Pfizer; Roche; Amgen; MedImmune; Ziopharm Oncology; Polynoma; Polaris; Jounce Therapeutics; Merck Serono; Genentech; Ventana Medical Systems FX Dr. Eggermont reports receiving fees for serving on scientific advisory boards from Actelion Pharmaceuticals, Agenus, Bristol-Myers Squibb, GlaxoSmithKline, HalioDx, Incyte, Merck Sharp & Dohme, Novartis, and Pfizer; Dr. Chiarion-Sileni, receiving consulting fees and travel support from Bristol-Myers Squibb, Roche, GlaxoSmithKline, and Merck Sharp & Dohme, and lecture fees from Bristol-Myers Squibb, Roche, and GlaxoSmithKline; Dr. Grob, receiving consulting fees from Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Roche, Merck, and Amgen, lecture fees from Bristol-Myers Squibb, GlaxoSmithKline, and Roche, travel support from Roche, and research funding from Bristol-Myers Squibb and Roche; Dr. Dummer, receiving consulting fees, honoraria, and research funding from Bristol-Myers Squibb, Roche, GlaxoSmithKline, Merck Sharp & Dohme, and Novartis; Dr. Wolchok, receiving consulting fees from Bristol-Myers Squibb, Merck, MedImmune, Ziopharm Oncology, Polynoma, Polaris, GlaxoSmithKline, and Jounce Therapeutics, honoraria from EMD Serono and Janssen Oncology, institutional research funding from Bristol-Myers Squibb, Merck, MedImmune, and GlaxoSmithKline, and holding a pending patent related to compositions and methods for the treatment of melanoma (U. S. patent number, US7556805); Dr. Hamid, receiving consulting fees from Amgen, Novartis, Roche, Bristol-Myers Squibb, Merck, Merck Serono, Pfizer, and Genentech, and lecture fees from Novartis, Bristol-Myers Squibb, and Genentech; Dr. Robert, receiving consulting fees from Bristol-Myers Squibb, Merck, Roche, and Amgen, and honoraria from Bristol-Myers Squibb, Merck, GlaxoSmithKline, Roche, Novartis, and Amgen; Dr. Ascierto, receiving consulting fees from Bristol-Myers Squibb, Roche (formerly Genentech), GlaxoSmithKline, Merck Sharp & Dohme, Ventana Medical Systems, Novartis, and Amgen, honoraria from Bristol-Myers Squibb, Roche (formerly Genentech), and GlaxoSmithKline, and grant support to his institution from Bristol-Myers Squibb, Roche (formerly Genentech), and Ventana Medical Systems; Dr. Lebbe, receiving fees for serving on advisory boards from Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, GlaxoSmithKline, and Novartis; Dr. Smylie, receiving consulting fees and honoraria from Bristol-Myers Squibb, Roche, GlaxoSmithKline, and Merck, and lecture fees from Bristol-Myers Squibb and Roche; Dr. Weber, receiving consulting fees and honoraria from Bristol-Myers Squibb, Merck, GlaxoSmithKline, Roche, and Genentech, research funding from Bristol-Myers Squibb, Merck, GlaxoSmithKline, Roche, and Genentech, and MacroGenics, and holding stock in Celldex Therapeutics, Altor BioScience, and cCAM Biotherapeutics; Dr. Maio, receiving consulting fees, honoraria, and travel support from Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, GlaxoSmithKline, and MedImmune, and research funding from Bristol-Myers Squibb and MedImmune; Dr. Bastholt, receiving fees for serving on advisory boards from Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, and GlaxoSmithKline; Dr. Mortier, receiving fees for serving on an advisory board from Bristol-Myers Squibb and clinical-trial support from Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, and Roche; Dr.; Hauschild, receiving consulting fees and honoraria from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, MedImmune, Nektar Therapeutics, OncoSec Medical, Philogen, Provectus Biopharmaceuticals, and Regeneron Pharmaceuticals, and grant support from Amgen, Bristol-Myers Squibb, Celgene, Eisai, GlaxoSmithKline, Merck Serono, Merck Sharp & Dohme, Novartis, and Roche; Dr. Hassel, receiving consulting fees from GlaxoSmithKline and Amgen, honoraria and lecture fees from Bristol-Myers Squibb, GlaxoSmithKline, Roche, Merck Sharp & Dohme, and Amgen, and travel support from Bristol-Myers Squibb and Amgen; Dr. Hodi, receiving consulting fees and grant support to his institution from Bristol-Myers Squibb, holding a patent related to therapeutic peptides (U. S. patent number, 20160046716), and holding a pending patent related to methods for treating MHC class I polypeptide-related sequence A (MICA) related disorders (U. S. patent number, 20140037630); Dr. Taitt and Ms. de Pril, being employees of Bristol-Myers Squibb; and Dr. Taitt, holding stock in Bristol-Myers Squibb. No other potential conflict of interest relevant to this article was reported. NR 22 TC 10 Z9 10 U1 5 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD NOV 10 PY 2016 VL 375 IS 19 BP 1845 EP 1855 DI 10.1056/NEJMoa1611299 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EB6ZK UT WOS:000387534200008 PM 27717298 ER PT J AU Ferris, RL Blumenschein, G Fayette, J Guigay, J Colevas, AD Licitra, L Harrington, K Kasper, S Vokes, EE Even, C Worden, F Saba, NF Docampo, LCI Haddad, R Rordorf, T Kiyota, N Tahara, M Monga, M Lynch, M Geese, WJ Kopit, J Shaw, JW Gillison, ML AF Ferris, R. L. Blumenschein, G., Jr. Fayette, J. Guigay, J. Colevas, A. D. Licitra, L. Harrington, K. Kasper, S. Vokes, E. E. Even, C. Worden, F. Saba, N. F. Iglesias Docampo, L. C. Haddad, R. Rordorf, T. Kiyota, N. Tahara, M. Monga, M. Lynch, M. Geese, W. J. Kopit, J. Shaw, J. W. Gillison, M. L. TI Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID QUALITY-OF-LIFE; OPEN-LABEL; PHASE-3 TRIAL; LUNG-CANCER; CHEMOTHERAPY; DOCETAXEL; THERAPY; SCORES; EGFR AB BACKGROUND Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition. METHODS In this randomized, open-label, phase 3 trial, we assigned, in a 2: 1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life. RESULTS The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group. CONCLUSIONS Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. C1 [Ferris, R. L.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Ferris, R. L.] Inst Canc Res, Pittsburgh, PA USA. [Blumenschein, G., Jr.] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA. [Fayette, J.] Ctr Leon Berard, Lyon, France. [Guigay, J.] Ctr Antoine Lacassagne, Nice, France. [Even, C.] Inst Gustave Roussy, Villejuif, France. [Colevas, A. D.] Stanford Canc Inst, Stanford, CA USA. [Licitra, L.] Fdn Ist Ricovero & Cura Carattere Sci, Ist Nazl Tumori, Milan, Italy. [Harrington, K.] Inst Canc Res, Royal Marsden Natl Inst Hlth Res, Biomed Res Ctr, London, England. [Kasper, S.] Univ Hosp Essen, Essen, Germany. [Vokes, E. E.] Univ Chicago, Chicago, IL 60637 USA. [Worden, F.] Univ Michigan, Ann Arbor, MI 48109 USA. [Saba, N. F.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Iglesias Docampo, L. C.] Hosp Univ 12 Octubre, Madrid, Spain. [Haddad, R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Rordorf, T.] Univ Spital Zurich, Zurich, Switzerland. [Kiyota, N.] Kobe Univ Hosp, Kobe, Hyogo, Japan. [Tahara, M.] Natl Canc Ctr Hosp East, Kashiwa, Chiba, Japan. [Monga, M.; Lynch, M.; Geese, W. J.; Kopit, J.; Shaw, J. W.] Bristol Myers Squibb Co, Princeton, NJ USA. [Gillison, M. L.] Ohio State Univ, Columbus, OH 43210 USA. RP Gillison, ML (reprint author), Ohio State Univ, Ctr Comprehens Canc, 420 W 12th Ave,Rm 690, Columbus, OH 43210 USA. EM maura.gillison@osumc.edu RI Licitra, Lisa/C-6271-2017 OI Licitra, Lisa/0000-0003-0623-4118 FU Bristol-Myers Squibb FX Supported by Bristol-Myers Squibb. NR 24 TC 21 Z9 21 U1 11 U2 11 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 NOV 10 PY 2016 VL 375 IS 19 BP 1856 EP 1867 DI 10.1056/NEJMoa1602252 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EB6ZK UT WOS:000387534200009 PM 27718784 ER PT J AU Sweetser, DA Lin, AE Troulis, MJ Chen, TC Westra, SJ AF Sweetser, David A. Lin, Angela E. Troulis, Maria J. Chen, Teresa C. Westra, Sjirk J. TI Case 34-2016: A 17-Year-Old Boy with Myopia and Craniofacial and Skeletal Abnormalities SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID WEILL-MARCHESANI-SYNDROME; MARFAN-SYNDROME; HOMOCYSTINURIA C1 [Sweetser, David A.; Lin, Angela E.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Troulis, Maria J.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Westra, Sjirk J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Sweetser, David A.; Lin, Angela E.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Chen, Teresa C.] Harvard Med Sch, Dept Ophthalmol, Boston, MA USA. [Westra, Sjirk J.] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Troulis, Maria J.] Harvard Sch Dent Med, Dept Oral & Maxillofacial Surg, Boston, MA USA. [Chen, Teresa C.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. RP Sweetser, DA (reprint author), Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA.; Sweetser, DA (reprint author), Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. NR 17 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 NOV 10 PY 2016 VL 375 IS 19 BP 1879 EP 1890 DI 10.1056/NEJMcpc1610096 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EB6ZK UT WOS:000387534200012 PM 27959664 ER PT J AU Johnson, BE AF Johnson, Bruce E. TI Divide and Conquer to Treat Lung Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID CHEMOTHERAPY; NIVOLUMAB; EGFR; CRIZOTINIB; DOCETAXEL C1 [Johnson, Bruce E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Johnson, Bruce E.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Johnson, BE (reprint author), Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. NR 11 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 NOV 10 PY 2016 VL 375 IS 19 BP 1892 EP 1893 DI 10.1056/NEJMe1611003 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EB6ZK UT WOS:000387534200013 PM 27718875 ER PT J AU Wang, ZG Wang, XJ Li, MH Gao, Y Hu, ZQ Nan, TX Liang, XF Chen, HH Yang, J Cash, S Sun, NX AF Wang, Zhiguang Wang, Xinjun Li, Menghui Gao, Yuan Hu, Zhongqiang Nan, Tianxiang Liang, Xianfeng Chen, Huaihao Yang, Jia Cash, Syd Sun, Nian-Xiang TI Highly Sensitive Flexible Magnetic Sensor Based on Anisotropic Magnetoresistance Effect SO ADVANCED MATERIALS LA English DT Article ID MAGNETOELECTRONICS; PERFORMANCE; ELECTRONICS; LOCALIZATION; DETECTOR; DISPLAY; OBJECTS; FIELD; GMR AB A highly sensitive flexible magnetic sensor based on the anisotropic magnetoresistance effect is fabricated. A limit of detection of 150 nT is observed and excellent deformation stability is achieved after wrapping of the flexible sensor, with bending radii down to 5 mm. The flexible AMR sensor is used to read a magnetic pattern with a thickness of 10 mu m that is formed by ferrite magnetic inks. C1 [Wang, Zhiguang; Wang, Xinjun; Li, Menghui; Gao, Yuan; Hu, Zhongqiang; Nan, Tianxiang; Liang, Xianfeng; Chen, Huaihao; Sun, Nian-Xiang] Northeastern Univ, Dept Elect & Comp Engn, Boston, MA 02115 USA. [Yang, Jia] Boston Univ, Dept Mech Engn, Boston, MA 02215 USA. [Wang, Zhiguang; Cash, Syd] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Cambridge, MA 02114 USA. RP Wang, ZG; Sun, NX (reprint author), Northeastern Univ, Dept Elect & Comp Engn, Boston, MA 02115 USA.; Wang, ZG (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Cambridge, MA 02114 USA. EM nanozgwang@gmail.com; n.sun@neu.edu RI Gao, Yuan/E-4277-2016 OI Gao, Yuan/0000-0002-2444-1180 FU W. M. Keck Foundation FX The work was financially supported by W. M. Keck Foundation. The authors thank Scott McNamara and Sivasubramanian Somu for useful discussion about microfabricaiton. And they thank Kostas Nanoscale Research Center in Northeastern University and Center for Nanoscale Systems in Harvard University for fabrication and characterization facilities. NR 44 TC 1 Z9 1 U1 18 U2 18 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 NOV 9 PY 2016 VL 28 IS 42 BP 9370 EP + DI 10.1002/adma.201602910 PG 9 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 EG6RV UT WOS:000391174600014 PM 27593972 ER PT J AU Natarajan, P Gold, NB Bick, AG McLaughlin, H Kraft, P Rehm, HL Peloso, GM Wilson, JG Correa, A Seidman, JG Seidman, CE Kathiresan, S Green, RC AF Natarajan, Pradeep Gold, Nina B. Bick, Alexander G. McLaughlin, Heather Kraft, Peter Rehm, Heidi L. Peloso, Gina M. Wilson, James G. Correa, Adolfo Seidman, Jonathan G. Seidman, Christine E. Kathiresan, Sekar Green, Robert C. TI Aggregate penetrance of genomic variants for actionable disorders in European and African Americans SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID LONG-QT SYNDROME; RIGHT-VENTRICULAR CARDIOMYOPATHY; HEAVY-CHAIN GENE; AUTOSOMAL-DOMINANT HYPERCHOLESTEROLEMIA; FAMILIAL HYPERTROPHIC CARDIOMYOPATHY; MALIGNANT HYPERTHERMIA FAMILIES; EXPLORATORY RESEARCH CONSORTIUM; DEFECTIVE APOLIPOPROTEIN B-100; MISMATCH REPAIR GENES; BREAST AND/OR OVARIAN AB In populations that have not been selected for family history of disease, it is unclear how commonly pathogenic variants (PVs) in disease-associated genes for rare Mendelian conditions are found and how often they are associated with clinical features of these conditions. We conducted independent, prospective analyses of participants in two community-based epidemiological studies to test the hypothesis that persons carrying PVs in any of 56 genes that lead to 24 dominantly inherited, actionable conditions are more likely to exhibit the clinical features of the corresponding diseases than those without PVs. Among 462 European American Framingham Heart Study (FHS) and 3223 African-American Jackson Heart Study (JHS) participants who were exome-sequenced, we identified and classified 642 and 4429 unique variants, respectively, in these 56 genes while blinded to clinical data. In the same participants, we ascertained related clinical features from the participants' clinical history of cancer and most recent echocardiograms, electrocardiograms, and lipid measurements, without knowledge of variant classification. PVs were found in 5 FHS (1.1%) and 31 JHS (1.0%) participants. Carriers of PVs were more likely than expected, on the basis of incidence in noncarriers, to have related clinical features in both FHS (80.0% versus 12.4%) and JHS (26.9% versus 5.4%), yielding standardized incidence ratios of 6.4 [95% confidence interval (CI), 1.7 to 16.5; P = 7 x 10(-4)) in FHS and 4.7 (95% CI, 1.9 to 9.7; P = 3 x 10(-4)) in JHS. Individuals unselected for family history who carry PVs in 56 genes for actionable conditions have an increased aggregated risk of developing clinical features associated with the corresponding diseases. C1 [Natarajan, Pradeep; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Dept Med, Cardiol Div, Boston, MA 02114 USA. [Natarajan, Pradeep; Kathiresan, Sekar; Green, Robert C.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Dept Med, Cardiol Div, Boston, MA 02114 USA. [Natarajan, Pradeep; Gold, Nina B.; Bick, Alexander G.; McLaughlin, Heather; Rehm, Heidi L.; Peloso, Gina M.; Seidman, Jonathan G.; Seidman, Christine E.; Kathiresan, Sekar; Green, Robert C.] Harvard Med Sch, Boston, MA 02115 USA. [Natarajan, Pradeep; Bick, Alexander G.; Peloso, Gina M.; Kathiresan, Sekar; Green, Robert C.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Gold, Nina B.] Boston Childrens Hosp, Boston, MA 02115 USA. [Bick, Alexander G.; Seidman, Jonathan G.; Seidman, Christine E.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [McLaughlin, Heather; Rehm, Heidi L.; Green, Robert C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [McLaughlin, Heather; Rehm, Heidi L.; Green, Robert C.] Partners Hlthcare Personalized Med, Boston, MA 02115 USA. [Kraft, Peter] Partners Hlthcare Personalized Med, Dept Epidemiol, Boston, MA 02115 USA. [Kraft, Peter] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Wilson, James G.; Green, Robert C.] Univ Mississippi Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Correa, Adolfo] Univ Mississippi, Med Ctr, Dept Pediat & Med, Jackson, MS 39216 USA. [Seidman, Christine E.; Green, Robert C.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Seidman, Christine E.] Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Green, RC (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Dept Med, Cardiol Div, Boston, MA 02114 USA.; Green, RC (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Green, RC (reprint author), Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA.; Green, RC (reprint author), Univ Mississippi Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. EM rcgreen@bwh.harvard.edu FU NIH [U01HG006500, U19HD077671, U41HG006834, T32GM007753, R01CA154517, R01HG06615]; Howard Hughes Medical Institute; NHLBI [N01HC25195, 6R01NS17950, HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities FX This work was supported by NIH grants U01HG006500, U19HD077671, U41HG006834, T32GM007753, R01CA154517, and R01HG06615, and the Howard Hughes Medical Institute. The FHS was supported by contracts N01HC25195 and 6R01NS17950 from NHLBI. The JHS was supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268201300050C from NHLBI and the National Institute on Minority Health and Health Disparities. NR 170 TC 0 Z9 0 U1 0 U2 0 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 NOV 9 PY 2016 VL 8 IS 364 AR 364ra151 DI 10.1126/scitranslmed.aag2367 PG 13 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EE2XF UT WOS:000389448100002 ER PT J AU Saung, MT Sharei, A Adalsteinsson, VA Cho, N Kamath, T Ruiz, C Kirkpatrick, J Patel, N Mino-Kenudson, M Thayer, SP Langer, R Jensen, KF Liss, AS Love, JC AF Saung, May Tun Sharei, Armon Adalsteinsson, Viktor A. Cho, Nahyun Kamath, Tushar Ruiz, Camilo Kirkpatrick, Jesse Patel, Nehal Mino-Kenudson, Mari Thayer, Sarah P. Langer, Robert Jensen, Klavs F. Liss, Andrew S. Love, J. Christopher TI A Size-Selective Intracellular Delivery Platform SO SMALL LA English DT Article ID CIRCULATING TUMOR-CELLS; CANCER; MIGRATION; REPAIR; DNA AB Identifying and separating a subpopulation of cells from a heterogeneous mixture are essential elements of biological research. Current approaches require detailed knowledge of unique cell surface properties of the target cell population. A method is described that exploits size differences of cells to facilitate selective intracellular delivery using a high throughput microfluidic device. Cells traversing a constriction within this device undergo a transient disruption of the cell membrane that allows for cytoplasmic delivery of cargo. Unique constriction widths allow for optimization of delivery to cells of different sizes. For example, a 4 mu m wide constriction is effective for delivery of cargo to primary human T-cells that have an average diameter of 6.7 mu m. In contrast, a 6 or 7 mu m wide constriction is best for large pancreatic cancer cell lines BxPc3 (10.8 mu m) and PANC-1 (12.3 mu m). These small differences in cell diameter are sufficient to allow for selective delivery of cargo to pancreatic cancer cells within a heterogeneous mixture containing T-cells. The application of this approach is demonstrated by selectively delivering dextran-conjugated fluorophores to circulating tumor cells in patient blood allowing for their subsequent isolation and genomic characterization. C1 [Saung, May Tun; Sharei, Armon; Adalsteinsson, Viktor A.; Cho, Nahyun; Kamath, Tushar; Ruiz, Camilo; Kirkpatrick, Jesse; Langer, Robert; Jensen, Klavs F.; Love, J. Christopher] MIT, Dept Chem Engn, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Saung, May Tun] Massachusetts Gen Hosp, Dept Med, Hosp Med Unit, Boston, MA 02114 USA. [Patel, Nehal] Massachusetts Gen Hosp, Adv Tissue Resources Core, Charlestown, MA 02129 USA. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Thayer, Sarah P.; Liss, Andrew S.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Love, J. Christopher] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Thayer, Sarah P.] Fred & Pamela Buffett Canc Ctr, Div Surg Oncol, 986345 Univ Nebraska Med Ctr, Omaha, NE 68198 USA. RP Love, JC (reprint author), MIT, Dept Chem Engn, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA.; Liss, AS (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA.; Love, JC (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. EM aliss@mgh.harvard.edu; clove@mit.edu FU National Institutes of Health [R01GM101420-01A1, P01CA117969]; Kathy and Curt Marble Cancer Research Fund; Ragon Institute of Harvard/MIT/MGH; Koch Institute from the National Cancer Institute [P30-CA14051] FX M.T.S., A.S., and V.K.A. contributed equally to this work. This work was supported by National Institutes of Health under Grant Nos. R01GM101420-01A1 and P01CA117969, the Kathy and Curt Marble Cancer Research Fund, the Ragon Institute of Harvard/MIT/MGH, and the Koch Institute Support (core) GrantP30-CA14051 from the National Cancer Institute. NR 26 TC 0 Z9 0 U1 12 U2 12 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 NOV 9 PY 2016 VL 12 IS 42 BP 5873 EP 5881 DI 10.1002/smll.201601155 PG 9 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 EE2HF UT WOS:000389403900009 ER PT J AU Bargieri, DY Thiberge, S Tay, CL Carey, AF Rantz, A Hischen, F Lorthiois, A Straschil, U Singh, P Singh, S Triglia, T Tsuboi, T Cowman, A Chitnis, C Alano, P Baum, J Pradel, G Lavazec, C Menard, R AF Bargieri, Daniel Y. Thiberge, Sabine Tay, Chwen L. Carey, Alison F. Rantz, Alice Hischen, Florian Lorthiois, Audrey Straschil, Ursula Singh, Pallavi Singh, Shailja Triglia, Tony Tsuboi, Takafumi Cowman, Alan Chitnis, Chetan Alano, Pietro Baum, Jake Pradel, Gabriele Lavazec, Catherine Menard, Robert TI Plasmodium Merozoite TRAP Family Protein Is Essential for Vacuole Membrane Disruption and Gamete Egress from Erythrocytes SO CELL HOST & MICROBE LA English DT Article ID RED-BLOOD-CELL; MALARIA PARASITE; GLIDING MOTILITY; FALCIPARUM GAMETOCYTES; APICOMPLEXAN PARASITES; OSMIOPHILIC BODIES; ACTIN CYTOSKELETON; IN-VITRO; TRANSMISSION; BERGHEI AB Surface-associated TRAP (thrombospondin-related anonymous protein) family proteins are conserved across the phylum of apicomplexan parasites. TRAP proteins are thought to play an integral role in parasite motility and cell invasion by linking the extracellular environment with the parasite submembrane actomyosin motor. Blood stage forms of the malaria parasite Plasmodium express a TRAP family protein called merozoite-TRAP (MTRAP) that has been implicated in erythrocyte invasion. Using MTRAP-deficient mutants of the rodent-infecting P. berghei and human-infecting P. falciparum parasites, we show that MTRAP is dispensable for erythrocyte invasion. Instead, MTRAP is essential for gamete egress from erythrocytes, where it is necessary for the disruption of the gamete-containing parasitophorous vacuole membrane, and thus for parasite transmission to mosquitoes. This indicates that motor-binding TRAP family members function not just in parasite motility and cell invasion but also in membrane disruption and cell egress. C1 [Bargieri, Daniel Y.; Thiberge, Sabine; Carey, Alison F.; Rantz, Alice; Menard, Robert] Inst Pasteur, Malaria Biol & Genet Unit, F-75015 Paris, France. [Bargieri, Daniel Y.] Univ Sao Paulo, Dept Parasitol, BR-05508000 Sao Paulo, SP, Brazil. [Tay, Chwen L.; Straschil, Ursula; Baum, Jake] Imperial Coll London, Dept Life Sci, London SW7 2AZ, England. [Carey, Alison F.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hischen, Florian; Pradel, Gabriele] Rhein Westfal TH Aachen, Inst Zool, Div Cellular & Appl Infect Biol, D-52074 Aachen, Germany. [Lorthiois, Audrey; Lavazec, Catherine] Univ Paris 05, Inst Cochin, INSERM, CNRS,U1016,UMR 8104, F-75014 Paris, France. [Singh, Pallavi; Singh, Shailja; Chitnis, Chetan] Inst Pasteur, Malaria Parasite Biol & Vaccines Unit, F-75015 Paris, France. [Triglia, Tony; Cowman, Alan] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia. [Cowman, Alan] Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, Australia. [Tsuboi, Takafumi] Ehime Univ, Div Malaria Res, Proteosci Ctr, Matsuyama, Ehime 7908577, Japan. [Alano, Pietro] Ist Super Sanita, Dipartimento Malattie Infett Parassitarie & Immun, I-00161 Rome, Italy. RP Bargieri, DY (reprint author), Inst Pasteur, Malaria Biol & Genet Unit, F-75015 Paris, France.; Bargieri, DY (reprint author), Univ Sao Paulo, Dept Parasitol, BR-05508000 Sao Paulo, SP, Brazil. EM danielbargieri@gmail.com OI alano, pietro/0000-0003-0092-9840 FU FAPESP [2013/13119-6]; JSPS KAKENHI in Japan [JP26253026]; EU-FP7 grant EVIMalaR [242095]; Bill & Melinda Gates Foundation [OPP1040394]; Wellcome Trust [100993/Z/13/Z]; DFG [SPP1580] FX D.Y.B. is supported by a FAPESP grant (2013/13119-6). T. Tsuboi acknowledges JSPS KAKENHI (JP26253026) in Japan. P.A. acknowledges funding from the EU-FP7 grant EVIMalaR (n.242095) and the Bill & Melinda Gates Foundation grant OPP1040394. J.B. is supported by the Wellcome Trust through an Investigator Award (100993/Z/13/Z). G.P. acknowledges funding by the Priority Programme SPP1580 of the DFG. NR 59 TC 2 Z9 2 U1 5 U2 5 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 NOV 9 PY 2016 VL 20 IS 5 BP 618 EP 630 DI 10.1016/j.chom.2016.10.015 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EE3FA UT WOS:000389472000011 PM 27832590 ER PT J AU Karat, AS Omar, T von Gottberg, A Tlali, M Chihota, VN Churchyard, GJ Fielding, KL Johnson, S Martinson, NA McCarthy, K Wolter, N Wong, EB Charalambous, S Grant, AD AF Karat, Aaron S. Omar, Tanvier von Gottberg, Anne Tlali, Mpho Chihota, Violet N. Churchyard, Gavin J. Fielding, Katherine L. Johnson, Suzanne Martinson, Neil A. McCarthy, Kerrigan Wolter, Nicole Wong, Emily B. Charalambous, Salome Grant, Alison D. TI Autopsy Prevalence of Tuberculosis and Other Potentially Treatable Infections among Adults with Advanced HIV Enrolled in Out-Patient Care in South Africa SO PLOS ONE LA English DT Article ID TIME PCR ASSAY; ANTIRETROVIRAL THERAPY; POSTMORTEM BACTERIOLOGY; HOSPITALIZED ADULTS; CLINICAL SPECIMENS; POSITIVE PATIENTS; DEATH; VALIDATION; MORTALITY; ROUTINE AB Background Early mortality among HIV-positive adults starting antiretroviral therapy (ART) remains high in resource-limited settings, with tuberculosis (TB) the leading cause of death. However, current methods to estimate TB-related deaths are inadequate and most autopsy studies do not adequately represent those attending primary health clinics (PHCs). This study aimed to determine the autopsy prevalence of TB and other infections in adults enrolled at South African PHCs in the context of a pragmatic trial of empiric TB treatment ("TB Fast Track"). Methods and Findings Adults with CD4 <= 150 cells/mu L, not on ART or TB treatment, were enrolled to TB Fast Track and followed up for at least six months. Minimally invasive autopsy (MIA) was conducted as soon as possible after death. Lungs, liver, and spleen were biopsied; blood, CSF, and urine aspirated; and bronchoalveolar lavage fluid obtained. Samples underwent mycobacterial, bacterial, and fungal culture; molecular testing (including Xpert (R) MTB/RIF); and histological examination. 34 MIAs were conducted: 18 (53%) decedents were female; median age was 39 (interquartile range 33-44) years; 25 (74%) deaths occurred in hospitals; median time from death to MIA was five (IQR 3-6) days. 16/34 (47%) had evidence of TB (14/16 [88%] with extrapulmonary disease; 6/16 [38%] not started on treatment antemortem); 23 (68%) had clinically important bacterial infections; four (12%) cryptococcal disease; three (9%) non-tuberculous mycobacterial disease; and two (6%) Pneumocystis pneumonia. Twenty decedents (59%) had evidence of two or more concurrent infections; 9/ 16 (56%) individuals with TB had evidence of bacterial disease and two (13%) cryptococcal disease. Conclusions TB, followed by bacterial infections, were the leading findings at autopsy among adults with advanced HIV enrolled from primary care clinics. To reduce mortality, strategies are needed to identify and direct those at highest risk into a structured pathway that includes expedited investigation and/or treatment of TB and other infections. C1 [Karat, Aaron S.; Churchyard, Gavin J.; Fielding, Katherine L.; Grant, Alison D.] London Sch Hyg & Trop Med, TB Ctr, London, England. [Omar, Tanvier] Natl Hlth Lab Serv, Dept Anat Pathol, Johannesburg, South Africa. [Omar, Tanvier] Univ Witwatersrand, Johannesburg, South Africa. [von Gottberg, Anne; Wolter, Nicole] Natl Hlth Lab Serv, Natl Inst Communicable Dis, Ctr Resp Dis & Meningitis, Johannesburg, South Africa. [von Gottberg, Anne; Wolter, Nicole] Univ Witwatersrand, Fac Hlth Sci, Sch Pathol, Johannesburg, South Africa. [Tlali, Mpho; Chihota, Violet N.; Churchyard, Gavin J.; McCarthy, Kerrigan; Charalambous, Salome] Aurum Inst, Johannesburg, South Africa. [Chihota, Violet N.; Churchyard, Gavin J.; Fielding, Katherine L.; McCarthy, Kerrigan; Charalambous, Salome; Grant, Alison D.] Univ Witwatersrand, Fac Hlth Sci, Sch Publ Hlth, Johannesburg, South Africa. [Johnson, Suzanne] Fdn Profess Dev, Pretoria, South Africa. [Martinson, Neil A.] Univ Witwatersrand, Perinatal HIV Res Unit, Johannesburg, South Africa. [Martinson, Neil A.] Univ Witwatersrand, Med Res Council, Soweto Matlosana Collaborating Ctr HIV AIDS & TB, Johannesburg, South Africa. [Martinson, Neil A.] Johns Hopkins Univ, Ctr TB Res, Baltimore, MD USA. [Martinson, Neil A.] Univ Witwatersrand, Dept Sci & Technol, Natl Res Fdn, Ctr Excellence Biomed TB Res, Johannesburg, South Africa. [McCarthy, Kerrigan] Natl Hlth Lab Serv, Natl Inst Communicable Dis, Div Publ Hlth Surveillance & Response, Johannesburg, South Africa. [Wong, Emily B.] Africa Hlth Res Inst, Durban, South Africa. [Wong, Emily B.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Grant, Alison D.] Univ KwaZulu Natal, Durban, South Africa. RP Karat, AS (reprint author), London Sch Hyg & Trop Med, TB Ctr, London, England. EM aaron.karat@lshtm.ac.uk OI Karat, Aaron/0000-0001-9643-664X FU Bill and Melinda Gates Foundation [OPP1083118] FX This study was funded by the Bill and Melinda Gates Foundation (Global Health Grant number OPP1083118; http://www.gatesfoundation.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 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 NOV 9 PY 2016 VL 11 IS 11 AR e0166158 DI 10.1371/journal.pone.0166158 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB9OG UT WOS:000387724300092 PM 27829072 ER PT J AU Dutt, S Binney, RJ Heuer, HW Luong, P Attygalle, S Bhatt, P Marx, GA Elofson, J Tartaglia, MC Litvan, I McGinnis, SM Dickerson, BC Kornak, J Waltzman, D Voltarelli, L Schuff, N Rabinovici, GD Kramer, JH Jack, CR Miller, BL Rosen, HJ Boxer, AL AF Dutt, Shubir Binney, Richard J. Heuer, Hilary W. Luong, Phi Attygalle, Suneth Bhatt, Priyanka Marx, Gabe A. Elofson, Jonathan Tartaglia, Maria C. Litvan, Irene McGinnis, Scott M. Dickerson, Bradford C. Kornak, John Waltzman, Dana Voltarelli, Lisa Schuff, Norbert Rabinovici, Gil D. Kramer, Joel H. Jack, Clifford R. Miller, Bruce L. Rosen, Howard J. Boxer, Adam L. CA AL-108-231 Investigators TI Progression of brain atrophy in PSP and CBS over 6 months and 1 year SO NEUROLOGY LA English DT Article ID MULTIPLE SYSTEM ATROPHY; SUPRANUCLEAR PALSY; CORTICOBASAL DEGENERATION; MIDBRAIN ATROPHY; CEREBRAL ATROPHY; PONS RATIO; MRI; DIAGNOSIS; CRITERIA; RATES AB Objective: To examine the utility and reliability of volumetric MRI in measuring disease progression in the 4 repeat tauopathies, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), to support clinical development of new tau-directed therapeutic agents. Methods: Six- and 12-month changes in regional MRI volumes and PSP Rating Scale scores were examined in 55 patients with PSP and 33 patients with CBS (78% amyloid PET negative) compared to 30 normal controls from a multicenter natural history study. Longitudinal voxel-based morphometric analyses identified patterns of volume loss, and region-of-interest analyses examined rates of volume loss in brainstem (midbrain, pons, superior cerebellar peduncle), cortical, and subcortical regions based on previously validated atlases. Results were compared to those in a replication cohort of 226 patients with PSP with MRI data from the AL-108-231 clinical trial. Results: Patients with CBS exhibited greater baseline atrophy and greater longitudinal atrophy rates in cortical and basal ganglia regions than patients with PSP; however, midbrain and pontine atrophy rates were similar. Voxel-wise analyses showed distinct patterns of regional longitudinal atrophy in each group as compared to normal controls. The midbrain/pons volumetric ratio differed between diagnoses but remained stable over time. In both patient groups, brainstem atrophy rates were correlated with disease progression measured using the PSP Rating Scale. Conclusions: Volume loss is quantifiable over a period of 6 months in CBS and PSP. Future clinical trials may be able to combine CBS and PSP to measure therapeutic effects. C1 [Dutt, Shubir; Binney, Richard J.; Heuer, Hilary W.; Luong, Phi; Attygalle, Suneth; Bhatt, Priyanka; Marx, Gabe A.; Elofson, Jonathan; Waltzman, Dana; Voltarelli, Lisa; Rabinovici, Gil D.; Kramer, Joel H.; Miller, Bruce L.; Rosen, Howard J.; Boxer, Adam L.] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA 94143 USA. [Binney, Richard J.] Temple Univ, Saffran Ctr Cognit Neurosci, Dept Commun Sci & Disorders, Philadelphia, PA 19122 USA. [Tartaglia, Maria C.] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON M5S 1A1, Canada. [Litvan, Irene] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [McGinnis, Scott M.; Dickerson, Bradford C.] Harvard Med Sch, Massachusetts Gen Hosp, Gerontol Res Unit, Charlestown, MA USA. [Kornak, John] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Schuff, Norbert] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. [Waltzman, Dana] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Jack, Clifford R.] Mayo Clin, Dept Radiol, Rochester, MN USA. RP Boxer, AL (reprint author), Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA 94143 USA. EM adam.boxer@ucsf.edu RI corvol, jean-christophe/I-6387-2012 OI corvol, jean-christophe/0000-0001-7325-0199 FU NIH [R01AG038791, U54NS092089, P01AG019724, P50AG023501]; Corticobasal Degeneration Solutions; Tau Research Consortium FX This study was supported by NIH grants R01AG038791, U54NS092089, P01AG019724, and P50AG023501, Corticobasal Degeneration Solutions, and the Tau Research Consortium. NR 34 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 NOV 8 PY 2016 VL 87 IS 19 BP 2016 EP 2025 DI 10.1212/WNL.0000000000003305 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA EI1JP UT WOS:000392233600013 PM 27742814 ER PT J AU Gurol, ME Becker, JA Fotiadis, P Riley, G Schwab, K Johnson, KA Greenberg, SM AF Gurol, M. Edip Becker, J. Alex Fotiadis, Panagiotis Riley, Grace Schwab, Kristin Johnson, Keith A. Greenberg, Steven M. TI Florbetapir-PET to diagnose cerebral amyloid angiopathy A prospective study SO NEUROLOGY LA English DT Article ID PITTSBURGH COMPOUND-B; INTRACEREBRAL HEMORRHAGE; ATRIAL-FIBRILLATION; STROKE PREVENTION; LOBAR MICROBLEEDS; DECISION-ANALYSIS; METAANALYSIS; AUTOPSY; MARKERS; BURDEN AB Objective: We hypothesized that florbetapir, a Food and Drug Administration-approved PET tracer, could distinguish cerebral amyloid angiopathy (CAA)-related intracerebral hemorrhage (ICH) from hypertensive ICH (HTN-ICH). Methods: We prospectively enrolled survivors of primary ICH related to probable CAA (per Boston Criteria, n = 10) and HTN-ICH (n = 9) without dementia. All patients underwent florbetapir-PET and multimodal MRI, and patients with CAA had additional Pittsburgh compound B (PiB) PET. Amyloid burden was assessed quantitatively (standard uptake value ratio [SUVR]) and visually classified as positive or negative. Results: The CAA and HTN-ICH groups had similar age (66.9 vs 67.1), sex, and leukoaraiosis volumes (31 vs 30 mL, all p > 0.8). Florbetapir uptake and PiB retention strongly correlated in patients with CAA both globally within cerebral cortex (r = 0.96, p < 0.001) and regionally in lobar cortices (all r > 0.8, all p <= 0.01). Mean global cortical florbetapir uptake was substantially higher in CAA than HTN-ICH (SUVR: 1.41 +/- 0.17 vs 1.15 +/- 0.08, p = 0.001), as was mean occipital SUVR (1.44 +/- 0.12 vs 1.17 +/- 0.08, p < 0.001), even after correcting for global SUVR (p = 0.03). Visual rating for positive/negative florbetapir demonstrated perfect interrater agreement (k = 1) and was positive for all 10 patients with CAA vs 1 of 9 HTN-ICH patients (sensitivity 100%, specificity 89%). Conclusions: Florbetapir appears to label vascular amyloid in patients with CAA-related ICH. The approved florbetapir binary visual reading method can have diagnostic value in appropriate clinical settings. Classification of evidence: This study provides Class II evidence that florbetapir-PET provides a sensitivity of 100% (95% confidence interval [CI] 66%-100%) and specificity of 89% (95% CI 51%-99%) for determination of probable CAA among cognitively normal patients. C1 [Gurol, M. Edip; Fotiadis, Panagiotis; Riley, Grace; Schwab, Kristin; Greenberg, Steven M.] Harvard Med Sch, Hemorrhag Stroke Res Ctr, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Becker, J. Alex; Johnson, Keith A.] Harvard Med Sch, Div Nucl Med & Mol Imaging, Massachusetts Gen Hosp, Boston, MA USA. RP Gurol, ME (reprint author), Harvard Med Sch, Hemorrhag Stroke Res Ctr, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM edip@mail.harvard.edu FU NIH [R01 NS070834, K23 NS083711] FX M. Gurol is funded by NIH grant K23 NS083711. J. Becker, P. Fotiadis, G. Riley, K. Schwab, and K. Johnson report no disclosures relevant to the manuscript. S. Greenberg is funded by NIH grant R01 NS070834. Go to Neurology.org for full disclosures. NR 38 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 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD NOV 8 PY 2016 VL 87 IS 19 BP 2043 EP 2049 DI 10.1212/WNL.0000000000003197 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA EI1JP UT WOS:000392233600016 PM 27605173 ER PT J AU Pucci, F Rickelt, S Newton, AP Garris, C Nunes, E Evavold, C Pfirschke, C Engblom, C Mino-Kenudson, M Hynes, RO Weissleder, R Pittet, MJ AF Pucci, Ferdinando Rickelt, Steffen Newton, Andita P. Garris, Christopher Nunes, Ernesto Evavold, Charles Pfirschke, Christina Engblom, Camilla Mino-Kenudson, Mari Hynes, Richard O. Weissleder, Ralph Pittet, Mikael J. TI PF4 Promotes Platelet Production and Lung Cancer Growth SO CELL REPORTS LA English DT Article ID TUMOR-GROWTH; IN-VIVO; BONE-MARROW; P-SELECTIN; STEM-CELL; METASTASIS; PLATELET-FACTOR-4; MICE; ADENOCARCINOMA; EXPRESSION AB Co-option of host components by solid tumors facilitates cancer progression and can occur in both local tumor microenvironments and remote locations. At present, the signals involved in long-distance communication remain insufficiently understood. Here, we identify platelet factor 4 (PF4, CXCL4) as an endocrine factor whose overexpression in tumors correlates with decreased overall patient survival. Furthermore, engineered PF4 over-production in a Kras-driven lung adenocarcinoma genetic mouse model expanded megakaryopoiesis in bone marrow, augmented platelet accumulation in lungs, and accelerated de novo adenocarcinogenesis. Additionally, anti-platelet treatment controlled mouse lung cancer progression, further suggesting that platelets can modulate the tumor microenvironment to accelerate tumor outgrowth. These findings support PF4 as a cancer-enhancing endocrine signal that controls discrete aspects of bone marrow hematopoiesis and tumor microenvironment and that should be considered as a molecular target in anticancer therapy. C1 [Pucci, Ferdinando; Newton, Andita P.; Garris, Christopher; Evavold, Charles; Pfirschke, Christina; Engblom, Camilla; Weissleder, Ralph; Pittet, Mikael J.] Harvard Med Sch, Massachusetts Gen Hosp, Res Inst, Ctr Syst Biol, Boston, MA 02114 USA. [Rickelt, Steffen; Hynes, Richard O.] MIT, Koch Inst Integrat Canc Res, Howard Hughes Med Inst, Cambridge, MA 02139 USA. [Garris, Christopher; Evavold, Charles; Engblom, Camilla] Harvard Med Sch, Grad Program Immunol, Boston, MA 02115 USA. [Nunes, Ernesto] Univ Minnesota, Dept Comp Sci & Engn, Minneapolis, MN 55455 USA. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Weissleder, Ralph; Pittet, Mikael J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA. [Pucci, Ferdinando] Torque Therapeut Inc, Cambridge, MA 02142 USA. RP Pittet, MJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Res Inst, Ctr Syst Biol, Boston, MA 02114 USA.; Pittet, MJ (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. EM mpittet@mgh.harvard.edu FU Samana Cay MGH Research Scholar Fund; NIH [R21-CA190344, P50-CA86355, R01-AI084880, U54-CA126515, U54-CA163109, F31-CA196035]; European Molecular Biology Organization (EMBO) [ALTF 1535-2011]; Massachusetts General Hospital Executive Committee On Research (ECOR) Funds for Medical Discovery Fellowship; Deutsche Forschungsgemeinschaft [PF809/1-1, RI2408/1-1]; Metastasis/Cancer Research Postdoc fellowship from MIT Ludwig Center for Molecular Oncology Research; Boehringer Ingelheim Funds; Howard Hughes Medical Institute FX This work was supported in part by the Samana Cay MGH Research Scholar Fund to M.J.P.; NIH grants R21-CA190344, P50-CA86355, and R01-AI084880 to M.J.P., U54-CA126515 to R.W., U54-CA163109 to R.O.H., and F31-CA196035 to C.G.; European Molecular Biology Organization (EMBO) long-term fellowship (ALTF 1535-2011) and Massachusetts General Hospital Executive Committee On Research (ECOR) Funds for Medical Discovery Fellowship to F.P.; Deutsche Forschungsgemeinschaft PF809/1-1 to C.P. and RI2408/1-1 to S.R.; Metastasis/Cancer Research Postdoc fellowship from MIT Ludwig Center for Molecular Oncology Research to S.R.; Boehringer Ingelheim Funds to C. Engblom; and the Howard Hughes Medical Institute to R.O.H. The authors thank the members of the Hope Babette Tang Histology Facility at the Koch Institute Swanson Biotechnology Center, Yoshiko Iwamoto of the Center for System Biology for technical support, and Dr. Wouter Meuleman for help with R coding. NR 38 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 NOV 8 PY 2016 VL 17 IS 7 BP 1764 EP 1772 DI 10.1016/j.celrep.2016.10.031 PG 9 WC Cell Biology SC Cell Biology GA EF7YS UT WOS:000390545900007 PM 27829148 ER PT J AU Siwicki, M Engblom, C Pittet, MJ AF Siwicki, Marie Engblom, Camilla Pittet, Mikael J. TI Gal3 Links Inflammation and Insulin Resistance SO Cell Metabolism LA English DT Editorial Material ID MACROPHAGES; GALECTIN-3 AB The connection between obesity-induced insulin resistance and inflammation is established, but targeting inflammatory mediators like TNF-alpha and IL-1 beta have had limited success improving insulin sensitivity in patients. Now, Li et al. (2016) indicate that galectin-3 could be a targetable link between inflammation and insulin sensitivity. C1 [Siwicki, Marie; Engblom, Camilla; Pittet, Mikael J.] Massachusetts Gen Hosp, Ctr Syst Biol, Res Inst, Boston, MA 02114 USA. [Siwicki, Marie; Engblom, Camilla; Pittet, Mikael J.] Harvard Med Sch, Boston, MA 02114 USA. [Siwicki, Marie; Engblom, Camilla] Harvard Med Sch, Grad Program Immunol, Boston, MA 02115 USA. RP Pittet, MJ (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Res Inst, Boston, MA 02114 USA.; Pittet, MJ (reprint author), Harvard Med Sch, Boston, MA 02114 USA. EM mpittet@mgh.harvard.edu NR 8 TC 0 Z9 0 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 NOV 8 PY 2016 VL 24 IS 5 BP 655 EP 656 DI 10.1016/j.cmet.2016.10.014 PG 2 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EE3QC UT WOS:000389508000007 PM 27829136 ER PT J AU Gui, DY Sullivan, LB Luengo, A Hosios, AM Bush, LN Gitego, N Davidson, SM Freinkman, E Thomas, CJ Vander Heiden, MG AF Gui, Dan Y. Sullivan, Lucas B. Luengo, Alba Hosios, Aaron M. Bush, Lauren N. Gitego, Nadege Davidson, Shawn M. Freinkman, Elizaveta Thomas, Craig J. Vander Heiden, Matthew G. TI Environment Dictates Dependence on Mitochondrial Complex I for NAD plus and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin SO Cell Metabolism LA English DT Article ID RESPIRATORY-CHAIN; DIABETIC-PATIENTS; PROSTATE-CANCER; BREAST-CANCER; LUNG-CANCER; METABOLISM; BIGUANIDES; INHIBITION; PHARMACOKINETICS; TUMORIGENESIS AB Metformin use is associated with reduced cancer mortality, but how metformin impacts cancer outcomes is controversial. Although metformin can act on cells autonomously to inhibit tumor growth, the doses of metformin that inhibit proliferation in tissue culture are much higher than what has been described in vivo. Here, we show that the environment drastically alters sensitivity to metformin and other complex I inhibitors. We find that complex I supports proliferation by regenerating nicotinamide adenine dinucleotide (NAD)+, and metformin's anti-proliferative effect is due to loss of NAD+/NADH homeostasis and inhibition of aspartate biosynthesis. However, complex I is only one of many inputs that determines the cellular NAD+/NADH ratio, and dependency on complex I is dictated by the activity of other pathways that affect NAD+ regeneration and aspartate levels. This suggests that cancer drug sensitivity and resistance are not intrinsic properties of cancer cells, and demonstrates that the environment can dictate sensitivity to therapies that impact cell metabolism. C1 [Gui, Dan Y.; Sullivan, Lucas B.; Luengo, Alba; Hosios, Aaron M.; Bush, Lauren N.; Gitego, Nadege; Davidson, Shawn M.; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA. [Gui, Dan Y.; Sullivan, Lucas B.; Luengo, Alba; Hosios, Aaron M.; Bush, Lauren N.; Gitego, Nadege; Davidson, Shawn M.; Vander Heiden, Matthew G.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02142 USA. [Freinkman, Elizaveta] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Thomas, Craig J.] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Vander Heiden, MG (reprint author), MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA.; Vander Heiden, MG (reprint author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02142 USA.; Vander Heiden, MG (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM mvh@mit.edu FU Burroughs Wellcome Fund [SU2C]; Ludwig Center at the Massachusetts Institute of Technology; NIH [P30CA1405141, GG006413, R01 CA168653, R01 CA201276, T32 GM007753]; American Cancer Society [PF-15-096-01-TBE]; National Science Foundation [GRFP DGE-1122374] FX This work was supported by the Burroughs Wellcome Fund, SU2C, the Ludwig Center at the Massachusetts Institute of Technology, and the NIH (P30CA1405141, GG006413, R01 CA168653, and R01 CA201276) to M.G.V.H., NIH (T32 GM007753) to D.Y.G., a postdoctoral fellowship (PF-15-096-01-TBE) from the American Cancer Society to L.B.S., and the National Science Foundation (GRFP DGE-1122374) to A.L. and S.M.D. We thank members of the M.G.V.H. laboratory for thoughtful discussion. NR 54 TC 2 Z9 2 U1 4 U2 4 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 NOV 8 PY 2016 VL 24 IS 5 BP 716 EP 727 DI 10.1016/j.cmet.2016.09.006 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EE3QC UT WOS:000389508000012 PM 27746050 ER PT J AU Taylor, NE Van Dort, CJ Kenny, JD Pei, J Guidera, JA Vlasov, KY Lee, JT Boyden, ES Brown, EN Solt, K AF Taylor, Norman E. Van Dort, Christa J. Kenny, Jonathan D. Pei, JunZhu Guidera, Jennifer A. Vlasov, Ksenia Y. Lee, Justin T. Boyden, Edward S. Brown, Emery N. Solt, Ken TI Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE anesthesia; ventral tegmental area; dopamine; optogenetics; arousal ID POSITIVE REINFORCEMENT; ELECTRICAL-STIMULATION; ISOFLURANE ANESTHESIA; ACETYLCHOLINE-RELEASE; BEHAVIORAL AROUSAL; BASAL GANGLIA; SLEEP; EMERGENCE; PROPOFOL; WAKING AB Dopamine (DA) promotes wakefulness, and DA transporter inhibitors such as dextroamphetamine and methylphenidate are effective for increasing arousal and inducing reanimation, or active emergence from general anesthesia. DA neurons in the ventral tegmental area (VTA) are involved in reward processing, motivation, emotion, reinforcement, and cognition, but their role in regulating wakefulness is less clear. The current study was performed to test the hypothesis that selective optogenetic activation of VTA DA neurons is sufficient to induce arousal from an unconscious, anesthetized state. Floxed-inverse (FLEX)-Channelrhodopsin2 (ChR2) expression was targeted to VTA DA neurons in DA transporter (DAT)-cre mice (ChR2+ group; n = 6). Optical VTA stimulation in ChR2+ mice during continuous, steady-state general anesthesia (CSSGA) with isoflurane produced behavioral and EEG evidence of arousal and restored the righting reflex in 6/6 mice. Pretreatment with the D1 receptor antagonist SCH-23390 before optical VTA stimulation inhibited the arousal responses and restoration of righting in 6/6 ChR2+ mice. In control DAT-cre mice, the VTA was targeted with a viral vector lacking the ChR2 gene (ChR2-group; n = 5). VTA optical stimulation in ChR2-mice did not restore righting or produce EEG changes during isoflurane CSSGA in 5/5 mice. These results provide compelling evidence that selective stimulation of VTA DA neurons is sufficient to induce the transition from an anesthetized, unconscious state to an awake state, suggesting critical involvement in behavioral arousal. C1 [Taylor, Norman E.; Van Dort, Christa J.; Kenny, Jonathan D.; Pei, JunZhu; Guidera, Jennifer A.; Vlasov, Ksenia Y.; Lee, Justin T.; Brown, Emery N.; Solt, Ken] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Taylor, Norman E.; Van Dort, Christa J.; Brown, Emery N.; Solt, Ken] Harvard Med Sch, Dept Anaesthesia, Boston, MA 02114 USA. [Taylor, Norman E.; Van Dort, Christa J.; Kenny, Jonathan D.; Pei, JunZhu; Guidera, Jennifer A.; Vlasov, Ksenia Y.; Lee, Justin T.; Boyden, Edward S.; Brown, Emery N.; Solt, Ken] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Boyden, Edward S.] MIT, Media Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Boyden, Edward S.] MIT, McGovern Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Boyden, Edward S.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Picower Inst Learning & Memory, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Brown, EN (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA.; Brown, EN (reprint author), Harvard Med Sch, Dept Anaesthesia, Boston, MA 02114 USA.; Brown, EN (reprint author), MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA.; Brown, EN (reprint author), MIT, Picower Inst Learning & Memory, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Brown, EN (reprint author), MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM enb@neurostat.mit.edu FU National Institutes of Health [TR01-GM104948, T32-GM07592]; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital FX This work was funded by Grants TR01-GM104948 and T32-GM07592 from the National Institutes of Health (https://www.nih.gov) and the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital (www.massgeneral.org/anesthesia). NR 55 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 NOV 8 PY 2016 VL 113 IS 45 BP 12826 EP 12831 DI 10.1073/pnas.1614340113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC4CL UT WOS:000388073300077 ER PT J AU Shaffer, JS Moore, PL Kardar, M Chakraborty, AK AF Shaffer, J. Scott Moore, Penny L. Kardar, Mehran Chakraborty, Arup K. TI Optimal immunization cocktails can promote induction of broadly neutralizing Abs against highly mutable pathogens SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HIV; broadly neutralizing antibodies; statistical mechanics; evolutionary biology; biophysics ID IMMUNODEFICIENCY-VIRUS TYPE-1; CHRONIC HIV-1 INFECTION; B-CELL SELECTION; IG KNOCKIN MICE; AFFINITY MATURATION; GERMINAL-CENTERS; VACCINE DESIGN; ENVELOPE TRIMER; IMMUNOGEN DESIGN; SHAPE SPACE AB Strategies to elicit Abs that can neutralize diverse strains of a highly mutable pathogen are likely to result in a potent vaccine. Broadly neutralizing Abs (bnAbs) against HIV have been isolated from patients, proving that the human immune system can evolve them. Using computer simulations and theory, we study immunization with diverse mixtures of variant antigens (Ags). Our results show that particular choices for the number of variant Ags and the mutational distances separating them maximize the probability of inducing bnAbs. The variant Ags represent potentially conflicting selection forces that can frustrate the Darwinian evolutionary process of affinity maturation. An intermediate level of frustration maximizes the chance of evolving bnAbs. A simple model makes vivid the origin of this principle of optimal frustration. Our results, combined with past studies, suggest that an appropriately chosen permutation of immunization with an optimally designed mixture (using the principles that we describe) and sequential immunization with variant Ags that are separated by relatively large mutational distances may best promote the evolution of bnAbs. C1 [Shaffer, J. Scott; Chakraborty, Arup K.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Moore, Penny L.] Ctr HIV & Sexually Transmitted Infect, Natl Inst Communicable Dis, Natl Hlth Lab Serv, ZA-2131 Johannesburg, South Africa. [Moore, Penny L.] Univ Witwatersrand, Fac Hlth Sci, ZA-2193 Johannesburg, South Africa. [Moore, Penny L.] Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa, ZA-4041 Durban, South Africa. [Kardar, Mehran; Chakraborty, Arup K.] MIT, Dept Phys, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA 02139 USA. RP Chakraborty, AK (reprint author), MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Chakraborty, AK (reprint author), MIT, Dept Phys, Cambridge, MA 02139 USA.; Chakraborty, AK (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA.; Chakraborty, AK (reprint author), MIT, Dept Chem, Cambridge, MA 02139 USA.; Chakraborty, AK (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Chakraborty, AK (reprint author), Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA 02139 USA. EM arupc@mit.edu FU South African Research Chairs Initiative of the Department of Science and Technology; South African Medical Research Council Strategic Health Innovation Partnerships Program; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University; National Research Foundation of South Africa FX We thank Joy E. Louveau, Jinal N. Bhiman, and Shenshen Wang for helpful discussions. Financial support was provided by the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University. P.L.M. is supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa and the South African Medical Research Council Strategic Health Innovation Partnerships Program. NR 63 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 NOV 8 PY 2016 VL 113 IS 45 BP E7039 EP E7048 DI 10.1073/pnas.1614940113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC4CL UT WOS:000388073300019 ER PT J AU Michaelidis, CI Fine, MJ Lin, CJ Linder, JA Nowalk, MP Shields, RK Zimmerman, RK Smith, KJ AF Michaelidis, Constantinos I. Fine, Michael J. Lin, Chyongchiou Jeng Linder, Jeffrey A. Nowalk, Mary Patricia Shields, Ryan K. Zimmerman, Richard K. Smith, Kenneth J. TI The hidden societal cost of antibiotic resistance per antibiotic prescribed in the United States: an exploratory analysis SO BMC INFECTIOUS DISEASES LA English DT Article DE Societal costs; Antibiotic resistance; Primary care; Stewardship; Negative externality ID RESPIRATORY-TRACT INFECTIONS; ANTIMICROBIAL RESISTANCE; AMBULATORY-CARE; HEALTH; OUTCOMES; ADULTS; MANAGEMENT; PROGRAM AB Background: Ambulatory antibiotic prescribing contributes to the development of antibiotic resistance and increases societal costs. Here, we estimate the hidden societal cost of antibiotic resistance per antibiotic prescribed in the United States. Methods: In an exploratory analysis, we used published data to develop point and range estimates for the hidden societal cost of antibiotic resistance (SCAR) attributable to each ambulatory antibiotic prescription in the United States. We developed four estimation methods that focused on the antibiotic-resistance attributable costs of hospitalization, second-line inpatient antibiotic use, second-line outpatient antibiotic use, and antibiotic stewardship, then summed the estimates across all methods. Results: The total SCAR attributable to each ambulatory antibiotic prescription was estimated to be $13 (range: $3-$95). The greatest contributor to the total SCAR was the cost of hospitalization ($9; 69 % of the total SCAR). The costs of second-line inpatient antibiotic use ($1; 8 % of the total SCAR), second-line outpatient antibiotic use ($2; 15 % of the total SCAR) and antibiotic stewardship ($1; 8 %). This apperars to be an error.; of the total SCAR) were modest contributors to the total SCAR. Assuming an average antibiotic cost of $20, the total SCAR attributable to each ambulatory antibiotic prescription would increase antibiotic costs by 65 % (range: 15-475 %) if incorporated into antibiotic costs paid by patients or payers. Conclusions: Each ambulatory antibiotic prescription is associated with a hidden SCAR that substantially increases the cost of an antibiotic prescription in the United States. This finding raises concerns regarding the magnitude of misalignment between individual and societal antibiotic costs. C1 [Michaelidis, Constantinos I.; Linder, Jeffrey A.] Harvard Med Sch, Brigham & Womens Hosp, Div Gen Med & Primary Care, Boston, MA 02115 USA. [Fine, Michael J.; Shields, Ryan K.; Smith, Kenneth J.] Univ Pittsburgh, Sch Med, Div Gen Internal Med, Pittsburgh, PA USA. [Fine, Michael J.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Lin, Chyongchiou Jeng; Nowalk, Mary Patricia; Zimmerman, Richard K.] Univ Pittsburgh, Sch Med, Dept Family Med, Pittsburgh, PA USA. [Michaelidis, Constantinos I.] Brigham & Womens Hosp, Internal Med, PGY 3, 75 Frances St, Boston, MA 02115 USA. RP Michaelidis, CI (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Gen Med & Primary Care, Boston, MA 02115 USA.; Michaelidis, CI (reprint author), Brigham & Womens Hosp, Internal Med, PGY 3, 75 Frances St, Boston, MA 02115 USA. EM cmichaelidis@partners.org FU National Institutes of Health [T32AG21885, RC4 AG039115, KL2TR000146]; National Institute of Allergy and Infectious Diseases [R21 AI097759, R01AI076256]; Agency for Healthcare Research and Quality [R18 HS018419]; Doris Duke Charitable Foundation; University of Pittsburgh School of Medicine Clinical Scientist Training Program FX This work was supported by the National Institutes of Health [grant numbers T32AG21885 to CIM, RC4 AG039115 to JAL, KL2TR000146 to RKS], the National Institute of Allergy and Infectious Diseases [grant numbers R21 AI097759 to JAL, R01AI076256 to KJS], the Agency for Healthcare Research and Quality [grant number R18 HS018419 to JAL], the Doris Duke Charitable Foundation, and the University of Pittsburgh School of Medicine Clinical Scientist Training Program. NR 39 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 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD NOV 8 PY 2016 VL 16 AR 655 DI 10.1186/s12879-016-1990-4 PG 8 WC Infectious Diseases SC Infectious Diseases GA EB9PQ UT WOS:000387727900002 PM 27825306 ER PT J AU Johansson, H Gray, KP Pagani, O Regan, MM Viale, G Aristarco, V Macis, D Puccio, A Roux, S Maibach, R Colleoni, M Rabaglio, M Price, KN Coates, AS Gelber, RD Goldhirsch, A Kammler, R Bonanni, B Walley, BA AF Johansson, Harriet Gray, Kathryn P. Pagani, Olivia Regan, Meredith M. Viale, Giuseppe Aristarco, Valentina Macis, Debora Puccio, Antonella Roux, Susanne Maibach, Rudolf Colleoni, Marco Rabaglio, Manuela Price, Karen N. Coates, Alan S. Gelber, Richard D. Goldhirsch, Aron Kammler, Roswitha Bonanni, Bernardo Walley, Barbara A. CA Text Principal Investigators TI Impact of CYP19A1 and ESR1 variants on early-onset side effects during combined endocrine therapy in the TEXT trial SO BREAST CANCER RESEARCH LA English DT Article DE Side effects; Aromatase inhibitors; Tamoxifen; Ovarian suppression; Breast cancer; CYP19A1; ESR1 ID BREAST-CANCER RISK; ESTROGEN-RECEPTOR-ALPHA; AROMATASE INHIBITORS; POSTMENOPAUSAL WOMEN; HOT FLASHES; VASOMOTOR SYMPTOMS; GENE POLYMORPHISMS; MENOPAUSAL STATUS; ADVERSE EVENTS; METAANALYSIS AB Background: Single nucleotide polymorphisms (SNPs) in the estrogen receptor 1 (ESR1) and cytochrome P450 19A1 (CYP19A1) genes have been associated with breast cancer risk, endocrine therapy response and side effects, mainly in postmenopausal women with early breast cancer. This analysis aimed to assess the association of selected germline CYP19A1 and ESR1 SNPs with early-onset hot flashes, sweating and musculoskeletal symptoms in premenopausal patients enrolled in the Tamoxifen and Exemestane Trial (TEXT). Methods: Blood was collected from consenting premenopausal women with hormone-responsive early breast cancer, randomly assigned to 5-years of tamoxifen plus ovarian suppression (OFS) or exemestane plus OFS. DNA was extracted with QIAamp kits and genotyped for two CYP19A1 (rs4646 and rs10046) and three ESR1 (rs2077647, rs2234693 and rs9340799) SNPs by a real-time pyrosequencing technique. Adverse events (AEs) were recorded at baseline and 3-monthly during the first year. Associations of the genotype variants with grade >= 2 early-onset targeted AEs of hot flashes/sweating or musculoskeletal events were assessed using logistic regression models. Results: There were 2660 premenopausal patients with breast cancer in the intention-to-treat population of TEXT, and 1967 (74 %) are included in this translational study. The CYP19A1 rs10046 variant T/T, represented in 23 % of women, was associated with a reduced incidence of grade >= 2 hot flashes/sweating (univariate odds ratio (OR) =0.78; 95 % CI 0.63-0. 97; P = 0.03), more strongly in patients assigned exemestane + OFS (TT vs CT/CC: OR = 0.65, 95 % CI = 0.48-0.89) than assigned tamoxifen + OFS (OR = 0.94, 95 % CI = 0.69-1.27, interaction P = 0.03). No association with any of the CYP19A1/ESR1 genotypes and musculoskeletal AEs was found. Conclusion: The CYP19A1 rs10046 variant T/T favors lower incidence of hot flashes/sweating under exemestane + OFS treatment, suggesting endocrine-mediated effects. Based on findings from others, this SNP may potentially enhance treatment adherence and treatment efficacy. We plan to evaluate the clinical impact of this polymorphism during time, pending sufficient median follow up. C1 [Johansson, Harriet; Aristarco, Valentina; Macis, Debora; Puccio, Antonella; Bonanni, Bernardo] European Inst Oncol, Div Canc Prevent & Genet, Via Ripamonti 435, I-20141 Milan, Italy. [Gray, Kathryn P.] Harvard TH Chan Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, IBCSG,Stat Ctr, 450 Brookline Ave, Boston, MA 02215 USA. [Pagani, Olivia] Inst Oncol Southern Switzerland IOSI, Bellinzona, Switzerland. [Pagani, Olivia] Int Breast Canc Study Grp, Bern, Switzerland. [Pagani, Olivia] Swiss Grp Clin Canc Res SAKK, Lugano Viganello, Switzerland. [Regan, Meredith M.] Harvard Med Sch, Dana Farber Canc Inst, Dept Biostat & Computat Biol, IBCSG Stat Ctr, 450 Brookline Ave, Boston, MA 02215 USA. [Viale, Giuseppe] European Inst Oncol, Dept Pathol & Lab Med, IBCSG Cent Pathol Lab, Via Ripamonti 435, I-20141 Milan, Italy. [Viale, Giuseppe] Univ Milan, Via Ripamonti 435, I-20141 Milan, Italy. [Roux, Susanne; Maibach, Rudolf] IBCSG, Coordinating Ctr, Effingerstr 40, CH-3008 Bern, Switzerland. [Colleoni, Marco] European Inst Oncol, Div Med Senol, Via Ripamonti 435, I-20141 Milan, Italy. [Rabaglio, Manuela; Price, Karen N.] Frontier Sci & Technol Res Fdn Inc, IBCSG Stat Ctr, Boston, MA USA. [Coates, Alan S.] Int Breast Canc Study Grp, Sydney, NSW, Australia. [Coates, Alan S.] Univ Sydney, Sch Publ Hlth, Sydney, NSW, Australia. [Gelber, Richard D.] Harvard Med Sch, Harvard TH Chan Sch Publ Hlth, Frontier Sci & Technol Res Fdn, IBCSG Stat Ctr,Dept Biostat & Computat Biol,Dana, 450 Brookline Ave, Boston, MA 02215 USA. [Goldhirsch, Aron] European Inst Oncol, Program Breast Hlth, Via Ripamonti 435, I-20141 Milan, Italy. [Kammler, Roswitha] IBCSG Coordinating Ctr, Translat Res Coordinat & Cent Pathol Off, Effingerstr 40, CH-3008 Bern, Switzerland. [Walley, Barbara A.] Breast Unit Southern Switzerland, Bellinzona, Switzerland. [Walley, Barbara A.] Natl Canc Inst Canada, Kingston, ON, Canada. [Price, Karen N.] Dana Farber Canc Inst, Dept Biostat & Computatonal Biol, 450 Brookline Ave, Boston, MA 02215 USA. RP Johansson, H (reprint author), European Inst Oncol, Div Canc Prevent & Genet, Via Ripamonti 435, I-20141 Milan, Italy. EM harriet.johansson@ieo.it FU Susan G. Komen for the Cure Promise Grant [KG080081]; Australia and New Zealand Breast Cancer Trials Group (ANZBCTG) Discretionary Funding Research Grant; Pfizer; International Breast Cancer Study Group; US National Cancer Institute; Ipsen; IBCSG: Frontier Science and Technology Research Foundation; Swiss Group for Clinical Cancer Research (SAKK); US National Cancer Institute (NCI) [CA75362]; Cancer Research Switzerland/Oncosuisse; Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK); ANZBCTG (NHMRC) [351161, 510788, 1105058]; SWOG (US NIH) [CA32102]; Alliance/CALGB (US NIH) [U10CA180821]; ECOG-ACRIN (US NIH) [CA21115, CA16116]; NSABP/NRG (US NIH) [U10-CA-12027, U10-CA-69651, U10-CA-37377, U10-CA-69974]; NCIC (US NIH) [CA077202]; NCIC (CCSRI) [015469, 021039] FX The translational project presented here is supported by Susan G. Komen for the Cure Promise Grant (KG080081 to GV, OP, MMR). The translational project in Australia and New Zealand was supported by an Australia and New Zealand Breast Cancer Trials Group (ANZBCTG) Discretionary Funding Research Grant (PF, AC). TEXT receives financial support for trial conduct from Pfizer, the International Breast Cancer Study Group and the US National Cancer Institute. Pfizer and Ipsen provided the drug supply, and the IBCSG received funding from Ipsen for additional data analyses. Support for the coordinating group, IBCSG: Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research (SAKK), US National Cancer Institute (NCI) (CA75362), Cancer Research Switzerland/Oncosuisse, and the Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK). Neither the pharmaceutical companies nor Susan G. Koment for the Cure have a role in the reporting or interpretation of the results, other than a minority representation on the Steering Committee. Grant support of cooperative groups: ANZBCTG (NHMRC 351161, 510788, 1105058); SWOG (US NIH CA32102); Alliance/CALGB (US NIH U10CA180821); ECOG-ACRIN (US NIH CA21115 and CA16116); NSABP/NRG (US NIH U10-CA-12027, U10-CA-69651, U10-CA-37377, U10-CA-69974); NCIC (US NIH CA077202 and CCSRI 015469 and 021039). NR 42 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD NOV 8 PY 2016 VL 18 AR 110 DI 10.1186/s13058-016-0771-8 PG 12 WC Oncology SC Oncology GA EB3UV UT WOS:000387295100001 PM 27825388 ER PT J AU Oran, AR Adams, CM Zhang, XY Gennaro, VJ Pfeiffer, HK Mellert, HS Seidel, HE Mascioli, K Kaplan, J Gaballa, MR Shen, C Rigoutsos, I King, MP Cotney, JL Arnold, JJ Sharma, SD Martinez-Outschoorn, UE Vakoc, CR Chodosh, LA Thompson, JE Bradner, JE Cameron, CE Shadel, GS Eischen, CM McMahon, SB AF Oran, Amanda R. Adams, Clare M. Zhang, Xiao-yong Gennaro, Victoria J. Pfeiffer, Haria K. Mellert, Hestia S. Seidel, Hans E. Mascioli, Kirsten Kaplan, Jordan Gaballa, Mahmoud R. Shen, Chen Rigoutsos, Isidore King, Michael P. Cotney, Justin L. Arnold, Jamie J. Sharma, Suresh D. Martinez-Outschoorn, Ubaldo E. Vakoc, Christopher R. Chodosh, Lewis A. Thompson, James E. Bradner, James E. Cameron, Craig E. Shadel, Gerald S. Eischen, Christine M. McMahon, Steven B. TI Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer SO ONCOTARGET LA English DT Article DE MYC; mitochondria; mitochondrial gene expression; tigecycline; synthetic lethality ID ACUTE MYELOID-LEUKEMIA; HUMAN C-MYC; RNA-POLYMERASE; B-CELLS; ESSENTIAL COFACTOR; DNA-DAMAGE; IN-VITRO; BIOGENESIS; APOPTOSIS; INHIBITION AB Despite ubiquitous activation in human cancer, essential downstream effector pathways of the MYC transcription factor have been difficult to define and target. Using a structure/function-based approach, we identified the mitochondrial RNA polymerase (POLRMT) locus as a critical downstream target of MYC. The multifunctional POLRMT enzyme controls mitochondrial gene expression, a process required both for mitochondrial function and mitochondrial biogenesis. We further demonstrate that inhibition of this newly defined MYC effector pathway causes robust and selective tumor cell apoptosis, via an acute, checkpoint-like mechanism linked to aberrant electron transport chain complex assembly and mitochondrial reactive oxygen species (ROS) production. Fortuitously, MYC-dependent tumor cell death can be induced by inhibiting the mitochondrial gene expression pathway using a variety of strategies, including treatment with FDA-approved antibiotics. In vivo studies using a mouse model of Burkitt's Lymphoma provide pre-clinical evidence that these antibiotics can successfully block progression of MYC-dependent tumors. C1 [Oran, Amanda R.; Adams, Clare M.; Zhang, Xiao-yong; Gennaro, Victoria J.; Pfeiffer, Haria K.; Mascioli, Kirsten; Kaplan, Jordan; Gaballa, Mahmoud R.; Rigoutsos, Isidore; Martinez-Outschoorn, Ubaldo E.; Eischen, Christine M.; McMahon, Steven B.] Thomas Jefferson Univ, Dept Canc Biol, Philadelphia, PA 19107 USA. [Mellert, Hestia S.] Univ Penn, Biomed Grad Studies, Philadelphia, PA 19104 USA. [Seidel, Hans E.; Chodosh, Lewis A.] Univ Penn, Sch Med, Dept Canc Biol, Philadelphia, PA 19104 USA. [Seidel, Hans E.; Chodosh, Lewis A.] Univ Penn, Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Shen, Chen; Vakoc, Christopher R.] Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA. [Shen, Chen] SUNY Stony Brook, Mol & Cellular Biol Program, Stony Brook, NY 11794 USA. [King, Michael P.] Thomas Jefferson Univ, Dept Biochem, Philadelphia, PA 19107 USA. [Cotney, Justin L.] Univ Connecticut Hlth, Genet & Genome Sci, Farmington, CT USA. [Arnold, Jamie J.; Sharma, Suresh D.; Cameron, Craig E.] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Thompson, James E.] Roswell Pk Canc Inst, Dept Med, Leukemia Serv, Buffalo, NY 14263 USA. [Bradner, James E.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Shadel, Gerald S.] Yale Sch Med, Dept Pathol, New Haven, CT USA. [Shadel, Gerald S.] Yale Sch Med, Dept Genet, New Haven, CT USA. RP McMahon, SB (reprint author), Thomas Jefferson Univ, Dept Canc Biol, Philadelphia, PA 19107 USA. EM steven.mcmahon@jefferson.edu FU NIH [CA090465, CA141070, F31CA183158, CA148950, F31CA165728, AG047632]; Cancer Center Support Grant [5P30CA056036-17] FX This work was supported by grants from the NIH: CA090465 and CA141070 (to SBM), F31CA183158 (to ARO), CA148950 (to CME), F31CA165728 (to CMA). GSS is a Joseph A. and Lucille K. Madri Professor of Experimental Pathology and also supported NIH grant AG047632. The Kimmel Cancer Center Flow Cytometry shared resource is supported by Cancer Center Support Grant 5P30CA056036-17. NR 77 TC 0 Z9 0 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 8 PY 2016 VL 7 IS 45 BP 72395 EP 72414 DI 10.18632/oncotarget.11718 PG 20 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5WT UT WOS:000387452100002 PM 27590350 ER PT J AU Allen, JE Kline, CLB Prabhu, VV Wagner, J Ishizawa, J Madhukar, N Lev, A Baumeister, M Zhou, LL Lulla, A Stogniew, M Schalop, L Benes, C Kaufman, HL Pottorf, RS Nallaganchu, BR Olson, GL Al-Mulla, F Duvic, M Wu, GS Dicker, DT Talekar, MK Lim, B Elemento, O Oster, W Bertino, J Flaherty, K Wang, ML Borthakur, G Andreeff, M Stein, M El-Deiry, WS AF Allen, Joshua E. Kline, C. Leah B. Prabhu, Varun V. Wagner, Jessica Ishizawa, Jo Madhukar, Neel Lev, Avital Baumeister, Marie Zhou, Lanlan Lulla, Amriti Stogniew, Martin Schalop, Lee Benes, Cyril Kaufman, Howard L. Pottorf, Richard S. Nallaganchu, B. Rao Olson, Gary L. Al-Mulla, Fahd Duvic, Madeleine Wu, Gen Sheng Dicker, David T. Talekar, Mala K. Lim, Bora Elemento, Olivier Oster, Wolfgang Bertino, Joseph Flaherty, Keith Wang, Michael L. Borthakur, Gautam Andreeff, Michael Stein, Mark El-Deiry, Wafik S. TI Discovery and clinical introduction of first-in-class imipridone ONC201 SO ONCOTARGET LA English DT Review DE ONC201; TIC10; integrated stress response; ATF4; DRD2 ID PROTEASOME INHIBITOR BORTEZOMIB; NON-HODGKINS-LYMPHOMA; SMALL-MOLECULE ONC201/TIC10; INTEGRATED STRESS-RESPONSE; LIGAND TRAIL GENE; T-CELL LYMPHOMA; ANTICANCER AGENT; PROSTATE-CANCER; STEM-CELLS; PHASE-II AB ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in preclinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials. C1 [Allen, Joshua E.; Prabhu, Varun V.; Stogniew, Martin; Schalop, Lee; Oster, Wolfgang] Oncoceutics Inc, Philadelphia, PA USA. [Kline, C. Leah B.; Wagner, Jessica; Lev, Avital; Baumeister, Marie; Zhou, Lanlan; Lulla, Amriti; Dicker, David T.; El-Deiry, Wafik S.] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Ishizawa, Jo; Duvic, Madeleine; Lim, Bora; Wang, Michael L.; Borthakur, Gautam; Andreeff, Michael] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Madhukar, Neel; Elemento, Olivier] Weill Cornell Med, New York, NY USA. [Benes, Cyril; Flaherty, Keith] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Benes, Cyril; Flaherty, Keith] Harvard Med Sch, Boston, MA USA. [Kaufman, Howard L.; Bertino, Joseph; Stein, Mark] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. [Pottorf, Richard S.; Nallaganchu, B. Rao; Olson, Gary L.] Provid Pharmaceut, Monmouth Jct, NJ USA. [Al-Mulla, Fahd] Kuwait Univ, Sch Med, Safat, Kuwait. [Wu, Gen Sheng] Karmanos Canc Inst, Detroit, MI USA. [Talekar, Mala K.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP El-Deiry, WS (reprint author), Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. EM wafik.eldeiry@fccc.edu FU Oncoceutics, Inc.; State of Pennsylvania Department of Health; Musella Foundation; NIH [R01 CA174949, R01 CA173453, R43 CA177002]; ASCO's Conquer Cancer Foundation; ACS [RP-14-233-07] FX This work was supported by Oncoceutics, Inc., a State of Pennsylvania Department of Health grant to L.S., Musella Foundation grant to J.E.A., NIH grant R01 CA174949 to G.S.W., ASCO's Conquer Cancer Foundation grant to M.K.T., NIH grant R01 CA173453 to W.S.E-D., NIH grant R43 CA177002 to W.S.E-D. and G.L.O., and ACS grant RP-14-233-07 to W.S.E-D. NR 46 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 8 PY 2016 VL 7 IS 45 BP 74380 EP 74392 DI 10.18632/oncotarget.11814 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5WT UT WOS:000387452100148 PM 27602582 ER PT J AU Strate, LL Singh, P Boylan, MR Piawah, S Cao, Y Chan, AT AF Strate, Lisa L. Singh, Prashant Boylan, Matthew R. Piawah, Sorbarikor Cao, Yin Chan, Andrew T. TI A Prospective Study of Alcohol Consumption and Smoking and the Risk of Major Gastrointestinal Bleeding in Men SO PLOS ONE LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; COLONIC DIVERTICULAR HEMORRHAGE; HELICOBACTER-PYLORI INFECTION; MALE HEALTH-PROFESSIONALS; ACUTE CORONARY SYNDROMES; HUMAN GASTRIC-MUCOSA; LONG-TERM USE; UNITED-STATES; ASPIRIN; ULCER AB Background and Aims Data regarding smoking and alcohol consumption and risk of gastrointestinal bleeding (GIB) are sparse and conflicting. We assessed the risk of major GIB associated with smoking and alcohol consumption in a large, prospective cohort. Methods We prospectively studied 48,000 men in the Health Professional follow-up Study (HPFS) who were aged 40-75 years at baseline in 1986. We identified men with major GIB requiring hospitalization and/or blood transfusion via biennial questionnaires and chart review. Results We documented 305 episodes of major GIB during 26 years of follow-up. Men who consumed >30 g/day of alcohol had a multivariable relative risk (RR) of 1.43 (95% confidence interval (CI), 0.88-2.35; P for trend 0.006) for major GIB when compared with nondrinkers. Alcohol consumption appeared to be primarily related to upper GIB (multivariable RR for >30 g/day vs. nondrinkers was 1.35; 95% CI, 0.66-2.77; P for trend 0.02). Men who consumed >= 5 drinks/week vs. < 1 drink/month of liquor had a multivariable RR of 1.72 (95% CI, 1.26-2.35, P for trend <0.001). Wine and beer were not significantly associated with major GIB. The risk of GIB associated with NSAIDs/aspirin use increased with greater alcohol consumption (multivariable RR 1.37; 95% CI, 0.85-2.19 for 1-14g/day of alcohol, RR 1.75; 95% CI, 1.07-2.88 for-15g/ day compared to nondrinkers). Smoking was not significantly associated with GIB. Conclusions Alcohol consumption, but not smoking, was associated with an increased risk of major GIB. Associations were most notable for upper GIB associated with liquor intake. Alcohol appeared to potentiate the risk of NSAID-associated GIB. C1 [Strate, Lisa L.] Univ Washington, Sch Med, Dept Med, Div Gastroenterol, Seattle, WA 98195 USA. [Singh, Prashant] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Boylan, Matthew R.; Cao, Yin; Chan, Andrew T.] Harvard Med Sch, Massachusetts Gen Hosp, Div Gastroenterol, Dept Med, Boston, MA 02115 USA. [Boylan, Matthew R.; Cao, Yin; Chan, Andrew T.] Harvard Med Sch, Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02115 USA. [Piawah, Sorbarikor] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA USA. [Cao, Yin] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Chan, Andrew T.] Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA 02115 USA. RP Chan, AT (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Gastroenterol, Dept Med, Boston, MA 02115 USA.; Chan, AT (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02115 USA.; Chan, AT (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA 02115 USA. EM achan@partners.org FU National Institutes of Health, National Cancer Institute [UM1 CM 67552]; National Institutes of Health, National Institute for Diabetes and Digestive and Kidney Diseases [R01 DK095964, K24 DK098311] FX The work was supported by the following: National Institutes of Health, National Cancer Institute UM1 CM 67552; National Institutes of Health, National Institute for Diabetes and Digestive and Kidney Diseases R01 DK095964 ATC; and National Institutes of Health, National Institute for Diabetes and Digestive and Kidney Diseases K24 DK098311 ATC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 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 NOV 8 PY 2016 VL 11 IS 11 AR e0165278 DI 10.1371/journal.pone.0165278 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB8BE UT WOS:000387615200015 PM 27824864 ER PT J AU Lin, H Mueller-Nurasyid, M Smith, AV Arking, DE Barnard, J Bartz, TM Lunetta, KL Lohman, K Kleber, ME Lubitz, SA Geelhoed, B Trompet, S Niemeijer, MN Kacprowski, T Chasman, DI Klarin, D Sinner, MF Waldenberger, M Meitinger, T Harris, TB Launer, LJ Soliman, EZ Chen, LY Smith, JD Van Wagoner, DR Rotter, JI Psaty, BM Xie, Z Hendricks, AE Ding, J Delgado, GE Verweij, N van der Harst, P Macfarlane, PW Ford, I Hofman, A Uitterlinden, A Heeringa, J Franco, OH Kors, JA Weiss, S Volzke, H Rose, LM Natarajan, P Kathiresan, S Kaab, S Gudnason, V Alonso, A Chung, MK Heckbert, SR Benjamin, EJ Liu, Y Marz, W Rienstra, M Jukema, JW Stricker, BH Dorr, M Albert, CM Ellinor, PT AF Lin, Honghuang Mueller-Nurasyid, Martina Smith, Albert V. Arking, Dan E. Barnard, John Bartz, Traci M. Lunetta, Kathryn L. Lohman, Kurt Kleber, Marcus E. Lubitz, Steven A. Geelhoed, Bastiaan Trompet, Stella Niemeijer, Maartje N. Kacprowski, Tim Chasman, Daniel I. Klarin, Derek Sinner, Moritz F. Waldenberger, Melanie Meitinger, Thomas Harris, Tamara B. Launer, Lenore J. Soliman, Elsayed Z. Chen, Lin Y. Smith, Jonathan D. Van Wagoner, David R. Rotter, Jerome I. Psaty, Bruce M. Xie, Zhijun Hendricks, Audrey E. Ding, Jingzhong Delgado, Graciela E. Verweij, Niek van der Harst, Pim Macfarlane, Peter W. Ford, Ian Hofman, Albert Uitterlinden, Andre Heeringa, Jan Franco, Oscar H. Kors, Jan A. Weiss, Stefan Volzke, Henry Rose, Lynda M. Natarajan, Pradeep Kathiresan, Sekar Kaab, Stefan Gudnason, Vilmundur Alonso, Alvaro Chung, Mina K. Heckbert, Susan R. Benjamin, Emelia J. Liu, Yongmei Marz, Winfried Rienstra, Michiel Jukema, J. Wouter Stricker, Bruno H. Dorr, Marcus Albert, Christine M. Ellinor, Patrick T. TI Gene-gene Interaction Analyses for Atrial Fibrillation SO SCIENTIFIC REPORTS LA English DT Article ID PROTEIN-INTERACTION MAPS; FAMILIAL AGGREGATION; MISSING HERITABILITY; BREAST-CANCER; ASSOCIATION; RISK; VARIANTS; DISEASE; SUSCEPTIBILITY; METAANALYSIS AB Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed a large-scale association analysis of gene-gene interactions with AF in 8,173 AF cases, and 65,237 AF-free referents collected from 15 studies for discovery. We examined putative interactions between genome-wide SNPs and 17 known AF-related SNPs. The top interactions were then tested for association in an independent cohort for replication, which included more than 2,363 AF cases and 114,746 AF-free referents. One interaction, between rs7164883 at the HCN4 locus and rs4980345 at the SLC28A1 locus, was found to be significantly associated with AF in the discovery cohorts (interaction OR = 1.44, 95% CI: 1.27-1.65, P = 4.3 x 10(-8)). Eight additional gene-gene interactions were also marginally significant (P < 5 x 10(-7)). However, none of the top interactions were replicated. In summary, we did not find significant interactions that were associated with AF susceptibility. Future increases in sample size and denser genotyping might facilitate the identification of gene-gene interactions associated with AF. C1 [Lin, Honghuang; Lunetta, Kathryn L.; Hendricks, Audrey E.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Lin, Honghuang; Lunetta, Kathryn L.; Hendricks, Audrey E.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Lin, Honghuang; Xie, Zhijun] Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA. [Mueller-Nurasyid, Martina] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Mueller-Nurasyid, Martina; Sinner, Moritz F.; Kaab, Stefan] Ludwig Maximilians Univ Munchen, Dept Med 1, Munich, Germany. [Mueller-Nurasyid, Martina; Waldenberger, Melanie; Meitinger, Thomas; Kaab, Stefan] Partner Site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Barnard, John; Smith, Jonathan D.; Van Wagoner, David R.; Chung, Mina K.] Cleveland Clin, Cleveland, OH 44106 USA. [Bartz, Traci M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Lunetta, Kathryn L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Lohman, Kurt] Wake Forest Sch Med, Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Kleber, Marcus E.; Waldenberger, Melanie; Delgado, Graciela E.] Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany. [Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Lubitz, Steven A.; Natarajan, Pradeep; Kathiresan, Sekar; Ellinor, Patrick T.] Harvard Med Sch, Boston, MA USA. [Geelhoed, Bastiaan; Verweij, Niek; van der Harst, Pim; Rienstra, Michiel] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Trompet, Stella] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Niemeijer, Maartje N.; Hofman, Albert; Heeringa, Jan; Franco, Oscar H.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Kacprowski, Tim; Weiss, Stefan] Univ Med, Interfac Inst Genet & Funct Genom, Dept Funct Genom, Greifswald, Germany. [Kacprowski, Tim; Weiss, Stefan] Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany. [Kacprowski, Tim; Weiss, Stefan; Volzke, Henry; Dorr, Marcus] Partner Site Greifswald, DZHK German Ctr Cardiovasc Res, Greifswald, Germany. [Chasman, Daniel I.; Rose, Lynda M.; Albert, Christine M.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Klarin, Derek; Natarajan, Pradeep; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Klarin, Derek; Natarajan, Pradeep; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Klarin, Derek] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Klarin, Derek; Natarajan, Pradeep; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Waldenberger, Melanie] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Meitinger, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, Munich, Germany. [Harris, Tamara B.; Launer, Lenore J.] NIA, NIH, Bethesda, MD 20892 USA. [Soliman, Elsayed Z.] Wake Forest Sch Med, Epidemiol Cardiol Res Ctr, Winston Salem, NC USA. [Chen, Lin Y.] Univ Minnesota, Sch Med, Dept Med, Cardiovasc Div, Minneapolis, MN 55455 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, LABioMed, Dept Pediat, Inst Translat Genom & Populat Sci JIR, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, LABioMed, Dept Med, Inst Translat Genom & Populat Sci JIR, Torrance, CA 90509 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.; Heckbert, Susan R.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Hendricks, Audrey E.] Univ Colorado, Math & Stat Sci, Denver, CO 80202 USA. [Ding, Jingzhong] Wake Forest Sch Med, Dept Gerontol & Geriatr Med, Winston Salem, NC USA. [Macfarlane, Peter W.] Univ Glasgow, Coll Vet Med & Life Sci, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Uitterlinden, Andre; Stricker, Bruno H.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol & Internal Med, Rotterdam, Netherlands. [Kors, Jan A.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Med Informat, Rotterdam, Netherlands. [Volzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Alonso, Alvaro] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med & Prevent Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Liu, Yongmei] Wake Forest Sch Med, Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Marz, Winfried] Synlab Acad, Synlab Serv, GmbH P5,7, D-68161 Mannheim, Germany. [Marz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Marz, Winfried] Heidelberg Univ, Med Fac Mannheim, Med Clin Nephrol 5, Hypertensiol,Rheumatol,Endocrinol,Diabetol, Mannheim, Germany. [Stricker, Bruno H.] Inspectorate Hlth Care, Utrecht, Netherlands. [Dorr, Marcus] Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany. RP Lin, H (reprint author), NHLBI, Framingham, MA USA.; Lin, H (reprint author), Boston Univ, Framingham Heart Study, Framingham, MA USA.; Lin, H (reprint author), Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA. EM hhlin@bu.edu RI Alonso, Alvaro/A-4917-2010; Verweij, Niek/A-4499-2017; OI Alonso, Alvaro/0000-0002-2225-8323; Hendricks, Audrey/0000-0002-7152-0287 FU German Federal Ministry of Education and Research (BMBF); German National Competence network on atrial fibrillation (AFNET); Leducq Foundation [07-CVD 03]; D.W. Reynolds Foundation Clinical Cardiovascular Research Center at Johns Hopkins University; Bioinformatics for the Functional Analysis of Mammalian Genomes program (BFAM) [01GS0499, 01GI0204, 01GS0838]; Helmholtz Zentrum Munchen - German Research Center for Environmental Health; State of Bavaria; Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat; German Heart Foundation; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005]; American Heart Association [16EIA26410001, 13EIA14220013]; NIH Roadmap for Medical Research; NINDS; NIA [AG-023629, AG-15928, AG-20098, AG-027058]; NIH [R01HL090620, R01HL111314, 1RO1HL092577, 2R01LM010098, HL104156, HL105780, HL065962, K23HL114724]; NIH/NCRR CTSA grant [1UL-RR024989]; Heart and Vascular Institute Philanthropic grant, Department of Cardiovascular Medicine, Cleveland Clinic (Chung); Leducq Fondation [07-CVD-03]; Boston University [N01-HC-25195, HHSN268201500001I]; Benjamin and Ellinor [1R01HL128914]; 7th Framework Program (AtheroRemo) [201668, 305739]; Dutch Kidney Foundation [E0.13]; Netherlands organization for health research and development [175.010.2007.006, 90.700.441]; Dutch Inter University Cardiology Institute Netherlands (ICIN); Netherlands Heart Foundation [NHS2010B280]; Netherlands Organization for Scientific Research [016.136.055]; Bristol-Myers Squibb; Established Clinical Investigator of the Netherlands Heart Foundation [2001 D 032]; European commission [223004]; Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) [050-060-810]; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03IS2061A, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015]; Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]; Erasmus MC; Erasmus University Rotterdam; Netherlands Organisation for Scientific Research (NWO); Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE) the Netherlands Genomics Initiative (NGI); Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sport; European Commission (DG XII); Municipality of Rotterdam; Fondation Leducq [14CVD01]; Doris Duke Charitable Foundation Clinical Scientist Development Award [2014105]; [N01-HC-85239]; [N01-HC-85079]; [N01-HC-85080]; [N01-HC-85081]; [N01-HC-85082]; [N01-HC-85083]; [N01-HC-85084]; [N01-HC-85085]; [N01-HC-85086]; [N01-HC-35129]; [N01 HC-15103]; [N01 HC-55222]; [N01-HC-75150]; [N01-HC-45133]; [HHSN268200800007C]; [HHSN268201200036C]; [HL080295]; [HL087652]; [HL103612]; [HL105756]; [HL120393] FX The study was supported by the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN), the German National Competence network on atrial fibrillation (AFNET), the Leducq Foundation (07-CVD 03), the D.W. Reynolds Foundation Clinical Cardiovascular Research Center at Johns Hopkins University, and the Bioinformatics for the Functional Analysis of Mammalian Genomes program (BFAM) by grants to Stefan Kaab (01GS0499, 01GI0204, 01GS0838). 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. Dr. Sinner is supported by the German Heart Foundation. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C,), R01HL087641, R01HL59367, R01HL086694, and R01HL111314; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Dr. Alonso is supported by grant 16EIA26410001 from the American Heart Association. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. This CHS research was supported by NHLBI contracts N01-HC-85239, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268200800007C, HHSN268201200036C and NHLBI grants HL080295, HL087652, HL103612, HL105756, HL120393 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. The Cleveland Clinic AF study was supported by NIH grants to Drs. Chung, Barnard, Smith, and Van Wagoner (R01HL090620, R01HL111314), an NIH/NCRR CTSA grant (1UL-RR024989), Heart and Vascular Institute Philanthropic grant, Department of Cardiovascular Medicine, Cleveland Clinic (Chung), and a Leducq Fondation grant 07-CVD-03 (Van Wagoner). The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. N01-HC-25195; HHSN268201500001I). This project also was supported by NIH grants to Drs. Ellinor, Benjamin, and Lunetta (1RO1HL092577) and Benjamin and Ellinor (1R01HL128914). LURIC was supported by the 7th Framework Program (AtheroRemo, grant agreement number 201668 and RiskyCAD, grant agreement number 305739) of the EU. The PREVEND study is supported by the Dutch Kidney Foundation (grant E0.13), the National Institutes of Health (grant 2R01LM010098), The Netherlands organization for health research and development (NWO-Groot grant 175.010.2007.006, ZonMw grant 90.700.441), and the Dutch Inter University Cardiology Institute Netherlands (ICIN), and the Netherlands Heart Foundation (grant NHS2010B280). Dr. M. Rienstra is supported by a grant from the Netherlands Organization for Scientific Research (Veni grant 016.136.; 055). There are no relations with industry. The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Prof. Dr. J. W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network 'Greifswald Approach to Individualized Medicine (GANI_MED)' funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG and the Cache Campus program of the InterSystems GmbH. The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is supported by the Erasmus MC and Erasmus University Rotterdam; the Netherlands Organisation for Scientific Research (NWO); the Netherlands Organisation for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE) the Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sport; the European Commission (DG XII); and the Municipality of Rotterdam. Dr. Ellinor is supported by grants from the National Institutes of Health (HL104156, HL105780, HL065962). Dr. Ellinor is also supported by an Established Investigator Award from the American Heart Association (13EIA14220013) and by support from the Fondation Leducq (14CVD01). Dr. Lubitz is supported by NIH grants K23HL114724, and a Doris Duke Charitable Foundation Clinical Scientist Development Award 2014105. NR 32 TC 1 Z9 1 U1 2 U2 2 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 NOV 8 PY 2016 VL 6 AR 35371 DI 10.1038/srep35371 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB3RL UT WOS:000387283300001 PM 27824142 ER PT J AU Verhulst, S Best, J Syn, WK Reynaert, H Hellemans, KH Canbay, A Dolle, L van Grunsven, LA AF Verhulst, Stefaan Best, Jan Syn, Wing-Kin Reynaert, Hendrik Hellemans, Karine H. Canbay, Ali Dolle, Laurent van Grunsven, Leo A. TI Infliximab and Dexamethasone Attenuate the Ductular Reaction in Mice SO SCIENTIFIC REPORTS LA English DT Article ID LIVER PROGENITOR CELLS; ETHIONINE-SUPPLEMENTED DIET; SEVERE ALCOHOLIC HEPATITIS; TUMOR-NECROSIS-FACTOR; INDUCED MOUSE MODEL; OVAL CELL; STEM/PROGENITOR CELLS; CHOLINE-DEFICIENT; DISEASE SEVERITY; TNF-ALPHA AB Chronic hepatic injury is accompanied by a ductular response that is strongly correlated with disease severity and progression of fibrosis. To investigate whether anti-inflammatory drugs can modulate the ductular response, we treated mice suffering from a steatotic or cholestatic injury with anti-TNF-alpha antibodies (Infliximab) or glucocorticoids (Dexamethasone). We discovered that Dexamethasone and Infliximab can both modulate the adaptive remodeling of the biliary architecture that occurs upon liver injury and limit extracellular matrix deposition. Infliximab treatment, at least in these steatotic and cholestatic mouse models, is the safer approach since it does not increase liver injury, allows inflammation to take place but inhibits efficiently the ductular response and extracellular matrix deposition. Infliximab-based therapy could, thus, still be of importance in multiple chronic liver disorders that display a ductular response such as alcoholic liver disease or sclerosing cholangitis. C1 [Verhulst, Stefaan; Best, Jan; Reynaert, Hendrik; Dolle, Laurent; van Grunsven, Leo A.] Vrije Univ Brussel, Lab Liver Cell Biol, Brussels, Belgium. [Best, Jan; Canbay, Ali] Univ Duisburg Essen, Dept Gastroenterol & Hepatol, Duisburg, Germany. [Syn, Wing-Kin] Ralph H Johnson VAMC, Gastroenterol Sect, Charleston, SC USA. [Syn, Wing-Kin] Med Univ South Carolina, Div Gastroenterol & Hepatol, Charleston, SC USA. [Hellemans, Karine H.] VUB, Unit Diabet Pathol & Therapy, Brussels, Belgium. RP van Grunsven, LA (reprint author), Vrije Univ Brussel, Lab Liver Cell Biol, Brussels, Belgium. EM lvgrunsv@vub.ac.be RI van Grunsven, Leo/E-5839-2010 OI van Grunsven, Leo/0000-0002-0990-7034 FU Institute for the Promotion of Innovation through Science and Technology in Flanders [IWT/SB/121548]; Foundation for Liver Research, UK; Research Foundation Flanders (FWO) [G.0428.09N]; VUB-research council [OZR1914]; Interuniversity Attraction Poles (Federal Science Policy) [BELSPO P7/47]; Innoviris-Impulse program (Brussels Government) [2011-IPLS-104-Brustem]; FWO [G.0348.13N] FX We thank D. Blyweert and K. Lagaisse for their excellent technical assistance. The TROMA-III antibody was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of NICHD and maintained by The University of Iowa. We are grateful to Prof. P. In 't Veld for the use of the Nikon microscope. S.V. was supported by the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT/SB/121548), W.K.S.: Foundation for Liver Research, UK; K.H.: Research Foundation Flanders (FWO; G.0428.09N); VUB-research council-OZR1914; L.D., J.B. and L.v.G.: Interuniversity Attraction Poles (Federal Science Policy -BELSPO P7/47); Innoviris-Impulse program 2011-IPLS-104-Brustem (Brussels Government) and FWO G.0348.13N. NR 52 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 8 PY 2016 VL 6 AR 36586 DI 10.1038/srep36586 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB4EI UT WOS:000387322300001 PM 27824131 ER PT J AU Aspberg, S Chang, YC Atterman, A Bottai, M Go, AS Singer, DE AF Aspberg, Sara Chang, Yuchiao Atterman, Adriano Bottai, Matteo Go, Alan S. Singer, Daniel E. TI Comparison of the ATRIA, CHADS(2), and CHA(2)DS(2)-VASc stroke risk scores in predicting ischaemic stroke in a large Swedish cohort of patients with atrial fibrillation SO EUROPEAN HEART JOURNAL LA English DT Article DE Atrial fibrillation; Ischaemic stroke; Anticoagulation; ATRIA; CHADS(2); CHA(2)DS(2)-VASc ID STRATIFICATION SCHEMES; ROC CURVE; THROMBOEMBOLISM; VALIDATION; REGISTER; CARE AB Aims Better stroke risk prediction is needed to optimize the anticoagulation decision in atrial fibrillation (AF). The ATRIA stroke risk score (ATRIA) was developed and validated in two large California community AF cohorts. We compared the performance of the ATRIA, CHADS(2), and CHA(2)DS(2)-VASc scores in a national Swedish AF (SAF) cohort. Methods and results We examined all Swedish patients hospitalized, or visiting a hospital-based outpatient clinic, with a diagnosis of AF from July 2005 through December 2010. Variables were determined from comprehensive national databases. Risk scores were assessed via C-index (C) and net reclassification improvement (NRI). The cohort included 152 153 AF patients not receiving warfarin. Overall, 11 053 acute ischaemic strokes were observed with mean rate 3.2%/year, higher than the 2%/year in the California cohorts. Using entire point scores, ATRIA had a good C of 0.708 (0.704-0.713), significantly better than CHADS2 0.690 (0.685-0.695) or CHA(2)DS(2)-VASc 0.694 (0.690-0.700). Using published cut-points for low/moderate/high risk, C deteriorated but ATRIA remained superior. Net reclassification improvement favoured ATRIA 0.16 (0.14-0.17) vs. CHADS(2) and 0.21 (0.20-0.23) vs. CHA(2)DS(2)-VASc. Net reclassification improvement decreased when cut-points were altered to better fit the cohort's stroke rates. Conclusion In this SAF cohort, the ATRIA score predicted ischaemic stroke risk better than CHADS(2) or CHA(2)DS(2)-VASc. However, relative performance of the categorical scores varied by population stroke rates. Score cut-points may need to be optimized to better fit local population stroke rates. C1 [Aspberg, Sara; Atterman, Adriano] Karolinska Inst, Dept Clin Sci, Div Cardiovasc Med, Danderyd Hosp, Stockholm, Sweden. [Chang, Yuchiao; Singer, Daniel E.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Chang, Yuchiao; Singer, Daniel E.] Harvard Med Sch, Boston, MA USA. [Bottai, Matteo] Karolinska Inst, Inst Environm Med, Stockholm, Sweden. [Go, Alan S.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Go, Alan S.] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Go, Alan S.] Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. [Go, Alan S.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Go, Alan S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. RP Aspberg, S (reprint author), Danderyd Hosp, Dept Cardiol, S-18288 Stockholm, Sweden. EM sara.aspberg@ds.se FU Swedish Society of Medicine; Stockholm County Council; Massachusetts General Hospital (Boston, MA, USA) FX S.A. was supported by the Swedish Society of Medicine and by the Stockholm County Council. D.E.S. was supported, in part, by the Eliot B. and Edith C. Shoolman fund of the Massachusetts General Hospital (Boston, MA, USA). NR 23 TC 8 Z9 8 U1 6 U2 6 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 NOV 7 PY 2016 VL 37 IS 42 BP 3203 EP 3210 DI 10.1093/eurheartj/ehw077 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EF4MS UT WOS:000390303800010 PM 26941204 ER PT J AU Aguet, F Upadhyayula, S Gaudin, R Chou, YY Cocucci, E He, KM Chen, BC Mosaliganti, K Pasham, M Skillern, W Legant, WR Liu, TL Findlay, G Marino, E Danuser, G Megason, S Betzig, E Kirchhausen, T AF Aguet, Francois Upadhyayula, Srigokul Gaudin, Raphael Chou, Yi-ying Cocucci, Emanuele He, Kangmin Chen, Bi-Chang Mosaliganti, Kishore Pasham, Mithun Skillern, Wesley Legant, Wesley R. Liu, Tsung-Li Findlay, Greg Marino, Eric Danuser, Gaudenz Megason, Sean Betzig, Eric Kirchhausen, Tom TI Membrane dynamics of dividing cells imaged by lattice light-sheet microscopy SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CLATHRIN-MEDIATED ENDOCYTOSIS; MASS MEASUREMENTS SHOW; COATED PITS; PLASMA-MEMBRANE; MAMMALIAN-CELLS; MITOSIS; VOLUME; ACTIN; RECRUITMENT; INVAGINATION AB Membrane remodeling is an essential part of transferring components to and from the cell surface and membrane-bound organelles and for changes in cell shape, which are particularly critical during cell division. Earlier analyses, based on classical optical live-cell imaging and mostly restricted by technical necessity to the attached bottom surface, showed persistent formation of endocytic clathrin pits and vesicles during mitosis. Taking advantage of the resolution, speed, and noninvasive illumination of the newly developed lattice light-sheet fluorescence microscope, we reexamined their assembly dynamics over the entire cell surface and found that clathrin pits form at a lower rate during late mitosis. Full-cell imaging measurements of cell surface area and volume throughout the cell cycle of single cells in culture and in zebrafish embryos showed that the total surface increased rapidly during the transition from telophase to cytokinesis, whereas cell volume increased slightly in metaphase and was relatively constant during cytokinesis. These applications demonstrate the advantage of lattice light-sheet microscopy and enable a new standard for imaging membrane dynamics in single cells and multicellular assemblies. C1 [Aguet, Francois; Upadhyayula, Srigokul; Gaudin, Raphael; Chou, Yi-ying; Cocucci, Emanuele; He, Kangmin; Pasham, Mithun; Skillern, Wesley; Findlay, Greg; Marino, Eric; Kirchhausen, Tom] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. [Mosaliganti, Kishore; Megason, Sean] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA. [Upadhyayula, Srigokul; Gaudin, Raphael; Chou, Yi-ying; Cocucci, Emanuele; He, Kangmin; Pasham, Mithun; Skillern, Wesley; Findlay, Greg; Marino, Eric; Kirchhausen, Tom] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Chen, Bi-Chang; Legant, Wesley R.; Liu, Tsung-Li; Betzig, Eric] Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA. [Danuser, Gaudenz] UT Southwestern Med Ctr, Lyda Hill Dept Bioinformat, Dallas, TX 75390 USA. [Kirchhausen, Tom] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Aguet, Francois] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Cocucci, Emanuele] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43202 USA. [Chen, Bi-Chang] Acad Sinica, Res Ctr Appl Sci, Taipei 11529, Taiwan. RP Kirchhausen, T (reprint author), Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.; Kirchhausen, T (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Kirchhausen, T (reprint author), Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. EM kirchhausen@crystal.harvard.edu RI Chen , Bi-Chang /F-3480-2014 FU Biogen; IONIS Pharmaceuticals; National Institutes of Health [R01 GM075252, K25 HD071969]; Janelia Visitor Program FX We thank Ian Swinburne from Sean Megason's laboratory for helpful advice and discussions associated with the zebrafish work and Margaret Robinson for the CD chimera constructs. S.U. is a Fellow at the Image and Data Analysis Core at Harvard Medical School and thanks Hunter Elliott and Tiao Xie for helpful discussions. T.K. gratefully acknowledges support from the Janelia Visitor Program. The construction of the lattice light-sheet microscope LLSM. 2 in the Kirchhausen laboratory was generously supported by grants from Biogen and IONIS Pharmaceuticals (to T.K.). This work was supported by National Institutes of Health Grants R01 GM075252 (T.K.) and K25 HD071969 (K.M.). NR 50 TC 1 Z9 1 U1 9 U2 9 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD NOV 7 PY 2016 VL 27 IS 22 BP 3418 EP 3435 DI 10.1091/mbc.E16-03-0164 PG 18 WC Cell Biology SC Cell Biology GA EB5CR UT WOS:000387391400006 PM 27535432 ER PT J AU Chen, XG Wang, YY Nelson, D Tian, S Mulvey, E Patel, B Conti, I Jaen, J Rollins, BJ AF Chen, Xuguang Wang, Yunyue Nelson, David Tian, Sara Mulvey, Erin Patel, Bhumi Conti, Ilaria Jaen, Juan Rollins, Barrett J. TI CCL2/CCR2 Regulates the Tumor Microenvironment in HER-2/neu-Driven Mammary Carcinomas in Mice SO PLOS ONE LA English DT Article ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CHEMOKINE RECEPTOR 2; BREAST-CANCER; MACROPHAGE RECRUITMENT; INFLAMMATORY MONOCYTES; MCP-1; ANGIOGENESIS; EXPRESSION; CELLS AB Chronic inflammation is a hallmark of cancer. Inflammatory chemokines, such as C-C chemokine ligand 2 (CCL2), are often present in tumors but their roles in cancer initiation and maintenance are not clear. Here we report that CCL2 promotes mammary carcinoma development in a clinically relevant murine model of breast cancer. Targeted disruption of Ccl2 slowed the growth of activated Her2/neu-driven mammary tumors and prolonged host survival. Disruption of Ccl2 was associated with a decrease in the development and mobilization of endothelial precursor cells (EPCs) which can contribute to tumor neovascularization. In contrast, disruption of Ccr2, which encodes CCL2's sole signaling receptor, accelerated tumor development, shortened host survival, and mobilized EPCs. However, pharmacological inhibition of CCR2 phenocopied Ccl2 disruption rather than Ccr2 disruption, suggesting that the Ccr2(-/-) phenotype is a consequence of unanticipated alterations not linked to intact CCL2/CCR2 signaling. Consistent with this explanation, Ccr2(-/-) monocytes are more divergent from wild type monocytes than Ccl2(-/-) monocytes in their expression of genes involved in key developmental and functional pathways. Taken together, our data suggest a tumor-promoting role for CCL2 acting through CCR2 on the tumor microenvironment and support the targeting of this chemokine/receptor pair in breast cancer. C1 [Chen, Xuguang; Wang, Yunyue; Nelson, David; Tian, Sara; Mulvey, Erin; Patel, Bhumi; Conti, Ilaria; Rollins, Barrett J.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Chen, Xuguang; Wang, Yunyue; Nelson, David; Tian, Sara; Mulvey, Erin; Patel, Bhumi; Conti, Ilaria; Rollins, Barrett J.] Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. [Chen, Xuguang; Wang, Yunyue; Rollins, Barrett J.] Harvard Med Sch, Boston, MA 02115 USA. [Jaen, Juan] ChemoCentryx Inc, Mountain View, CA 94043 USA. [Conti, Ilaria] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Jaen, Juan] Arcus Biosci Inc, Hayward, CA 94545 USA. RP Rollins, BJ (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Rollins, BJ (reprint author), Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA.; Rollins, BJ (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM Barrett_Rollins@dfci.harvard.edu 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 NOV 7 PY 2016 VL 11 IS 11 AR e0165595 DI 10.1371/journal.pone.0165595 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB8BB UT WOS:000387614800013 PM 27820834 ER PT J AU Rogal, SS Mankaney, G Udawatta, V Chinman, M Good, CB Zickmund, S Bielefeldt, K Chidi, A Jonassaint, N Jazwinski, A Shaikh, O Hughes, C Fontes, P Humar, A DiMartini, A AF Rogal, Shari S. Mankaney, Gautham Udawatta, Viyan Chinman, Matthew Good, Chester B. Zickmund, Susan Bielefeldt, Klaus Chidi, Alexis Jonassaint, Naudia Jazwinski, Alison Shaikh, Obaid Hughes, Christopher Fontes, Paulo Humar, Abhinav DiMartini, Andrea TI Pre-Transplant Depression Is Associated with Length of Hospitalization, Discharge Disposition, and Survival after Liver Transplantation SO PLOS ONE LA English DT Article ID HEALTH-CARE UTILIZATION; LONG-TERM SURVIVAL; HEART-FAILURE; ANTIDEPRESSANT USE; ELDERLY-PATIENTS; HEPATITIS-C; MORTALITY; SYMPTOMS; OUTCOMES; DISEASE AB Depression after liver transplantation has been associated with decreased survival, but the effects of pre-transplant depression on early and late post-transplant outcomes remain incompletely evaluated. We assessed all patients who had undergone single-organ liver transplantation at a single center over the prior 10 years. A diagnosis of pre-transplant depression, covariates, and the outcomes of interest were extracted from the electronic medical record. Potential covariates included demographics, etiology and severity of liver disease, comorbidities, donor age, graft type, immunosuppression, and ischemic times. In multivariable models adjusting for these factors, we evaluated the effect of pre-transplant depression on transplant length of stay (LOS), discharge disposition (home vs. facility) and long-term survival. Among 1115 transplant recipients with a median follow-up time of 5 years, the average age was 56 +/- 11 and MELD was 12 +/- 9. Nineteen percent of the study population had a history of pre-transplant depression. Pre-transplant depression was associated with longer LOS (median = 19 vs. 14 days, IRR = 1.25, CI = 1.13,1.39), discharge to a facility (36% vs. 25%, OR 1.70, CI = 1.18,2.45), and decreased survival (HR = 1.54, CI = 1.14,2.08) in this cohort, accounting for other potential confounders. In conclusion, pre-transplant depression was significantly associated with longer transplant length of stay, discharge to a facility, and mortality in this cohort. C1 [Rogal, Shari S.; Chinman, Matthew; Good, Chester B.; Zickmund, Susan; Chidi, Alexis] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15261 USA. [Rogal, Shari S.; Shaikh, Obaid; Hughes, Christopher; Fontes, Paulo; Humar, Abhinav] Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15260 USA. [Rogal, Shari S.; Bielefeldt, Klaus; Jonassaint, Naudia; Jazwinski, Alison; Shaikh, Obaid] Univ Pittsburgh, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15260 USA. [Mankaney, Gautham; Udawatta, Viyan; Good, Chester B.; Zickmund, Susan; Chidi, Alexis] Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA USA. [Chinman, Matthew] RAND Corp, Pittsburgh, PA USA. [DiMartini, Andrea] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. RP Rogal, SS (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15261 USA.; Rogal, SS (reprint author), Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15260 USA.; Rogal, SS (reprint author), Univ Pittsburgh, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15260 USA. EM rogalss@upmc.edu FU Rand Corporation FX The authors received no specific funding for this work. MC is employed by Rand Corporation. Rand Corporation provided support in the form of salaries for author MC, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the "author contributions" section. NR 28 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 NOV 7 PY 2016 VL 11 IS 11 AR e0165517 DI 10.1371/journal.pone.0165517 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB8BB UT WOS:000387614800010 PM 27820828 ER PT J AU Grassberger, C Paganetti, H AF Grassberger, C. Paganetti, H. TI Methodologies in the modeling of combined chemo-radiation treatments SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Review DE outcome modeling; radiation therapy; chemotherapy ID RANDOMIZED PHASE-III; BREAST-CANCER; TUMOR-GROWTH; NECK-CANCER; LUNG-CANCER; MATHEMATICAL-MODEL; DRUG-RESISTANCE; CONCURRENT CHEMORADIATION; SYNCHRONOUS CHEMOTHERAPY; ADJUVANT TEMOZOLOMIDE AB The variety of treatment options for cancer patients has increased significantly in recent years. Not only do we combine radiation with surgery and chemotherapy, new therapeutic approaches such as immunotherapy and targeted therapies are starting to play a bigger role. Physics has made significant contributions to radiation therapy treatment planning and delivery. In particular, treatment plan optimization using inverse planning techniques has improved dose conformity considerably. Furthermore, medical physics is often the driving force behind tumor control and normal tissue complication modeling. While treatment optimization and outcome modeling does focus mainly on the effects of radiation, treatment modalities such as chemotherapy are treated independently or are even neglected entirely. This review summarizes the published efforts to model combined modality treatments combining radiation and chemotherapy. These models will play an increasing role in optimizing cancer therapy not only from a radiation and drug dosage standpoint, but also in terms of spatial and temporal optimization of treatment schedules. C1 [Grassberger, C.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA 02114 USA. RP Grassberger, C (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM Grassberger.Clemens@mgh.harvard.edu NR 109 TC 0 Z9 0 U1 1 U2 1 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 NOV 7 PY 2016 VL 61 IS 21 BP R344 EP R369 DI 10.1088/0031-9155/61/21/R344 PG 26 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA EA4MD UT WOS:000386585900001 PM 27758980 ER PT J AU Allareddy, V Ching, N Macklin, EA Voelz, L Weintraub, G Davidson, E Prock, LA Rosen, D Brunn, R Skotko, BG AF Allareddy, Veerasathpurush Ching, Nicholas Macklin, Eric A. Voelz, Lauren Weintraub, Gil Davidson, Emily Prock, Lisa Albers Rosen, Dennis Brunn, Richard Skotko, Brian G. TI Craniofacial features as assessed by lateral cephalometric measurements in children with Down syndrome SO PROGRESS IN ORTHODONTICS LA English DT Article ID OBSTRUCTIVE SLEEP-APNEA; MONGOLISM; BIRTHS; AGE AB Objective: The objective of the present study is to examine the craniofacial development of patients with Down syndrome (DS) and compare them with a neurotypical population. Methods: This study is a cross-sectional analysis of lateral cephalometric radiographs of participants with DS. The study population consisted of children and young adults with DS aged 3-25 years. Cephalometric data were summarized by age and sex. Raw and normalized z-scores were computed. One-sample t tests were used to test whether mean z-scores differed from zero. The demographic characteristics between those with or without lateral cephalograms among all study participants were compared by Fisher's exact tests. Results: The study sample comprised of 27 participants with DS. Study subjects demonstrated a class III skeletal pattern. This was more pronounced in the older age groups as compared to younger age groups. Subjects also had an increased proportionate lower anterior face height to total facial height compared to normative standards. Gonial angles, mandibular plane angles, and airway measurements increased with age. Conclusions: Patients with Down syndrome present typically with class III skeletal pattern and long lower anterior facial heights. In patients with Down syndrome, comprehensive phase of orthodontic treatment may be best initiated following cessation of growth. C1 [Allareddy, Veerasathpurush] Univ Iowa, Coll Dent, Dept Orthodont, Iowa City, IA 52242 USA. [Allareddy, Veerasathpurush] Univ Iowa, Dent Clin, Iowa City, IA 52242 USA. [Ching, Nicholas] Childrens Dent, El Cerrito, CA USA. [Macklin, Eric A.] Massachusetts Gen Hosp, Biostat Ctr, Boston, MA 02114 USA. [Macklin, Eric A.] Harvard Med Sch, Boston, MA USA. [Voelz, Lauren; Davidson, Emily; Prock, Lisa Albers] Boston Childrens Hosp, Div Dev Med, Syndrome Program, Dept Med, Boston, MA USA. [Weintraub, Gil] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Davidson, Emily; Prock, Lisa Albers; Rosen, Dennis; Skotko, Brian G.] Harvard Med Sch, Dept Pediat, Boston, MA USA. [Rosen, Dennis] Boston Childrens Hosp, Div Resp Dis, Dept Med, Boston, MA USA. [Brunn, Richard] Boston Childrens Hosp, Dept Dent, Boston, MA USA. [Skotko, Brian G.] Massachusetts Gen Hosp, Div Med Genet, Syndrome Program, Dept Pediat, Boston, MA 02114 USA. RP Allareddy, V (reprint author), Univ Iowa, Coll Dent, Dept Orthodont, Iowa City, IA 52242 USA.; Allareddy, V (reprint author), Univ Iowa, Dent Clin, Iowa City, IA 52242 USA. EM sathpurush@gmail.com FU NCRR NIH HHS [UL1 RR025758]; NICHD NIH HHS [F32 HD068101]; NIGMS NIH HHS [T32 GM007748] NR 19 TC 0 Z9 0 U1 65 U2 65 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2196-1042 J9 PROG ORTHOD JI Prog. Orthod. PD NOV 7 PY 2016 VL 17 AR 35 DI 10.1186/s40510-016-0148-7 PG 12 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA EB1BO UT WOS:000387081500001 PM 27722998 ER PT J AU Henihan, AM McCombe, G Klimas, J Swan, D Leahy, D Anderson, R Bury, G Dunne, CP Keenan, E Lambert, JS Meagher, D O'Gorman, C O'Toole, TP Saunders, J Shorter, GW Smyth, BP Kaner, E Cullen, W AF Henihan, Anne Marie McCombe, Geoff Klimas, Jan Swan, Davina Leahy, Dorothy Anderson, Rolande Bury, Gerard Dunne, Colum P. Keenan, Eamon Lambert, John S. Meagher, David O'Gorman, Clodagh O'Toole, Tom P. Saunders, Jean Shorter, Gillian W. Smyth, Bobby P. Kaner, Eileen Cullen, Walter TI Feasibility of alcohol screening among patients receiving opioid treatment in primary care SO BMC FAMILY PRACTICE LA English DT Article DE Alcohol; Primary care; Screening; Agonist treatment; Methadone; General practice; Implementation; Feasibility; Brief intervention; SBIRT ID PRIMARY-HEALTH-CARE; PROBLEM DRUG-USERS; GENERAL-PRACTITIONERS; BRIEF INTERVENTIONS; TREATMENT SBIRT; AUDIT-C; PILOT; IMPLEMENTATION; CONSUMPTION; STRATEGIES AB Background: Identifying and treating problem alcohol use among people who also use illicit drugs is a challenge. Primary care is well placed to address this challenge but there are several barriers which may prevent this occurring. The objective of this study was to determine if a complex intervention designed to support screening and brief intervention for problem alcohol use among people receiving opioid agonist treatment is feasible and acceptable to healthcare providers and their patients in a primary care setting. Methods: A randomised, controlled, pre- and-post design measured feasibility and acceptability of alcohol screening based on recruitment and retention rates among patients and practices. Efficacy was measured by screening and brief intervention rates and the proportion of patients with problem alcohol use. Results: Of 149 practices that were invited, 19 (12.8 %) agreed to participate. At follow up, 13 (81.3 %) practices with 81 (62.8 %) patients were retained. Alcohol screening rates in the intervention group were higher at follow up than in the control group (53 % versus 26 %) as were brief intervention rates (47 % versus 19 %). Four (18 %) people reduced their problem drinking (measured by AUDIT-C), compared to two (7 %) in the control group. Conclusions: Alcohol screening among people receiving opioid agonist treatment in primary care seems feasible. A definitive trial is needed. Such a trial would require over sampling and greater support for participating practices to allow for challenges in recruitment of patients and practices. C1 [Henihan, Anne Marie; McCombe, Geoff; Klimas, Jan; Swan, Davina; Leahy, Dorothy; Dunne, Colum P.; Meagher, David; O'Gorman, Clodagh; Saunders, Jean; Cullen, Walter] Univ Limerick, Grad Entry Med Sch, Fac Educ & Hlth Sci, Limerick, Ireland. [Henihan, Anne Marie; McCombe, Geoff; Klimas, Jan; Swan, Davina; Bury, Gerard; Lambert, John S.; Cullen, Walter] Univ Coll Dublin, UCD Sch Med, Dublin 4, Ireland. [Klimas, Jan] St Pauls Hosp, British Columbia Ctr Excellence HIV AIDS, 608-1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada. [Swan, Davina] Kings Coll London, Inst Psychiat Psychol & Neurosci, Addict Dept, 4 Windsor Walk,Denmark Hill, London SE5 8BB, England. [Anderson, Rolande] Addict Counsellor, Suite 33,Morrison Chambers 32,Nassau St, Dublin 2, Ireland. [Keenan, Eamon] Hlth Serv Execut, Addict Serv, Dublin, Ireland. [O'Toole, Tom P.] Brown Alpert Med Sch, Providence, RI USA. [Saunders, Jean] Univ Limerick, CSTAR Ctr, Limerick, Ireland. [Shorter, Gillian W.; Smyth, Bobby P.] Trinity Coll Dublin, Sch Nursing & Midwifery, Trinity Ctr Practice & Healthcare Innovat, Dublin, Ireland. [Smyth, Bobby P.] Trinity Coll Dublin, Dept Publ Hlth & Primary Care, Dublin, Ireland. [Kaner, Eileen] Newcastle Univ, Inst Hlth & Soc, Newcastle Upon Tyne, Tyne & Wear, England. [Cullen, Walter] US Dept Vet Affairs, Washington, DC USA. RP Cullen, W (reprint author), Univ Limerick, Grad Entry Med Sch, Fac Educ & Hlth Sci, Limerick, Ireland.; Cullen, W (reprint author), Univ Coll Dublin, UCD Sch Med, Dublin 4, Ireland.; Cullen, W (reprint author), US Dept Vet Affairs, Washington, DC USA. EM Walter.Cullen@ucd.ie RI Smyth, Bobby/D-1205-2017; OI Kaner, Eileen/0000-0002-7169-9344 FU Health Research Board of Ireland [HRA-HSR-2012-14]; ELEVATE: Irish Research Council International Career Development Fellowship (Marie Cure Actions) [ELEVATEPD/2014/6]; 'Hepcare Europe' (European Commission 3rd Health Programme) FX Health Research Board of Ireland funded the study (Grant ID: HRA-HSR-2012-14). Dr Klimas work was also part funded by ELEVATE: Irish Research Council International Career Development Fellowship (Marie Cure Actions ELEVATEPD/2014/6); Dr Lambert's work on the project was part funded by 'Hepcare Europe' (European Commission 3rd Health Programme). NR 38 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2296 J9 BMC FAM PRACT JI BMC Fam. Pract. PD NOV 5 PY 2016 VL 17 AR 153 DI 10.1186/s12875-016-0548-2 PG 10 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA EA9QD UT WOS:000386978000002 PM 27816057 ER PT J AU Patel, D Antwi, J Koneru, PC Serrao, E Forli, S Kessl, JJ Feng, L Deng, NJ Levy, RM Fuchs, JR Olson, AJ Engelman, AN Bauman, JD Kvaratskhelia, M Arnold, E AF Patel, Disha Antwi, Janet Koneru, Pratibha C. Serrao, Erik Forli, Stefano Kessl, Jacques J. Feng, Lei Deng, Nanjie Levy, Ronald M. Fuchs, James R. Olson, Arthur J. Engelman, Alan N. Bauman, Joseph D. Kvaratskhelia, Mamuka Arnold, Eddy TI A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE drug discovery; drug screening; human immunodeficiency virus (HIV); integrase; medicinal chemistry; X-ray crystallography; HIV-1; HIV-1 integrase; allosteric inhibitor; fragment screening ID SMALL-MOLECULE INHIBITORS; DNA INTEGRATION; FORCE-FIELD; LEDGF/P75 PROTEIN; HIGH-THROUGHPUT; LIGAND DOCKING; MULTIMERIZATION; REPLICATION; DISCOVERY; MECHANISM AB HIV-1 integrase (IN) is essential for virus replication and represents an important multifunctional therapeutic target. Recently discovered quinoline-based allosteric IN inhibitors (ALLINIs) potently impair HIV-1 replication and are currently in clinical trials. ALLINIs exhibit a multimodal mechanism of action by inducing aberrant IN multimerization during virion morphogenesis and by competing with IN for binding to its cognate cellular cofactor LEDGF/p75 during early steps of HIV-1 infection. However, quinoline-based ALLINIs impose a low genetic barrier for the evolution of resistant phenotypes, which highlights a need for discovery of second-generation inhibitors. Using crystallographic screening of a library of 971 fragments against the HIV-1 IN catalytic core domain (CCD) followed by a fragment expansion approach, we have identified thiophenecarboxylic acid derivatives that bind at the CCD-CCD dimer interface at the principal lens epithelium-derived growth factor (LEDGF)/p75 binding pocket. The most active derivative (5) inhibited LEDGF/p75-dependent HIV-1 IN activity in vitro with an IC50 of 72 m and impaired HIV-1 infection of T cells at an EC50 of 36 m. The identified lead compound, with a relatively small molecular weight (221 Da), provides an optimal building block for developing a new class of inhibitors. Furthermore, although structurally distinct thiophenecarboxylic acid derivatives target a similar pocket at the IN dimer interface as the quinoline-based ALLINIs, the lead compound, 5, inhibited IN mutants that confer resistance to quinoline-based compounds. Collectively, our findings provide a plausible path for structure-based development of second-generation ALLINIs. C1 [Patel, Disha; Bauman, Joseph D.; Arnold, Eddy] Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Antwi, Janet; Fuchs, James R.] Ohio State Univ, Div Med Chem & Pharmacognosy, Coll Pharm, Columbus, OH 43210 USA. [Koneru, Pratibha C.; Feng, Lei; Kvaratskhelia, Mamuka] Ohio State Univ, Ctr Retrovirus Res, Columbus, OH 43210 USA. [Koneru, Pratibha C.; Feng, Lei; Kvaratskhelia, Mamuka] Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. [Serrao, Erik; Engelman, Alan N.] Harvard Med Sch, Dept Canc Immunol & Virol, Dana Farber Canc Inst, Boston, MA 02215 USA. [Serrao, Erik; Engelman, Alan N.] Harvard Med Sch, Dept Med, Boston, MA 02215 USA. [Forli, Stefano; Olson, Arthur J.] Scripps Res Inst, Mol Graph Lab, Dept Integrat Struct & Computat Biol, MB 112, La Jolla, CA 92037 USA. [Kessl, Jacques J.] Univ Southern Mississippi, Dept Chem & Biochem, Hattiesburg, MS 39406 USA. [Deng, Nanjie; Levy, Ronald M.] Temple Univ, Ctr Biophys & Computat Biol, Philadelphia, PA 19122 USA. RP Arnold, E (reprint author), Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA.; Kvaratskhelia, M (reprint author), Ohio State Univ, Ctr Retrovirus Res, Columbus, OH 43210 USA.; Kvaratskhelia, M (reprint author), Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. EM kvaratskhelia.1@osu.edu; arnold@cabm.rutgers.edu FU National Institutes of Health [P50GM103368, R01AI110310, R21AI127282] FX This work was supported in whole or in part by National Institutes of Health Grants P50GM103368 (to E. A., M. K., A. N. E., R. M. L., and A. J. O.), R01AI110310 (to M. K. and J. R. F.), and R21AI127282 (to J. J. K.). 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 64 TC 0 Z9 0 U1 8 U2 8 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 NOV 4 PY 2016 VL 291 IS 45 BP 23569 EP 23577 DI 10.1074/jbc.M116.753384 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EC1RH UT WOS:000387884400018 PM 27645997 ER PT J AU Sahni, JM Gayle, SS Bonk, KLW Vite, LC Yori, JL Webb, B Ramos, EK Seachrist, DD Landis, MD Chang, JC Bradner, JE Keri, RA AF Sahni, Jennifer M. Gayle, Sylvia S. Bonk, Kristen L. Weber Vite, Leslie Cuellar Yori, Jennifer L. Webb, Bryan Ramos, Erika K. Seachrist, Darcie D. Landis, Melissa D. Chang, Jenny C. Bradner, James E. Keri, Ruth A. TI Bromodomain and Extraterminal Protein Inhibition Blocks Growth of Triple-negative Breast Cancers through the Suppression of Aurora Kinases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE anticancer drug; apoptosis; breast cancer; bromodomain-containing protein 4 (BRD4); cellular senescence; inhibition mechanism; Aurora kinase ID SELECTIVE-INHIBITION; GENE-EXPRESSION; CELLS; SUBTYPES; PROGRESSION; RESISTANCE; TUMORS; MODELS; BRD4; OVEREXPRESSION AB Bromodomain and extraterminal (BET) proteins are epigenetic readers that recognize acetylated histones and mark areas of the genome for transcription. BRD4, a BET family member protein, has been implicated in a number of types of cancer, and BET protein inhibitors (BETi) are efficacious in many preclinical cancer models. However, the drivers of response to BETi vary depending on tumor type, and little is known regarding the target genes conveying BETi activity in triple-negative breast cancer (TNBC). Here, we show that BETi repress growth of multiple in vitro and in vivo models of TNBC by inducing two terminal responses: apoptosis and senescence. Unlike in other cancers, response to BETi in TNBC is not dependent upon suppression of MYC. Instead, both end points are preceded by the appearance of polyploid cells caused by the suppression of Aurora kinases A and B (AURKA/B), which are critical mediators of mitosis. In addition, AURKA/B inhibitors phenocopy the effects of BETi. These results indicate that Aurora kinases play an important role in the growth suppressive activity of BETi in TNBC. Elucidating the mechanism of response to BETi in TNBC should 1) facilitate the prediction of how distinct TNBC tumors will respond to BETi and 2) inform the rational design of drug combination therapies. C1 [Sahni, Jennifer M.; Gayle, Sylvia S.; Bonk, Kristen L. Weber; Vite, Leslie Cuellar; Yori, Jennifer L.; Webb, Bryan; Ramos, Erika K.; Seachrist, Darcie D.; Keri, Ruth A.] Case Western Reserve Univ, Dept Pharmacol, Cleveland, OH 44106 USA. [Keri, Ruth A.] Case Western Reserve Univ, Dept Genet & Genome Sci & Gen Med Sci Oncol, Cleveland, OH 44106 USA. [Landis, Melissa D.; Chang, Jenny C.] Houston Methodist Hosp, Methodist Canc Ctr, Houston, TX 77030 USA. [Bradner, James E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bradner, James E.] Novartis Inst BioMed Res, Cambridge, MA 02139 USA. RP Keri, RA (reprint author), Case Western Reserve Univ, Dept Pharmacol, Cleveland, OH 44106 USA.; Keri, RA (reprint author), Case Western Reserve Univ, Dept Genet & Genome Sci & Gen Med Sci Oncol, Cleveland, OH 44106 USA. EM keri@case.edu FU National Institutes of Health [P30043703, T32CA059366, R25GM075207, T32GM008056, RO1CA154384, RO1CA206505] FX This work was supported by National Institutes of Health Grants P30043703 (to the Core Facilities of the Case Comprehensive Cancer Center), T32CA059366 (to J.M.S. and S. S. G.), R25GM075207 (to L. C. V. and E. K. R.), T32GM008056 (to L. C. V.), RO1CA154384 (to R. A. K.), and RO1CA206505 (to R. A. K.). 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 44 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 4 PY 2016 VL 291 IS 45 BP 23756 EP 23768 DI 10.1074/jbc.M116.738666 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EC1RH UT WOS:000387884400035 PM 27650498 ER PT J AU Tardivel, M Begard, S Bousset, L Dujardin, S Coens, A Melki, R Buee, L Colin, M AF Tardivel, Meryem Begard, Severine Bousset, Luc Dujardin, Simon Coens, Audrey Melki, Ronald Buee, Luc Colin, Morvane TI Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies SO ACTA NEUROPATHOLOGICA COMMUNICATIONS LA English DT Article ID MEMBRANE NANOTUBES; ALZHEIMERS-DISEASE; IN-VIVO; CEREBROSPINAL-FLUID; MAMMALIAN-CELLS; ENDOGENOUS TAU; TNT FORMATION; ANIMAL-CELLS; BRAIN; MICROTUBULE AB A given cell makes exchanges with its neighbors through a variety of means ranging from diffusible factors to vesicles. Cells use also tunneling nanotubes (TNTs), filamentous-actin-containing membranous structures that bridge and connect cells. First described in immune cells, TNTs facilitate HIV-1 transfer and are found in various cell types, including neurons. We show that the microtubule-associated protein Tau, a key player in Alzheimer's disease, is a bona fide constituent of TNTs. This is important because Tau appears beside filamentous actin and myosin 10 as a specific marker of these fine protrusions of membranes and cytosol that are difficult to visualize. Furthermore, we observed that exogenous Tau species increase the number of TNTs established between primary neurons, thereby facilitating the intercellular transfer of Tau fibrils. In conclusion, Tau may contribute to the formation and function of the highly dynamic TNTs that may be involved in the prion-like propagation of Tau assemblies. C1 [Tardivel, Meryem; Begard, Severine; Dujardin, Simon; Buee, Luc; Colin, Morvane] Univ Lille, INSERM, CHU Lille, UMR S1172,Alzheimer & Tauopathies, F-59000 Lille, France. [Bousset, Luc; Coens, Audrey; Melki, Ronald] Univ Paris Saclay, Paris Saclay Inst Neurosci, CNRS, F-91190 Gif Sur Yvette, France. [Dujardin, Simon] Massachusetts Gen Hosp, Dept Neurol, Mass Gen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Buee, Luc; Colin, Morvane] JPArc, Alzheimer & Tauopathies, INSERM, UMR S1172, Pl Verdun, F-59045 Lille, France. RP Buee, L; Colin, M (reprint author), Univ Lille, INSERM, CHU Lille, UMR S1172,Alzheimer & Tauopathies, F-59000 Lille, France.; Buee, L; Colin, M (reprint author), JPArc, Alzheimer & Tauopathies, INSERM, UMR S1172, Pl Verdun, F-59045 Lille, France. EM luc.buee@inserm.fr; morvane.colin@inserm.fr NR 72 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 2051-5960 J9 ACTA NEUROPATHOL COM JI Acta Neuropathol. Commun. PD NOV 4 PY 2016 VL 4 AR 117 DI 10.1186/s40478-016-0386-4 PG 14 WC Neurosciences SC Neurosciences & Neurology GA EC2BJ UT WOS:000387914000001 PM 27809932 ER PT J AU Movila, A Mawardi, H Nishimura, K Kiyama, T Egashira, K Kim, JY Villa, A Sasaki, H Woo, SB Kawai, T AF Movila, Alexandru Mawardi, Hani Nishimura, Kazuaki Kiyama, Tomomi Egashira, Kenji Kim, Jae-Young Villa, Alessandro Sasaki, Hajime Woo, Sook-Bin Kawai, Toshihisa TI Possible pathogenic engagement of soluble Semaphorin 4D produced by gamma delta T cells in medication-related osteonecrosis of the jaw (MRONJ) SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE gamma delta T cells; Semaphorin 4D; Medication-related osteonecrosis of jaw; TNF-alpha; Inflammation; Monoclonal antibody ID BISPHOSPHONATE-RELATED OSTEONECROSIS; IMMUNE; CD100; ACTIVATION; RESPONSES; SURFACE; CONTRIBUTES; LYMPHOCYTES; EXPRESSION; BACTERIA AB Prior consensus held that medication-related osteonecrosis of the jaw (MRONJ) lesion was composed of necrotic bone; however, more recent studies have identified inflammatory infiltrates in the lesion. Herein, we report that remarkably elevated infiltrating gamma delta T cells (90% of lymphocytes) express Semaphorin 4D (Sema4D) in human patient with MRONJ lesion, whereas gamma delta T cells only account for 2-5% of lymphocytes in blood. Importantly, Sema4D is implicated in the pathogenesis of T cell-mediated inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. Indeed, in a mouse model of MRONJ, an elevated number of gamma delta T, but not alpha beta T, cells infiltrating in the MRONJ-like lesion was observed. Both elevated soluble Sema4D (sSema4D) production accompanied by pro-inflammatory cytokines, including TNF-alpha IFN-gamma and IL-1 beta, and Sema4D-expressing gamma delta T cells were detected in mouse MRONJ-like lesion. Activated gamma delta T cells produced sSema4D in vitro, which could promote TNF-alpha production from macrophages. Meanwhile, gamma delta T cell-KO mice were resistant to the induction of MRONJ and, hence, showed no elevation of local productions of Sema4D and TNF-alpha. Finally, systemic administration of anti-Sema4D neutralizing mAb suppressed the onset of MRONJ in wild-type mice in conjunction with diminished level of TNF-alpha. These results suggested a critical pathogenic engagement of Sema4D produced by gamma delta T cells in the development of MRONJ. (C) 2016 Published by Elsevier Inc. C1 [Movila, Alexandru; Egashira, Kenji; Kim, Jae-Young; Sasaki, Hajime; Kawai, Toshihisa] Forsyth Inst, Dept Immunol & Infect Dis, 245 First St, Cambridge, MA 02142 USA. [Mawardi, Hani] King Abdulaziz Univ, Fac Dent, Jeddah, Saudi Arabia. [Nishimura, Kazuaki] Tohoku Univ Hosp, Maxillooral Disorders, Sendai, Miyagi, Japan. [Nishimura, Kazuaki] Tohoku Univ, Grad Sch Dens, Div Oral Dysfunct Sci, Sendai, Miyagi, Japan. [Kiyama, Tomomi] Tohoku Univ, Div Oral Mol Regulat, Sendai, Miyagi, Japan. [Egashira, Kenji] LION Corp, Res & Dev Headquarters, Odawara, Kanagawa, Japan. [Kim, Jae-Young; Villa, Alessandro; Woo, Sook-Bin] Brigham & Womens Hosp, Div Oral Med & Dent, 75 Francis St, Boston, MA 02115 USA. [Villa, Alessandro; Sasaki, Hajime; Woo, Sook-Bin; Kawai, Toshihisa] Harvard Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA USA. RP Kawai, T (reprint author), Forsyth Inst, Dept Immunol & Infect Dis, 245 First St, Cambridge, MA 02142 USA. EM tkawai@forsyth.org FU NIH from NIDCR [T32 DE 7327, DE-018499, DE-019917]; ITI foundation; AAIDF student research grant FX This research was partly supported by NIH Grants T32 DE 7327 (AM), DE-018499and DE-019917 (TIC) from NIDCR, ITI foundation (TIC) and AAIDF student research grant (J-Y K). NR 30 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 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD NOV 4 PY 2016 VL 480 IS 1 BP 42 EP 47 DI 10.1016/j.bbrc.2016.10.012 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA EC3YZ UT WOS:000388064300008 PM 27720716 ER PT J AU Ritter, DI Roychowdhury, S Roy, A Rao, S Landrum, MJ Sonkin, D Shekar, M Davis, CF Hart, RK Micheel, C Weaver, M Van Allen, EM Parsons, DW McLeod, HL Watson, MS Plon, SE Kulkarni, S Madhavan, S AF Ritter, Deborah I. Roychowdhury, Sameek Roy, Angshumoy Rao, Shruti Landrum, Melissa J. Sonkin, Dmitriy Shekar, Mamatha Davis, Caleb F. Hart, Reece K. Micheel, Christine Weaver, Meredith Van Allen, Eliezer M. Parsons, Donald W. McLeod, Howard L. Watson, Michael S. Plon, Sharon E. Kulkarni, Shashikant Madhavan, Subha CA ClinGen Somatic Canc Working Grp TI Somatic cancer variant curation and harmonization through consensus minimum variant level data SO GENOME MEDICINE LA English DT Article DE Cancer genomics; Somatic variant interpretation; Data standard; Somatic variant curation ID MICROARRAY EXPERIMENT MIAME; DECISION-SUPPORT; MEDICINE; GENOME; INFORMATION; PLATFORM; CHALLENGES; STANDARDS; ONCOLOGY; TUMOR AB Background: To truly achieve personalized medicine in oncology, it is critical to catalog and curate cancer sequence variants for their clinical relevance. The Somatic Working Group (WG) of the Clinical Genome Resource (ClinGen), in cooperation with ClinVar and multiple cancer variant curation stakeholders, has developed a consensus set of minimal variant level data (MVLD). MVLD is a framework of standardized data elements to curate cancer variants for clinical utility. With implementation of MVLD standards, and in a working partnership with ClinVar, we aim to streamline the somatic variant curation efforts in the community and reduce redundancy and time burden for the interpretation of cancer variants in clinical practice. Methods: We developed MVLD through a consensus approach by i) reviewing clinical actionability interpretations from institutions participating in the WG, ii) conducting extensive literature search of clinical somatic interpretation schemas, and iii) survey of cancer variant web portals. A forthcoming guideline on cancer variant interpretation, from the Association of Molecular Pathology (AMP), can be incorporated into MVLD. Results: Along with harmonizing standardized terminology for allele interpretive and descriptive fields that are collected by many databases, the MVLD includes unique fields for cancer variants such as Biomarker Class, Therapeutic Context and Effect. In addition, MVLD includes recommendations for controlled semantics and ontologies. The Somatic WG is collaborating with ClinVar to evaluate MVLD use for somatic variant submissions. ClinVar is an open and centralized repository where sequencing laboratories can report summary-level variant data with clinical significance, and ClinVar accepts cancer variant data. Conclusions: We expect the use of the MVLD to streamline clinical interpretation of cancer variants, enhance interoperability among multiple redundant curation efforts, and increase submission of somatic variants to ClinVar, all of which will enhance translation to clinical oncology practice. C1 [Ritter, Deborah I.; Roy, Angshumoy; Parsons, Donald W.; Plon, Sharon E.; Kulkarni, Shashikant] Baylor Coll Med, Houston, TX 77030 USA. [Ritter, Deborah I.; Roy, Angshumoy; Parsons, Donald W.; Plon, Sharon E.; Kulkarni, Shashikant] Texas Childrens Hosp, Houston, TX 77030 USA. [Roychowdhury, Sameek] Ohio State Univ, Columbus, OH 43210 USA. [Rao, Shruti; Madhavan, Subha] Georgetown Univ, Med Ctr, Innovat Ctr Biomed Informat, Washington, DC 20007 USA. [Rao, Shruti; Madhavan, Subha] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Landrum, Melissa J.] Natl Ctr Biotechnol Informat, Bethesda, MD USA. [Sonkin, Dmitriy] NCI, Rockville, MD USA. [Shekar, Mamatha] Illumina, San Diego, CA USA. [Davis, Caleb F.] MolecularMatch, Houston, TX USA. [Hart, Reece K.] Invitae, San Francisco, CA USA. [Micheel, Christine] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Weaver, Meredith] Amer Coll Med Genet & Genom, Bethesda, MD USA. [Van Allen, Eliezer M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [McLeod, Howard L.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. RP Madhavan, S (reprint author), Georgetown Univ, Med Ctr, Innovat Ctr Biomed Informat, Washington, DC 20007 USA.; Madhavan, S (reprint author), Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. EM sm696@georgetown.edu OI Micheel, Christine/0000-0002-7744-9039; Hart, Reece/0000-0003-3463-0775 FU National Human Genome Research Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute [U41 HG006834, U01 HG007436, U01 HG007437, HHSN261200800001E]; Intramural Research Program of the NIH, National Library of Medicine; NHGRI, BD2K Program [01HG008390]; NHGRI/NCI [1U01HG006485]; [U01HG006492]; [K08CA188615] FX ClinGen is funded by the National Human Genome Research Institute, with additional funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Cancer Institute (U41 HG006834, U01 HG007436, U01 HG007437, HHSN261200800001E). ClinVar is supported by the Intramural Research Program of the NIH, National Library of Medicine. Additional funding: 01HG008390 (NHGRI, BD2K Program) to SM; U01HG006492 and K08CA188615 to EMV. The BASIC3 study is a Clinical Sequencing Exploratory Research (CSER) program project supported by NHGRI/NCI 1U01HG006485 to AR, SEP, and DWP. NR 33 TC 2 Z9 2 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD NOV 4 PY 2016 VL 8 AR 117 DI 10.1186/s13073-016-0367-z PG 9 WC Genetics & Heredity SC Genetics & Heredity GA EB8DS UT WOS:000387621800001 PM 27814769 ER PT J AU Konig, MF Andrade, F AF Konig, Maximilian F. Andrade, Felipe TI A Critical Reappraisal of Neutrophil Extracellular Traps and NETosis Mimics Based on Differential Requirements for Protein Citrullination SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE NETosis; leukotoxic hypercitrullination; citrullination; rheumatoid arthritis; systemic lupus erythematosus; NADPH oxidase; peptidylarginine deiminase; mitophagy ID CHRONIC GRANULOMATOUS-DISEASE; PHORBOL-MYRISTATE ACETATE; PEPTIDYLARGININE DEIMINASE INHIBITION; LYSOSOMAL ENZYME-SECRETION; HUMAN POLYMORPHONUCLEAR LEUKOCYTES; HISTONE ARGININE METHYLATION; SYSTEMIC-LUPUS-ERYTHEMATOSUS; ARTHRITIS SYNOVIAL-FLUID; TUMOR-NECROSIS-FACTOR; PORE-FORMING TOXINS AB NETosis, an antimicrobial form of neutrophil cell death, is considered a primary source of citrullinated autoantigens in rheumatoid arthritis (RA) and immunogenic DNA in systemic lupus erythematosus (SLE). Activation of the citrullinating enzyme peptidylarginine deiminase type 4 (PAD4) is believed to be essential for neutrophil extracellular trap (NET) formation and NETosis. PAD4 is therefore viewed as a promising therapeutic target to inhibit the formation of NETs in both diseases. In this review, we examine the evidence for PAD4 activation during NETosis and provide experimental data to suggest that protein citrullination is not a universal feature of NETs. We delineate two distinct biological processes, leukotoxic hypercitrullination (LTH) and defective mitophagy, which have been erroneously classified as "NETosis." While these NETosis mimics share morphological similarities with NETosis (i.e., extracellular DNA release), they are biologically distinct. As such, these processes can be readily classified by their stimuli, activation of distinct biochemical pathways, the presence of hypercitrullination, and antimicrobial effector function. NETosis is an antimicrobial form of cell death that is NADPH oxidase-dependent and not associated with hypercitrullination. In contrast, LTH is NADPH oxidase-independent and not bactericidal. Rather, LTH represents a bacterial strategy to achieve immune evasion. It is triggered by pore-forming pathways and equivalent signals that cumulate in calcium-dependent hyperactivation of PADs, protein hypercitrullination, and neutrophil death. The generation of citrullinated autoantigens in RA is likely driven by LTH, but not NETosis. Mitochondrial DNA (mtDNA) expulsion, the result of a constitutive defect in mitophagy, represents a second NETosis mimic. In the presence of interferon-alpha and immune complexes, this process can generate highly interferogenic oxidized mtDNA, which has previously been mistaken for NETosis in SLE. Distinguishing NETosis from LTH and defective mitophagy is paramount to understanding the role of neutrophil damage in immunity and the pathogenesis of human diseases. This provides a framework to design specific inhibitors of these distinct biological processes in human disease. C1 [Konig, Maximilian F.; Andrade, Felipe] Johns Hopkins Univ, Sch Med, Div Rheumatol, Baltimore, MD 21218 USA. [Konig, Maximilian F.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. RP Andrade, F (reprint author), Johns Hopkins Univ, Sch Med, Div Rheumatol, Baltimore, MD 21218 USA. EM andrade@jhmi.edu FU NIH [R01AR069569]; Rheumatology Research Foundation; Jerome L. Greene Foundation; Ira T. Fine Discovery Fund; Donald B. and Dorothy L. Stabler Foundation FX The authors would like to thank Janelle M. Montagne, Department of Pathology, Johns Hopkins University for thoughtful revision of the manuscript. FA was supported by NIH grant R01AR069569, Rheumatology Research Foundation, The Jerome L. Greene Foundation, Ira T. Fine Discovery Fund, The Donald B. and Dorothy L. Stabler Foundation. MK was supported by The Donald B. and Dorothy L. Stabler Foundation. NR 178 TC 6 Z9 6 U1 7 U2 7 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 NOV 4 PY 2016 VL 7 AR 461 DI 10.3389/fimmu.2016.00461 PG 18 WC Immunology SC Immunology GA EA9YF UT WOS:000386999900001 PM 27867381 ER PT J AU Cho, S Humar, M Martino, N Yun, SH AF Cho, Sangyeon Humar, Matjaz Martino, Nicola Yun, Seok Hyun TI Laser Particle Stimulated Emission Microscopy SO PHYSICAL REVIEW LETTERS LA English DT Article ID NANOWIRE LASERS; FLUORESCENCE; LIMIT AB We introduce an optical microscopy technique that utilizes micro- or nanolasers embedded in a sample as imaging probes. The narrow spectra and nonlinear power dependence of stimulated emission from the laser particles yield optical sectioning, subdiffraction resolution, and low out-of-focus background. A proof of concept is demonstrated using perovskite nanowires. C1 [Cho, Sangyeon; Humar, Matjaz; Martino, Nicola; Yun, Seok Hyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, Cambridge, MA 02139 USA. [Cho, Sangyeon; Humar, Matjaz; Martino, Nicola; Yun, Seok Hyun] Harvard Med Sch, Cambridge, MA 02139 USA. [Cho, Sangyeon; Yun, Seok Hyun] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Humar, Matjaz] J Stefan Inst, Condensed Matter Dept, Jamova 39, SL-1000 Ljubljana, Slovenia. RP Yun, SH (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Cambridge, MA 02139 USA.; Yun, SH (reprint author), Harvard Med Sch, Cambridge, MA 02139 USA.; Yun, SH (reprint author), MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. EM syun@hms.harvard.edu FU U.S. National Science Foundation [ECCS-1505569]; National Institutes of Health [DP1EB024242, P41EB015903]; MGH Research Scholar Award Program; Samsung Scholarship; Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme [627274] FX We thank the U.S. National Science Foundation (Grant No. ECCS-1505569), National Institutes of Health (Grants No. DP1EB024242, No. P41EB015903), and MGH Research Scholar Award Program for funding. S. C. acknowledges support from Samsung Scholarship. M. H. was supported in part by the Marie Curie International Outgoing Fellowship No. 627274 within the 7th European Community Framework Programme. NR 21 TC 0 Z9 0 U1 14 U2 14 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 EI 1079-7114 J9 PHYS REV LETT JI Phys. Rev. Lett. PD NOV 4 PY 2016 VL 117 IS 9 AR 193902 DI 10.1103/PhysRevLett.117.193902 PG 5 WC Physics, Multidisciplinary SC Physics GA EA8QS UT WOS:000386903400012 PM 27858427 ER PT J AU Sinatra, R Wang, D Deville, P Song, CM Barabasi, AL AF Sinatra, Roberta Wang, Dashun Deville, Pierre Song, Chaoming Barabasi, Albert-Laszlo TI Quantifying the evolution of individual scientific impact SO SCIENCE LA English DT Article ID SCIENCE; CAREER; UNIVERSALITY; PERFORMANCE; CREATIVITY; LANDMARKS; METRICS; AUTHOR; TEAMS; MODEL C1 [Sinatra, Roberta; Deville, Pierre; Barabasi, Albert-Laszlo] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. [Sinatra, Roberta; Deville, Pierre; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Sinatra, Roberta] Cent European Univ, Ctr Network Sci & Math Dept, Budapest, Hungary. [Wang, Dashun] Northwestern Univ, Kellogg Sch Management, Evanston, IL 60208 USA. [Wang, Dashun] Northwestern Univ, Northwestern Inst Complex Syst, Evanston, IL 60208 USA. [Deville, Pierre] Catholic Univ Louvain, Dept Appl Math, Louvain La Neuve, Belgium. [Song, Chaoming] Univ Miami, Dept Phys, Coral Gables, FL 33124 USA. [Barabasi, Albert-Laszlo] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Cent European Univ, Ctr Network Sci, Budapest, Hungary. [Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. RP Barabasi, AL (reprint author), Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA.; Barabasi, AL (reprint author), Northeastern Univ, Dept Phys, Boston, MA 02115 USA.; Barabasi, AL (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA.; Barabasi, AL (reprint author), Cent European Univ, Ctr Network Sci, Budapest, Hungary.; Barabasi, AL (reprint author), Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. EM alb@neu.edu FU Air Force Office of Scientific Research (AFOSR) [FA9550-15-1-0077, FA9550-15-1-0364]; Future and Emerging Technologies Project - European Commission [317 532 "Multiplex"]; AFOSR [FA9550-15-1-0162]; Young Investigator Award; National Foundation for Scientific Research; Research Department of the Communaute francaise de Belgique (Large Graph Concerted Research Action) FX The Physical Review data set can be requested from the APS at http://journals.aps. org/datasets. Data with the result of the disambiguation procedure, described in section S1.1, can be found as supplementary materials. An interactive visualization of the data sets, focusing on the random-impact rule, can be found at www.barabasilab.com/scienceofsuccess/. We thank J. A. Evans, S. Fortunato, S. Lehmann, B. Uzzi, B. Coutinho, S. Gil, E. Guney, J. Huang, J. Menche, F. Simini, M. Szell, and all other colleagues at the Center for Complex Network Research (CCNR) for the valuable discussions and comments. We thank H. Shen for the help with the credit share analysis. R.S. and A.-L. B. were supported by Air Force Office of Scientific Research (AFOSR) grants FA9550-15-1-0077 and FA9550-15-1-0364. A.-L. B. was also supported by the Future and Emerging Technologies Project 317 532 "Multiplex" financed by the European Commission. D.W. was supported by AFOSR grant FA9550-15-1-0162 and a Young Investigator Award. P.D. acknowledges support by the National Foundation for Scientific Research and the Research Department of the Communaute francaise de Belgique (Large Graph Concerted Research Action). R. S. developed the majority of this work during her stay at the CCNR, supported by the J. S. McDonnell Foundation. All authors designed and did the research. R. S. analyzed the empirical data, developed the models and controls, and performed the calculations. A.-L. B. was the lead writer of the manuscript. NR 45 TC 3 Z9 3 U1 52 U2 52 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 NOV 4 PY 2016 VL 354 IS 6312 AR aaf5239 DI 10.1126/science.aaf5239 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA8FD UT WOS:000386869800040 ER PT J AU Ansaloni, L Pisano, M Coccolini, F Peitzmann, AB Fingerhut, A Catena, F Agresta, F Allegri, A Bailey, I Balogh, ZJ Bendinelli, C Biffl, W Bonavina, L Borzellino, G Brunetti, F Burlew, CC Camapanelli, G Campanile, FC Ceresoli, M Chiara, O Civil, I Coimbra, R De Moya, M Di Saverio, S Fraga, GP Gupta, S Kashuk, J Kelly, MD Khokha, V Jeekel, H Latifi, R Leppaniemi, A Maier, RV Marzi, I Moore, F Piazzalunga, D Sakakushev, B Sartelli, M Scalea, T Stahel, PF Taviloglu, K Tugnoli, G Uraneus, S Velmahos, GC Wani, I Weber, DG Viale, P Sugrue, M Ivatury, R Kluger, Y Gurusamy, KS Moore, EE AF Ansaloni, L. Pisano, M. Coccolini, F. Peitzmann, A. B. Fingerhut, A. Catena, F. Agresta, F. Allegri, A. Bailey, I. Balogh, Z. J. Bendinelli, C. Biffl, W. Bonavina, L. Borzellino, G. Brunetti, F. Burlew, C. C. Camapanelli, G. Campanile, F. C. Ceresoli, M. Chiara, O. Civil, I. Coimbra, R. De Moya, M. Di Saverio, S. Fraga, G. P. Gupta, S. Kashuk, J. Kelly, M. D. Khokha, V. Jeekel, H. Latifi, R. Leppaniemi, A. Maier, R. V. Marzi, I. Moore, F. Piazzalunga, D. Sakakushev, B. Sartelli, M. Scalea, T. Stahel, P. F. Taviloglu, K. Tugnoli, G. Uraneus, S. Velmahos, G. C. Wani, I. Weber, D. G. Viale, P. Sugrue, M. Ivatury, R. Kluger, Y. Gurusamy, K. S. Moore, E. E. TI 2016 WSES guidelines on acute calculous cholecystitis (vol 11, 25, 2016) SO WORLD JOURNAL OF EMERGENCY SURGERY LA English DT Correction C1 [Ansaloni, L.; Pisano, M.; Coccolini, F.; Allegri, A.; Piazzalunga, D.] Papa Giovanni XXIII Hosp, Gen Surg 1, Piazza OMS 1, I-24127 Bergamo, Italy. [Peitzmann, A. B.] Univ Pittsburgh, Dept Surg, UPMC, Sch Med, Pittsburgh, PA USA. [Fingerhut, A.] Med Univ Graz, Dept Surg Res, Graz, Austria. [Catena, F.] Univ Hosp Parma, Dept Emergency & Trauma Surg, Parma, Italy. [Agresta, F.] Adria Civil Hosp, Dept Gen Surg, Adria, RO, Italy. [Bailey, I.] Southampton Univ Hosp, Southampton, Hants, England. [Balogh, Z. J.; Bendinelli, C.] John Hunter Hosp, Dept Traumatol, Newcastle, NSW, Australia. [Balogh, Z. J.; Bendinelli, C.] Univ Newcastle, Newcastle, NSW, Australia. [Biffl, W.] Univ Hawaii, Acute Care Surg, Queens Med Ctr, Sch Med, Honolulu, HI 96822 USA. [Bonavina, L.] Univ Milan, Dept Surg, IRCCS Policlin San Donato, Sch Med, Milan, Italy. [Borzellino, G.] Univ Verona, Verona, Italy. [Brunetti, F.] Univ Paris Est UPEC, Unit Digest Hepatopancreato Biliary Surg & Liver, Henri Mondor Hosp, AP HP, Creteil, France. [Burlew, C. C.] Univ Colorado, Denver Hlth Med Ctr, Dept Surg, Sch Med,Surg Intens Care Unit, Denver, CO USA. [Camapanelli, G.] Insubria Univ, Gen Surg Day Surg Ist Clini SantAmbrogio, Milan, Italy. [Camapanelli, G.] Osped San Giovanni Decollato Andosilla, Civita Castellana, Italy. [Chiara, O.] Osped Niguarda Ca Granda, Emergency Dept, Ctr Trauma, Milan, Italy. [Civil, I.] Auckland City Hosp, Dept Surg, Auckland, New Zealand. [Coimbra, R.] Univ Calif San Diego, Div Trauma Surg Crit Care Burns & Acute Care Surg, Hlth Sci, San Diego, CA 92103 USA. [De Moya, M.] Harvard Univ, Cambridge, MA 02138 USA. [Di Saverio, S.; Tugnoli, G.] Maggiore Hosp Trauma Ctr, Gen Emergency & Trauma Surg, Bologna, Italy. [Fraga, G. P.] Univ Estadual Campinas, Div Trauma Surg, Campinas, SP, Brazil. [Gupta, S.] Govt Med Coll, Dept Surg, Chandigarh, India. [Kashuk, J.] Tel Aviv Univ, Sackler Sch Med, Assia Med Grp, IL-69978 Tel Aviv, Israel. [Kelly, M. D.] Canberra Hosp, Acute Surg Unit, Canberra, ACT, Australia. [Khokha, V.] Mozyr City Hosp, Dept Surg, Mozyr, Byelarus. [Jeekel, H.] Erasmus MC, Rotterdam, Holland, Netherlands. [Latifi, R.] Univ Arizona, Tucson, AZ USA. [Leppaniemi, A.] Meilahti Hosp, Helsinki, Finland. [Maier, R. V.] Harborview Med Ctr, Dept Surg, Seattle, WA USA. [Marzi, I.] Goethe Univ Frankfurt, Univ Hosp, Dept Trauma Hand & Reconstruct Surg, Frankfurt, Germany. [Moore, F.] Univ Florida, Dept Surg, Gainesville, FL USA. [Sakakushev, B.] Univ Hosp St George Med Univ, Gen Surg Clin 1, Plovdiv, Bulgaria. [Sartelli, M.] Macerata Hosp, Dept Surg, Macerata, Italy. [Scalea, T.] Univ Maryland, Sch Med, Crit Care Serv, Ctr Shock Trauma, Baltimore, MD 21201 USA. [Stahel, P. F.] Denver Hlth Med Ctr, Denver, CO USA. [Taviloglu, K.; Moore, E. E.] Taviloglu Proctol Ctr, Istanbul, Turkey. [Uraneus, S.] Med Univ Graz, Dept Surg, Graz, Austria. [Velmahos, G. C.] Massachusetts Gen Hosp, Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Wani, I.] DHS, Srinagar, Kashmir, India. [Weber, D. G.] Trauma & Gen Surg, Perth, WA, Australia. [Weber, D. G.] Univ Western Australia, Royal Perth Hosp, Perth, WA, Australia. [Viale, P.] Univ Bologna, Teaching Hosp, Infect Dis Unit, S Orsola Malpighi Alma Mater Studiorum, Bologna, Italy. [Sugrue, M.] Letterkenny Univ Hosp, Donegal, Ireland. [Sugrue, M.] Donegal Clin Res Acad, Donegal, Ireland. [Ivatury, R.] Virginia Commonwealth Univ, Richmond, VA USA. [Kluger, Y.] Div Gen Surg, Rambam Hlth Care Campus, Haifa, Israel. [Gurusamy, K. S.] UCL, Royal Free Campus, London, England. RP Pisano, M (reprint author), Papa Giovanni XXIII Hosp, Gen Surg 1, Piazza OMS 1, I-24127 Bergamo, Italy. EM aiace63@gmail.com NR 2 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 1749-7922 J9 WORLD J EMERG SURG JI World J. Emerg. Surg. PD NOV 4 PY 2016 VL 11 AR 52 DI 10.1186/s13017-016-0088-z PG 1 WC Emergency Medicine; Surgery SC Emergency Medicine; Surgery GA EA9JC UT WOS:000386958300001 PM 27822294 ER PT J AU Zimmerman, B Kelly, B McMillan, BJ Seegar, TCM Dror, RO Kruse, AC Blacklow, SC AF Zimmerman, Brandon Kelly, Brendan McMillan, Brian J. Seegar, Tom C. M. Dror, Ron O. Kruse, Andrew C. Blacklow, Stephen C. TI Crystal Structure of a Full-Length Human Tetraspanin Reveals a Cholesterol-Binding Pocket SO CELL LA English DT Article ID METALLOPROTEASE 10 ADAM10; CELL-SURFACE EXPRESSION; HEPATITIS-C-VIRUS; TSPANC8 TETRASPANINS; MOLECULAR-DYNAMICS; FORCE-FIELD; EVOLUTIONARY CONSERVATION; MEMBRANE-PROTEINS; NOTCH ACTIVATION; CD81 AB Tetraspanins comprise a diverse family of four-pass transmembrane proteins that play critical roles in the immune, reproductive, genitourinary, and auditory systems. Despite their pervasive roles in human physiology, little is known about the structure of tetraspanins or the molecular mechanisms underlying their various functions. Here, we report the crystal structure of human CD81, a full-length tetraspanin. The transmembrane segments of CD81 pack as two largely separated pairs of helices, capped by the large extracellular loop (EC2) at the outer membrane leaflet. The two pairs of helices converge at the inner leaflet to create an intramembrane pocket with additional electron density corresponding to a bound cholesterol molecule within the cavity. Molecular dynamics simulations identify an additional conformation in which EC2 separates substantially from the transmembrane domain. Cholesterol binding appears to modulate CD81 activity in cells, suggesting a potential mechanism for regulation of tetraspanin function. C1 [Zimmerman, Brandon; McMillan, Brian J.; Seegar, Tom C. M.; Kruse, Andrew C.; Blacklow, Stephen C.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Zimmerman, Brandon; McMillan, Brian J.; Seegar, Tom C. M.; Blacklow, Stephen C.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Kelly, Brendan; Dror, Ron O.] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Kelly, Brendan; Dror, Ron O.] Stanford Univ, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA. [Kelly, Brendan; Dror, Ron O.] Stanford Univ, Inst Computat & Math Engn, Stanford, CA 94305 USA. [Blacklow, Stephen C.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. RP Kruse, AC; Blacklow, SC (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Blacklow, SC (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.; Blacklow, SC (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM andrew_kruse@hms.harvard.edu; stephen_blacklow@hms.harvard.edu FU NIH [NCI 5 RO1 CA092433, 1 DP5 OD021345]; Terman Faculty Fellowship; CIHR postdoctoral fellowship; [2T32HL007627] FX We would like to thank beamline staff at APS GM/CA beamline 23ID-B for their superb technical assistance and support and N. Latorraca for helpful suggestions regarding simulation analysis. Financial support for this work was provided by NIH grants NCI 5 RO1 CA092433 (S.C.B.) and 1 DP5 OD021345 (A.C.K.) and by a Terman Faculty Fellowship (R.O.D.). B.Z. was supported by a CIHR postdoctoral fellowship, and T.C.M.S. was supported by training grant 2T32HL007627. NR 65 TC 4 Z9 4 U1 14 U2 14 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 NOV 3 PY 2016 VL 167 IS 4 BP 1041 EP + DI 10.1016/j.cell.2016.09.056 PG 22 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE3EB UT WOS:000389469000020 PM 27881302 ER PT J AU Li, Y Oosting, M Smeekens, SP Jaeger, M Aguirre-Gamboa, R Le, KTT Deelen, P Ricano-Ponce, I Schoffelen, T Jansen, AFM Swertz, MA Withoff, S van de Vosse, E van Deuren, M van de Veerdonk, F Zhernakova, A van der Meer, JWM Xavier, RJ Franke, L Joosten, LAB Wijmenga, C Kumar, V Netea, MG AF Li, Yang Oosting, Marije Smeekens, Sanne P. Jaeger, Martin Aguirre-Gamboa, Raul Le, Kieu T. T. Deelen, Patrick Ricano-Ponce, Isis Schoffelen, Teske Jansen, Anne F. M. Swertz, Morris A. Withoff, Sebo van de Vosse, Esther van Deuren, Marcel van de Veerdonk, Frank Zhernakova, Alexandra van der Meer, Jos W. M. Xavier, Ramnik J. Franke, Lude Joosten, Leo A. B. Wijmenga, Cisca Kumar, Vinod Netea, Mihai G. TI A Functional Genomics Approach to Understand Variation in Cytokine Production in Humans SO CELL LA English DT Article ID HUMAN IMMUNE-SYSTEM; WIDE ASSOCIATION; GENETIC-VARIANTS; LOW-FREQUENCY; DISEASE; SUSCEPTIBILITY; HERITABILITY; AUTOIMMUNITY; MICROBIOME; COMPLEMENT AB As part of the Human Functional Genomics Project, which aims to understand the factors that determine the variability of immune responses, we investigated genetic variants affecting cytokine production in response to ex vivo stimulation in two independent cohorts of 500 and 200 healthy individuals. We demonstrate a strong impact of genetic heritability on cytokine production capacity after challenge with bacterial, fungal, viral, and non-microbial stimuli. In addition to 17 novel genome-wide significant cytokine QTLs (cQTLs), our study provides a comprehensive picture of the genetic variants that influence six different cytokines in whole blood, blood mononuclear cells, and macrophages. Important biological pathways that contain cytokine QTLs map to pattern recognition receptors (TLR1-6-10 cluster), cytokine and complement inhibitors, and the kallikrein system. The cytokine QTLs show enrichment for monocyte-specific enhancers, are more often located in regions under positive selection, and are significantly enriched among SNPs associated with infections and immune-mediated diseases. C1 [Li, Yang; Aguirre-Gamboa, Raul; Le, Kieu T. T.; Deelen, Patrick; Ricano-Ponce, Isis; Swertz, Morris A.; Withoff, Sebo; Zhernakova, Alexandra; Franke, Lude; Wijmenga, Cisca; Kumar, Vinod] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [Oosting, Marije; Smeekens, Sanne P.; Jaeger, Martin; Schoffelen, Teske; Jansen, Anne F. M.; van Deuren, Marcel; van de Veerdonk, Frank; van der Meer, Jos W. M.; Joosten, Leo A. B.; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 HP Nijmegen, Netherlands. [Oosting, Marije; Smeekens, Sanne P.; Jaeger, Martin; Schoffelen, Teske; Jansen, Anne F. M.; van Deuren, Marcel; van de Veerdonk, Frank; van der Meer, Jos W. M.; Joosten, Leo A. B.; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis, NL-6525 HP Nijmegen, Netherlands. [Deelen, Patrick; Swertz, Morris A.] Univ Groningen, Univ Med Ctr Groningen, Genom Coordinat Ctr, NL-9700 RB Groningen, Netherlands. [van de Vosse, Esther] Leiden Univ, Med Ctr, Dept Infect Dis, NL-2333 ZA Leiden, Netherlands. [Xavier, Ramnik J.] Harvard Sch Med, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik J.] Harvard Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Xavier, Ramnik J.] Broad Inst MIT & Harvard Univ, Cambridge, MA 02142 USA. [Wijmenga, Cisca] Univ Oslo, Oslo Univ Hosp, Dept Immunol, Rikshosp, N-0372 Oslo, Norway. RP Li, Y; Wijmenga, C; Kumar, V (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands.; Joosten, LAB; Netea, MG (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 HP Nijmegen, Netherlands.; Joosten, LAB; Netea, MG (reprint author), Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis, NL-6525 HP Nijmegen, Netherlands.; Wijmenga, C (reprint author), Univ Oslo, Oslo Univ Hosp, Dept Immunol, Rikshosp, N-0372 Oslo, Norway. EM y.li01@umcg.nl; leo.joosten@radboudumc.nl; c.wijmenga@umcg.nl; v.kumar@umcg.nl; mihai.netea@radboudumc.nl RI Oosting, Marije/H-7437-2015; van de Vosse, Esther/B-7285-2009 OI van de Vosse, Esther/0000-0001-5199-3426 FU ERC Consolidator grant [3310372]; IN-CONTROL CVON grant [CVON2012-03]; Spinoza prize [NWO SPI 94-212, NWO SPI 92266]; ERC advanced grant (FP7/ERC grant) [2012-322698]; Dutch Digestive Diseases Foundation grant [MLDS WO11-30]; European Union Seventh Framework Programme grant (EU FP7) TANDEM project [HEALTH-F3-2012-305279]; Netherlands Organization for Scientific Research (NWO) VENI grant [863.13.011]; BBMRI-NL; Netherlands Organization for Scientific Research (NWO) [184.021.007] FX We thank all volunteers in the 500FG and 200FG cohorts of the Human Functional Genomics Project (HFGP) for their participation. We thank Kate McIntyre and Jackie Senior for editing the text. The HFGP is supported by an ERC Consolidator grant (3310372), an IN-CONTROL CVON grant (CVON2012-03), and a Spinoza prize (NWO SPI 94-212) to M.G.N.; an ERC advanced grant (FP/2007-2013/ERC grant 2012-322698) and a Spinoza prize (NWO SPI 92266) to C.W.; a Dutch Digestive Diseases Foundation grant (MLDS WO11-30) to C.W. and V.K.; a European Union Seventh Framework Programme grant (EU FP7) TANDEM project (HEALTH-F3-2012-305279) to C.W. and V.K.; and a Netherlands Organization for Scientific Research (NWO) VENI grant (863.13.011) to Y.L. The creation and hosting of the online database has been supported by BBMRI-NL, a research infrastructure financed by the Netherlands Organization for Scientific Research (NWO), grant number 184.021.007. We thank Edith Adriaanse, Marije van der Geest, and Marieke Bijlsma for structuring the data into the online database and the MOLGENIS open source team (Dennis Hendriksen, Erwin Winder, Bart Charbon, Fleur Kelpin, Jonathan Jetten, Mark de Haan, Tommy de Boer, David van Enckevort, Chao Pang, and Joeri van der Velde) for designing and implementing the database software. NR 47 TC 5 Z9 5 U1 5 U2 5 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 NOV 3 PY 2016 VL 167 IS 4 BP 1099 EP + DI 10.1016/j.cell.2016.10.017 PG 26 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE3EB UT WOS:000389469000025 PM 27814507 ER PT J AU ter Horst, R Jaeger, M Smeekens, SP Oosting, M Swertz, MA Li, Y Kumar, V Diavatopoulos, DA Jansen, AFM Lemmers, H Toenhake-Dijkstra, H van Herwaarden, AE Janssen, M van der Molen, RG Joosten, I Sweep, FCGJ Smit, JW Netea-Maier, RT Koenders, MMJF Xavier, RJ van der Meer, JWM Dinarello, CA Pavelka, N Wijmenga, C Notebaart, RA Joosten, LAB Netea, MG AF ter Horst, Rob Jaeger, Martin Smeekens, Sanne P. Oosting, Marije Swertz, Morris A. Li, Yang Kumar, Vinod Diavatopoulos, Dimitri A. Jansen, Anne F. M. Lemmers, Heidi Toenhake-Dijkstra, Helga van Herwaarden, Antonius E. Janssen, Matthijs van der Molen, Renate G. Joosten, Irma Sweep, Fred C. G. J. Smit, Johannes W. Netea-Maier, Romana T. Koenders, Mieke M. J. F. Xavier, Ramnik J. van der Meer, Jos W. M. Dinarello, Charles A. Pavelka, Norman Wijmenga, Cisca Notebaart, Richard A. Joosten, Leo A. B. Netea, Mihai G. TI Host and Environmental Factors Influencing Individual Human Cytokine Responses SO CELL LA English DT Article ID C-REACTIVE PROTEIN; BODY-MASS INDEX; PROGESTERONE-RECEPTOR IMMUNOREACTIVITY; ORGAN-TRANSPLANT RECIPIENTS; MULTIPLE-SCLEROSIS; IMMUNE-SYSTEM; ORAL-CONTRACEPTIVES; GENDER-DIFFERENCES; DIABETES-MELLITUS; SERUM-LEVELS AB Differences in susceptibility to immune-mediated diseases are determined by variability in immune responses. In three studies within the Human Functional Genomics Project, we assessed the effect of environmental and non-genetic host factors of the genetic make-up of the host and of the intestinal microbiome on the cytokine responses in humans. We analyzed the association of these factors with circulating mediators and with six cytokines after stimulation with 19 bacterial, fungal, viral, and non-microbial metabolic stimuli in 534 healthy subjects. In this first study, we show a strong impact of non-genetic host factors (e.g., age and gender) on cytokine production and circulating mediators. Additionally, annual seasonality is found to be an important environmental factor influencing cytokine production. Alpha-1-antitrypsin concentrations partially mediate the seasonality of cytokine responses, whereas the effect of vitamin D levels is limited. The complete dataset has been made publicly available as a comprehensive resource for future studies. C1 [ter Horst, Rob; Jaeger, Martin; Smeekens, Sanne P.; Oosting, Marije; Jansen, Anne F. M.; Lemmers, Heidi; Toenhake-Dijkstra, Helga; Smit, Johannes W.; Netea-Maier, Romana T.; van der Meer, Jos W. M.; Dinarello, Charles A.; Pavelka, Norman; Notebaart, Richard A.; Joosten, Leo A. B.; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6500 HB Nijmegen, Gelderland, Netherlands. [ter Horst, Rob; Jaeger, Martin; Smeekens, Sanne P.; Oosting, Marije; Jansen, Anne F. M.; Lemmers, Heidi; Toenhake-Dijkstra, Helga; Smit, Johannes W.; Netea-Maier, Romana T.; van der Meer, Jos W. M.; Dinarello, Charles A.; Pavelka, Norman; Notebaart, Richard A.; Joosten, Leo A. B.; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Radboudumc, Ctr Infect Dis, NL-6500 HB Nijmegen, Gelderland, Netherlands. [Swertz, Morris A.; Li, Yang; Kumar, Vinod; Wijmenga, Cisca] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [Diavatopoulos, Dimitri A.] Radboud Univ Nijmegen, Med Ctr, Lab Pediat Infect Dis, NL-6500 HB Nijmegen, Gelderland, Netherlands. [Diavatopoulos, Dimitri A.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, NL-6500 HB Nijmegen, Gelderland, Netherlands. [van Herwaarden, Antonius E.; van der Molen, Renate G.; Joosten, Irma; Sweep, Fred C. G. J.] Radboud Univ Nijmegen, Med Ctr, Dept Lab Med, NL-6500 HB Nijmegen, Gelderland, Netherlands. [Smit, Johannes W.; Netea-Maier, Romana T.] Radboud Univ Nijmegen, Med Ctr, Div Endocrinol, NL-6500 HB Nijmegen, Gelderland, Netherlands. [Koenders, Mieke M. J. F.] Elkerliek Hosp, Clin Chem, NL-5700 AB Helmond, Noord Brabant, Netherlands. [Xavier, Ramnik J.] Broad Inst Massachusetts Inst Technol MIT, Cambridge, MA 02142 USA. [Xavier, Ramnik J.] Harvard Univ, Cambridge, MA 02142 USA. [Xavier, Ramnik J.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Cambridge, MA 02139 USA. [Dinarello, Charles A.] Univ Colorado Denver, Div Med, Aurora, CO 80045 USA. [Pavelka, Norman] ASTAR, Singapore Immunol Network SIgN, Singapore 138648, Singapore. [Janssen, Matthijs] Rijnstate Hosp, Dept Rheumatol, NL-6815 AD Arnhem, Gelderland, Netherlands. [Wijmenga, Cisca] Univ Oslo, Oslo Univ Hosp, Ctr Immune Regulat, N-0027 Oslo, Norway. [Wijmenga, Cisca] Univ Oslo, Oslo Univ Hosp, Dept Immunol, N-0027 Oslo, Norway. RP Joosten, LAB; Netea, MG (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6500 HB Nijmegen, Gelderland, Netherlands.; Joosten, LAB; Netea, MG (reprint author), Radboud Univ Nijmegen, Med Ctr, Radboudumc, Ctr Infect Dis, NL-6500 HB Nijmegen, Gelderland, Netherlands. EM leo.joosten@radboudumc.nl; mihai.netea@radboudumc.nl RI Oosting, Marije/H-7437-2015; van der Molen, Renate/I-2398-2014; OI van der Molen, Renate/0000-0003-3113-6587; Pavelka, Norman/0000-0003-4542-9970 FU ERC Consolidator Grant [310372]; Spinoza grant [94-212]; IN-CONTROL CVON grant [CVON2012-03]; ERC Advanced Grant (ERC) [2012-322698]; Spinoza Prize [NWO SPI 92-266]; Dutch Digestive Diseases Foundation [MLDS WO11-30]; European Union's Seventh Framework Programme (EU FP7) TANDEM project [HEALTH-F3-2012-305279]; Netherlands Organization for Scientific Research (NWO) VENI grant [863.13.011]; Interleukin Foundation; NIH grant [AI15614]; STW grant [STW13546]; BBMRI-NL; Netherlands Organization for Scientific Research (NWO) [184.021.007] FX The authors thank all volunteers from the 500FG cohort of the Human Functional Genomics Study for participation in the study. The HFGP is supported by an ERC Consolidator Grant (310372), A Spinoza grant (94-212) and IN-CONTROL CVON grant to M.G.N. (CVON2012-03), an ERC Advanced Grant (ERC grant 2012-322698) and a Spinoza Prize (NWO SPI 92-266) both to C.W., the Dutch Digestive Diseases Foundation (MLDS WO11-30 to C.W. and V.K.), the European Union's Seventh Framework Programme (EU FP7) TANDEM project (HEALTH-F3-2012-305279 to C.W. and V.K.), Netherlands Organization for Scientific Research (NWO) VENI grant (863.13.011 to Y.L.), and the Interleukin Foundation and NIH grant AI15614 to C.A.D. S.P.S. was financially supported by an STW grant (STW13546). The creation and hosting of the online Database has been supported by BBMRI-NL, a research infrastructure financed by the Netherlands Organization for Scientific Research (NWO), grant number 184.021.007. We thank Edith Adriaanse, Marije van der Geest, and Marieke Bijlsma voor for structuring the data into the online Database, and we thank the MOLGENIS open source team, Morris Swertz, Dennis Hendriksen, Erwin Winder, Bart Charbon, Fleur Kelpin, Jonathan Jetten, Mark de Haan, Tommy de Boer, David van Enckevort, Chao Pang, and Joeri van der Velde for designing and implementing the Database software. We thank Isak W. Tengesdal for operating the Ella (TM) microfluidic analyzer (Bio-Techne) and A.J. Olthaar for excellent technical assistance with the Vitamin D and hormone measurements. The authors thank Mark Gresnigt for helping to construct the list of genes involved in cytokine production. We thank Kiki Schraa and Inge van den Munckhof for measuring IL-6 in the validation cohort. We would also like to thank Nathan E. Lewis for his helpful comments on the manuscript. We additionally thank Ana Felix, Marie Van den Broeck, and Joao Santon for providing the figure icons "Obesity'', "Male Aging''/"Female Aging'', and "Mouse'', respectively, as deposited on https://thenounproject.com. Charles A. Dinarello is a member of the Bio-Techne Company Board which owns R and D Systems. NR 94 TC 5 Z9 5 U1 8 U2 8 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 NOV 3 PY 2016 VL 167 IS 4 BP 1111 EP + DI 10.1016/j.cell.2016.10.018 PG 27 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE3EB UT WOS:000389469000026 PM 27814508 ER PT J AU Schirmer, M Smeekens, SP Vlamakis, H Jaeger, M Oosting, M Franzosa, EA ter Horst, R Jansen, T Jacobs, L Bonder, MJ Kurilshikov, A Fu, JY Joosten, LAB Zhernakova, A Huttenhower, C Wijmenga, C Netea, MG Xavier, RJ AF Schirmer, Melanie Smeekens, Sanne P. Vlamakis, Hera Jaeger, Martin Oosting, Marije Franzosa, Eric A. ter Horst, Rob Jansen, Trees Jacobs, Liesbeth Bonder, Marc Jan Kurilshikov, Alexander Fu, Jingyuan Joosten, Leo A. B. Zhernakova, Alexandra Huttenhower, Curtis Wijmenga, Cisca Netea, Mihai G. Xavier, Ramnik J. TI Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity SO CELL LA English DT Article ID CANDIDA-ALBICANS; CARDIOVASCULAR-DISEASE; RHEUMATOID-ARTHRITIS; IMMUNE-RESPONSE; FATTY-ACIDS; METABOLITES; TRYPTOPHAN; COLITIS; BLOOD; SUSCEPTIBILITY AB Gut microbial dysbioses are linked to aberrant immune responses, which are often accompanied by abnormal production of inflammatory cytokines. As part of the Human Functional Genomics Project (HFGP), we investigate how differences in composition and function of gut microbial communities may contribute to inter-individual variation in cytokine responses to microbial stimulations in healthy humans. We observe microbiome-cytokine interaction patterns that are stimulus specific, cytokine specific, and cytokine and stimulus specific. Validation of two predicted host-microbial interactions reveal that TNF alpha and IFN gamma production are associated with specific microbial metabolic pathways: palmitoleic acid metabolism and tryptophan degradation to tryptophol. Besides providing a resource of predicted microbially derived mediators that influence immune phenotypes in response to common microorganisms, these data can help to define principles for understanding disease susceptibility. The three HFGP studies presented in this issue lay the groundwork for further studies aimed at understanding the interplay between microbial, genetic, and environmental factors in the regulation of the immune response in humans. C1 [Schirmer, Melanie; Vlamakis, Hera; Franzosa, Eric A.; Huttenhower, Curtis; Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Schirmer, Melanie; Franzosa, Eric A.; Huttenhower, Curtis] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Smeekens, Sanne P.; Jaeger, Martin; Oosting, Marije; ter Horst, Rob; Jansen, Trees; Jacobs, Liesbeth; Joosten, Leo A. B.; Netea, Mihai G.] Radboudumc, Dept Internal Med, NL-6525 GA Nijmegen, Netherlands. [Smeekens, Sanne P.; Jaeger, Martin; Oosting, Marije; ter Horst, Rob; Jansen, Trees; Jacobs, Liesbeth; Joosten, Leo A. B.; Netea, Mihai G.] Radboudumc, Radboud Ctr Infect Dis RCI, NL-6525 GA Nijmegen, Netherlands. [Bonder, Marc Jan; Kurilshikov, Alexander; Fu, Jingyuan; Zhernakova, Alexandra; Wijmenga, Cisca] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 EX Groningen, Netherlands. [Kurilshikov, Alexander] RAS, SB, Inst Chem Biol & Fundamental Med, Novosibirsk 630090, Russia. [Kurilshikov, Alexander] Novosibirsk State Univ, Novosibirsk 630090, Russia. [Fu, Jingyuan] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, NL-9713 EX Groningen, Netherlands. [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. [Xavier, Ramnik J.] MIT, Ctr Microbiome Informat & Therapeut, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Xavier, RJ (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Netea, MG (reprint author), Radboudumc, Dept Internal Med, NL-6525 GA Nijmegen, Netherlands.; Netea, MG (reprint author), Radboudumc, Radboud Ctr Infect Dis RCI, NL-6525 GA Nijmegen, Netherlands.; Xavier, RJ (reprint author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA.; Xavier, RJ (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA.; Xavier, RJ (reprint author), Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA.; Xavier, RJ (reprint author), MIT, Ctr Microbiome Informat & Therapeut, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM mihai.netea@radboudumc.nl; xavier@molbio.mgh.harvard.edu RI Oosting, Marije/H-7437-2015; OI Bonder, Marc Jan/0000-0002-8431-3180 FU ERC Consolidator Grant [3310372]; Spinoza Prize [NOW SPI 94-212, NWO SPI 92-266]; IN-CONTROL CVON grant [CVON 2012-03]; ERC Advanced Grant [FP/ERC grant] [2012-322698]; Dutch Digestive Diseases Foundation [MLDS WO11-30]; European Union's Seventh Framework Programme[EU FP7] TANDEM project [HEALTH-F3-2012-305279]; NIH [U54DK102557, R01DK092405]; Helmsley Charitable Trust [2014PG-IBD016]; JDRF [17-2011-529]; CCFA [20144126]; CVON grant [CVON 2012-03]; STW grant [STW13546]; Rosalind Franklin Fellowship (University of Groningen); Netherlands Organisation for Scientific Research [NWO-VIDI 864.13.013]; BBMRI-NL; Netherlands Organisation for Scientific Research (NWO) [184.021.007] FX The authors thank all volunteers from the 500FG cohort for participating. The HFGP is supported by grants to M.G.N. (ERC Consolidator Grant [3310372], Spinoza Prize [NOW SPI 94-212], and IN-CONTROL CVON grant [CVON 2012-03]) and C.W. (ERC Advanced Grant [FP/2007-2013/ERC grant 2012-322698], Spinoza Prize [NWO SPI 92-266], the Dutch Digestive Diseases Foundation [MLDS WO11-30], and the European Union's Seventh Framework Programme[EU FP7] TANDEM project [HEALTH-F3-2012-305279]). R.J.X. was supported by grants from NIH (U54DK102557 and R01DK092405), Helmsley Charitable Trust (2014PG-IBD016), JDRF (17-2011-529), and CCFA (20144126). A.Z., J.F., and A.K. were supported by a CVON grant (CVON 2012-03). S.P.S. was financially supported by STW grant STW13546. A.Z. holds a Rosalind Franklin Fellowship (University of Groningen). J.F. is funded by the Netherlands Organisation for Scientific Research (NWO-VIDI 864.13.013). We thank Tiffany Poon for help in sequence production and sample management and Natalia Nedelsky (Massachusetts General Hospital) for editorial help and help with figure generation. We also thank Edith Adriaanse, Marije van der Geest, and Marieke Bijlsma for structuring the online database and the MOLGENIS open source team, Dennis Hendriksen, ErwinWinder, Bart Charbon, Fleur Kelpin, Jonathan Jetten, Mark de Haan, Tommy de Boer, David van Enckevort, Chao Pang, Joeri van der Velde, and Morris Swertz for designing and implementing the database software. The creation and hosting of the online database was supported by BBMRI-NL, a research infrastructure financed by the Netherlands Organisation for Scientific Research (NWO), grant number 184.021.007. We thank Maria Carmen Cenit, Astrid Maatman, Mathieu Plateel, and Jody Arends for technical support, and Daniel Graham for helpful advice and discussions. We also thank https://thenounproject.comfor providing the figure icons "Male Aging''/''Female Aging'' by Marie Van den Broeck. NR 48 TC 8 Z9 8 U1 28 U2 28 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 NOV 3 PY 2016 VL 167 IS 4 BP 1125 EP + DI 10.1016/j.cell.2016.10.020 PG 20 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE3EB UT WOS:000389469000027 PM 27814509 ER PT J AU Collins-Fekete, CA Brousmiche, S Portillo, SKN Beaulieu, L Seco, J AF Collins-Fekete, Charles-Antoine Brousmiche, Sebastien Portillo, Stephen K. N. Beaulieu, Luc Seco, Joao TI A maximum likelihood method for high resolution proton radiography/proton CT SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE proton imaging; proton radiography; multiple Coulomb scattering; proton computed tomography ID COMPUTED-TOMOGRAPHY; STOPPING POWER; MONTE-CARLO; RANGE CALCULATIONS; PATH FORMALISM; LIKELY PATH; X-RAY; THERAPY; CALIBRATION; SCATTERING AB Multiple Coulomb scattering (MCS) is the largest contributor to blurring in proton imaging. In this work, we developed a maximum likelihood least squares estimator that improves proton radiography's spatial resolution. The water equivalent thickness (WET) through projections defined from the source to the detector pixels were estimated such that they maximizes the likelihood of the energy loss of every proton crossing the volume. The length spent in each projection was calculated through the optimized cubic spline path estimate. The proton radiographies were produced using Geant4 simulations. Three phantoms were studied here: a slanted cube in a tank of water to measure 2D spatial resolution, a voxelized head phantom for clinical performance evaluation as well as a parametric Catphan phantom (CTP528) for 3D spatial resolution. Two proton beam configurations were used: a parallel and a conical beam. Proton beams of 200 and 330 MeV were simulated to acquire the radiography. Spatial resolution is increased from 2.44 lp cm(-1) to 4.53 lp cm(-1) in the 200 MeV beam and from 3.49 lp cm(-1) to 5.76 lp cm(-1) in the 330 MeV beam. Beam configurations do not affect the reconstructed spatial resolution as investigated between a radiography acquired with the parallel (3.49 lp cm(-1) to 5.76 lp cm(-1)) or conical beam (from 3.49 lp cm(-1) to 5.56 lp cm(-1)). The improved images were then used as input in a photon tomography algorithm. The proton CT reconstruction of the Catphan phantom shows high spatial resolution (from 2.79 to 5.55 lp cm(-1) for the parallel beam and from 3.03 to 5.15 lp cm(-1) for the conical beam) and the reconstruction of the head phantom, although qualitative, shows high contrast in the gradient region. The proposed formulation of the optimization demonstrates serious potential to increase the spatial resolution (up by 65%) in proton radiography and greatly accelerate proton computed tomography reconstruction. C1 [Collins-Fekete, Charles-Antoine; Beaulieu, Luc] Univ Laval, Dept Phys Genie Phys & Opt, Quebec City, PQ, Canada. [Collins-Fekete, Charles-Antoine; Beaulieu, Luc] Univ Laval, Ctr Rech Canc, Quebec City, PQ, Canada. [Collins-Fekete, Charles-Antoine; Beaulieu, Luc] CHU Quebec, Dept Radiooncol, Quebec City, PQ, Canada. [Collins-Fekete, Charles-Antoine; Beaulieu, Luc] CHU Quebec, CRCHU Quebec, Quebec City, PQ, Canada. [Collins-Fekete, Charles-Antoine; Seco, Joao] Massachusetts Gen Hosp, Francis H Burr Proton Therapy Ctr, Dept Radiat Oncol, Boston, MA 02114 USA. [Brousmiche, Sebastien] IBA, Louvain La Neuve, Belgium. [Portillo, Stephen K. N.] Harvard Smithsonian Ctr Astrophys, 60 Garden St, Cambridge, MA 02138 USA. [Seco, Joao] Deutsch Krebsforschungszentrum Heidelberg, Baden Baden, DE, Germany. [Seco, Joao] Heidelberg Univ, Dept Phys & Astron Heidelberg, Baden Baden, DE, Germany. RP Collins-Fekete, CA (reprint author), Univ Laval, Dept Phys Genie Phys & Opt, Quebec City, PQ, Canada.; Collins-Fekete, CA (reprint author), Univ Laval, Ctr Rech Canc, Quebec City, PQ, Canada.; Collins-Fekete, CA (reprint author), CHU Quebec, Dept Radiooncol, Quebec City, PQ, Canada.; Collins-Fekete, CA (reprint author), CHU Quebec, CRCHU Quebec, Quebec City, PQ, Canada.; Collins-Fekete, CA (reprint author), Massachusetts Gen Hosp, Francis H Burr Proton Therapy Ctr, Dept Radiat Oncol, Boston, MA 02114 USA. EM charles-antoine.collins-fekete.1@ulaval.ca OI Portillo, Stephen/0000-0001-8132-8056 FU Fonds de Recherche du Quebec-Nature et technologies; CREATE Medical Physics Research Training Network grant of the Natural Sciences and Engineering Research Council [432290]; Canada Foundation for Innovation (CFI); NanoQuebec; RMGA; Fonds de Recherche du Quebec-Nature et Technologies (FRQ-NT) FX The authors would like to acknowledge Zachary Slepian for helpful discussions and help in text revision. Charles-Antoine Collins-Fekete is supported by a scholarship from Fonds de Recherche du Quebec-Nature et technologies. CACF acknowledges partial support by the CREATE Medical Physics Research Training Network grant of the Natural Sciences and Engineering Research Council (Grant number: 432290). Computations were made on the supercomputer Colosse from Universite Laval, managed by Calcul Quebec and Compute Canada. The operation of this supercomputer is funded by the Canada Foundation for Innovation (CFI), NanoQuebec, RMGA and the Fonds de Recherche du Quebec-Nature et Technologies (FRQ-NT). NR 33 TC 0 Z9 0 U1 1 U2 1 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 NOV 3 PY 2016 VL 61 IS 23 BP 8232 EP 8248 DI 10.1088/0031-9155/61/23/8232 PG 17 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA EC1QS UT WOS:000387882600001 PM 27811399 ER PT J AU Ordulu, Z Kammin, T Brand, H Pillalamarri, V Redin, CE Collins, RL Blumenthal, I Hanscom, C Pereira, S Bradley, I Crandall, BF Gerrol, P Hayden, MA Hussain, N Kanengisser-Pines, B Kantarci, S Levy, B Macera, MJ Quintero-Rivera, F Spiegel, E Stevens, B Ulm, JE Warburton, D Wilkins-Haug, LE Yachelevich, N Gusella, JF Talkowski, ME Morton, CC AF Ordulu, Zehra Kammin, Tammy Brand, Harrison Pillalamarri, Vamsee Redin, Claire E. Collins, Ryan L. Blumenthal, Ian Hanscom, Carrie Pereira, Shahrin Bradley, India Crandall, Barbara F. Gerrol, Pamela Hayden, Mark A. Hussain, Naveed Kanengisser-Pines, Bibi Kantarci, Sibel Levy, Brynn Macera, Michael J. Quintero-Rivera, Fabiola Spiegel, Erica Stevens, Blair Ulm, Janet E. Warburton, Dorothy Wilkins-Haug, Louise E. Yachelevich, Naomi Gusella, James F. Talkowski, Michael E. Morton, Cynthia C. TI Structural Chromosomal Rearrangements Require Nucleotide-Level Resolution: Lessons from Next-Generation Sequencing in Prenatal Diagnosis SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID PIERRE ROBIN-SEQUENCE; APPARENTLY BALANCED TRANSLOCATIONS; CRYPTIC GENOMIC IMBALANCES; LINKED MYOTUBULAR MYOPATHY; COPY-NUMBER VARIATION; DE-NOVO; DEVELOPMENTAL DELAY; TRANSCRIPTION FACTOR; MENTAL-RETARDATION; SONIC HEDGEHOG AB In this exciting era of "next-gen cytogenetics," integrating genomic sequencing into the prenatal diagnostic setting is possible within an actionable time frame and can provide precise delineation of balanced chromosomal rearrangements at the nucleotide level. Given the increased risk of congenital abnormalities in newborns with de novo balanced chromosomal rearrangements, comprehensive interpretation of breakpoints could substantially improve prediction of phenotypic outcomes and support perinatal medical care. Herein, we present and evaluate sequencing results of balanced chromosomal rearrangements in ten prenatal subjects with respect to the location of regulatory chromatin domains (topologically associated domains [TADS]). The genomic material from all subjects was interpreted to be "normal" by microarray analyses, and their rearrangements would not have been detected by cell-free DNA (cfDNA) screening. The findings of our systematic approach correlate with phenotypes of both pregnancies with untoward outcomes (5/10) and with healthy newborns (3/10). Two pregnancies, one with a chromosomal aberration predicted to be of unknown clinical significance and another one predicted to be likely benign, were terminated prior to phenotype-genotype correlation (2/10). We demonstrate that the clinical interpretation of structural rearrangements should not be limited to interruption, deletion, or duplication of specific genes and should also incorporate regulatory domains of the human genome with critical ramifications for the control of gene expression. As detailed in this study, our molecular approach to both detecting and interpreting the breakpoints of structural rearrangements yields unparalleled information in comparison to other commonly used first-tier diagnostic methods, such as non-invasive cfDNA screening and microarray analysis, to provide improved genetic counseling for phenotypic outcome in the prenatal setting. C1 [Ordulu, Zehra; Kammin, Tammy; Pereira, Shahrin; Gerrol, Pamela; Hayden, Mark A.; Wilkins-Haug, Louise E.; Morton, Cynthia C.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, 75 Francis St, Boston, MA 02115 USA. [Ordulu, Zehra; Redin, Claire E.; Wilkins-Haug, Louise E.; Talkowski, Michael E.; Morton, Cynthia C.] Harvard Med Sch, Boston, MA 02115 USA. [Brand, Harrison; Pillalamarri, Vamsee; Redin, Claire E.; Collins, Ryan L.; Blumenthal, Ian; Hanscom, Carrie; Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Brand, Harrison; Redin, Claire E.; Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Brand, Harrison; Redin, Claire E.; Gusella, James F.; Talkowski, Michael E.] Harvard Med Sch, Boston, MA 02114 USA. [Brand, Harrison; Redin, Claire E.; Gusella, James F.; Talkowski, Michael E.; Morton, Cynthia C.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Bradley, India; Crandall, Barbara F.] Univ Calif Los Angeles, David Geffen Sch Med, Prenatal Diag Ctr, Dept Psychiat, Med Plaza, Los Angeles, CA 90095 USA. [Hussain, Naveed] Univ Connecticut, Connecticut Childrens Med Ctr, Dept Pediat, Farmington, CT 06030 USA. [Kanengisser-Pines, Bibi] Kaplan Med Ctr, Dept Obstet & Gynecol, IL-76100 Rehovot, Israel. [Kantarci, Sibel; Quintero-Rivera, Fabiola] Univ Calif Los Angeles, David Geffen Sch Med, UCLA Clin Genom Ctr, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Levy, Brynn] Columbia Univ, Coll Phys & Surg, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Macera, Michael J.] Columbia Univ, New York Presbyterian Hosp, Med Ctr, New York, NY 10032 USA. [Spiegel, Erica] Columbia Univ, Dept Maternal Fetal Med, Med Ctr, New York, NY 10032 USA. [Stevens, Blair] Univ Texas Med Sch Houston, Dept Obstet Gynecol & Reprod Sci, Houston, TX 77030 USA. [Ulm, Janet E.] Reg Obstetr Consultants, Chattanooga, TN 37403 USA. [Warburton, Dorothy] Columbia Univ, Dept Genet & Dev, New York, NY 10032 USA. [Warburton, Dorothy] Columbia Univ, Dept Pediat, New York, NY 10032 USA. [Yachelevich, Naomi] NYU, Sch Med, Dept Pediat, Clin Genet Serv, New York, NY 10003 USA. [Gusella, James F.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Talkowski, Michael E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Talkowski, Michael E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Morton, Cynthia C.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Morton, Cynthia C.] Univ Manchester, Div Evolut & Genom Sci, Sch Biol Sci, Manchester Acad Hlth Sci Ctr, Manchester 03101, Lancs, England. RP Morton, CC (reprint author), Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, 75 Francis St, Boston, MA 02115 USA.; Morton, CC (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Morton, CC (reprint author), Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA.; Morton, CC (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA.; Morton, CC (reprint author), Univ Manchester, Div Evolut & Genom Sci, Sch Biol Sci, Manchester Acad Hlth Sci Ctr, Manchester 03101, Lancs, England. EM cmorton@partners.org FU NIH [GM061354, HD081256]; NIH (March of Dimes) [6-FY15-255] FX We are grateful to the families of the subjects for their participation. We thank Christina Jabbour, Amelia Lindgren, Samantha Schilit, and Drs. Ozden Altiok Clark and Frederick Bieber for their contributions. We dedicate this article in loving memory of Dorothy Warburton, a co-author on this study and the author of an article also published in The Journal,4 which has served as a foundation for the Developmental Genome Anatomy Project. This study was funded by the NIH (GM061354 to C.C.M., M.E.T., and J.F.G.; HD081256 and March of Dimes 6-FY15-255 to M.E.T.). NR 84 TC 1 Z9 1 U1 6 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD NOV 3 PY 2016 VL 99 IS 5 BP 1015 EP 1033 DI 10.1016/j.ajhg.2016.08.022 PG 19 WC Genetics & Heredity SC Genetics & Heredity GA EB6XT UT WOS:000387529600002 PM 27745839 ER PT J AU O'Grady, GL Best, HA Sztal, TE Schartner, V Sanjuan-Vazquez, T Donkervoort, S Neto, OA Sutton, RB Ilkovski, B Romero, NB Stojkovic, T Dastgir, J Waddell, LB Boland, A Hu, Y Williams, C Ruparelia, AA Maisonobe, T Peduto, AJ Reddel, SW Lek, M Tukiainen, T Cummings, BB Joshi, H Nectoux, J Brammah, S Deleuze, JF Ing, VO Ramm, G Ardicli, D Nowak, KJ Talim, B Topaloglu, H Laing, NG North, KN MacArthur, DG Friant, S Clarke, NF Bryson-Richardson, RJ Bonnemann, CG Laporte, J Cooper, ST AF O'Grady, Gina L. Best, Heather A. Sztal, Tamar E. Schartner, Vanessa Sanjuan-Vazquez, Tvlyriam Donkervoort, Sandra Neto, Osorio Abath Sutton, Roger Bryan Ilkovski, Biljana Romero, Norma Beatriz Stojkovic, Tanya Dastgir, Jahannaz Waddell, Leigh B. Boland, Anne Hu, Ying Williams, Caitlin Ruparelia, Avnika A. Maisonobe, Thierry Peduto, Anthony J. Reddel, Stephen W. Lek, Monkol Tukiainen, Tam Cummings, Beryl B. Joshi, Himanshu Nectoux, Juliette Brammah, Susan Deleuze, Jean-Francois Ing, Viola Oorschot Ramm, Georg Ardicli, Didem Nowak, Kristen J. Talim, Beril Topaloglu, Haluk Laing, Nigel G. North, Kathryn N. MacArthur, Daniel G. Friant, Sylvie Clarke, Nigel F. Bryson-Richardson, Robert J. Bonnemann, Carsten G. Laporte, Jocelyn Cooper, Sandra T. TI Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CONGENITAL MYOPATHIES; PHYLOGENETIC ANALYSIS; NEMALINE MYOPATHY; ZEBRAFISH MODELS; GENETIC-VARIANTS; GENERATION; DIAGNOSIS; DISEASE; MUSCLE AB This study establishes PYROXD1 variants as a cause of early-onset myopathy and uses biospecimens and cell lines, yeast, and zebrafish models to elucidate the fundamental role of PYROXD1 in skeletal muscle. Exome sequencing identified recessive variants in PYROXD1 in nine probands from five families. Affected individuals presented in infancy or childhood with slowly progressive proximal and distal weakness, facial weakness, nasal speech, swallowing difficulties, and normal to moderately elevated creatine kinase. Distinctive histopathology showed abundant internalized nuclei, myofibrillar disorganization, desmin-positive inclusions, and thickened Z-bands. PYROXD1 is a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins (FAD-binding) and catalyze pyridine-nucleotide-dependent (NAD/NADH) reduction of thiol residues in other proteins. Complementation experiments in yeast lacking glutathione reductase girl show that human PYROXD1 has reductase activity that is strongly impaired by the disease-associated missense mutations. Immunolocalization studies in human muscle and zebrafish myofibers demonstrate that PYROXD1 localizes to the nucleus and to striated sarcomeric compartments. Zebrafish with ryroxD1 knock-down recapitulate features of PYROXD1 myopathy with sarcomeric disorganization, myofibrillar aggregates, and marked swimming defect. We characterize variants in the oxidoreductase PYROXD1 as a cause of early-onset myopathy with distinctive histopathology and introduce altered redox regulation as a primary cause of congenital muscle disease. C1 [O'Grady, Gina L.; Best, Heather A.; Ilkovski, Biljana; Waddell, Leigh B.; Joshi, Himanshu; North, Kathryn N.; Clarke, Nigel F.; Cooper, Sandra T.] Childrens Hosp Westmead, Kids Res Inst, Inst Neurosci & Muscle Res, Sydney, NSW 2145, Australia. [O'Grady, Gina L.; Best, Heather A.; Clarke, Nigel F.; Cooper, Sandra T.] Univ Sydney, Discipline Paediat & Child Hlth, Fac Med, Sydney, NSW 2006, Australia. [O'Grady, Gina L.] Starship Childrens Hlth, Paediat Neurol Serv, Auckland 1023, New Zealand. [Sztal, Tamar E.; Williams, Caitlin; Ruparelia, Avnika A.; Bryson-Richardson, Robert J.] Monash Univ, Sch Biol Sci, Melbourne, Vic 3800, Australia. [Schartner, Vanessa; Neto, Osorio Abath; Laporte, Jocelyn] IGBMC, F-67400 Illkirch Graffenstaden, France. [Sanjuan-Vazquez, Tvlyriam; Friant, Sylvie] Univ Strasbourg, CNRS, UMR7156, Dept Mol & Cellular Genet, F-67081 Strasbourg, France. [Donkervoort, Sandra; Dastgir, Jahannaz; Hu, Ying; Bonnemann, Carsten G.] NINDS, Neurogenet Branch, Neuromuscular & Neurogenet Disorders Childhood Se, NIH, Bethesda, MD 20892 USA. [Sutton, Roger Bryan] Texas Tech Univ, Hlth Sci Ctr, Dept Cell Physiol & Mol Biophys, Lubbock, TX 79430 USA. [Sutton, Roger Bryan] Texas Tech Univ, Hlth Sci Ctr, Ctr Membrane Prot Res, Lubbock, TX 79430 USA. [Romero, Norma Beatriz] UPMC Univ Paris 06, INSERM, UMRS974,CNRS FRE3617, Sorbonne Univ,Ctr Res Myol,GH Pitie Salpetriere, 47 Blvd Hop, F-75013 Paris, France. [Romero, Norma Beatriz; Stojkovic, Tanya; Maisonobe, Thierry] GHU La Pitie Salpetriere, AP HP, Inst Myol, Ctr Reference Pathol Neuromusculaire Paris Est, F-7503 Paris, France. [Boland, Anne; Deleuze, Jean-Francois] CEA, Ctr Natl Genotypage, Inst Genom, CP5721, F-91057 Evry, France. [Peduto, Anthony J.] Univ Sydney, Dept Radiol, Westmead Hosp, Western Clin Sch, Sydney, NSW 1024, Australia. [Reddel, Stephen W.] Univ Sydney, Concord Clin Sch, Dept Neurol, Sydney, NSW 2139, Australia. [Lek, Monkol; Tukiainen, Tam; Cummings, Beryl B.; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Lek, Monkol; Tukiainen, Tam; Cummings, Beryl B.; MacArthur, Daniel G.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA. [Nectoux, Juliette] HUPC Hop Cochin, Serv Biochim & Genet Mol, F-75014 Paris, France. [Nectoux, Juliette] Univ Paris 05, INSERM, U1016, Inst Cochin,CNRS UMR8104, F-75014 Paris, France. [Brammah, Susan] Concord Repatriat Gen Hosp, Electron Microscope Unit, Concord, NSW 2139, Australia. [Ing, Viola Oorschot; Ramm, Georg] Monash Univ, Clive & Vera Ramaciotti Ctr Struct Cryoelectron M, Melbourne, Vic 3800, Australia. [Ramm, Georg] Monash Univ, Dept Biochem & Mol Biol, Melbourne, Vic 3800, Australia. [Ardicli, Didem; Talim, Beril; Topaloglu, Haluk] Hacettepe Univ, Dept Pediat Neurol, Childrens Hosp, TR-06100 Ankara, Turkey. [Nowak, Kristen J.; Laing, Nigel G.] Univ Western Australia, Ctr Med Res, Perth, WA 6009, Australia. [Nowak, Kristen J.; Laing, Nigel G.] Harry Perkins Inst Med Res, Perth, WA 6009, Australia. [North, Kathryn N.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Flemington Rd, Parkville, Vic 3052, Australia. [Laporte, Jocelyn] Univ Strasbourg, F-67081 Illkirch Graffenstaden, France. RP Cooper, ST (reprint author), Childrens Hosp Westmead, Kids Res Inst, Inst Neurosci & Muscle Res, Sydney, NSW 2145, Australia.; Cooper, ST (reprint author), Univ Sydney, Discipline Paediat & Child Hlth, Fac Med, Sydney, NSW 2006, Australia. EM sandra.cooper@sydney.edu.au RI North, Kathryn/K-6476-2012; OI North, Kathryn/0000-0003-0841-8009; Friant, Sylvie/0000-0002-5412-6288 FU Australian National Health and Medical Research Council (NHMRC) [1080587, 1022707, 1031893, 1048816, 1056285]; Muscular Dystrophy New South Wales; Royal Australasian College of Physicians; Australian Research Council [FT100100734]; National Human Genome Research Institute of the NIH [U54 HG003067]; Division of Intramural Research of the National Institutes of Neurological Disorders and Stroke, France Genomique National infrastructure grant Investissements d'Avenir and Agence Nationale pour la Recherche [ANR-10-INBS-09, ANR-11-BSV1-026]; Fondation Maladies Rares "Myocapture" sequencing project; Association Frangaise contre les Myopathies [AFM-15352, AFM-16551]; Muscular Dystrophy Association [MDA-186985]; Myotubular Trust; IDEX-Universite de Strasbourg PhD fellowship; NINDS/NIH FX This study was supported by the following funding: The Australian National Health and Medical Research Council (NHMRC) 1080587 (S.T.C., N.F.C., D.G.M., K.N.N., R.B.R., K.J.N., N.G.L.), 1022707 and 1031893 (K.N.N., N.F.C., and N.G.L.), 1048816 (S.T.C.), and 1056285 (G.L.O.), Muscular Dystrophy New South Wales (G.L.O.), Royal Australasian College of Physicians (G.L.O.), Australian Research Council FT100100734 (K.J.N.), National Human Genome Research Institute of the NIH (D.G.M., Medical Sequencing Program grant U54 HG003067 to the Broad Institute principal investigator, Lander), Division of Intramural Research of the National Institutes of Neurological Disorders and Stroke, France Genomique National infrastructure grant Investissements d'Avenir and Agence Nationale pour la Recherche (ANR-10-INBS-09 and ANR-11-BSV1-026), Fondation Maladies Rares "Myocapture" sequencing project, Association Frangaise contre les Myopathies (AFM-15352 and AFM-16551), Muscular Dystrophy Association (MDA-186985), Myotubular Trust and IDEX-Universite de Strasbourg PhD fellowship (M.S.-V), and intramural funds of the NINDS/NIH (C.G.B. and S.D.). NR 35 TC 1 Z9 1 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD NOV 3 PY 2016 VL 99 IS 5 BP 1086 EP 1105 DI 10.1016/j.ajhg.2016.09.005 PG 20 WC Genetics & Heredity SC Genetics & Heredity GA EB6XT UT WOS:000387529600007 PM 27745833 ER PT J AU Marin, JR Abo, AM Arroyo, AC Doniger, SJ Fischer, JW Rempell, R Gary, B Holmes, JF Kessler, DO Lam, SHF Levine, MC Levy, JA Murray, A Ng, L Noble, VE Ramirez-Schrempp, D Riley, DC Saul, T Shah, V Sivitz, AB Tay, ET Teng, D Chaudoin, L Tsung, JW Vieira, RL Vitberg, YM Lewiss, RE AF Marin, Jennifer R. Abo, Alyssa M. Arroyo, Alexander C. Doniger, Stephanie J. Fischer, Jason W. Rempell, Rachel Gary, Brandi Holmes, James F. Kessler, David O. Lam, Samuel H. F. Levine, Marla C. Levy, Jason A. Murray, Alice Ng, Lorraine Noble, Vicki E. Ramirez-Schrempp, Daniela Riley, David C. Saul, Turandot Shah, Vaishali Sivitz, Adam B. Tay, Ee Tein Teng, David Chaudoin, Lindsey Tsung, James W. Vieira, Rebecca L. Vitberg, Yaffa M. Lewiss, Resa E. TI Pediatric emergency medicine point-of-care ultrasound: summary of the evidence SO CRITICAL ULTRASOUND JOURNAL LA English DT Review DE Pediatric emergency medicine; Point-of-care ultrasound; Diagnostic; Procedures ID HYPERTROPHIC PYLORIC-STENOSIS; OPTIC-NERVE SHEATH; RANDOMIZED CONTROLLED-TRIAL; SOFT-TISSUE INFECTIONS; DEEP-VEIN THROMBOSIS; INFERIOR VENA-CAVA; RAISED INTRACRANIAL-PRESSURE; HUMAN CHORIONIC-GONADOTROPIN; CENTRAL VENOUS CANNULATION; ASSISTED LUMBAR PUNCTURE AB The utility of point-of-care ultrasound is well supported by the medical literature. Consequently, pediatric emergency medicine providers have embraced this technology in everyday practice. Recently, the American Academy of Pediatrics published a policy statement endorsing the use of point-of-care ultrasound by pediatric emergency medicine providers. To date, there is no standard guideline for the practice of point-of-care ultrasound for this specialty. This document serves as an initial step in the detailed "how to" and description of individual point-of-care ultrasound examinations. Pediatric emergency medicine providers should refer to this paper as reference for published research, objectives for learners, and standardized reporting guidelines. C1 [Marin, Jennifer R.] Childrens Hosp Pittsburgh, 4401 Penn Ave,AOB Suite 2400, Pittsburgh, PA 15224 USA. [Abo, Alyssa M.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Arroyo, Alexander C.] Maimonides Hosp, Brooklyn, NY 11219 USA. [Doniger, Stephanie J.] New York Methodist Hosp, Brooklyn, NY USA. [Fischer, Jason W.] Hosp Sick Children, Toronto, ON, Canada. [Rempell, Rachel; Levy, Jason A.; Vieira, Rebecca L.] Boston Childrens Hosp, Boston, MA USA. [Gary, Brandi] Queens Med Ctr, Honolulu, HI USA. [Holmes, James F.] Univ Calif Davis, Sacramento, CA 95817 USA. [Kessler, David O.; Ng, Lorraine; Chaudoin, Lindsey] Morgan Stanley Childrens Hosp, New York, NY USA. [Lam, Samuel H. F.] Univ Calif San Diego, San Diego, CA 92103 USA. [Levine, Marla C.] Dell Childrens Med Ctr, Austin, TX USA. [Murray, Alice] Boston Med Ctr, Boston, MA USA. [Noble, Vicki E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ramirez-Schrempp, Daniela] Boston Univ, Med Ctr, Boston, NY USA. [Riley, David C.] Columbia Univ, Med Ctr, New York, NY USA. [Saul, Turandot] St Lukes Roosevelt Hosp, New York, NY 10025 USA. [Shah, Vaishali] Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA. [Sivitz, Adam B.] Newark Beth Israel Med Ctr, Newark, NJ USA. [Tay, Ee Tein; Tsung, James W.] Mt Sinai Hosp, New York, NY 10029 USA. [Teng, David] Cohen Childrens Med Ctr, New Hyde Pk, NY USA. [Vitberg, Yaffa M.] Weill Cornell Med Ctr, New York, NY USA. [Lewiss, Resa E.] Univ Colorado, Aurora, CO USA. RP Marin, JR (reprint author), Childrens Hosp Pittsburgh, 4401 Penn Ave,AOB Suite 2400, Pittsburgh, PA 15224 USA. EM jrmmarin@yahoo.com NR 425 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 2036-3176 EI 2036-7902 J9 CRIT ULTRASOUND J JI Crit. Ultrasound J. PD NOV 3 PY 2016 VL 8 AR 16 DI 10.1186/s13089-016-0049-5 PG 83 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EB4DU UT WOS:000387320900001 PM 27812885 ER PT J AU Chu, JH Hart, JE Chhabra, D Garshick, E Raby, BA Laden, F AF Chu, Jen-hwa Hart, Jaime E. Chhabra, Divya Garshick, Eric Raby, Benjamin A. Laden, Francine TI Gene expression network analyses in response to air pollution exposures in the trucking industry SO ENVIRONMENTAL HEALTH LA English DT Article DE Air pollution; Trucking industry; Gene expression; Network analysis ID CANDIDATE TUMOR-SUPPRESSOR; LUNG-CANCER; DIESEL EXHAUST; COLON-CANCER; MYOCARDIAL-INFARCTION; ELEMENTAL CARBON; UP-REGULATION; PARTICULATE; BLOOD; CELLS AB Background: Exposure to air pollution, including traffic-related pollutants, has been associated with a variety of adverse health outcomes, including increased cardiopulmonary morbidity and mortality, and increased lung cancer risk. Methods: To better understand the cellular responses induced by air pollution exposures, we performed genome-wide gene expression microarray analysis using whole blood RNA sampled at three time-points across the work weeks of 63 non-smoking employees at 10 trucking terminals in the northeastern US. We defined genes and gene networks that were differentially activated in response to PM2.5 (particulate matter <= 2.5 microns in diameter) and elemental carbon (EC) and organic carbon (OC). Results: Multiple transcripts were strongly associated (p(adj) < 0.001) with pollutant levels (48, 260, and 49 transcripts for EC, OC, and PM2.5, respectively), including 63 that were statistically significantly correlated with at least two out of the three exposures. These genes included many that have been implicated in ischemic heart disease, chronic obstructive pulmonary disease (COPD), lung cancer, and other pollution-related illnesses. Through the combination of Gene Set Enrichment Analysis and network analysis (using GeneMANIA), we identified a core set of 25 interrelated genes that were common to all three exposure measures and were differentially expressed in two previous studies assessing gene expression attributable to air pollution. Many of these are members of fundamental cancer-related pathways, including those related to DNA and metal binding, and regulation of apoptosis and also but include genes implicated in chronic heart and lung diseases. Conclusions: These data provide a molecular link between the associations of air pollution exposures with health effects. C1 [Chu, Jen-hwa] Yale Univ, Sch Med, Dept Internal Med, Sect Pulm Crit Care & Sleep Med, New Haven, CT 06510 USA. [Hart, Jaime E.; Chhabra, Divya; Garshick, Eric; Raby, Benjamin A.; Laden, Francine] Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA USA. [Hart, Jaime E.; Laden, Francine] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Garshick, Eric] VA Boston Healthcare Syst, Pulm Allergy Sleep & Crit Care Med Sect, Boston, MA USA. [Raby, Benjamin A.] Harvard Med Sch, Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA USA. [Laden, Francine] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Chu, JH (reprint author), Yale Univ, Sch Med, Dept Internal Med, Sect Pulm Crit Care & Sleep Med, New Haven, CT 06510 USA. EM jen-hwa.chu@yale.edu OI Chu, Jen-hwa/0000-0001-7179-9428 FU National Institutes of Health [R01 ES016284]; NIH/NHLBI [K99HL114651] FX This work is supported by grant R01 ES016284 from the National Institutes of Health. JC is supported by NIH/NHLBI grant K99HL114651. NR 52 TC 0 Z9 0 U1 16 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD NOV 3 PY 2016 VL 15 AR 101 DI 10.1186/s12940-016-0187-z PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA EB2IU UT WOS:000387183700001 PM 27809917 ER PT J AU Hirakawa, M Matos, T Liu, HY Koreth, J Kim, HT Paul, NE Murase, K Whangbo, J Alho, AC Nikiforow, S Cutler, C Ho, VT Armand, P Alyea, EP Antin, JH Blazar, BR Lacerda, JF Soiffer, RJ Ritz, J AF Hirakawa, Masahiro Matos, Tiago Liu, Hongye Koreth, John Kim, Haesook T. Paul, Nicole E. Murase, Kazuyuki Whangbo, Jennifer Alho, Ana C. Nikiforow, Sarah Cutler, Corey Ho, Vincent T. Armand, Philippe Alyea, Edwin P. Antin, Joseph H. Blazar, Bruce R. Lacerda, Joao F. Soiffer, Robert J. Ritz, Jerome TI Low-dose IL-2 selectively activates subsets of CD4(+) Tregs and NK cells SO JCI INSIGHT LA English DT Article ID REGULATORY T-CELLS; VERSUS-HOST-DISEASE; NATURAL-KILLER-CELLS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; MASS CYTOMETRY; CHRONIC GVHD; B-CELLS; INTERLEUKIN-2; TRANSPLANTATION; EXPRESSION AB CD4(+) regulatory T cells (CD4Tregs) play a critical role in the maintenance of immune tolerance and prevention of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. IL-2 supports the proliferation and survival of CD4Tregs and previous studies have demonstrated that IL-2 induces selective expansion of CD4Tregs and improves clinical manifestations of chronic GVHD. However, mechanisms for selective activation of CD4Tregs and the effects of low-dose IL-2 on other immune cells are not well understood. Using mass cytometry, we demonstrate that low concentrations of IL-2 selectively induce STAT5 phosphorylation in Helios(+) CD4Tregs and CD56(bright)CD16(-) NK cells in vitro. Preferential activation and expansion of Helios(+) CD4Tregs and CD56(bright)CD16(-) NK cells was also demonstrated in patients with chronic GVHD receiving low-dose IL-2. With prolonged IL-2 treatment for 48 weeks, phenotypic changes were also observed in Helios-CD4Tregs. The effects of low-dose IL-2 therapy on conventional CD4(+) T cells and CD8(+) T cells were limited to increased expression of PD-1 on effector memory T cells. These studies reveal the selective effects of low-dose IL-2 therapy on Helios(+) CD4Tregs and CD56(bright) NK cells that constitutively express high-affinity IL-2 receptors as well as the indirect effects of prolonged exposure to low concentrations of IL-2 in vivo. C1 [Hirakawa, Masahiro; Matos, Tiago; Liu, Hongye; Koreth, John; Paul, Nicole E.; Murase, Kazuyuki; Whangbo, Jennifer; Alho, Ana C.; Nikiforow, Sarah; Cutler, Corey; Ho, Vincent T.; Armand, Philippe; Alyea, Edwin P.; Antin, Joseph H.; Soiffer, Robert J.; Ritz, Jerome] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Hirakawa, Masahiro; Matos, Tiago; Liu, Hongye; Koreth, John; Paul, Nicole E.; Murase, Kazuyuki; Whangbo, Jennifer; Alho, Ana C.; Nikiforow, Sarah; Cutler, Corey; Ho, Vincent T.; Armand, Philippe; Alyea, Edwin P.; Antin, Joseph H.; Soiffer, Robert J.; Ritz, Jerome] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hirakawa, Masahiro; Matos, Tiago; Liu, Hongye; Koreth, John; Murase, Kazuyuki; Whangbo, Jennifer; Alho, Ana C.; Nikiforow, Sarah; Cutler, Corey; Ho, Vincent T.; Armand, Philippe; Alyea, Edwin P.; Antin, Joseph H.; Soiffer, Robert J.; Ritz, Jerome] Harvard Med Sch, Boston, MA USA. [Matos, Tiago; Alho, Ana C.; Lacerda, Joao F.] Univ Lisbon, Fac Med, Inst Mol Med, Lisbon, Portugal. [Kim, Haesook T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Kim, Haesook T.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Whangbo, Jennifer] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Blazar, Bruce R.] Univ Minnesota, Div Blood & Marrow Transplantat, Minneapolis, MN USA. RP Ritz, J (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,M530, Boston, MA 02215 USA. EM Jerome_Ritz@dfci.harvard.edu FU NCI NIH HHS [P01 CA142106, R01 CA183559, R01 CA183560]; NHLBI NIH HHS [R01 HL118979]; NIAID NIH HHS [P01 AI056299] NR 63 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD NOV 3 PY 2016 VL 1 IS 18 AR e89278 DI 10.1172/jci.insight.89278 PG 18 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1PK UT WOS:000387125700009 PM 27812545 ER PT J AU Simpkin, AL Schwartzstein, RM AF Simpkin, Arabella L. Schwartzstein, Richard M. TI Tolerating Uncertainty - The Next Medical Revolution? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Simpkin, Arabella L.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Schwartzstein, Richard M.] Harvard Med Sch, Boston, MA USA. [Schwartzstein, Richard M.] Beth Israel Deaconess Med Ctr, Div Pulm Crit Care & Sleep Med, Boston, MA 02215 USA. RP Simpkin, AL (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. NR 4 TC 4 Z9 4 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 NOV 3 PY 2016 VL 375 IS 18 BP 1713 EP 1715 DI 10.1056/NEJMp1606402 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EB0BB UT WOS:000387007300004 PM 27806221 ER PT J AU Hortobagyi, GN Stemmer, SM Burris, HA Yap, YS Sonke, GS Paluch-Shimon, S Campone, M Blackwell, KL Andre, F Winer, EP Janni, W Verma, S Conte, P Arteaga, CL Cameron, DA Petrakova, K Hart, LL Villanueva, C Chan, A Jakobsen, E Nusch, A Burdaeva, O Grischke, EM Alba, E Wist, E Marschner, N Favret, AM Yardley, D Bachelot, T Tseng, LM Blau, S Xuan, F Souami, F Miller, M Germa, C Hirawat, S O'Shaughnessy, J AF Hortobagyi, G. N. Stemmer, S. M. Burris, H. A. Yap, Y. -S. Sonke, G. S. Paluch-Shimon, S. Campone, M. Blackwell, K. L. Andre, F. Winer, E. P. Janni, W. Verma, S. Conte, P. Arteaga, C. L. Cameron, D. A. Petrakova, K. Hart, L. L. Villanueva, C. Chan, A. Jakobsen, E. Nusch, A. Burdaeva, O. Grischke, E. -M. Alba, E. Wist, E. Marschner, N. Favret, A. M. Yardley, D. Bachelot, T. Tseng, L. -M. Blau, S. Xuan, F. Souami, F. Miller, M. Germa, C. Hirawat, S. O'Shaughnessy, J. TI Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID POSTMENOPAUSAL WOMEN; CONTROLLED-TRIAL; CLINICAL-TRIALS; DOUBLE-BLIND; ESTROGEN; PALBOCICLIB; CRITERIA; PLACEBO; CDK4/6 AB BACKGROUND The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). METHODS In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P < 1.29x10(-5). RESULTS The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P = 3.29x10(-6) for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [ CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P < 0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively. CONCLUSIONS Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021.) C1 [Hortobagyi, G. N.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [O'Shaughnessy, J.] Baylor Charles A Sammons Canc Ctr, Texas Oncol, Dallas, TX USA. [O'Shaughnessy, J.] US Oncol Network, Dallas, TX USA. [Stemmer, S. M.] Tel Aviv Univ, Rabin Med Ctr, Davidoff Ctr, Tel Aviv, Israel. [Paluch-Shimon, S.] Sheba Med Ctr, Ramat Gan, Israel. [Burris, H. A.; Yardley, D.] Sarah Cannon Res Inst, Nashville, TN USA. [Arteaga, C. L.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Yardley, D.] Tennessee Oncol, Nashville, TN USA. [Yap, Y. -S.] Natl Canc Ctr Singapore, Singapore, Singapore. [Sonke, G. S.] Netherlands Canc Inst, Amsterdam, Netherlands. [Sonke, G. S.] BOOG Study Ctr, Amsterdam, Netherlands. [Campone, M.] Inst Cancerol Ouest Rene Gauducheau, St Herblain, France. [Andre, F.] Univ Paris 11, Inst Gustave Roussy, Villejuif, France. [Villanueva, C.] Univ Hosp Besancon, Besancon, France. [Bachelot, T.] Ctr Leon Berard, Lyon, France. [Blackwell, K. L.] Duke Univ, Med Ctr, Durham, NC USA. [Winer, E. P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Janni, W.] Univ Ulm, Ulm, Germany. [Grischke, E. -M.] Univ Tubingen, Tubingen, Germany. [Marschner, N.] Joint Practice Interdisciplinary Oncol & Hematol, Freiburg, Germany. [Verma, S.] Tom Baker Canc Clin, Calgary, AB, Canada. [Conte, P.] Univ Padua, Padua, Italy. [Conte, P.] Ist Ricovero & Cura Carattere Sci, Ist Oncol Veneto, Padua, Italy. [Cameron, D. A.] Univ Edinburgh, Edinburgh Canc Res Ctr, Edinburgh, Midlothian, Scotland. [Petrakova, K.] Masaryk Mem Canc Inst, Brno, Czech Republic. [Hart, L. L.] Florida Canc Specialists Sarah Cannon Res Inst, Ft Myers, WA, Australia. [Chan, A.] Breast Canc Res Ctr Western Australia, Perth, WA, Australia. [Chan, A.] Curtin Univ, Perth, WA, Australia. [Jakobsen, E.] Vejle Hosp, Dept Oncol, Vejle, Denmark. [Burdaeva, O.] Arkhangelsk Clin Oncol Dispensary, Arkhangelsk, Russia. [Alba, E.] Hosp Univ Virgen de la Victoria, Inst Biomed Res Malaga, Malaga, Spain. [Wist, E.] Oslo Univ Hosp, Oslo, Norway. [Favret, A. M.] Virginia Canc Specialists, Arlington, VA USA. [Tseng, L. -M.] Natl Yang Ming Univ, Taipei Vet Gen Hosp, Taipei, Taiwan. [Blau, S.] Northwest Med Specialties, Rainier Hematol Oncol, Puyallup, WA USA. [Xuan, F.; Miller, M.; Germa, C.; Hirawat, S.] Novartis Pharmaceut, E Hanover, NJ USA. [Souami, F.] Novartis Pharmaceut, Basel, Switzerland. RP Hortobagyi, GN (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Div Canc Med, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM ghortoba@mdanderson.org OI Jakobsen, Erik/0000-0002-0052-7705 FU Novartis Pharmaceuticals; Eli Lilly; Pfizer; Novartis; Roche; AstraZeneca; Amgen; Celgene; Genentech; Eisai; GE Healthcare; Hospira; Rockwell; spectrum; Incyte; Sandoz; Janssen; Bayer; Oncovis; GlaxoSmithKline FX Supported by Novartis Pharmaceuticals.; Dr. Hortobagyi reports receiving consulting fees from Eli Lilly and Pfizer; Dr. Stemmer, Dr. Villanueva, and Dr. O'Shaughnessy, receiving fees for serving on advisory hoards from Novartis; Dr. Yap, receiving consulting fees and fees for serving on advisory boards from Novartis; Dr. Paluch-Shimon, receiving consulting lees from Novartis and Pfizer; Dr. Campone, receiving consulting fees from Novartis, Roche, Pfizer, and AstraZeneca and grant support from Novartis; Dr. Blackwell, receiving consulting lees from Amgen, AstraZeneca, Celgene, Genentech, Eli Lilly, Eisai, GE Healthcare, Hospira, Pfizer, Roche, Rockwell, spectrum, Incyte, Sandoz, Janssen, and Bayer and grant support to her institution from Celgene, Genentech, and Pfizer; Dr. Andre, receiving grant support from Novartis, AstraZeneca, Pfizer, and Eli Lilly; Dr. Winer, receiving grant support from Genentech; Drs. Janni and Hart, receiving grant support from Novartis; Dr. Verma, receiving fees for serving on advisory hoards from Amgen, Eli Lilly, AstraZeneca, Novartis, Pfizer, and Roche and being cofounder and medical director (uncompensated) of OncologyEducation.com; Dr. Cameron, receiving consulting fees from Pfizer and Novartis, fees for participating on a data monitoring committee from Eli Lilly, and clinical trial support from Novartis, all paid to his institution; Dr. Jakobsen, receiving travel support from Novartis; Dr. Alba, receiving consulting and lecture fees from Roche, Pfizer, Novartis, Celgene, and Eli Lilly; Dr. Marschner, receiving grant support from Novartis, Pfizer, Roche, Celgene, Oncovis, and GlaxoSmithKline and clinical trial support from Novartis; Dr. Bachelot, receiving consulting fees and grant support from Novartis, Roche, and AstraZeneca and honoraria and travel support from Novartis and Roche; and Drs. Xuan, Souami, Miller, Germa, and Hirawat, being employees or and having an equity interest in Novartis. No other potential conflict of interest relevant to this article was reported. NR 29 TC 19 Z9 19 U1 12 U2 12 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 NOV 3 PY 2016 VL 375 IS 18 BP 1738 EP 1748 DI 10.1056/NEJMoa1609709 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EB0BB UT WOS:000387007300007 PM 27717303 ER PT J AU Manian, FA Chiappa, V AF Manian, Farrin A. Chiappa, Victor TI Case 23-2016: A Man with Somnolence after Orthopedic Surgery Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID FAT-EMBOLISM SYNDROME C1 [Manian, Farrin A.; Chiappa, Victor] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Manian, FA (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 5 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 NOV 3 PY 2016 VL 375 IS 18 BP 1805 EP 1806 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EB0BB UT WOS:000387007300030 PM 27806240 ER PT J AU Ghogawala, Z Barker, FG Benzel, EC AF Ghogawala, Zoher Barker, Fred G., II Benzel, Edward C. TI More on Fusion Surgery for Lumbar Spinal Stenosis Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID LOW-BACK-PAIN; SCORES C1 [Ghogawala, Zoher] Lahey Hosp & Med Ctr, Burlington, MA 01805 USA. [Barker, Fred G., II] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Benzel, Edward C.] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. RP Ghogawala, Z (reprint author), Lahey Hosp & Med Ctr, Burlington, MA 01805 USA. EM zoher.ghogawala@lahey.org 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 NOV 3 PY 2016 VL 375 IS 18 BP 1807 EP 1807 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EB0BB UT WOS:000387007300032 PM 27806223 ER PT J AU Jung, D Hwang, YJ Ryu, H Kano, M Sakimura, K Cho, J AF Jung, Dahee Hwang, Yu J. Ryu, Hoon Kano, Masanobu Sakimura, Kenji Cho, Jeiwon TI Conditional Knockout of Cav2.1 Disrupts the Accuracy of Spatial Recognition of CA1 Place Cells and Spatial/Contextual Recognition Behavior SO FRONTIERS IN BEHAVIORAL NEUROSCIENCE LA English DT Article DE P/Q type calcium channels; burst; hippocampus; place cell; learning and memory ID HIPPOCAMPAL PYRAMIDAL CELLS; P/Q-TYPE; CALCIUM-CHANNELS; SYNAPTIC-TRANSMISSION; NMDA RECEPTOR; CA2+ CHANNEL; NEURAL INFORMATION; ENTORHINAL CORTEX; SPIKE BURSTS; MICE LACKING AB Hippocampal pyramidal neurons play an essential role in processing spatial information as implicated with its place-dependent firing. Although, previous slice physiology studies have reported that voltage gated calcium channels contribute to spike shapes and corresponding firing rate in the hippocampus, the roles of P/Q type calcium channels (Cav2.1) underlying neural activity in behaving mice have not been well-investigated. To determine physiological and behavioral roles of Cav2.1, we conducted place cell recordings in CA1 and hippocampus dependent learning/memory tasks using mice lacking Cav2.1 in hippocampal pyramidal neurons under CamK2 alpha-Cre recombinase expression. Results suggested that impairments shown in behavioral tasks requiring spatial and contextual information processing were statistically significant while general neurological behaviors did not differ between groups. In particular, deficits were more profound in recognition than in acquisition. Furthermore, place cell recordings also revealed that the ability to recollect spatial representation on re-visit in the conditional knockout was also altered in terms of the cue recognition while the capability of a place cell to encode a place was intact compared to the control group. Interestingly, CA1 pyramidal neurons of conditional knockout mice showed reduced burst frequency as well as abnormal temporal patterns of burst spiking. These results provide potential evidence that Cav2.1 in hippocampal pyramidal cells modulates temporal integration of bursts, which, in turn, might influence the recognition of place field and consequently disrupt spatial recognition ability. C1 [Jung, Dahee; Cho, Jeiwon] Korea Inst Sci & Technol, Ctr Neurosci, Seoul, South Korea. [Jung, Dahee; Cho, Jeiwon] Korea Univ Sci & Technol, Neurosci Program, Daejeon, South Korea. [Hwang, Yu J.; Ryu, Hoon] Korea Inst Sci & Technol, Ctr Neuromed, Brain Sci Inst, Seoul, South Korea. [Ryu, Hoon] Boston Univ, Sch Med, Dept Nephrol, VA Boston Healthcare Syst, Boston, MA 02215 USA. [Ryu, Hoon] Boston Univ, Sch Med, Alzheimers Dis Ctr, Boston, MA 02215 USA. [Kano, Masanobu] Univ Tokyo, Grad Sch Med, Dept Neurophysiol, Tokyo, Japan. [Sakimura, Kenji] Niigata Univ, Brain Res Inst, Dept Celular Neurobiol, Niigata, Japan. RP Cho, J (reprint author), Korea Inst Sci & Technol, Ctr Neurosci, Seoul, South Korea.; Cho, J (reprint author), Korea Univ Sci & Technol, Neurosci Program, Daejeon, South Korea. EM jeiwon@kist.re.kr FU National Research Foundation of Korea (NRF) grants by the Korean government (MSIP) [2015M3C7A1028392, 2015R1A2A2A04005487]; KIST intramural grant [2E26640] FX This work was supported by National Research Foundation of Korea (NRF) grants by the Korean government (MSIP) (2015M3C7A1028392 and 2015R1A2A2A04005487) (JC), and KIST intramural grant (2E26640). We thank Frances S. Cho for English proofreading and helpful comments. NR 50 TC 0 Z9 0 U1 4 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5153 J9 FRONT BEHAV NEUROSCI JI Front. Behav. Neurosci. PD NOV 3 PY 2016 VL 10 AR 214 DI 10.3389/fnbeh.2016.00214 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA EA7ZP UT WOS:000386852500001 PM 27857685 ER PT J AU Cho, H Du, XL Rizzi, JP Liberzon, E Chakraborty, AA Gao, WH Carvo, I Signoretti, S Bruick, RK Josey, JA Wallace, EM Kaelin, WG AF Cho, Hyejin Du, Xinlin Rizzi, James P. Liberzon, Ella Chakraborty, Abhishek A. Gao, Wenhua Carvo, Ingrid Signoretti, Sabina Bruick, Richard K. Josey, John A. Wallace, Eli M. Kaelin, William G., Jr. TI On-target efficacy of a HIF-2 alpha antagonist in preclinical kidney cancer models SO NATURE LA English DT Article ID PAS-B DOMAIN; TRANSCRIPTION FACTOR; CELL; INHIBITION; CARCINOMA; GENE AB Clear cell renal cell carcinoma, the most common form of kidney cancer, is usually linked to inactivation of the pVHL tumour suppressor protein and consequent accumulation of the HIF-2 alpha transcription factor (also known as EPAS1)(1). Here we show that a small molecule (PT2399) that directly inhibits HIF-2 alpha causes tumour regression in preclinical mouse models of primary and metastatic pVHL-defective clear cell renal cell carcinoma in an ontarget fashion. pVHL-defective clear cell renal cell carcinoma cell lines display unexpectedly variable sensitivity to PT2399, however, suggesting the need for predictive biomarkers to be developed to use this approach optimally in the clinic. C1 [Cho, Hyejin; Liberzon, Ella; Chakraborty, Abhishek A.; Gao, Wenhua; Carvo, Ingrid; Signoretti, Sabina; Kaelin, William G., Jr.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Cho, Hyejin; Liberzon, Ella; Chakraborty, Abhishek A.; Gao, Wenhua; Carvo, Ingrid; Signoretti, Sabina; Kaelin, William G., Jr.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02215 USA. [Du, Xinlin; Rizzi, James P.; Josey, John A.; Wallace, Eli M.] Peloton Therapeut Inc, Dallas, TX 75235 USA. [Carvo, Ingrid; Signoretti, Sabina] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Bruick, Richard K.] Univ Texas Southwestern Med Ctr Dallas, Dept Biochem, Dallas, TX 75235 USA. [Kaelin, William G., Jr.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Kaelin, WG (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Wallace, EM; Kaelin, WG (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02215 USA.; Wallace, EM (reprint author), Peloton Therapeut Inc, Dallas, TX 75235 USA.; Kaelin, WG (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. EM eli.wallace@pelotontx.com; william_kaelin@dfci.harvard.edu FU NIH; Cancer Prevention and Research Institute of Texas [RP130513] FX We thank J. Massague for 786-M1A and M2A cells. Supported by grants from the NIH. W.G.K. is an HHMI Investigator. R.K.B. is the Michael L. Rosenberg Scholar in Medical Research and was supported by the Cancer Prevention and Research Institute of Texas (RP130513). NR 15 TC 6 Z9 6 U1 12 U2 12 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 NOV 3 PY 2016 VL 539 IS 7627 BP 107 EP + DI 10.1038/nature19795 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA5OJ UT WOS:000386670100039 PM 27595393 ER PT J AU Hirako, IC Ataide, MA Faustino, L Assis, PA Sorensen, EW Ueta, H Araujo, NM Menezes, GB Luster, AD Gazzinelli, RT AF Hirako, Isabella C. Ataide, Marco A. Faustino, Lucas Assis, Patricia A. Sorensen, Elizabeth W. Ueta, Hisashi Araujo, Natalia M. Menezes, Gustavo B. Luster, Andrew D. Gazzinelli, Ricardo T. TI Splenic differentiation and emergence of CCR5(+)CXCL9(+)CXCL10(+) monocyte-derived dendritic cells in the brain during cerebral malaria SO NATURE COMMUNICATIONS LA English DT Article ID CD8(+) T-CELLS; STAGE PLASMODIUM-CHABAUDI; FALCIPARUM-INFECTED ERYTHROCYTES; INNATE IMMUNE-RESPONSE; TUMOR-NECROSIS-FACTOR; IFN-GAMMA; INTERFERON-GAMMA; PROTECTIVE IMMUNITY; CUTTING EDGE; NK CELLS AB Dendritic cells have an important role in immune surveillance. After being exposed to microbial components, they migrate to secondary lymphoid organs and activate T lymphocytes. Here we show that during mouse malaria, splenic inflammatory monocytes differentiate into monocyte-derived dendritic cells (MO-DCs), which are CD11b(+)F4/80(+) CD11c(+)MHCII(high)DC-SIGN(high)Ly6c(+) and express high levels of CCR5, CXCL9 and CXCL10 (CCR5(+)CXCL9/10(+) MO-DCs). We propose that malaria-induced splenic MO-DCs take a reverse migratory route. After differentiation in the spleen, CCR5(+)CXCL9/10(+) MO-DCs traffic to the brain in a CCR2-independent, CCR5-dependent manner, where they amplify the influx of CD8(+) T lymphocytes, leading to a lethal neuropathological syndrome. C1 [Hirako, Isabella C.; Ataide, Marco A.; Assis, Patricia A.; Araujo, Natalia M.; Gazzinelli, Ricardo T.] Fundacao Oswaldo Cruz, Ctr Pesquisas Rene Rachou, Ave Augusto de Lima 1715, BR-30190002 Belo Horizonte, MG, Brazil. [Hirako, Isabella C.; Faustino, Lucas; Sorensen, Elizabeth W.; Ueta, Hisashi; Luster, Andrew D.] Harvard Med Sch, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, 149 Thirteenth St, Charlestown, MA 02129 USA. [Ataide, Marco A.; Araujo, Natalia M.; Menezes, Gustavo B.; Gazzinelli, Ricardo T.] Univ Fed Minas Gerais, Dept Bioquim & Imunol, Ave Antonio Carlos 6627, BR-31270901 Belo Horizonte, MG, Brazil. [Ataide, Marco A.; Araujo, Natalia M.; Menezes, Gustavo B.; Gazzinelli, Ricardo T.] Univ Fed Minas Gerais, Ctr Biol Gastrointestinal, Dept Morfol, Ave Antonio Carlos 6627, BR-31270901 Belo Horizonte, MG, Brazil. [Gazzinelli, Ricardo T.] Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, 364 Plantat St, Worcester, MA 01655 USA. RP Gazzinelli, RT (reprint author), Fundacao Oswaldo Cruz, Ctr Pesquisas Rene Rachou, Ave Augusto de Lima 1715, BR-30190002 Belo Horizonte, MG, Brazil.; Luster, AD (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, 149 Thirteenth St, Charlestown, MA 02129 USA.; Gazzinelli, RT (reprint author), Univ Fed Minas Gerais, Dept Bioquim & Imunol, Ave Antonio Carlos 6627, BR-31270901 Belo Horizonte, MG, Brazil.; Gazzinelli, RT (reprint author), Univ Fed Minas Gerais, Ctr Biol Gastrointestinal, Dept Morfol, Ave Antonio Carlos 6627, BR-31270901 Belo Horizonte, MG, Brazil.; Gazzinelli, RT (reprint author), Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, 364 Plantat St, Worcester, MA 01655 USA. EM aluster@mgh.harvard.edu; ricardo.gazzinelli@umassmed.edu FU US National Institutes of Health [R01NS098747, R01AI079293]; Rede Mineira de Biomoleculas from Fundacao de Amparo a Pesquisa de Minas Gerais (Fapemig) [RED-00012-14]; Brazilian National Institute of Science and Technology for Vaccines - Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)/Fapemig/Ministerio da Saude [573547/2008-4]; Coordenacao de Aperfeicoamento de Pessoal de Ensino Superior (CAPES); David Rockefeller Center for Latin American Studies at Harvard University; Science without Borders; CNPq; CAPES FX This work was supported by grants from the US National Institutes of Health to A.D.L. and R.T.G (R01NS098747 and R01AI079293). R.T.G. laboratory is also supported by Rede Mineira de Biomoleculas from Fundacao de Amparo a Pesquisa de Minas Gerais (Fapemig, RED-00012-14) and Brazilian National Institute of Science and Technology for Vaccines granted by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)/Fapemig/Ministerio da Saude (573547/2008-4). R.T.G. was the recipient of a Scholar Fellowship from Coordenacao de Aperfeicoamento de Pessoal de Ensino Superior (CAPES) and the David Rockefeller Center for Latin American Studies at Harvard University. I.C.H., M.A.A. and N.M.A. are recipient of Science without Borders and Graduate Student fellowships from CNPq and CAPES. R.T.G. and G.B.M. are research fellows from CNPq. We thank Barbara Louzada for technical assistance in the laboratory. EISAI Pharmaceuticals has kindly provided E6446 under an MTA. 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 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD NOV 3 PY 2016 VL 7 AR 13277 DI 10.1038/ncomms13277 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA7YL UT WOS:000386849100001 PM 27808089 ER PT J AU Bhatt, S Stender, JD Joshi, S Wu, G Katzenellenbogen, BS AF Bhatt, S. Stender, J. D. Joshi, S. Wu, G. Katzenellenbogen, B. S. TI OCT-4: a novel estrogen receptor-alpha collaborator that promotes tamoxifen resistance in breast cancer cells SO ONCOGENE LA English DT Article ID ACTIVATED PROTEIN-KINASE; GENE-EXPRESSION; STEM-CELLS; PROSTATE CARCINOGENESIS; MOLECULAR DETERMINANTS; ENDOCRINE RESISTANCE; ER-ALPHA; PHOSPHORYLATION; TRANSCRIPTION; THERAPY AB Tamoxifen has shown great success in the treatment of breast cancer; however, long-term treatment can lead to acquired tamoxifen (TOT) resistance and relapse. TOT classically antagonizes estradiol (E2) -dependent breast cancer cell growth, but exerts partial agonist/antagonist behavior on gene expression. Although both E2 and TOT treatment of breast cancer cells results in recruitment of the estrogen receptor (ER) to common and distinct genomic sites, the mechanisms and proteins underlying TOT preferential recruitment of the ER remains poorly defined. To this end, we performed in silico motif-enrichment analyses within the ER-binding peaks in response to E2 or TOT, to identify factors that would specifically recruit ER to genomic binding sites in the presence of TOT as compared to E2. Intriguingly, we found Nkx3-1 and Oct-transcription factor homodimer motifs to be enriched in TOT preferential binding sites and confirmed the critical role of Oct-3/4 (aka Oct-4) in directing ER recruitment to TOT preferential genomic binding sites, by chromatin immunoprecipitation (ChIP) analyses. Further investigation revealed Oct-4 expression to be basally repressed by Nkx3-1 in MCF-7 cells and TOT treatment appeared to elevate Nkx3-1 degradation through a p38MAPK-dependent phosphorylation of the E3 ligase, Skp2 at serine-64 residue, as observed by quantitative mass-spectrometry analyses. Consistently, Oct-4 upon induction by phospho-Ser64-Skp2-mediated proteasomal degradation of Nkx3-1, participated in ER transcriptional complexes along with p38MAPK and Skp2 in a tamoxifen-dependent manner leading to TOT-dependent gene activation and cell proliferation of the TOT-resistant MCF-7-tam(r) breast cancer cells. Notably, Oct-4 levels were highly elevated in MCF-7-tam(r) cells, and appeared critical for their TOT sensitivity in cell proliferation assays. Furthermore, overexpression of Oct-4 enhanced tumor growth in the presence of tamoxifen in mice in vivo. Collectively, our work presents a novel mechanism for tamoxifen-specific gene activation by ER, secondary to its TOT preferential recruitment to genomic sites by specific activation of Oct-4, a phenomenon that appears to underlie tamoxifen resistance in breast cancer cells and in xenograft tumor models, and could be useful in designing therapeutic interventions to improve treatment outcome. C1 [Bhatt, S.; Stender, J. D.] Univ Illinois, Dept Biochem, Urbana, IL USA. [Joshi, S.] Agilent Technol, Cedar Creek, TX USA. [Wu, G.] Harvard Med Sch, Joslin Diabet Ctr, Res Div, Boston, MA USA. [Katzenellenbogen, B. S.] Univ Illinois, Mol & Integrat Physiol, Urbana, IL USA. RP Katzenellenbogen, BS (reprint author), Univ Illinois, Dept Mol & Integrat Physiol, 524 Burrill Hall,407 South Goodwin Ave, Urbana, IL 61801 USA. EM katzenel@illinois.edu FU NIH [5RO1 CA18119]; Breast Cancer Research Foundation; Juvenile Diabetes Research Foundation FX We thank Dr Peter Yau, Biotechnology Core, UIUC, for contributions to the mass-spectrometry analyses. This work was supported by grants from the NIH 5RO1 CA18119 (BSK), The Breast Cancer Research Foundation (BSK) and Juvenile Diabetes Research Foundation (GW). SB conceived of, designed and executed the study, performed experiments, data analyses and interpretation and wrote the manuscript. JDS conceived the study, performed computational analysis and contributed to experimental data. GW and SJ contributed to experimental data. BSK conceived and designed the study, performed data analyses and interpretation and wrote the manuscript. NR 51 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 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD NOV 3 PY 2016 VL 35 IS 44 BP 5722 EP 5734 DI 10.1038/onc.2016.105 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA EA9XQ UT WOS:000386998400004 PM 27065334 ER PT J AU Abbasi, SA Shah, RV McNulty, SE Hernandez, AF Semigran, MJ Lewis, GD Jerosch-Herold, M Kim, RJ Redfield, MM Kwong, RY AF Abbasi, Siddique A. Shah, Ravi V. McNulty, Steven E. Hernandez, Adrian F. Semigran, Marc J. Lewis, Gregory D. Jerosch-Herold, Michael Kim, Raymond J. Redfield, Margaret M. Kwong, Raymond Y. TI Left Atrial Structure and Function in Heart Failure with Preserved Ejection Fraction: A RELAX Substudy SO PLOS ONE LA English DT Article ID EXERCISE CAPACITY; CARDIAC STRUCTURE; TRIAL; VOLUME AB Given the emerging recognition of left atrial structure and function as an important marker of disease in heart failure with preserved ejection fraction (HF-pEF), we investigated the association between left atrial volume and function with markers of disease severity and cardiac structure in HF-pEF. We studied 100 patients enrolled in the PhosphdiesteRasE-5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure (RELAX) trial who underwent cardiac magnetic resonance (CMR), cardiopulmonary exercise testing, and blood collection before randomization. Maximal left atrial volume index (LAVi; N = 100), left atrial emptying fraction (LAEF; N = 99; including passive and active components (LAEF(P), LAEF(A); N = 80, 79, respectively) were quantified by CMR. After adjustment for multiple testing, maximal LAVi was only associated with age (rho = 0.39), transmitral filling patterns (medial E/e' rho = 0.43), and N-terminal pro-BNP (NT-proBNP; rho = 0.65; all p< 0.05). Lower LAEF was associated with older age, higher transmitral E/A ratio and higher NT-proBNP. Peak VO2 and V-E/VCO2 slope were not associated with left atrial structure or function. After adjustment for age, sex, transmitral E/A ratio, CMR LV mass, LV ejection fraction, and creatinine clearance, NT-proBNP remained associated with maximal LAVi (beta = 0.028, p = 0.0007) and total LAEF (beta = -0.033, p = 0.001). Passive and active LAEF were most strongly associated with age and NT-proBNP, but not gas exchange or other markers of ventricular structure or filling properties. Left atrial volume and emptying function are associated most strongly with NT-proBNP and diastolic filling properties, but not significantly with gas exchange, in HFpEF. Further research to explore the relevance of left atrial structure and function in HF-pEF is warranted. C1 [Abbasi, Siddique A.; Jerosch-Herold, Michael; Kwong, Raymond Y.] Brigham & Womens Hosp, Noninvas Cardiovasc Imaging Sect, 75 Francis St, Boston, MA 02115 USA. [Shah, Ravi V.; Semigran, Marc J.; Lewis, Gregory D.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [McNulty, Steven E.; Hernandez, Adrian F.] Duke Clin Res Inst, Durham, NC USA. [Kim, Raymond J.] Duke Univ, Med Ctr, Duke Cardiovasc Magnet Resonance Ctr, Durham, NC USA. [Redfield, Margaret M.] Mayo Clin Rochester, Rochester, MN USA. [Abbasi, Siddique A.] Providence VA Med Ctr, Div Cardiol, Providence, RI USA. [Abbasi, Siddique A.] Brown Univ, Alpert Med Sch, Cardiovasc Inst, Providence, RI 02912 USA. RP Kwong, RY (reprint author), Brigham & Womens Hosp, Noninvas Cardiovasc Imaging Sect, 75 Francis St, Boston, MA 02115 USA. EM rykwong@partners.org OI Abbasi, Siddique/0000-0002-9601-7565 FU National Heart, Lung, and Blood Institute [U10HL084904, U10HL084861, U10HL084875, U10HL084877, U10HL084889, U10HL084890, U10HL084891, U10HL084899, U10HL084907, U10HL084931]; Heart Failure National Institutes of Health Clinical Research Network [U01-HL084877]; National Institutes of Health [5T32HL094301-04]; NIH [5R01HL091157] FX This work was supported by grants U10HL084904 (for the data coordinating center), and U10HL084861, U10HL084875, U10HL084877, U10HL084889, U10HL084890, U10HL084891, U10HL084899, U10HL084907, and U10HL084931 (for the clinical centers) from the National Heart, Lung, and Blood Institute. Dr. Shah was supported by a training grant from the Heart Failure National Institutes of Health Clinical Research Network (U01-HL084877). Dr. Abbasi was supported by a T32 training grant (5T32HL094301-04) from the National Institutes of Health. Dr. Kwong was supported by NIH 5R01HL091157. Pfizer provided study drug (sildenafil and matched placebo). All other authors have no financial disclosures relevant to the content of this manuscript. NR 17 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 NOV 3 PY 2016 VL 11 IS 11 AR e0164914 DI 10.1371/journal.pone.0164914 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA8SX UT WOS:000386910000017 PM 27812147 ER PT J AU Lee, J Horan, WP Wynn, JK Green, MF AF Lee, Junghee Horan, William P. Wynn, Jonathan K. Green, Michael F. TI Neural Correlates of Belief and Emotion Attribution in Schizophrenia SO PLOS ONE LA English DT Article ID SOCIAL COGNITION; BRAIN IMAGES; MIND; FMRI; METAANALYSIS; EMPATHY; ROBUST; OPTIMIZATION; REGISTRATION; IMPAIRMENT AB Impaired mental state attribution is a core social cognitive deficit in schizophrenia. With functional magnetic resonance imaging (fMRI), this study examined the extent to which the core neural system of mental state attribution is involved in mental state attribution, focusing on belief attribution and emotion attribution. Fifteen schizophrenia outpatients and 14 healthy controls performed two mental state attribution tasks in the scanner. In a Belief Attribution Task, after reading a short vignette, participants were asked infer either the belief of a character (a false belief condition) or a physical state of an affair (a false photograph condition). In an Emotion Attribution Task, participants were asked either to judge whether character(s) in pictures felt unpleasant, pleasant, or neutral emotion (other condition) or to look at pictures that did not have any human characters (view condition). fMRI data were analyzing focusing on a priori regions of interest (ROIs) of the core neural systems of mental state attribution: the medial prefrontal cortex (mPFC), temporoparietal junction (TPJ) and precuneus. An exploratory whole brain analysis was also performed. Both patients and controls showed greater activation in all four ROIs during the Belief Attribution Task than the Emotion Attribution Task. Patients also showed less activation in the precuneus and left TPJ compared to controls during the Belief Attribution Task. No significant group difference was found during the Emotion Attribution Task in any of ROIs. An exploratory whole brain analysis showed a similar pattern of neural activations. These findings suggest that while schizophrenia patients rely on the same neural network as controls do when attributing beliefs of others, patients did not show reduced activation in the key regions such as the TPJ. Further, this study did not find evidence for aberrant neural activation during emotion attribution or recruitment of compensatory brain regions in schizophrenia. C1 [Lee, Junghee; Horan, William P.; Wynn, Jonathan K.; Green, Michael F.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Lee, Junghee; Horan, William P.; Wynn, Jonathan K.; Green, Michael F.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Lee, J (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA.; Lee, J (reprint author), VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. EM jungheelee@ucla.edu FU Department of Veterans Affairs, Desert Pacific Mental Illness Research, Education and Clinical Center (MIRECC) PALA Pilot Grant; National Institute of Mental Health [MH43292, MH065707]; Brain Mapping Medical Research Organization; Brain Mapping Support Foundation; Pierson-Lovelace Foundation; Tamkin Foundation; Jennifer Jones-Simon Foundation; Capital Group Companies Charitable Foundation; Robson Family; Northstar Fund FX This study is supported by Department of Veterans Affairs, Desert Pacific Mental Illness Research, Education and Clinical Center (MIRECC) PALA Pilot Grant (PI: JL), and National Institute of Mental Health Grants MH43292 and MH065707 (PI: MFG). For generous support, we would like to thank the Brain Mapping Medical Research Organization, the Brain Mapping Support Foundation, the Pierson-Lovelace Foundation, the Tamkin Foundation, the Jennifer Jones-Simon Foundation, the Capital Group Companies Charitable Foundation, the Robson Family and the Northstar Fund. 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 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 NOV 3 PY 2016 VL 11 IS 11 AR e0165546 DI 10.1371/journal.pone.0165546 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA8SX UT WOS:000386910000035 PM 27812142 ER PT J AU Yu, XQ Wang, YH Lin, J Hu, Y Kawai, T Taubman, MA Han, XZ AF Yu, Xiaoqian Wang, Yuhua Lin, Jiang Hu, Yang Kawai, Toshihisa Taubman, Martin A. Han, Xiaozhe TI Lipopolysaccharides-Induced Suppression of Innate-Like B Cell Apoptosis Is Enhanced by CpG Oligodeoxynucleotide and Requires Toll-Like Receptors 2 and 4 SO PLOS ONE LA English DT Article ID PORPHYROMONAS-GINGIVALIS LIPOPOLYSACCHARIDE; NF-KAPPA-B; PERIODONTAL-DISEASE; IMMUNE-RESPONSES; ACTIVATION; MICE; LPS; DYSBIOSIS; SUBSETS; CYCLE AB Innate-like B lymphocytes play an important role in innate immunity in periodontal disease through Toll-like receptor (TLR) signaling. However, it is unknown how innate-like B cell apoptosis is affected by the periodontal infection-associated innate signals. This study is to determine the effects of two major TLR ligands, lipopolysaccharide (LPS) and CpG-oligodeoxynucleotides (CpG-ODN), on innate-like B cell apoptosis. Spleen B cells were isolated from wild type (WT), TLR2 knockout (KO) and TLR4 KO mice and cultured with E. coli LPS alone, P. gingivalis LPS alone, or combined with CpG-ODN for 2 days. B cell apoptosis and expressions of specific apoptosis-related genes were analyzed by flow cytometry and real-time PCR respectively. P. gingivalis LPS, but not E. coli LPS, reduced the percentage of AnnexinV(+)/7-AAD(-) cells within IgM(high)CD23(low)CD43(-)CD93(-) marginal zone (MZ) B cell sub-population and IgM(high)CD23(low)CD43(+)CD93(+) innate response activator (IRA) B cell subpopulation in WT but not TLR2KO or TLR4KO mice. CpG-ODN combined with P. gingivalis LPS further reduced the percentage of AnnexinV(+)/7-AAD(-) cells within MZ B cells and IRA B cells in WT but not TLR2 KO or TLR4 KO mice. Pro-apoptotic CASP4, CASP9 and Dapk1 were significantly down-regulated in P. gingivalis LPS- and CpG-ODN-treated B cells from WT but not TLR2 KO or TLR4 KO mice. Anti-apoptotic IL-10 was significantly up-regulated in P. gingivalis LPS-and CpG-ODN-treated B cells from WT and TLR2 KO but not TLR4 KO mice. These results suggested that both TLR2 and TLR4 signaling are required for P. gingivalis LPS-induced, CpG-ODN-enhanced suppression of innate-like B cell apoptosis. C1 [Yu, Xiaoqian; Wang, Yuhua; Lin, Jiang; Hu, Yang; Kawai, Toshihisa; Taubman, Martin A.; Han, Xiaozhe] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA USA. [Yu, Xiaoqian] Peking Univ, Sch & Hosp Stomatol, Dept Periodontol, Beijing, Peoples R China. [Wang, Yuhua] Shanghai Jiao Tong Univ, Sch Med, Dept Prosthodont, Peoples Hosp 9,Coll Stomatol,Shanghai Key Lab, Shanghai, Peoples R China. [Lin, Jiang] Harbin Med Univ, Dept Stomatol, Hosp 4, Harbin, Peoples R China. RP Han, XZ (reprint author), Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA USA. EM Xhan@forsyth.org FU National Natural Science Foundation of China [81470740]; National Institute of Dental and Craniofacial Research [R21DE021837, R56DE023807] FX National Natural Science Foundation of China 81470740 to X Yu; National Institute of Dental and Craniofacial Research R21DE021837 and R56DE023807 to X Han. NR 52 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 NOV 3 PY 2016 VL 11 IS 11 AR e0165862 DI 10.1371/journal.pone.0165862 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA8SX UT WOS:000386910000073 PM 27812176 ER PT J AU Pereira, NRP Janssen, SJ van Dijk, E Harris, MB Hornicek, FJ Ferrone, ML Schwab, JH AF Pereira, Nuno Rui Paulino Janssen, Stein J. van Dijk, Eva Harris, Mitchel B. Hornicek, Francis J. Ferrone, Marco L. Schwab, Joseph H. TI Development of a Prognostic Survival Algorithm for Patients with Metastatic Spine Disease SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID SCORING SYSTEM; PREOPERATIVE EVALUATION; PREDICTION MODEL; TUMOR PROGNOSIS; CORD-INJURY; OF-LIFE; SURGERY; CANCER; INDEX; MORBIDITY AB Background: Current prognostication models for survival estimation in patients with metastatic spine disease lack accuracy. Identifying new risk factors could improve existing models. We assessed factors associated with survival in patients surgically treated for spine metastases, created a classic scoring algorithm, nomogram, and boosting algorithm, and tested the predictive accuracy of the three created algorithms at estimating survival. Methods: We included 649 patients from two tertiary care referral centers in this retrospective study (2002 to 2014). A multivariate Cox model was used to identify factors independently associated with survival. We created a classic scoring system, a nomogram, and a boosting (i.e., machine learning) algorithm and calculated their accuracy by receiver operating characteristic analysis. Results: Older age (hazard ratio [HR], 1.01; p = 0.009), poor performance status (HR, 1.54; p = 0.001), primary cancer type (HR, 1.68; p < 0.001), > 1 spine metastasis (HR, 1.32; p = 0.009), lung and/or liver metastasis (HR, 1.35; p = 0.005), brain metastasis (HR, 1.90; p < 0.001), any systemic therapy for cancer prior to a surgical procedure (e.g., chemotherapy, immunotherapy, hormone therapy) (HR, 1.65; p < 0.001), higher white blood-cell count (HR, 1.03; p = 0.002), and lower hemoglobin levels (HR, 0.92; p = 0.009) were independently associated with decreased survival. The boosting algorithm was best at predicting survival on the training data sets (p < 0.001); the nomogram was more reliable at estimating survival on the test data sets, with an accuracy of 0.75 (30 days), 0.73 (90 days), and 0.75 (365 days). Conclusions: We identified risk factors associated with survival that should be considered in prognostication. Performance of the boosting algorithm and nomogram were comparable on the testing data sets. However, the nomogram is easier to apply and therefore more useful to aid surgical decision-making. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Pereira, Nuno Rui Paulino; Janssen, Stein J.; van Dijk, Eva; Hornicek, Francis J.; Schwab, Joseph H.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, Orthopaed Oncol Serv, Boston, MA 02115 USA. [Harris, Mitchel B.; Ferrone, Marco L.] Harvard Med Sch, Brigham & Womens Hosp, Dept Orthopaed Surg, Orthopaed Oncol Serv, Boston, MA USA. RP Pereira, NRP (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, Orthopaed Oncol Serv, Boston, MA 02115 USA. EM nunorui.pp@gmail.com; steinjanssen@gmail.com; e.c.vandijk2@students.uu.nl; mbharris@partners.org; fhornicek@mgh.harvard.edu; mferrone@bwh.harvard.edu; jhschwab@partners.org NR 37 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 NOV 2 PY 2016 VL 98 IS 21 BP 1767 EP 1776 DI 10.2106/JBJS.15.00975 PG 10 WC Orthopedics; Surgery SC Orthopedics; Surgery GA EN4AE UT WOS:000395948600005 ER PT J AU Agarwal-Harding, KJ von Keudell, A Zirkle, LG Meara, JG Dyer, GSM AF Agarwal-Harding, Kiran J. von Keudell, Arvind Zirkle, Lewis G. Meara, John G. Dyer, George S. M. TI Current Concepts Review Understanding and Addressing the Global Need for Orthopaedic Trauma Care SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Review ID MIDDLE-INCOME COUNTRIES; FEMORAL-SHAFT FRACTURES; SYSTEMATIC ANALYSIS; COST-EFFECTIVENESS; INTRAMEDULLARY NAIL; SIERRA-LEONE; MUSCULOSKELETAL INJURIES; NONPHYSICIAN CLINICIAN; AFRICAN COUNTRIES; SURGICAL SERVICES AB The burden of musculoskeletal trauma is high worldwide, disproportionately affecting the poor, who have the least access to quality orthopaedic trauma care. Orthopaedic trauma care is essential, and must be a priority in the horizontal development of global health systems. The education of surgeons, nonphysician clinicians, and ancillary staff in low and middle income countries is central to improving access to and quality of care. Volunteer surgical missions from rich countries can sustainably expand and strengthen orthopaedic trauma care only when they serve a local need and build local capacity. Innovative business models may help to pay for care of the poor. Examples include reducing costs through process improvements and cross-subsidizing from profitable high-volume activities. Resource-poor settings may foster innovations in devices or systems with universal applicability in orthopaedics. C1 [Agarwal-Harding, Kiran J.; von Keudell, Arvind; Zirkle, Lewis G.; Meara, John G.; Dyer, George S. M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Agarwal-Harding, Kiran J.; von Keudell, Arvind] Massachusetts Gen Hosp, Harvard Combined Orthopaed Residency Program, Boston, MA 02114 USA. [Zirkle, Lewis G.] SIGN Fracture Care Int, Richland, WA USA. [Meara, John G.] Harvard Med Sch, Boston Childrens Hosp, Program Global Surg & Social Change, Boston, MA USA. [Dyer, George S. M.] Brigham & Womens Hosp, Dept Orthoped Surg, 75 Francis St, Boston, MA 02115 USA. RP Agarwal-Harding, KJ (reprint author), Massachusetts Gen Hosp, Harvard Combined Orthopaed Residency Program, Boston, MA 02114 USA. EM kagarwal-harding@partners.org; gdyer@partners.org NR 118 TC 0 Z9 0 U1 1 U2 1 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 NOV 2 PY 2016 VL 98 IS 21 BP 1844 EP 1853 DI 10.2106/JBJS.16.00323 PG 10 WC Orthopedics; Surgery SC Orthopedics; Surgery GA EN4AE UT WOS:000395948600014 PM 27807118 ER PT J AU Lohr, JG Kim, S Gould, J Knoechel, B Drier, Y Cotton, MJ Gray, D Birrer, N Wong, B Ha, G Zhang, CZ Guo, GW Meyerson, M Yee, AJ Boehm, JS Raje, N Golub, TR AF Lohr, Jens G. Kim, Sora Gould, Joshua Knoechel, Birgit Drier, Yotam Cotton, Matthew J. Gray, Daniel Birrer, Nicole Wong, Bang Ha, Gavin Zhang, Cheng-Zhong Guo, Guangwu Meyerson, Matthew Yee, Andrew J. Boehm, Jesse S. Raje, Noopur Golub, Todd R. TI Genetic interrogation of circulating multiple myeloma cells at single-cell resolution SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID UNDETERMINED SIGNIFICANCE MGUS; PLASMA-CELLS; MONOCLONAL GAMMOPATHY; PERIPHERAL-BLOOD; RNA-SEQ; B-CELLS; EXPRESSION; CANCER; GENOME; DIFFERENTIATION AB Multiple myeloma (MM) remains an incurable disease, with a treatment-refractory state eventually developing in all patients. Constant clonal evolution and genetic heterogeneity of MM are a likely explanation for the emergence of drug-resistant disease. Monitoring of MM genomic evolution on therapy by serial bone marrowbiopsy is unfortunately impractical because it involves an invasive and painful procedure. We describe how noninvasive and highly sensitive isolation and characterization of circulating tumor cells (CTCs) from peripheral blood at single-cell resolution recapitulate MM in the bone marrow. We demonstrate that CTCs provide the same genetic information as bone marrow MM cells and even reveal mutations with greater sensitivity than bone marrow biopsies in some cases. Single CTC RNA sequencing enables classification of MM and quantitative assessment of genes that are relevant for prognosis. We propose that the genomic characterization of CTCs should be included in clinical trials to follow the emergence of resistant subclones after MM therapy. C1 [Lohr, Jens G.; Kim, Sora; Gould, Joshua; Knoechel, Birgit; Drier, Yotam; Cotton, Matthew J.; Gray, Daniel; Wong, Bang; Ha, Gavin; Zhang, Cheng-Zhong; Guo, Guangwu; Meyerson, Matthew; Boehm, Jesse S.; Golub, Todd R.] Broad Inst & Harvard, Cambridge, MA 02142 USA. [Lohr, Jens G.; Knoechel, Birgit; Ha, Gavin; Zhang, Cheng-Zhong; Guo, Guangwu; Meyerson, Matthew; Golub, Todd R.] Dana Farber Canc Inst, Dept Med Oncol, Dept Pathol, Boston, MA 02214 USA. [Lohr, Jens G.; Knoechel, Birgit; Drier, Yotam; Guo, Guangwu; Meyerson, Matthew; Golub, Todd R.] Harvard Med Sch, Boston, MA 02115 USA. [Drier, Yotam; Cotton, Matthew J.; Birrer, Nicole; Yee, Andrew J.; Raje, Noopur] Massachusetts Gen Hosp Canc Ctr, Div Hematol, Dept Oncol & Pathol, Boston, MA 02114 USA. [Cotton, Matthew J.; Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Lohr, JG; Golub, TR (reprint author), Broad Inst & Harvard, Cambridge, MA 02142 USA.; Lohr, JG; Golub, TR (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Dept Pathol, Boston, MA 02214 USA.; Lohr, JG; Golub, TR (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Golub, TR (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. EM jlohr@partners.org; golub@broadinstitute.org FU National Cancer Institute [K08CA191026]; Multiple Myeloma Research Foundation; Wong Family award; Howard Hughes Medical Institute FX This project was supported by an award from the National Cancer Institute (K08CA191026) (to J.G.L.), by a research fellow award from the Multiple Myeloma Research Foundation (to J.G.L.), by the Wong Family award (to J.G.L.), and by the Howard Hughes Medical Institute (to T.R.G.). NR 47 TC 1 Z9 1 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 NOV 2 PY 2016 VL 8 IS 363 AR 363ra147 DI 10.1126/scitranslmed.aac7037 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EE2XD UT WOS:000389447800001 PM 27807282 ER PT J AU Weinberger, F Breckwoldt, K Pecha, S Kelly, A Geertz, B Starbatty, J Yorgan, T Cheng, KH Lessmann, K Stolen, T Scherrer-Crosbie, M Smith, G Reichenspurner, H Hansen, A Eschenhagen, T AF Weinberger, Florian Breckwoldt, Kaja Pecha, Simon Kelly, Allen Geertz, Birgit Starbatty, Jutta Yorgan, Timur Cheng, Kai-Hung Lessmann, Katrin Stolen, Tomas Scherrer-Crosbie, Marielle Smith, Godfrey Reichenspurner, Hermann Hansen, Arne Eschenhagen, Thomas TI Cardiac repair in guinea pigs with human engineered heart tissue from induced pluripotent stem cells SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID MYOCARDIAL-INFARCTION; RABBIT HEARTS; LONG-TERM; CARDIOMYOCYTES; MODEL; THERAPY; DIFFERENTIATION; RAT; REGENERATION; ACTIVATION AB Myocardial injury results in a loss of contractile tissue mass that, in the absence of efficient regeneration, is essentially irreversible. Transplantation of human pluripotent stem cell-derived cardiomyocytes has beneficial but variable effects. We created human engineered heart tissue (hEHT) strips from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and hiPSC-derived endothelial cells. The hEHTs were transplanted onto large defects (22% of the left ventricular wall, 35% decline in left ventricular function) of guinea pig hearts 7 days after cryoinjury, and the results were compared with those obtained with human endothelial cell patches (hEETs) or cell-free patches. Twenty-eight days after transplantation, the hearts repaired with hEHT strips exhibited, within the scar, human heart muscle grafts, which had remuscularized 12% of the infarct area. These grafts showed cardiomyocyte proliferation, vascularization, and evidence for electrical coupling to the intact heart tissue in a subset of engrafted hearts. hEHT strips improved left ventricular function by 31% compared to that before implantation, whereas the hEET or cell-free patches had no effect. Together, our study demonstrates that three-dimensional human heart muscle constructs can repair the injured heart. C1 [Weinberger, Florian; Breckwoldt, Kaja; Geertz, Birgit; Starbatty, Jutta; Lessmann, Katrin; Hansen, Arne; Eschenhagen, Thomas] Univ Med Ctr Hamburg Eppendorf, Dept Expt Pharmacol & Toxicol, Cardiovascu Res Ctr, D-20246 Hamburg, Germany. [Weinberger, Florian; Breckwoldt, Kaja; Pecha, Simon; Geertz, Birgit; Starbatty, Jutta; Lessmann, Katrin; Reichenspurner, Hermann; Hansen, Arne; Eschenhagen, Thomas] German Ctr Cardiovascu Res DZHK, Hamburg, Germany. [Pecha, Simon; Reichenspurner, Hermann] Univ Med Ctr Hamburg Eppendorf, Cardiovascu Res Ctr, Dept Cardiovascu Surg, D-20246 Hamburg, Germany. [Kelly, Allen; Stolen, Tomas; Smith, Godfrey] Norwegian Univ Sci & Technol, KG Jebsen Ctr Exercise Med, Dept Circulat & Med Imaging, N-7030 Trondheim, Norway. [Kelly, Allen; Stolen, Tomas] Norwegian Council Cardiovasc Dis, Oslo, Norway. [Yorgan, Timur] Univ Med Ctr Hamburg Eppendorf, Dept Osteol & Biomech, D-20246 Hamburg, Germany. [Cheng, Kai-Hung; Scherrer-Crosbie, Marielle] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. [Smith, Godfrey] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8QQ, Lanark, Scotland. RP Eschenhagen, T (reprint author), Univ Med Ctr Hamburg Eppendorf, Dept Expt Pharmacol & Toxicol, Cardiovascu Res Ctr, D-20246 Hamburg, Germany.; Eschenhagen, T (reprint author), German Ctr Cardiovascu Res DZHK, Hamburg, Germany. EM t.eschenhagen@uke.de FU German Centre for Cardiovascular Research (DZHK) [NCCR 3.1 HF]; German Ministry of Research and Education (BMBF); Deutsche Herzstiftung [F/36/12]; European Research Council Advanced Grant; German Research Foundation [Es 88/12-1]; European Union (EU FP7 Biodesign) FX This work was supported by the German Centre for Cardiovascular Research (DZHK; NCCR 3.1 HF for A.H. and T.E.), the German Ministry of Research and Education (BMBF), Deutsche Herzstiftung (F/36/12 for F.W. and T.E.), a European Research Council Advanced Grant (IndivuHeart for T.E.), the German Research Foundation (Es 88/12-1 for T.E.), and the European Union (EU FP7 Biodesign for T.E.). NR 34 TC 1 Z9 1 U1 6 U2 6 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 NOV 2 PY 2016 VL 8 IS 363 AR 363ra148 DI 10.1126/scitranslmed.aaf8781 PG 13 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EE2XD UT WOS:000389447800002 PM 27807283 ER PT J AU Song, C Liu, YB Fontana, R Makrigiorgos, A Mamon, H Kulke, MH Makrigiorgos, GM AF Song, Chen Liu, Yibin Fontana, Rachel Makrigiorgos, Alexander Mamon, Harvey Kulke, Matthew H. Makrigiorgos, G. Mike TI Elimination of unaltered DNA in mixed clinical samples via nuclease-assisted minor-allele enrichment SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RESOLUTION MELTING ANALYSIS; CIRCULATING TUMOR DNA; COLD-PCR ENRICHMENT; MUTATION DETECTION; COLORECTAL-CANCER; RARE MUTATIONS; LUNG-CANCER; MUTANT-DNA; KRAS; QUANTIFICATION AB Presence of excess unaltered, wild-type (WT) DNA providing no information of biological or clinical value often masks rare alterations containing diagnostic or therapeutic clues in cancer, prenatal diagnosis, infectious diseases or organ transplantation. With the surge of high-throughput technologies there is a growing demand for removing unaltered DNA over large pools-of-sequences. Here we present nuclease-assisted minor-allele enrichment with probe-overlap (NaME-PrO), a single-step approach with broad genome coverage that can remove WT-DNA from numerous sequences simultaneously, prior to genomic analysis. NaME-PrO employs a double-strand-DNA-specific nuclease and overlapping oligonucleotide-probes interrogating WT-DNA targets and guiding nuclease digestion to these sites. Mutation-containing DNA creates probe-DNA mismatches that inhibit digestion, thus subsequent DNA-amplification magnifies DNA-alterations at all selected targets. We demonstrate several-hundred-fold mutation enrichment in diverse human samples on multiple clinically relevant targets including tumor samples and circulating DNA in 50-plex reactions. Enrichment enables routine mutation detection at 0.01% abundance while by adjusting conditions it is possible to sequence mutations down to 0.00003% abundance, or to scan tumor-suppressor genes for rare mutations. NaME-PrO introduces a simple and highly parallel process to remove un-informative DNA sequences and unmask clinically and biologically useful alterations. C1 [Song, Chen; Liu, Yibin; Fontana, Rachel; Makrigiorgos, Alexander; Mamon, Harvey; Makrigiorgos, G. Mike] Harvard Med Sch, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Song, Chen; Liu, Yibin; Fontana, Rachel; Makrigiorgos, Alexander; Mamon, Harvey; Makrigiorgos, G. Mike] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA. [Kulke, Matthew H.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Makrigiorgos, GM (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA.; Makrigiorgos, GM (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA. EM mmakrigiorgos@partners.org FU National Cancer Institute [R21CA-175542]; NCI/CANCURE [R25 CA17465002] FX National Cancer Institute [R21CA-175542, in part]; R.F. was supported by NCI/CANCURE to Northeastern University [R25 CA17465002]. Funding for open access charge: Departmental funds. NR 47 TC 3 Z9 3 U1 12 U2 12 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 NOV 2 PY 2016 VL 44 IS 19 DI 10.1093/nar/gkw650 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EC3HK UT WOS:000388016900001 ER PT J AU Aasted, CM Yucel, MA Steele, SC Peng, K Boas, DA Becerra, L Borsook, D AF Aasted, Christopher M. Yucel, Meryem A. Steele, Sarah C. Peng, Ke Boas, David A. Becerra, Lino Borsook, David TI Frontal Lobe Hemodynamic Responses to Painful Stimulation: A Potential Brain Marker of Nociception SO PLOS ONE LA English DT Article ID NEAR-INFRARED SPECTROSCOPY; FUNCTIONAL CONNECTIVITY; RATING-SCALES; HUMAN CORTEX; INTENSITY; DISTRACTION; HUMANS; GYRUS AB The purpose of this study was to use functional near-infrared spectroscopy (fNIRS) to examine patterns of both activation and deactivation that occur in the frontal lobe in response to noxious stimuli. The frontal lobe was selected because it has been shown to be activated by noxious stimuli in functional magnetic resonance imaging studies. The brain region is located behind the forehead which is devoid of hair, providing a relative ease of placement for fNIRS probes on this area of the head. Based on functional magnetic resonance imaging studies showing blood-oxygenation-level dependent changes in the frontal lobes, we evaluated functional near-infrared spectroscopy measures in response to two levels of electrical pain in awake, healthy human subjects (n = 10; male = 10). Each subject underwent two recording sessions separated by a 30-minute resting period. Data collected from 7 subjects were analyzed, containing a total of 38/36 low/high intensity pain stimuli for the first recording session and 27/31 pain stimuli for the second session. Our results show that there is a robust and significant deactivation in sections of the frontal cortices. Further development and definition of the specificity and sensitivity of the approach may provide an objective measure of nociceptive activity in the brain that can be easily applied in the surgical setting. C1 [Aasted, Christopher M.; Steele, Sarah C.; Peng, Ke; Becerra, Lino; Borsook, David] Harvard Med Sch, Ctr Pain & Brain, Boston, MA 02115 USA. [Aasted, Christopher M.; Steele, Sarah C.; Peng, Ke; Becerra, Lino; Borsook, David] Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Aasted, Christopher M.; Yucel, Meryem A.; Steele, Sarah C.; Peng, Ke; Boas, David A.; Becerra, Lino; Borsook, David] Harvard Med Sch, Boston, MA 02115 USA. [Aasted, Christopher M.; Yucel, Meryem A.; Steele, Sarah C.; Peng, Ke; Boas, David A.; Becerra, Lino; Borsook, David] Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Borsook, D (reprint author), Harvard Med Sch, Ctr Pain & Brain, Boston, MA 02115 USA.; Borsook, D (reprint author), Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA.; Borsook, D (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Borsook, D (reprint author), Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. EM david.borsook@childrens.harvard.edu FU Mayday Foundation; Anesthesia Research Distinguished Trailblazer Award; National Institute of General Medical Science of the National Institutes of Health [R01GM104986] FX Research reported in this article was supported by the Mayday Foundation, the Anesthesia Research Distinguished Trailblazer Award, and the National Institute of General Medical Science of the National Institutes of Health under award number R01GM104986. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 32 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 NOV 2 PY 2016 VL 11 IS 11 AR e0165226 DI 10.1371/journal.pone.0165226 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA6DJ UT WOS:000386715500022 PM 27806119 ER PT J AU Pal, A Rhoads, DB Tavakkoli, A AF Pal, Atanu Rhoads, David B. Tavakkoli, Ali TI Effect of Portal Glucose Sensing on Systemic Glucose Levels in SD and ZDF Rats SO PLOS ONE LA English DT Article ID HEPATIC NERVES; CONSCIOUS DOG; DELIVERY; SENSOR; METABOLISM; CAPSAICIN; INFUSION; LIVER AB Background The global epidemic of Type-2-Diabetes (T2D) highlights the need for novel therapeutic targets and agents. Roux-en-Y-Gastric-Bypass (RYGB) is the most effective treatment. Studies investigating the mechanisms of RYGB suggest a role for post-operative changes in portal glucose levels. We investigate the impact of stimulating portal glucose sensors on systemic glucose levels in health and T2D, and evaluated the role of sodium-glucose-cotransporter-3 (SGLT3) as the possible sensor. Methods Systemic glucose and hormone responses to portal stimulation were measured. In Sprague-Dawley (SD) rats, post-prandial state was simulated by infusing glucose into the portal vein. The SGLT3 agonist, alpha-methyl-glucopyranoside (alpha MG), was then added to further stimulate the portal sensor. To elucidate the neural pathway, vagotomy or portal denervation was followed by alpha MG+glucose co-infusion. The therapeutic potential of portal glucose sensor stimulation was investigated by alpha MG-only infusion (vs. saline) in SD and Zucker Diabetic-Fatty (ZDF) rats. Hepatic mRNA expression was also measured. Results alpha MG+glucose co-infusion reduced peak systemic glucose (vs. glucose alone), and lowered hepatic G6Pase expression. Portal denervation, but not vagotomy, abolished this effect. alpha MG-only infusion lowered systemic glucose levels. This glucose-lowering effect was more pronounced in ZDF rats, where portal alpha MG infusion increased insulin, C-peptide and GIP levels compared to saline infusions. Conclusions The portal vein is capable of sensing its glucose levels, and responds by altering hepatic glucose handling. The enhanced effect in T2D, mediated through increased GIP and insulin, highlights a therapeutic target that could be amenable to pharmacological modulation or minimally-invasive surgery. C1 [Pal, Atanu; Tavakkoli, Ali] Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. [Pal, Atanu; Rhoads, David B.; Tavakkoli, Ali] Harvard Med Sch, 25 Shattuck St, Boston, MA 02115 USA. [Rhoads, David B.] MassGen Hosp Children, Pediat Endocrine Unit, 55 Fruit St, Boston, MA 02114 USA. [Tavakkoli, Ali] Brigham & Womens Hosp, Ctr Weight Management & Metab Surg, 75 Francis St, Boston, MA 02115 USA. RP Tavakkoli, A (reprint author), Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA.; Tavakkoli, A (reprint author), Harvard Med Sch, 25 Shattuck St, Boston, MA 02115 USA.; Tavakkoli, A (reprint author), Brigham & Womens Hosp, Ctr Weight Management & Metab Surg, 75 Francis St, Boston, MA 02115 USA. EM atavakkoli@partners.org FU National Institutes of Health [1 R01 DK084064] FX This work was supported by National Institutes of Health Grant 1 R01 DK084064 (AT). NR 25 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 NOV 2 PY 2016 VL 11 IS 11 AR e0165592 DI 10.1371/journal.pone.0165592 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA6DJ UT WOS:000386715500039 PM 27806092 ER PT J AU Guo, YY Lin, C Xu, P Wu, S Fu, XJ Xia, WD Yao, M AF Guo, Yuanyuan Lin, Cai Xu, Peng Wu, Shan Fu, Xiujun Xia, Weidong Yao, Min TI AGEs Induced Autophagy Impairs Cutaneous Wound Healing via Stimulating Macrophage Polarization to M1 in Diabetes SO SCIENTIFIC REPORTS LA English DT Article ID GLYCATION END-PRODUCTS; CELLS; INFLAMMATION; ACTIVATION; SIROLIMUS; INJURY; MICE; COMPLICATIONS; DEFICIENCY; CLEARANCE AB Autophagy is essential in physiological and pathological processes, however, the role of autophagy in cutaneous wound healing and the underlying molecular mechanism remain elusive. We hypothesized that autophagy plays an important role in regulating wound healing. Here, we show that enhanced autophagy negatively impacts on normal cutaneous healing process and is related to chronic wounds as demonstrated by the increased LC3 in diabetic mice skin or patients' chronic wounds. In addition, inhibition of autophagy by 3-MA restores delayed healing in C57BL/6 or db/db mice, demonstrating that autophagy is involved in regulating wound healing. Furthermore, we identify that macrophage is a major cell type underwent autophagy in wounds and increased autophagy induces macrophages polarization into M1 with elevated CD11c population and gene expressions of proinflammatory cytokines. To explore the mechanism underlying autophagy-impaired wound healing, we tested the role of IRF8, a regulator of autophagy, in autophagy-modulated macrophages polarization. IRF8 activation is up-regulating autophagy and M1 polarization of macrophages after AGEs ( advanced glycation endproducts) treatment, blocking the IRF8 with shIRF8 inhibits autophagic activity and M1 polarization. In summary, this study elucidates that AGEs induces autophagy and modulates macrophage polarization to M1 via IRF8 activation in impairment of cutaneous wound healing. C1 [Guo, Yuanyuan; Xu, Peng; Wu, Shan; Fu, Xiujun; Yao, Min] Shanghai Ninth Peoples Hosp, Inst Traumat Med, Dept Burns & Plast Surg, Shanghai 201900, Peoples R China. [Guo, Yuanyuan; Xu, Peng; Wu, Shan; Fu, Xiujun; Yao, Min] Shanghai Jiao Tong Univ, Sch Med, Shanghai 201900, Peoples R China. [Lin, Cai; Xia, Weidong] Wenzhou Med Univ, Burn & Wound Ctr, Affiliated Hosp 1, Wenzhou 325000, Peoples R China. [Fu, Xiujun; Yao, Min] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Yao, M (reprint author), Shanghai Ninth Peoples Hosp, Inst Traumat Med, Dept Burns & Plast Surg, Shanghai 201900, Peoples R China.; Yao, M (reprint author), Shanghai Jiao Tong Univ, Sch Med, Shanghai 201900, Peoples R China.; Yao, M (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM my058@vip.sina.com FU National Natural Science Foundation of China [81272113, 81201469] FX This work was supported partially by the National Natural Science Foundation of China (No. 81272113, 81201469). We are grateful for constructive discussions and technical assistance of Professor Jinke Chen. We appreciate Dr. Zhaofan Xia's suggestion; we also thank Dr. Juan Guo and Kezhou Wang for technical support. NR 38 TC 0 Z9 0 U1 9 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 2 PY 2016 VL 6 AR 36416 DI 10.1038/srep36416 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA8ZU UT WOS:000386930300001 PM 27805071 ER PT J AU Kim, BG Fujita, T Stankovic, KM Welling, DB Moon, IS Choi, JY Yun, J Kang, JS Lee, JD AF Kim, Bo Gyung Fujita, Takeshi Stankovic, Konstantina M. Welling, D. Bradley Moon, In Seok Choi, Jae Young Yun, Jieun Kang, Jong Soon Lee, Jong Dae TI Sulforaphane, a natural component of broccoli, inhibits vestibular schwannoma growth in vitro and in vivo SO SCIENTIFIC REPORTS LA English DT Article ID HISTONE DEACETYLASE INHIBITORS; NEUROFIBROMATOSIS TYPE-2; PRECLINICAL VALIDATION; PROSTATE-CANCER; PHASE-II; THERAPY; CELLS; CHEMOPREVENTION; PREVENTION; APOPTOSIS AB Vestibular schwannoma (VS) is an intracranial tumor that causes significant morbidity, including hearing loss, tinnitus, dizziness, and possibly even death from brainstem compression. However, FDA-approved pharmacologic treatments for VS do not exist. Sulforaphane (SFN) is a naturally occurring isothiocyanate found in cruciferous vegetables, such as broccoli, with potent chemoprotective effects in several cell types. Our objective was to determine whether SFN is effective against VS in vitro and in vivo. Human primary VS cells, HEI-193 schwannoma cells, and SC4 Nf2(-/-) Schwann cells were used to investigate the inhibitory effects of SFN in vitro. Cell proliferation was assessed by bromodeoxyuridine (BrdU) incorporation, and cell viability and metabolic activity was calculated by MTT assay. Apoptosis was measured by flow cytometry, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and Western blot for cleaved caspases. A mouse model with a murine schwannoma allograft was also used to examine the antitumor activity of SFN. SFN exhibited significant antiproliferative activity in schwannoma cells in vitro, via the inhibition of HDAC activity and the activation of ERK. SFN treatment induced apoptosis and cell cycle arrest at the G2/M phase. SFN also significantly inhibited schwannoma growth in vivo. Our preclinical studies motivate a future prospective clinical study of SFN for the treatment of VS. C1 [Kim, Bo Gyung; Lee, Jong Dae] Soonchunhyang Univ, Dept Otorhinolaryngol Head & Neck Surg, Coll Med, Bucheon, South Korea. [Fujita, Takeshi] Kindai Univ, Dept Otolaryngol, Fac Med, Osaka, Japan. [Fujita, Takeshi; Stankovic, Konstantina M.; Lee, Jong Dae] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Eaton Peabody Labs, 243 Charles St, Boston, MA 02114 USA. [Fujita, Takeshi; Stankovic, Konstantina M.; Welling, D. Bradley; Lee, Jong Dae] Harvard Med Sch, Dept Otol & Laryngol, Boston, MA 02115 USA. [Moon, In Seok; Choi, Jae Young] Yonsei Univ, Dept Otorhinolaryngol, Coll Med, Seoul, South Korea. [Yun, Jieun; Kang, Jong Soon] Korea Res Inst Biosci & Biotechnol, Bioevaluat Ctr, Cheongju, South Korea. RP Lee, JD (reprint author), Soonchunhyang Univ, Dept Otorhinolaryngol Head & Neck Surg, Coll Med, Bucheon, South Korea.; Lee, JD (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Eaton Peabody Labs, 243 Charles St, Boston, MA 02114 USA.; Lee, JD (reprint author), Harvard Med Sch, Dept Otol & Laryngol, Boston, MA 02115 USA. EM ljdent@schmc.ac.kr FU Basic Science Research Program through the National Research Foundation of Korea; Ministry of Education, Science and Technology [2013R1A1A2010381]; Soonchunhyang University Research Fund; Department of Defense [W81XWH-14-1-0091] FX We would like to thank Dr. M. Giovannini (UCLA, Los Angeles, CA) for providing HEI-193 and SC4 cells. We thank Bo Ra Lee, of Biostatistic Consulting, Soonchunhyang Medical Center, for her assistance with statistical advice throughout the preparation of this manuscript. We are grateful for Jessica Sagers' critical reading of the manuscript. This work was supported by the Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Education, Science and Technology grant 2013R1A1A2010381 (J.D. Lee), the Soonchunhyang University Research Fund (J.D. Lee) and the Department of Defense grant W81XWH-14-1-0091 (K.M. Stankovic). NR 32 TC 0 Z9 0 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 2 PY 2016 VL 6 AR 36215 DI 10.1038/srep36215 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EB1TF UT WOS:000387137200001 PM 27805058 ER PT J AU Pantziarka, P Hutchinson, L Andre, N Benzekry, S Bertolini, F Bhattacharjee, A Chiplunkar, S Duda, DG Gota, V Gupta, S Joshi, A Kannan, S Kerbel, R Kieran, M Palazzo, A Parikh, A Pasquier, E Patil, V Prabhash, K Shaked, Y Sholler, GS Sterba, J Waxman, DJ Banavali, S AF Pantziarka, Pan Hutchinson, Lisa Andre, Nicolas Benzekry, Sebastien Bertolini, Francesco Bhattacharjee, Atanu Chiplunkar, Shubhada Duda, Dan G. Gota, Vikram Gupta, Sudeep Joshi, Amit Kannan, Sadhana Kerbel, Robert Kieran, Mark Palazzo, Antonella Parikh, Aparna Pasquier, Eddy Patil, Vijay Prabhash, Kumar Shaked, Yuval Sholler, Giselle Saulnier Sterba, Jaroslav Waxman, David J. Banavali, Shripad TI Next generation metronomic chemotherapy-report from the Fifth Biennial International Metronomic and Anti-angiogenic Therapy Meeting, 6-8 May 2016, Mumbai SO ECANCERMEDICALSCIENCE LA English DT Article DE Metronomic chemotherapy; drug repurposing; anti-angiogenics; cancer; LMIC ID NEGATIVE BREAST-CANCER; ANTITUMOR INNATE IMMUNITY; PHASE-II; LIPID MEDIATORS; BETA-BLOCKERS; ANTICANCER AGENTS; SURVIVAL BENEFIT; PREDICT SURVIVAL; TUMOR-REGRESSION; RECTAL-CANCER AB The 5th Biennial Metronomic and Anti-angiogenic Therapy Meeting was held on 6th - 8th May in the Indian city of Mumbai. The meeting brought together a wide range of clinicians and researchers interested in metronomic chemotherapy, anti-angiogenics, drug repurposing and combinations thereof. Clinical experiences, including many from India, were reported and discussed in three symposia covering breast cancer, head and neck cancers and paediatrics. On the pre-clinical side research into putative mechanisms of action, and the interactions between low dose metronomic chemotherapy and angiogenesis and immune responses, were discussed in a number of presentations. Drug repurposing was discussed both in terms of clinical results, particularly with respect to angiosarcoma and high-risk neuroblastoma, and in pre-clinical settings, particularly the potential for peri-operative interventions. However, it was clear that there remain a number of key areas of challenge, particularly in terms of definitions, perceptions in the wider oncological community, mechanisms of action and predictive biomarkers. While the potential for metronomics and drug repurposing in low and middle income countries remains a key theme, it is clear that there is also considerable potential for clinically relevant improvements in patient outcomes even in high income economies. C1 [Pantziarka, Pan] Anticanc Fund, B-1853 Brussels, Strombeek Bever, Belgium. [Pantziarka, Pan] George Pantziarka TP53 Trust, London, England. [Hutchinson, Lisa] Nat Reviews Clin Oncol, London N1 9XW, England. [Andre, Nicolas] Aix Marseille Univ, Ctr Hosp Univ Timone Enfants, AP HM, Serv Hematol & Oncol Pediat,INSERM,CRO2 UMR S 911, Marseille, France. [Andre, Nicolas; Pasquier, Eddy; Banavali, Shripad] Metron Global Hlth Initiat, Marseille, France. [Benzekry, Sebastien] Inria Team MONC, Talence, France. [Benzekry, Sebastien] Inst Math Bordeaux, Talence, France. [Bertolini, Francesco] European Inst Oncol, Via Ripamonti 435, I-20141 Milan, Italy. [Bhattacharjee, Atanu] Malabar Canc Ctr, Thalassery, India. [Chiplunkar, Shubhada; Gota, Vikram; Gupta, Sudeep; Kannan, Sadhana] Tata Mem Hosp, ACTREC, Kharghar 410210, Navi Mumbai, India. [Duda, Dan G.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Joshi, Amit; Patil, Vijay; Prabhash, Kumar; Banavali, Shripad] Tata Mem Hosp, Bombay, Maharashtra, India. [Kerbel, Robert] Univ Toronto, Sunnybrook Res Inst, Biol Sci Platform, Toronto, ON, Canada. [Kieran, Mark] Dana Farber Canc Inst, Boston, MA 02115 USA. [Parikh, Aparna] PRA Hlth Sci, Bombay, Maharashtra, India. [Pasquier, Eddy] Aix Marseille Univ, Ctr Rech Oncol Biol & Oncopharmacol, INSERM, UMR 911, Marseille, France. [Shaked, Yuval] Technion Israel Inst Technol, Rappaport Fac Med, Dept Cell Biol & Canc Sci, Haifa, Israel. [Sholler, Giselle Saulnier] Helen DeVos Childrens Hosp, Grand Rapids, MI USA. [Sterba, Jaroslav] Univ Hosp Brno, Dept Pediat Oncol, Cernopolni 9, Brno 61300, Czech Republic. [Sterba, Jaroslav] Masaryk Univ, Fac Med, Cernopolni 9, Brno 61300, Czech Republic. [Sterba, Jaroslav] St Annes Univ Hosp, Int Clin Res Ctr, Brno, Czech Republic. [Sterba, Jaroslav] Masaryk Mem Canc Inst, RECAMO, Brno, Czech Republic. [Waxman, David J.] Boston Univ, Dept Biol, 5 Cummington St, Boston, MA 02215 USA. [Palazzo, Antonella] European Inst Oncol, Div Med Senol, Via Ripamonti 435, I-20141 Milan, Italy. RP Pantziarka, P (reprint author), Anticanc Fund, B-1853 Brussels, Strombeek Bever, Belgium.; Pantziarka, P (reprint author), George Pantziarka TP53 Trust, London, England. EM pan.pantziarka@anticancerfund.org NR 121 TC 0 Z9 0 U1 6 U2 6 PU CANCER INTELLIGENCE LTD PI BRISTOL PA 11 ALMA VALE RD,, BRISTOL, BS8 2HL, ENGLAND SN 1754-6605 J9 ECANCERMEDICALSCIENC JI eCancerMedicalScience PD NOV 2 PY 2016 VL 10 AR 689 DI 10.3332/ecancer.2016.689 PG 19 WC Oncology SC Oncology GA EA6FX UT WOS:000386723100001 PM 27994645 ER PT J AU Schinder, AF Bonhoeffer, T Sperling, R Dudai, Y Marin, O Morris, R Mrsic-Flogel, T AF Schinder, Alejandro F. Bonhoeffer, Tobias Sperling, Reisa Dudai, Yadin Marin, Oscar Morris, Richard Mrsic-Flogel, Thomas TI Organizing Brain Science on an International Scale SO NEURON LA English DT Editorial Material AB Examples from the last decade of neuroscience research point to an increase in international collaborations, big consortia, global data gathering, and the development of atlases and databases. How might global initiatives coordinate conceptual breakthroughs and promote discoveries without taking away from the freedom of individual labs? Scientists from around the world lent their voices to the discussion of how to address the organizational challenges of these large-scale initiatives. C1 [Schinder, Alejandro F.] Consejo Nacl Invest Cient & Tecn, Fdn Inst Leloir, Buenos Aires, DF, Argentina. [Bonhoeffer, Tobias] Max Planck Inst Neurobiol, Martinsried, Germany. [Sperling, Reisa] Brigham & Womens Hosp, Ctr Alzheimer Res & Treatment, Boston, MA 02115 USA. [Sperling, Reisa] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Dudai, Yadin] Weizmann Inst Sci, Rehovot, Israel. [Dudai, Yadin] NYU, New York, NY 10003 USA. [Marin, Oscar] Kings Coll London, MRC Ctr Neurodev Disorders, London, England. [Morris, Richard] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Mrsic-Flogel, Thomas] Univ Basel, Biozentrum, Sainsbury Wellcome Ctr Neural Circuits & Behav, Basel, Switzerland. RP Schinder, AF (reprint author), Consejo Nacl Invest Cient & Tecn, Fdn Inst Leloir, Buenos Aires, DF, Argentina. NR 0 TC 1 Z9 1 U1 3 U2 3 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 NOV 2 PY 2016 VL 92 IS 3 BP 567 EP 569 PG 3 WC Neurosciences SC Neurosciences & Neurology GA EA6TU UT WOS:000386762700005 ER PT J AU Nyendak, M Swarbrick, GM Duncan, A Cansler, M Huff, EW Hokey, D Evans, T Barker, L Blatner, G Sadoff, J Douoguih, M Pau, MG Lewinsohn, DA Lewinsohn, DM AF Nyendak, Melissa Swarbrick, Gwendolyn M. Duncan, Amanda Cansler, Meghan Huff, Ervina Winata Hokey, David Evans, Tom Barker, Lewellys Blatner, Gretta Sadoff, Jerald Douoguih, Macaya Pau, Maria Grazia Lewinsohn, Deborah A. Lewinsohn, David M. TI Adenovirally-Induced Polyfunctional T Cells Do Not Necessarily Recognize the Infected Target: Lessons from a Phase I Trial of the AERAS-402 Vaccine SO SCIENTIFIC REPORTS LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS INFECTION; PROTECTIVE IMMUNITY; CD8+T CELLS; BCG; CD4(+); RESPONSES; ANTIGEN; EPITOPE; MEMORY; ESAT-6 AB The development of a vaccine for Mycobacterium tuberculosis (Mtb) has been impeded by the absence of correlates of protective immunity. One correlate would be the ability of cells induced by vaccination to recognize the Mtb-infected cell. AERAS-402 is a replication-deficient serotype 35 adenovirus containing DNA expressing a fusion protein of Mtb antigens 85A, 85B and TB10.4. We undertook a phase I double-blind, randomized placebo controlled trial of vaccination with AERAS-402 following BCG. Analysis of the vaccine-induced immune response revealed strong antigen-specific polyfunctional CD4(+) and CD8(+) T cell responses. However, analysis of the vaccine-induced CD8(+) T cells revealed that in many instances these cells did not recognize the Mtb-infected cell. Our findings highlight the measurement of vaccine-induced, polyfunctional T cells may not reflect the extent or degree to which these cells are capable of identifying the Mtb-infected cell and correspondingly, the value of detailed experimental medicine studies early in vaccine development. C1 [Nyendak, Melissa; Lewinsohn, David M.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Swarbrick, Gwendolyn M.; Duncan, Amanda; Cansler, Meghan; Lewinsohn, Deborah A.; Lewinsohn, David M.] Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR 97201 USA. [Swarbrick, Gwendolyn M.; Huff, Ervina Winata; Lewinsohn, David M.] Portland VA Med Ctr, Dept Med, Portland, OR 97239 USA. [Hokey, David; Evans, Tom; Barker, Lewellys; Blatner, Gretta] Aeras, Rockville, MD USA. [Sadoff, Jerald; Douoguih, Macaya; Pau, Maria Grazia] Janssen Infect Dis & Vaccines, Leiden, Netherlands. RP Nyendak, M; Lewinsohn, DM (reprint author), Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA.; Lewinsohn, DM (reprint author), Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR 97201 USA.; Lewinsohn, DM (reprint author), Portland VA Med Ctr, Dept Med, Portland, OR 97239 USA. EM nyendakm@ohsu.edu; lewinsod@ohsu.edu FU Aeras Global Tuberculosis Vaccine Foundation; NIH [HHSN272200900053C, R01 AI048090]; NIH National Center for Research Resources grant [KL2RR02414]; Merit Review Awards from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development [I01 BX000533] FX The authors acknowledge the contributions of Sean Bennett MD (AERAS), Melissa Kumagai, Phyllis Carello and staff from the Oregon Clinical and Translational Institute at Oregon Health and Science University, and Erin Merrifield (OHSU) for IRB support. We also acknowledge Jenny Hendriks and Maria Grazia Pau for review of the manuscript. We thank the study participants without whom this study would not be possible. This work was supported by the following agency and institutes: the Aeras Global Tuberculosis Vaccine Foundation, NIH contract, HHSN272200900053C, and the NIH National Center for Research Resources grant KL2RR02414 (MN). This work was also supported by Merit Review Awards I01 BX000533 (DML) from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development and resources and the use of facilities at the VA Portland Health Care System and from the NIH R01 AI048090 (DML); The contents of this manuscript do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. NR 44 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 NOV 2 PY 2016 VL 6 AR 36355 DI 10.1038/srep36355 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA6TP UT WOS:000386762200001 PM 27805026 ER PT J AU Krajinovic, M Elbared, J Drouin, S Bertout, L Rezgui, A Ansari, M Raboisson, MJ Lipshultz, SE Silverman, LB Sallan, SE Neuberg, DS Kutok, JL Laverdiere, C Sinnett, D Andelfinger, G AF Krajinovic, M. Elbared, J. Drouin, S. Bertout, L. Rezgui, A. Ansari, M. Raboisson, M-J Lipshultz, S. E. Silverman, L. B. Sallan, S. E. Neuberg, D. S. Kutok, J. L. Laverdiere, C. Sinnett, D. Andelfinger, G. TI Polymorphisms of ABCC5 and NOS3 genes influence doxorubicin cardiotoxicity in survivors of childhood acute lymphoblastic leukemia SO PHARMACOGENOMICS JOURNAL LA English DT Article ID ANTHRACYCLINE-INDUCED CARDIOTOXICITY; NITRIC-OXIDE SYNTHASE; MYOCARDIAL CONTRACTILE FUNCTION; CYCLIC-NUCLEOTIDES; CARDIAC DAMAGE; EXPORT PUMP; CHILDREN; CANCER; HEART; MICE AB Anthracyclines are efficient chemotherapy agents. However, their use is limited by anthracycline-induced cardiotoxicity (CT). We investigated the influence of polymorphisms in doxorubicin metabolic and functional pathways on late-onset CT as estimated by echocardiography in 251 childhood acute lymphoblastic leukemia (cALL) patients. Association analyses revealed a modulating effect of two variants: A-1629 T in ABCC5, an ATP-binding cassette transporter, and G894T in the NOS3 endothelial nitric oxide synthase gene. Individuals with the ABCC5 TT-1629 genotype had an average of 8-12% reduction of ejection (EF) and shortening fractions (SF; EF: P < 0.0001, and SF: P = 0.001, respectively). A protective effect of the NOS3 TT894 genotype on EF was seen in high-risk patients (P = 0.02), especially in those who did not receive dexrazoxane (P = 0.002). Analysis of an additional cohort of 44 cALL patients replicated the ABCC5 association but was underpowered for NOS3. In summary, we identified two biomarkers that may contribute to cALL anthracycline CT risk stratification. C1 [Krajinovic, M.; Elbared, J.; Drouin, S.; Bertout, L.; Rezgui, A.; Ansari, M.; Raboisson, M-J; Laverdiere, C.; Sinnett, D.; Andelfinger, G.] CHU St Justine, Res Ctr, 3175 Chemin Cote St Catherine, Montreal, PQ H3T 1C5, Canada. [Krajinovic, M.; Laverdiere, C.; Sinnett, D.; Andelfinger, G.] Univ Montreal, Dept Pediat, Montreal, PQ, Canada. [Krajinovic, M.; Andelfinger, G.] Univ Montreal, Dept Pharmacol, Montreal, PQ, Canada. [Ansari, M.] Univ Hosp Geneva, Dept Paediat, CANSEARCH Labs, Geneva, Switzerland. [Lipshultz, S. E.] Wayne State Univ, Childrens Hosp Michigan, Sch Med, Dept Pediat, Detroit, MI USA. [Silverman, L. B.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Silverman, L. B.] Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. [Sallan, S. E.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Neuberg, D. S.] Infin Pharmaceut, Mol Pathol, Cambridge, MA USA. [Kutok, J. L.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Krajinovic, M (reprint author), CHU St Justine, Res Ctr, 3175 Chemin Cote St Catherine, Montreal, PQ H3T 1C5, Canada. EM maja.krajinovic@umontreal.ca FU Canadian Institutes of Health Research; National Cancer Institute/NIH [5 P01CA068484] FX We thank all patients and their parents who consented to participate in genetics studies related to leukemia. Canadian Institutes of Health Research supported this study. We thank Kristen Stevenson for retrieving the DFCI data. Dana-Farber Cancer Institute ALL treatment protocols are supported by the National Cancer Institute/NIH grant 5 P01CA068484. NR 48 TC 4 Z9 4 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1470-269X EI 1473-1150 J9 PHARMACOGENOMICS J JI Pharmacogenomics J. PD NOV PY 2016 VL 16 IS 6 BP 530 EP 535 DI 10.1038/tpj.2015.63 PG 6 WC Genetics & Heredity; Pharmacology & Pharmacy SC Genetics & Heredity; Pharmacology & Pharmacy GA ED5CD UT WOS:000388868200007 PM 26345518 ER PT J AU Bryant, A Blake-Lamb, T Hatoum, I Kotelchuck, M AF Bryant, Allison Blake-Lamb, Tiffany Hatoum, Ida Kotelchuck, Milton TI Women's Use of Health Care in the First 2 Years Postpartum: Occurrence and Correlates SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Postpartum care; Interconception care; Disparities; Life course; Late postpartum care ID GESTATIONAL DIABETES-MELLITUS; PRECONCEPTION CARE; RISK-FACTORS; PREGNANCY; RECOMMENDATIONS; PREECLAMPSIA; PREDICTORS; PROVIDERS; OUTCOMES; HISTORY AB Objectives We sought to determine rates and correlates of accessing health care in the 2 years following delivery among women at an urban academic medical center. Methods We used electronic medical records, discharge, and billing data to determine the occurrence of primary care, other non-primary outpatient care, emergency department visits, and inpatient admissions among women delivering at a single medical center who had a known primary care affiliation to that medical center over a 5 year period. We explored sociodemographic, clinical, and health care-related factors as correlates of care, using bivariate and multivariable modeling. Results Of 6216 women studied, most (91 %) had had at least one health care visit in the window between 2 months and 2 years postpartum (the "late postpartum period"). The majority (81 %) had had a primary care visit. Factors associated with use of health care in this period included a chronic medical condition diagnosed prior to pregnancy (adjusted odds ratio (AOR) 1.42, 95 % CI [1.19, 1.71]), prenatal care received in an urban community health center (AOR 1.35 [1.06, 1.73]), having received obstetric (AOR 1.90 [1.51, 2.37]), primary (AOR 2.30 [1.68, 3.23]), or other non-primary outpatient care (AOR 2.35 [1.72, 3.39]) in the first 2 months postpartum, and living closer to the hospital [AOR for residence >17.8 miles from the medical center ( AOR 0.74 [0.61, 0.90])]. Having had an obstetrical complication did not increase the likelihood of receipt of care during this window. Conclusions for Practice Among women already enrolled in a primary care practice at our medical center, health care utilization in the late postpartum period is high, but not universal. Understanding the characteristics of women who return for health care during this window, and where they are seen, can improve transitions of care across the life course and can provide opportunities for important and consistent interconception and well-woman messaging. C1 [Bryant, Allison; Blake-Lamb, Tiffany; Kotelchuck, Milton] Massachusetts Gen Hosp, Vincent Dept Obstet & Gynecol, 55 Fruit St, Boston, MA 02114 USA. [Hatoum, Ida] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Kotelchuck, Milton] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. RP Bryant, A (reprint author), Massachusetts Gen Hosp, Vincent Dept Obstet & Gynecol, 55 Fruit St, Boston, MA 02114 USA. EM abryant@partners.org FU Deborah Kelly Center for Outcomes Research (Massachusetts General Hospital Vincent Department of Obstetrics and Gynecology) FX This work was funded in part by a Grant from the Deborah Kelly Center for Outcomes Research (Massachusetts General Hospital Vincent Department of Obstetrics and Gynecology). NR 28 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD NOV PY 2016 VL 20 SU 1 BP S81 EP S91 DI 10.1007/s10995-016-2168-9 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EK9VU UT WOS:000394272800011 PM 27502197 ER PT J AU Bovin, MJ Marx, BP Weathers, FW Gallagher, MW Rodriguez, P Schnurr, PP Keane, TM AF Bovin, Michelle J. Marx, Brian P. Weathers, Frank W. Gallagher, Matthew W. Rodriguez, Paola Schnurr, Paula P. Keane, Terence M. TI Psychometric Properties of the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (PCL-5) in Veterans SO PSYCHOLOGICAL ASSESSMENT LA English DT Article DE posttraumatic stress disorder; DSM-5; psychometrics; veterans ID POSTTRAUMATIC STRESS SYMPTOMS; FIT INDEXES; DIMENSIONAL STRUCTURE; DISORDER SYMPTOMS; PROBLEM-DRINKING; PRIMARY-CARE; DSM-5; SAMPLE; MODEL; CRITERIA AB This study examined the psychometric properties of the posttraumatic stress disorder (PTSD) Checklist for Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (PCL-5; Weathers, Litz, et al., 2013b) in 2 independent samples of veterans receiving care at a Veterans Affairs Medical Center (N = 468). A subsample of these participants (n = 140) was used to define a valid diagnostic cutoff score for the instrument using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5; Weathers, Blake, et al., 2013) as the reference standard. The PCL-5 test scores demonstrated good internal consistency (alpha = .96), test-retest reliability (r = .84), and convergent and discriminant validity. Consistent with previous studies (Armour et al., 2015; Liu et al., 2014), confirmatory factor analysis revealed that the data were best explained by a 6-factor anhedonia model and a 7-factor hybrid model. Signal detection analyses using the CAPS-5 revealed that PCL-5 scores of 31 to 33 were optimally efficient for diagnosing PTSD (kappa (. 5) = .58). Overall, the findings suggest that the PCL-5 is a psychometrically sound instrument that can be used effectively with veterans. Further, by determining a valid cutoff score using the CAPS-5, the PCL-5 can now be used to identify veterans with probable PTSD. However, findings also suggest the need for research to evaluate cluster structure of DSM-5. C1 [Bovin, Michelle J.; Marx, Brian P.; Gallagher, Matthew W.; Rodriguez, Paola; Keane, Terence M.] VA Boston Healthcare Syst, Natl Ctr PTSD, 116B-4,150 South Huntington Ave, Boston, MA 02130 USA. [Bovin, Michelle J.; Marx, Brian P.; Gallagher, Matthew W.; Keane, Terence M.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Weathers, Frank W.] Auburn Univ, Dept Psychol, Auburn, AL 36849 USA. [Schnurr, Paula P.] VA Med Ctr, Natl Ctr PTSD, River Junction, VT USA. [Schnurr, Paula P.] Geisel Sch Med, Dept Psychiat, Dartmouth, NS, Canada. RP Marx, BP (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, 116B-4,150 South Huntington Ave, Boston, MA 02130 USA. EM brian.marx@va.gov FU Department of Defense [W81XWH-08-2-0028] FX This project was supported by Award W81XWH-08-2-0028 from the Department of Defense to Brian P. Marx. NR 47 TC 10 Z9 10 U1 1 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1040-3590 EI 1939-134X J9 PSYCHOL ASSESSMENT JI Psychol. Assess. PD NOV PY 2016 VL 28 IS 11 BP 1379 EP 1391 DI 10.1037/pas0000254 PG 13 WC Psychology, Clinical SC Psychology GA EE0YY UT WOS:000389307800004 PM 26653052 ER PT J AU Wint, AJ Smith, DL Iezzoni, LI AF Wint, Amy J. Smith, Diane L. Iezzoni, Lisa I. TI Mothers With Physical Disability: Child Care Adaptations at Home SO AMERICAN JOURNAL OF OCCUPATIONAL THERAPY LA English DT Article DE disabled persons; environment design; infant care; mothers; parenting ID MOBILITY DISABILITY; CURRENT PREGNANCY; US WOMEN; EXPERIENCES AB OBJECTIVE. This study describes how women with physical disability experience caregiving for a new infant and how they adapt their home environment and care tasks. METHOD. In 2013, we conducted 2-hr telephone interviews with 22 women with significant physical disability who had delivered babies within the previous 10 yr. The semistructured, open-ended interview protocol addressed wide-ranging pregnancy-related topics. NVivo was used to sort the texts for content analysis. RESULTS. Night care, bathing, and carrying the baby were identified as the biggest challenges. Typical adaptations (with and without occupational therapy consultation) included use of a wrap for carrying the infant, furniture adaptations for mothers using wheelchairs, and assistance from caregivers. CONCLUSION. Women with physical disability can be fully capable of caring for an infant and can find ways to adapt their environment. Further research may determine the role of occupation therapy. C1 [Wint, Amy J.; Iezzoni, Lisa I.] Massachusetts Gen Hosp, Mongan Inst, Ctr Hlth Policy, Boston, MA 02114 USA. [Smith, Diane L.] MGH Inst Hlth Profess, Dept Occupat Therapy, Boston, MA USA. [Iezzoni, Lisa I.] Harvard Med Sch, Dept Med, Boston, MA USA. RP Wint, AJ (reprint author), Massachusetts Gen Hosp, Mongan Inst, Ctr Hlth Policy, Boston, MA 02114 USA. EM awint@mgh.harvard.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [1R21HD068756-02] FX The Eunice Kennedy Shriver National Institute of Child Health and Human Development funded this study (Grant 1R21HD068756-02). NR 16 TC 0 Z9 0 U1 0 U2 0 PU AMER OCCUPATIONAL THERAPY ASSOC, INC PI BETHESDA PA 4720 MONTGOMERY LANE, BETHESDA, MD 20814-3425 USA SN 0272-9490 EI 1943-7676 J9 AM J OCCUP THER JI Am. J. Occup. Ther. PD NOV-DEC PY 2016 VL 70 IS 6 AR 7006220060 DI 10.5014/ajot.2016.021477 PG 7 WC Rehabilitation SC Rehabilitation GA EK8RN UT WOS:000394191600009 ER PT J AU Podgaetz, E Kriegsmann, M Dincer, EH Allan, JS AF Podgaetz, Eitan Kriegsmann, Mark Dincer, Erhan H. Allan, James S. TI Myeloid sarcoma: an unusual presentation for acute tracheal stenosis SO CLINICAL RESPIRATORY JOURNAL LA English DT Article DE airway obstruction; AML; chloroma; ganulocytic sarcoma; myeloid sarcoma; tracheal stenosis ID LEUKEMIA AB Background and Aims: Extramedullary involvement of acute myelogenous leukemia (AML) is rare and has been reported under the terms myeloid sarcoma (MS), granulocytic sarcoma, chloroma, extramedullary acute myeloid leukemia, myeloblastoma and myelosarcoma. The most common extramedullary involvement includes soft tissues and lymph nodes, but it may arise in different sites of the body. There are only very few reports about MS in the pulmonary system, and involvement of the trachea is extremely rare. Methods: This is the first report of initial presentation of MS by severe acute tracheal stenosis. Results: After failed tracheal dilatation, a tracheostomy was performed where tracheal tissue was submitted for pathology. Histology of the tracheal biopsy and bone marrow revealed AML. The patient was subsequently referred to our oncology service for further management. Conclusion: Myeloid sarcoma should be part of the differential for acute tracheal stenosis. C1 [Podgaetz, Eitan] Univ Minnesota, Dept Surg, Thorac Surg Sect, Box 242 UMHC, Minneapolis, MN 55455 USA. [Kriegsmann, Mark] Inst Mol Pathol, MVZ Histol Cytol & Mol Diagnost, Trier, Germany. [Dincer, Erhan H.] Univ Minnesota, Div Pulm Med & Crit Care, Minneapolis, MN USA. [Allan, James S.] Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. [Allan, James S.] Harvard Med Sch, Boston, MA USA. RP Podgaetz, E (reprint author), Univ Minnesota, Div Thorac Surg, 55 Fruit St,Blake 1570, Boston, MA 02114 USA. EM eitanp@gmail.com NR 8 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1752-6981 EI 1752-699X J9 CLIN RESPIR J JI Clin. Respir. J. PD NOV PY 2016 VL 10 IS 6 BP 800 EP 804 DI 10.1111/crj.12287 PG 5 WC Respiratory System SC Respiratory System GA EK1VJ UT WOS:000393713600017 PM 25763656 ER PT J AU Almario, CV Chey, WD Khanna, D Mosadeghi, S Ahmed, S Afghani, E Whitman, C Fuller, G Reid, M Bolus, R Dennis, B Encarnacion, R Martinez, B Soares, J Modi, R Agarwal, N Lee, A Kubomoto, S Sharma, G Bolus, S Spiegel, BMR AF Almario, Christopher V. Chey, William D. Khanna, Dinesh Mosadeghi, Sasan Ahmed, Shahzad Afghani, Elham Whitman, Cynthia Fuller, Garth Reid, Mark Bolus, Roger Dennis, Buddy Encarnacion, Rey Martinez, Bibiana Soares, Jennifer Modi, Rushaba Agarwal, Nikhil Lee, Aaron Kubomoto, Scott Sharma, Gobind Bolus, Sally Spiegel, Brennan M. R. TI Impact of National Institutes of Health Gastrointestinal PROMIS Measures in Clinical Practice: Results of a Multicenter Controlled Trial SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID PATIENT-REPORTED OUTCOMES; INFORMATION-SYSTEM PROMIS; PSYCHOMETRIC PROPERTIES; SYMPTOM SCALES; LIFE; CARE; DISPARITIES; COMPUTER AB OBJECTIVES: The National Institutes of Health (NIH) created the Patient Reported Outcomes Measurement Information System (PROMIS) to allow efficient, online measurement of patient-reported outcomes (PROs), but it remains untested whether PROMIS improves outcomes. Here, we aimed to compare the impact of gastrointestinal (GI) PROMIS measures vs. usual care on patient outcomes. METHODS: We performed a pragmatic clinical trial with an off-on study design alternating weekly between intervention (GI PROMIS) and control arms at one Veterans Affairs and three university-affiliated specialty clinics. Adults with GI symptoms were eligible. Intervention patients completed GI PROMIS symptom questionnaires on an e-portal 1 week before their visit; PROs were available for review by patients and their providers before and during the clinic visit. Usual care patients were managed according to customary practices. Our primary outcome was patient satisfaction as determined by the Consumer Assessment of Healthcare Providers and Systems questionnaire. Secondary outcomes included provider interpersonal skills (Doctors' Interpersonal Skills Questionnaire (DISQ)) and shared decision-making (9-item Shared Decision Making Questionnaire (SDM-Q-9)). RESULTS: There were 217 and 154 patients in the GI PROMIS and control arms, respectively. Patient satisfaction was similar between groups (P>0.05). Intervention patients had similar assessments of their providers' interpersonal skills (DISQ 89.4 +/- 11.7 vs. 89.8 +/- 16.0, P=0.79) and shared decisionmaking (SDM-Q-9 79.3 +/- 12.4 vs. 79.0 +/- 22.0, P=0.85) vs. controls. CONCLUSIONS: This is the first controlled trial examining the impact of NIH PROMIS in clinical practice. One-time use of GI PROMIS did not improve patient satisfaction or assessment of provider interpersonal skills and shared decision-making. Future studies examining how to optimize PROs in clinical practice are encouraged before widespread adoption. C1 [Almario, Christopher V.; Afghani, Elham; Whitman, Cynthia; Fuller, Garth; Martinez, Bibiana; Soares, Jennifer; Spiegel, Brennan M. R.] Cedars Sinai Med Ctr, Div Gastroenterol, Pacific Theatres Bldg,116 North Robertson Blvd, Los Angeles, CA 90048 USA. [Almario, Christopher V.; Reid, Mark; Martinez, Bibiana; Soares, Jennifer; Spiegel, Brennan M. R.] VA Greater Angeles Healthcare Syst, Div Gastroenterol, Los Angeles, CA USA. [Almario, Christopher V.; Mosadeghi, Sasan; Ahmed, Shahzad; Whitman, Cynthia; Fuller, Garth; Reid, Mark; Bolus, Roger; Martinez, Bibiana; Soares, Jennifer; Modi, Rushaba; Agarwal, Nikhil; Lee, Aaron; Kubomoto, Scott; Sharma, Gobind; Bolus, Sally; Spiegel, Brennan M. R.] CS CORE, Los Angeles, CA USA. [Chey, William D.] Univ Michigan, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Khanna, Dinesh] Univ Michigan, Div Rheumatol, Ann Arbor, MI 48109 USA. [Dennis, Buddy; Encarnacion, Rey] Univ Calif Los Angeles, CTRL, Los Angeles, CA USA. RP Spiegel, BMR (reprint author), Cedars Sinai Med Ctr, Div Gastroenterol, Pacific Theatres Bldg,116 North Robertson Blvd, Los Angeles, CA 90048 USA. EM Brennan.Spiegel@cshs.org FU NIH/NIAMS research grant [U01 AR057936-05]; Career Development Award from the American College of Gastroenterology; Ironwood Pharmaceuticals FX This study was supported by an NIH/NIAMS research grant (U01 AR057936-05). Dr Almario was supported by a Career Development Award from the American College of Gastroenterology. The PROMIS-triggered HPI generator was developed under a separate grant from Ironwood Pharmaceuticals. 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 NOV PY 2016 VL 111 IS 11 BP 1546 EP 1556 DI 10.1038/ajg.2016.305 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK6PT UT WOS:000394047300016 PM 27481311 ER PT J AU Khalili, H Neovius, M Ekbom, A Ludvigsson, JF Askling, J Chan, AT Olen, O AF Khalili, Hamed Neovius, Martin Ekbom, Anders Ludvigsson, Jonas F. Askling, Johan Chan, Andrew T. Olen, Ola TI Oral Contraceptive Use and Risk of Ulcerative Colitis Progression: A Nationwide Study SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; POPULATION-BASED COHORT; CROHNS-DISEASE; BARRIER FUNCTION; REGISTER; METAANALYSIS; AGE AB OBJECTIVES: Oral contraceptive (OC) use has been consistently linked to increased risk of inflammatory bowel disease. Nonetheless, a specific role of OC in the natural history of ulcerative colitis (UC) is unknown. METHODS: We identified 6,104 incident female UC cases aged 16-51 years at diagnosis from the Swedish National Patient Register starting in January of 2003. Information on current OC use was obtained from the Prescribed Drug Register starting in July of 2005. We followed cases through December of 2014 for primary outcome defined as first UC-related surgery, and the secondary outcomes defined by recipient of the first prescription of oral steroids or anti-tumor necrosis factor (anti-TNF) use. We used Cox proportional hazard modeling with time-varying covariates to estimate multivariable-adjusted hazard ratio (aHR) and 95% confidence interval (CI). RESULTS: Over 31,421 person-years of follow up, we observed 162 cases of UC-related surgery. Compared with nonusers, current and past use of OC were not significantly associated with risk of UC-related surgery (aHR= 0.79; 95% CI, 0.52-1.18; and aHR= 0.74, 95% CI, 0.46-1.18, respectively). The association did not appear to be modified by type of OC use (progestin-only vs. combination of progestin and estrogen), longer duration of use, or higher number of dispensed prescriptions (All P-trend > 0.28). Similarly, longer use or higher cumulative number of OC prescriptions were not associated with increased risk of receiving a steroid prescription (P-trend = 0.68 and 0.63, respectively). In exploratory analyses restricted to Stockholm county, current OC use was not associated with increased risk of receiving anti-TNF therapy (aHR= 0.83, 95% CI, 0.59-1.18). CONCLUSIONS: In a large nationwide registry of UC patients, we found no association between OC use and UC progression. Our data offer reassurance regarding the safety of OC assessed by its effect on risk of surgery and steroid or anti-TNF use in women with established UC. C1 [Khalili, Hamed; Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Khalili, Hamed; Chan, Andrew T.] Harvard Med Sch, Boston, MA USA. [Khalili, Hamed; Chan, Andrew T.] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA. [Khalili, Hamed; Neovius, Martin; Ekbom, Anders; Askling, Johan; Olen, Ola] Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden. [Ludvigsson, Jonas F.] Karolinska Inst, Dept Med Epidemiol & Biostat, Solna, Sweden. [Ludvigsson, Jonas F.] Orebro Univ Hosp, Dept Pediat, Orebro, Sweden. [Ludvigsson, Jonas F.] Univ Nottingham, Sch Med, Div Epidemiol & Publ Hlth, Nottingham NG7 2RD, England. [Ludvigsson, Jonas F.] Columbia Coll Phys & Surg, Div Digest & Liver Dis, New York, NY USA. [Chan, Andrew T.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Olen, Ola] Sachs Childrens Hosp, Dept Pediat Gastroenterol, Stockholm, Sweden. RP Khalili, H (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, Digest Healthcare Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM hkhalili@mgh.harvard.edu OI Neovius, Martin/0000-0003-2300-3055 FU Crohn's and Colitis Foundation of America (CCFA) [K24 DK098311]; American Gastroenterological Association (AGA); Swedish Foundation for Strategic Research; Stockholm County Council (ALF); Bengt Ihre research fellowship in gastroenterology; Mjolkdroppen foundation; National Institute of Diabetes and Digestive and Kidney Diseases [K23 DK099681]; American College of Gastroenterology (ACG) FX This study was funded by K23 DK099681. Dr Chan is supported by a senior investigator grant from the Crohn's and Colitis Foundation of America (CCFA) and K24 DK098311. Dr Khalili is supported by a career development award from the American Gastroenterological Association (AGA) and by National Institute of Diabetes and Digestive and Kidney Diseases (K23 DK099681). This work was also supported by a travel grant from the American College of Gastroenterology (ACG), the Swedish Foundation for Strategic Research, Stockholm County Council (ALF), the Bengt Ihre research fellowship in gastroenterology, and the Mjolkdroppen foundation. NR 31 TC 0 Z9 0 U1 1 U2 1 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 NOV PY 2016 VL 111 IS 11 BP 1614 EP 1620 DI 10.1038/ajg.2016.464 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK6PT UT WOS:000394047300026 PM 27725646 ER PT J AU Adler, J Dominitz, JA AF Adler, Jeffrey Dominitz, Jason A. TI Financial Incentives to Improve Colorectal Cancer Screening: Does it Make Cents? SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Editorial Material ID OCCULT BLOOD-TESTS; COST-EFFECTIVENESS; RANDOMIZED-TRIAL; UNITED-STATES; COLONOSCOPY; NAVIGATION; ADHERENCE; INCREASES; VETERANS; CARE AB While colorectal cancer screening reduces colorectal cancer incidence and mortality, there is much room for improvement in screening adherence particularly among the uninsured and ethnic minorities. In this issue, Gupta et al. conducted a randomized controlled study to test the impact of a small financial incentive on screening adherence. Their negative study, taken in the context of prior studies and behavioral economics literature, leads us to conclude that it does not pay to add this small financial incentive to community outreach. Instead, we should invest in a systematic approach to screening, including patient navigation. C1 [Adler, Jeffrey] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Dominitz, Jason A.] Univ Washington, Sch Med, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. RP Adler, J (reprint author), Dartmouth Hitchcock Med Ctr, Gastroenterol & Hepatol, 1 Med Ctr Dr, Lebanon, NH 03766 USA. EM jeffrey.m.adler@hitchcock.org FU Veterans Health Administration FX This material is the result of work supported in part by resources from The Veterans Health Administration. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 25 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 NOV PY 2016 VL 111 IS 11 BP 1637 EP 1639 DI 10.1038/ajg.2016.459 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK6PT UT WOS:000394047300029 PM 27808152 ER PT J AU Liang, KC Ahsen, OO Lee, HC Wang, Z Potsaid, BM Figueiredo, M Jayaraman, V Cable, AE Huang, Q Mashimo, H Fujimoto, JG AF Liang, Kaicheng Ahsen, Osman O. Lee, Hsiang-Chieh Wang, Zhao Potsaid, Benjamin M. Figueiredo, Marisa Jayaraman, Vijaysekhar Cable, Alex E. Huang, Qin Mashimo, Hiroshi Fujimoto, James G. TI Volumetric Mapping of Barrett's Esophagus and Dysplasia With en face Optical Coherence Tomography Tethered Capsule SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Letter ID HIGH-GRADE DYSPLASIA; ENDOMICROSCOPY; OCT C1 [Liang, Kaicheng; Ahsen, Osman O.; Lee, Hsiang-Chieh; Wang, Zhao; Fujimoto, James G.] MIT, Dept Elect Engn & Comp Sci, Elect Res Lab, Cambridge, MA 02139 USA. [Potsaid, Benjamin M.; Cable, Alex E.] Thorlabs, Newton, NJ USA. [Figueiredo, Marisa; Huang, Qin; Mashimo, Hiroshi] VA Boston Healthcare Syst, Boston, MA USA. [Jayaraman, Vijaysekhar] Praevium Res, Santa Barbara, CA USA. [Huang, Qin; Mashimo, Hiroshi] Harvard Med Sch, Boston, MA USA. RP Fujimoto, JG (reprint author), MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA.; Fujimoto, JG (reprint author), MIT, Elect Res Lab, Cambridge, MA 02139 USA. EM jgfuji@mit.edu FU National Institutes of Health (NIH) [R01-CA075289-19, R44-CA101067-05, R01-CA178636-03, R01-EY011289-29]; Air Force Office of Scientific Research (AFOSR) [FA9550-15-1-0473, FA9550-12-1-0499]; Agency for Science, Technology and Research (Singapore) FX National Institutes of Health (NIH) R01-CA075289-19, R44-CA101067-05, R01-CA178636-03, R01-EY011289-29 and Air Force Office of Scientific Research (AFOSR) FA9550-15-1-0473 and FA9550-12-1-0499. Graduate fellowship (K.C.L.) from Agency for Science, Technology and Research (Singapore). NR 9 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 NOV PY 2016 VL 111 IS 11 BP 1664 EP 1666 DI 10.1038/ajg.2016.419 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK6PT UT WOS:000394047300041 PM 27808130 ER PT J AU Feinberg, TY Rowe, RG Saunders, TL Weiss, SJ AF Feinberg, Tamar Y. Rowe, R. Grant Saunders, Thomas L. Weiss, Stephen J. TI Functional roles of MMP14 and MMP15 in early postnatal mammary gland development SO DEVELOPMENT LA English DT Article DE Morphogenesis; Mammary gland; Matrix metalloproteinases; Mouse ID MEMBRANE-TYPE-1 MATRIX-METALLOPROTEINASE; BRANCHING MORPHOGENESIS; BASEMENT-MEMBRANE; EXTRACELLULAR-MATRIX; CELL-MIGRATION; CANCER-CELLS; ADAPTIVE THERMOGENESIS; EPITHELIAL-CELLS; COLLAGEN MATRIX; ADIPOSE-TISSUE AB During late embryogenesis, mammary epithelial cells initiate migration programs that drive ductal invasion into the surrounding adipose-rich mesenchyme. Currently, branching morphogenesis is thought to depend on the mobilization of the membrane-anchored matrix metalloproteinases MMP14 (MT1-MMP) and MMP15 (MT2-MMP), which drive epithelial cell invasion by remodeling the extracellular matrix and triggering associated signaling cascades. However, the roles that these proteinases play during mammary gland development in vivo remain undefined. Here, we characterize the impact of global Mmp14 and Mmp15 targeting on early postnatal mammary gland development in mice. Unexpectedly, both Mmp14(-/-) and Mmp15(-/-) mammary glands retain the ability to generate intact ductal networks. Although neither proteinase is required for branching morphogenesis, transcriptome profiling reveals a key role for MMP14 and MMP15 in regulating mammary gland adipocyte differentiation. Whereas MMP14 promotes the generation of white fat depots crucial for energy storage, MMP15 differentially controls the formation of thermogenic brown fat. Taken together, these data not only indicate that current paradigms relevant to proteinase-dependent morphogenesis need be revisited, but also identify new roles for the enzymes in regulating adipocyte fate determination in the developing mammary gland. C1 [Feinberg, Tamar Y.; Rowe, R. Grant; Saunders, Thomas L.; Weiss, Stephen J.] Univ Michigan, Div Mol Med & Genet, Dept Internal Med, Ann Arbor, MI 48109 USA. [Feinberg, Tamar Y.; Weiss, Stephen J.] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. [Feinberg, Tamar Y.; Weiss, Stephen J.] Univ Michigan, Cellular & Mol Biol Grad Program, Ann Arbor, MI 48109 USA. [Saunders, Thomas L.] Univ Michigan, Transgen Anim Model Core, Biomed Res Core Facil, Ann Arbor, MI 48109 USA. [Rowe, R. Grant] Dana Farber Canc Inst, Pediat Hematol Oncol, Boston, MA 02215 USA. RP Weiss, SJ (reprint author), Univ Michigan, Div Mol Med & Genet, Dept Internal Med, Ann Arbor, MI 48109 USA.; Weiss, SJ (reprint author), Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA.; Weiss, SJ (reprint author), Univ Michigan, Cellular & Mol Biol Grad Program, Ann Arbor, MI 48109 USA. EM sjweiss@umich.edu FU Breast Cancer Research Foundation; National Institutes of Health [CA071699] FX This work was supported by grants from the Breast Cancer Research Foundation and the National Institutes of Health [CA071699] to S.J.W. Deposited in PMC for release after 12 months. NR 81 TC 0 Z9 0 U1 1 U2 1 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 NOV 1 PY 2016 VL 143 IS 21 BP 3956 EP 3968 DI 10.1242/dev.136259 PG 13 WC Developmental Biology SC Developmental Biology GA EJ8CU UT WOS:000393452900011 PM 27633994 ER PT J AU Okita, K Mandelkern, MA London, ED AF Okita, Kyoji Mandelkern, Mark A. London, Edythe D. TI Cigarette Use and Striatal Dopamine D2/3 Receptors: Possible Role in the Link between Smoking and Nicotine Dependence SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE nicotine dependence; dopamine; D2 receptors; positron emission tomography ID REFERENCE TISSUE MODEL; UNITED-STATES; BINDING; PET; RELEASE; HUMANS; AVAILABILITY; IMPULSIVITY; TRENDS AB Background: Cigarette smoking induces dopamine release in the striatum, and smoking- or nicotine-induced ventral striatal dopamine release is correlated with nicotine dependence. Smokers also exhibit lower dopamine D2/3 receptor availability in the dorsal striatum than nonsmokers. Negative correlations of striatal dopamine D2/3 receptor availability with smoking exposure and nicotine dependence, therefore, might be expected but have not been tested. Methods: Twenty smokers had positron emission tomography scans with [F-18] fallypride to measure dopamine D2/3 receptor availability in ventral and dorsal regions of the striatum and provided self-report measures of recent and lifetime smoking and of nicotine dependence. Results: As reported before, lifetime smoking was correlated with nicotine dependence. New findings were that ventral striatal dopamine D2/3 receptor availability was negatively correlated with recent and lifetime smoking and also with nicotine dependence. Conclusion: The results suggest an effect of smoking on ventral striatal D2/3 dopamine receptors that may contribute to nicotine dependence. C1 [Okita, Kyoji; London, Edythe D.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [London, Edythe D.] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA USA. [London, Edythe D.] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90024 USA. [Okita, Kyoji; Mandelkern, Mark A.; London, Edythe D.] VA Greater Los Angeles Healthcare Syst, Dept Res, Los Angeles, CA USA. [Mandelkern, Mark A.] Univ Calif Irvine, Dept Phys, Irvine, CA 92717 USA. RP London, ED (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, 740 Westwood Plaza,POB 175919, Los Angeles, CA 90024 USA. EM elondon@mednet.ucla.edu FU National Institute on Drug Abuse [R01 DA015179, R01 DA020726, P20 DA022539, T32 DA024635]; National Center for Research Resources [M01 RR00865]; Department of Psychiatry, Chiba University, DOMONKAI fund FX This research was supported, in part, by grants from the National Institute on Drug Abuse (R01 DA015179, R01 DA020726, P20 DA022539, T32 DA024635, E.D.L.) and the National Center for Research Resources (M01 RR00865), and endowments from the Thomas P. and Katherine K. Pike Chair in Addiction Studies and the Marjorie M. Greene Trust. K.O. was, in part, supported by Department of Psychiatry, Chiba University, DOMONKAI fund. NR 25 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD NOV PY 2016 VL 19 IS 11 DI 10.1093/ijnpp/pyw074 PG 5 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EK4QO UT WOS:000393912100009 ER PT J AU Waldron, L Riester, M Ramos, M Parmigiani, G Birrer, M AF Waldron, Levi Riester, Markus Ramos, Marcel Parmigiani, Giovanni Birrer, Michael TI The Doppelganger Effect: Hidden Duplicates in Databases of Transcriptome Profiles SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID OVARIAN-CANCER; EXPRESSION SIGNATURE; BREAST-CANCER; SURVIVAL AB Whole-genome analysis of cancer specimens is commonplace, and investigators frequently share or re-use specimens in later studies. Duplicate expression profiles in public databases will impact re-analysis if left undetected, a so-called "doppelganger" effect. We propose a method that should be routine practice to accurately match duplicate cancer transcriptomes when nucleotide-level sequence data are unavailable, even for samples profiled by different microarray technologies or by both microarray and RNA sequencing. We demonstrate the effectiveness of the method in databases containing dozens of datasets and thousands of ovarian, breast, bladder, and colorectal cancer microarray profiles and of matching microarray and RNA sequencing expression profiles from The Cancer Genome Atlas (TCGA). We identified probable duplicates among more than 50% of studies, originating in different continents, using different technologies, published years apart, and even within the TCGA itself. Finally, we provide the doppelgangR Bioconductor package for screening transcriptome databases for duplicates. Given the potential for unrecognized duplication to falsely inflate prediction accuracy and confidence in differential expression, doppelganger-checking should be a part of standard procedure for combining multiple genomic datasets. C1 [Waldron, Levi; Ramos, Marcel] CUNY, Sch Publ Hlth, New York, NY 10021 USA. [Riester, Markus] Novartis Inst BioMed Res, Cambridge, MA USA. [Parmigiani, Giovanni] Harvard Med Sch, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA USA. [Birrer, Michael] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. RP Birrer, M (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Gillette Ctr Gynecol Oncol, YAW 9-072, Boston, MA 02114 USA. EM mbirrer@partners.org OI Waldron, Levi/0000-0003-2725-0694 FU National Cancer Institute at the National Institutes of Health [1RC4CA156551-01, 5R01CA142832, 1R03CA191447-01A1, U24CA180996]; Julie Fund FX This work was supported by grants from the National Cancer Institute at the National Institutes of Health (1RC4CA156551-01 and 5R01CA142832 to MB, 1R03CA191447-01A1 and U24CA180996 to LW). Additional funding was generously provided by the Julie Fund (MB). NR 13 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 NOV PY 2016 VL 108 IS 11 AR djw146 DI 10.1093/jnci/djw146 PG 4 WC Oncology SC Oncology GA EK4LD UT WOS:000393897300008 ER PT J AU Rabago, CA Clouser, M Dearth, CL Farrokhi, S Galarneau, MR Highsmith, MJ Wilken, JM Wyatt, MP Hill, OT AF Rabago, Christopher A. Clouser, Mary Dearth, Christopher L. Farrokhi, Shawn Galarneau, Michael R. Highsmith, M. Jason Wilken, Jason M. Wyatt, Marilynn P. Hill, Owen T. TI The Extremity Trauma and Amputation Center of Excellence: Overview of the Research and Surveillance Division SO MILITARY MEDICINE LA English DT Article ID LOWER-LIMB LOSS; ACTIVITY MOBILITY PREDICTOR; OPERATION IRAQI FREEDOM; ANKLE-FOOT PROSTHESES; TRANSTIBIAL AMPUTATION; DESTABILIZING ENVIRONMENTS; MALE SERVICEMEMBERS; C-LEG; TRANSFEMORAL AMPUTATION; DYNAMIC STABILITY AB Congress authorized creation of the Extremity Trauma and Amputation Center of Excellence (EACE) as part of the 2009 National Defense Authorization Act. The legislation mandated the Department of Defense (DoD) and Department of Veterans Affairs (VA) to implement a comprehensive plan and strategy for the mitigation, treatment, and rehabilitation of traumatic extremity injuries and amputation. The EACE also was tasked with conducting clinically relevant research, fostering collaborations, and building partnerships across multidisciplinary international, federal, and academic networks to optimize the quality of life of service members and veterans who have sustained extremity trauma or amputations. To fulfill themandate to conduct research, the EACE developed a Research and Surveillance Division that complements and collaborates with outstanding DoD, VA, and academic research programs across the globe. The EACE researchers have efforts in four key research focus areas relevant to extremity trauma and amputation: (1) Novel Rehabilitation Interventions, (2) Advanced Prosthetic and Orthotic Technologies, (3) Epidemiology and Surveillance, and (4) Medical and Surgical Innovations. This overview describes the EACE efforts to innovate, discover, and translate knowledge gleaned from collaborative research partnerships into clinical practice and policy. C1 [Rabago, Christopher A.; Clouser, Mary; Dearth, Christopher L.; Farrokhi, Shawn; Galarneau, Michael R.; Highsmith, M. Jason; Wilken, Jason M.; Hill, Owen T.] Extrem Trauma & Amputat Ctr Excellence, 2748 Worth Rd,Suite 29, Joint Base San Antonio F, TX 78234 USA. [Rabago, Christopher A.; Wilken, Jason M.; Hill, Owen T.] Brooke Army Med Ctr, Dept Rehabil Med, Ctr Intrepid, 3551 Roger Brooke Dr, Joint Base San Antonio F, TX 78234 USA. [Clouser, Mary; Galarneau, Michael R.] Naval Hlth Res Ctr, 140 Sylvester Rd, San Diego, CA 92106 USA. [Dearth, Christopher L.] Walter Reed Natl Mil Med Ctr, Dept Rehabil, Res & Dev Sect, 8901 Rockville Pike, Bethesda, MD 20889 USA. [Farrokhi, Shawn; Wyatt, Marilynn P.] Naval Med Ctr San Diego, Dept Phys & Occupat Therapy, 34800 Bob Wilson Dr, San Diego, CA 92134 USA. [Highsmith, M. Jason] James A Haley Vet Adm Hosp, Ctr Innovat Disabil & Rehabil Res, 8900 Grand Oak Circle 151R, Tampa, FL 33637 USA. [Highsmith, M. Jason] Univ S Florida, Morsani Coll Med, Sch Phys Therapy & Rehabil Sci, 3515 E Fletcher Ave, Tampa, FL 33612 USA. [Highsmith, M. Jason] US Dept Vet Affairs, Rehabil Serv, 810 Vermont Ave NW, Washington, DC 20420 USA. [Highsmith, M. Jason] US Dept Vet Affairs, Prosthet Serv, 810 Vermont Ave NW, Washington, DC 20420 USA. RP Rabago, CA (reprint author), Extrem Trauma & Amputat Ctr Excellence, 2748 Worth Rd,Suite 29, Joint Base San Antonio F, TX 78234 USA.; Rabago, CA (reprint author), Brooke Army Med Ctr, Dept Rehabil Med, Ctr Intrepid, 3551 Roger Brooke Dr, Joint Base San Antonio F, TX 78234 USA. OI Rabago, Christopher/0000-0002-4484-0613 NR 74 TC 0 Z9 0 U1 1 U2 1 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD NOV PY 2016 VL 181 SU 4 SI SI BP 3 EP 12 DI 10.7205/MILMED-D-16-00279 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EL3EA UT WOS:000394501200002 PM 27849455 ER PT J AU Highsmith, MJ Kahle, JT Miro, RM Lura, DJ Carey, SL Wernke, MM Kim, SH Quillen, WS AF Highsmith, M. Jason Kahle, Jason T. Miro, Rebecca M. Lura, Derek J. Carey, Stephanie L. Wernke, Matthew M. Kim, Seok Hun Quillen, William S. TI Differences in Military Obstacle Course Performance Between Three Energy-Storing and Shock-Adapting Prosthetic Feet in High-Functioning Transtibial Amputees: A Double-Blind, Randomized Control Trial SO MILITARY MEDICINE LA English DT Article ID BELOW-KNEE AMPUTEES; PHYSICAL PERFORMANCE; CURRENT CONFLICTS; GAIT; AMPUTATION; RETURN; FOOT; AFGHANISTAN; EXPENDITURE; AMBULATION AB Background: Approximately 683 persons engaged in military service experienced transtibial amputation (TTA) related to recent war in Iraq and Afghanistan. Military TTAs function at a level beyond basic ambulation. No empirical data demonstrate which higher functioning prosthetic feet maximize injured service personnel's ability to continue performing at a level commensurate with return to duty. This study's purpose was to determine which of three high-functioning, energy-storing prosthetic feet maximize performance and preference in a field obstacle course (OC) and to quantify physical performance differences between TTAs and high-functioning nonamputees. Procedures: A randomized, double-blind, repeated measures experimental design compared three prosthetic feet (Ossur Variflex, Endolite Elite Blade, and Ossur Re-Flex Rotate) during performance on a field OC. TTAs accommodated with study feet and the OC before assessment. 14 TTAs and 14 nonamputee controls completed the course. Subjective and objective performance differences were compared across feet conditions and between groups. Results: Total OC completion times were similar between prosthetic feet: Elite-Blade (419 seconds +/- 130), Variflex (425 seconds +/- 144), and Re-Flex Rotate (444 seconds +/- 220). Controls' OC completion time (287.2 seconds +/- 58) was less (p <= 0.05) than TTA times. In total, controls had faster completion times (p <= 0.05) compared to all prosthetic feet conditions in 13/17 obstacles. Re-Flex Rotate had 2 additional obstacles different (p <= 0.05) than controls and required more time to complete. Median RPE values were lower (p <= 0.05) for controls than TTA regardless of foot. Regarding foot preference for OC completion, 7/14 (50%) preferred Elite Blade, 5/14 (36%) preferred Re-Flex Rotate, and the remaining 2/14 (14%) preferred Variflex. Conclusion: Controls completed the OC faster and with less effort than TTAs regardless of prosthetic foot. No clear differences in prosthetic feet emerged during OC completion; however, individual task performance, perceived effort, and preference resulted in trends of slight performance improvement with and preference for Elite Blade, a dual function energy-storing and return foot combined with vertical shock absorption. Understanding how to maximally improve performance in such functional tasks may allow service members to best sustain physical fitness, return to their military occupational specialty and possibly in-theater duty. C1 [Highsmith, M. Jason] Extrem Trauma & Amputat Ctr Excellence, 2748 Worth Rd,Suite 29, Ft Sam Houston, TX 78234 USA. [Highsmith, M. Jason] James A Haley Vet Adm Hosp, Ctr Innovat Disabil & Rehabil Res, 8900 Grand Oak Circle 151R, Tampa, FL 33637 USA. [Highsmith, M. Jason; Kahle, Jason T.; Miro, Rebecca M.; Kim, Seok Hun; Quillen, William S.] Univ S Florida, Sch Phys Therapy & Rehabil Sci, 3515 E,Fletcher Ave, Tampa, FL 33612 USA. [Highsmith, M. Jason] US Dept Vet Affairs, Rehabil Serv, 810 Vermont Ave NW, Washington, DC 20420 USA. [Highsmith, M. Jason] US Dept Vet Affairs, Prosthet Serv, 810 Vermont Ave NW, Washington, DC 20420 USA. [Miro, Rebecca M.; Quillen, William S.] Univ S Florida, Ctr Neuromusculoskeletal Res, 3515 E,Fletcher Ave, Tampa, FL 33612 USA. [Lura, Derek J.] Florida Gulf Coast Univ, Dept Bioengn & Software Engn, 10501 FGCU Blvd South, Ft Myers, FL 33965 USA. [Carey, Stephanie L.] Univ S Florida, Dept Mech Engn, 4202 E,Fowler Ave,ENB 118, Tampa, FL 33612 USA. [Wernke, Matthew M.] Willow Wood, 15441 Scioto Darby Rd,POB 130, Mt Sterling, OH 43143 USA. RP Highsmith, MJ (reprint author), Extrem Trauma & Amputat Ctr Excellence, 2748 Worth Rd,Suite 29, Ft Sam Houston, TX 78234 USA.; Highsmith, MJ (reprint author), James A Haley Vet Adm Hosp, Ctr Innovat Disabil & Rehabil Res, 8900 Grand Oak Circle 151R, Tampa, FL 33637 USA.; Highsmith, MJ (reprint author), Univ S Florida, Sch Phys Therapy & Rehabil Sci, 3515 E,Fletcher Ave, Tampa, FL 33612 USA.; Highsmith, MJ (reprint author), US Dept Vet Affairs, Rehabil Serv, 810 Vermont Ave NW, Washington, DC 20420 USA.; Highsmith, MJ (reprint author), US Dept Vet Affairs, Prosthet Serv, 810 Vermont Ave NW, Washington, DC 20420 USA. FU U.S. Department of Defense, Congressionally Directed Medical Research Program (DOD-CDMRP) Project [W81XWH-112-0170, 10193006] FX We wish to thank Ms. Kaitlin Lostroscio for assistance processing study data and Mr. Steven Springer for assistance with subject recruitment. Sheriff David Gee, Maj Alan Hill, and Sgt. Edmond Shea of the Hillsborough County Sheriff's Department provided vital assistance with facility access, training, and safety monitoring throughout study activities. This project was funded by the U.S. Department of Defense, Congressionally Directed Medical Research Program (DOD-CDMRP) Project No. W81XWH-112-0170 (U.S.F. Grant No. 10193006). NR 37 TC 0 Z9 0 U1 1 U2 1 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD NOV PY 2016 VL 181 SU 4 SI SI BP 45 EP 54 DI 10.7205/MILMED-D-16-00286 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EL3EA UT WOS:000394501200008 PM 27849461 ER PT J AU Randolph, BJ Nelson, LM Highsmith, MJ AF Randolph, Billie J. Nelson, Leif M. Highsmith, M. Jason TI A Review of Unique Considerations for Female Veterans With Amputation SO MILITARY MEDICINE LA English DT Review ID GENDER-DIFFERENCES; LIMB; AMPUTEES; PREVALENCE; SERVICES; WOMEN AB This article explores unique considerations that face both women living with limb loss and their health care providers. This demographic of patient has a higher rate of artificial limb rejection, thus challenging providers to address needs for cosmesis and function that varies from those of male counterparts. Health care providers for women with amputations, such as the Veterans Affairs, must evolve health care delivery, research practices, and work jointly with industry in order to meet the needs of this population. C1 [Randolph, Billie J.; Nelson, Leif M.; Highsmith, M. Jason] Extrem Trauma & Amputat Ctr Excellence, 2748 Worth Rd,Suite 29, Ft Sam Houston, TX 78234 USA. [Randolph, Billie J.; Nelson, Leif M.; Highsmith, M. Jason] US Dept Vet Affairs, Rehabil Serv, 810 Vermont Ave NW, Washington, DC 20420 USA. [Randolph, Billie J.; Nelson, Leif M.; Highsmith, M. Jason] US Dept Vet Affairs, Prosthet Serv, 810 Vermont Ave NW, Washington, DC 20420 USA. [Highsmith, M. Jason] Univ S Florida, Morsani Coll Med, Sch Phys Therapy & Rehabil Sci, 3515 E,Fletcher Ave, Tampa, FL 33613 USA. RP Randolph, BJ (reprint author), Extrem Trauma & Amputat Ctr Excellence, 2748 Worth Rd,Suite 29, Ft Sam Houston, TX 78234 USA.; Randolph, BJ (reprint author), US Dept Vet Affairs, Rehabil Serv, 810 Vermont Ave NW, Washington, DC 20420 USA.; Randolph, BJ (reprint author), US Dept Vet Affairs, Prosthet Serv, 810 Vermont Ave NW, Washington, DC 20420 USA. NR 23 TC 0 Z9 0 U1 1 U2 1 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD NOV PY 2016 VL 181 SU 4 SI SI BP 66 EP 68 DI 10.7205/MILMED-D-16-00262 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EL3EA UT WOS:000394501200011 PM 27849464 ER PT J AU Highsmith, MJ Nelson, LM Carbone, NT Klenow, TD Kahle, JT Hill, OT Maikos, JT Kartel, MS Randolph, BJ AF Highsmith, M. Jason Nelson, Leif M. Carbone, Neil T. Klenow, Tyler D. Kahle, Jason T. Hill, Owen T. Maikos, Jason T. Kartel, Mike S. Randolph, Billie J. TI Outcomes Associated With the Intrepid Dynamic Exoskeletal Orthosis (IDEO): A Systematic Review of the Literature SO MILITARY MEDICINE LA English DT Review ID LOWER-EXTREMITY TRAUMA; LIMB SALVAGE; PRISMA STATEMENT; AMPUTATION; PERFORMANCE; WALKING; RETURN; METAANALYSES; DISABILITY; INJURY AB High-energy lower extremity trauma is a consequence of modern war and it is unclear if limb amputation or limb salvage enables greater recovery. To improve function in the injured extremity, a passive dynamic ankle-foot orthosis, the Intrepid Dynamic Exoskeletal Orthosis (IDEO), was introduced with specialized return to run (RTR) therapy program. Recent research suggests, these interventions may improve function and return to duty rates. This systematic literature review sought to rate available evidence and formulate empirical evidence statements (EESs), regarding outcomes associated with IDEO utilization. PubMed, CINAHL, and Google Scholar were systematically searched for pertinent articles. Articles were screened and rated. EESs were formulated based upon data and conclusions from included studies. Twelve studies were identified and rated. Subjects (n = 487, 6 females, mean age 29.4 year) were studied following limb trauma and salvage. All included studies had high external validity, whereas internal validity was mixed because of reporting issues. Moderate evidence supported development of four EESs regarding IDEO use with specialized therapy. Following high-energy lower extremity trauma and limb salvage, use of IDEO with RTR therapy can enable return to duty, return to recreation and physical activity, and decrease pain in some high-functioning patients. In higher functioning patients following limb salvage or trauma, IDEO use improved agility, power and speed, compared with no-brace or conventional bracing alternatives. C1 [Highsmith, M. Jason; Nelson, Leif M.; Hill, Owen T.; Randolph, Billie J.] Extrem Trauma & Amputat Ctr Excellence, 2748 Worth Rd,Suite 29, Ft Sam Houston, TX 78234 USA. [Highsmith, M. Jason; Nelson, Leif M.; Randolph, Billie J.] US Dept Vet Affairs, Rehabil & Serv, 810 Vermont Ave NW, Washington, DC 20420 USA. [Highsmith, M. Jason; Nelson, Leif M.; Randolph, Billie J.] US Dept Vet Affairs, Prosthet Serv, 810 Vermont Ave NW, Washington, DC 20420 USA. [Highsmith, M. Jason; Kahle, Jason T.] Univ S Florida, Morsani Coll Med, Sch Phys Therapy & Rehabil Sci, 3515 E,Fletcher Ave, Tampa, FL 33613 USA. [Carbone, Neil T.; Maikos, Jason T.] Vet Affairs New York Harbor Healthcare Syst, 423 E,23rd St, New York, NY USA. [Klenow, Tyler D.; Kartel, Mike S.] James A Haley Vet Adm Hosp, 13000 Bruce B Downs Blvd, Tampa, FL 33612 USA. [Hill, Owen T.] Brooke Army Med Ctr, Headquarters & Headquarters Co, 3551 Roger Brooke Dr, Ft Sam Houston, TX 78234 USA. RP Highsmith, MJ (reprint author), Extrem Trauma & Amputat Ctr Excellence, 2748 Worth Rd,Suite 29, Ft Sam Houston, TX 78234 USA.; Highsmith, MJ (reprint author), US Dept Vet Affairs, Rehabil & Serv, 810 Vermont Ave NW, Washington, DC 20420 USA.; Highsmith, MJ (reprint author), US Dept Vet Affairs, Prosthet Serv, 810 Vermont Ave NW, Washington, DC 20420 USA.; Highsmith, MJ (reprint author), Univ S Florida, Morsani Coll Med, Sch Phys Therapy & Rehabil Sci, 3515 E,Fletcher Ave, Tampa, FL 33613 USA. NR 32 TC 0 Z9 0 U1 0 U2 0 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD NOV PY 2016 VL 181 SU 4 SI SI BP 69 EP 76 DI 10.7205/MILMED-D-16-00280 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA EL3EA UT WOS:000394501200012 PM 27849465 ER PT J AU Slane, JD Levine, MD Borrero, S Mattocks, KM Ozier, AD Silliker, N Bathulapalli, H Brandt, C Haskell, SG AF Slane, Jennifer D. Levine, Michele D. Borrero, Sonya Mattocks, Kristin M. Ozier, Amy D. Silliker, Norman Bathulapalli, Harini Brandt, Cynthia Haskell, Sally G. TI Eating Behaviors: Prevalence, Psychiatric Comorbidity, and Associations With Body Mass Index Among Male and Female Iraq and Afghanistan Veterans SO MILITARY MEDICINE LA English DT Article ID POSTTRAUMATIC-STRESS; GENDER-DIFFERENCES; NATIONAL SAMPLE; SEXUAL TRAUMA; HEALTH-CARE; DISORDERS; OBESITY; QUESTIONNAIRE; OVERWEIGHT; APPRAISAL AB Objective: There is a dearth of research examining eating behaviors, such as binge eating, among male and female veterans. The present study evaluated the prevalence of self-reported eating problems as well as associations with body mass index and psychiatric disorders among male and female Iraq and Afghanistan veterans. Methods: Participants were 298 male and 364 female veterans (M = 33.3 +/- 10.6 years old) from the Women Veterans Cohort Study, a study of male and female veterans enrolled for Veterans Affairs care in New England or Indiana. Veterans self-reported on emotion-and stress-related eating, eating disorder diagnoses, and disordered eating behaviors. Diagnoses of post-traumatic stress disorder, major depressive disorder, and alcohol abuse were obtained from administrative records. Results: Female veterans reported higher rates of eating problems than did their male counterparts. Women and men who engage in disordered eating had higher rates of post-traumatic stress disorder and major depressive disorder, and women who engage in disordered eating had greater rates of alcohol abuse than did female veterans without eating disordered behaviors. Conclusions: Disordered eating may be a significant issue among Iraq and Afghanistan veterans, and veterans with eating problems are more likely to have comorbid mental health conditions that further increase their health risks. C1 [Slane, Jennifer D.; Borrero, Sonya] VA Pittsburgh Healthcare Syst, Res Off Bldg,Univ Dr C, Pittsburgh, PA 15240 USA. [Slane, Jennifer D.; Levine, Michele D.] Univ Pittsburgh, Dept Psychiat, Med Ctr, 3811 OHara St, Pittsburgh, PA 15213 USA. [Borrero, Sonya] Univ Pittsburgh, Dept Med, 230 McKee Pl, Pittsburgh, PA 15213 USA. [Mattocks, Kristin M.] VA Cent Western Massachusetts, 421 North Main St, Leeds, MA 01053 USA. [Mattocks, Kristin M.; Ozier, Amy D.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, 55 Lake Ave North, Worcester, MA 01655 USA. [Mattocks, Kristin M.; Ozier, Amy D.] Univ Massachusetts, Sch Med, Dept Psychiat, 55 Lake Ave North, Worcester, MA 01655 USA. [Ozier, Amy D.] Northern Illinois Univ, Sch Family Consumer & Nutr Sci, 118 Wirtz Hall, De Kalb, IL 60115 USA. [Silliker, Norman; Bathulapalli, Harini; Brandt, Cynthia; Haskell, Sally G.] VA Connecticut Healthcare Syst, 950 Campbell Ave, West Haven, CT 06516 USA. [Silliker, Norman; Bathulapalli, Harini; Brandt, Cynthia; Haskell, Sally G.] Yale Sch Med, 333 Cedar St, New Haven, CT 06510 USA. RP Slane, JD (reprint author), VA Pittsburgh Healthcare Syst, Res Off Bldg,Univ Dr C, Pittsburgh, PA 15240 USA.; Slane, JD (reprint author), Univ Pittsburgh, Dept Psychiat, Med Ctr, 3811 OHara St, Pittsburgh, PA 15213 USA. RI Bathulapalli, Harini/B-7451-2015 FU VA Health Services Research and Development [DHI 07-065] FX This research was supported by VA Health Services Research and Development, Project no. DHI 07-065-Women Veterans Cohort Study (2007-2012). NR 28 TC 0 Z9 0 U1 3 U2 3 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD NOV PY 2016 VL 181 IS 11 BP E1650 EP E1656 DI 10.7205/MILMED-D-15-00482 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA EL3DS UT WOS:000394500400028 PM 27849502 ER PT J AU Morales, ME Epstein, MH Marable, DE Oo, SA Berkowitz, SA AF Morales, Mary E. Epstein, Michael H. Marable, Danelle E. Oo, Sarah A. Berkowitz, Seth A. TI Food Insecurity and Cardiovascular Health in Pregnant Women: Results From the Food for Families Program, Chelsea, Massachusetts, 2013-2015 SO PREVENTING CHRONIC DISEASE LA English DT Article ID GLYCEMIC CONTROL; BLOOD-PRESSURE; PRIMARY-CARE; WEIGHT; STRESS; IMPACT AB Background Food insecurity, uncertainty about the ability to acquire adequate food, is associated with cardiometabolic disease in pregnant women. Whether food insecurity interventions improve cardiometabolic health is unknown. Methods We conducted a retrospective analysis of women who visited the obstetrics clinic in a community health center from 2013 through 2015. Patients could be referred to the Food for Families (Food for Families) program, which connects food insecure women to food resources. We hypothesized that participation in Food for Families would be associated with better blood pressure and blood glucose trends during pregnancy. We used a propensity score-matched design to reduce bias from differential entry into Food for Families. Results Eleven percent of women who visited the obstetrics clinic were referred to Food for Families. In propensity score-matched analyses, we found no difference in baseline systolic blood pressure (SBP) between those who were referred and enrolled in Food for Families (113.5 mm Hg), those who were referred and did not enroll in Food for Families (113.9 mm Hg), and those who were not referred to Food for Families (114 mm Hg) (P=.79). However, during pregnancy, women who were referred to and enrolled in Food for Families had a better SBP trend (0.2015 mm Hg/wk lower, P=.006). SBP trends did not differ between women who were referred and did not enroll in Food for Families and those who were not referred. We observed no differences in blood glucose trends between groups (P=.40). Conclusions Food for Families participation was associated with better blood pressure trends in pregnant women but no differences in blood glucose trends. Food insecurity reduction programs may improve cardiovascular health for vulnerable pregnant women, and this topic deserves further study incorporating randomized program entry. C1 [Morales, Mary E.] Harvard Med Sch, Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. [Epstein, Michael H.; Marable, Danelle E.] Massachusetts Gen Hosp, Ctr Community Hlth Improvement, Boston, MA 02114 USA. [Oo, Sarah A.] Massachusetts Gen Hosp, Chelsea HealthCare Ctr, Ctr Community Hlth Improvement, Chelsea, MA USA. [Berkowitz, Seth A.] Harvard Med Sch, Div Gen Internal Med, Boston, MA USA. [Berkowitz, Seth A.] Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. RP Berkowitz, SA (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA.; Berkowitz, SA (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Diabet Populat Hlth Res Ctr, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM SABerkowitz@partners.org FU Division of General Internal Medicine at Massachusetts General Hospital FX Mary E. Morales and Seth A. Berkowitz conceived the study and drafted the article. Michael Epstein, Sarah Oo, and Danelle Marable made substantial contributions to the design of the study and revised the article critically for important intellectual content. All authors gave final approval of the version to be published and agreed to accountability. An early version of these analyses was presented as a poster at the Massachusetts Medical Society symposium on December 4, 2015. This work is not under consideration for publication elsewhere. All authors declare that they have no conflicts of interest. Mary E. Morales and Seth A. Berkowitz were supported by the Division of General Internal Medicine at Massachusetts General Hospital. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of data; or preparation, review, or approval of the manuscript. NR 25 TC 0 Z9 0 U1 0 U2 0 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD NOV PY 2016 VL 13 AR 160212 DI 10.5888/pcd13.160212 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ3JU UT WOS:000393109300002 ER PT J AU Cheng, FX Murray, JL Rubin, DH AF Cheng, Feixiong Murray, James L. Rubin, Donald H. TI Drug Repurposing: New Treatments for Zika Virus infection? SO TRENDS IN MOLECULAR MEDICINE LA English DT Editorial Material ID INHIBITORS; TARGETS; SCREEN AB To date, no antiviral agents have been approved for treating Zika virus (ZIKV) infection. Two recent drug-repurposing studies published in Cell Host & Microbe and Nature Medicine demonstrated that screening FDA-approved drugs for antiviral activity is a promising strategy for identifying therapeutics with novel activity against ZIKV infection. C1 [Cheng, Feixiong] Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA. [Cheng, Feixiong] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA. [Murray, James L.] GeneTAG Technol Inc, Atlanta, GA 30340 USA. [Rubin, Donald H.] Vanderbilt Univ, Sch Med, Dept Med, Div Infect Dis, Nashville, TN 37232 USA. [Rubin, Donald H.] Vanderbilt Univ, Sch Med, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA. [Rubin, Donald H.] VA Tennessee Valley Healthcare Syst, Res Med, Nashville, TN 37212 USA. RP Cheng, FX (reprint author), Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA.; Cheng, FX (reprint author), Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA. EM fxcheng1988@gmail.com NR 9 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 1471-4914 EI 1471-499X J9 TRENDS MOL MED JI Trends Mol. Med PD NOV PY 2016 VL 22 IS 11 BP 919 EP 921 DI 10.1016/j.molmed.2016.09.006 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA EK8RF UT WOS:000394190600001 PM 27692879 ER PT J AU Rempell, JS Saldana, F DiSalvo, D Kumar, N Stone, MB Chan, W Luz, J Noble, VE Liteplo, A Kimberly, H Kohler, MJ AF Rempell, Joshua S. Saldana, Fidencio DiSalvo, Donald Kumar, Navin Stone, Michael B. Chan, Wilma Luz, Jennifer Noble, Vicki E. Liteplo, Andrew Kimberly, Heidi Kohler, Minna J. TI Pilot Point-of-Care Ultrasound Curriculum at Harvard Medical School: Early Experience SO WESTERN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID HAND-CARRIED ULTRASOUND; TEACHING PHYSICAL-EXAMINATION; STUDENTS; EDUCATION; ULTRASONOGRAPHY; SONOGRAPHY; PROGRAM AB Introduction: Point-of-care ultrasound (POCUS) is expanding across all medical specialties. As the benefits of US technology are becoming apparent, efforts to integrate US into pre-clinical medical education are growing. Our objective was to describe our process of integrating POCUS as an educational tool into the medical school curriculum and how such efforts are perceived by students. Methods: This was a pilot study to introduce ultrasonography into the Harvard Medical School curriculum to first-and second-year medical students. Didactic and hands-on sessions were introduced to first-year students during gross anatomy and to second-year students in the physical exam course. Student-perceived attitudes, understanding, and knowledge of US, and its applications to learning the physical exam, were measured by a post-assessment survey. Results: All first-year anatomy students (n=176) participated in small group hands-on US sessions. In the second-year physical diagnosis course, 38 students participated in four sessions. All students (91%) agreed or strongly agreed that additional US teaching should be incorporated throughout the four-year medical school curriculum. Conclusion: POCUS can effectively be integrated into the existing medical school curriculum by using didactic and small group hands-on sessions. Medical students perceived US training as valuable in understanding human anatomy and in learning physical exam skills. This innovative program demonstrates US as an additional learning modality. Future goals include expanding on this work to incorporate US education into all four years of medical school. C1 [Rempell, Joshua S.; Saldana, Fidencio; DiSalvo, Donald; Kumar, Navin; Stone, Michael B.; Chan, Wilma; Luz, Jennifer; Noble, Vicki E.; Liteplo, Andrew; Kimberly, Heidi] Harvard Med Sch, Boston, MA USA. [Rempell, Joshua S.; Stone, Michael B.; Chan, Wilma; Kimberly, Heidi] Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. [Saldana, Fidencio] Brigham & Womens Hosp, Dept Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Kumar, Navin] Brigham & Womens Hosp, Dept Internal Med, 75 Francis St, Boston, MA 02115 USA. [DiSalvo, Donald] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Luz, Jennifer] Harvard Med Sch, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Charlestown, MA USA. [Noble, Vicki E.; Liteplo, Andrew] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Kohler, Minna J.] Harvard Med Sch, Div Rheumatol, Dept Med, Allergy,Immunol, Boston, MA USA. RP Rempell, JS (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. EM jrempell@partners.org FU Academy of Harvard Medical School FX The authors thank Trudy Van Houten, PhD, Cynthia McDermott, PhD, (referred to as TV and CM in manuscript), and Evan Sanders for their organizational assistance with the anatomy ultrasound sessions, Sara Durfee, MD, for instructional and curriculum contributions in the physical diagnosis course, and the resident/fellow instructors from emergency medicine, radiology, internal medicine, pediatrics, physical medicine and rehabilitation, and rheumatology. We also thank Edward Hundert, MD, Dean for Medical Education, Harvard Medical School, for his continued mentorship and support of this effort. The primary author also thanks the Academy of Harvard Medical School for fellowship support during development of this project. NR 23 TC 1 Z9 1 U1 0 U2 0 PU WESTJEM PI ORANGE PA C/O SHAHRAM LOTFIPOUR, MD, MPH, 333 CITY BLVD W STE 640, RT 128-01, ORANGE, CA 92868 USA SN 1936-900X EI 1936-9018 J9 WEST J EMERG MED JI West. J. Emerg. Med. PD NOV PY 2016 VL 17 IS 6 BP 734 EP 740 DI 10.5811/westjem.2016.8.31387 PG 7 WC Emergency Medicine SC Emergency Medicine GA EL1ER UT WOS:000394363800012 PM 27833681 ER PT J AU Gane, EJ Kowdley, KV Pound, D Stedman, CAM Davis, M Etzkorn, K Gordon, SC Bernstein, D Everson, G Rodriguez-Torres, M Tsai, N Khalid, O Yang, JC Lu, S Dvory-Sobol, H Stamm, LM Brainard, DM McHutchison, JG Tong, M Chung, RT Beavers, K Poulos, JE Kwo, PY Nguyen, MH AF Gane, Edward J. Kowdley, Kris V. Pound, David Stedman, Catherine A. M. Davis, Mitchell Etzkorn, Kyle Gordon, Stuart C. Bernstein, David Everson, Gregory Rodriguez-Torres, Maribel Tsai, Naoky Khalid, Omer Yang, Jenny C. Lu, Sophia Dvory-Sobol, Hadas Stamm, Luisa M. Brainard, Diana M. McHutchison, John G. Tong, Myron Chung, Raymond T. Beavers, Kimberly Poulos, John E. Kwo, Paul Y. Nguyen, Mindie H. TI Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients With Hepatitis C Virus Genotype 2, 3, 4, or 6 Infections in an Open-Label, Phase 2 Trial SO GASTROENTEROLOGY LA English DT Article DE Clinical Trial; Direct-Acting Antiviral; DAA; Non-Genotype 1 HCV ID PROTEASE INHIBITOR GS-9857; HCV AB BACKGROUND & AIMS: Studies are needed to determine the optimal regimen for patients with chronic hepatitis C virus (HCV) genotype 2, 3, 4, or 6 infections whose prior course of antiviral therapy has failed, and the feasibility of shortening treatment duration. We performed a phase 2 study to determine the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in these patients. METHODS: We performed a multicenter, open-label trial at 32 sites in the United States and 2 sites in New Zealand from March 3, 2015 to April 27, 2015. Our study included 128 treatment-naive and treatment-experienced patients (1 with HCV genotype 1b; 33 with HCV genotype 2; 74 with HCV genotype 3; 17 with genotype HCV 4; and 3 with HCV genotype 6), with or without compensated cirrhosis. All patients received sofosbuvir-velpatasvir (400 mg/100 mg fixed-dose combination tablet) and GS-9857 (100 mg) once daily for 6-12 weeks. The primary end point was sustained virologic response 12 weeks after treatment (SVR12). RESULTS: After 6 weeks of treatment, SVR12s were achieved by 88% of treatment-naive patients without cirrhosis (29 of 33; 95% confidence interval, 72%-97%). After 8 weeks of treatment, SVR12s were achieved by 93% of treatment-naive patients with cirrhosis (28 of 30; 95% CI, 78%-99%). After 12 weeks of treatment, SVR12s were achieved by all treatment experienced patients without cirrhosis (36 of 36; 95% CI, 90%-100%) and 97% of treatment-experienced patients with cirrhosis (28 of 29; 95% CI, 82%-100%). The most common adverse events were headache, diarrhea, fatigue, and nausea. Three patients (1%) discontinued treatment due to adverse events. CONCLUSIONS: In a phase 2 open-label trial, we found sofosbuvir-velpatasvir plus GS-9857 (8 weeks in treatment-naive patients or 12 weeks in treatment-experienced patients) to be safe and effective for patients with HCV genotype 2, 3, 4, or 6 infections, with or without compensated cirrhosis. C1 [Gane, Edward J.] Auckland Clin Studies, Auckland, New Zealand. [Kowdley, Kris V.] Swedish Med Ctr, Seattle, WA USA. [Pound, David] Indianapolis Gastroenterol Res Fdn, Indianapolis, IN USA. [Stedman, Catherine A. M.] Christchurch Hosp, Christchurch, New Zealand. [Stedman, Catherine A. M.] Univ Otago, Christchurch, New Zealand. [Davis, Mitchell] South Florida Ctr Gastroenterol, Digest CARE, Wellington, FL USA. [Etzkorn, Kyle] Borland Groover Clin, Jacksonville, MS USA. [Gordon, Stuart C.] Henry Ford Hosp & Hlth Syst, Detroit, MI USA. [Bernstein, David] North Shore Long Isl Jewish PRIME, Manhasset, NY USA. [Everson, Gregory] Univ Colorado, Aurora, CO USA. [Rodriguez-Torres, Maribel] Fdn Invest De Diego, San Juan, PR USA. [Tsai, Naoky] Queens Liver Ctr, Honolulu, HI USA. [Khalid, Omer] Digest Hlth Specialists, Winston Salem, NC USA. [Yang, Jenny C.; Lu, Sophia; Dvory-Sobol, Hadas; Stamm, Luisa M.; Brainard, Diana M.; McHutchison, John G.] Gilead Sci, Foster City, CA USA. [Tong, Myron] Huntington Med Res Inst, Liver Ctr, Pasadena, CA USA. [Chung, Raymond T.] Massachusetts Gen Hosp, Boston, MA USA. [Beavers, Kimberly] Med Univ South Carolina, Charleston, SC 29425 USA. [Poulos, John E.] Cumberland Res Associates LLC, Fayetteville, GA USA. [Kwo, Paul Y.] Indiana Univ Sch Med, Indianapolis, IN USA. [Nguyen, Mindie H.] Stanford Univ, Med Ctr, Palo Alto, CA 94304 USA. RP Gane, EJ (reprint author), Auckland City Hosp, New Zealand Liver Transplant Unit, Private Bag 1142, Auckland, New Zealand. EM edgane@adhb.govt.nz FU Gilead Sciences FX This study was sponsored by Gilead Sciences. NR 21 TC 2 Z9 2 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 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD NOV PY 2016 VL 151 IS 5 BP 902 EP 909 DI 10.1053/j.gastro.2016.07.038 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EG3OM UT WOS:000390954600030 PM 27486033 ER PT J AU Armand, P Shipp, MA Ribrag, V Michot, JM Zinzani, PL Kuruvilla, J Snyder, ES Ricart, AD Balakumaran, A Rose, S Moskowitz, CH AF Armand, Philippe Shipp, Margaret A. Ribrag, Vincent Michot, Jean-Marie Zinzani, Pier Luigi Kuruvilla, John Snyder, Ellen S. Ricart, Alejandro D. Balakumaran, Arun Rose, Shelonitda Moskowitz, Craig H. TI Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID STEM-CELL TRANSPLANTATION; CANCER; SAFETY; PD-1; ANTIBODY; TRIAL; PIDILIZUMAB; INTERFERON; TOLERANCE AB Purpose Classical Hodgkin lymphoma (HL) frequently exhibits genetic alterations leading to overexpression of the programmed death-1 (PD-1) ligands, suggesting a possible vulnerability to PD-1 blockade. The phase Ib study KEYNOTE-013 (NCT01953692) tested the safety and efficacy of the anti-PD-1 antibody pembrolizumab in patients with hematologic malignancies. Based on its genetics, HL was included as an independent cohort. Methods We enrolled patients with relapsed or refractory HL whose disease progressed on or after treatment with brentuximab vedotin. Patients received pembrolizumab, 10 mg/kg every 2 weeks, until disease progression occurred. Response to treatment was assessed at week 12 and every 8 weeks thereafter. Principal end points were safety and complete remission (CR) rate. Results Thirty-one patients were enrolled; 55% had more than four lines of prior therapy, and 71% had relapsed after autologous stem cell transplantation. Five patients (16%) experienced grade 3 drug-related adverse events (AEs); there were no grade 4 AEs or deaths related to treatment. The CR rate was 16% (90% CI, 7% to 31%). In addition, 48% of patients achieved a partial remission, for an overall response rate of 65% (90% CI, 48% to 79%). Most of the responses (70%) lasted longer than 24 weeks (range, 0.14+ to 74+ weeks), with a median follow-up of 17 months. The progression-free survival rate was 69% at 24 weeks and 46% at 52 weeks. Biomarker analyses demonstrated a high prevalence of PD-L1 and PD-L2 expression, treatment-induced expansion of T cells and natural killer cells, and activation of interferon-g, T-cell receptor, and expanded immune-related signaling pathways. Conclusions Pembrolizumab was associated with a favorable safety profile. Pembrolizumab treatment induced favorable responses in a heavily pretreated patient cohort, justifying further studies. (C) 2016 by American Society of Clinical Oncology C1 [Armand, Philippe; Shipp, Margaret A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ribrag, Vincent; Michot, Jean-Marie] Inst Gustave Roussy, Villejuif, France. [Zinzani, Pier Luigi] Univ Bologna, Inst Hematol Seragnoli, Bologna, Italy. [Kuruvilla, John] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Kuruvilla, John] Univ Toronto, Toronto, ON, Canada. [Snyder, Ellen S.; Ricart, Alejandro D.; Balakumaran, Arun; Rose, Shelonitda] Merck, Kenilworth, NJ USA. [Moskowitz, Craig H.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA. RP Moskowitz, CH (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA. EM moskowic@mskcc.org FU MSK Cancer Center Support Grant [P30 CA008748]; Merck FX C.H.M. received an MSK Cancer Center Support Grant/Core Grant (P30 CA008748).; Funded by Merck. NR 24 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 1 PY 2016 VL 34 IS 31 BP 3733 EP + DI 10.1200/JCO.2016.67.3467 PG 9 WC Oncology SC Oncology GA ED5WP UT WOS:000388923800006 ER PT J AU Osarogiagbon, RU Rodriguez, HP Hicks, D Signore, RS Roark, K Kedia, SK Ward, KD Lathan, C Santarella, S Gould, MK Krasna, MJ AF Osarogiagbon, Raymond U. Rodriguez, Hector P. Hicks, Danielle Signore, Raymond S. Roark, Kristi Kedia, Satish K. Ward, Kenneth D. Lathan, Christopher Santarella, Scott Gould, Michael K. Krasna, Mark J. TI Deploying Team Science Principles to Optimize Interdisciplinary Lung Cancer Care Delivery: Avoiding the Long and Winding Road to Optimal Care SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Article ID PERFORMANCE AB The complexity of lung cancer care mandates interaction between clinicians with different skill sets and practice cultures in the routine delivery of care. Using team science principles and a case-based approach, we exemplify the need for the development of real care teams for patients with lung cancer to foster coordination among the multiple specialists and staff engaged in routine care delivery. Achieving coordinated lung cancer care is a high-priority public health challenge because of the volume of patients, lethality of disease, and well-described disparities in quality and outcomes of care. Coordinating mechanisms need to be cultivated among different types of specialist physicians and care teams, with differing technical expertise and practice cultures, who have traditionally functioned more as coactively working groups than as real teams. Coordinating mechanisms, including shared mental models, high-quality communication, mutual trust, and mutual performance monitoring, highlight the challenge of achieving well-coordinated care and illustrate how team science principles can be used to improve quality and outcomes of lung cancer care. To develop the evidence base to support coordinated lung cancer care, research comparing the effectiveness of a diverse range of multidisciplinary care team approaches and interorganizational coordinating mechanisms should be promoted. C1 Univ Memphis, Multidisciplinary Thorac Oncol Program, Baptist Canc Ctr, Sch Publ Hlth, Memphis, TN 38152 USA. Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. Kaiser Permanente Southern Calif, Bonnie J Addario Lung Canc Fdn, Pasadena, CA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Meridian Canc Care, Neptune, NJ USA. Rutgers Med Sch, Neptune, NJ USA. RP Osarogiagbon, RU (reprint author), Baptist Canc Ctr, Thorac Oncol Res Grp, Multidisciplinary Thorac Oncol Program, 80 Humphreys Ctr Dr,Ste 220, Memphis, TN 38120 USA. EM rosarogi@bmhcc.org FU Conquer Cancer Foundation Mission Endowment; Patient-Centered Outcomes Research Institute (PCORI) Award [IH-1304-6147] FX The production of this manuscript was funded by the Conquer Cancer Foundation Mission Endowment. Supported, in part, through a Patient-Centered Outcomes Research Institute (PCORI) Award (No. IH-1304-6147). All statements in this report, including its findings and conclusions, are solely those of the authors and do not necessarily represent the views of the PCORI or its Board of Governors or Methodology Committee. NR 37 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD NOV PY 2016 VL 12 IS 11 BP 983 EP + DI 10.1200/JOP.2016.013813 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EI3HS UT WOS:000392381400006 PM 27650844 ER PT J AU Campbell, JP Kalpathy-Cramer, J Erdogmus, D Tian, P Kedarisetti, D Moleta, C Reynolds, JD Hutcheson, K Shapiro, MJ Repka, MX Ferrone, P Drenser, K Horowitz, J Sonmez, K Swan, R Ostmo, S Jonas, KE Chan, RVP Chiang, MF AF Campbell, J. Peter Kalpathy-Cramer, Jayashree Erdogmus, Deniz Tian, Peng Kedarisetti, Dharanish Moleta, Chace Reynolds, James D. Hutcheson, Kelly Shapiro, Michael J. Repka, Michael X. Ferrone, Philip Drenser, Kimberly Horowitz, Jason Sonmez, Kemal Swan, Ryan Ostmo, Susan Jonas, Karyn E. Chan, R. V. Paul Chiang, Michael F. CA Imaging Informatics Retinopathy TI Plus Disease in Retinopathy of Prematurity A Continuous Spectrum of Vascular Abnormality as a Basis of Diagnostic Variability SO OPHTHALMOLOGY LA English DT Article ID ACUTE-PHASE RETINOPATHY; EXPERT DIAGNOSIS; IMAGE-ANALYSIS; INTEREXPERT AGREEMENT; TELEMEDICINE; ACCURACY; TORTUOSITY; FELLOWS; OPHTHALMOLOGY; RELIABILITY AB Purpose: To identify patterns of interexpert discrepancy in plus disease diagnosis in retinopathy of prematurity (ROP). Design: We developed 2 datasets of clinical images as part of the Imaging and Informatics in ROP study and determined a consensus reference standard diagnosis (RSD) for each image based on 3 independent image graders and the clinical examination results. We recruited 8 expert ROP clinicians to classify these images and compared the distribution of classifications between experts and the RSD. Participants: Eight participating experts with more than 10 years of clinical ROP experience and more than 5 peer-reviewed ROP publications who analyzed images obtained during routine ROP screening in neonatal intensive care units. Methods: Expert classification of images of plus disease in ROP. Main Outcome Measures: Interexpert agreement (weighted kappa statistic) and agreement and bias on ordinal classification between experts (analysis of variance [ANOVA]) and the RSD (percent agreement). Results: There was variable interexpert agreement on diagnostic classifications between the 8 experts and the RSD (weighted k, 0-0.75; mean, 0.30). The RSD agreement ranged from 80% to 94% for the dataset of 100 images and from 29% to 79% for the dataset of 34 images. However, when images were ranked in order of disease severity (by average expert classification), the pattern of expert classification revealed a consistent systematic bias for each expert consistent with unique cut points for the diagnosis of plus disease and preplus disease. The 2-way ANOVA model suggested a highly significant effect of both image and user on the average score (dataset A: P < 0.05 and adjusted R-2 = 0.82; and dataset B: P < 0.05 and adjusted R-2 = 0.6615). Conclusions: There is wide variability in the classification of plus disease by ROP experts, which occurs because experts have different cut points for the amounts of vascular abnormality required for presence of plus and preplus disease. This has important implications for research, teaching, and patient care for ROP and suggests that a continuous ROP plus disease severity score may reflect more accurately the behavior of expert ROP clinicians and may better standardize classification in the future. (C) 2016 by the American Academy of Ophthalmology C1 [Campbell, J. Peter; Moleta, Chace; Ostmo, Susan; Chiang, Michael F.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Casey Eye Inst, Portland, OR 97201 USA. [Kalpathy-Cramer, Jayashree] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Erdogmus, Deniz; Tian, Peng; Kedarisetti, Dharanish] Northeastern Univ, Cognit Syst Lab, Boston, MA 02115 USA. [Reynolds, James D.] SUNY Buffalo, Dept Ophthalmol, Ross Eye Inst, Buffalo, NY USA. [Hutcheson, Kelly] Sidra Med & Res Ctr, Dept Ophthalmol, Doha, Qatar. [Shapiro, Michael J.] Retina Consultants, Chicago, IL USA. [Repka, Michael X.] Johns Hopkins Univ, Sch Med, Wilmer Inst, Baltimore, MD 21205 USA. [Ferrone, Philip] Long Isl Vitreoretinal Consultants, Great Neck, NY USA. [Drenser, Kimberly] Oakland Univ, Associated Retinal Consultants, Royal Oak, MI USA. [Horowitz, Jason] Columbia Univ, Dept Ophthalmol, New York, NY 10027 USA. [Sonmez, Kemal; Swan, Ryan; Chiang, Michael F.] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Portland, OR 97201 USA. [Jonas, Karyn E.; Chan, R. V. Paul] Univ Illinois, Illinois Eye & Ear Infirm, Dept Ophthalmol & Visual Sci, Chicago, IL USA. RP Chiang, MF (reprint author), Oregon Hlth & Sci Univ, Dept Ophthalmol, 3375 SW Terwilliger Blvd, Portland, OR 97239 USA.; Chiang, MF (reprint author), Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, 3375 SW Terwilliger Blvd, Portland, OR 97239 USA. EM chiangm@ohsu.edu OI Jonas, Karyn /0000-0001-9038-6979 FU National Institutes of Health, Bethesda, Maryland [R01 EY19474, P30 EY010572, R21 EY022387, T32 EY23211]; National Center for Advancing Translational Sciences at the National Institutes of Health, Bethesda, MD (Oregon Clinical and Translational Research Institute grant) [TL1TR000129]; Research to Prevent Blindness, New York, New York; iNsight Foundation, New York, NY FX Supported by the National Institutes of Health, Bethesda, Maryland (grant nos.: R01 EY19474 [J.K.C., D.E., S.O., K.E.J., R.V.P.C., M.F.C.], P30 EY010572 [J.P.C., S.O., M.F.C.], R21 EY022387 (J.K.C., D.E., M.F.C.], and T32 EY23211 (M.F.C., R.S.); the National Center for Advancing Translational Sciences at the National Institutes of Health, Bethesda, MD (Oregon Clinical and Translational Research Institute grant no.: TL1TR000129); Research to Prevent Blindness, New York, New York (J.P.C., S.N.P., J.D.R., M.X.R., S.O., K.E.J., R.V.P.C., M.F.C.); and the iNsight Foundation, New York, NY (R.V.P.C., K.E.J.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. No funding organizations had any role in the design or conduct of this research. Dr. Michael F. Chiang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 46 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 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD NOV PY 2016 VL 123 IS 11 BP 2338 EP 2344 DI 10.1016/j.ophtha.2016.07.026 PG 7 WC Ophthalmology SC Ophthalmology GA EE3QK UT WOS:000389509500018 PM 27591053 ER PT J AU Brama, H Goldental, A Vardi, R Stern, EA Kanter, I AF Brama, H. Goldental, A. Vardi, R. Stern, E. A. Kanter, I. TI Hours of high-frequency stimulations reveal intracellular neuronal trends in vivo SO EPL LA English DT Article ID NETWORK ACTIVITY; CORTEX; VARIABILITY; PRECISION; SPIKING; SYNCHRONIZATION; PROPAGATION; INHIBITION; EXCITATION; SYNAPSES AB The neuronal response to controlled stimulations in vivo has been classically estimated using a limited number of events. Here we show that hours of high-frequency stimulations and recordings of neurons in vivo reveal previously unknown response phases of neurons in the intact brain. Results indicate that for stimulation frequencies below a critical neuronal characteristic frequency, f(c), response timings are stabilized to tens-of-microseconds accuracy. For stimulation frequencies exceeding f(c) the firing frequency is saturated and independent of the stimulation frequency, as a result of random neuronal response failures. This neuronal plasticity, previously shown in vitro, supports a robust mechanism for low firing rates on a network level. Copyright (C) EPLA, 2016 C1 [Brama, H.; Vardi, R.; Stern, E. A.; Kanter, I.] Bar Ilan Univ, Gonda Multidisciplinary Brain Res Ctr, IL-52900 Ramat Gan, Israel. [Brama, H.; Vardi, R.; Stern, E. A.; Kanter, I.] Bar Ilan Univ, Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel. [Goldental, A.; Vardi, R.; Kanter, I.] Bar Ilan Univ, Dept Phys, IL-52900 Ramat Gan, Israel. [Stern, E. A.] Massachusetts Gen Hosp, Dept Neurol, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02119 USA. RP Kanter, I (reprint author), Bar Ilan Univ, Gonda Multidisciplinary Brain Res Ctr, IL-52900 Ramat Gan, Israel.; Kanter, I (reprint author), Bar Ilan Univ, Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel.; Kanter, I (reprint author), Bar Ilan Univ, Dept Phys, IL-52900 Ramat Gan, Israel. EM Ido.kanter@biu.ac.il NR 28 TC 0 Z9 0 U1 1 U2 1 PU EPL ASSOCIATION, EUROPEAN PHYSICAL SOCIETY PI MULHOUSE PA 6 RUE DES FRERES LUMIERE, MULHOUSE, 68200, FRANCE SN 0295-5075 EI 1286-4854 J9 EPL-EUROPHYS LETT JI EPL PD NOV PY 2016 VL 116 IS 4 AR 46002 DI 10.1209/0295-5075/116/46002 PG 7 WC Physics, Multidisciplinary SC Physics GA EJ1HN UT WOS:000392961200020 ER PT J AU Wisco, BE Marx, BP Miller, MW Wolf, EJ Mota, NP Krystal, JH Southwick, SM Pietrzak, RH AF Wisco, Blair E. Marx, Brian P. Miller, Mark W. Wolf, Erika J. Mota, Natalie P. Krystal, John H. Southwick, Steven M. Pietrzak, Robert H. TI Probable Posttraumatic Stress Disorder in the US Veteran Population According to DSM-5: Results From the National Health and Resilience in Veterans Study SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID MENTAL-DISORDERS; PTSD CHECKLIST; PREVALENCE; IV; CRITERIA; CLASSIFICATION; AFGHANISTAN; VALIDATION; DEPRESSION; PROPOSALS AB Objective: With the publication of DSM-5, important changes were made to the diagnostic criteria for posttraumatic stress disorder (PTSD), including the addition of 3 new symptoms. Some have argued that these changes will further increase the already high rates of comorbidity between PTSD and other psychiatric disorders. This study examined the prevalence of DSM-5 PTSD, conditional probability of PTSD given certain trauma exposures, endorsement of specific PTSD symptoms, and psychiatric comorbidities in the US veteran population. Methods: Data were analyzed from the National Health and Resilience in Veterans Study (NHRVS), a Web-based survey of a cross-sectional, nationally representative, population-based sample of 1,484 US veterans, which was fielded from September through October 2013. Probable PTSD was assessed using the PTSD Checklist-5. Results: The weighted lifetime and past-month prevalence of probable DSM-5 PTSD was 8.1% (SE = 0.7%) and 4.7% (SE = 0.6%), respectively. Conditional probability of lifetime probable PTSD ranged from 10.1% (sudden death of close family member or friend) to 28.0% (childhood sexual abuse). The DSM-5 PTSD symptoms with the lowest prevalence among veterans with probable PTSD were trauma-related amnesia and reckless and self-destructive behavior. Probable PTSD was associated with increased odds of mood and anxiety disorders (OR = 7.6-62.8, P < .001), substance use disorders (OR = 3.9-4.5, P < .001), and suicidal behaviors (OR = 6.7-15.1, P < .001). Conclusions: In US veterans, the prevalence of DSM-5 probable PTSD, conditional probability of probable PTSD, and odds of psychiatric comorbidity were similar to prior findings with DSM-IV-based measures; we found no evidence that changes in DSM-5 increase psychiatric comorbidity. Results underscore the high rates of exposure to both military and nonmilitary trauma and the high public health burden of DSM-5 PTSD and comorbid conditions in veterans. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Wisco, Blair E.] Univ North Carolina Greensboro, Dept Psychol, POB 26170, Greensboro, NC 27402 USA. [Marx, Brian P.; Miller, Mark W.; Wolf, Erika J.] Boston Univ, Sch Med, Natl Ctr PTSD, VA Boston Healthcare Syst, Boston, MA 02215 USA. [Marx, Brian P.; Miller, Mark W.; Wolf, Erika J.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Mota, Natalie P.; Krystal, John H.; Southwick, Steven M.; Pietrzak, Robert H.] Yale Univ, Sch Med, Natl Ctr PTSD, VA Connecticut Healthcare Syst, New Haven, CT USA. [Mota, Natalie P.; Krystal, John H.; Southwick, Steven M.; Pietrzak, Robert H.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. RP Wisco, BE (reprint author), Univ North Carolina Greensboro, Dept Psychol, POB 26170, Greensboro, NC 27402 USA. EM bewisco@uncg.edu FU US Department of Veterans Affairs National Center for Posttraumatic Stress Disorder; National Institute of Mental Health [1R01MH095737-01A1]; Department of Defense [W81XVVH-10-2-0181, W81XWH-12-2-0117-PTSD-IIRA-INT]; Defense Advanced Research Programs Agency [N66001-11-C-4006]; Department of Veterans Affairs (Cooperative Studies Program) [591]; Career Development Award from the United States (U.S.) Department of Veterans Affairs, Clinical Sciences Research and Development Program FX This study was funded by the US Department of Veterans Affairs National Center for Posttraumatic Stress Disorder and a private donation. Dr Marx was supported by funding from the National Institute of Mental Health (1R01MH095737-01A1), Department of Defense (W81XVVH-10-2-0181, W81XWH-12-2-0117-PTSD-IIRA-INT), Defense Advanced Research Programs Agency (N66001-11-C-4006), and Department of Veterans Affairs (Cooperative Studies Program # 591). This work was also supported by a Career Development Award to Dr Wolf from the United States (U.S.) Department of Veterans Affairs, Clinical Sciences Research and Development Program. NR 32 TC 1 Z9 1 U1 4 U2 4 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 NOV PY 2016 VL 77 IS 11 BP 1503 EP 1510 DI 10.4088/JCP.15m10188 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EJ2DY UT WOS:000393021300013 PM 27631148 ER PT J AU Afinogenova, Y Schmelkin, C Plessow, F Thomas, JJ Pulumo, R Micali, N Miller, KK Eddy, KT Lawson, EA AF Afinogenova, Yuliya Schmelkin, Cindy Plessow, Franziska Thomas, Jennifer J. Pulumo, Reitumetse Micali, Nadia Miller, Karen K. Eddy, Kamryn T. Lawson, Elizabeth A. TI Low Fasting Oxytocin Levels Are Associated With Psychopathology in Anorexia Nervosa in Partial Recovery SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID QUESTIONNAIRE EDE-Q; DISORDERED EATING PSYCHOPATHOLOGY; DEPRESSIVE SYMPTOMS; INTRANASAL OXYTOCIN; DEFICIENT MICE; MALE-RATS; Q NORMS; ANXIETY; WOMEN; BEHAVIOR AB Objective: Anorexia nervosa (AN), a psychiatric disorder characterized by restriction of food intake despite severe weight loss, is associated with increased comorbid anxiety and depression. Secretion of oxytocin, an appetite-regulating neurohormone with anxiolytic and antidepressant properties, is abnormal in AN. The link between oxytocin levels and psychopathology in AN has not been well explored. Methods: We performed a cross-sectional study of 79 women aged 18-45 years (19 AN, 26 AN in partial recovery [ANPR], and 34 healthy controls [HC]) investigating the relationship between basal oxytocin levels and disordered eating psychopathology, anxiety, and depressive symptoms. AN diagnoses were based on DSM-5 criteria. Data acquisition took place between December 2008 and March 2014. Fasting serum oxytocin levels were obtained, and the following selfreport measures were used to assess psychopathology: Eating Disorder Examination Questionnaire, State-Trait Anxiety Inventory, and Beck Depression Inventory-II. Results: Fasting oxytocin levels were low in ANPR compared to HC (P =.0004). In ANPR but not AN, oxytocin was negatively associated with disordered eating psychopathology (r = -0.39, P =.0496) and anxiety symptoms (state anxiety: r = -0.53, P =.006; trait anxiety: r = -0.49, P =.01). Furthermore, ANPR with significant disordered eating psychopathology, anxiety symptoms, or depressive symptoms had lower oxytocin levels compared to those with minimal or no symptoms (P =.04,.02, and.007, respectively). Conclusions: We speculate that a dysregulation of oxytocin pathways may contribute to persistent psychopathology after partial weight recovery from anorexia nervosa. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Afinogenova, Yuliya; Schmelkin, Cindy; Plessow, Franziska; Pulumo, Reitumetse; Miller, Karen K.; Lawson, Elizabeth A.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Afinogenova, Yuliya; Schmelkin, Cindy; Plessow, Franziska; Thomas, Jennifer J.; Pulumo, Reitumetse; Miller, Karen K.; Eddy, Kamryn T.; Lawson, Elizabeth A.] Harvard Med Sch, Boston, MA USA. [Thomas, Jennifer J.; Eddy, Kamryn T.] Massachusetts Gen Hosp, Dept Psychiat, Eating Disorders Clin & Res Program, Boston, MA 02114 USA. [Micali, Nadia] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Micali, Nadia] UCL Inst Child Hlth, Behav & Brain Sci Unit, London, England. RP Lawson, EA (reprint author), Harvard Med Sch, Med, Bulfinch 457-D, Boston, MA 02114 USA.; Lawson, EA (reprint author), Massachusetts Gen Hosp, Interdisciplinary Oxytocin Res Program, Neuroendocrine Unit, Bulfinch 457-D, Boston, MA 02114 USA. EM ealawson@partners.org FU National Institutes of Health [P30 DK40561, UL1 RR025758, K23 MH092560] FX The study was supported by National Institutes of Health grants P30 DK40561, UL1 RR025758, and K23 MH092560. NR 53 TC 0 Z9 0 U1 2 U2 2 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD NOV PY 2016 VL 77 IS 11 BP E1483 EP E1490 DI 10.4088/JCP.15m10217 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EJ2DY UT WOS:000393021300008 PM 28076675 ER PT J AU Back, SE McCauley, JL Korte, KJ Gros, DF Leavitt, V Gray, KM Hamner, MB DeSantis, SM Malcolm, R Brady, KT Kalivas, PW AF Back, Sudie E. McCauley, Jenna L. Korte, Kristina J. Gros, Daniel F. Leavitt, Virginia Gray, Kevin M. Hamner, Mark B. DeSantis, Stacia M. Malcolm, Robert Brady, Kathleen T. Kalivas, Peter W. TI A double-Blind, Randomized,Controlled pilot Trial of N-Acetylcysteine in Veterans With Posttraumatic Stress Disorder and Substance Use Disorders SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; COMORBID ALCOHOL DEPENDENCE; FUNCTIONAL CONNECTIVITY; DSM-IV; PTSD; ADDICTION; STATE; MECHANISMS; PLACEBO; MINI AB Objective:The antioxidant N-acetylcysteine is being increasingly investigated as a therapeutic agent in the treatment of substance use disorders (SUDs). This study explored the efficacy of N-acetylcysteine in the treatment of posttraumatic stress disorder (PTSD), which frequently co-occurs with SUD and shares impaired prefrontal cortex regulation of basal ganglia circuitry, in particular at glutamate synapses in the nucleus accumbens. Methods: Veterans with PTSD and SUD per D5M-IV/criteria (N=35) were randomly assigned to receive a double-blind, 8-week course of N-acetylcysteine (2,400 mg/d) or placebo plus cognitive-behavioral therapy for SUD (between March 2013 and April 2014). Primary outcome measures included PTSD symptoms (Clinician-Administered PTSD Scale, PTSD Checklist-Military) and craving (Visual Analog Scale). Substance use and depression were also assessed. Results: Participants treated with N-acetylcysteine compared to placebo evidenced significant improvements in PTSD symptoms, craving, and depression (p values< 0.33; P values <.05). Substance use was low for both groups, and no significant between-group differences were observed. N-acetylcysteine was well tolerated, and retention was high. Conclusions:This is the first randomized controlled trial to investigate N-acetylcysteine as a pharrnacologic treatment for PTSD and SUD. Although preliminary, the findings provide initial support for the use of N-acetylcysteine in combination with psychotherapy among individuals with co-occurring PTSD and SUD. (C) Copyright 2016 Physicians Postgraduate Press,inc. C1 [Back, Sudie E.; McCauley, Jenna L.; Korte, Kristina J.; Gros, Daniel F.; Leavitt, Virginia; Gray, Kevin M.; Hamner, Mark B.; DeSantis, Stacia M.; Malcolm, Robert; Brady, Kathleen T.] Med Univ South Carolina, Dept Psychiat & Behav Sci, 5 Charleston Ctr Dr,Ste 151, Charleston, SC 29407 USA. [Kalivas, Peter W.] Med Univ South Carolina, Dept Neurosci, Charleston, SC USA. [Back, Sudie E.; Korte, Kristina J.; Gros, Daniel F.; Hamner, Mark B.; Malcolm, Robert; Brady, Kathleen T.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Back, SE (reprint author), Med Univ South Carolina, Dept Psychiat & Behav Sci, 5 Charleston Ctr Dr,Ste 151, Charleston, SC 29407 USA. EM backs@musc.edu FU US Department of Defense [W81XWH-11-2-0145]; National Institute on Drug Abuse [K02 DA039229]; Department of Veterans Affairs Clinical Science Research and Development Career Development Award [CX000845] FX The authors acknowledge support from the US Department of Defense grant number W81XWH-11-2-0145 (Dr Kalivas), National Institute on Drug Abuse grant number K02 DA039229 (Dr Back), and Department of Veterans Affairs Clinical Science Research and Development Career Development Award CX000845 (Dr Gros). NR 42 TC 0 Z9 0 U1 3 U2 3 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD NOV PY 2016 VL 77 IS 11 BP E1439 EP E1446 DI 10.4088/JCP.15m10239 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EJ2DY UT WOS:000393021300002 PM 27736051 ER PT J AU York, J Sternke, LM Myrick, D Lauerer, J Hair, C AF York, Janet Sternke, Lisa Marie Myrick, Donald (Hugh) Lauerer, Joy Hair, Carole TI Development of Veteran-Centric Competency Domains for Psychiatric-Mental Health Nurse Practitioner Residents SO JOURNAL OF PSYCHOSOCIAL NURSING AND MENTAL HEALTH SERVICES LA English DT Article ID CULTURAL COMPETENCE; MEDICAL-EDUCATION; CARE; IMPLEMENTATION; PREVENTION; PROGRAMS AB The mental health needs of military service members, Veterans, and their families are a designated national priority; however, there has been little emphasis on the inclusion of Veteran-centric domains in competency-based nursing education for psychiatric-mental health nurse practitioners (PMHNPs). The current article describes the identification and application of Veteran-centric domains in an innovative pilot residency program for PMHNPs, funded by the Veterans Health Administration Office of Academic Affiliations. Fourteen Veteran-centric competency domains were developed from literature review, including knowledge, attitudes, and skill behaviors. Adoption and application of these domains in curricular components included the resident competency evaluation, baseline assessment of military experience, and evidence-based practice seminars and training. Methods of competency domain evaluation are presented, along with gaps related to the evaluation of competency skills. The delivery of mental health services reflecting these domains is consistent with the VA core values and goal of developing a positive service culture. C1 [York, Janet] VISN7, Duluth, GA USA. [York, Janet] Mental Hlth Serv Line, Mental Hlth, Decatur, GA USA. [Sternke, Lisa Marie] Ralph H Johnson VA Med Ctr, Staffs Off, Charleston, SC USA. [York, Janet; Lauerer, Joy] Med Univ South Carolina, Coll Nursing, Charleston, SC USA. [Myrick, Donald (Hugh)] Med Univ South Carolina, Dept Psychiat, Charleston, SC USA. [Hair, Carole] VA Off Acad Affiliat, Washington, DC USA. RP York, J (reprint author), Ralph H Johnson VAMC, Mental Hlth Serv Line, Room A575,109 Bee St, Charleston, SC 29425 USA. EM Janet.York@va.gov FU Office of Academic Affiliations (OAA); Department of Veterans Affairs FX The RHJ VAMC Psychiatric Mental Health Nurse Practitioner Residency is supported by the Office of Academic Affiliations (OAA) and the Department of Veterans Affairs. The authors acknowledge the mentorship of Dr. Mary Dougherty, Nursing Education, VA Office of Academic Affiliations; the RHJ VAMC Center for Innovation; and the contributions of Teena McGuinness, PhD, CRNP, Professor of Nursing, University of Alabama at Birmingham, and Co-Director of BVAMC/UAB SON Mental Health Nurse Practitioner Residency, Birmingham VAMC, and Audry Gorman, PMHNP, previous Director of Birmingham Residency. NR 38 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0279-3695 EI 1938-2413 J9 J PSYCHOSOC NURS MEN JI J. Psychosoc. Nurs. Ment. Health Serv. PD NOV PY 2016 VL 54 IS 11 BP 31 EP + DI 10.3928/02793695-20161024-06 PG 9 WC Nursing SC Nursing GA EJ2SF UT WOS:000393060700012 PM 27805714 ER PT J AU Weinrauch, LA D'Elia, JA AF Weinrauch, Larry A. D'Elia, John A. TI Diabetic microvascular triopathy, smoking, and risk of cardiovascular events SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Editorial Material ID TRIAL C1 [Weinrauch, Larry A.; D'Elia, John A.] Harvard Med Sch, Joslin Diabet Ctr, Kidney & Hypertens Sect, Boston, MA 02472 USA. RP Weinrauch, LA (reprint author), Harvard Med Sch, Joslin Diabet Ctr, Kidney & Hypertens Sect, Boston, MA 02472 USA. EM lweinrauch@hms.harvard.edu NR 6 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 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD NOV PY 2016 VL 4 IS 11 BP 888 EP 888 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EJ2FM UT WOS:000393025500015 PM 27793320 ER PT J AU Papakostas, TD Jakobiec, FA Stagner, AM Eliott, D Kim, LA AF Papakostas, Thanos D. Jakobiec, Frederick A. Stagner, Anna M. Eliott, Dean Kim, Leo A. TI Small-Caliber Retinal Vasculitis Associated With Giant Cell Arteritis: A New Finding SO OPHTHALMIC SURGERY LASERS & IMAGING RETINA LA English DT Article; Proceedings Paper CT Meeting of the Atlantic-Coast-Retinal-Club CY JAN 08-09, 2016 CL New York, NY SP Atlantic Coast Retinal Club ID COTTON-WOOL SPOTS; TEMPORAL ARTERITIS; VISUAL-LOSS AB Giant cell arteritis (GCA) can present with cotton-wool spots in the retina and usually affects medium and large vessels. The authors present herein a 75-year-old man with GCA manifesting with cotton-wool spots and widespread retinal vasculitis affecting small-size retinal arterioles. The retinal vasculitis and the cotton-wool spots resolved after initiation of systemic corticosteroids and his vision returned to normal. GCA can uncommonly present with retinal vasculitis affecting small-size arterioles. C1 [Papakostas, Thanos D.; Eliott, Dean; Kim, Leo A.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Retina Serv, Dept Ophthalmol, Boston, MA USA. [Jakobiec, Frederick A.; Stagner, Anna M.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Boston, MA USA. RP Eliott, D (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, Ophthalmol, Boston, MA 02115 USA.; Eliott, D (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, Retina Serv, Boston, MA 02115 USA. EM dean_eliott@meei.harvard.edu NR 8 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 NOV PY 2016 VL 47 IS 11 BP 1054 EP 1056 DI 10.3928/23258160-20161031-11 PG 3 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA EJ3HY UT WOS:000393104400011 PM 27842201 ER PT J AU Brandao, R Ott, PA AF Brandao, Raphael Ott, Patrick A. TI Resistance mechanisms to PD-1 inhibition in melanoma SO TRANSLATIONAL CANCER RESEARCH LA English DT Editorial Material ID ADAPTIVE IMMUNE RESISTANCE; METASTATIC MELANOMA; BLOCKADE; IMMUNOTHERAPY; RESPONSES; ANTI-PD-1 C1 Dana Farber Canc Inst, Boston, MA 02115 USA. [Ott, Patrick A.] Harvard Med Sch, Boston, MA 02115 USA. [Ott, Patrick A.] Brigham & Womens Hosp, Dept Med Oncol, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. RP Ott, PA (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Ott, PA (reprint author), Brigham & Womens Hosp, Dept Med Oncol, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. EM Patrick_Ott@dfci.harvard.edu NR 16 TC 0 Z9 0 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 2218-676X EI 2219-6803 J9 TRANSL CANCER RES JI Transl. Cancer Res. PD NOV PY 2016 VL 5 SU 6 BP S1123 EP S1125 DI 10.21037/tcr.2016.11.03 PG 3 WC Oncology SC Oncology GA EJ6KM UT WOS:000393328100024 ER PT J AU Michot, JM Armand, P Ding, W Ribrag, V Christian, B Marinello, P Chlosta, S Zhang, Y Shipp, M Zinzani, PL AF Michot, J-M. Armand, P. Ding, W. Ribrag, V. Christian, B. Marinello, P. Chlosta, S. Zhang, Y. Shipp, M. Zinzani, P. L. TI KEYNOTE-170: Phase 2 study of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma (rrPMBCL) or relapsed or refractory Richter syndrome (rrRS) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT ESMO Symposium on Immuno-Oncology CY NOV 04-06, 2016 CL Lausanne, SWITZERLAND SP ESMO C1 [Michot, J-M.; Ribrag, V.] Inst Gustave Roussy, Oncol, Villejuif, France. [Armand, P.; Shipp, M.] Dana Farber Canc Inst, Oncol, Boston, MA 02115 USA. [Ding, W.] Mayo Clin, Oncol, Rochester, MN USA. [Christian, B.] Ohio State Univ, Internal Med, Columbus, OH 43210 USA. [Marinello, P.; Chlosta, S.; Zhang, Y.] Merck & Co Inc, Oncol, Kenilworth, NJ USA. [Zinzani, P. L.] Univ Bologna, Inst Hematol L & A Seragnoli, Oncol, Bologna, Italy. FU Merck Co., Inc. FX Merck & Co., Inc. NR 0 TC 0 Z9 0 U1 3 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD NOV PY 2016 VL 27 SU 8 MA 49TiP PG 1 WC Oncology SC Oncology GA EI9LT UT WOS:000392830300050 ER PT J AU Bensing, BA Khedri, Z Deng, LQ Yu, H Prakobphol, A Fisher, SJ Chen, X Iverson, TM Varki, A Sullam, PM AF Bensing, Barbara A. Khedri, Zahra Deng, Lingquan Yu, Hai Prakobphol, Akraporn Fisher, Susan J. Chen, Xi Iverson, Tina M. Varki, Ajit Sullam, Paul M. TI Novel aspects of sialoglycan recognition by the Siglec-like domains of streptococcal SRR glycoproteins SO GLYCOBIOLOGY LA English DT Article DE endocarditis; MUC7; platelet GPIb; sialyl-T antigen; Siglec ID ACID-BINDING ADHESIN; EXPERIMENTAL BACTERIAL-ENDOCARDITIS; WEIGHT SALIVARY MUCIN; SURFACE PROTEIN; GORDONII DL1; IB-ALPHA; HUMAN PLATELETS; GSPB; FAMILY; HSA AB Serine-rich repeat glycoproteins are adhesins expressed by commensal and pathogenic Gram-positive bacteria. A subset of these adhesins, expressed by oral streptococci, binds sialylated glycans decorating human salivary mucin MG2/MUC7, and platelet glycoprotein GPIb. Specific sialoglycan targets were previously identified for the ligand-binding regions (BRs) of GspB and Hsa, two serine-rich repeat glycoproteins expressed by Streptococcus gordonii. While GspB selectively binds sialyl-T antigen, Hsa displays broader specificity. Here we examine the binding properties of four additional BRs from Streptococcus sanguinis or Streptococcus mitis and characterize the molecular determinants of ligand selectivity and affinity. Each BR has two domains that are essential for sialoglycan binding by GspB. One domain is structurally similar to the glycan-binding module of mammalian Siglecs (sialic acid-binding immunoglobulin-like lectins), including an arginine residue that is critical for glycan recognition, and that resides within a novel, conserved YTRY motif. Despite low sequence similarity to GspB, one of the BRs selectively binds sialyl-T antigen. Although the other three BRs are highly similar to Hsa, each displayed a unique ligand repertoire, including differential recognition of sialyl Lewis antigens and sulfated glycans. These differences in glycan selectivity were closely associated with differential binding to salivary and platelet glycoproteins. Specificity of sialoglycan adherence is likely an evolving trait that may influence the propensity of streptococci expressing Siglec-like adhesins to cause infective endocarditis. C1 [Bensing, Barbara A.; Sullam, Paul M.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA 94121 USA. [Bensing, Barbara A.; Sullam, Paul M.] Univ Calif San Francisco, San Francisco, CA 94121 USA. [Khedri, Zahra; Deng, Lingquan; Varki, Ajit] Univ Calif San Diego, Glycobiol Res & Training Ctr, San Diego, CA 92093 USA. [Khedri, Zahra; Deng, Lingquan; Varki, Ajit] Univ Calif San Diego, Dept Cellular & Mol Med, San Diego, CA 92093 USA. [Yu, Hai; Chen, Xi] Univ Calif Davis, Dept Chem, Davis, CA 95616 USA. [Prakobphol, Akraporn; Fisher, Susan J.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. [Iverson, Tina M.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 27232 USA. [Deng, Lingquan] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. RP Bensing, BA (reprint author), VA Med Ctr 111W2, Dept Med, 4150 Clement St, San Francisco, CA 94121 USA. EM barbara.bensing@ucsf.edu FU Department of Veterans Affairs; Northern California Institute for Research and Education; National Institutes of Health [AI41513, R21CA199881, AI106987, R01GM32373, U01CA199792, R01DE021041]; American Heart Association [14GRNT20390021] FX This work was supported by the Department of Veterans Affairs, the Northern California Institute for Research and Education, the National Institutes of Health (AI41513 and R21CA199881 to P.M.S.; AI106987 to P.M.S./T.M.I.; R01GM32373 and U01CA199792 to A.V.; R01DE021041 to S.J.F.) and the American Heart Association (14GRNT20390021 to T.M.I.). NR 42 TC 5 Z9 5 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 NOV PY 2016 VL 26 IS 11 BP 1222 EP 1234 DI 10.1093/glycob/cww042 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EJ0XF UT WOS:000392933600010 PM 27037304 ER PT J AU Keel, SB Scott, A Sanchez-Bonilla, M Ho, PA Gulsuner, S Pritchard, CC Abkowitz, JL King, MC Walsh, T Shimamura, A AF Keel, Sioban B. Scott, Angela Sanchez-Bonilla, Marilyn Ho, Phoenix A. Gulsuner, Suleyman Pritchard, Colin C. Abkowitz, Janis L. King, Mary-Claire Walsh, Tom Shimamura, Akiko TI Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients SO HAEMATOLOGICA LA English DT Article ID TELOMERASE REVERSE-TRANSCRIPTASE; ACUTE MYELOGENOUS LEUKEMIA; BONE-MARROW FAILURE; DYSKERATOSIS-CONGENITA; FANCONI-ANEMIA; OVARIAN-CANCER; MUTATIONS; TRANSPLANTATION; CLASSIFICATION; CHILDREN AB The clinical and histopathological distinctions between inherited versus acquired bone marrow failure and myelodysplastic syndromes are challenging. The identification of inherited bone marrow failure/myelodysplastic syndromes is critical to inform appropriate clinical management. To investigate whether a subset of pediatric and young adults undergoing transplant for aplastic anemia or myelodysplastic syndrome have germline mutations in bone marrow failure/myelodysplastic syndrome genes, we performed a targeted genetic screen of samples obtained between 1990-2012 from children and young adults with aplastic anemia or myelodysplastic syndrome transplanted at the Fred Hutchinson Cancer Research Center. Mutations in inherited bone marrow failure/myelodysplastic syndrome genes were found in 5.1% (5/98) of aplastic anemia patients and 13.6% (15/110) of myelodysplastic syndrome patients. While the majority of mutations were constitutional, a RUNX1 mutation present in the peripheral blood at a 51% variant allele fraction was confirmed to be somatically acquired in one myelodysplastic syndrome patient. This highlights the importance of distinguishing germline versus somatic mutations by sequencing DNA from a second tissue or from parents. Pathological mutations were present in DKC1, MPL, and TP53 among the aplastic anemia cohort, and in FANCA, GATA2, MPL, RTEL1, RUNX1, SBDS, TERT, TINF2, and TP53 among the myelodysplastic syndrome cohort. Family history or physical examination failed to reliably predict the presence of germline mutations. This study shows that while any single specific bone marrow failure/myelodysplastic syndrome genetic disorder is rare, screening for these disorders in aggregate identifies a significant subset of patients with inherited bone marrow failure/myelodysplastic syndrome. C1 [Keel, Sioban B.; Abkowitz, Janis L.] Univ Washington, Dept Med, Div Hematol, Seattle, WA 98195 USA. [Scott, Angela; Ho, Phoenix A.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Scott, Angela; Ho, Phoenix A.] Seattle Childrens Hosp, Dept Pediat Hematol Oncol, Seattle, WA USA. [Scott, Angela; Ho, Phoenix A.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Sanchez-Bonilla, Marilyn; Shimamura, Akiko] Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Sanchez-Bonilla, Marilyn; Shimamura, Akiko] Harvard Med Sch, Boston, MA 02115 USA. [Gulsuner, Suleyman; King, Mary-Claire; Walsh, Tom] Univ Washington, Dept Med, Seattle, WA USA. [Gulsuner, Suleyman; King, Mary-Claire; Walsh, Tom] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Pritchard, Colin C.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. RP Keel, SB (reprint author), Univ Washington, Dept Med, Div Hematol, Seattle, WA 98195 USA.; Shimamura, A (reprint author), Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA.; Shimamura, A (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM sioban@u.washington.edu; akiko.shimamura@childrens.harvard.edu FU NIH/NIDDK [R24DK099808]; Aplastic Anemia & Myelodysplastic Syndrome International Foundation; Ghiglione Aplastic Anemia Fund; Julian's Dinosaur Guild at Seattle Children's Hospital FX The authors would like to thank Sharon Savage, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, and Keith Loeb, Department of Pathology, University of Washington, Seattle, WA and J. Arturo Londono-Vallejo, Institut Curie, Paris, France and Simon Boulton, Francis Crick Institute, UK for helpful discussions. This work was supported by NIH/NIDDK grant R24DK099808 (AS, MCK, and JA), the Aplastic Anemia & Myelodysplastic Syndrome International Foundation, the Ghiglione Aplastic Anemia Fund, and the Julian's Dinosaur Guild at Seattle Children's Hospital (AS). NR 29 TC 2 Z9 2 U1 1 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD NOV PY 2016 VL 101 IS 11 BP 1343 EP 1350 DI 10.3324/haematol.2016.149476 PG 8 WC Hematology SC Hematology GA EI5QU UT WOS:000392550200010 PM 27418648 ER PT J AU Allen, JD Leyva, B Hilaire, DM Reich, AJ Martinez, LS AF Allen, Jennifer D. Leyva, Bryan Hilaire, Dany M. Reich, Amanda J. Martinez, Linda Sprague TI Priorities, concerns and unmet needs among Haitians in Boston after the 2010 earthquake SO HEALTH & SOCIAL CARE IN THE COMMUNITY LA English DT Article DE cancer screening; community assessments; earthquake; Haitian; health behaviour; beliefs; attitudes; immigrant health ID CANCER CONTROL; MINORITY COMMUNITIES; DIETARY INTERVENTION; SERVICE UTILIZATION; HEALTH PROJECT; CHURCH; PREVENTION; IMPLEMENTATION; BEHAVIORS; BREAST AB In January 2010, a massive earthquake struck Haiti. The devastation not only affected those living in Haiti at the time but also those Haitians living in the United States (U.S.). Few studies have assessed the degree of impact of the earthquake in U.S. Haitian communities. The purpose of this study was to elicit information about health priorities, concerns and resources needed to improve the delivery of health and social care for Haitians in Boston, MA. We conducted six focus groups among 78 individuals in the spring of 2011. Participants were recruited through community organisations, including churches, Haitian social service centres, restaurants and by word of mouth. Analysis of qualitative data revealed an enormous psychological, emotional, financial and physical toll experienced by Boston-area Haitians following the earthquake. Participants described increased distress, depressive episodes, headaches and financial hardship. They also noted insufficient resources to meet the increased needs of those living in the U.S., and those who had immigrated after the earthquake. Most participants cited an increased need for mental health services, as well as assistance with finding employment, navigating the immigration system, and balancing the health and financial needs of families in the U.S. and in Haiti. Despite this, many reported that the tragedy created a sense of unity and solidarity within the Haitian community. These findings corroborate the need for culturally and linguistically appropriate mental health services, as well as for employment, immigration and healthcare navigation services. Participants suggested that interventions be offered through Haitian radio and television stations, as well as group events held in churches. Further research should assess the need for and barriers to utilisation of mental health services among the Haitian community. A multi-faceted approach that includes a variety of outreach strategies implemented through multiple channels may offer a means of improving awareness of and access to health and social services. C1 [Allen, Jennifer D.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Allen, Jennifer D.; Martinez, Linda Sprague] Tufts Univ, Dept Publ Hlth & Community Med, Medford, MA 02155 USA. [Leyva, Bryan] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Hilaire, Dany M.] Univ Massachusetts Boston, Boston, MA USA. [Reich, Amanda J.] Tufts Univ, Community Hlth, Medford, MA 02155 USA. RP Allen, JD (reprint author), Tufts Univ, Medford, MA 02155 USA. EM jennifer.allen@tufts.edu FU National Cancer Institute [5U56CA118641-05]; National Institutes of Health (NIH)/National Cancer Institute (NCI) [3U56CA118641-05S1]; Centers for Disease Control and Prevention with the National Cancer Institute [1U48DP001946-01] FX This study was supported in part by the National Cancer Institute (Grant 5U56CA118641-05, UMB/DFHCC Comprehensive Cancer Partnership Program), National Institutes of Health (NIH)/National Cancer Institute (NCI) (Grant 3U56CA118641-05S1, UMB/DFHCC Comprehensive Cancer Partnership Program) and through a co-operative agreement by the Centers for Disease Control and Prevention with the National Cancer Institute (1U48DP001946-01, Massachusetts Cancer Prevention and Control Research Network). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention, the National Cancer Institute, the Department of Health and Human Services or the U.S. Government. The funding sources had no involvement in study design, in the collection, analysis and interpretation of data, in the writing of the articles or in the decision to submit it for publication. The authors gratefully acknowledge the time and insights provided by study participants and our Community Advisory Board, including Rev. Nicolas Homicil, Guy Apollon and Riche Zamor. In addition, we note the invaluable contributions of Gerald Iralien, Dana Mars, Chantal Louis, Josh Gagne, Marjorie Bern, Elizabeth Harden and Laura Tom to this work. NR 49 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0966-0410 EI 1365-2524 J9 HEALTH SOC CARE COMM JI Health Soc. Care Community PD NOV PY 2016 VL 24 IS 6 BP 687 EP 698 DI 10.1111/hsc.12217 PG 12 WC Public, Environmental & Occupational Health; Social Work SC Public, Environmental & Occupational Health; Social Work GA EI8JQ UT WOS:000392753000012 PM 25736232 ER PT J AU Kitahara, S Matsui, A Yoshii, A Kuwahara, Y Nishio, M Saeki, K Ezaki, T AF Kitahara, Shuji Matsui, Aya Yoshii, Asuka Kuwahara, Yoshikazu Nishio, Miwako Saeki, Kumiko Ezaki, Taichi TI Endothelial cell transplantation in tumors restores normal vasculature, reduces tumor hypoxia, and suppresses tumor outgrowth SO Journal of Oral Biosciences LA English DT Article DE Tumor vessel; Normalization; Hypoxia ID EMBRYONIC STEM-CELLS; ANTIANGIOGENIC THERAPY; BLOOD-VESSELS; GROWTH-FACTOR; NECK-CANCER; NORMALIZATION; ANGIOGENESIS; ABNORMALITIES; SPROUTS; HEAD AB Objectives: Vascular normalization, or restoration of the normal structure and function of blood vessels, using molecular-targeted therapy, has emerged as a potential strategy for treating malignant cancer and other vascular disorders. We hypothesized that restoring tumor blood vessels to their normal state would alleviate hypoxic conditions and potentially enhance the delivery of anticancer drugs. Our objective was to determine if transplanting normal endothelial cells into tumor-bearing mice could trigger vascular normalization. Methods: Tumor cells were injected into the dorsal subcutis of severe combined immunodeficiency (SCID) mice (day 0). Tumor-bearing mice were injected intraperitoneally with cisplatin at day 14 to create scaffolds for blood vessel formation in the tumors. At day 28, human microvascular endothelial cells (HMVECs) or human embryonic stem-derived endothelial cells (ESECs) were transplanted into the necrotic regions of the tumor to induce normal angiogenesis. Results: Microscopic observation revealed that the transplanted HMVECs or ESECs formed anastomoses with the host mouse vasculature. In addition, blood vessels with blood flow could be detected after 14 d. Blood vessels reconstituted by HMVECs or ESECs exhibited normal vasculature, and tumor growth was significantly inhibited upon treatment. Conclusion: Reconstruction of tumor blood vessels to their normal state alleviated hypoxic conditions and improved the efficiency of drug delivery; the present approach provides a useful model for the development of new cancer therapies. (C) 2016 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved. C1 [Kitahara, Shuji; Matsui, Aya; Yoshii, Asuka; Ezaki, Taichi] Tokyo Womens Med Univ, Sch Med, Dept Anat & Dev Biol, Tokyo, Japan. [Kitahara, Shuji] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA USA. [Yoshii, Asuka] Boston Univ, Sch Med, Dept Pharmacol, Boston, MA 02215 USA. [Yoshii, Asuka] Boston Univ, Sch Med, Dept Expt Therapeut, Boston, MA 02215 USA. [Kuwahara, Yoshikazu] Tohoku Univ, Dept Pathol, Inst Dev Aging & Canc, Sendai, Miyagi, Japan. [Nishio, Miwako; Saeki, Kumiko] Natl Ctr Global Hlth & Med, Res Inst, Dept Dis Control, Tokyo, Japan. RP Kitahara, S (reprint author), Tokyo Womens Med Univ, Dept Anat & Dev Biol, Shinjuku Ku, 8-1 Kawada Cho, Tokyo 1628666, Japan. EM skitahara@mgh.harvard.edu FU Ministry of Education, Culture, Sports, Science, and Technology of Japan [25861218, 24659904]; Global COE program of the Multidisciplinary Education and Research Center for Regenerative Medicine; Japan Society for the Promotion of Science [26.12011] FX We would like to thank Drs. S. Morikawa, K. Shimizu, M. Morishima, and S. Kikuta (Department of Anatomy and Developmental Biology, School of Medicine, Tokyo Women's Medical University, Tokyo, Japan) for their invaluable advice, and Mrs. H. Sagawa and K. Motomaru for their technical assistance. We would also like to thank Dr. M. Mori (Department of Oral Surgery at National Tokyo Medical Center) for her advice and expertise. This study was mainly supported by a Grant-in-Aid for Scientific Research (B) (No. 25861218) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, by a Grant-in-Aid for Challenging Exploratory Research (No. 24659904) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, by the Global COE program of the Multidisciplinary Education and Research Center for Regenerative Medicine, and by a Grant-in-Aid for Research Fellow (DC1) of Japan Society for the Promotion of Science (26.12011). NR 25 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1880-3865 EI 2213-3232 J9 J ORAL BIOSCI JI J. Oral Biosci. PD NOV PY 2016 VL 58 IS 4 BP 150 EP 157 DI 10.1016/j.job.2016.05.003 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA EJ1IK UT WOS:000392963600006 ER PT J AU Leaf, DE Cheng, XXS Sanders, JL Mendu, M Schiff, GD Mount, DB Bazari, H AF Leaf, David E. Cheng, Xingxing S. Sanders, Jason L. Mendu, Mallika Schiff, Gordon D. Mount, David B. Bazari, Hasan TI An electronic alert to decrease Kayexalate ordering SO RENAL FAILURE LA English DT Article DE Electronic alert; hyperkalemia; patient safety; potassium; quality improvement ID HYPERKALEMIA; INHIBITORS AB Important safety concerns have recently emerged regarding the use of sodium polystyrene sulfonate (Kayexalate), a cation-exchange resin commonly used for the treatment of hyperkalemia. We implemented an electronic alert system at a tertiary care academic medical center to warn providers of the safety concerns of Kayexalate. We assessed the number of Kayexalate prescriptions per month, as well as the number of grams of Kayexalate ordered per month, one year before versus one year after implementing the alert. The mean (+/- SD) number of Kayexalate orders decreased from 123 (+/- 12) to 76 (+/- 14) orders/month (38% absolute reduction, p<0.001) after implementing the alert. Additionally, the mean (+/- SD) amount of Kayexalate prescribed decreased from 3332 (+/- 329) to 1885 (+/- 358) g/month (43% absolute reduction, p<0.001). We conclude that an electronic alert is an effective tool to decrease Kayexalate ordering. C1 [Leaf, David E.; Mendu, Mallika; Mount, David B.] Brigham & Womens Hosp, Div Renal Med, 75 Francis St, Boston, MA 02115 USA. [Cheng, Xingxing S.; Bazari, Hasan] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Cheng, Xingxing S.] Stanford Univ, Div Nephrol, Palo Alto, CA 94304 USA. [Sanders, Jason L.] Brigham & Womens Hosp, Harvard Affiliated Emergency Med Residency, 75 Francis St, Boston, MA 02115 USA. [Sanders, Jason L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Schiff, Gordon D.] Brigham & Womens Hosp, Div Gen Internal Med, Ctr Patient Safety Res & Practice, 75 Francis St, Boston, MA 02115 USA. EM DELEAF@partners.org FU National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases [K23DK106448] FX D.E.L. is supported by K23DK106448 from the National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases. NR 6 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 0886-022X EI 1525-6049 J9 RENAL FAILURE JI Ren. Fail. PD NOV PY 2016 VL 38 IS 10 BP 1752 EP 1754 DI 10.1080/0886022X.2016.1185353 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA EI3ZD UT WOS:000392430900029 PM 27183825 ER PT J AU Miyamoto, DT Lee, RJ AF Miyamoto, David T. Lee, Richard J. TI Cell-free and circulating tumor cell-based biomarkers in men with metastatic prostate cancer: Tools for real-time precision medicine? SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Review DE Prostate cancer; CTCs; ctDNA; Circulating biomarkers; AR ID ANDROGEN RECEPTOR MUTATIONS; FREE DNA; COPY NUMBER; ANTIANDROGEN RESISTANCE; ABIRATERONE ACETATE; PROGNOSTIC MARKER; LIQUID BIOPSY; DIGITAL PCR; SWOG S0421; SURVIVAL AB The recent expansion of therapeutic options for the treatment of metastatic prostate cancer highlights the need for precision medicine approaches to enable the rational selection of appropriate therapies for individual patients. In this context, circulating biomarkers in the peripheral blood are attractive as readily accessible tools for predicting and monitoring therapeutic response. In the case of circulating tumor cells and circulating tumor DNA, they may also serve as a noninvasive means of assessing molecular aberrations in tumors at multiple time points before and during therapy. These so-called "liquid biopsies" can provide a snapshot view of tumor molecular architecture and may enable clinicians to monitor the molecular status of tumors as they evolve during treatment, thus allowing for individualized precision therapeutic decisions for patients over time. In this review, we outline recent progress in the field of circulating biomarkers in metastatic prostate cancer and evaluate their potential for enabling this vision of real-time precision medicine. (C) 2016 Elsevier Inc. All rights reserved. C1 [Miyamoto, David T.; Lee, Richard J.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Miyamoto, David T.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Lee, Richard J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Miyamoto, David T.; Lee, Richard J.] Harvard Med Sch, Boston, MA 02115 USA. EM dmiyamoto@mgh.harvard.edu FU Department of Defense [W81XWH-12-1-0153]; Prostate Cancer Foundation; Janssen FX This work was supported by the Department of Defense (DTM) (Grant no. W81XWH-12-1-0153) and the Prostate Cancer Foundation (D.T.M. and R.J.L.). R.J.L. has received research funding from Janssen. NR 92 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 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD NOV PY 2016 VL 34 IS 11 BP 490 EP 501 DI 10.1016/j.urolonc.2016.09.001 PG 12 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA EI6XY UT WOS:000392642100022 PM 27771279 ER PT J AU Millstein, RA Celano, CM Beale, EE Beach, SR Suarez, L Belcher, AM Januzzi, JL Huffman, JC AF Millstein, Rachel A. Celano, Christopher M. Beale, Eleanor E. Beach, Scott R. Suarez, Laura Belcher, Arianna M. Januzzi, James L. Huffman, Jeff C. TI The effects of optimism and gratitude on adherence, functioning and mental health following an acute coronary syndrome SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE Optimism; Gratitude; Acute coronary syndrome; Mental health; Adherence ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; AMERICAN-HEART-ASSOCIATION; PHYSICAL-ACTIVITY; POSITIVE-AFFECT; CARDIOVASCULAR-DISEASE; DISPOSITIONAL OPTIMISM; RATE-VARIABILITY; CARDIAC-DISEASE; DEPRESSION AB Objective: This study examined the effects of optimism and gratitude on self-reported health behavior adherence, physical functioning and emotional well-being after an acute coronary syndrome (ACS). Methods: Among 156 patients, we examined associations between optimism and gratitude measured 2 weeks post-ACS and 6-month outcomes: adherence to medical recommendations, mental and physical health-related quality of life (HRQoL), physical functioning, depressive symptoms and anxiety. Multivariable linear regression models were used, controlling for increasing levels of adjustment. Results: Optimism [beta=.11, standard error (S.E.)=.05, P=.038] and gratitude (beta=.10, S.E.=.05, P=.027) at 2 weeks were associated with subsequent self-reported adherence to medical recommendations (diet, exercise, medication adherence, stress reduction) at 6 months in fully adjusted models. Two-week optimism and gratitude were associated with improvements in mental HRQoL (optimism: beta=.44, S.E.=.13, P=.001; gratitude: beta=.33, S.E.=.12, P=.005) and reductions in symptoms of depression (optimism: beta=-.11, S.E.=.05, P=.039; gratitude: beta=-.10, S.E.=.05, P=.028) and anxiety (optimism: beta=-.15, S.E.=.05, P=.004; gratitude: beta=-.10, S.E.=.05, P=.034) at 6 months. Conclusion: Optimism and gratitude at 2 weeks post-ACS were associated with higher self-reported adherence and improved emotional well-being 6 months later, independent of negative emotional states. Optimism and gratitude may help recovery from an ACS. Interventions promoting these positive constructs could help improve adherence and well-being. (C) 2016 Elsevier Inc. All rights reserved. C1 [Millstein, Rachel A.; Celano, Christopher M.; Beale, Eleanor E.; Beach, Scott R.; Januzzi, James L.; Huffman, Jeff C.] Harvard Med Sch, 55 Fruit St, Boston, MA 02114 USA. [Millstein, Rachel A.; Celano, Christopher M.; Beach, Scott R.; Suarez, Laura; Huffman, Jeff C.] Massachusetts Gen Hosp, Dept Psychiat, 55 Fruit St, Boston, MA 02114 USA. [Belcher, Arianna M.; Januzzi, James L.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, 55 Fruit St, Boston, MA 02114 USA. RP Millstein, RA (reprint author), Massachusetts Gen Hosp, 55 Fruit St Warren 1220, Boston, MA 02114 USA. EM ramillstein@mgh.harvard.edu FU UC Berkeley's Greater Good Science Center; John Templeton Foundation [15627]; NIH [R01HL113272, K23HL123607] FX This work was supported by UC Berkeley's Greater Good Science Center with funding from the John Templeton Foundation (grant number 15627). Additional funding for analysis and interpretation time was funded by NIH grant to the senior author (grant number R01HL113272) and by NIH grant to the second author (grant number K23HL123607). The authors declare no conflicts of interest regarding the publication of this paper [61-67]. NR 67 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 0163-8343 EI 1873-7714 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD NOV-DEC PY 2016 VL 43 BP 17 EP 22 DI 10.1016/j.genhosppsych.2016.08.006 PG 6 WC Psychiatry SC Psychiatry GA EI6SL UT WOS:000392626800004 PM 27796252 ER PT J AU Nobles, CJ Valentine, SE Gerber, MW Shtasel, DL Marques, L AF Nobles, Carrie J. Valentine, Sarah E. Gerber, Monica W. Shtasel, Derri L. Marques, Luana TI Predictors of treatment utilization and unmet treatment need among individuals with posttraumatic stress disorder from a national sample SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE Posttraumatic stress; Treatment utilization; Epidemiology; Health disparities ID INTERNATIONAL DIAGNOSTIC INTERVIEW; MENTAL-HEALTH-SERVICES; COMORBIDITY SURVEY REPLICATION; UNITED-STATES; TREATMENT-SEEKING; REPRESENTATIVE SURVEY; CLINICAL REAPPRAISAL; AMERICAN LIFE; PRIMARY-CARE; CIDI AB Objective: Posttraumatic stress disorder (PTSD) is a chronic psychiatric condition associated with significant disability that often remains untreated. Sociodemographic and family-level factorsmay serve as predictors of unmet treatment need, identifying groups thatwouldmost benefit frompolicies aimed at increasing access to themental health care system. Method: Data from the nationally representative Collaborative Psychiatric Epidemiologic Surveys were used to identify predictors of mental health treatment utilization, bothwith a mental health specialist andwith a general health practitioner, and self-reported unmet treatment need among individuals who endorsed past-year PTSD. We defined unmet treatment need as self-reporting a mental health problem and not accessing mental health care in the general or specialty mental health care system. Results: Among 600 participants, predictors of unmet treatment need included being non-Latino black [odds ratio (OR) 2.11, 95% confidence interval (CI) 1.25-3.54], having a high school education versus some college (OR 2.45, 95% CI 1.34-4.48), and being employed or unemployed versus not being in the workforce (OR 1.74, 95% CI 1.00-3.02 and OR 4.95, 95% CI 1.60-15.34, respectively). Recursive partitioning identified younger age and being married as predictors of low treatment utilization. Conclusions: Future research should elucidate barriers to accessing treatment among those with PTSD in these underserved groups. (C) 2016 Elsevier Inc. All rights reserved. C1 [Nobles, Carrie J.; Valentine, Sarah E.; Gerber, Monica W.; Marques, Luana] Massachusetts Gen Hosp, Dept Psychiat, 70 Everett Ave Suite 516, Chelsea, MA 02150 USA. [Nobles, Carrie J.; Valentine, Sarah E.; Shtasel, Derri L.; Marques, Luana] Harvard Med Sch, Boston, MA USA. [Shtasel, Derri L.] Massachusetts Gen Hosp, Dept Psychiat, 25 New Chardon St, Boston, MA 02114 USA. RP Nobles, CJ (reprint author), Massachusetts Gen Hosp, Community Psychiat PRIDE, Dept Psychiat, 70 Everett Ave,Suite 516, Chelsea, MA 02150 USA. EM cnobles@mgh.harvard.edu OI Nobles, Carrie/0000-0002-2182-8486 FU National Institute of Mental Health (NIMH) [K23 MH096029-01A1] FX Time for this manuscript was funded in part by a grant from the National Institute of Mental Health (NIMH K23 MH096029-01A1) awarded to Dr. Luana Marques. NR 43 TC 0 Z9 0 U1 10 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 EI 1873-7714 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD NOV-DEC PY 2016 VL 43 BP 38 EP 45 DI 10.1016/j.genhosppsych.2016.09.001 PG 8 WC Psychiatry SC Psychiatry GA EI6SL UT WOS:000392626800008 PM 27796256 ER PT J AU Avedschmidt, SE Stagner, AM Eagle, RC Harocopos, GJ Dou, YL Rao, RC AF Avedschmidt, Sarah E. Stagner, Anna M. Eagle, Ralph C., Jr. Harocopos, George J. Dou, Yali Rao, Rajesh C. TI The Targetable Epigenetic Tumor Protein EZH2 is Enriched in Intraocular Medulloepithelioma SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE medulloepithelioma; epigenetics; EZH2 ID MULTILAYERED ROSETTES; EMBRYONAL TUMORS; FREQUENT AB PURPOSE. Intraocular medulloepithelioma (IM), the second most common primary neuroepithelial tumor of the eye, can lead to blindness in the affected eye and in rare cases, is deadly. Intraocular medulloepithelioma lacks targetable biomarkers for potential pharmacologic therapy. The purpose of this study was to identify actionable, tumor-specific proteins for potential diagnostic or therapeutic strategies. We hypothesize that the tumor-specific epigenetic enzyme EZH2 is selectively expressed in IM. METHODS. We conducted a retrospective case series study of five IM from five eyes of four children and one adult. Hematoxylin and eosin (H&E) stains of sections from formalin-fixed, paraffin-embedded blocks of IM tumors were used to localize IM tumor cells in each case. Using an EZH2-specific antibody for immunohistochemistry, we semiquantitatively calculated the proportion of IM tumor cells positive for EZH2, and also assayed for EZH2 staining intensity. RESULTS. We found that EZH2 was expressed in all IM cases but this protein was absent in nontumor ciliary body or retinal tissues. However, not all IM tumor cells expressed EZH2. Similar to retinoblastoma, moderately to poorly differentiated (primitive appearing) IM tumor cells strongly expressed EZH2; expression was weaker or absent in areas of well-formed neuroepithelial units. CONCLUSIONS. To our knowledge, this is the first study to identify an actionable tumor-specific maker, EZH2, in IM. Our findings point to the possibility of exploring the potential of EZH2 inhibitors, already in clinical trials for other cancers, for IM. C1 [Avedschmidt, Sarah E.; Dou, Yali; Rao, Rajesh C.] Univ Michigan, Dept Pathol, 1000 Wall St,Brehm Roomm 8333, Ann Arbor, MI 48105 USA. [Stagner, Anna M.] Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Stagner, Anna M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Eagle, Ralph C., Jr.] Thomas Jefferson Univ, Wills Eye Hosp, Dept Ophthalm Pathol, Philadelphia, PA 19107 USA. [Harocopos, George J.] Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, St Louis, MO 63110 USA. [Harocopos, George J.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Dou, Yali] Univ Michigan, Dept Biol Chem, 1000 Wall St,Brehm Roomm 8333, Ann Arbor, MI 48105 USA. [Dou, Yali; Rao, Rajesh C.] Univ Michigan, Ctr Comprehens Canc, 1000 Wall St,Brehm Roomm 8333, Ann Arbor, MI 48105 USA. [Rao, Rajesh C.] Univ Michigan, Dept Ophthalmol & Visual Sci, WK Kellogg Eye Ctr, 1000 Wall St,Brehm Roomm 8333, Ann Arbor, MI 48105 USA. [Rao, Rajesh C.] Univ Michigan, A Alfred Taubman Med Res Inst, 1000 Wall St,Brehm Roomm 8333, Ann Arbor, MI 48105 USA. [Rao, Rajesh C.] Vet Adm Ann Arbor Healthcare Syst, Surg Serv, Sect Ophthalmol, Ann Arbor, MI USA. RP Rao, RC (reprint author), Univ Michigan, Sch Med, WK Kellogg Eye Ctr, 1000 Wall St,Brehm Roomm 8333, Ann Arbor, MI 48105 USA. EM rajeshr@umich.edu FU National Eye Institute (Bethseda, MD, USA) [K12EY022299]; National Cancer Institute-University of Michigan Comprehensive Cancer Center Support Grant (Bethseda, MD, USA) [P30CA046592]; Leonard G. Miller Ophthalmic Research Fund at the Kellogg Eye Center (Ann Arbor, MI, USA); Barbara Dunn Research Fund (Ann Arbor, MI, USA); Beatrice & Reymont Paul Foundation (Bloomfield Hills, MI, USA); March Hoops to Beat Blindness (Ann Arbor, MI, USA); A. Alfred Taubman Medical Research Institute FX Supported by the National Eye Institute (K12EY022299; Bethseda, MD, USA), National Cancer Institute-University of Michigan Comprehensive Cancer Center Support Grant (P30CA046592; Bethseda, MD, USA), The Leonard G. Miller Ophthalmic Research Fund at the Kellogg Eye Center (Ann Arbor, MI, USA), Barbara Dunn Research Fund (Ann Arbor, MI, USA), Beatrice & Reymont Paul Foundation (Bloomfield Hills, MI, USA), and March Hoops to Beat Blindness (RCR; Ann Arbor, MI, USA). The Leslie H. and Abigail S. Wexner Emerging Scholar Award of the A. Alfred Taubman Medical Research Institute, which supported, in part, this study (RCR). None of the sponsors participated 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 8 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 NOV PY 2016 VL 57 IS 14 BP 6242 EP 6246 DI 10.1167/iovs.16-20463 PG 5 WC Ophthalmology SC Ophthalmology GA EI3HG UT WOS:000392380000045 PM 27842164 ER PT J AU Lee, SJC Clark, MA Cox, JV Needles, BM Seigel, C Balasubramanian, BA AF Lee, Simon J. Craddock Clark, Mark A. Cox, John V. Needles, Burton M. Seigel, Carole Balasubramanian, Bijal A. TI Achieving Coordinated Care for Patients With Complex Cases of Cancer: A Multiteam System Approach SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; MULTIPLE CHRONIC CONDITIONS; IMPROVING PRIMARY-CARE; HEALTH-CARE; CHRONIC ILLNESS; SURVIVORSHIP CARE; CONTEXT MATTERS; CENTERED CARE; MENTAL MODELS; FOLLOW-UP AB Patients with cancer with multiple chronic conditions pose a unique challenge to how primary care and specialty care teams provide well-coordinated, patient-centered care. Effectiveness of these care teams in providing optimal health care depends on the extent to which they coordinate their goals and knowledge as components of a multiteam system (MTS). This article outlines challenges of care coordination in the context of an MTS, illustrated through the care experience of "Mr Fuentes," a patient in the Dallas County integrated safety-net system, Parkland. As a continuing patient with chronic illnesses, the patient being discussed is managed through one of the Parkland community-oriented primary care clinics. However, a cancer diagnosis triggered an additional need for augmented coordination between his different provider teams. Further research and practice should investigate the relationships of MTS coordination for shared care management, transfer to and from specialty care, treatment compliance, barriers to care, and health outcomes of chronic comorbid conditions, as well as cancer control and surveillance. C1 Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. Harold C Simmons Comprehens Canc Ctr, Dallas, TX USA. Parkland Hlth & Hosp Syst, Dallas, TX USA. Univ Texas Sch Publ Hlth, Dallas, TX USA. Amer Univ, Kogod Sch Business, Washington, DC 20016 USA. Mercy Hosp, St Louis, MO USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Lee, SJC (reprint author), Univ Texas Southwestern Med Ctr Dallas, Dept Clin Sci, 5323 Harry Hines Blvd,Mail Code 9066, Dallas, TX 75390 USA. EM SimonCraddock.Lee@utsouthwestern.edu OI Lee, Simon J. Craddock/0000-0001-6345-1237 FU US Oncology FX US Oncology NR 129 TC 1 Z9 1 U1 8 U2 8 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 NOV PY 2016 VL 12 IS 11 BP 1029 EP + DI 10.1200/JOP.2016.013664 PG 14 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EI3HS UT WOS:000392381400011 PM 27577621 ER PT J AU D'Ambruoso, SF Coscarelli, A Hurvitz, S Wenger, N Coniglio, D Donaldson, D Pietras, C Walling, AM AF D'Ambruoso, Sarah F. Coscarelli, Anne Hurvitz, Sara Wenger, Neil Coniglio, David Donaldson, Dusty Pietras, Christopher Walling, Anne M. TI Use of a Shared Mental Model by a Team Composed of Oncology, Palliative Care, and Supportive Care Clinicians to Facilitate Shared Decision Making in a Patient With Advanced Cancer SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Article ID OF-LIFE; PERFORMANCE; ROLES AB Our case describes the efforts of team members drawn from oncology, palliative care, supportive care, and primary care to assist a woman with advanced cancer in accepting care for her psychosocial distress, integrating prognostic information so that she could share in decisions about treatment planning, involving family in her care, and ultimately transitioning to hospice. Team members in our setting included a medical oncologist, oncology nurse practitioner, palliative care nurse practitioner, oncology social worker, and primary care physician. The core members were the patient and her sister. Our team grew organically as a result of patient need and, in doing so, operationalized an explicitly shared understanding of care priorities. We refer to this shared understanding as a shared mental model for care delivery, which enabled our team to jointly set priorities for care through a series of warm handoffs enabled by the team's close proximity within the same clinic. When care providers outside our integrated team became involved in the case, significant communication gaps exposed the difficulty in extending our shared mental model outside the integrated team framework, leading to inefficiencies in care. Integration of this shared understanding for care and close proximity of team members proved to be key components in facilitating treatment of our patient's burdensome cancer-related distress so that she could more effectively participate in treatment decision making that reflected her goals of care. C1 Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. Simms Mann UCLA Ctr Integrat Oncol, Los Angeles, CA USA. Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA USA. RAND Corp, Santa Monica, CA USA. Campbell Univ, Coll Pharm & Hlth Sci, Buies Creek, NC 27506 USA. Dusty Joy Fdn LiveLung, High Point, NC USA. RP Walling, AM (reprint author), UCLA Div Gen Internal Med, 911 Broxton Plaza, Los Angeles, CA 90024 USA. EM awalling@mednet.ucla.edu FU Genentech (Inst); Novartis (Inst); GlaxoSmithKline (Inst); Boehringer Ingelheim (Inst); Sanofi (Inst); Pfizer (Inst); Amgen (Inst); OBI Pharma (Inst); Puma Biotechnology (Inst); Dignitana (Inst); Bayer (Inst); Biomarin (Inst); Lilly (Inst); Merrimack (Inst) FX Genentech (Inst), Novartis (Inst), GlaxoSmithKline (Inst), Boehringer Ingelheim (Inst), Sanofi (Inst), Pfizer (Inst), Amgen (Inst), OBI Pharma (Inst), Puma Biotechnology (Inst), Dignitana (Inst), Bayer (Inst), Biomarin (Inst), Lilly (Inst), Merrimack (Inst) NR 31 TC 1 Z9 1 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 NOV PY 2016 VL 12 IS 11 BP 1039 EP + DI 10.1200/JOP.2016.013722 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EI3HS UT WOS:000392381400012 PM 27577617 ER PT J AU Gross, AH Leib, RK Tonachel, A Tonachel, R Bowers, DM Burnard, RA Rhinehart, CA Valentim, R Bunnell, CA AF Gross, Anne H. Leib, Ryan K. Tonachel, Anne Tonachel, Richard Bowers, Danielle M. Burnard, Rachel A. Rhinehart, Catherine A. Valentim, Rahila Bunnell, Craig A. TI Teamwork and Electronic Health Record Implementation: A Case Study of Preserving Effective Communication and Mutual Trust in a Changing Environment SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Article ID PATIENT-SAFETY GOALS; CARE AB This article describes how trust among team members and in the technology supporting them was eroded during implementation of an electronic health record (EHR) in an adult outpatient oncology practice at a comprehensive cancer center. Delays in care of a 38-year-old woman with high-risk breast cancer occurred because of ineffective team communication and are illustrated in a case study. The case explores how the patient's trust and mutual trust between team members were disrupted because of inaccurate assumptions about the functionality of the EHR's communication tool, resultant miscommunications between team members and the patient, and the eventual recognition that care was not being effectively coordinated, as it had been previously. Despite a well-established, team-based culture and significant preparation for the EHR implementation, the challenges that occurred point to underlying human and system failures from which other organizations going through a similar process may learn. Through an analysis and evaluation of events that transpired before and during the EHR rollout, suggested interventions for preventing this experience are offered, which include: a thorough crosswalk between old and new communication mechanisms before implementation; understanding and mitigation of gaps in the communication tool's functionality; more robust training for staff, clinicians, and patients; greater consideration given to the pace of change expected of individuals; and development of models of collaboration between EHR users and vendors in developing products that support high-quality, team-based care in the oncology setting. These interventions are transferable to any organizational or system change that threatens mutual trust and effective communication. C1 [Gross, Anne H.; Leib, Ryan K.; Tonachel, Anne; Tonachel, Richard; Bowers, Danielle M.; Burnard, Rachel A.; Rhinehart, Catherine A.; Valentim, Rahila; Bunnell, Craig A.] Dana Farber Canc Inst, Boston, MA 02215 USA. RP Gross, AH (reprint author), Dana Farber Canc Inst, Adult Nursing Serv, 450 Brookline Ave, Boston, MA 02215 USA.; Gross, AH (reprint author), Dana Farber Canc Inst, Clin Serv, 450 Brookline Ave, Boston, MA 02215 USA. EM anne_gross@dfci.harvard.edu FU Conquer Cancer Foundation Mission Endowment FX The production of this manuscript was funded by the Conquer Cancer Foundation Mission Endowment. NR 31 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 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD NOV PY 2016 VL 12 IS 11 BP 1075 EP + DI 10.1200/JOP.2016.013649 PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EI3HS UT WOS:000392381400017 PM 27601513 ER PT J AU Kauffman, RC Bhuiyan, TR Nakajima, R Mayo-Smith, LM Rashu, R Hoq, MR Chowdhury, F Khan, AI Rahman, A Bhaumik, SK Harris, L O'Neal, JT Trost, JF Alam, NH Jasinskas, A Dotsey, E Kelly, M Charles, RC Xu, P Kovac, P Calderwood, SB Ryan, ET Felgner, PL Qadri, F Wrammert, J Harrise, JB AF Kauffman, Robert C. Bhuiyan, Taufiqur R. Nakajima, Rie Mayo-Smith, Leslie M. Rashu, Rasheduzzaman Hoq, Mohammad Rubel Chowdhury, Fahima Khan, Ashraful Islam Rahman, Atiqur Bhaumik, Siddhartha K. Harris, Levelle O'Neal, Justin T. Trost, Jessica F. Alam, Nur Haq Jasinskas, Algis Dotsey, Emmanuel Kelly, Meagan Charles, Richelle C. Xu, Peng Kovac, Pavol Calderwood, Stephen B. Ryan, Edward T. Felgner, Phillip L. Qadri, Firdausi Wrammert, Jens Harrise, Jason B. TI Single-Cell Analysis of the Plasmablast Response to Vibrio cholerae Demonstrates Expansion of Cross-Reactive Memory B Cells SO MBIO LA English DT Article ID HUMAN MONOCLONAL-ANTIBODIES; DENGUE VIRUS-INFECTION; O1 EL-TOR; SALMONELLA-TYPHIMURIUM; HOUSEHOLD CONTACTS; IMMUNE-RESPONSES; TOXIN; BANGLADESH; LIPOPOLYSACCHARIDE; DYNAMICS AB We characterized the acute B cell response in adults with cholera by analyzing the repertoire, specificity, and functional characteristics of 138 monoclonal antibodies (MAbs) generated from single-cell-sorted plasmablasts. We found that the cholera-induced responses were characterized by high levels of somatic hypermutation and large clonal expansions. A majority of the expansions targeted cholera toxin (CT) or lipopolysaccharide (LPS). Using a novel proteomics approach, we were able to identify sialidase as another major antigen targeted by the antibody response to Vibrio cholerae infection. Antitoxin MAbs targeted both the A and B subunits, and most were also potent neutralizers of enterotoxigenic Escherichia coli heat-labile toxin. LPS-specific MAbs uniformly targeted the O-specific polysaccharide, with no detectable responses to either the core or the lipid moiety of LPS. Interestingly, the LPS-specific antibodies varied widely in serotype specificity and functional characteristics. One participant infected with the Ogawa serotype produced highly mutated LPS-specific antibodies that preferentially bound the previously circulating Inaba serotype. This demonstrates durable memory against a polysaccharide antigen presented at the mucosal surface and provides a mechanism for the long-term, partial heterotypic immunity seen following cholera. IMPORTANCE Cholera is a diarrheal disease that results in significant mortality. While oral cholera vaccines are beneficial, they do not achieve equivalent protection compared to infection with Vibrio cholerae. Although antibodies likely mediate protection, the mechanisms of immunity following cholera are poorly understood, and a detailed understanding of antibody responses to cholera is of significance for human health. In this study, we characterized the human response to cholera at the single-plasmablast, monoclonal antibody level. Although this approach has not been widely applied to the study of human bacterial infection, we were able to uncover the basis of cross-reactivity between different V. cholerae serotypes and the likely impact of prior enterotoxigenic Escherichia coli exposure on the response to cholera, as well as identify novel antigenic targets. In addition to improving our understanding of the repertoire and function of the antibody response to cholera in humans, this study has implications for future cholera vaccination efforts. C1 [Kauffman, Robert C.; Mayo-Smith, Leslie M.; Bhaumik, Siddhartha K.; Trost, Jessica F.; Wrammert, Jens] Emory Univ, Sch Med, Dept Pediat, Div Infect Dis, Atlanta, GA 30322 USA. [Kauffman, Robert C.; Bhaumik, Siddhartha K.; Harris, Levelle; O'Neal, Justin T.; Trost, Jessica F.; Wrammert, Jens] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Bhuiyan, Taufiqur R.; Rashu, Rasheduzzaman; Hoq, Mohammad Rubel; Chowdhury, Fahima; Khan, Ashraful Islam; Rahman, Atiqur; Alam, Nur Haq; Qadri, Firdausi] Int Ctr Diarrhoeal Dis Res, Div Infect Dis, Dhaka, Bangladesh. [Nakajima, Rie; Jasinskas, Algis; Dotsey, Emmanuel; Felgner, Phillip L.] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. [Rahman, Atiqur; Kelly, Meagan; Charles, Richelle C.; Calderwood, Stephen B.; Ryan, Edward T.; Harrise, Jason B.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Charles, Richelle C.; Calderwood, Stephen B.; Ryan, Edward T.] Harvard Med Sch, Dept Med, Boston, MA USA. [Xu, Peng; Kovac, Pavol] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Ryan, Edward T.] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA. [Harrise, Jason B.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. RP Wrammert, J (reprint author), Emory Univ, Sch Med, Dept Pediat, Div Infect Dis, Atlanta, GA 30322 USA.; Wrammert, J (reprint author), Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA.; Harrise, JB (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA.; Harrise, JB (reprint author), Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. EM jwramme@emory.edu; jbharris@partners.org FU HHS | National Institutes of Health (NIH) [AI103055, AI099243, AI106878, AI058935, AI074492, TW005572] FX This work, including the efforts of Firdausi Qadri, Jens Wrammert, and Jason B. Harris, was funded by HHS | National Institutes of Health (NIH) (AI103055). This work, including the efforts of Firdausi Qadri and Jason B. Harris, was funded by HHS | National Institutes of Health (NIH) (AI099243). This work, including the efforts of Edward T Ryan and Firdausi Qadri, was funded by HHS | National Institutes of Health (NIH) (AI106878). This work, including the efforts of Edward T Ryan and Firdausi Qadri, was funded by HHS | National Institutes of Health (NIH) (AI058935). This work, including the efforts of Robert C. Kauffman, was funded by HHS | National Institutes of Health (NIH) (AI074492). This work, including the efforts of Taufiqur Bhuiyan, was funded by HHS | National Institutes of Health (NIH) (TW005572). NR 44 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD NOV-DEC PY 2016 VL 7 IS 6 AR e02021 DI 10.1128/mBio.02021-16 PG 11 WC Microbiology SC Microbiology GA EH9GK UT WOS:000392079500066 ER PT J AU Roongpiboonsopit, D Charidimou, A William, CM Lauer, A Falcone, GJ Martinez-Ramirez, S Biffi, A Ayres, A Vashkevich, A Awosika, OO Rosand, J Gurol, ME Silverman, SB Greenberg, SM Viswanathan, A AF Roongpiboonsopit, Duangnapa Charidimou, Andreas William, Christopher M. Lauer, Arne Falcone, Guido J. Martinez-Ramirez, Sergi Biffi, Alessandro Ayres, Alison Vashkevich, Anastasia Awosika, Oluwole O. Rosand, Jonathan Gurol, M. Edip Silverman, Scott B. Greenberg, Steven M. Viswanathan, Anand TI Cortical superficial siderosis predicts early recurrent lobar hemorrhage SO NEUROLOGY LA English DT Article ID CEREBRAL AMYLOID ANGIOPATHY; PRIMARY INTRACEREBRAL HEMORRHAGE; TRANSIENT ISCHEMIC ATTACK; SUBARACHNOID HEMORRHAGE; APOLIPOPROTEIN-E; BLOOD-PRESSURE; WARNING SIGN; RISK; DISEASE AB Objective: To identify predictors of early lobar intracerebral hemorrhage (ICH) recurrence, defined as a new ICH within 6 months of the index event, in patients with cerebral amyloid angiopathy (CAA). Methods: Participants were consecutive survivors (age >= 55 years) of spontaneous symptomatic probable or possible CAA-related lobar ICH according to the Boston criteria, drawn from an ongoing single-center cohort study. Neuroimaging markers ascertained in CT or MRI included focal (<= 3 sulci) or disseminated (>3 sulci) cortical superficial siderosis (cSS), acute convexity subarachnoid hemorrhage (cSAH), cerebral microbleeds, white matter hyperintensities burden and location, and baseline ICH volume. Participants were followed prospectively for recurrent symptomatic ICH. Cox proportional hazards models were used to identify predictors of early recurrent ICH adjusting for potential confounders. Results: A total of 292 patients were enrolled. Twenty-one patients (7%) had early recurrent ICH. Of these, 24% had disseminated cSS on MRI and 19% had cSAH on CT scan. In univariable analysis, the presence of disseminated cSS, cSAH, and history of previous ICH were predictors of early recurrent ICH (p < 0.05 for all comparisons). After adjusting for age and history of previous ICH, disseminated cSS on MRI and cSAH on CT were independent predictors of early recurrent ICH (hazard ratio [HR] 3.92, 95% confidence interval [CI] 1.38-11.17, p = 0.011, and HR 3.48, 95% CI 1.13-10.73, p = 0.030, respectively). Conclusions: Disseminated cSS on MRI and cSAH on CT are independent imaging markers of increased risk for early recurrent ICH. These markers may provide additional insights into the mechanisms of ICH recurrence in patients with CAA. C1 [Roongpiboonsopit, Duangnapa; Charidimou, Andreas; Lauer, Arne; Falcone, Guido J.; Martinez-Ramirez, Sergi; Ayres, Alison; Vashkevich, Anastasia; Gurol, M. Edip; Silverman, Scott B.; Greenberg, Steven M.; Viswanathan, Anand] Harvard Med Sch, Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Hemorrhag Stroke Res Program, Boston, MA 02115 USA. [Biffi, Alessandro] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Div Behav Neurol, Boston, MA USA. [Biffi, Alessandro] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Div Neuropsychiat, Boston, MA USA. [William, Christopher M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Neuropathol Serv, Boston, MA USA. [Falcone, Guido J.; Rosand, Jonathan] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA USA. [Roongpiboonsopit, Duangnapa] Naresuan Univ, Fac Med, Dept Med, Phitsanulok, Thailand. [Awosika, Oluwole O.] NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Roongpiboonsopit, D (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Hemorrhag Stroke Res Program, Boston, MA 02115 USA.; Roongpiboonsopit, D (reprint author), Naresuan Univ, Fac Med, Dept Med, Phitsanulok, Thailand. EM duangnapar@nu.ac.th FU NIH [R01AG047975, R01AG026484, P50AG005134, K23AG028726, K23 NS083711, R01 NS070834] FX Supported by NIH (R01AG047975, R01AG026484, P50AG005134, K23AG028726, K23 NS083711, and R01 NS070834). NR 33 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 NOV 1 PY 2016 VL 87 IS 18 BP 1863 EP 1870 DI 10.1212/WNL.0000000000003281 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EI1JG UT WOS:000392232600008 PM 27694268 ER PT J AU Ligibel, JA AF Ligibel, Jennifer A. TI Jennifer Ligibel Discusses New Data Strengthening the Link Between Obesity and Cancer SO ONCOLOGY-NEW YORK LA English DT Editorial Material C1 [Ligibel, Jennifer A.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ligibel, JA (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD NOV PY 2016 VL 30 IS 11 BP 952 EP + PG 2 WC Oncology SC Oncology GA EI0WC UT WOS:000392194900001 ER PT J AU Neuwelt, E Ambady, P Muldoon, L McConnell, H Doolittle, N AF Neuwelt, Edward Ambady, Prakash Muldoon, Leslie McConnell, Heather Doolittle, Nancy TI Outwitting the Blood-Brain Barrier SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID PRIMARY CNS LYMPHOMA; FERUMOXYTOL; PSEUDOPROGRESSION; THERAPY; GLIOBLASTOMA; GADOTERIDOL; EFFICACY C1 [Neuwelt, Edward; Ambady, Prakash; Muldoon, Leslie; McConnell, Heather; Doolittle, Nancy] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Neuwelt, Edward] Oregon Hlth & Sci Univ, Dept Neurosurg, Portland, OR 97201 USA. [Neuwelt, Edward] Portland VA Med Ctr, Portland, OR USA. RP Neuwelt, E (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA.; Neuwelt, E (reprint author), Oregon Hlth & Sci Univ, Dept Neurosurg, Portland, OR 97201 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD NOV PY 2016 VL 30 IS 11 BP 963 EP 967 PG 3 WC Oncology SC Oncology GA EI0WC UT WOS:000392194900003 ER PT J AU White, A Swanson, SJ AF White, Abby Swanson, Scott J. TI Minimally Invasive Surgery for Early-Stage Lung Cancer: From Innovation to Standard of Care SO ONCOLOGY-NEW YORK LA English DT Article ID ASSISTED THORACIC-SURGERY; ADENOCARCINOMA IN-SITU; THORACOSCOPIC LOBECTOMY; PULMONARY-FUNCTION; VATS LOBECTOMY; CELL; CARCINOMA; THORACOTOMY; MORTALITY; PATHOLOGY AB The era of minimally invasive surgery for lung cancer follows decades of research; the collection and interpretation of countless qualitative and quantitative data points; and tireless efforts by a few pioneering thoracic surgeons who believed they could deliver a safe and oncologically sound operation with less tissue trauma, an improved physiologic profile, and fewer complications than traditional open surgery. This review highlights those efforts and the role of minimally invasive surgery for early-stage lung cancer in light of evolving technology, the emerging understanding of the biology of early-stage lung cancer, and lung cancer screening. C1 [White, Abby; Swanson, Scott J.] Brigham & Womens Hosp, Dept Surg, Div Thorac Surg, 75 Francis St, Boston, MA 02115 USA. [White, Abby; Swanson, Scott J.] Harvard Med Sch, Boston, MA 02115 USA. [White, Abby; Swanson, Scott J.] Dana Farber Canc Inst, Thorac Oncol Program, Boston, MA 02115 USA. [Swanson, Scott J.] Brigham & Womens Hosp, Div Thorac Surg, Minimally Invas Thorac Surg, 75 Francis St, Boston, MA 02115 USA. RP White, A (reprint author), Brigham & Womens Hosp, Dept Surg, Div Thorac Surg, 75 Francis St, Boston, MA 02115 USA.; White, A (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; White, A (reprint author), Dana Farber Canc Inst, Thorac Oncol Program, Boston, MA 02115 USA. NR 31 TC 1 Z9 1 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD NOV PY 2016 VL 30 IS 11 BP 982 EP 987 PG 6 WC Oncology SC Oncology GA EI0WC UT WOS:000392194900005 ER PT J AU Brown, JR AF Brown, Jennifer R. TI Using Targeted Inhibitors in the Management of Chronic Lymphocytic Leukemia: Are We There Yet? SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID IBRUTINIB; CYCLOPHOSPHAMIDE; FLUDARABINE; RITUXIMAB; OUTCOMES; CLL C1 [Brown, Jennifer R.] Dana Farber Canc Inst, Ctr Hematol Oncol, Boston, MA 02115 USA. RP Brown, JR (reprint author), Dana Farber Canc Inst, Ctr Hematol Oncol, Boston, MA 02115 USA. NR 14 TC 0 Z9 0 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD NOV PY 2016 VL 30 IS 11 BP 1016 EP 1018 PG 2 WC Oncology SC Oncology GA EI0WC UT WOS:000392194900010 ER PT J AU Jakobiec, FA Stagner, AM Sutula, FC Freitag, SK Yoon, MK AF Jakobiec, Frederick A. Stagner, Anna M. Sutula, Francis C. Freitag, Suzanne K. Yoon, Michael K. TI Pigmentation of the Lacrimal Sac Epithelium SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID PRIMARY ACQUIRED MELANOSIS; MALIGNANT-MELANOMA; MUCOSAL MELANOMAS; NASAL CAVITY; MELANOCYTIC LESIONS; NASOLACRIMAL DUCT; BLOODY TEARS; CONJUNCTIVA; NECK; HEAD AB Purpose: To describe the patterns of the melanocytic populations of 3 cases of lacrimal sac benign melanosis and 1 of atypical primary-acquired sac melanosis with a melanomatous nodule secondary to spread of atypical conjunctival primaryacquired melanosis to the sac. Methods: Clinical records, photographs, and paraffin sections stained with hematoxylin and eosin and the Fontana reaction were critically reviewed. Additional sections were immunoreacted for melanoma antigen recognized by T cells and microphthalmia-associated transcription factor. Five nonpigmented pterygia and 4 nonpigmented lacrimal sacs served as controls. Results: Three patients with obstructive dacryocystitis and benign melanosis were African-Americans whose sacs disclosed the presence of nonclustering, melanoma antigen recognized by T cells, and microphthalmia-associated transcription factorpositive intraepithelial dendritic melanocytes at all levels of the epithelium. The transferred melanin granules were concentrated in the adlumenal apical region of the epithelial cells. No fusiform melanocytes were found in the lamina propria. The fourth patient, a white, had atypical conjunctival and sac primary-acquired melanosis and conjunctival and sac melanomas. The intraepithelial sac melanocytes in this case were strikingly atypical and profusely distributed in a back to back fashion at all levels of a thickened epithelial layer focally approximating the appearance of a melanoma in situ. Five nonpigmented pterygia and 4 nonpigmented lacrimal sacs served as controls. Each displayed nonnesting dendritic melanocytes of various densities without back to back contact. Conclusion: Low densities of intraepithelial melanocytes were discovered in all controls and therefore represent a normal subpopulation within the conjunctival and lacrimal sacs. Due to the pseudostratification of the sac epithelium, melanocytes can move to higher levels without implying atypia. Benign melanosis is produced by small diffusely distributed individual intraepithelial melanocytes, whereas primary- acquired melanosis with atypia exhibits back to back, dense proliferations of large atypical melanocytes. C1 [Jakobiec, Frederick A.; Stagner, Anna M.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, David G Cogan Ophthalm Pathol Lab, Boston, MA USA. [Sutula, Francis C.; Freitag, Suzanne K.; Yoon, Michael K.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Ophthalm Plast Surg Serv, Boston, MA USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, 243 Charles St,Suite 328, Boston, MA 02114 USA. EM Fred_Jakobiec@meei.harvard.edu NR 53 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 0740-9303 EI 1537-2677 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD NOV-DEC PY 2016 VL 32 IS 6 BP 415 EP 423 DI 10.1097/IOP.0000000000000541 PG 9 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA EI1PN UT WOS:000392250000002 PM 26348325 ER PT J AU Davies, EC Jakobiec, FA Stagner, AM Iwamoto, MA AF Davies, Emma C. Jakobiec, Frederick A. Stagner, Anna M. Iwamoto, Mami A. TI A Rapidly Enlarging Recurrent Eyebrow Pilomatrixoma in a Nonagenarian SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID ADIPOPHILIN; CARCINOMAS; ONSET; MASS AB A rapidly growing, large (horizontal diameter of 3.1 cm) eyebrow lesion in a nonagenarian patient was found on pathologic examination to demonstrate an admixture of islands of anucleated, washed out eosinophilic "ghost" cells with surrounding nucleated, small germinal basaloid cells. Further analysis disclosed adipophilin granular positivity in the necrotic zones, negative nuclear staining for androgen receptor and strong nuclear positivity for Ki67 in the basaloid cells (proliferation index of 50%). These findings are consistent with a highly mitotically active pilomatrixoma. The lesion recurred after initial resection but returned the same histopathologic features as the primary. Several clinical features were notably atypical for pilomatrixoma-specifically, the age of the patient, rapid lesion growth and recurrence, and clinical appearance and large size of the mass. The immunohistochemical findings can help to distinguish this tumor from other skin neoplasms, especially sebaceous carcinoma in an older individual. C1 [Jakobiec, Frederick A.; Stagner, Anna M.] Massachusetts Eye & Ear Infirmary, David G Cogan Lab Ophthalm Pathol, Boston, MA USA. [Davies, Emma C.; Jakobiec, Frederick A.; Stagner, Anna M.] Massachusetts Eye & Ear Infirmary, Boston, MA USA. [Davies, Emma C.; Jakobiec, Frederick A.; Stagner, Anna M.] Harvard Med Sch, Dept Ophthalmol, Boston, MA USA. [Iwamoto, Mami A.] Ophthalm Consultants Boston, Boston, MA USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, Cogan Ophthalm Pathol Lab, 243 Charles St Room 321, Boston, MA 02114 USA. EM Fred_Jakobiec@meei.harvard.edu NR 18 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 0740-9303 EI 1537-2677 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD NOV-DEC PY 2016 VL 32 IS 6 BP E157 EP E160 DI 10.1097/IOP.0000000000000355 PG 5 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA EI1PN UT WOS:000392250000037 PM 25514663 ER PT J AU Grob, SR Jakobiec, FA Rashid, A MacIntosh, P Kelly, H Fay, A AF Grob, Seanna R. Jakobiec, Frederick A. Rashid, Alia MacIntosh, Peter Kelly, Hillary Fay, Aaron TI Pediatric Optic Nerve Meningioma: Diagnostic and Therapeutic Challenges SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID SHEATH MENINGIOMA; RADIATION-THERAPY; TUMORS; CHILDHOOD; PROTON; RADIOTHERAPY; SURGERY AB A 13-year-old female presented with left unilateral proptosis, blurry vision, and diplopia. Clinical examination showed left sided visual acuity of 20/50, limited extraocular movement, 5-mm proptosis, and optic disc edema. CT and MRI displayed a large, intraconal, well-demarcated soft tissue mass with inferotemporal displacement of the optic nerve. The imaging appearance was unusual and diagnosis remained uncertain. Histopathologic analysis of the biopsy specimen confirmed the diagnosis of atypical syncytial meningioma. The tumor cells were positive for both androgen and progesterone receptors and the Ki67 stain was positive (proliferation index of 8%). The patient was treated with proton beam radiation therapy (total dose 50.4 GyE) that suppressed tumor growth and has preserved visual acuity to date (20/40). Differential diagnosis and approaches to therapy are explored. C1 [Jakobiec, Frederick A.; Rashid, Alia; MacIntosh, Peter; Fay, Aaron] Harvard Med Sch, Dept Ophthalmol, Boston, MA USA. [Grob, Seanna R.; Jakobiec, Frederick A.; Rashid, Alia] Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Suite 328,243 Charles St., Boston, MA 02114 USA. [MacIntosh, Peter] Massachusetts Eye & Ear Infirm, Ophthalm Plast & Reconstruct Surg, Boston, MA 02114 USA. [Kelly, Hillary] Massachusetts Eye & Ear Infirm, Head & Neck Radiol Dept, Boston, MA 02114 USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Suite 328,243 Charles St., Boston, MA 02114 USA. EM Fred_Jakobiec@meei.harvard.edu NR 30 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 0740-9303 EI 1537-2677 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD NOV-DEC PY 2016 VL 32 IS 6 BP E160 EP E164 DI 10.1097/IOP.0000000000000357 PG 6 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA EI1PN UT WOS:000392250000038 PM 25585303 ER PT J AU Jakobiec, FA Rashid, A Yoon, MK AF Jakobiec, Frederick A. Rashid, Alia Yoon, Michael K. TI Isolated Nonsyndromic Intraneural Neuroma of the Eyelid Skin SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID SCHWANNOMA AB A 56-year-old man developed a 2 x 2 mm, yellow-orange painless, smooth-surfaced nodule in the middle third of his left upper eyelid. Microscopic evaluation disclosed a spindle cell tumor that was well circumscribed by a perineurium. The tumor cells manifested wavy, bland nuclei displaying comma-shaped and pointed ends. These cells were uniformly S100 positive. Immunohistochemical analysis further revealed an even dispersion of numerous dot-like neurofilaments diagnostic of an isolated intraneural neuroma. A neuroma differs from a schwannoma which fails to exhibit neurofilaments except in a peripherally located compressed nerve of origin. Simple excision is recommended. C1 [Jakobiec, Frederick A.; Rashid, Alia] Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, 243 Charles St,Suite 328, Boston, MA 02114 USA. [Jakobiec, Frederick A.; Rashid, Alia; Yoon, Michael K.] Harvard Med Sch, Dept Ophthalmol, Boston, MA USA. [Yoon, Michael K.] Massachusetts Eye & Ear Infirm, Ophthalm Plast Surg, Boston, MA 02114 USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, 243 Charles St,Suite 328, Boston, MA 02114 USA. EM fred_jakobiec@meei.harvard.edu NR 10 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 0740-9303 EI 1537-2677 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD NOV-DEC PY 2016 VL 32 IS 6 BP E147 EP E149 DI 10.1097/IOP.0000000000000341 PG 4 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA EI1PN UT WOS:000392250000032 PM 27828924 ER PT J AU Manchikanti, L Hirsch, JA AF Manchikanti, Laxmaiah Hirsch, Joshua A. TI Repeal and Replace of Affordable Care: A Complex, but Not an Impossible Task SO PAIN PHYSICIAN LA English DT Review DE Affordable Care Act; ObamaCare; Medicaid; exchanges; Trump plan; repeal; replace ID HEALTH-INSURANCE EXPERIMENT; PHYSICIAN-PAYMENT SCHEDULE; PAIN MANAGEMENT-PRACTICES; UNITED-STATES; STICK POLICY; NO HARM; FUTURE; ICD-10-CM; GROWTH; 1ST AB The Affordable Care Act (ACA), signature legislation of President Obama, was arguably the most consequential and comprehensive health care reform since Medicare was introduced as part of President Lyndon B. Johnson's great society. It has been claimed that many of the law's reforms are now so integrated in the health system that full repeal would be impractical, while others including President Elect Trump have rejected that idea and called for full repeal and replacement claiming ACA law cannot be fixed. A tsunami of increasing regulatory burden over the past 8 years, the current health care milieu has moved independent practitioners towards hospital employment in great numbers. In addition, public opinion has been slowly climbing against ObamaCare with 54% of Americans now opposing the law. President Obama has indicated that the law has accomplished many of its goals, including increasing accessibility, affordability, and quality of health care. However, others have contradicted these assertions and described the ACA as "insurance for many with coverage for few." Some believe that the ACA might be more appropriately labeled the "Medicaid Expansion Act." There are multiple plans developed over the years by republican members of the congress; however, of significant consequence and importance are President-elect Trump's proposals and the plan developed by Speaker Paul Ryan to repeal and replace the ACA. The President-elect has described the problems he perceives with the ACA; rapidly rising premiums and deductibles, narrow networks, and limits of coverage imposed by health insurance companies. The President-elect has indicated that his goal will be to create a patient-centered health care system that promotes choice, quality, and affordability with health insurance and health care, and take any needed action to alleviate the burdens imposed on American families and businesses by law. C1 [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Manchikanti, Laxmaiah] Univ Louisville, Louisville, KY 40292 USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Med Sch, Boston, MA USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com NR 45 TC 0 Z9 0 U1 4 U2 4 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD NOV PY 2016 VL 19 IS 8 BP E1109 EP E1114 PG 6 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA EI1UU UT WOS:000392272300001 PM 27906931 ER PT J AU Basnet, KM Bentley-Lewis, R Wexler, DJ Kilic, F Roberts, DJ AF Basnet, Kristen M. Bentley-Lewis, Rhonda Wexler, Deborah J. Kilic, Fusun Roberts, Drucilla J. TI Prevalence of Intervillous Thrombi Is Increased in Placentas from Pregnancies Complicated by Diabetes SO PEDIATRIC AND DEVELOPMENTAL PATHOLOGY LA English DT Article DE apoptosis; gestational diabetes; intervillous thrombi; placental pathology; pregestational diabetes; SERT; trophoblast ID SEROTONIN TRANSPORTER; TROPHOBLAST; APOPTOSIS; MELLITUS; OLIGOMERIZATION; PATHOLOGY; INFARCTS; STRESS; ERP44 AB Intervillous thrombus (IVT) is a placental pathology of unclear cause. One possible cause is that IVT protects against fetomaternal transfusion due to trophoblastic disruption. A role for hyperglycemia in trophoblast apoptosis has been suggested. We sought to determine whether placentas from pregnancies complicated by diabetes had an increased incidence of IVT. Medical records of 206 patients with type 1 diabetes (n = 39), type 2 diabetes (n = 37), and gestational diabetes (GDM, n = 130) at the Massachusetts General Hospital were identified. Placental pathology reports were reviewed to determine prevalence of IVT. Gestational and maternal age-matched controls were selected from the pathology archives consisting of placentas examined only for the indication of group B streptococcus screen positivity; controls were confirmed euglycemic and reviewed for IVT. Fisher exact test was used for statistical analysis. An increased incidence of IVT was present in all diabetics (type 1, type 2, and GDM; 32 of 206; 15.5%; P = 0.04) and GDM exclusively (22 of 130; 16.9%; P = 0.03) versus controls (7 of 99; 7.1%). IVT were also increased in patients with type 1 diabetes (4 of 39; 10.3%) and type 2 diabetes (6 of 37; 16.2%) compared to controls (7 of 99; 7.1%), but the results did not attain statistical significance (P = 0.73 and 0.19, respectively). The incidence of IVT was increased in the placentas of patients with diabetes as a group (type 1, type 2, and GDM), and in patients with GDM in particular. This is the first report of an association between diabetes and an increased incidence of placental IVT. C1 [Basnet, Kristen M.; Roberts, Drucilla J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Bentley-Lewis, Rhonda; Wexler, Deborah J.] Massachusetts Gen Hosp, Dept Med, Diabet Unit, Boston, MA 02114 USA. [Kilic, Fusun] Univ Arkansas Med Sci, Dept Biochem & Mol Biol, Little Rock, AR 72205 USA. RP Roberts, DJ (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM djroberts@partners.org NR 29 TC 1 Z9 1 U1 0 U2 0 PU ALLIANCE COMMUNICATIONS GROUP DIVISION ALLEN PRESS PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 1093-5266 EI 1615-5742 J9 PEDIATR DEVEL PATHOL JI Pediatr. Dev. Pathol. PD NOV-DEC PY 2016 VL 19 IS 6 BP 502 EP 505 DI 10.2350/15-11-1734-OA.1 PG 4 WC Pathology; Pediatrics SC Pathology; Pediatrics GA EI1AE UT WOS:000392206400007 PM 26669929 ER PT J AU Odajima, J Saini, S Jung, P Ndassa-Colday, Y Ficaro, S Geng, Y Marco, E Michowski, W Wang, YE DeCaprio, JA Litovchick, L Marto, J Sicinski, P AF Odajima, Junko Saini, Siddharth Jung, Piotr Ndassa-Colday, Yasmine Ficaro, Scott Geng, Yan Marco, Eugenio Michowski, Wojciech Wang, Yaoyu E. DeCaprio, James A. Litovchick, Larisa Marto, Jarrod Sicinski, Piotr TI Proteomic Landscape of Tissue-Specific Cyclin E Functions in Vivo SO PLOS GENETICS LA English DT Article ID HISTONE GENE-TRANSCRIPTION; CDK2-DEPENDENT PHOSPHORYLATION; DEPENDENT KINASES; P300 COACTIVATOR; MALE MEIOSIS; A-MYB; MICE; CDK2; SPERMATOGENESIS; SENESCENCE AB E-type cyclins (cyclins E1 and E2) are components of the cell cycle machinery that has been conserved from yeast to humans. The major function of E-type cyclins is to drive cell division. It is unknown whether in addition to their 'core' cell cycle functions, E-type cyclins also perform unique tissue-specific roles. Here, we applied high-throughput mass spectrometric analyses of mouse organs to define the repertoire of cyclin E protein partners in vivo. We found that cyclin E interacts with distinct sets of proteins in different compartments. These cyclin E interactors are highly enriched for phosphorylation targets of cyclin E and its catalytic partner, the cyclin-dependent kinase 2 (Cdk2). Among cyclin E interactors we identified several novel tissue-specific substrates of cyclin E-Cdk2 kinase. In proliferating compartments, cyclin E-Cdk2 phosphorylates Lin proteins within the DREAM complex. In the testes, cyclin E-Cdk2 phosphorylates Mybl1 and Dmrtc2, two meiotic transcription factors that represent key regulators of spermatogenesis. In embryonic and adult brains cyclin E interacts with proteins involved in neurogenesis, while in adult brains also with proteins regulating microtubule-based processes and microtubule cytoskeleton. We also used quantitative proteomics to demonstrate re-wiring of the cyclin E interactome upon ablation of Cdk2. This approach can be used to study how protein interactome changes during development or in any pathological state such as aging or cancer. C1 [Odajima, Junko; Jung, Piotr; Ndassa-Colday, Yasmine; Ficaro, Scott; Geng, Yan; Michowski, Wojciech; Marto, Jarrod; Sicinski, Piotr] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Odajima, Junko; Jung, Piotr; Geng, Yan; Michowski, Wojciech; Sicinski, Piotr] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Saini, Siddharth; Litovchick, Larisa] Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA USA. [Saini, Siddharth; Litovchick, Larisa] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. [Ndassa-Colday, Yasmine; Ficaro, Scott; Marto, Jarrod] Harvard Med Sch, Dept Biochem & Mol Pharmacol, Boston, MA USA. [Marco, Eugenio] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Marco, Eugenio] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Wang, Yaoyu E.] Dana Farber Canc Inst, Ctr Canc Computat Biol, Boston, MA 02115 USA. [DeCaprio, James A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [DeCaprio, James A.] Harvard Med Sch, Dept Med, Boston, MA USA. RP Sicinski, P (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA.; Sicinski, P (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. EM peter_sicinski@dfci.harvard.edu FU NIH [R01CA083688, R01 CA202634] FX This work was supported by NIH grant R01CA083688 and R01 CA202634 (to PS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 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 1553-7404 J9 PLOS GENET JI PLoS Genet. PD NOV PY 2016 VL 12 IS 11 AR e1006429 DI 10.1371/journal.pgen.1006429 PG 27 WC Genetics & Heredity SC Genetics & Heredity GA EH9ZA UT WOS:000392129600033 PM 27828963 ER PT J AU Lourdault, K Matsunaga, J Haake, DA AF Lourdault, Kristel Matsunaga, James Haake, David A. TI High-Throughput Parallel Sequencing to Measure Fitness of Leptospira interrogans Transposon Insertion Mutants during Acute Infection SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID GENE-EXPRESSION; BORRELIA-BURGDORFERI; MOLECULAR-CLONING; URBAN EPIDEMIC; VIRULENCE; GENOME; PROTEINS; HOST; DISSEMINATION; PATHOGENESIS AB Pathogenic species of Leptospira are the causative agents of leptospirosis, a zoonotic disease that causes mortality and morbidity worldwide. The understanding of the virulence mechanisms of Leptospira spp is still at an early stage due to the limited number of genetic tools available for this microorganism. The development of random transposon mutagenesis in pathogenic strains a decade ago has contributed to the identification of several virulence factors. In this study, we used the transposon sequencing (Tn-Seq) technique, which combines transposon mutagenesis with massive parallel sequencing, to study the in vivo fitness of a pool of Leptospira interrogans mutants. We infected hamsters with a pool of 42 mutants (input pool), which included control mutants with insertions in four genes previously analyzed by virulence testing (loa22, ligB, flaA1, and lic20111) and 23 mutants with disrupted signal transduction genes. We quantified the mutants in different tissues (blood, kidney and liver) at 4 days post-challenge by high-throughput sequencing and compared the frequencies of mutants recovered from tissues to their frequencies in the input pool. Control mutants that were less fit in the Tn-Seq experiment were attenuated for virulence when tested separately in the hamster model of lethal leptospirosis. Control mutants with unaltered fitness were as virulent as the wild-type strain. We identified two mutants with the transposon inserted in the same putative adenylate/guanylate cyclase gene (lic12327) that had reduced in vivo fitness in blood, kidney and liver. Both lic12327 mutants were attenuated for virulence when tested individually in hamsters. Growth of the control mutants and lic12327 mutants in culture medium were similar to that of the wild-type strain. These results demonstrate the feasibility of screening large pools of L. interrogans transposon mutants for those with altered fitness, and potentially attenuated virulence, by transposon sequencing. C1 [Lourdault, Kristel; Matsunaga, James; Haake, David A.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Lourdault, Kristel; Matsunaga, James; Haake, David A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Haake, David A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. [Haake, David A.] Univ Calif Los Angeles, Dept Microbiol, Los Angeles, CA 90024 USA. [Haake, David A.] Univ Calif Los Angeles, Dept Immunol, Los Angeles, CA USA. [Haake, David A.] Univ Calif Los Angeles, Dept Mol Genet, Los Angeles, CA USA. RP Lourdault, K (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA.; Lourdault, K (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. EM kristel.lourdault@gmail.com FU Veterans Affairs Merit Award; National Institutes of Health [R01 AI 034431] FX This work was supported by a Veterans Affairs Merit Award to DAH (http://www.research.va.gov/services/shared_docs/merit_review.cfm) and a National Institutes of Health grant R01 AI 034431 to DAH (https://www.niaid.nih.gov/research/research-funded-niaid). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 2 Z9 2 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD NOV PY 2016 VL 10 IS 11 AR e0005117 DI 10.1371/journal.pntd.0005117 PG 27 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA EI0HR UT WOS:000392154400039 PM 27824878 ER PT J AU Uddin, MI Islam, S Nishat, NS Hossain, M Rafique, TA Rashu, R Hoq, MR Zhang, Y Saha, A Harris, JB Calderwood, SB Bhuiyan, TR Ryan, ET Leung, DT Qadri, F AF Uddin, Muhammad Ikhtear Islam, Shahidul Nishat, Naoshin S. Hossain, Motaher Rafique, Tanzeem Ahmed Rashu, Rasheduzzaman Hoq, Mohammad Rubel Zhang, Yue Saha, Amit Harris, Jason B. Calderwood, Stephen B. Bhuiyan, Taufiqur Rahman Ryan, Edward T. Leung, Daniel T. Qadri, Firdausi TI Biomarkers of Environmental Enteropathy are Positively Associated with Immune Responses to an Oral Cholera Vaccine in Bangladeshi Children SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID B-CELL RESPONSES; KILLED CHOLERA; ENTERIC DYSFUNCTION; LIPOPOLYSACCHARIDE; INFANTS; INFECTION; GROWTH; TOXIN; O1; CONSEQUENCES AB Environmental enteropathy (EE) is a poorly understood condition that refers to chronic alterations in intestinal permeability, absorption, and inflammation, which mainly affects young children in resource-limited settings. Recently, EE has been linked to suboptimal oral vaccine responses in children, although immunological mechanisms are poorly defined. The objective of this study was to determine host factors associated with immune responses to an oral cholera vaccine (OCV). We measured antibody and memory T cell immune responses to cholera antigens, micronutrient markers in blood, and EE markers in blood and stool from 40 Bangladeshi children aged 3-14 years who received two doses of OCV given 14 days apart. EE markers included stool myeloperoxidase (MPO) and alpha anti-trypsin (AAT), and plasma endotoxin core antibody (EndoCab), intestinal fatty acid binding protein (i-FABP), and soluble CD14 (sCD14). We used multiple linear regression analysis with LASSO regularization to identify host factors, including EE markers, micronutrient (nutritional) status, age, and HAZ score, predictive for each response of interest. We found stool MPO to be positively associated with IgG antibody responses to the B subunit of cholera toxin (P = 0.03) and IgA responses to LPS (P = 0.02); plasma sCD14 to be positively associated with LPS IgG responses (P = 0.07); plasma i-FABP to be positively associated with LPS IgG responses (P = 0.01) and with memory T cell responses specific to cholera toxin (P = 0.01); stool AAT to be negatively associated with IL-10 (regulatory) T cell responses specific to cholera toxin (P = 0.02), and plasma EndoCab to be negatively associated with cholera toxin-specific memory T cell responses (P = 0.02). In summary, in a cohort of children 3-14 years old, we demonstrated that the majority of biomarkers of environmental enteropathy were positively associated with immune responses after vaccination with an OCV. C1 [Uddin, Muhammad Ikhtear; Islam, Shahidul; Nishat, Naoshin S.; Hossain, Motaher; Rafique, Tanzeem Ahmed; Rashu, Rasheduzzaman; Hoq, Mohammad Rubel; Saha, Amit; Bhuiyan, Taufiqur Rahman; Leung, Daniel T.; Qadri, Firdausi] Icddr B, Div Infect Dis, Mucosal Immunol & Vaccinol Lab, Dhaka, Bangladesh. [Zhang, Yue] Univ Utah, Sch Med, Dept Internal Med, Div Epidemiol, Salt Lake City, UT USA. [Leung, Daniel T.] Univ Utah, Sch Med, Dept Internal Med, Div Infect Dis, Salt Lake City, UT USA. [Leung, Daniel T.] Univ Utah, Sch Med, Dept Pathol, Div Microbiol & Immunol, Salt Lake City, UT USA. [Harris, Jason B.; Calderwood, Stephen B.; Ryan, Edward T.] Massachusetts Gen Hosp, Dept Immunol & Infect Dis, Div Infect Dis, Boston, MA 02114 USA. [Harris, Jason B.] Harvard Med Sch, Dept Pediat, Boston, MA USA. [Calderwood, Stephen B.; Ryan, Edward T.] Harvard Med Sch, Dept Med, Boston, MA USA. RP Qadri, F (reprint author), Icddr B, Div Infect Dis, Mucosal Immunol & Vaccinol Lab, Dhaka, Bangladesh. EM fqadri@icddrb.org OI leung, daniel/0000-0001-8401-0801 FU icddr,b; National Institutes of Health, including the National Institute of Allergy and Infectious Diseases [R01 AI106878, U01 AI058935, R03 AI063079, K08AI100923, R01AI103055]; Fogarty International Center, Training Grant in Vaccine Development and Public Health [TW005572]; Swedish Sida grant [INT-ICDDR,B-HN-01-AV]; Thrasher Research Fund Early Career Award FX This research was supported by the icddr,b and by grants from the National Institutes of Health, including the National Institute of Allergy and Infectious Diseases (R01 AI106878 [ETR], U01 AI058935 [SBC, ETR], R03 AI063079 [FQ]), K08AI100923 [DTL], R01AI103055 [JBH]) and the Fogarty International Center, Training Grant in Vaccine Development and Public Health (TW005572 [MIU, RR, MRH, TRB]), as well as by Swedish Sida grant INT-ICDDR,B-HN-01-AV (FQ), and a Thrasher Research Fund Early Career Award (DTL). icddr,b is thankful to the donors for their support to its research efforts. icddr,b is also grateful to the Government of Bangladesh, Canada, Sweden and the UK for providing core/unrestricted support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD NOV PY 2016 VL 10 IS 11 AR e0005039 DI 10.1371/journal.pntd.0005039 PG 10 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA EI0HR UT WOS:000392154400014 PM 27824883 ER PT J AU Berrios, C Padi, M Keibler, MA Park, DE Molla, V Cheng, JW Lee, SM Stephanopoulos, G Quackenbush, J DeCaprio, JA AF Berrios, Christian Padi, Megha Keibler, Mark A. Park, Donglim Esther Molla, Vadim Cheng, Jingwei Lee, Soo Mi Stephanopoulos, Gregory Quackenbush, John DeCaprio, James A. TI Merkel Cell Polyomavirus Small T Antigen Promotes Pro-Glycolytic Metabolic Perturbations Required for Transformation SO PLOS PATHOGENS LA English DT Article ID TUMOR-CELLS; LUNG-CANCER; MYC; EXPRESSION; PROLIFERATION; PROTEIN; GROWTH; VIRUS; AMPLIFICATION; REPLICATION AB Merkel cell polyomavirus (MCPyV) is an etiological agent of Merkel cell carcinoma (MCC), a highly aggressive skin cancer. The MCPyV small tumor antigen (ST) is required for maintenance of MCC and can transform normal cells. To gain insight into cellular perturbations induced by MCPyV ST, we performed transcriptome analysis of normal human fibroblasts with inducible expression of ST. MCPyV ST dynamically alters the cellular transcriptome with increased levels of glycolytic genes, including the monocarboxylate lactate transporter SLC16A1 (MCT1). Extracellular flux analysis revealed increased lactate export reflecting elevated aerobic glycolysis in ST expressing cells. Inhibition of MCT1 activity suppressed the growth of MCC cell lines and impaired MCPyV-dependent transformation of IMR90 cells. Both NF-kappa B and MYC have been shown to regulate MCT1 expression. While MYC was required for MCT1 induction, MCPyV-induced MCT1 levels decreased following knockdown of the NF-kappa B subunit RelA, supporting a synergistic activity between MCPyV and MYC in regulating MCT1 levels. Several MCC lines had high levels of MYCL and MYCN but not MYC. Increased levels of MYCL was more effective than MYC or MYCN in increasing extracellular acidification in MCC cells. Our results demonstrate the effects of MCPyV ST on the cellular transcriptome and reveal that transformation is dependent, at least in part, on elevated aerobic glycolysis. C1 [Berrios, Christian; Park, Donglim Esther; Molla, Vadim; Cheng, Jingwei; DeCaprio, James A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Berrios, Christian; Park, Donglim Esther; Lee, Soo Mi; DeCaprio, James A.] Harvard Univ, Grad Sch Arts & Sci, Program Virol, Cambridge, MA 02138 USA. [Padi, Megha; Quackenbush, John] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Quackenbush, John] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Keibler, Mark A.; Stephanopoulos, Gregory] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Cheng, Jingwei; DeCaprio, James A.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Padi, Megha] Harvard Med Sch, Dept Med, Boston, MA USA. RP DeCaprio, JA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; DeCaprio, JA (reprint author), Harvard Univ, Grad Sch Arts & Sci, Program Virol, Cambridge, MA 02138 USA.; DeCaprio, JA (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. EM james_decaprio@dfci.harvard.edu OI Quackenbush, John/0000-0002-2702-5879 FU US Public Health Service [R01CA63113, R01CA173023, P01CA050661, F31CA177274, K25HG006031, R01HL111759, R01DK075850, R01CM 60458] FX This work was supported in part by US Public Health Service (http://www.nih.gov/), grants R01CA63113, R01CA173023, and P01CA050661 to JAD; F31CA177274 to CB; K25HG006031 to MP; R01HL111759 to JQ; R01DK075850 and R01CM 60458 to GS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 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 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD NOV PY 2016 VL 12 IS 11 AR e1006020 DI 10.1371/journal.ppat.1006020 PG 21 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EI0VO UT WOS:000392193200042 PM 27880818 ER PT J AU Mima, K Cao, Y Chan, AT Qian, ZR Nowak, JA Masugi, Y Shi, Y Song, M da Silva, A Gu, MC Li, W Hamada, T Kosumi, K Hanyuda, A Liu, L Kostic, AD Giannakis, M Bullman, S Brennan, CA Milner, DA Baba, H Garraway, LA Meyerhardt, JA Garrett, WS Huttenhower, C Meyerson, M Giovannucci, EL Fuchs, CS Nishihara, R Ogino, S AF Mima, Kosuke Cao, Yin Chan, Andrew T. Qian, Zhi Rong Nowak, Jonathan A. Masugi, Yohei Shi, Yan Song, Mingyang da Silva, Annacarolina Gu, Mancang Li, Wanwan Hamada, Tsuyoshi Kosumi, Keisuke Hanyuda, Akiko Liu, Li Kostic, Aleksandar D. Giannakis, Marios Bullman, Susan Brennan, Caitlin A. Milner, Danny A. Baba, Hideo Garraway, Levi A. Meyerhardt, Jeffrey A. Garrett, Wendy S. Huttenhower, Curtis Meyerson, Matthew Giovannucci, Edward L. Fuchs, Charles S. Nishihara, Reiko Ogino, Shuji TI Fusobacterium nucleatum in Colorectal Carcinoma Tissue According to Tumor Location SO CLINICAL AND TRANSLATIONAL GASTROENTEROLOGY LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; COLON-CANCER; PIK3CA MUTATION; SERRATED PATHWAY; PATIENT SURVIVAL; GUT MICROBIOTA; KRAS MUTATION; BRAF MUTATION; 2 SIDES AB OBJECTIVES: Evidence suggests a possible role of Fusobacterium nucleatum in colorectal carcinogenesis, especially in right-sided proximal colorectum. Considering a change in bowel contents and microbiome from proximal to distal colorectal segments, we hypothesized that the proportion of colorectal carcinoma enriched with F. nucleatum might gradually increase along the bowel subsites from rectum to cecum. METHODS: A retrospective, cross-sectional analysis was conducted on 1,102 colon and rectal carcinomas in molecular pathological epidemiology databases of the Nurses' Health Study and the Health Professionals Follow-up Study. We measured the amount of F. nucleatum DNA in colorectal tumor tissue using a quantitative PCR assay and equally dichotomized F. nucleatum-positive cases (high vs. low). We used multivariable logistic regression analysis to examine the relationship of a bowel subsite variable (rectum, rectosigmoid junction, sigmoid colon, descending colon, splenic flexure, transverse colon, hepatic flexure, ascending colon, and cecum) with the amount of F. nucleatum. RESULTS: The proportion of F. nucleatum-high colorectal cancers gradually increased from rectal cancers (2.5%; 4/157) to cecal cancers (11%; 19/178), with a statistically significant linear trend along all subsites (P<0.0001) and little evidence of non-linearity. The proportion of F. nucleatum-low cancers was higher in rectal, ascending colon, and cecal cancers than in cancers of middle segments. CONCLUSIONS: The proportion of F. nucleatum-high colorectal cancers gradually increases from rectum to cecum. Our data support the colorectal continuum model that reflects pathogenic influences of the gut microbiota on neoplastic and immune cells and challenges the prevailing two-colon (proximal vs. distal) dichotomy paradigm. C1 [Mima, Kosuke; Qian, Zhi Rong; Masugi, Yohei; Shi, Yan; da Silva, Annacarolina; Gu, Mancang; Li, Wanwan; Hamada, Tsuyoshi; Kosumi, Keisuke; Hanyuda, Akiko; Liu, Li; Giannakis, Marios; Bullman, Susan; Garraway, Levi A.; Meyerhardt, Jeffrey A.; Garrett, Wendy S.; Meyerson, Matthew; Fuchs, Charles S.; Nishihara, Reiko; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Room M422, Boston, MA 02215 USA. [Mima, Kosuke; Cao, Yin; Chan, Andrew T.; Qian, Zhi Rong; Nowak, Jonathan A.; Masugi, Yohei; Shi, Yan; Song, Mingyang; da Silva, Annacarolina; Gu, Mancang; Li, Wanwan; Hamada, Tsuyoshi; Kosumi, Keisuke; Hanyuda, Akiko; Liu, Li; Kostic, Aleksandar D.; Giannakis, Marios; Bullman, Susan; Milner, Danny A.; Garraway, Levi A.; Meyerhardt, Jeffrey A.; Garrett, Wendy S.; Huttenhower, Curtis; Meyerson, Matthew; Giovannucci, Edward L.; Fuchs, Charles S.; Nishihara, Reiko; Ogino, Shuji] Harvard Med Sch, Boston, MA USA. [Cao, Yin; Chan, Andrew T.; Song, Mingyang] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA. [Cao, Yin; Chan, Andrew T.; Song, Mingyang] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Cao, Yin; Song, Mingyang; Giovannucci, Edward L.; Nishihara, Reiko] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Chan, Andrew T.; Giovannucci, Edward L.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Nowak, Jonathan A.; Milner, Danny A.; Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Div MPE Mol Pathol Epidemiol, Boston, MA 02215 USA. [Kostic, Aleksandar D.; Huttenhower, Curtis] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Kostic, Aleksandar D.; Giannakis, Marios; Bullman, Susan; Garraway, Levi A.; Garrett, Wendy S.; Huttenhower, Curtis; Meyerson, Matthew] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Kostic, Aleksandar D.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Giannakis, Marios; Garraway, Levi A.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Brennan, Caitlin A.; Milner, Danny A.; Garrett, Wendy S.] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA. [Baba, Hideo] Kumamoto Univ, Grad Sch Med Sci, Dept Surg Gastroenterol, Kumamoto, Japan. [Huttenhower, Curtis] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Giovannucci, Edward L.; Nishihara, Reiko; Ogino, Shuji] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Nishihara, R (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Room M422, Boston, MA 02215 USA.; Ogino, S (reprint author), Brigham & Womens Hosp, Dept Pathol, Div MPE Mol Pathol Epidemiol, Boston, MA 02215 USA. EM rnishiha@hsph.harvard.edu; shuji_ogino@dfci.harvard.edu OI Masugi, Yohei/0000-0002-6952-4043 FU US National Institutes of Health (NIH) [P01 CA87969, UM1 CA186107, P01 CA55075, UM1 CA167552, P50 CA127003, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673]; Project P Fund; Friends of the Dana-Farber Cancer Institute; Bennett Family Fund; Entertainment Industry Foundation through National Colorectal Cancer Research Alliance; Japan Society for the Promotion of Science FX This work was supported by US National Institutes of Health (NIH) grants (P01 CA87969 to M.J. Stampfer; UM1 CA186107 to M.J. Stampfer; P01 CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; P50 CA127003 to C.S.F.; R01 CA137178 to A.T.C.; R01 CA151993 to S.O.; R35 CA197735 to S.O.; and K07 CA190673 to R.N.); and by grants from the Project P Fund, The Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. K.M. is supported by a grant from Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers from Japan Society for the Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 2 Z9 2 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2155-384X J9 CLIN TRANSL GASTROEN JI Clin. Transl. Gastroenterol. PD NOV PY 2016 VL 7 AR e200 DI 10.1038/ctg.2016.53 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EH5MF UT WOS:000391816500001 PM 27811909 ER PT J AU Ben-Hamo, M Larson, TA Duge, LS Sikkema, C Wilkinson, CW de la Iglesia, HO Gonzalez, MMC AF Ben-Hamo, Miriam Larson, Tracy A. Duge, Leanne S. Sikkema, Carl Wilkinson, Charles W. de la Iglesia, Horacio O. Gonzalez, Monica M. C. TI Circadian Forced Desynchrony of the Master Clock Leads to Phenotypic Manifestation of Depression in Rats SO ENEURO LA English DT Article DE behavior; circadian rhythms; depression; emotion; rat ID MOOD DISORDERS; SUPRACHIASMATIC NUCLEUS; SEXUAL DYSFUNCTION; MAJOR DEPRESSION; LIGHT THERAPY; RHYTHM DISTURBANCES; PREFRONTAL CORTEX; CHRONIC STRESS; SLEEP-WAKE; BEHAVIOR AB In mammals, a master circadian clock within the suprachiasmatic nucleus (SCN) of the hypothalamus maintains the phase coherence among a wide array of behavioral and physiological circadian rhythms. Affective disorders are typically associated with disruption of this fine-tuned "internal synchronization," but whether this internal misalignment is part of the physiopathology of mood disorders is not clear. To date, depressive-like behavior in animal models has been induced by methods that fail to specifically target the SCN regulation of internal synchronization as the mode to generate depression. In the rat, exposure to a 22-h light-dark cycle (LD22) leads to the uncoupling of two distinct populations of neuronal oscillators within the SCN. This genetically, neurally, and pharmacologically intact animal model represents a unique opportunity to assess the effect of a systematic challenge to the central circadian pacemaker on phenotypic manifestations of mood disorders. We show that LD22 circadian forced desynchrony in rats induces depressive-like phenotypes including anhedonia, sexual dysfunction, and increased immobility in the forced swim test (FST), as well as changes in the levels and turnover rates of monoamines within the prefrontal cortex. Desynchronized rats show increased FST immobility during the dark (active) phase but decreased immobility during the light (rest) phase, suggesting a decrease in the amplitude of the normal daily oscillation in this behavioral manifestation of depression. Our results support the notion that the prolonged internal misalignment of circadian rhythms induced by environmental challenge to the central circadian pacemaker may constitute part of the etiology of depression. C1 [Ben-Hamo, Miriam; Larson, Tracy A.; Duge, Leanne S.; de la Iglesia, Horacio O.; Gonzalez, Monica M. C.] Univ Washington, Dept Biol, Seattle, WA 98195 USA. [Ben-Hamo, Miriam; de la Iglesia, Horacio O.] Univ Washington, Program Neurosci, Seattle, WA 98195 USA. [Sikkema, Carl; Wilkinson, Charles W.] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Sikkema, Carl; Wilkinson, Charles W.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Gonzalez, Monica M. C.] Inst Ferrero Neurol & Sueno, Buenos Aires, DF, Argentina. [Larson, Tracy A.] Univ Virginia, Dept Biol, Charlottesville, VA USA. RP de la Iglesia, HO (reprint author), Univ Washington, Dept Biol, Seattle, WA 98195 USA.; Gonzalez, MMC (reprint author), Inst Ferrero Neurol & Sueno IFN, RA-1120 Junin, Caba, Argentina. EM horaciod@uw.edu; mgonzalez@ifn.com.ar OI Ben-Hamo, Miriam/0000-0002-4879-3658 FU HHS, National Institutes of Health [R01MH075016, R01NS094211]; National Science Foundation [IOS0909716]; National Alliance for Research on Schizophrenia and Depression; Israeli Committee for Higher Education; Washington Research Foundation Innovation postdoctoral fellowship in Neuroengineering]; Geriatric Research, Education and Clinical Center; Research and Development Service of the VA Puget Sound Health Care System FX Supported by HHS, National Institutes of Health [R01MH075016 R01NS094211]; National Science Foundation [IOS0909716]; National Alliance for Research on Schizophrenia and Depression [Young Investigator Award]; Israeli Committee for Higher Education [Postdoctoral Fellowship for Women]; Washington Research Foundation Innovation postdoctoral fellowship in Neuroengineering]; Geriatric Research, Education and Clinical Center, and the Research and Development Service of the VA Puget Sound Health Care System. NR 63 TC 0 Z9 0 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 2373-2822 J9 ENEURO JI eNeuro PD NOV-DEC PY 2016 VL 3 IS 6 AR UNSP e0237 DI 10.1523/ENEURO.0237-16.2016 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EH7CQ UT WOS:000391930900019 ER PT J AU Hodkinson, DJ Veggeberg, R Kucyi, A van Dijk, KRA Wilcox, SL Scrivani, SJ Burstein, R Becerra, L Borsook, D AF Hodkinson, Duncan J. Veggeberg, Rosanna Kucyi, Aaron van Dijk, Koene R. A. Wilcox, Sophie L. Scrivani, Steven J. Burstein, Rami Becerra, Lino Borsook, David TI Cortico-Cortical Connections of Primary Sensory Areas and Associated Symptoms in Migraine SO ENEURO LA English DT Article DE connectivity; cortico-cortical; headache; migraine; pain; sensory ID INTRINSIC FUNCTIONAL CONNECTIVITY; PRIMARY SOMATOSENSORY CORTEX; GLOBAL SIGNAL REGRESSION; HUMAN CEREBRAL-CORTEX; RESTING STATE FMRI; AUDITORY-CORTEX; MULTISENSORY INTEGRATION; HUMAN BRAIN; PREMONITORY FEATURES; CUTANEOUS ALLODYNIA AB Migraine is a recurring, episodic neurological disorder characterized by headache, nausea, vomiting, and sensory disturbances. These events are thought to arise from the activation and sensitization of neurons along the trigeminovascular pathway. From animal studies, it is known that thalamocortical projections play an important role in the transmission of nociceptive signals from the meninges to the cortex. However, little is currently known about the potential involvement of cortico-cortical feedback projections from higher-order multisensory areas and/or feedforward projections from principle primary sensory areas or subcortical structures. In a large cohort of human migraine patients (N = 40) and matched healthy control subjects (N = 40), we used resting-state intrinsic functional connectivity to examine the cortical networks associated with the three main sensory perceptual modalities of vision, audition, and somatosensation. Specifically, we sought to explore the complexity of the sensory networks as they converge and become functionally coupled in multimodal systems. We also compared self-reported retrospective migraine symptoms in the same patients, examining the prevalence of sensory symptoms across the different phases of the migraine cycle. Our results show widespread and persistent disturbances in the perceptions of multiple sensory modalities. Consistent with this observation, we discovered that primary sensory areas maintain local functional connectivity but express impaired long-range connections to higher-order association areas (including regions of the default mode and salience network). We speculate that cortico-cortical interactions are necessary for the integration of information within and across the sensory modalities and, thus, could play an important role in the initiation of migraine and/or the development of its associated symptoms. C1 [Hodkinson, Duncan J.; Veggeberg, Rosanna; Wilcox, Sophie L.; Becerra, Lino; Borsook, David] Harvard Med Sch, Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, 1 Autumn St, Boston, MA 02115 USA. [Kucyi, Aaron] Stanford Univ, Dept Neurol & Neurol Sci, Palo Alto, CA 94305 USA. [van Dijk, Koene R. A.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Scrivani, Steven J.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02115 USA. [Burstein, Rami] Harvard Med Sch, Dept Anesthesia & Crit Care, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. RP Hodkinson, DJ (reprint author), Harvard Med Sch, Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, 1 Autumn St, Boston, MA 02115 USA. EM duncan.hodkinson@childrens.harvard.edu OI Becerra, Lino/0000-0002-5840-1160; Van Dijk, Koene/0000-0001-6137-4282 FU National Institutes of Health [RO1-NS-073977, K24-NS-064050] FX National Institutes of Health Grants RO1-NS-073977 and K24-NS-064050 funded this study. NR 82 TC 0 Z9 0 U1 4 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 2373-2822 J9 ENEURO JI eNeuro PD NOV-DEC PY 2016 VL 3 IS 6 AR UNSP e0163 DI 10.1523/ENEURO.0163-16.2016 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EH7CQ UT WOS:000391930900008 ER PT J AU Mul, JD Zheng, J Goodyear, LJ AF Mul, Joram D. Zheng, Jia Goodyear, Laurie J. TI Validity Assessment of 5 Day Repeated Forced-Swim Stress to Model Human Depression in Young-Adult C57BL/6J and BALB/cJ Mice SO ENEURO LA English DT Article DE anhedonia; animal model; depression; forced swimming; stress; voluntary wheel running ID CHRONIC MILD STRESS; SOCIAL DEFEAT STRESS; ANTIDEPRESSANT; SUSCEPTIBILITY; DISORDERS; BEHAVIOR; STRAIN AB The development of animal models with construct, face, and predictive validity to accurately model human depression has been a major challenge. One proposed rodent model is the 5 d repeated forced swim stress (5d-RFSS) paradigm, which progressively increases floating during individual swim sessions. The onset and persistence of this floating behavior has been anthropomorphically characterized as a measure of depression. This interpretation has been under debate because a progressive increase in floating over time may reflect an adaptive learned behavioral response promoting survival, and not depression (Molendijk and de Kloet, 2015). To assess construct and face validity, we applied 5d-RFSS to C57BL/6J and BALB/cJ mice, two mouse strains commonly used in neuropsychiatric research, and measured a combination of emotional, homeostatic, and psychomotor symptoms indicative of a depressive-like state. We also compared the efficacy of 5d-RFSS and chronic social defeat stress (CSDS), a validated depression model, to induce a depressive-like state in C57BL/6J mice. In both strains, 5d-RFSS progressively increased floating behavior that persisted for at least 4 weeks. 5d-RFSS did not alter sucrose preference, body weight, appetite, locomotor activity, anxiety-like behavior, or immobility behavior during a tail-suspension test compared with nonstressed controls. In contrast, CSDS altered several of these parameters, suggesting a depressive-like state. Finally, predictive validity was assessed using voluntary wheel running (VWR), a known antidepressant intervention. Four weeks of VWR after 5d-RFSS normalized floating behavior toward nonstressed levels. These observations suggest that 5d-RFSS has no construct or face validity but might have predictive validity to model human depression. C1 [Mul, Joram D.; Zheng, Jia; Goodyear, Laurie J.] Harvard Med Sch, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. [Goodyear, Laurie J.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. [Mul, Joram D.] Univ Amsterdam, Acad Med Ctr, Dept Endocrinol & Metab, Postbus 22660, NL-1100 AD Amsterdam, Netherlands. [Mul, Joram D.] Inst Royal Netherlands Acad Arts & Sci, Netherlands Inst Neurosci, Meibergdreef 47, NL-1105 BA Amsterdam, Netherlands. RP Mul, JD (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Endocrinol & Metab, Postbus 22660, NL-1100 AD Amsterdam, Netherlands. EM joramdmul@gmail.com OI Mul, Joram/0000-0003-0453-2568 FU Department of Health and Human Services/National Institutes of Health/National Institute for Health Research [R01-DK-099511, R01-DK-101043, 5P30-DK-36836]; American Diabetes Association [7-08-MN-21] FX This work was supported by Department of Health and Human Services/National Institutes of Health/National Institute for Health Research Grants R01-DK-099511 and R01-DK-101043 (to L.J.G.) and 5P30-DK-36836 (to Diabetes and Endocrinology Research Center, Joslin Diabetes Center). J.D.M. was supported by a mentor-based fellowship (7-08-MN-21) awarded to L.J.G. from the American Diabetes Association. NR 23 TC 0 Z9 0 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 2373-2822 J9 ENEURO JI eNeuro PD NOV-DEC PY 2016 VL 3 IS 6 AR UNSP e0201 DI 10.1523/ENEURO.0201-16.2016 PG 9 WC Neurosciences SC Neurosciences & Neurology GA EH7CQ UT WOS:000391930900014 ER PT J AU Koudriavtseva, T Mainero, C AF Koudriavtseva, Tatiana Mainero, Caterina TI Neuroinflammation, neurodegeneration and regeneration in multiple sclerosis: intercorrelated manifestations of the immune response SO NEURAL REGENERATION RESEARCH LA English DT Review DE multiple sclerosis; neuroinflammation; neurodegeneration; regeneration; immune response; innate immunity ID MATTER PATHOLOGY; PROCESS SEPARATE; INFLAMMATION; DISEASES AB Multiple sclerosis (MS) is a chronic immune-mediated inflammatory-demyelinating disorder of the central nervous system, with a strong neurodegenerative component. The question whether neurodegeneration in MS is independent or related to neuroinflammation has been long debated, but not yet fully clarified. Furthermore, little is still known on how neuroinflammation and neurodegeneration in MS are related to potential regenerative processes. In this perspective, we briefly discuss main clinical, pathological and experimental evidence on the relationship between neuroinflammation and neurodegeneration in MS, and on their connection with regeneration. We discuss that these processes in MS might represent intercorrelated manifestations of the immune response, especially of the innate immunity. C1 [Koudriavtseva, Tatiana] Tor Vergata Univ, Dept Syst Med, Multiple Sclerosis Clin & Res Unit, Rome, Italy. [Mainero, Caterina] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Mainero, Caterina] Harvard Med Sch, Boston, MA USA. RP Koudriavtseva, T (reprint author), Tor Vergata Univ, Dept Syst Med, Multiple Sclerosis Clin & Res Unit, Rome, Italy. EM tatiana.koud@gmail.com NR 12 TC 0 Z9 0 U1 2 U2 2 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 1673-5374 EI 1876-7958 J9 NEURAL REGEN RES JI Neural Regen. Res. PD NOV PY 2016 VL 11 IS 11 BP 1727 EP 1730 DI 10.4103/1673-5374.194804 PG 4 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA EH2DW UT WOS:000391578600005 PM 28123401 ER PT J AU Pau, CT Cheang, KI Modi, BP Kasippillai, T Keefe, CC Shulleeta, M Evans, WS Pal, L Strauss, JF Nestler, JE Welt, CK AF Pau, Cindy T. Cheang, Kai I. Modi, Bhavi P. Kasippillai, Thushiga Keefe, Candace C. Shulleeta, Maria Evans, William S. Pal, Lubna Strauss, Jerome F., III Nestler, John E. Welt, Corrine K. TI The role of variants regulating metformin transport and action in women with polycystic ovary syndrome SO PHARMACOGENOMICS LA English DT Article DE glucose; insulin; MATE; OCT; testosterone ID ORGANIC CATION TRANSPORTER; GLUCOSE-TOLERANCE TEST; GENETIC-VARIATION; INSULIN SENSITIVITY; FUNCTIONAL-CHARACTERIZATION; RESPIRATORY-CHAIN; DOUBLE-BLIND; COMPLEX I; POLYMORPHISMS; RESISTANCE AB Aims: Variants in genes encoding metformin transport proteins and the ATM gene are associated with metformin response. We hypothesized that these gene variants contribute to variable metformin treatment response in polycystic ovary syndrome. Materials & methods: The discovery cohort (n = 38) was studied in an open-label study. Results were replicated in two additional cohorts (n = 26 and n = 131). Response was assessed after 3-6 months of treatment with metformin extended-release 1500-2000 mg/day. Results: The rs683369 variant was associated with less weight loss in the discovery cohort (p = 0.003), but these results were not replicated (p = 0.8). There were no differences in glucose parameters, testosterone levels or ovulatory frequency as a function of genotype. Conclusion: Variants in organic ion transporters do not explain the variable metformin response in polycystic ovary syndrome. C1 [Pau, Cindy T.; Kasippillai, Thushiga; Keefe, Candace C.; Welt, Corrine K.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. [Cheang, Kai I.; Modi, Bhavi P.; Shulleeta, Maria; Strauss, Jerome F., III; Nestler, John E.] Virginia Commonwealth Univ, Dept Obstet & Gynecol, Med Coll Virginia Campus, Richmond, VA 23298 USA. [Cheang, Kai I.; Modi, Bhavi P.; Shulleeta, Maria; Strauss, Jerome F., III; Nestler, John E.] Virginia Commonwealth Univ, Dept Internal Med, Med Coll Virginia Campus, Richmond, VA 23298 USA. [Cheang, Kai I.; Modi, Bhavi P.; Shulleeta, Maria; Strauss, Jerome F., III; Nestler, John E.] Virginia Commonwealth Univ, Dept Human & Mol Genet, Med Coll Virginia Campus, Richmond, VA 23298 USA. [Kasippillai, Thushiga] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Evans, William S.] Univ Virginia, Div Endocrinol, Charlottesville, VA 22908 USA. [Pal, Lubna] Yale Univ, Dept Obstet & Gynecol, New Haven, CT 06520 USA. [Welt, Corrine K.] Univ Utah, Div Endocrinol Diabet & Metab, Salt Lake City, UT 84112 USA. RP Welt, CK (reprint author), Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA.; Welt, CK (reprint author), Univ Utah, Div Endocrinol Diabet & Metab, Salt Lake City, UT 84112 USA. EM cwelt@genetics.utah.edu FU NIH [1F32HD081844, 1R01HD065029]; American Diabetes Association [1-10-CT-57]; Harvard Clinical and Translational Science Center [1 UL1 RR025758]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [U54 HD034449]; VCU Center for Clinical and Translational Research [UL1RR031990] FX This work was supported by the NIH 1F32HD081844 (CT Pau) and 1R01HD065029 (CK Welt), the American Diabetes Association 1-10-CT-57 (CK Welt), the 1 UL1 RR025758 Harvard Clinical and Translational Science Center, the U54 HD034449 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (JE Nestler, JF Strauss) and the UL1RR031990 VCU Center for Clinical and Translational Research. CT Pau, KI Cheang, BP Modi, T Kasippillai, CC Keefe, M Shulleeta, WS Evans, L Pal and JE Nestler have nothing to declare. CK Welt and JF Strauss III consulted for Takeda. Clinical trial's number: NCT01389778. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 43 TC 0 Z9 0 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 EI 1744-8042 J9 PHARMACOGENOMICS JI Pharmacogenomics PD NOV PY 2016 VL 17 IS 16 BP 1765 EP 1773 DI 10.2217/pgs-2016-0079 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH6EL UT WOS:000391865500004 ER PT J AU Powell, ME Deliyski, DD Hillman, RE Zeitels, SM Burns, JA Mehta, DD AF Powell, Maria E. Deliyski, Dimitar D. Hillman, Robert E. Zeitels, Steven M. Burns, James A. Mehta, Daryush D. TI Comparison of Videostroboscopy to Stroboscopy Derived From High-Speed Videoendoscopy for Evaluating Patients With Vocal Fold Mass Lesions SO AMERICAN JOURNAL OF SPEECH-LANGUAGE PATHOLOGY LA English DT Article ID PHASE ASYMMETRIES; LARYNGOSCOPY; DISORDERS; PROTOCOL; SPEAKERS AB Purpose: Videostroboscopy (VS) uses an indirect physiological signal to predict the phase of the vocal fold vibratory cycle for sampling. Simulated stroboscopy (SS) extracts the phase of the glottal cycle directly from the changing glottal area in the high-speed videoendoscopy (HSV) image sequence. The purpose of this study is to determine the reliability of SS relative to VS for clinical assessment of vocal fold vibratory function in patients with mass lesions. Methods: VS and SS recordings were obtained from 28 patients with vocal fold mass lesions before and after phonomicrosurgery and 17 controls who were vocally healthy. Two clinicians rated clinically relevant vocal fold vibratory features using both imaging techniques, indicated their internal level of confidence in the accuracy of their ratings, and provided reasons for low or no confidence. Results: SS had fewer asynchronous image sequences than VS. Vibratory outcomes were able to be computed for more patients using SS. In addition, raters demonstrated better interrater reliability and reported equal or higher levels of confidence using SS than VS. Conclusion: Stroboscopic techniques on the basis of extracting the phase directly from the HSV image sequence are more reliable than acoustic-based VS. Findings suggest that SS derived from high-speed videoendoscopy is a promising improvement over current VS systems. C1 [Powell, Maria E.] Univ Cincinnati, Dept Commun Sci & Disorders, Cincinnati, OH 45221 USA. [Powell, Maria E.] Vanderbilt Univ, Laryngeal Biol Lab, 221 Kirkland Hall, Nashville, TN 37235 USA. [Deliyski, Dimitar D.] Michigan State Univ, Dept Commun Sci & Disorders, E Lansing, MI 48824 USA. [Hillman, Robert E.; Zeitels, Steven M.; Burns, James A.; Mehta, Daryush D.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Hillman, Robert E.; Zeitels, Steven M.; Burns, James A.; Mehta, Daryush D.] Harvard Med Sch, Dept Surg, Boston, MA USA. [Hillman, Robert E.; Mehta, Daryush D.] MGH Inst Hlth Profess, Dept Commun Sci & Disorders, Boston, MA USA. RP Powell, ME (reprint author), Univ Cincinnati, Dept Commun Sci & Disorders, Cincinnati, OH 45221 USA.; Powell, ME (reprint author), Vanderbilt Univ, Laryngeal Biol Lab, 221 Kirkland Hall, Nashville, TN 37235 USA. EM maria.e.powell@vanderbilt.edu FU National Institute on Deafness and Other Communication Disorders [R01-DC007640] FX This study was fully supported by the National Institute on Deafness and Other Communication Disorders Grant R01-DC007640, "Efficacy of Laryngeal High-Speed Videoendoscopy", awarded to Dimitar Deliyski. Research was conducted in the Department of Communication Sciences and Disorders at the University of Cincinnati. Portions of this study have been presented at the Voice Foundation's 44th Annual Symposium: Care of the Professional Voice, Philadelphia, PA, May 2015. The authors thank the following researchers for their contributions to the execution of the study: Terri Gerlach, Stephanie Zacharias, Keiko Ishikawa, and Resmi Gupta. NR 33 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 NOV PY 2016 VL 25 IS 4 BP 576 EP 589 DI 10.1044/2016_AJSLP-15-0050 PG 14 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA EG9RG UT WOS:000391396400010 PM 27716854 ER PT J AU Mehta, DD Cheyne, HA Wehner, A Heaton, JT Hillman, RE AF Mehta, Daryush D. Cheyne, Harold A., II Wehner, Asa Heaton, James T. Hillman, Robert E. TI Accuracy of Self-Reported Estimates of Daily Voice Use in Adults With Normal and Disordered Voices SO AMERICAN JOURNAL OF SPEECH-LANGUAGE PATHOLOGY LA English DT Article ID SOUND PRESSURE LEVEL; SPEAKING TIME; DOSE MEASURES; ACCUMULATOR; TEACHERS; BIOFEEDBACK; VALIDATION; BEHAVIOR AB Purpose: Accurate estimation of daily patterns of vocal behavior is essential to understanding the role of voice use in voice disorders. Given that clinicians currently rely on patient self-report to assess daily vocal behaviors, this study sought to assess the accuracy with which adults with and without voice disorders can estimate their amount of daily voice use in terms of phonation time. Method: Eighteen subjects (6 patients, 6 matched members of a control group without voice disorders, 6 low voice users) wore the accelerometer-based Ambulatory Phonation Monitor (APM; model 3200, KayPENTAX, Montvale, NJ) for at least 5 workdays. Subjects were instructed to provide hourly self-reports of time spent talking using a visual analog scale. Spearman correlation coefficients and errors between self-reported and APM-based estimates of phonation time revealed subject-and group-specific characteristics. Results: A majority of subjects exhibited a significant bias toward overestimating their phonation times, with an average absolute error of 113%. Correlation coefficients between self-reported and APM-based estimates of phonation time ranged from statistically nonsignificant to .91, reflecting large intersubject variability. Conclusions: Subjects in all 3 groups were moderately accurate at estimating their hourly voice use, with a consistent bias toward overestimation. The results support the potential role that ambulatory monitoring could play in improving the clinical assessment of voice disorders. C1 [Mehta, Daryush D.; Wehner, Asa; Heaton, James T.; Hillman, Robert E.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Mehta, Daryush D.; Heaton, James T.; Hillman, Robert E.] Harvard Med Sch, Boston, MA 02115 USA. [Mehta, Daryush D.; Heaton, James T.; Hillman, Robert E.] Massachusetts Gen Hosp, Inst Hlth Profess, Boston, MA 02114 USA. [Cheyne, Harold A., II] Cornell Univ, Ornithol Lab, Bioacoust Res Program, Ithaca, NY USA. RP Mehta, DD (reprint author), Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA.; Mehta, DD (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Mehta, DD (reprint author), Massachusetts Gen Hosp, Inst Hlth Profess, Boston, MA 02114 USA. EM daryush.mehta@alum.mit.edu NR 33 TC 0 Z9 0 U1 2 U2 2 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 NOV PY 2016 VL 25 IS 4 BP 634 EP 641 DI 10.1044/2016_AJSLP-15-0105 PG 8 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA EG9RG UT WOS:000391396400015 PM 27788279 ER PT J AU Hasegawa, K Mansbach, JM Ajami, NJ Espinola, JA Henke, DM Petrosino, JF Piedra, PA Shaw, CA Sullivan, AF Camargo, CA AF Hasegawa, Kohei Mansbach, Jonathan M. Ajami, Nadim J. Espinola, Janice A. Henke, David M. Petrosino, Joseph F. Piedra, Pedro A. Shaw, Chad A. Sullivan, Ashley F. Camargo, Carlos A., Jr. CA MARC-35 Investigators TI Association of nasopharyngeal microbiota profiles with bronchiolitis severity in infants hospitalised for bronchiolitis SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; PROSPECTIVE MULTICENTER; HAEMOPHILUS-INFLUENZAE; RHINOVIRUS INFECTION; PATHOGENIC BACTERIA; VIRAL-INFECTIONS; UNITED-STATES; GENOMIC LOAD; CHILDREN; AIRWAY AB Little is known about the relationship between the specific airway microbiota composition and severity of bronchiolitis. We aimed to identify nasopharyngeal microbiota profiles and link these profiles to acute severity in infants hospitalised for bronchiolitis. We conducted a multicentre prospective cohort study of 1005 infants (age <1 year) hospitalised for bronchiolitis over three winters, 2011-2014. By applying a 16S rRNA gene sequence and clustering approach to the nasopharyngeal aspirates collected within 24 h of hospitalisation, we determined nasopharyngeal microbiota profiles and their association with bronchiolitis severity. The primary outcome was intensive care use, i.e. admission to an intensive care unit or use of mechanical ventilation. We identified four nasopharyngeal microbiota profiles: three profiles were dominated by one of Haemophilus, Moraxella or Streptococcus, while the fourth profile had the highest bacterial richness. The rate of intensive care use was highest in infants with a Haemophilus-dominant profile and lowest in those with a Moraxella-dominant profile (20.2% versus 12.3%; unadjusted OR 1.81, 95% CI 1.07-3.11, p=0.03). After adjusting for 11 patient-level confounders, the rate remained significantly higher in infants with Haemophilus-dominant profiles (OR 1.98, 95% CI 1.08-3.62, p=0.03). These findings were externally validated in a separate cohort of 307 children hospitalised for bronchiolitis. C1 [Hasegawa, Kohei; Espinola, Janice A.; Sullivan, Ashley F.; Camargo, Carlos A., Jr.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA USA. [Mansbach, Jonathan M.] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Ajami, Nadim J.; Petrosino, Joseph F.] Baylor Coll Med, Dept Mol Virol & Microbiol, Alkek Ctr Metagen & Microbiome Res, Houston, TX 77030 USA. [Shaw, Chad A.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Piedra, Pedro A.] Baylor Coll Med, Dept Mol Virol & Microbiol & Pediat, Houston, TX 77030 USA. RP Hasegawa, K (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, 125 Nashua St,Suite 920, Boston, MA 02114 USA. EM khasegawa1@partners.org FU National Institutes of Health (Bethesda, MD, USA) [U01 AI-087881, R01 AI-114552, R01 AI-108588, R21 HL-129909]; William F. Milton Fund (Boston, MA, USA) FX This study was supported by the grants U01 AI-087881, R01 AI-114552, R01 AI-108588, and R21 HL-129909 from the National Institutes of Health (Bethesda, MD, USA) and a grant from the William F. Milton Fund (Boston, MA, USA). Funding information for this article has been deposited with the Open Funder Registry. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 46 TC 1 Z9 1 U1 1 U2 1 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD NOV PY 2016 VL 48 IS 5 BP 1329 EP 1339 DI 10.1183/13993003.00152-2016 PG 11 WC Respiratory System SC Respiratory System GA EG3VW UT WOS:000390973800012 PM 27799386 ER PT J AU Carter-Harris, L Tan, ASL Salloum, RG Young-Wolff, KC AF Carter-Harris, Lisa Tan, Andy S. L. Salloum, Ramzi G. Young-Wolff, Kelly C. TI Patient-provider discussions about lung cancer screening pre- and post-guidelines: Health Information National Trends Survey (HINTS) SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Lung cancer screening; Shared decision making; Health communication; Patient-provider discussion; Health Information National Trends Survey; HINTS ID PHYSICIAN RECOMMENDATION; MAMMOGRAPHY; ATTITUDES; BELIEFS; WOMEN AB Objective: In 2013, the USPSTF issued a Grade B recommendation that long-term current and former smokers receive lung cancer screening. Shared decision-making is important for individuals considering screening, and patient-provider discussions an essential component of the process. We examined prevalence and predictors of lung cancer screening discussions pre- and post-USPSTF guidelines. Methods: Data were obtained from two cycles of the Health Information National Trends Survey (2012; 2014). The analyzed sample comprised screening-eligible current and former smokers with no personal history of lung cancer (n = 746 in 2012; n = 795 in 2014). Descriptive and multiple logistic regression analyses were conducted; patient-reported discussion about lung cancer screening with provider was the outcome of interest. Results: Contrary to expectations, patient-provider discussions about lung cancer screening were more prevalent pre-guideline, but overall patient-provider discussions were low in both years (17% in 2012; 10% in 2014). Current smokers were more likely to have had a discussion than former smokers. Significant predictors of patient-provider discussions included family history of cancer and having healthcare coverage. Conclusions: The prevalence of patient-provider discussions about lung cancer screening is suboptimal. Practice implications: There is a critical need for patient and provider education about shared decisionmaking and its importance in cancer screening decisions. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Carter-Harris, Lisa] Indiana Univ, Sch Nursing, 600 Barnhill Dr,NU W427, Indianapolis, IN 46202 USA. [Tan, Andy S. L.] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Hlth, Boston, MA USA. [Tan, Andy S. L.] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. [Salloum, Ramzi G.] Univ Florida, Coll Med, Dept Hlth Outcomes & Policy, Gainesville, FL 32611 USA. [Salloum, Ramzi G.] Univ Florida, Coll Med, Inst Child Hlth Policy, Gainesville, FL 32611 USA. [Young-Wolff, Kelly C.] Kaiser Permanente Northern Calif Div Res, Oakland, CA USA. RP Carter-Harris, L (reprint author), Indiana Univ, Sch Nursing, 600 Barnhill Dr,NU W427, Indianapolis, IN 46202 USA. EM lcharris@iu.edu OI Carter-Harris, PhD, Lisa/0000-0002-6448-6033 FU Cancer Research Network Scholar [U24 CA171524] FX Effort for Drs. Carter-Harris, Tan, and Salloum on this project was supported as part of their role as a Cancer Research Network Scholar (U24 CA171524; PI: Dr. Larry Kushi). NR 19 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 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD NOV PY 2016 VL 99 IS 11 BP 1772 EP 1777 DI 10.1016/j.pec.2016.05.014 PG 6 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA EG7JC UT WOS:000391222100004 PM 27241830 ER PT J AU Ishikawa, Y Kondo, N Kawachi, I Viswanath, K AF Ishikawa, Yoshiki Kondo, Naoki Kawachi, Ichiro Viswanath, Kasisomayajula TI Are socioeconomic disparities in health behavior mediated by differential media use? Test of the communication inequality theory SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Communication inequality; Multiple risk behaviors; Socioeconomic status ID INFORMATION-SEEKING; RISK BEHAVIORS AB Objective: Communication inequality has been offered as one potential mechanism through which social determinants influence multiple health behaviors. The purpose of this study was to examine the underlying mechanisms between communication inequality and health behaviors. Methods: Data from a nationally representative cross-sectional survey of 18,426 people aged 18 years and above in the United States were used for secondary analysis. Measures included socio-demographic characteristics, social participation (structural social capital), health media use (TV, print, and the Internet), and five health behaviors (physical activity, cigarette smoking, alcohol use, and intake of fruit and vegetable). Path analysis was performed to examine the linkages between social determinants, health media use, social participation, and social gradients in health behaviors. Results: Path analysis revealed that socioeconomic gradients in health behaviors is mediated by: 1) inequalities in health media use; 2) disparities in social participation, which leads to differential media use; and 3) disparities in social participation that are not mediated by media use. Conclusions: Consistent with the theory of communication inequality, socioeconomic disparities in media use partially mediate disparities in multiple health behaviors. Practice implications: To address health inequalities, it is important to utilize health media to target populations with low socioeconomic statuses. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Ishikawa, Yoshiki; Kondo, Naoki] Univ Tokyo, Sch Publ Hlth, Dept Hlth & Social Behav, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan. [Ishikawa, Yoshiki] Canc Scan, Shibuya Ku, Tokyo, Japan. [Kawachi, Ichiro; Viswanath, Kasisomayajula] Harvard Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Viswanath, Kasisomayajula] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. RP Ishikawa, Y (reprint author), Univ Tokyo, Sch Publ Hlth, Dept Hlth & Social Behav, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan. EM ishikun@gmail.com FU Health Labour Sciences Research Grant [26-Choju-Ippan-006, H25-Kenki-Wakate-015]; AXA Life Insurance Co. LTD. (CR Fixed Income Fund); [20345705]; [26670306] FX This study was supported by Health Labour Sciences Research Grant (26-Choju-Ippan-006 and H25-Kenki-Wakate-015); Grant-in-Aid for Scientific Research (20345705 and 26670306); and AXA Life Insurance Co. LTD. (CR Fixed Income Fund). 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 3 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD NOV PY 2016 VL 99 IS 11 BP 1803 EP 1807 DI 10.1016/j.pec.2016.05.018 PG 5 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA EG7JC UT WOS:000391222100008 PM 27349600 ER PT J AU Kumbhar, SS O'Malley, RB Robinson, TJ Maximin, S Lalwani, N Byrd, DR Wang, CL AF Kumbhar, Sachin S. O'Malley, Ryan B. Robinson, Tracy J. Maximin, Suresh Lalwani, Neeraj Byrd, David R. Wang, Carolyn L. TI Why Thyroid Surgeons Are Frustrated with Radiologists: Lessons Learned from Pre- and Postoperative US SO RADIOGRAPHICS LA English DT Article ID CONSENSUS STATEMENT; NECK DISSECTION; LYMPH-NODES; CANCER; ULTRASOUND; NODULES; CARCINOMA; ULTRASONOGRAPHY; CLASSIFICATION; MALIGNANCY AB Optimal treatment of thyroid cancer is highly dependent on accurate staging of the extent of disease at presentation. Preoperative ultrasonography (US) is the most sensitive method for detecting metastatic lymph nodes and is recommended as part of the standard preoperative workup. Missed findings on preoperative scans may lead to understaging and inadequate surgical management, which subsequently predispose these patients to residual disease postoperatively and a higher risk for recurrence, possibly requiring repeat surgery. Traditionally, thyroid US for pre- and postoperative staging has been performed by radiologists. However, there is a growing trend away from radiologist-performed US in favor of surgeon-performed US. Recent surgical and endocrinology literature has shown that, when compared with surgeon-performed US, radiologist-performed preoperative staging US is less accurate and is inadequate for presurgical planning, with higher local recurrence rates. This review highlights the importance of accurate preoperative US for patients with differentiated thyroid cancer, with specific attention to deficiencies that exist in general radiology department thyroid US reports. We present a standardized approach to neck US reporting that incorporates the newly updated 2015 recommendations from the American Thyroid Association and also addresses the pertinent questions for thyroid surgeons. By ensuring comprehensive preoperative assessment and improving thyroid US reporting, we seek to improve patient access to optimized care. (C) RSNA, 2016 center dot radiographics.rsna.org C1 [Kumbhar, Sachin S.; O'Malley, Ryan B.; Lalwani, Neeraj; Wang, Carolyn L.] Univ Washington, Dept Radiol, 1959 NE Pacific St,Box 357115, Seattle, WA 98195 USA. [Byrd, David R.] Univ Washington, Dept Surg, 1959 NE Pacific St,Box 357115, Seattle, WA 98195 USA. [Robinson, Tracy J.] Seattle Radiologists, Western Div Integra Imaging, Seattle, WA USA. [Maximin, Suresh] VA Puget Sound Hlth Care Syst, Dept Radiol, Seattle, WA USA. RP Wang, CL (reprint author), Univ Washington, Dept Radiol, 1959 NE Pacific St,Box 357115, Seattle, WA 98195 USA. EM wangcl@uw.edu NR 35 TC 0 Z9 0 U1 4 U2 4 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD NOV-DEC PY 2016 VL 36 IS 7 BP 2141 EP 2153 DI 10.1148/rg.2016150250 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EH0AO UT WOS:000391424800013 PM 27768542 ER PT J AU Godoy, IRB Donahue, DM Torriani, M AF Godoy, Ivan R. B. Donahue, Dean M. Torriani, Martin TI Botulinum Toxin Injections in Musculoskeletal Disorders SO SEMINARS IN MUSCULOSKELETAL RADIOLOGY LA English DT Article DE botulinum toxin; muscle injection; ultrasound; intervention ID THORACIC OUTLET SYNDROME; RANDOMIZED CONTROLLED-TRIAL; PIRIFORMIS MUSCLE SYNDROME; RESISTANT CERVICAL DYSTONIA; CHRONIC PLANTAR FASCIITIS; PLACEBO-CONTROLLED TRIAL; LOW-BACK-PAIN; CEREBRAL-PALSY; DOUBLE-BLIND; A TOXIN AB Botulinurn toxin (BTX) is used for multiple clinical indications due to its ability to induce temporary chemodenervation and muscle paralysis. This property has supported its application in treating a variety of musculoskeletal conditions, especially those involving muscular hyperactivity and contractures such as cerebral palsy and dystonia. However, off-label use of BTX injection in other musculoskeletal disorders is gaining increased acceptance, such as in neurogenic thoracic outlet syndrome, epicondylitis, and shoulder pain after stroke. This review discusses the mechanism of action, best practices, and current indications of BTX injections in the musculoskeletal system. We also discuss the state of the science regarding BTX injections for musculoskeletal disorders and the available evidence supporting its use. C1 [Godoy, Ivan R. B.; Torriani, Martin] Massachusetts Gen Hosp, Div Musculoskeletal Imaging & Intervent, Boston, MA 02114 USA. [Godoy, Ivan R. B.; Donahue, Dean M.; Torriani, Martin] Harvard Med Sch, Boston, MA USA. [Donahue, Dean M.] Massachusetts Gen Hosp, Dept Surg, Div Thorac Surg, Boston, MA 02114 USA. RP Torriani, M (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, 55 Fruit St,YAW 6048, Boston, MA 02114 USA. EM mtorriani@mgh.harvard.edu NR 115 TC 0 Z9 0 U1 1 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1089-7860 EI 1098-898X J9 SEMIN MUSCULOSKEL R JI Semin. Musculoskelet. Radiol. PD NOV PY 2016 VL 20 IS 5 BP 441 EP 452 DI 10.1055/s-0036-1594284 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EG5IT UT WOS:000391078200007 PM 28002866 ER PT J AU Huang, AJ AF Huang, Ambrose J. TI Radiofrequency Ablation of Osteoid Osteoma: Difficult-to-Reach Places SO SEMINARS IN MUSCULOSKELETAL RADIOLOGY LA English DT Article DE osteoid osteoma; radiofrequency ablation; benign bone tumor ID OPERATIVE TREATMENT; BONE; MANAGEMENT; DIAGNOSIS; BENIGN; LESIONS; PROBE; WATER AB Osteoid osteomas are small painful benign bone tumors that can be effectively treated by radiofrequency ablation (RFA) in most situations. This article briefly reviews the typical imaging findings of osteoid osteomas and the RFA technique used to treat them at our institution. It concludes with several examples of osteoid osteomas in difficult-to reach places and the approaches used to access and treat them. C1 [Huang, Ambrose J.] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Huang, Ambrose J.] Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. RP Huang, AJ (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. EM ajhuang@mgh.harvard.edu NR 33 TC 0 Z9 0 U1 1 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1089-7860 EI 1098-898X J9 SEMIN MUSCULOSKEL R JI Semin. Musculoskelet. Radiol. PD NOV PY 2016 VL 20 IS 5 BP 486 EP 495 DI 10.1055/s-0036-1594280 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EG5IT UT WOS:000391078200011 PM 28002870 ER PT J AU Kohli, P Schlosser, RJ Storck, K Soler, ZM AF Kohli, Preeti Schlosser, Rodney J. Storck, Kristina Soler, Zachary M. TI Olfactory cleft computed tomography analysis and olfaction in chronic rhinosinusitis SO AMERICAN JOURNAL OF RHINOLOGY & ALLERGY LA English DT Article ID ENDOSCOPIC SINUS; NASAL POLYPOSIS; SURGERY; RECOVERY; QUALITY; LIFE AB Background: Volumetric analysis of the olfactory cleft by using computed tomography has been associated with olfaction in patients with chronic rhinosinusitis (CRS). However, existing studies have not comprehensively measured olfaction, and it thus remains unknown whether correlations differ across specific dimensions of odor perception. Objective: To use comprehensive measures of patient-reported and objective olfaction to evaluate the relationship between volumetric olfactory cleft opacification and olfaction. Methods: Olfaction in patients with CRS was evaluated by using "Sniffin' Sticks"tests and a modified version of the Questionnaire of Olfactory Disorders. Olfactory cleft opacification was quantified by using two-and three-dimensional, computerized volumetric analysis. Correlations between olfactory metrics and olfactory cleft opacification were then calculated. Results: The overall CRS cohort included 26 patients without nasal polyposis (CRSsNP) (68.4%) and 12 patients with nasal polyposis (CRSwNP) (31.6%). Across the entire cohort, total olfactory cleft opacification was 82.8%, with greater opacification in the CRSwNP subgroup compared with CRSsNP (92.3 versus 78.4%, p < 0.001). The percent total volume opacification correlated with the total Sniffin' Sticks score (r = -0.568, p < 0.001) as well as individual threshold, discrimination, and identification scores (p < 0.001 for all). Within the CRSwNP subgroup, threshold (r = -0.616, p = 0.033) and identification (r = -0.647, p = 0.023) remained highly correlated with total volume opacification. In patients with CRSsNP, the threshold correlated with total volume scores (r = -0.457, p = 0.019), with weaker and nonsignificant correlations for discrimination and identification. Correlations between total volume opacification and the Questionnaire of Olfactory Disorders were qualitatively similar to objective olfactory findings in both CRSwNP (r = -0.566, p = 0.070) and CRSsNP (r = -0.310, p = 0.141) subgroups, although neither reached significance. When examined by two-dimensional planes, the percent opacification of the anterior plane had the strongest correlations with objective olfaction. Conclusion: Olfactory cleft opacification correlated with objective measures of olfaction in patients with CRS, which correlated with threshold values in patients with CRSsNP and all dimensions of olfaction in those with CRSwNP. C1 [Kohli, Preeti; Schlosser, Rodney J.; Storck, Kristina; Soler, Zachary M.] Med Univ South Carolina, Dept Otolaryngol Head & Neck Surg, 135 Rutledge Ave,MSC550, Charleston, SC 29425 USA. [Schlosser, Rodney J.] Ralph H Johnson VA Med Ctr, Dept Surg, Charleston, SC USA. RP Soler, ZM (reprint author), Med Univ South Carolina, Dept Otolaryngol Head & Neck Surg, 135 Rutledge Ave,MSC550, Charleston, SC 29425 USA. EM solerz@musc.edu FU National Institute on Deafness and Other Communication Disorders, National Institutes of Health [R03 DC013651-01]; OptiNose; IntersectENT FX Z.M. Soler is supported for this investigation by a grant from the National Institute on Deafness and Other Communication Disorders, National Institutes of Health (P.I., Z.M. Soler; R03 DC013651-01); is a consultant for Olympus, which is not affiliated with this manuscript. R.J. Schlosser is supported by grants from OptiNose and IntersectENT, neither are associated with this manuscript; is also a consultant for Olympus, Meda, and Arrinex, which are not affiliated with this study. The remaining authors have no conflicts of interest pertaining to this article NR 21 TC 0 Z9 0 U1 1 U2 1 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1945-8924 EI 1945-8932 J9 AM J RHINOL ALLERGY JI Am. J. Rhinol. Allergy PD NOV-DEC PY 2016 VL 30 IS 6 BP 402 EP 406 DI 10.2500/ajra.2016.30.4365 PG 5 WC Otorhinolaryngology SC Otorhinolaryngology GA EG2EW UT WOS:000390857000012 ER PT J AU Stirman, SW Gutner, CA Langdon, K Graham, JR AF Stirman, Shannon Wiltsey Gutner, Cassidy A. Langdon, Kirsten Graham, Jessica R. TI Bridging the Gap Between Research and Practice in Mental Health Service Settings: An Overview of Developments in Implementation Theory and Research SO BEHAVIOR THERAPY LA English DT Article DE implementation; dissemination; evidence-based psychotherapy ID COGNITIVE-BEHAVIORAL THERAPY; EMPIRICALLY SUPPORTED TREATMENTS; EVIDENCE-BASED PSYCHOTHERAPY; POSTTRAUMATIC-STRESS-DISORDER; RANDOMIZED CONTROLLED-TRIAL; LARGE-SCALE IMPLEMENTATION; PSYCHOLOGICAL TREATMENTS; CONTINGENCY MANAGEMENT; ORGANIZATIONAL CULTURE; NATIONAL-DISSEMINATION AB Twenty years after Sobell's (1996) influential call to integrate advances in behavior therapy into clinical settings, significant progress has been made in implementation science. In this narrative review, we provide an overview of implementation research findings and highlight recent findings that can inform efforts to bridge the gap between research and practice in mental health service settings. Key findings are summarized, organized according to levels of influence described in two implementation frameworks: The Exploration, Planning, Implementation, and Sustainment Framework (EPIS; Aarons et al., 2011) and the Consolidated Framework for Implementation Research (CFIR; Dams chroder et al., 2009). Important levels of influence to consider when implementing new treatments include the outer context, inner context, characteristics of the individual, and characteristics of the innovation. Research on strategies to prepare clinicians to deliver evidence-based psychosocial treatments (EBPTs) and to address contextual barriers to implementation at each level is described, with discussion of implications for the implementation of EBPTs and next steps for research. C1 [Stirman, Shannon Wiltsey] Stanford Univ, VA Palo Alto Healthcare Syst, Natl Ctr PTSD, Stanford, CA 94305 USA. [Gutner, Cassidy A.] Boston Univ, VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA 02215 USA. [Langdon, Kirsten] Rhode Isl Hosp, Dept Psychiat, Providence, RI USA. [Graham, Jessica R.] Salem State Univ, Salem, MA USA. RP Stirman, SW (reprint author), Natl Ctr PTSD, Disseminat & Training Div, 795 Willow Rd, White River Jct, VT 05009 USA. EM sws1@stanford.edu OI Wiltsey Stirman, Shannon/0000-0001-9917-5078 FU VA Women's Health Fellowship Program; [K23 MH103396] FX Effort on this review was funded in part by a career development award (K23 MH103396; PI: Gutner) and through the VA Women's Health Fellowship Program. The authors wish to thank Joan Cook, Ph.D, for her comments on an earlier draft of this manuscript. NR 129 TC 1 Z9 1 U1 12 U2 12 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 0005-7894 EI 1878-1888 J9 BEHAV THER JI Behav. Therapy PD NOV PY 2016 VL 47 IS 6 SI SI BP 920 EP 936 PG 17 WC Psychology, Clinical SC Psychology GA EG3YF UT WOS:000390979900011 PM 27993341 ER PT J AU Cao, Y Nishihara, R Qian, ZR Song, MY Mima, K Inamura, K Nowak, JA Drew, DA Lochhead, P Nosho, K Morikawa, T Zhang, XH Wu, KN Wang, ML Garrett, WS Giovannucci, EL Fuchs, CS Chan, AT Ogino, S AF Cao, Yin Nishihara, Reiko Qian, Zhi Rong Song, Mingyang Mima, Kosuke Inamura, Kentaro Nowak, Jonathan A. Drew, David A. Lochhead, Paul Nosho, Katsuhiko Morikawa, Teppei Zhang, Xuehong Wu, Kana Wang, Molin Garrett, Wendy S. Giovannucci, Edward L. Fuchs, Charles S. Chan, Andrew T. Ogino, Shuji TI Regular Aspirin Use Associates With Lower Risk of Colorectal Cancers With Low Numbers of Tumor-Infiltrating Lymphocytes SO GASTROENTEROLOGY LA English DT Article DE Immunoprevention; Molecular Pathological Epidemiology; NSAID; Pharmacoepidemiology ID CHRONIC DISEASE; IMMUNE CELLS; PREVENTION; PROGNOSIS; METAANALYSIS; SURVIVAL; MICROENVIRONMENT; CHEMOPREVENTION; INFLAMMATION; EXPRESSION AB BACKGROUND & AIMS: Aspirin use reduces colorectal cancer risk. Aspirin, a nonsteroidal anti-inflammatory drug, inhibits prostaglandin-endoperoxide synthase 2 (PTGS2 or cyclooxygenase-2); PTGS2 promotes inflammation and suppresses T-cell-mediated adaptive immunity. We investigated whether the inverse association of aspirin use with colorectal carcinoma risk was stronger for tumors with lower degrees of lymphocytic infiltrates than for tumors with higher degrees of lymphocytic infiltrates. METHODS: We collected aspirin use data biennially from participants in the Nurses' Health Study and Health Professionals Follow-up Study. Participants were asked whether they took aspirin in most weeks, the number of tablets taken per week, and years of aspirin use. We collected available tumor specimens (n = 1458) from pathology laboratories in the United States. A pathologist confirmed the diagnosis of colorectal adenocarcinoma (excluding anal squamous cell carcinoma), and evaluated histopathology features, including patterns and degrees of lymphocytic infiltrates within and around tumor areas. Person-years of follow-up evaluation were accrued from the date of return of questionnaires until dates of colorectal cancer diagnosis, death, or the end of follow-up evaluation (June 2010). Duplication-method Cox proportional hazards regression was used to assess the association of aspirin with the incidence of colorectal carcinoma subgroups according to the degree of tumor-infiltrating lymphocytes (TILs), intratumoral periglandular reaction, peritumoral reaction, or Crohn's-like reaction. RESULTS: We documented 1458 rectal and colon cancers. The inverse association between regular aspirin use and colorectal cancer risk significantly differed by concentrations of TILs (P-heterogeneity = .007). Compared with nonregular use, regular aspirin use was associated with a lower risk of tumors that had low levels of TILs (relative risk, 0.72; 95% confidence interval, 0.63-0.81), and strength of the association depended on aspirin dose and duration (both P-trend < .001). In contrast, aspirin use was not associated with a risk of tumors having intermediate or high levels of TILs. This differential association was consistent regardless of the status of tumor microsatellite instability, mutations in BRAF, or expression of PTGS2. Regular aspirin use was associated with a lower risk of tumors that contained low levels of CD3(+) T cells, CD8(+) T cells, or CD45RO (PTPRC)(+) T cells (measured by immunohistochemistry and computer-assisted image analysis). CONCLUSIONS: Based on data from the prospective cohort studies, regular use of aspirin is associated with a lower risk of colorectal carcinomas with low concentrations of TILs. These findings indicate that the immune response in the tumor microenvironment could be involved in the chemopreventive effects of aspirin. C1 [Cao, Yin; Nishihara, Reiko; Song, Mingyang; Wu, Kana; Giovannucci, Edward L.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Nishihara, Reiko; Wang, Molin; Giovannucci, Edward L.; Ogino, Shuji] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Nishihara, Reiko; Wang, Molin] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Garrett, Wendy S.] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA. [Cao, Yin; Song, Mingyang; Drew, David A.; Lochhead, Paul; Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Cao, Yin; Nishihara, Reiko; Qian, Zhi Rong; Song, Mingyang; Lochhead, Paul; Zhang, Xuehong; Giovannucci, Edward L.; Fuchs, Charles S.; Chan, Andrew T.; Ogino, Shuji] Harvard Med Sch, Boston, MA USA. [Cao, Yin; Song, Mingyang; Drew, David A.; Lochhead, Paul; Chan, Andrew T.] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, 55 Fruit St, Boston, MA 02114 USA. [Nishihara, Reiko; Qian, Zhi Rong; Mima, Kosuke; Fuchs, Charles S.; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Inamura, Kentaro] Japan Fdn Canc Res, Inst Canc, Div Pathol, Tokyo, Japan. [Nowak, Jonathan A.; Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Div MPE Mol Pathol Epidemiol, Boston, MA 02115 USA. [Zhang, Xuehong; Giovannucci, Edward L.; Fuchs, Charles S.; Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Nosho, Katsuhiko] Sapporo Med Univ, Sch Med, Dept Gastroenterol Rheumatol & Clin Immunol, Sapporo, Hokkaido, Japan. [Morikawa, Teppei] Tokyo Univ Hosp, Dept Pathol, Tokyo, Japan. [Garrett, Wendy S.] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. RP Chan, AT (reprint author), Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, 55 Fruit St, Boston, MA 02114 USA.; Ogino, S (reprint author), Brigham & Womens Hosp, Div MPE Mol Pathol Epidemiol, 450 Brookline Ave,DFCI Room M422, Boston, MA 02215 USA. EM achan@mgh.harvard.edu; shuji_ogino@dfci.harvard.edu FU US National Institutes of Health [P01 CA87969, UM1 CA186107, P01 CA55075, UM1 CA167552, P50 CA127003, R01 CA137178, K24 DK098311, R01 CA1R35, R35 CA197735, K07 CA190673, K07 CA188126]; Nodal Award from the Dana-Farber Harvard Cancer Center; Raymond P. Lavietes Foundation; Project P Fund; Friends of the Dana-Farber Cancer Institute; Bennett Family Fund; Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance; Uehara Memorial Foundation; Japan Society for the Promotion of Science FX This work was supported by US National Institutes of Health grants P01 CA87969 (M.J.S.), UM1 CA186107 (M.J.S.), P01 CA55075 (W.C.W.), UM1 CA167552 (W.C.W.), P50 CA127003 (C.S.F.), R01 CA137178 (A.T.C.), K24 DK098311 (A.T.C.), R01 CA151993 (S.O.), R35 CA197735 (S.O.), K07 CA190673 (R.N.), and K07 CA188126 (X.Z.); the Nodal Award (S.O.) from the Dana-Farber Harvard Cancer Center; by grants from The Raymond P. Lavietes Foundation (Y.C.); the Project P Fund; The Friends of the Dana-Farber Cancer Institute; the Bennett Family Fund; and the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance; and by a fellowship grant from the Uehara Memorial Foundation and a grant from Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers from Japan Society for the Promotion of Science (K.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 3 Z9 3 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 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD NOV PY 2016 VL 151 IS 5 BP 879 EP + DI 10.1053/j.gastro.2016.07.030 PG 18 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EG3OM UT WOS:000390954600028 PM 27475305 ER PT J AU Khalili, H Olen, O AF Khalili, Hamed Olen, Ola TI Oral Contraceptive Use and Crohn's Disease Complications Reply SO GASTROENTEROLOGY LA English DT Letter ID ASSOCIATION; RISK C1 [Khalili, Hamed; Olen, Ola] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Khalili, Hamed] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA. [Khalili, Hamed; Olen, Ola] Harvard Med Sch, Boston, MA 02115 USA. [Khalili, Hamed] Kasolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden. RP Khalili, H (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA.; Khalili, H (reprint author), Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA.; Khalili, H (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Khalili, H (reprint author), Kasolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden. NR 7 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 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD NOV PY 2016 VL 151 IS 5 BP 1039 EP 1040 DI 10.1053/j.gastro.2016.09.043 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EG3OM UT WOS:000390954600047 PM 27713051 ER PT J AU Tucker, PW Evans, DD Clevenger, CK Ardisson, M Hwang, U AF Tucker, Paula W. Evans, Dian Dowling Clevenger, Carolyn K. Ardisson, Michelle Hwang, Ula TI Feasibility of nurses measuring gait speed in older community-dwelling Emergency Department patients SO GERIATRIC NURSING LA English DT Article DE Gait speed; Emergency Department; Screening; Routine assessment ID GERIATRIC ASSESSMENT; ADULTS; PEOPLE; CARE AB Gait speed assessment is a rapid, simple and objective measure for predicting risk of unfavorable outcomes which may provide better prognostic and reliable information than existing geriatric ED (Emergency Department) screening tools. This descriptive pilot project was designed to determine feasibility of implementing gait speed screening into routine nursing practice by objectively identifying patients with sub-optimal gait speeds. Participants included community-dwelling adults 65 years and older with plans for discharge following ED treatment Patients with a gait speed <1.0 m/s were identified as "high-risk" for an adverse event, and referred to the ED social worker for individualized resources prior to discharge. Thirty-five patients were screened and nurse initiated gait speed screens were completed 60% of the time. This project demonstrates ED gait speed screening may be feasible. Implications for practice should consider incorporating gait speed screening into routine nursing assessment to improve provider ED decision-making and disposition planning. Published by Elsevier Inc. C1 [Tucker, Paula W.; Clevenger, Carolyn K.] Atlanta VA Med Ctr, 1670 Clairmont Rd, Decatur, GA 30033 USA. [Tucker, Paula W.; Evans, Dian Dowling] Emory Univ Hosp, Emergency Dept, 1364 Clifton Rd NE, Atlanta, GA 30322 USA. [Tucker, Paula W.; Evans, Dian Dowling; Clevenger, Carolyn K.] Nell Hodgson Woodruff Sch Nursing, 1520 Clifton Rd, Atlanta, GA 30322 USA. [Ardisson, Michelle] Vanderbilt Univ, Sch Nursing, 461 21st Ave South, Nashville, TN 37240 USA. [Hwang, Ula] Icahn Sch Med Mt Sinai, Brookdale Dept Geriatr & Palliat Med, Dept Emergency Med, One Gustave L Levy Pl,POB 1620, New York, NY 10029 USA. [Hwang, Ula] James J Peters VA Med Ctr, GRECC, 130 Kingsbridge Rd, Bronx, NY 10468 USA. RP Tucker, PW (reprint author), 3425 Sims Rd, Snellville, GA 30039 USA. EM paula.tucker@emory.edu FU Department of Veterans Affairs FX This review is the result of work supported with resources and use of facilities by fellows in the VA Quality Scholars Fellowship Program located at the Atlanta VA Medical Center, Decatur, GA, funded by the Department of Veterans Affairs. The conclusions in this publication are those of the authors and they do not necessarily represent the views of the Department of Veterans Affairs or the United States government. NR 20 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 0197-4572 EI 1528-3984 J9 GERIATR NURS JI Geriatr. Nurs. PD NOV-DEC PY 2016 VL 37 IS 6 BP 453 EP 457 DI 10.1016/j.gerinurse.2016.06.015 PG 5 WC Geriatrics & Gerontology; Gerontology; Nursing SC Geriatrics & Gerontology; Nursing GA EG6LG UT WOS:000391157200006 PM 27477084 ER PT J AU Mihos, CG Larrauri-Reyes, M Hung, J Santana, O AF Mihos, Christos G. Larrauri-Reyes, Maiteder Hung, Judy Santana, Orlando TI Transaortic Edge-to-Edge Repair for Functional Mitral Regurgitation During Aortic Valve Replacement A 13-Year Experience SO INNOVATIONS-TECHNOLOGY AND TECHNIQUES IN CARDIOTHORACIC AND VASCULAR SURGERY LA English DT Article DE Aortic valve replacement; Edge-to-edge repair; Functional mitral regurgitation; Mitral valve repair; Transaortic approach ID DOUBLE-ORIFICE TECHNIQUE; ECHOCARDIOGRAPHY; ANNULOPLASTY; STENOSIS; SURGERY; SOCIETY; TIME; ERA AB Objective: The study evaluated the feasibility of a transaortic edge-to-edge mitral valve repair (Alfieri stitch) for moderate or greater (>= 2+) functional mitral regurgitation (MR) in high-risk patients undergoing aortic valve replacement. Methods: We retrospectively evaluated 40 consecutive patients who underwent aortic valve replacement combined with a transaortic edge-to-edge mitral valve repair for 2+ or greater functional MR, between February 2002 and April 2015. The MR was graded semiquantitatively as 0 (trace/none), mild (1+), moderate (2+), or moderate to severe (3-4+). Results: Thirty-two patients had aortic stenosis, and eight had aortic regurgitation. The mean +/- standard deviation (SD) age was 77.5 +/- 5 years, 34 (85%) were male, and the mean +/- SD EuroSCORE II was 14.3% +/- 12.9. At a median follow-up of 1 month (interquartile range, 0.75-10), there were significant improvements in preoperative versus postoperative median MR grade (3+ vs 1+, P < 0.001), mean left ventricular ejection fraction (34% vs 41%, P = 0.018), left ventricular end-diastolic diameter (54 vs 49 mm, P = 0.005), and pulmonary artery systolic pressure (49 vs 35 mm Hg, P < 0.001). Persistent 3 to 4+ MR occurred in two patients (5%). In 12 patients with at least 6-month follow-up (mean +/- SD, 18 +/- 11 months), a sustained improvement in all echocardiographic parameters was observed, with persistent 3 to 4+ MR occurring in one patient (8.3%). Actuarial survival at 1, 3, and 4.5 years was 82% +/- 6, 71% +/- 8, and 65% +/- 10, respectively. Conclusions: A transaortic edge-to-edge repair for 2+ or greater functional MR can be safely performed during aortic valve replacement and is associated with improvements in MR grade, left ventricular remodeling, and pulmonary hemodynamics. C1 [Mihos, Christos G.; Hung, Judy] Harvard Med Sch, Massachusetts Gen Hosp, Cardiac Ultrasound Lab, 55 Fruit St, Boston, MA 02114 USA. [Mihos, Christos G.; Larrauri-Reyes, Maiteder; Santana, Orlando] Columbia Univ, Mt Sinai Heart Inst, Div Cardiol, Miami Beach, FL USA. RP Mihos, CG (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Cardiac Ultrasound Lab, 55 Fruit St, Boston, MA 02114 USA. EM cmihos@mgh.harvard.edu NR 30 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1556-9845 EI 1559-0879 J9 INNOVATIONS JI Innovations PD NOV-DEC PY 2016 VL 11 IS 6 BP 425 EP 429 PG 5 WC Surgery SC Surgery GA EG4KP UT WOS:000391013100009 PM 27879530 ER PT J AU Moore, JC Tang, Q Yordan, NT Moore, FE Garcia, EG Lobbardi, R Ramakrishnan, A Marvin, DL Anselmo, A Sadreyev, RI Langenau, DM AF Moore, John C. Tang, Qin Yordan, Nora Torres Moore, Finola E. Garcia, Elaine G. Lobbardi, Riadh Ramakrishnan, Ashwin Marvin, Dieuwke L. Anselmo, Anthony Sadreyev, Ruslan I. Langenau, David M. TI Single-cell imaging of normal and malignant cell engraftment into optically clear prkdc-null SCID zebrafish SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; ACUTE LYMPHOBLASTIC-LEUKEMIA; STEM-CELLS; EMBRYONAL RHABDOMYOSARCOMA; TRANSPARENT ZEBRAFISH; LYMPHOID DEVELOPMENT; MUSCLE REGENERATION; CATALYTIC SUBUNIT; PROPAGATING CELLS; GENOMIC ANALYSIS AB Cell transplantation into immunodeficient mice has revolutionized our understanding of regeneration, stem cell self-renewal, and cancer; yet models for direct imaging of engrafted cells has been limited. Here, we characterize zebrafish with mutations in recombination activating gene 2 (rag2), DNA-dependent protein kinase (prkdc), and janus kinase 3 (jak3). Histology, RNA sequencing, and single-cell transcriptional profiling of blood showed that rag2 hypomorphic mutant zebrafish lack T cells, whereas prkdc deficiency results in loss of mature T and B cells and jak3 in T and putative Natural Killer cells. Although all mutant lines engraft fluorescently labeled normal and malignant cells, only the prkdc mutant fish reproduced as homozygotes and also survived injury after cell transplantation. Engraftment into optically clear casper, prkdc-mutant zebrafish facilitated dynamic live cell imaging of muscle regeneration, repopulation of muscle stem cells within their endogenous niche, and muscle fiber fusion at single-cell resolution. Serial imaging approaches also uncovered stochasticity in fluorescently labeled leukemia regrowth after competitive cell transplantation into prkdc mutant fish, providing refined models to assess clonal dominance and progression in the zebrafish. Our experiments provide an optimized and facile transplantation model, the casper, prkdc mutant zebrafish, for efficient engraftment and direct visualization of fluorescently labeled normal and malignant cells at single-cell resolution. C1 [Moore, John C.; Tang, Qin; Moore, Finola E.; Garcia, Elaine G.; Lobbardi, Riadh; Ramakrishnan, Ashwin; Langenau, David M.] Massachusetts Gen Hosp, Mol Pathol, Charlestown, MA 02129 USA. [Moore, John C.; Tang, Qin; Moore, Finola E.; Garcia, Elaine G.; Lobbardi, Riadh; Ramakrishnan, Ashwin; Marvin, Dieuwke L.; Langenau, David M.] Massachusetts Gen Hosp, Canc Ctr, Charlestown, MA 02129 USA. [Moore, John C.; Tang, Qin; Moore, Finola E.; Garcia, Elaine G.; Lobbardi, Riadh; Ramakrishnan, Ashwin; Langenau, David M.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Anselmo, Anthony; Sadreyev, Ruslan I.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Moore, John C.; Tang, Qin; Yordan, Nora Torres; Moore, Finola E.; Garcia, Elaine G.; Lobbardi, Riadh; Ramakrishnan, Ashwin; Langenau, David M.] Harvard Stem Cell Inst, Cambridge, MA 02139 USA. [Yordan, Nora Torres] Harvard Univ, Cambridge, MA 02138 USA. [Anselmo, Anthony; Sadreyev, Ruslan I.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. RP Langenau, DM (reprint author), Massachusetts Gen Hosp, Mol Pathol, Charlestown, MA 02129 USA.; Langenau, DM (reprint author), Massachusetts Gen Hosp, Canc Ctr, Charlestown, MA 02129 USA.; Langenau, DM (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA.; Langenau, DM (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02139 USA. EM dlangenau@mgh.harvard.edu FU Alex's Lemonade Stand Foundation; Live Like Bella Foundation for Childhood Cancer; American Cancer Society; Massachusetts General Hospital (MGH) Howard Goodman Fellowship; National Institutes of Health [R24OD016761, R01CA154923, U54CA168512]; China Scholarship Council; NIH [1S10OD012027-01A1, 1S10OD016372-01, S10RR020936-01, 1S10RR023440-01A1]; University of Utah Health and Sciences Genetic Mutation and Detection Core FX This work was supported by Alex's Lemonade Stand Foundation (D.M. Langenau), the Live Like Bella Foundation for Childhood Cancer (D.M. Langenau), American Cancer Society (D.M. Langenau), the Massachusetts General Hospital (MGH) Howard Goodman Fellowship (D.M. Langenau), and National Institutes of Health grants R24OD016761, R01CA154923, and U54CA168512. Q. Tang is funded by the China Scholarship Council. We thank the MGH Next Generation Sequencing Core, MGH Specialized Histopathology Services, and the Dana-Farber/Harvard Cancer Center (P30 CA06516), MGH Cancer Center/Molecular Pathology Confocal Core, the MGH Pathology Flow and Image Cytometry Research Core which obtained support from the NIH Shared Instrumentation program with 1S10OD012027-01A1, 1S10OD016372-01, S10RR020936-01, and 1S10RR023440-01A1, and the University of Utah Health and Sciences Genetic Mutation and Detection Core. NR 61 TC 0 Z9 0 U1 5 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD NOV PY 2016 VL 213 IS 12 BP 2575 EP 2589 DI 10.1084/jem.20160378 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EG5ZC UT WOS:000391122400005 PM 27810924 ER PT J AU Hu, Y Kim, JH He, KM Wan, Q Kim, J Flach, M Kirchhausen, T Vortkamp, A Winau, F AF Hu, Yu Kim, Ji Hyung He, Kangmin Wan, Qi Kim, Jessica Flach, Melanie Kirchhausen, Tom Vortkamp, Andrea Winau, Florian TI Scramblase TMEM16F terminates T cell receptor signaling to restrict T cell exhaustion SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID SUPRAMOLECULAR ACTIVATION CLUSTER; CHRONIC VIRAL-INFECTION; PHOSPHATIDYLSERINE EXPOSURE; IMMUNOLOGICAL SYNAPSE; CYTOPLASMIC DOMAIN; MEMBRANE CURVATURE; ENDOCYTOSIS; BINDING; PROTEIN; MICROCLUSTERS AB In chronic infection, T cells become hyporesponsive to antigenic stimulation to prevent immunopathology. Here, we show that TMEM16F is required to curb excessive T cell responses in chronic infection with virus. TMEM16F-deficient T cells are hyperactivated during the early phase of infection, exhibiting increased proliferation and cytokine production. Interestingly, this overactivation ultimately leads to severe T cell exhaustion and the inability of the host to control viral burden. Mechanistically, we identify TMEM16F as the dominant lipid scramblase in T lymphocytes that transports phospholipids across membranes. TMEM16F is located in late endosomes, where it facilitates the generation of multivesicular bodies for TCR degradation and signal termination. Consequently, TMEM16F deficiency results in sustained signaling and augmented T cell activation. Our results demonstrate that scramblase restricts TCR responses to avoid overactivation, ensuring a well-balanced immune response in chronic infectious disease. C1 [Hu, Yu; Kim, Ji Hyung; Wan, Qi; Kim, Jessica; Flach, Melanie; Winau, Florian] Harvard Med Sch, Boston Childrens Hosp, Dept Microbiol & Immunobiol, Program Cellular & Mol Med, Boston, MA 02115 USA. [He, Kangmin; Kirchhausen, Tom] Harvard Med Sch, Boston Childrens Hosp, Dept Cell Biol, Program Cellular & Mol Med, Boston, MA 02115 USA. [Vortkamp, Andrea] Univ Duisburg Essen, Dept Dev Biol, D-45117 Essen, Germany. RP Winau, F (reprint author), Harvard Med Sch, Boston Childrens Hosp, Dept Microbiol & Immunobiol, Program Cellular & Mol Med, Boston, MA 02115 USA. EM florian.winau@childrens.harvard.edu OI Hu, Yu/0000-0002-9511-9383 FU Neurobiology Imaging Facility at Harvard (NINDS Core Center Grant) [P30, NS072030]; National Institutes of Health [R01 GM075252, R01 AI083426] FX We thank L. Jan for providing TMEM16F antibody; N. Hacohen and T. Eisenhaure for help and advice on lentivirus production; K. Wucherpfennig and P. Zhou for providing pLKO-Thy1.1 lentiviral vector; S. Nagata for pMX-TMEM16F-RFP construct; L. Samelson for LAT-YFP vector; J. Wherry for LCMV clone 13; and W. Ebina and D. Rossi for pHAGE2-TRE lentiviral vector and helpful discussion. We thank M. Ericsson and L. Trakimas from the Electron Microscopy Facility at Harvard Medical School for electron microscopy technical support and instrumentation, M. Ocana from the Neurobiology Imaging Facility at Harvard (NINDS P30 Core Center Grant #NS072030). We thank the NIH tetramer facility for providing LCMV-specific tetramers.; This work was supported by National Institutes of Health grants R01 GM075252 (T. Kirchhausen) and R01 AI083426 (F. Winau). NR 48 TC 0 Z9 0 U1 1 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD NOV PY 2016 VL 213 IS 12 BP 2759 EP 2772 DI 10.1084/jem.20160612 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EG5ZC UT WOS:000391122400016 PM 27810927 ER PT J AU Saks, MJ Albright, T Bohan, TL Bierer, BE Bowers, CM Bush, MA Bush, PJ Casadevall, A Cole, SA Denton, MB Diamond, SS Dioso-Villa, R Epstein, J Faigman, D Faigman, L Fienberg, SE Garrett, BL Giannelli, PC Greely, HT Imwinkelried, E Jamieson, A Kafadar, K Kassirer, JP Koehler, J Korn, D Mnookin, J Morrison, AB Murphy, E Peerwani, N Peterson, JL Risinger, DM Sensabaugh, GF Spiegelman, C Stern, H Thompson, WC Wayman, JL Zabell, S Zumwalt, RE AF Saks, Michael J. Albright, Thomas Bohan, Thomas L. Bierer, Barbara E. Bowers, C. Michael Bush, Mary A. Bush, Peter J. Casadevall, Arturo Cole, Simon A. Denton, M. Bonner Diamond, Shari Seidman Dioso-Villa, Rachel Epstein, Jules Faigman, David Faigman, Lisa Fienberg, Stephen E. Garrett, Brandon L. Giannelli, Paul C. Greely, Henry T. Imwinkelried, Edward Jamieson, Allan Kafadar, Karen Kassirer, Jerome P. Koehler, Jonathan 'Jay' Korn, David Mnookin, Jennifer Morrison, Alan B. Murphy, Erin Peerwani, Nizam Peterson, Joseph L. Risinger, D. Michael Sensabaugh, George F. Spiegelman, Clifford Stern, Hal Thompson, William C. Wayman, James L. Zabell, Sandy Zumwalt, Ross E. TI Forensic bitemark identification: weak foundations, exaggerated claims SO JOURNAL OF LAW AND THE BIOSCIENCES LA English DT Article DE admissibility; bite mark; expert evidence; forensic science ID HUMAN DENTITION; MATCH RATES; STATISTICAL EVIDENCE; SCIENTIFIC BASIS; CADAVER MODEL; MARK OVERLAYS; HUMAN SKIN; ACCURACY; SCIENCE; SIMILARITY AB Several forensic sciences, especially of the pattern-matching kind, are increasingly seen to lack the scientific foundation needed to justify continuing admission as trial evidence. Indeed, several have been abolished in the recent past. A likely next candidate for elimination is bitemark identification. A number of DNA exonerations have occurred in recent years for individuals convicted based on erroneous bitemark identifications. Intense scientific and legal scrutiny has resulted. An important National Academies review found little scientific support for the field. The Texas Forensic Science Commission recently recommended a moratorium on the admission of bitemark expert testimony. The California Supreme Court has a case before it that could start a national dismantling of forensic odontology. This article describes the (legal) basis for the rise of bitemark identification and the (scientific) basis for its impending fall. The article explains the general logic of forensic identification, the claims of bitemark identification, and reviews relevant empirical research on bitemark identification-highlighting both the lack of research and the lack of support provided by what research does exist. The rise and possible fall of bitemark identification evidence has broader implications-highlighting the weak scientific culture of forensic science and the law's difficulty in evaluating and responding to unreliable and unscientific evidence. C1 [Saks, Michael J.] Arizona State Univ, Phoenix, AZ 85281 USA. [Albright, Thomas] Salk Inst Biol Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. [Bohan, Thomas L.] Forens Specialties Accreditat Board, La Jolla, CA USA. [Bierer, Barbara E.] HarvardMed Sch, Med, Boston, MA USA. [Bierer, Barbara E.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Bowers, C. Michael] USC, Ostrow Sch Dent, Los Angeles, CA USA. [Bush, Mary A.] SUNY Buffalo, Sch Dent Med, Buffalo, NY USA. [Bush, Peter J.] State Univ New York, Instrument Ctr, Sch Dent Med, South Campus, New York, NY USA. [Bush, Peter J.] Buffalo State Coll, Art Conservat, Buffalo, NY USA. [Casadevall, Arturo] Johns Hopkins Sch Publ Hlth, Mol Microbiol & Immunol Dept, Baltimore, MD USA. [Cole, Simon A.] Univ Calif Irvine, Criminol Law & Soc, Irvine, CA USA. [Denton, M. Bonner] Univ Arizona, Chem, Tucson, AZ USA. [Denton, M. Bonner] Univ Arizona, Geol Sci, Tucson, AZ USA. [Diamond, Shari Seidman] Northwestern Univ, Law, Chicago, IL USA. [Diamond, Shari Seidman] Northwestern Univ, Psychol, Chicago, IL USA. [Dioso-Villa, Rachel] Griffith Univ, Sch Criminol & Criminal Justice, Mt Gravatt, Qld, Australia. [Epstein, Jules] Temple Univ, Beasely Sch Law, Law, Philadelphia, PA 19122 USA. [Faigman, David; Faigman, Lisa] Univ Calif San Francisco, Hastings Coll Law, Law, San Francisco, CA 94102 USA. [Fienberg, Stephen E.] Falk Univ, Pittsburgh, PA USA. [Garrett, Brandon L.] Carnegie Mellon Univ, Stat & Social Sci, Pittsburgh, PA 15213 USA. [Garrett, Brandon L.] Univ Virginia, Law, Charlottesville, VA USA. [Giannelli, Paul C.] Case Western Reserve Univ, Law, Cleveland, OH 44106 USA. [Greely, Henry T.] Stanford Univ, Law, Stanford, CA USA. [Greely, Henry T.] Stanford Univ, Genet, Stanford, CA USA. [Imwinkelried, Edward] Univ Calif Davis, Davis, CA 95616 USA. [Jamieson, Allan] Forens Inst UK, Glasgow, Lanark, Scotland. [Jamieson, Allan] Staffordshire Univ, Stoke On Trent, Staffs, England. [Jamieson, Allan] Univ West Scotland, Hamilton, Scotland. [Kafadar, Karen] Univ Virginia, Stat, Charlottesville, VA USA. [Kassirer, Jerome P.] Tufts Univ, Sch Med, Med, Boston, MA 02111 USA. [Koehler, Jonathan 'Jay'] Northwestern Pritzker Sch Law, Law, Chicago, IL USA. [Korn, David] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Korn, David] Harvard Med Sch, Pathol, Cambridge, MA USA. [Mnookin, Jennifer] Univ Calif Los Angeles, Sch Law, Los Angeles, CA 90024 USA. [Morrison, Alan B.] George Washington Univ, Publ Interest & Publ Serv Law, Washington, DC USA. [Murphy, Erin] NYU, Sch Law, Law, New York, NY USA. [Peerwani, Nizam] Tarrant Cty, Ft Worth, TX USA. [Risinger, D. Michael] Calif State Univ Los Angeles, Sch Criminal Justice & Criminalist, Los Angeles, CA 90032 USA. [Sensabaugh, George F.] Seton Hall Univ, Sch Law, Newark, NJ USA. [Spiegelman, Clifford] Univ Calif Berkeley, Sch Publ Hlth, Biomed & Forens Sci, Berkeley, CA 94720 USA. [Spiegelman, Clifford] Texas A&M Univ, Stat, College Stn, TX USA. [Stern, Hal] Univ Calif Irvine, Dept Stat, Irvine, CA USA. [Thompson, William C.] Univ Calif Irvine, Dept Criminol Law & Soc, Dept Psychol & Social Behav, Irvine, CA USA. [Wayman, James L.] Univ Calif Irvine, Sch Law, Irvine, CA USA. [Wayman, James L.] San Jose State Univ, Res, San Jose, CA 95192 USA. [Zabell, Sandy] Northwestern Univ, Math & Stat, Evanston, IL USA. [Zumwalt, Ross E.] Univ New Mexico, New Mexico Off, Sch Med, Albuquerque, NM 87131 USA. [Zumwalt, Ross E.] Univ New Mexico, Pathol, Sch Med, Albuquerque, NM 87131 USA. RP Saks, MJ (reprint author), Arizona State Univ, Phoenix, AZ 85281 USA. EM saks@asu.edu NR 59 TC 0 Z9 0 U1 20 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2053-9711 J9 J LAW BIOSCI JI J. Law Biosci. PD NOV PY 2016 VL 3 IS 3 BP 538 EP 575 DI 10.1093/jlb/lsw045 PG 38 WC Law SC Government & Law GA EG5TE UT WOS:000391106400005 ER PT J AU Medford-Davis, LN Fonarow, GC Bhatt, DL Xu, HL Smith, EE Suter, R Peterson, ED Xian, Y Matsouaka, RA Schwamm, LH AF Medford-Davis, Laura N. Fonarow, Gregg C. Bhatt, Deepak L. Xu, Haolin Smith, Eric E. Suter, Robert Peterson, Eric D. Xian, Ying Matsouaka, Roland A. Schwamm, Lee H. TI Impact of Insurance Status on Outcomes and Use of Rehabilitation Services in Acute Ischemic Stroke: Findings From Get With The Guidelines-Stroke SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE health outcomes; health policy; health services research; insurance; stroke, ischemic ID PROFESSIONAL SHORTAGE AREAS; RACIAL-DIFFERENCES; UNINSURED ADULTS; POSTACUTE CARE; PAYER STATUS; HEALTH; ASSOCIATION; SURVIVAL; DISEASE; HYPERTENSION AB BACKGROUND-Insurance status affects access to care, which may affect health outcomes. The objective was to determine whether patients without insurance or with government-sponsored insurance had worse quality of care or in-hospital outcomes in acute ischemic stroke. METHODS AND RESULTS-Multivariable logistic regressions with generalized estimating equations stratified by age under or at least 65 years were adjusted for patient demographics and comorbidities, presenting factors, and hospital characteristics to determine differences in in-hospital mortality and postdischarge destination. We included 589 320 ischemic stroke patients treated at 1604 US hospitals participating in the Get With The Guidelines-Stroke program between 2012 and 2015. Uninsured patients with hypertension, high cholesterol, or diabetes mellitus were less likely to be taking appropriate control medications prior to stroke, to use an ambulance to arrive to the ED, or to arrive early after symptom onset. Even after adjustment, the uninsured were more likely than the privately insured to die in the hospital (<65 years, OR 1.33 [95% CI 1.22-1.45]; >= 65 years OR 1.54 [95% CI 1.34-1.75]), and among survivors, were less likely to go to inpatient rehab (<65 OR 0.63 [95% CI 0.6-0.67]; >= 65 OR 0.56 [95% CI 0.5-0.63]). In contrast, patients with Medicare and Medicaid were more likely to be discharged to a Skilled Nursing Facility (<65 years OR 2.08 [CI 1.96-2.2]; OR 2.01 [95% CI 1.91-2.13]; >= 65 years OR 1.1 [95% CI 1.07-1.13]; OR 1.41 [95% CI 1.35-1.46]). CONCLUSIONS-Preventative care prior to ischemic stroke, time to presentation for acute treatment, access to rehabilitation, and in-hospital mortality differ by patient insurance status. C1 [Medford-Davis, Laura N.] Baylor Coll Med, Sect Emergency Med, Houston, TX 77030 USA. [Fonarow, Gregg C.] Ronald Reagan UCLA Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Heart & Vasc Ctr, 75 Francis St, Boston, MA 02115 USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Schwamm, Lee H.] Harvard Med Sch, Boston, MA USA. [Xu, Haolin; Peterson, Eric D.; Xian, Ying; Matsouaka, Roland A.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Matsouaka, Roland A.] Duke Univ, Sch Med, Dept Biostat & Bioinformat, Durham, NC USA. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Dept Clin Neurosci, Calgary, AB, Canada. [Suter, Robert] Univ Texas Southwestern, Dept Emergency Med, Dallas, TX USA. [Peterson, Eric D.] Duke Univ, Med Ctr, Dept Cardiol, Durham, NC USA. [Xian, Ying] Duke Univ, Med Ctr, Dept Neurol, Durham, NC USA. RP Medford-Davis, LN (reprint author), Baylor Coll Med, Sect Emergency Med, Ben Taub Emergency Ctr, 1504 Taub Loop, Houston, TX 77030 USA. EM medford.davis@gmail.com FU American Heart Association FX The research analysis for this study was funded through a grant from the American Heart Association. NR 35 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD NOV PY 2016 VL 5 IS 11 AR e004282 DI 10.1161/JAHA.116.004282 PG 24 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EG1IU UT WOS:000390786600039 ER PT J AU Ponce, J DeMaria, EJ Nguyen, NT Hutter, M Sudan, R Morton, JM AF Ponce, Jaime DeMaria, Eric J. Nguyen, Ninh T. Hutter, Matthew Sudan, Ranjan Morton, John M. TI American Society for Metabolic and Bariatric Surgery estimation of bariatric surgery procedures in 2015 and surgeon workforce in the United States SO SURGERY FOR OBESITY AND RELATED DISEASES LA English DT Editorial Material C1 [Ponce, Jaime] Chattanooga Bariatr, Chattanooga, TN USA. [DeMaria, Eric J.] Bon Secours Hlth Syst, Hampton, VA USA. [Nguyen, Ninh T.] Univ Calif Irvine, Med Ctr, Dept Surg, Orange, CA USA. [Hutter, Matthew] Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Sudan, Ranjan] Duke Univ Med Ctr, Dept Surg, Durham, NC USA. [Morton, John M.] Stanford Univ, Dept Surg, Palo Alto, CA USA. RP Ponce, J (reprint author), 7405 Shallowford Rd,Suite 160, Chattanooga, TN 37421 USA. EM JPonceMD@gmail.com NR 8 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 1550-7289 EI 1878-7533 J9 SURG OBES RELAT DIS JI Surg. Obes. Relat. Dis. PD NOV PY 2016 VL 12 IS 9 BP 1637 EP 1639 DI 10.1016/j.soard.2016.08.488 PG 3 WC Surgery SC Surgery GA EG6ME UT WOS:000391159800001 PM 27692915 ER PT J AU Xie, HF Peng, C Huang, JL Li, BE Kim, W Smith, EC Fujiwara, Y Qi, J Cheloni, G Das, PP Nguyen, M Li, SG Bradner, JE Orkin, SH AF Xie, Huafeng Peng, Cong Huang, Jialiang Li, Bin E. Kim, Woojin Smith, Elenoe C. Fujiwara, Yuko Qi, Jun Cheloni, Giulia Das, Partha P. Minh Nguyen Li, Shaoguang Bradner, James E. Orkin, Stuart H. TI Chronic Myelogenous Leukemia-Initiating Cells Require Polycomb Group Protein EZH2 SO CANCER DISCOVERY LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; REPRESSIVE COMPLEX 2; CHROMOSOME-POSITIVE LEUKEMIAS; ACUTE LYMPHOBLASTIC-LEUKEMIA; METHYLTRANSFERASE GENE EZH2; HISTONE METHYLTRANSFERASE; STEM-CELLS; PROSTATE-CANCER; TYROSINE-KINASE; INHIBITOR AB Tyrosine kinase inhibitors (TKI) have revolutionized chronic myelogenous leukemia (CML) management. Disease eradication, however, is hampered by innate resistance of leukemia-initiating cells (LIC) to TKI-induced killing, which also provides the basis for subsequent emergence of TKI-resistant mutants. We report that EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), is overexpressed in CML LICs and required for colony formation and survival and cell-cycle progression of CML cell lines. A critical role for EZH2 is supported by genetic studies in a mouse CML model. Inactivation of Ezh2 in conventional conditional mice and through CRISPR/Cas9-mediated gene editing prevents initiation and maintenance of disease and survival of LICs, irrespective of BCR-ABL1 mutational status, and extends survival. Expression of the EZH2 homolog EZH1 is reduced in EZH2-deficient CML LICs, creating a scenario resembling complete loss of PRC2. EZH2 dependence of CML LICs raises prospects for improved therapy of TKI-resistant CML and/or eradication of disease by addition of EZH2 inhibitors. SIGNIFICANCE: This work defines EZH2 as a selective vulnerability for CML cells and their LICs, regardless of BCR-ABL1 mutational status. Our findings provide an experimental rationale for improving disease eradication through judicious use of EZH2 inhibitors within the context of standard-of-care TKI therapy. (C)2016 AACR. C1 [Xie, Huafeng; Peng, Cong; Huang, Jialiang; Li, Bin E.; Kim, Woojin; Smith, Elenoe C.; Fujiwara, Yuko; Das, Partha P.; Minh Nguyen; Orkin, Stuart H.] Harvard Med Sch, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Xie, Huafeng; Peng, Cong; Huang, Jialiang; Li, Bin E.; Kim, Woojin; Smith, Elenoe C.; Fujiwara, Yuko; Das, Partha P.; Minh Nguyen; Orkin, Stuart H.] Harvard Med Sch, Dept Pediat Oncol, Dana Farber Canc Inst, Harvard Stem Cell Inst, Boston, MA USA. [Huang, Jialiang] Harvard Sch Publ Heath, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA USA. [Qi, Jun; Bradner, James E.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Cheloni, Giulia; Li, Shaoguang] Univ Massachusetts, Sch Med, Dept Med, Div Hematol Oncol, Worcester, MA USA. [Cheloni, Giulia] Univ Florence, Dept Expt & Clin Biomed Sci Mario Serio, Florence, Italy. [Bradner, James E.] Harvard Med Sch, Dept Med, Boston, MA USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA USA. RP Orkin, SH (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM Stuart_Orkin@dfci.harvard.edu FU NIH [U01 CA105423]; Hyundai Hope on Wheels; Harvard Stem Cell Institute Blood Program; Jane Coffin Childs Memorial Fund for Medical Research Fellowship; Burroughs Wellcome Fund Postdoctoral Enrichment Program Award FX This work was funded in part by NIH U01 CA105423 (to S.H. Orkin), a Scholar Award from Hyundai Hope on Wheels, and the Harvard Stem Cell Institute Blood Program. H. Xie was a Leukemia and Lymphoma Society fellow. E.C. Smith is supported by a Jane Coffin Childs Memorial Fund for Medical Research Fellowship and a Burroughs Wellcome Fund Postdoctoral Enrichment Program Award. NR 45 TC 2 Z9 2 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD NOV PY 2016 VL 6 IS 11 BP 1237 EP 1247 DI 10.1158/2159-8290.CD-15-1439 PG 11 WC Oncology SC Oncology GA EF3VR UT WOS:000390253500022 PM 27630126 ER PT J AU Vijai, J Topka, S Villano, D Ravichandran, V Maxwell, KN Maria, A Thomas, T Gaddam, P Lincoln, A Kazzaz, S Wenz, B Carmi, S Schrader, KA Hart, SN Lipkin, SM Neuhausen, SL Walsh, MF Zhang, LY Lejbkowicz, F Rennert, H Stadler, ZK Robson, M Weitzel, JN Domchek, S Daly, MJ Couch, FJ Nathanson, KL Norton, L Rennert, G Offit, K AF Vijai, Joseph Topka, Sabine Villano, Danylo Ravichandran, Vignesh Maxwell, Kara N. Maria, Ann Thomas, Tinu Gaddam, Pragna Lincoln, Anne Kazzaz, Sarah Wenz, Brandon Carmi, Shai Schrader, Kasmintan A. Hart, Steven N. Lipkin, Steve M. Neuhausen, Susan L. Walsh, Michael F. Zhang, Liying Lejbkowicz, Flavio Rennert, Hedy Stadler, Zsofia K. Robson, Mark Weitzel, Jeffrey N. Domchek, Susan Daly, Mark J. Couch, Fergus J. Nathanson, Katherine L. Norton, Larry Rennert, Gad Offit, Kenneth TI A Recurrent ERCC3 Truncating Mutation Confers Moderate Risk for Breast Cancer SO CANCER DISCOVERY LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; DNA-REPAIR; XERODERMA-PIGMENTOSUM; GENE ERCC3; TRANSCRIPTION; TUMORS; H2AX; PREDISPOSITION; SUSCEPTIBILITY; HETEROGENEITY AB Known gene mutations account for approximately 50% of the hereditary risk for breast cancer. Moderate and low penetrance variants, discovered by genomic approaches, account for an as-yet-unknown proportion of the remaining heritability. A truncating mutation c.325C>T:p. Arg109* (R109X) in the ATP-dependent helicase ERCC3 was observed recurrently among exomes sequenced in BRCA wild-type, breast cancer-affected individuals of Ashkenazi Jewish ancestry. Modeling of the mutation in ERCC3-deficient or CRISPR/Cas9-edited cell lines showed a consistent pattern of reduced expression of the protein and concomitant hypomorphic functionality when challenged with UVC exposure or treatment with the DNA alkylating agent IlludinS. Overexpressing the mutant protein in ERCC3-deficient cells only partially rescued their DNA repair-deficient phenotype. Comparison of frequency of this recurrent mutation in over 6,500 chromosomes of breast cancer cases and 6,800 Ashkenazi controls showed significant association with breast cancer risk (ORBC = 1.53, ORER+ = 1.73), particularly for the estrogen receptor-positive subset (P < 0.007). SIGNIFICANCE : A functionally significant recurrent ERCC3 mutation increased the risk for breast cancer in a genetic isolate. Mutated cell lines showed lower survival after in vitro exposure to DNA-damaging agents. Thus, similar to tumors arising in the background of homologous repair defects, mutations in nucleotide excision repair genes such as ERCC3 could constitute potential therapeutic targets in a subset of hereditary breast cancers. (C)2016 AACR. C1 [Vijai, Joseph; Topka, Sabine; Villano, Danylo; Ravichandran, Vignesh; Maria, Ann; Thomas, Tinu; Gaddam, Pragna; Lincoln, Anne; Kazzaz, Sarah; Walsh, Michael F.; Stadler, Zsofia K.; Robson, Mark; Norton, Larry; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Vijai, Joseph; Topka, Sabine; Villano, Danylo; Ravichandran, Vignesh; Maria, Ann; Thomas, Tinu; Kazzaz, Sarah; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, 1275 York Ave, New York, NY 10021 USA. [Maxwell, Kara N.; Wenz, Brandon; Domchek, Susan; Nathanson, Katherine L.] Univ Penn, Dept Med, Perelman Sch Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Gaddam, Pragna; Walsh, Michael F.; Stadler, Zsofia K.; Offit, Kenneth] Mem Sloan Kettering, Dept Med, Clin Genet Serv, New York, NY USA. [Carmi, Shai] Hebrew Univ Jerusalem, Braun Sch Publ Hlth & Community Med, Jerusalem, Israel. [Schrader, Kasmintan A.] British Columbia Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada. [Hart, Steven N.; Couch, Fergus J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Lipkin, Steve M.; Stadler, Zsofia K.; Robson, Mark] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA USA. [Walsh, Michael F.] Mem Sloan Kettering Canc Ctr, Dept Pediat, 1275 York Ave, New York, NY 10021 USA. [Zhang, Liying] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. [Lejbkowicz, Flavio; Rennert, Hedy; Rennert, Gad] Clalit Natl Israeli Canc Control Ctr, Haifa, Israel. [Lejbkowicz, Flavio; Rennert, Hedy; Rennert, Gad] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel. [Lejbkowicz, Flavio; Rennert, Hedy; Rennert, Gad] B Rappaport Fac Med, Haifa, Israel. [Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Clin Canc Genet Community Res Network, Clin Canc Genet, Duarte, CA USA. [Domchek, Susan; Nathanson, Katherine L.] Univ Penn, Dept Med, Perelman Sch Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA. [Domchek, Susan; Nathanson, Katherine L.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Daly, Mark J.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Daly, Mark J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol & Hlth Sci Res, Rochester, MN USA. RP Offit, K (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave,Box 192, New York, NY 10021 USA. EM offitk@mskcc.org FU Sharon Corzine Cancer Research Fund; Robert and Kate Niehaus Center for Inherited Cancer Genomics; Miele family initiative; Andrew Sabin Family Fund; NIH [R01CA176785]; Breast Cancer Research Foundation; Department of Defense [W81XWH-13-1-0338]; City of Hope Clinical Cancer Genetics Community Research Network; Hereditary Cancer Research Registry from the National Cancer Institute [RC4CA153828]; Office of the Director, NIH; MSKCC [NIH P30CA008748]; [R21-CA139396] FX This work was supported by the Sharon Corzine Cancer Research Fund, The Robert and Kate Niehaus Center for Inherited Cancer Genomics, the Miele family initiative (K. Offit), and the Andrew Sabin Family Fund. This work was also supported by NIH R01CA176785 and the Breast Cancer Research Foundation (F.J. Couch, K.L. Nathanson, M. Robson, and K. Offit), R21-CA139396 (J. Vijai and Z.K. Stadler), and Department of Defense W81XWH-13-1-0338 (K.L. Nathanson). This work was also supported by funds from the City of Hope Clinical Cancer Genetics Community Research Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, NIH. This work was also supported by the MSKCC Core grant NIH P30CA008748. NR 36 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD NOV PY 2016 VL 6 IS 11 BP 1267 EP 1275 DI 10.1158/2159-8290.CD-16-0487 PG 9 WC Oncology SC Oncology GA EF3VR UT WOS:000390253500025 PM 27655433 ER PT J AU Paul, S Bach, D LeBoeuf, NR Devlin, PM Lipworth, AD AF Paul, Suchismita Bach, Daniel LeBoeuf, Nicole R. Devlin, Phillip M. Lipworth, Adam D. TI Successful use of brachytherapy for a severe hidradenitis suppurativa variant SO DERMATOLOGIC THERAPY LA English DT Article DE Brachytherapy; hidradenitis suppurativa; follicular occlusion tetrad; radiation therapy ID EXTERNAL-BEAM RADIATION; DISSECTING CELLULITIS; ACNE CONGLOBATA; THERAPY; SCALP AB Hidradenitis suppurativa is a member of the follicular occlusion tetrad, along with acne conglobata, dissecting cellulitis of the scalp and pilodinal sinus. These conditions share common pathophysiologic features, including follicle occlusion, bacterial overgrowth, severe suppurative inflammation, scarring, and sinus tract formation. Treatment of severe cases is challenging, and a novel treatment modality would be of significant value. We describe a 46-year-old man who presented with a 15-year history of suppurative and scarring nodules involving his groin, scalp, neck, face, and chest. Based on their distribution and morphology, these lesions were most characteristic of hidradenitis suppurativa, although he had features of acne conglobata and dissecting cellulitis as well. Over the years, he had been treated with several antimicrobial and immunomodulatory agents, the main conventional therapies for follicular occlusion syndromes, without much success. We then treated him with superficial brachytherapy to his right groin and occiput, which led to significant improvement. No toxic side effects were noted. This case demonstrates the successful application of superficial brachytherapy for the treatment of severe hidradenitis suppurativa, and possibly for other follicular occlusion syndromes. C1 [Paul, Suchismita; Bach, Daniel; LeBoeuf, Nicole R.; Lipworth, Adam D.] Brigham & Womens Hosp, Dept Dermatol, 221 Longwood Ave, Boston, MA 02115 USA. [Devlin, Phillip M.] Harvard Med Sch, Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, Boston, MA USA. RP Lipworth, AD (reprint author), Brigham & Womens Hosp, Dept Dermatol, 221 Longwood Ave, Boston, MA 02115 USA. EM alipworth@partners.org NR 15 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1396-0296 EI 1529-8019 J9 DERMATOL THER JI Dermatol. Ther. PD NOV-DEC PY 2016 VL 29 IS 6 BP 455 EP 458 DI 10.1111/dth.12393 PG 4 WC Dermatology SC Dermatology GA EF8EJ UT WOS:000390561300017 PM 27425163 ER PT J AU Grant, C Knight, J Milne, T Sinclair, J Camargo, C AF Grant, C. Knight, J. Milne, T. Sinclair, J. Camargo, C. TI Vitamin D supplementation during pregnancy and infancy reduces food allergen sensitisation and parental-reported food allergy: a randomised controlled trial SO EUROPEAN JOURNAL OF PEDIATRICS LA English DT Meeting Abstract C1 [Grant, C.; Milne, T.] Univ Auckland, Paediat Child & Youth Hlth, Auckland, New Zealand. [Knight, J.] Univ Auckland, Epidemiol & Biostat, Auckland, New Zealand. [Sinclair, J.] Starship Childrens Hosp, Allergy & Clin Immunol, Auckland, New Zealand. [Camargo, C.] Harvard Med Sch, Massachusetts Gen Hosp, Emergency Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6199 EI 1432-1076 J9 EUR J PEDIATR JI Eur. J. Pediatr. PD NOV PY 2016 VL 175 IS 11 MA 159 BP 1437 EP 1438 PG 2 WC Pediatrics SC Pediatrics GA EF0UD UT WOS:000390040700160 ER PT J AU Mahlman, M Karjalainen, MK Huusko, JM Andersson, S Kari, MA Tammela, OKT Sankilampi, U Lehtonen, L Marttila, RH Bassler, D Poets, CF Lacaze-Masmonteil, T Delacourt, C Palotie, A Muglia, LJ Lavoie, PM Ramet, M Hallman, M AF Mahlman, M. Karjalainen, M. K. Huusko, J. M. Andersson, S. Kari, M. A. Tammela, O. K. T. Sankilampi, U. Lehtonen, L. Marttila, R. H. Bassler, D. Poets, C. F. Lacaze-Masmonteil, T. Delacourt, C. Palotie, A. Muglia, L. J. Lavoie, P. M. Ramet, M. Hallman, M. TI GENOME-WIDE ASSOCIATION STUDY OF BRONCHOPULMONARY DYSPLASIA SO EUROPEAN JOURNAL OF PEDIATRICS LA English DT Meeting Abstract C1 [Mahlman, M.; Karjalainen, M. K.; Huusko, J. M.; Marttila, R. H.; Ramet, M.; Hallman, M.] Oulu Univ Hosp, Dept Children & Adolescents, Oulu, Finland. [Mahlman, M.; Karjalainen, M. K.; Huusko, J. M.; Marttila, R. H.; Ramet, M.; Hallman, M.] Univ Oulu, Med Res Ctr Oulu, PEDEGO Res Unit, Oulu, Finland. [Huusko, J. M.; Muglia, L. J.] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp Med Ctr, Perinatal Inst, Cincinnati, OH USA. [Huusko, J. M.; Muglia, L. J.] Dept Pediat, Cincinnati, OH USA. [Andersson, S.; Kari, M. A.] Helsinki Univ Hosp, Childrens Hosp, Helsinki, Finland. [Andersson, S.; Kari, M. A.] Univ Helsinki, Childrens Hosp, Helsinki, Finland. [Tammela, O. K. T.] Tampere Univ, Ctr Pediat Child Hlth, Tampere, Finland. [Tammela, O. K. T.] Tampere Univ Hosp, Ctr Pediat Child Hlth, Tampere, Finland. [Sankilampi, U.] Kuopio Univ Hosp, Dept Pediat, Kuopio, Finland. [Lehtonen, L.] Turku Univ Hosp, Dept Pediat, Turku, Finland. [Lehtonen, L.] Univ Turku, Dept Pediat, Turku, Finland. [Bassler, D.] Univ Zurich Hosp, Dept Neonatol, Zurich, Switzerland. [Bassler, D.] Univ Zurich, Dept Pediat, Zurich, Switzerland. [Poets, C. F.] Tuebingen Univ Hosp, Dept Neonatol, Tubingen, Germany. [Lacaze-Masmonteil, T.] Univ Calgary, Dept Paediat, Cumming Sch Med, Calgary, AB, Canada. [Delacourt, C.] INSERM, U955, Creteil, France. [Delacourt, C.] Univ Paris 05, Paris, France. [Delacourt, C.] Hop Necker Enfants Malad, Serv Pneumol Pediat, Paris, France. [Palotie, A.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Palotie, A.] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland. [Palotie, A.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Palotie, A.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Lavoie, P. M.] Child & Family Res Inst British Columbia, Dept Pediat, Vancouver, BC, Canada. [Ramet, M.] Univ Tampere, BioMediTech, Tampere, Finland. NR 0 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6199 EI 1432-1076 J9 EUR J PEDIATR JI Eur. J. Pediatr. PD NOV PY 2016 VL 175 IS 11 MA 403 BP 1534 EP 1535 PG 2 WC Pediatrics SC Pediatrics GA EF0UD UT WOS:000390040700402 ER PT J AU Spadafora, R Baudeaux, A Shi, Y Lerou, P AF Spadafora, R. Baudeaux, A. Shi, Y. Lerou, P. TI THE EPIGENOME OF THE LUNG DEVELOPMENT AMONG PRETERM NEWBORNS SO EUROPEAN JOURNAL OF PEDIATRICS LA English DT Meeting Abstract C1 [Spadafora, R.] Harvard Med Sch, Brigham & Womens Hosp, Pediat & Newborn Med, Boston, MA USA. [Baudeaux, A.; Shi, Y.] Boston Children Hosp, Newborn Med, Boston, MA USA. [Lerou, P.] Massachusetts Gen Hosp, Newborn Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6199 EI 1432-1076 J9 EUR J PEDIATR JI Eur. J. Pediatr. PD NOV PY 2016 VL 175 IS 11 MA 996 BP 1758 EP 1758 PG 1 WC Pediatrics SC Pediatrics GA EF0UD UT WOS:000390040701294 ER PT J AU Peters, AL Ahmann, AJ Battelino, T Evert, A Hirsch, IB Murad, MH Winter, WE Wolpert, H AF Peters, Anne L. Ahmann, Andrew J. Battelino, Tadej Evert, Alison Hirsch, Irl B. Murad, M. Hassan Winter, William E. Wolpert, Howard TI Diabetes Technology-Continuous Subcutaneous Insulin Infusion Therapy and Continuous Glucose Monitoring in Adults: An Endocrine Society Clinical Practice Guideline SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID MULTIPLE DAILY INJECTIONS; QUALITY-OF-LIFE; IMPROVED GLYCEMIC CONTROL; TERM METABOLIC-CONTROL; PUMP THERAPY; AMERICAN ASSOCIATION; SEVERE HYPOGLYCEMIA; BOLUS CALCULATOR; COMPLICATIONS TRIAL/EPIDEMIOLOGY; EUROPEAN ASSOCIATION AB Objective: To formulate clinical practice guidelines for the use of continuous glucose monitoring and continuous subcutaneous insulin infusion in adults with diabetes. Participants: The participants include an Endocrine Society-appointed Task Force of seven experts, a methodologist, and a medical writer. The American Association for Clinical Chemistry, the American Association of Diabetes Educators, and the European Society of Endocrinology co-sponsored this guideline. Evidence: The Task Force developed this evidence-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned one systematic review and used the best available evidence from other published systematic reviews and individual studies. Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, the American Association for Clinical Chemistry, the American Association of Diabetes Educators, and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Conclusions: Continuous subcutaneous insulin infusion and continuous glucose monitoring have an important role in the treatment of diabetes. Data from randomized controlled trials are limited on the use of medical devices, but existing studies support the use of diabetes technology for a wide variety of indications. This guideline presents a review of the literature and practice recommendations for appropriate device use. C1 [Peters, Anne L.] Univ Southern Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Ahmann, Andrew J.] Oregon Hlth & Sci Univ, Harold Schnitzer Diabet Hlth Ctr, Portland, OR 97239 USA. [Battelino, Tadej] Univ Ljubljana, Dept Med, Ljubljana 1104, Slovenia. [Battelino, Tadej] Univ Childrens Hosp, Ljubljana 1104, Slovenia. [Evert, Alison; Hirsch, Irl B.] Univ Washington, Med Ctr, Endocrine & Diabet Care Ctr, Seattle, WA 98195 USA. [Murad, M. Hassan] Mayo Clin, Evidence based Practice Ctr, Rochester, MN 55905 USA. [Winter, William E.] Univ Florida, UF Diabet Inst, Gainesville, FL 32611 USA. [Wolpert, Howard] Harvard Med Sch, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Peters, AL (reprint author), Endocrine Soc, 2055 L St NW,Suite 600, Washington, DC 20036 USA. EM govt-prof@endocrine.org FU Endocrine Society FX This article was funded by the Endocrine Society. NR 121 TC 2 Z9 2 U1 2 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD NOV PY 2016 VL 101 IS 11 BP 3922 EP 3937 DI 10.1210/jc.2016-2534 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG3MK UT WOS:000390948600007 PM 27588440 ER PT J AU Robinson, B Schlumberger, M Wirth, LJ Dutcus, CE Song, J Taylor, MH Kim, SB Krzyzanowska, MK Capdevila, J Sherman, SI Tahara, M AF Robinson, Bruce Schlumberger, Martin Wirth, Lori J. Dutcus, Corina E. Song, James Taylor, Matthew H. Kim, Sung-Bae Krzyzanowska, Monika K. Capdevila, Jaume Sherman, Steven I. Tahara, Makoto TI Characterization of Tumor Size Changes Over Time From the Phase 3 Study of Lenvatinib in Thyroid Cancer SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ANTITUMOR ACTIVITIES; INHIBITOR; SURVIVAL; E7080; TARGETS; KINASE AB Context: Lenvatinib improved the progression-free survival (PPS) and overall response rate of patients with radioiodine-refractory differentiated thyroid cancer vs placebo in the Phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT). Objective: The objective of the study was to characterize tumor size changes with lenvatinib treatment. Design: SELECT was a phase 3, randomized, double-blind, multicenter study. Setting: In this clinical trial, tumor assessments of lenvatinib (n = 261) and placebo-treated (n = 131) patients were performed by independent radiological review per Response Evaluation Criteria in Solid Tumors version, 1.1 at 8-week intervals. Patients: Patients with complete or partial response were defined as responders to lenvati nib (n = 169). Of the 92 nonresponders, 76 had at least one postbaseline tumor assessment and were included in this analysis. Interventions: Lenvatinib (24 mg once daily) or placebo in 28-day cycles until unacceptable toxicity, disease progression, or death. Main Outcome Measures:This was an exploratory analysis of key end points from SELECT, including PFS, overall response rate, and tumor reduction. Results: The median maximum percentage change in tumor size was 42.9% for patients receiving lenvatinib (responders, 51.9%; nonresponders, 20.2%). Tumor size reduction was most pronounced at first assessment (median, 24.7% at 8 wk after randomization); thereafter, the rate of change was slower but continuous (-1.3% per mo). In a multivariate model, percentage change in tumor size at the first assessment was a marginally significant positive predictor for PPS (P =.06). Conclusions: The change in tumor size conferred by lenvatinib was characterized by two phases: an initial, rapid decline, followed by slower, continuous shrinkage. C1 [Robinson, Bruce] Univ Sydney, Kolling Inst Med Res, Sydney, NSW 2006, Australia. [Schlumberger, Martin] Gustave Roussy, Dept Nucl Med & Endocrine Oncol, F-94805 Villejuif, France. [Schlumberger, Martin] Univ Paris Sud, F-94805 Villejuif, France. [Wirth, Lori J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Dutcus, Corina E.; Song, James] Eisai Inc, Woodcliff Lake, NJ 07677 USA. [Taylor, Matthew H.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA. [Kim, Sung-Bae] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Oncol, Seoul 138736, South Korea. [Krzyzanowska, Monika K.] Princess Margaret Canc Ctr, Div Med Oncol & Hematol, Toronto, ON M5G 2M9, Canada. [Capdevila, Jaume] Vall Hebron Univ Hosp, Vall Hebron Inst Oncol, Dept Med Oncol, Barcelona 08035, Spain. [Sherman, Steven I.] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Div Internal Med, Houston, TX 77030 USA. [Tahara, Makoto] Natl Canc Ctr Hosp East, Dept Head & Neck Med Oncol, Kashiwa, Chiba 2778577, Japan. RP Robinson, B (reprint author), St Leonards Univ Sydney, Royal North Shore Hosp, Kolling Inst Med Res, Room 201,Edward Ford Bldg A27, Sydney, NSW 2006, Australia.; Robinson, B (reprint author), St Leonards Univ Sydney, Royal North Shore Hosp, Dept Endocrinol, Room 201,Edward Ford Bldg A27, Sydney, NSW 2006, Australia. EM bruce.robinson@sydney.edu.au FU Eisai Inc. FX This work was supported by Eisai Inc. NR 12 TC 0 Z9 0 U1 1 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD NOV PY 2016 VL 101 IS 11 BP 4103 EP 4109 DI 10.1210/jc.2015-3989 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG3MK UT WOS:000390948600027 PM 27548104 ER PT J AU Nampoothiri, S Fernandez-Rebollo, E Yesodharan, D Gardella, TJ Rush, ET Langman, CB Juppner, H AF Nampoothiri, Sheela Fernandez-Rebollo, Eduardo Yesodharan, Dhanya Gardella, Thomas J. Rush, Eric T. Langman, Craig B. Juppner, Harald TI Jansen Metaphyseal Chondrodysplasia due to Heterozygous H223R-PTH1R Mutations With or Without Overt Hypercalcemia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PEPTIDE RECEPTOR MUTATION; HORMONE-RELATED PEPTIDE; GROWTH-FACTOR 23; PARATHYROID-HORMONE; PTH/PTHRP RECEPTOR; BREAST DEVELOPMENT; PRIMARY FAILURE; TOOTH ERUPTION; DYSPLASIA; PTH1R AB Context: Jansen's metaphyseal chondrodysplasia (JMC) is a rare skeletal dysplasia characterized by abnormal endochondral bone formation and typically severe hypercalcemia despite normal/low levels of PTH. Five different heterozygous activating PTH/PTHrP receptor (PTH1R) mutations that change one of three different amino acid residues are known to cause JMC. Objectives: Establishing the diagnosis of JMC during infancy or early childhood can be challenging, especially in the absence of family history and/or overt hypercalcemia. We therefore sought to provide radiographic findings supporting this diagnosis early in life. Patients and Methods: Three patients, a mother and her two sons, had radiographic evidence for JMC. However, obvious hypercalcemia and suppressed PTH levels were encountered only in both affected children. Sanger sequencing and endonuclease (Sphl)digestion of PCR-amplified genomic DNA were performed to search for the H223R-PTH1R mutation. Results: The heterozygous H223R mutation was identified in all three affected individuals. Surprisingly, however, the now 38-year-old mother was never overtly hypercalcemic and was therefore not diagnosed until her sons were found to be affected by JMC at the ages of 28 months and 40 days, respectively. The presented radiographic findings at different ages will help diagnose other infants/toddlers suspected of having JMC. Conclusion: The H223R mutation is typically associated with profound hypercalcemia despite low/ normal PTH levels. However, the findings presented herein show that overt hypercalcemia is not always encountered in JMC, even if caused by this relatively frequent mutation, which is similar to observations with other PTH1R mutations that show less constitutive activity. C1 [Nampoothiri, Sheela; Yesodharan, Dhanya] Amrita Inst Med Sci & Res Ctr, Dept Pediat Genet, Aims Ponekkara PO, Cochin 682041, Kerala, India. [Rush, Eric T.] Univ Nebraska Med Ctr, Munroe Meyer Inst Genet & Rehabil, Omaha, NE 68198 USA. [Langman, Craig B.] Northwestern Univ, Lurie Childrens Hosp Chicago, Dept Kidney Dis, Chicago, IL 60611 USA. [Langman, Craig B.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Fernandez-Rebollo, Eduardo; Gardella, Thomas J.; Juppner, Harald] Massachusetts Gen Hosp, Endocrine Unit, Thier 10,Blossom St, Boston, MA 02114 USA. [Juppner, Harald] Massachusetts Gen Hosp, Pediat Nephrol Unit, Boston, MA 02114 USA. [Juppner, Harald] Harvard Med Sch, Boston, MA 02114 USA. RP Nampoothiri, S (reprint author), Amrita Inst Med Sci & Res Ctr, Dept Pediat Genet, Aims Ponekkara PO, Cochin 682041, Kerala, India.; Juppner, H (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Thier 10,Blossom St, Boston, MA 02114 USA. EM sheelanampoothiri@aims.amrita.edu; jueppner@helix.mgh.harvard.edu FU National Institutes of Health [RO1 DK46718-20] FX This work was supported by the National Institutes of Health Grant RO1 DK46718-20 (to H.J.). NR 30 TC 0 Z9 0 U1 1 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD NOV PY 2016 VL 101 IS 11 BP 4283 EP 4289 DI 10.1210/jc.2016-2054 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG3MK UT WOS:000390948600048 PM 27410178 ER PT J AU Vergnes, L Davies, GR Lin, JY Yeh, MW Livhits, MJ Harari, A Symonds, ME Sacks, HS Reue, K AF Vergnes, Laurent Davies, Graeme R. Lin, Jason Y. Yeh, Michael W. Livhits, Masha J. Harari, Avital Symonds, Michael E. Sacks, Harold S. Reue, Karen TI Adipocyte Browning and Higher Mitochondrial Function in Periadrenal But Not SC Fat in Pheochromocytoma SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID WHITE ADIPOSE-TISSUE; ADULT HUMANS; NONSHIVERING THERMOGENESIS; GENE-EXPRESSION; MOUSE; TEMPERATURE; DISTINCT; OBESITY; BRITE; CELL AB Context: Patients with pheochromocytoma (pheo) show presence of multilocular adipocytes that express uncoupling protein 1 within periadrenal (pADR) and omental (OME) fat depots. It has been hypothesized that this is due to adrenergic stimulation by catecholamines produced by the pheo tumors. Objective: To characterize the prevalence and respiratory activity of brown-like adipocytes within pADR, OME, and SC fat depots in human adult pheo patients. Design: This was an observational cohort study. Setting: The study took place in a university hospital. Patients: We studied 46 patients who underwent surgery for benign adrenal tumors (21 pheos and 25 controls with adrenocortical adenomas). Main outcome measure: We characterized adipocyte browning in pADR, SC, and OME fat depots for histological and immunohistological features, mitochondrial respiration rate, and gene expression. We also determined circulating levels of catecholamines and other browning-related hormones. Results: Eleven of 21 pheo pADR adipose samples, but only one of 25 pADR samples from control patients exhibited multilocular adipocytes. The pADR browning phenotype was associated with higher plasma catecholamines and raised uncoupling protein 1. Mitochondria from multilocular pADR fat of pheo patients exhibited increased rates of coupled and uncoupled respiration. Global gene expression analysis in pADR fat revealed enrichment in beta-oxidation genes in pheo patients with multilocular adipocytes. No SC or OME fat depots exhibited aspects of browning. Conclusion: Browning of the pADR depot occurred in half of pheo patients and was associated with increased catecholamines and mitochondrial activity. No browning was detected in other fat depots, suggesting that other factors are required to promote browning in these depots. C1 [Vergnes, Laurent; Lin, Jason Y.; Reue, Karen] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, 695 Charles E Young Dr South, Los Angeles, CA 90095 USA. [Davies, Graeme R.; Symonds, Michael E.] Univ Nottingham, Queens Med Ctr, Acad Div Child Hlth Obstet & Gynaecol, Sch Med, Nottingham, England. [Yeh, Michael W.; Livhits, Masha J.; Harari, Avital] Univ Calif Los Angeles, David Geffen Sch Med, Sect Endocrine Surg, Los Angeles, CA 90095 USA. [Sacks, Harold S.] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Endocrinol & Diabet Div,Dept Med, Los Angeles, CA 90095 USA. [Reue, Karen] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA. RP Vergnes, L (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, 695 Charles E Young Dr South, Los Angeles, CA 90095 USA. EM lvergnes@ucla.edu FU Fondation Leducq [12CVD04]; National Institutes of Health [P01 HL28481]; National Center for Research Resources [S10RR026744] FX This work was supported by the Fondation Leducq 12CVD04 (L.V., K.R.), National Institutes of Health P01 HL28481 (K.R.), the National Center for Research Resources Grant S10RR026744 (K.R.). NR 40 TC 0 Z9 0 U1 1 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD NOV PY 2016 VL 101 IS 11 BP 4440 EP 4448 DI 10.1210/jc.2016-2670 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG3MK UT WOS:000390948600066 PM 27575944 ER PT J AU Galvagno, SM Duke, PG Eversole, DS George, EE AF Galvagno, Samuel M., Jr. Duke, Peggy G. Eversole, Daniel S. George, Edward E. TI Evaluation of respiratory volume monitoring (RVM) to detect respiratory compromise in advance of pulse oximetry and help minimize false desaturation alarms SO JOURNAL OF TRAUMA AND ACUTE CARE SURGERY LA English DT Article; Proceedings Paper CT 5th Military Health System Research Symposium CY AUG, 2015 CL Fort Lauderdale, FL DE Respiratory monitor; respiratory insufficiency; respiratory failure; pulse oximetry; respiratory volume monitor ID POSTANESTHESIA CARE-UNIT; MINUTE VENTILATION; RESPONSE-TIME; ANESTHESIA; DEPRESSION AB BACKGROUND: Monitoring respiratory function is important. By continuously monitoring respiratory volumes, respiratory depression could be identified before hypoxemia and drive earlier intervention. Here, we evaluate the temporal relationship of respiratory volume monitoring (providing real-time minute ventilation [MV], tidal volume, and respiratory rate in nonintubated patients) to hypoxemic episodes and its potential to help classify true vs false desaturations (related to patient movement/probe dislodgement). METHODS: Respiratory volume monitoring data, oxygen saturation (SpO(2)), oxygen supplementation, and opioid use were analyzed in 259 patients following orthopedic surgery. Detection of " low MV" (< 40% of predicted MV) in advance of low SpO(2) (<90%) was used to classify true and false desaturations. Patients were also stratified based on opioid use and development of low MV. Patient's length of stay (LOS) and number of SpO(2) alarms were compared across groups (+/- opioids; +/- low MV). RESULTS: The electronic health records reported 113 SpO(2) alarms; 105 (93%) not preceded by low MVand considered false. Low MV preceded the eight true desaturations by 12.8 +/- 2.8 minutes. One hundred ninety-eight patients (76%) of 259 experienced one or more low MV events. Patients with low MV had significantly longer postanesthesia care unit (PACU) LOS than those maintaining " adequate MV": 2.8 +/- 0.1 hours vs. 2.4 +/- 0.1 hours (p < 0.001). Patients receiving opioids had increased likelihood of low MV (69% vs. 80%; p < 0.05) and had significantly longer PACU LOS than those without opioids (2.9 +/- 0.1 hours vs. 2.3 +/- 0.1 hours; p < 0.001). In the opioid group, PACU LOS was 75% longer in patients developing low MV versus maintaining adequate MV (3.0 +/- 0.1 hours vs. 1.7 +/- 0.2 hours; p < 0.001). CONCLUSION: Respiratory volumemonitoring can provide advanced warning of impending oxygen desaturation and potentially reduce the number of false SpO(2) alarms. Opioid administration increased low MVevents correlating with increased LOS. Respiratory volume monitoring can help clinicians individualize patient care, decrease false alarms, adjust opioid dosing, and increase PACU throughput. Similar benefits may translate to the general care floor and prehospital and posthospital environments. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Galvagno, Samuel M., Jr.] Univ Maryland, Sch Med, Dept Anesthesiol, Baltimore, MD 21201 USA. [Duke, Peggy G.] Emory Univ, Sch Med, Dept Anesthesiol, Atlanta, GA 30322 USA. [Eversole, Daniel S.] Resp Mot Inc, 411 Waverley Oaks Rd,Suite 150, Waltham, MA 02452 USA. [George, Edward E.] Harvard Med Sch, Massachusetts Gen Hosp, Post Anesthesia Care Units, Boston, MA USA. RP Eversole, DS (reprint author), Resp Mot Inc, 411 Waverley Oaks Rd,Suite 150, Waltham, MA 02452 USA. EM daniel.eversole@respiratorymotion.com NR 30 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2163-0755 EI 2163-0763 J9 J TRAUMA ACUTE CARE JI J. Trauma Acute Care Surg. PD NOV PY 2016 VL 81 IS 5 SU 2 BP S162 EP S170 DI 10.1097/TA.0000000000001152 PG 9 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA EF3XH UT WOS:000390257800019 PM 27270857 ER PT J AU Brinson, CW Lu, ZY Li, YC Lopes-Virella, MF Huang, Y AF Brinson, Colleen W. Lu, Zhongyang Li, Yanchun Lopes-Virella, Maria F. Huang, Yan TI Lipopolysaccharide and IL-1 beta coordinate a synergy on cytokine production by upregulating MyD88 expression in human gingival fibroblasts SO MOLECULAR IMMUNOLOGY LA English DT Article DE Lipopolysaccharide; Interleukin-1 beta; Inflammation; MyD88 ID TOLL-LIKE RECEPTORS; PORPHYROMONAS-GINGIVALIS; PERIODONTITIS; LEUKOCYTES; DISEASE; ALPHA AB Both lipopolysaccharide (LPS) and interleukin (IL)-1 beta activate the MyD88-dependent signaling pathways to stimulate proinflammatory cytokine expression. However, it remains unknown how LPS and IL -1 beta interact with each other to coordinate the stimulation. In this study, we sought to investigate the interaction between LPS and IL -1 beta on MyD88-dependent signaling pathways in human gingival fibroblasts (HGFs). Results showed that LPS derived from Porphyromonas gingivalis (Pg LPS) and IL -1 beta cooperatively stimulated mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF kappa B) signaling pathways, and subsequent expression of proinflammatory cytokine expression. Furthermore, our results showed that Pg LPS and IL -1 beta exerted a synergy on MyD88 expression and knockdown of MyD88 expression by small interfering RNA diminished the synergistic effect of Pg LPS and IL -1 beta on 1L-6 expression, suggesting that upregulation of MyD88 is involved in the coordinated stimulation by Pg LPS and IL -1 beta of proinflammatory cytokine expression. Finally, our results showed that pharmacological inhibitors for MAPK and NF kappa B significantly reduced IL-6 secretion stimulated by Pg LPS and IL -1 beta, indicating that the MyD88-dependent MAPK and NF kappa B signaling pathways are essential for the upregulation of proinflammatory cytokine expression by Pg LPS and IL -1 beta. Taken together, this study showed that LPS and IL -1 beta coordinate a synergy on cytokine production by upregulating MyD88 expression in HGFs. Published by Elsevier Ltd. C1 [Brinson, Colleen W.; Lu, Zhongyang; Li, Yanchun; Lopes-Virella, Maria F.; Huang, Yan] Med Univ South Carolina, Div Endocrinol Diabet & Med Genet, Dept Med, 114 Doughty St, Charleston, SC 29403 USA. [Lopes-Virella, Maria F.; Huang, Yan] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. RP Huang, Y (reprint author), Med Univ South Carolina, Div Endocrinol Diabet & Med Genet, Dept Med, 114 Doughty St, Charleston, SC 29403 USA.; Huang, Y (reprint author), Med Univ South Carolina, Ralph H Johnson Vet Affairs Med Ctr, 114 Doughty St, Charleston, SC 29403 USA. EM huangyan@musc.edu FU Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs; NIH [R01 DE016353] FX This work was supported by a Merit Review grant from the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs and NIH grant R01 DE016353 (to Y.H.). NR 26 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD NOV PY 2016 VL 79 BP 47 EP 54 DI 10.1016/j.molimm.2016.09.020 PG 8 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA EG0JL UT WOS:000390718500006 PM 27697591 ER PT J AU Kocarnik, BM Boyko, EJ Matsumoto, AM Fujimoto, WY Hayashi, T Leonetti, DL Page, ST AF Kocarnik, Beverly M. Boyko, Edward J. Matsumoto, Alvin M. Fujimoto, Wilfred Y. Hayashi, Tomoshige Leonetti, Donna L. Page, Stephanie T. TI Baseline estradiol concentration in community-dwelling Japanese American men is not associated with intra-abdominal fat accumulation over 10 years SO OBESITY RESEARCH & CLINICAL PRACTICE LA English DT Article DE Estradiol; Intra-abdominal fat; Japanese Americans ID SEX STEROID-HORMONES; TO-HIP RATIO; ADIPOSE-TISSUE; BODY-COMPOSITION; COMPUTED-TOMOGRAPHY; WAIST CIRCUMFERENCE; SERUM TESTOSTERONE; VISCERAL ADIPOSITY; INSULIN-RESISTANCE; RISK-FACTORS AB Problem: The role of plasma estradiol in the accumulation of intra-abdominal fat (IAF) in men is uncertain. Cross-sectional studies using imaging of IAF have shown either a positive or no association. In contrast, a randomised controlled trial using an aromatase inhibitor to suppress estradiol production found an association between oestrogen deficiency and short-term IAF accumulation. No longitudinal study has been conducted to examine the relationship between plasma estradiol concentration and the change in IAF area measured using direct imaging. Methods: This is a longitudinal observational study in community-dwelling Japanese-American men (n = 215, mean age 52 years, BMI 25.4 kg/m(2)). IAF and subcutaneous fat areas were assessed using computerized tomography (CT) at baseline, 5 and 10 years. Baseline plasma estradiol concentrations were measured using liquid chromatography-tandem mass spectrometry. Results: Univariate analysis found no association between baseline estradiol concentration and baseline IAF, or 5- or 10-year changes in IAF area (r = -0.05 for both time points, p = 0.45 and p = 0.43, respectively). Multivariate linear regression analysis of the change in IAF area by baseline estradiol concentration adjusted for age, baseline IAF area, and weight change found no association with either the 5- or 10-year IAF area change (p = 0.52 and p = 0.55, respectively). Conclusions: Plasma estradiol concentration was not associated with baseline IAF nor with change in IAF area over 5 or 10 years based on serial CT scans in community-dwelling Japanese-American men. These results do not support a role for oestrogen deficiency in IAF accumulation in men. (C) 2015 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved. C1 [Kocarnik, Beverly M.; Boyko, Edward J.] Vet Affairs Puget Sound Hlth Care Syst, Gen Med & Hosp & Specialty Med Serv, Seattle, WA USA. [Kocarnik, Beverly M.; Boyko, Edward J.; Fujimoto, Wilfred Y.; Page, Stephanie T.] Univ Washington, Dept Med, Div Endocrinol Metab & Nutr, Seattle, WA USA. [Kocarnik, Beverly M.] Vet Affairs Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Boyko, Edward J.; Hayashi, Tomoshige] Univ Washington, Dept Med, Div Gen Internal Med, Seattle, WA USA. [Matsumoto, Alvin M.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Matsumoto, Alvin M.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA USA. [Hayashi, Tomoshige] Osaka City Univ, Dept Prevent Med & Environm Hlth, Grad Sch Med, Osaka, Japan. [Leonetti, Donna L.] Univ Washington, Dept Anthropol, Seattle, WA 98195 USA. RP Kocarnik, BM (reprint author), Univ Washington, Endocrinol Diabet Care Ctr, 3rd Floor,4245 Roosevelt Way NE, Seattle, WA 98105 USA. EM bmkocarnik@gmail.com FU Medical Research Service, Geriatric Research, Education and Clinical Center; NIH [DK-031170, HL-049293, DK-002654, DK-017047, DK-035816, RR-000037]; VA Advanced Fellowship in Geriatrics; Cooperative Studies Program of the Department of Veterans Affairs, Seattle, Washington FX This study was supported in part by the Medical Research Service, Geriatric Research, Education and Clinical Center and Cooperative Studies Program of the Department of Veterans Affairs, Seattle, Washington as well as NIH Grants DK-031170, HL-049293, DK-002654, DK-017047, DK-035816 and RR-000037. Dr. Kocarnik was supported by a VA Advanced Fellowship in Geriatrics. NR 35 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 1871-403X EI 1878-0318 J9 OBES RES CLIN PRACT JI Obes. Res. Clin. Pract. PD NOV-DEC PY 2016 VL 10 IS 6 BP 624 EP 632 DI 10.1016/j.orcp.2015.12.002 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA EF8AR UT WOS:000390551000002 PM 26747209 ER PT J AU Greka, A Gibson, D Mundel, P Demetri, G Hildebrandt, F Pollak, M Florez, J AF Greka, Anna Gibson, Deb Mundel, Peter Demetri, George Hildebrandt, Friedhelm Pollak, Martin Florez, Jose TI Personalized Comments on Challenges and Opportunities in Kidney Disease Therapeutics: The Glom-NExT Symposium SO SEMINARS IN NEPHROLOGY LA English DT Review DE Adaptive trials; consortium; patient-reported outcomes; kidney disease; proteinuria; nephrotic syndrome; podocyte; TRPC5; Rac1; cytoskeleton; clinical trials; precision medicine; B7-1; CD80; podocyte; synaptopodin; nephrotic syndrome; FSGS; integrin; rare disease; targeted therapy; recessive mutations; ADCK4; COQ6; ARHGDIA; APOL1; TRPC6; actinin-4; INF2; autosomal dominant ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; RESISTANT NEPHROTIC SYNDROME; ACTIN CYTOSKELETON; GLOMERULAR PROTEIN; MUTATIONS; PODOCYTES; CALCIUM; INJURY; TRPC5; RAT AB In the face of ever-increasing incidence and prevalence of kidney disease worldwide, the unmet need for new treatments is unprecedented. Precision medicine is defined as the use of modern technologies to identify mechanisms of diseases in individual patients, and thus deploy treatment using tailored, targeted approaches, in the hopes of avoiding unnecessary toxicities and complications. Is there a place for kidney disease therapeutics in this space? If so, what is required to make significant progress toward precision nephrology? To answer these critical questions, we present a series of personalized comments corresponding to the responses offered to these very questions during the Inaugural Glom-NExT Symposium held at Harvard Medical School on October 23, 2014, a national meeting focused exclusively on kidney disease therapeutics. C1 [Greka, Anna] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Greka, Anna] Brigham & Womens Hosp, Glom NExT Ctr Glomerular Kidney Dis & Novel Expt, 75 Francis St, Boston, MA 02115 USA. [Greka, Anna] Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA. [Greka, Anna; Mundel, Peter; Hildebrandt, Friedhelm; Pollak, Martin] Harvard Med Sch, Boston, MA USA. [Greka, Anna; Florez, Jose] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Gibson, Deb] Univ Michigan, Sch Med, Dept Pediat, Ann Arbor, MI USA. [Mundel, Peter] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Demetri, George] Dana Farber Canc Inst, Boston, MA 02115 USA. [Demetri, George] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Hildebrandt, Friedhelm] Childrens Hosp, Dept Med, Div Nephrol, Boston, MA 02115 USA. [Pollak, Martin] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Florez, Jose] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA USA. Harvard Med Sch, Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA USA. RP Greka, A (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Renal, Harvard Inst Med, 4 Blackfan Circle, Boston, MA 02115 USA. EM agreka@bwh.harvard.edu FU National Institutes of Health [DK095045, DK099465, DK103658, DK057683] FX Anna Greka was funded by National Institutes of Health grants DK095045, DK099465, DK103658, and DK057683. NR 45 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 0270-9295 EI 1558-4488 J9 SEMIN NEPHROL JI Semin. Nephrol. PD NOV PY 2016 VL 36 IS 6 BP 448 EP 452 DI 10.1016/j.semnephrol.2016.09.004 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA EG0NU UT WOS:000390730300003 PM 27987542 ER PT J AU Demetri, G AF Demetri, George TI Tales of Personalized Cancer Treatment SO SEMINARS IN NEPHROLOGY LA English DT Editorial Material DE Sarcoma; GIST tumors; targeted therapy; oncology trials; rare disease; kidney disease; fibrosis ID GASTROINTESTINAL STROMAL TUMORS; IMATINIB MESYLATE; KIT ONCOPROTEIN; TRIAL; GIST; MECHANISMS; INHIBITOR; SARCOMA C1 [Demetri, George] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Demetri, George] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. RP Demetri, G (reprint author), Dana Farber Canc Inst, Ludwig Ctr Harvard, Ctr Sarcoma & Bone Oncol, 44 Binney St, Boston, MA 02115 USA. EM gdemetri@partners.org NR 16 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 0270-9295 EI 1558-4488 J9 SEMIN NEPHROL JI Semin. Nephrol. PD NOV PY 2016 VL 36 IS 6 BP 462 EP 467 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA EG0NU UT WOS:000390730300006 PM 27987546 ER PT J AU Florez, JC AF Florez, Jose C. TI Genetics of Diabetic Kidney Disease SO SEMINARS IN NEPHROLOGY LA English DT Editorial Material DE Genome-wide association studies (GWAS); genomewide linkage studies; genomics; GENIE Consortium; diabetic nephropathy ID STAGE RENAL-DISEASE; URINARY ALBUMIN EXCRETION; COMPLEX HUMAN-DISEASES; FAMILIAL PREDISPOSITION; SUSCEPTIBILITY GENES; PIMA-INDIANS; NEPHROPATHY; ASSOCIATION; MELLITUS; TYPE-1 C1 [Florez, Jose C.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA USA. [Florez, Jose C.] Harvard Med Sch, Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA USA. [Florez, Jose C.] Broad Inst Massachusetts Inst Technol Harvard, Cambridge, MA USA. RP Florez, JC (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Diabet Unit, 185 Cambridge St,Simches Res Bldg,CPZN 5-250, Boston, MA 02114 USA. EM jcflorez@mgh.harvard.edu NR 65 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 0270-9295 EI 1558-4488 J9 SEMIN NEPHROL JI Semin. Nephrol. PD NOV PY 2016 VL 36 IS 6 BP 474 EP 480 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA EG0NU UT WOS:000390730300009 PM 27987549 ER PT J AU Oh, J Sinha, I Tan, KY Rosner, B Dreyfuss, JM Gjata, O Tran, P Shoelson, SE Wagers, AJ AF Oh, Juhyun Sinha, Indranil Tan, Kah Yong Rosner, Bernard Dreyfuss, Jonathan M. Gjata, Ornela Tran, Peter Shoelson, Steven E. Wagers, Amy J. TI Age-associated NF-KB signaling in myofibers alters the satellite cell niche and re-strains muscle stem cell function SO AGING-US LA English DT Article DE satellite cell; skeletal muscle; aging; regeneration ID FACTOR-KAPPA-B; SKELETAL-MUSCLE; MYOGENIC DIFFERENTIATION; TRANSCRIPTION FACTOR; INFLAMMATION; ACTIVATION; STRENGTH; EXERCISE; DISEASE; IMMOBILIZATION AB Skeletal muscle is a highly regenerative tissue, but muscle repair potential is increasingly compromised with advancing age. In this study, we demonstrate that increased NF-kappa B activity in aged muscle fibers contributes to diminished myogenic potential of their associated satellite cells. We further examine the impact of genetic modulation of NF-kappa B signaling in muscle satellite cells or myofibers on recovery after damage. These studies reveal that NF-kappa B activity in differentiated myofibers is sufficient to drive dysfunction of muscle regenerative cells via cell-non-autonomous mechanisms. Inhibition of NF-kappa B, or its downstream target Phospholipase A2, in myofibers rescued muscle regenerative potential in aged muscle. Moreover, systemic administration of sodium salicylate, an FDA-approved NF-kappa B inhibitor, decreased inflammatory gene expression and improved repair in aged muscle. Together, these studies identify a unique NF-kappa B regulated, non-cell autonomous mechanism by which stem cell function is linked to lipid signaling and homeostasis, and provide important new targets to stimulate muscle repair in aged individuals. C1 [Oh, Juhyun; Sinha, Indranil; Tan, Kah Yong; Gjata, Ornela; Wagers, Amy J.] Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Oh, Juhyun; Sinha, Indranil; Tan, Kah Yong; Gjata, Ornela; Wagers, Amy J.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Oh, Juhyun; Sinha, Indranil; Tan, Kah Yong; Dreyfuss, Jonathan M.; Tran, Peter; Shoelson, Steven E.; Wagers, Amy J.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Sinha, Indranil] Brigham & Womens Hosp, Div Plast Surg, Boston, MA 02115 USA. [Rosner, Bernard] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Dreyfuss, Jonathan M.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Shoelson, Steven E.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Oh, Juhyun; Wagers, Amy J.] Harvard Med Sch, Paul F Glenn Ctr Biol Aging, Boston, MA 02115 USA. RP Wagers, AJ (reprint author), Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.; Wagers, AJ (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA.; Wagers, AJ (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA.; Wagers, AJ (reprint author), Harvard Med Sch, Paul F Glenn Ctr Biol Aging, Boston, MA 02115 USA. OI Dreyfuss, Jonathan/0000-0001-7242-3991 FU Harvard Stem Cell Institute; NIH [RO1 AG033053, P30AG031679, F32AG034703, T32DK007260]; [P30DK036836] FX This work was funded in part by the Harvard Stem Cell Institute and NIH (RO1 AG033053 and P30AG031679) to A.J.W., NIH (F32AG034703) to I.S.; NIH (T32DK007260) to J.O; and J.M.D. was funded by P30DK036836. All experiments involving animals were approved by the appropriate Institutional Animal Care and Use Committee. NR 51 TC 1 Z9 1 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD NOV PY 2016 VL 8 IS 11 BP 2871 EP 2896 DI 10.18632/aging.101098 PG 26 WC Cell Biology SC Cell Biology GA EF4PA UT WOS:000390311900021 PM 27852976 ER PT J AU Hamid, T Xu, YY Ismahil, MA Li, QH Jones, SP Bhatnagar, A Bolli, R Prabhu, SD AF Hamid, Tariq Xu, Yuanyuan Ismahil, Mohamed Ameen Li, Qianhong Jones, Steven P. Bhatnagar, Aruni Bolli, Roberto Prabhu, Sumanth D. TI TNF receptor signaling inhibits cardiomyogenic differentiation of cardiac stem cells and promotes a neuroadrenergic-like fate SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE cardiac stem cell; tumor necrosis factor; TNF receptor; cell differentiation ID TUMOR-NECROSIS-FACTOR; HEART-FAILURE; MYOCARDIAL-INFARCTION; FACTOR-ALPHA; MURINE MODEL; KAPPA-B; REGENERATION; CARDIOMYOCYTES; EXPRESSION; PATHWAYS AB Despite expansion of resident cardiac stem cells (CSCs; c-kit(+) Lin(-)) after myocardial infarction, endogenous repair processes are insufficient to prevent adverse cardiac remodeling and heart failure (HF). This suggests that the microenvironment in post-ischemic and failing hearts compromises CSC regenerative potential. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF), are increased after infarction and in HF; whether they modulate CSC function is unknown. As the effects of TNF are specific to its two receptors (TNFRs), we tested the hypothesis that TNF differentially modulates CSC function in a TNFR-specific manner. CSCs were isolated from wild-type (WT), TNFR1 -/-, and TNFR2 -/- adult mouse hearts, expanded and evaluated for cell competence and differentiation in vitro in the absence and presence of TNF. Our results indicate that TNF signaling in murine CSCs is constitutively related primarily to TNFR1, with TNFR2 inducible after stress. TNFR1 signaling modestly diminished CSC proliferation, but, along with TNFR2, augmented CSC resistance to oxidant stress. Deficiency of either TNFR1 or TNFR2 did not impact CSC telomerase activity. Importantly, TNF, primarily via TNFR1, inhibited cardiomyogenic commitment during CSC differentiation, and instead promoted smooth muscle and endothelial fates. Moreover, TNF, via both TNFR1 and TNFR2, channeled an alternate CSC neuroadrenergic-like fate (capable of catecholamine synthesis) during differentiation. Our results suggest that elevated TNF in the heart restrains cardiomyocyte differentiation of resident CSCs and may enhance adrenergic activation, both effects that would reduce the effectiveness of endogenous cardiac repair and the response to exogenous stem cell therapy, while promoting adverse cardiac remodeling. C1 [Hamid, Tariq; Xu, Yuanyuan; Ismahil, Mohamed Ameen; Prabhu, Sumanth D.] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Hamid, Tariq; Xu, Yuanyuan; Ismahil, Mohamed Ameen; Prabhu, Sumanth D.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Li, Qianhong; Jones, Steven P.; Bhatnagar, Aruni; Bolli, Roberto] Univ Louisville, Dept Med, Inst Mol Cardiol, Diabet & Obes Ctr, Louisville, KY 40292 USA. RP Prabhu, SD (reprint author), Univ Alabama Birmingham, Div Cardiovasc Dis, 311 Tinsley Harrison Tower,1900 Univ Blvd, Birmingham, AL 35294 USA. EM sprabhu@uab.edu RI Jones, Steven/D-5092-2009 OI Jones, Steven/0000-0001-5376-8089 FU National Institutes of Health [HL-78825, RR-024489, HL-113530, HL-99014]; Veterans Affairs Merit Award FX This work was supported by National Institutes of Health Grants HL-78825 (to R. Bolli, S. D. Prabhu, A. Bhatnagar, and S. P. Jones), RR-024489 (to A. Bhatnagar and S. P. Jones), HL-113530 (to R. Bolli), and HL-99014 (to S. D. Prabhu), and a Veterans Affairs Merit Award (to S. D. Prabhu). NR 45 TC 0 Z9 0 U1 3 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD NOV PY 2016 VL 311 IS 5 BP H1189 EP H1201 DI 10.1152/ajpheart.00904.2015 PG 13 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA EF1WY UT WOS:000390117000012 PM 27591224 ER PT J AU Muller-Deile, J Teng, B Schenk, H Haller, H Reiser, J Sever, S Schiffer, M AF Mueller-Deile, Janina Teng, Beina Schenk, Heiko Haller, Hermann Reiser, Jochen Sever, Sanja Schiffer, Mario TI Drugs targeting dynamin can restore cytoskeleton and focal contact alterations of urinary podocytes derived from patients with nephrotic syndrome SO ANNALS OF TRANSLATIONAL MEDICINE LA English DT Letter ID SEGMENTAL GLOMERULOSCLEROSIS; KIDNEY-DISEASE; RENAL-DISEASE; GTPASE ACTIVITY; CELLS; OLIGOMERIZATION; PATHOGENESIS; NEPHRITIS; MUTATIONS; PROTEIN C1 [Mueller-Deile, Janina; Teng, Beina; Schenk, Heiko; Haller, Hermann; Schiffer, Mario] Hannover Med Sch, Dept Med Nephrol, Hannover, Germany. [Reiser, Jochen] Harvard Med Sch, Massachusetts Gen Hosp, Div Nephrol, Dept Med, Charlestown, MA USA. [Sever, Sanja] Rush Univ, Med Ctr, Dept Med, Chicago, IL 60612 USA. RP Muller-Deile, J; Schiffer, M (reprint author), Hannover Med Sch, Div Nephrol, Carl Neuberg Str 1, D-30625 Hannover, Germany. EM mueller-deile.janina@mh-hannover.de; schiffer.mario@mh-hannover.de NR 24 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 NOV PY 2016 VL 4 IS 21 AR 439 DI 10.21037/atm.2016.10.72 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EF0TX UT WOS:000390040100023 PM 27942530 ER PT J AU Chen, YW Muralidhar, V Mahal, BA Nezolosky, MD Beard, CJ Choueiri, TK Hoffman, KE Martin, NE Orio, PF Sweeney, CJ Feng, FY Trinh, QD Nguyen, PL AF Chen, Yu-Wei Muralidhar, Vinayak Mahal, Brandon A. Nezolosky, Michelle D. Beard, Clair J. Choueiri, Toni K. Hoffman, Karen E. Martin, Neil E. Orio, Peter F. Sweeney, Christopher J. Feng, Felix Y. Quoc-Dien Trinh Nguyen, Paul L. TI Factors associated with the omission of androgen deprivation therapy in radiation-managed high-risk prostate cancer SO BRACHYTHERAPY LA English DT Article DE Brachytherapy boost; Androgen deprivation therapy; High-risk prostate cancer; Prostate neoplasm ID RESULTS SEER PROGRAM; RANDOMIZED-TRIAL; INSURANCE STATUS; DOSE-ESCALATION; SURVIVAL; EPIDEMIOLOGY; SURVEILLANCE; RADIOTHERAPY; SUPPRESSION; FAILURE AB PURPOSE: Androgen deprivation therapy (ADT) has been shown to improve survival for men with unfavorable-risk prostate cancer (PCa). We investigated the utilization and factors associated with the omission of ADT in radiation-managed high-risk PCa. METHODS AND MATERIALS: We used the National Cancer Database to identify men with National Comprehensive Cancer Network high-risk PCa treated with external beam radiation therapy (EBRT) with or without brachytherapy boost from 2004 to 2012. Multivariable logistic regression adjusting for clinical and sociodemographic factors was used to identify independent predictors for ADT use. RESULTS: A total of 57,968 radiation-treated high-risk PCa men were included in our analysis. There were 49,363 patients (85.2%) treated with EBRT alone and 8605 patients (14.8%) treated with EBRT plus brachytherapy boost. Overall, 77% of men received ADT. In multivariable regression analysis, the use of brachytherapy boost was associated with a significantly lower utilization of ADT (70% vs. 78%; adjusted odds ratio [AOR]: 0.65; 95% CI: 0.62-0.69; p-Value <0.0001), as was treatment at an academic vs. nonacademic center (AOR: 0.90; 95% CI: 0.86-0.95; p-Value <0.0001) and treatment in 2010-2012 compared to 2004-2006 (AOR: 0.85; 95% CI: 0.810.90; p-Value <0.0001). Conversely, greater ADT use was seen with higher Gleason scores, PSA, and T-category (all p-Values <0.001). CONCLUSIONS: Approximately one in four men with radiation-managed high-risk PCa do not receive ADT, which may reflect concerns about its toxicity profile despite known improvements in overall survival. Practice patterns suggest that some providers believe dose escalation through brachytherapy boost may obviate the need for ADT in some high-risk patients, but this hypothesis requires further testing. (C) 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. C1 [Chen, Yu-Wei; Nezolosky, Michelle D.; Beard, Clair J.; Martin, Neil E.; Orio, Peter F.; Nguyen, Paul L.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Chen, Yu-Wei; Nezolosky, Michelle D.; Beard, Clair J.; Choueiri, Toni K.; Martin, Neil E.; Orio, Peter F.; Sweeney, Christopher J.; Nguyen, Paul L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Muralidhar, Vinayak] Harvard Med Sch, Harvard MIT Div Hlth Sci & Technol, Boston, MA USA. [Mahal, Brandon A.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Choueiri, Toni K.; Sweeney, Christopher J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hoffman, Karen E.] MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX USA. [Feng, Felix Y.] Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA USA. [Feng, Felix Y.] Univ Calif San Francisco, Dept Urol, San Francisco, CA USA. [Feng, Felix Y.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Quoc-Dien Trinh] Brigham & Womens Hosp, Dept Surg, Div Urol, Ctr Surg & Publ Hlth, 75 Francis St, Boston, MA 02115 USA. RP Nguyen, PL (reprint author), 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu FU Prostate Cancer Foundation; Fitz's Cancer Warriors; Scott Forbes and Gina Ventre Fund FX This work is supported by Prostate Cancer Foundation, Fitz's Cancer Warriors, David and Cynthia Chapin, Hugh Simons in Honor of Frank and Anne Simons, the Scott Forbes and Gina Ventre Fund, Jeffrey Campbell in Honor of Joan Campbell, and a grant from an anonymous family foundation. 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 1538-4721 EI 1873-1449 J9 BRACHYTHERAPY JI Brachytherapy PD NOV-DEC PY 2016 VL 15 IS 6 BP 695 EP 700 DI 10.1016/j.brachy.2016.07.001 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EE8GQ UT WOS:000389864100003 PM 27528590 ER PT J AU Orio, PF Nguyen, PL Buzurovic, I Cail, DW Chen, YW AF Orio, Peter F., III Nguyen, Paul L. Buzurovic, Ivan Cail, Daniel W. Chen, Yu-Wei TI The decreased use of brachytherapy boost for intermediate and high-risk prostate cancer despite evidence supporting its effectiveness SO BRACHYTHERAPY LA English DT Article DE Prostate cancer; Brachytherapy boost; National cancer database; ASCENDE-RT; Radiation therapy ID EXTERNAL-BEAM RADIOTHERAPY; ANDROGEN DEPRIVATION THERAPY; FREE SURVIVAL OUTCOMES; URETHRAL STRICTURES; DATA-BASE; EXPERIENCE; RADIATION; PROGRAM; IMPACT AB PURPOSE: The Canadian Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (ASCENDE-RT) randomized trial showed that brachytherapy boost reduces recurrence by 50% compared to dose-escalated radiation. We examined how men with identical inclusion criteria to the ASCENDE-RT trial were being treated in the United States. METHODS AND MATERIALS: We used the National Cancer Database to identify prostate cancer patients treated with radiation from 2004 through 2012 who met the inclusion criteria of the ASCENDE-RT trial (intermediate-/high-risk prostate cancer, excluding patients with prostate specific antigen >40 or tumor stage T3b/T4). The Mantel Haenszel test was used to investigate the trend for type of radiation modality used over the study period. RESULTS: A cohort of 156,411 patients was identified. Of those, 103,188 men (66%) were treated with external beam radiation therapy (EBRT) alone, 31,129 (20%) with brachytherapy alone, and 22,094 (14%) with EBRT plus brachytherapy. EBRT plus a brachytherapy boost demonstrated a significant decrease in utilization from 2004 to 2012 in both academic and nonacademic centers, declining from 15% to 8% in academic centers and from 19% to 11% in nonacademic centers (p-Value for trend <0.0001 for both). Academic centers were significantly less likely to use brachytherapy boost than nonacademic centers (adjusted odds ratio: 0.68; 95% confidence interval: -0.66-0.70; p-Value: <0.0001). CONCLUSIONS: Radiation oncology practices have demonstrated a significant reduction in the use of brachytherapy boost from 2004 to 2012, and the lowest utilization was in academic centers. In light of the superior results demonstrated for brachytherapy boost by the ASCENDE-RT trial, it is unclear whether academic centers are prepared to train the next generation of residents in this critical modality. (C) 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. C1 [Orio, Peter F., III; Nguyen, Paul L.; Buzurovic, Ivan; Cail, Daniel W.; Chen, Yu-Wei] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. [Orio, Peter F., III; Nguyen, Paul L.; Buzurovic, Ivan] Harvard Med Sch, Boston, MA USA. RP Orio, PF (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM PORIO@Iroc.harvard.edu OI /0000-0001-9632-3434 NR 27 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 1538-4721 EI 1873-1449 J9 BRACHYTHERAPY JI Brachytherapy PD NOV-DEC PY 2016 VL 15 IS 6 BP 701 EP 706 DI 10.1016/j.brachy.2016.05.001 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EE8GQ UT WOS:000389864100004 PM 27317191 ER PT J AU Tabung, FK Wang, WK Fung, TT Hu, FB Smith-Warner, SA Chavarro, JE Fuchs, CS Willett, WC Giovannucci, EL AF Tabung, Fred K. Wang, Weike Fung, Teresa T. Hu, Frank B. Smith-Warner, Stephanie A. Chavarro, Jorge E. Fuchs, Charles S. Willett, Walter C. Giovannucci, Edward L. TI Development and validation of empirical indices to assess the insulinaemic potential of diet and lifestyle SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE Hypothesis-driven indices; Dietary patterns; Lifestyle indices; Hyperinsulinaemia; Insulin resistance; C-peptide; TAG; HDL ID FOOD-FREQUENCY QUESTIONNAIRE; PHYSICAL-ACTIVITY QUESTIONNAIRE; MALE HEALTH-PROFESSIONALS; CORONARY-HEART-DISEASE; C-PEPTIDE MEASUREMENT; BODY-MASS INDEX; POSTMENOPAUSAL WOMEN; INFLAMMATORY INDEX; CARDIOMETABOLIC RISK; METABOLIC SYNDROME AB The glycaemic and insulin indices assess postprandial glycaemic and insulin response to foods, respectively, which may not reflect the long-term effects of diet on insulin response. We developed and evaluated the validity of four empirical indices to assess the insulinaemic potential of usual diets and lifestyles, using dietary, lifestyle and biomarker data from the Nurses' Health Study (NHS, n 5812 for hyperinsulinaemia, n 3929 for insulin resistance). The four indices were as follows: the empirical dietary index for hyperinsulinaemia (EDIH) and the empirical lifestyle index for hyperinsulinaemia (ELIH); the empirical dietary index for insulin resistance (EDIR) and the empirical lifestyle index for insulin resistance (ELIR). We entered thirty-nine FFQ-derived food groups in stepwise linear regression models, and defined indices as patterns most predictive of fasting plasma C-peptide, for the hyperinsulinaemia pathway (EDIH and ELIH), and of theTAG:HDL-cholesterol ratio, for the insulin-resistance pathway (EDIR and ELIR). We evaluated the validity of indices in two independent samples from NHS-II and Health Professionals Follow-up Study (HPFS) using multivariable-adjusted linear regression analyses to calculate relative concentrations of biomarkers. The EDIH is comprised of eighteen food groups; thirteen were positively associated with C-peptide and five were inversely associated. The EDIR is comprised of eighteen food groups; ten were positively associated with TAG: HDL-cholesterol and eight were inversely associated. Lifestyle indices had fewer dietary components, and included BMI and physical activity as components. In the validation samples, all indices significantly predicted biomarker concentrations - for example, the relative concentrations of the corresponding biomarkers comparing extreme index quintiles in the HPFS were EDIH, 1.29 (95% CI 1.22, 1.37); ELIH, 1.78 (95% CI 1.68, 1.88); EDIR, 1.44 (95% CI 1.34, 1.55); and ELIR, 2.03 (95% CI 1.89, 2.19); all P-trend <0.0001. The robust associations of these novel hypothesis-driven indices with insulin response biomarker concentrations suggest their usefulness in assessing the ability of whole diets and lifestyles to stimulate and/or sustain insulin secretion. C1 [Tabung, Fred K.; Wang, Weike; Fung, Teresa T.; Hu, Frank B.; Smith-Warner, Stephanie A.; Chavarro, Jorge E.; Willett, Walter C.; Giovannucci, Edward L.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Tabung, Fred K.; Wang, Weike; Hu, Frank B.; Smith-Warner, Stephanie A.; Chavarro, Jorge E.; Willett, Walter C.; Giovannucci, Edward L.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Fung, Teresa T.] Simmons Coll, Dept Nutr, Boston, MA 02115 USA. [Hu, Frank B.; Chavarro, Jorge E.; Fuchs, Charles S.; Willett, Walter C.; Giovannucci, Edward L.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Hu, Frank B.; Chavarro, Jorge E.; Fuchs, Charles S.; Willett, Walter C.; Giovannucci, Edward L.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Tabung, FK (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.; Tabung, FK (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM ftabung@hsph.harvard.edu OI Tabung, Fred/0000-0001-8193-7150 FU National Institutes of Health (NIH) grants [P30DK046200, U54 CA155426, UM1 CA 167552, UM1 CA 186107, UM1 CA 176726] FX Dr Jorge E. Chavarro and Dr Frank B. Hu were supported by National Institutes of Health (NIH) grants P30DK046200 and U54 CA155426. The HPFS, NHS and NHS-II cohorts are supported by the following NIH grants: UM1 CA 167552, UM1 CA 186107 and UM1 CA 176726, respectively. NR 49 TC 0 Z9 0 U1 1 U2 1 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 EI 1475-2662 J9 BRIT J NUTR JI Br. J. Nutr. PD NOV PY 2016 VL 116 IS 10 BP 1787 EP 1798 DI 10.1017/S0007114516003755 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EF5IH UT WOS:000390363400013 ER PT J AU Jackson, JW AF Jackson, John W. TI Diagnostics for Confounding of Time-varying and Other Joint Exposures SO EPIDEMIOLOGY LA English DT Article ID MARGINAL STRUCTURAL MODELS; CAUSAL INFERENCE; SELECTION BIAS; PROPENSITY SCORE; MISSING DATA; DIAGRAMS; OUTCOMES; WEIGHTS AB The effects of joint exposures (or exposure regimes) include those of adhering to assigned treatment versus placebo in a randomized controlled trial, duration of exposure in a cohort study, interactions between exposures, and direct effects of exposure, among others. Unlike the setting of a single point exposure (e.g., propensity score matching), there are few tools to describe confounding for joint exposures or how well a method resolves it. Investigators need tools that describe confounding in ways that are conceptually grounded and intuitive for those who read, review, and use applied research to guide policy. We revisit the implications of exchangeability conditions that hold in sequentially randomized trials, and the bias structure that motivates the use of g-methods, such as marginal structural models. From these, we develop covariate balance diagnostics for joint exposures that can (1) describe time-varying confounding, (2) assess whether covariates are predicted by prior exposures given their past, the indication for g-methods, and (3) describe residual confounding after inverse probability weighting. For each diagnostic, we present time-specific metrics that encompass a wide class of joint exposures, including regimes of multivariate time-varying exposures in censored data, with multivariate point exposures as a special case. We outline how to estimate these directly or with regression and how to average them over person-time. Using a simulated example, we show how these metrics can be presented graphically. This conceptually grounded framework can potentially aid the transparent design, analysis, and reporting of studies that examine joint exposures. We provide easy-to-use tools to implement it. C1 [Jackson, John W.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Jackson, John W.] Massachusetts Gen Hosp, Schizophrenia Clin & Res Program, Dept Psychiat, Chester M Pierce MD Div Global Psychiat, Boston, MA 02114 USA. RP Jackson, JW (reprint author), 677 Huntington Ave, Boston, MA 02115 USA. EM john.jackson@mail.harvard.edu FU Alonzo Smythe Yerby Fellowship at the Harvard T.H. Chan School of Public Health; NIMH [T32 MH017119] FX The author was funded by the Alonzo Smythe Yerby Fellowship at the Harvard T.H. Chan School of Public Health and also a NIMH Training Grant in Training in Psychiatric Genetics and Translational Research (T32 MH017119). NR 34 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD NOV PY 2016 VL 27 IS 6 BP 859 EP 869 DI 10.1097/EDE.0000000000000547 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EF3UZ UT WOS:000390251500016 PM 27479649 ER EF