FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Albadawi, H Tzika, AA Rask-Madsen, C Crowley, LM Koulopoulos, MW Yoo, HJ Watkins, MT AF Albadawi, Hassan Tzika, A. Aria Rask-Madsen, Christian Crowley, Lindsey M. Koulopoulos, Michael W. Yoo, Hyung-Jin Watkins, Michael T. TI Revascularization and muscle adaptation to limb demand ischemia in diet-induced obese mice SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Angiogenesis Demand ischemia; Granulocyte colony stimulating factor; Myofiber atrophy; Obesity; Peripheral arterial disease ID PERIPHERAL ARTERY-DISEASE; EXERCISE-INDUCED ANGIOGENESIS; COLONY-STIMULATING FACTOR; HUMAN SKELETAL-MUSCLE; INTERMITTENT CLAUDICATION; INFLAMMATION; MECHANISMS; IMPACT; GROWTH; GENES AB Background: Obesity and type 2 diabetes are major risk factors for peripheral arterial disease in humans, which can result in lower limb demand ischemia and exercise intolerance. Exercise triggers skeletal muscle adaptation including increased vasculogenesis. The goal of this study was to determine whether demand ischemia modulates revascularization, fiber size, and signaling pathways in the ischemic hind limb muscles of mice with diet-induced obesity (DIO). Materials and methods: DIO mice (n = 7) underwent unilateral femoral artery ligation and recovered for 2 wks followed by 4 wks with daily treadmill exercise to induce demand ischemia. A parallel sedentary ischemia (SI) group (n = 7) had femoral artery ligation without exercise. The contralateral limb muscles of SI served as control. Muscles were examined for capillary density, myofiber cross-sectional area, cytokine levels, and phosphorylation of STAT3 and ERK1/2. Results: Exercise significantly enhanced capillary density (P < 0.01) and markedly lowered cross-sectional area (P < 0.001) in demand ischemia compared with SI. These findings coincided with a significant increase in granulocyte colony-stimulating factor (P < 0.001) and interleukin-7 (P < 0.01) levels. In addition, phosphorylation levels of STAT3 and ERK1/2 (P < 0.01) were increased, whereas UCP1 and monocyte chemoattractant protein-1 protein levels were lower (P < 0.05) without altering vascular endothelial growth factor and tumor necrosis factor alpha protein levels. Demand ischemia increased the PGC1 alpha messenger RNA (P < 0.001) without augmenting PGC1 alpha protein levels. Conclusions: Exercise-induced limb demand ischemia in the setting of DIO causes myofiber atrophy despite an increase in muscle capillary density. The combination of persistent increase in tumor necrosis factor alpha, lower vascular endothelial growth factor, and failure to increase PGC1 alpha protein may reflect a deficient adaption to demand ischemia in DIO. (C) 2016 Elsevier Inc. All rights reserved. C1 [Albadawi, Hassan; Crowley, Lindsey M.; Koulopoulos, Michael W.; Yoo, Hyung-Jin; Watkins, Michael T.] Massachusetts Gen Hosp, Dept Surg, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. [Albadawi, Hassan; Tzika, A. Aria; Rask-Madsen, Christian; Watkins, Michael T.] Harvard Med Sch, Boston, MA USA. [Tzika, A. Aria] Massachusetts Gen Hosp, Dept Surg, Shriners Burns Inst, Boston, MA 02114 USA. [Rask-Madsen, Christian] Joslin Diabet Ctr, Sect Vasc Cell Biol, Boston, MA 02215 USA. RP Albadawi, H (reprint author), Massachusetts Gen Hosp, Div Vasc & Endovasc Surg, Vasc Res Lab, Edwards 301,70 Blossom St, Boston, MA 02114 USA. EM halbadawi@mgh.harvard.edu OI Albadawi, Hassan/0000-0001-5913-8571 FU NIH [R01AR055843]; Henry & Nod Meyer Research Fund, Department of Surgery, Division of Vascular and Endovascular Surgery FX This study was funded by NIH R01AR055843 and by Henry & Nod Meyer Research Fund, Department of Surgery, Division of Vascular and Endovascular Surgery. NR 39 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 SEP PY 2016 VL 205 IS 1 BP 49 EP 58 DI 10.1016/j.jss.2016.06.001 PG 10 WC Surgery SC Surgery GA DW0VE UT WOS:000383360300008 PM 27620999 ER PT J AU Phitayakorn, R Petrusa, E Hodin, RA AF Phitayakorn, Roy Petrusa, Emil Hodin, Richard A. TI Development and initial results of a mandatory department of surgery faculty mentoring pilot program SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Mentorship; Mentor-mentee relationship; Surgery faculty development ID ACADEMIC MEDICINE; CAREER; MENTORSHIP; SATISFACTION AB Background: Mentoring of junior faculty by senior faculty is an important part of promotion and/or tenure and enhanced job satisfaction. This study reports the development and results to date of a faculty mentorship program in surgery. Methods: We implemented a departmental faculty mentoring program in July 2014 that consisted of both structured and informal meetings between junior faculty mentees and assigned senior faculty mentors. All senior faculty mentors attended a brief mentor training session. We then developed an evidence-based mentorship instrument that featured standardized metrics of academic success. This instrument was completed by each mentee, and then reviewed at the junior faculty's annual career conference with their division chief. A survey was distributed in July 2015 to assess junior faculty satisfaction with the new mentorship program. Results: Junior or senior faculty consisted of six of three women and 16 of 11 men, respectively. Junior faculty members were aged 40 + 3 y and had been an attending for 4 + 2 y. Mentorship meetings occurred approximately three times during the year (range = 0-10). Total meeting time with senior mentors per meeting was a mean of 40 min (range = 0-300 min). Over 75% of junior faculty members were very or somewhat satisfied with the mentorship program and would like to continue in the program. The best aspect of the program was the opportunity to meet with an accomplished surgeon outside their division. Opportunities to improve the program included better matching of mentor to mentee by disease or research focus. Interestingly, almost the entire junior faculty members tended to have at least two other mentors besides the mentor assigned to them in this program. In terms of program outcomes, junior faculty members agreed that the mentorship program improved their overall career plans and enhanced their involvement in professional organizations but has not yet helped with academic productivity, home and/or work balance, and overall job satisfaction. Conclusions: A mandatory, structured mentorship program with senior surgeons benefits most junior faculty members in terms of academic career planning and becoming more involved with surgical organizations. More research is required to understand the best method to pair mentors and mentees and more objective measurements of academic surgery success. (C) 2016 Elsevier Inc. All rights reserved. C1 [Phitayakorn, Roy; Petrusa, Emil; Hodin, Richard A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. RP Phitayakorn, R (reprint author), Massachusetts Gen Hosp, Dept Surg, Wang ACC,Suite 460,15 Parkman St, Boston, MA 02114 USA. EM rphitayakorn@mgh.harvard.edu OI Phitayakorn, Roy/0000-0002-8327-1484 NR 17 TC 0 Z9 0 U1 3 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 EI 1095-8673 J9 J SURG RES JI J. Surg. Res. PD SEP PY 2016 VL 205 IS 1 BP 234 EP 237 DI 10.1016/j.jss.2016.06.048 PG 4 WC Surgery SC Surgery GA DW0VE UT WOS:000383360300034 PM 27621025 ER PT J AU Iyer, JG Parvathaneni, K Bhatia, S Tarabadkar, ES Blom, A Doumani, R McKenzie, J Asgari, MM Nghiem, P AF Iyer, Jayasri G. Parvathaneni, Kaushik Bhatia, Shailender Tarabadkar, Erica S. Blom, Astrid Doumani, Ryan McKenzie, Jill Asgari, Maryam M. Nghiem, Paul TI Paraneoplastic syndromes (PNS) associated with Merkel cell carcinoma (MCC): A case series of 8 patients highlighting different clinical manifestations SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE cerebellar degeneration; Lambert-Eaton myasthenic syndrome; malignancy-associated hyponatremia; Merkel cell carcinoma; neuroendocrine; paraneoplastic syndrome ID EATON MYASTHENIC SYNDROME; ANTI-HU ANTIBODIES; LUNG-CANCER; HYPONATREMIA; THERAPY; IMMUNOADSORPTION; MANAGEMENT; PROGNOSIS; DIAGNOSIS; SURVIVAL AB Background: Paraneoplastic syndromes (PNS) are commonly associated with neuroendocrine cancers, such as small cell lung cancer. Objectives: We examined the association of PNS in Merkel cell carcinoma (MCC), a rare neuroendocrine skin cancer. Methods: We identified PNS associated with MCC based on chart review of a Seattle-based repository and examined the incidence of MCC-associated hyponatremia in an independent cohort within Kaiser Permanente Northern California. Results: Eight PNS cases were identified from the Seattle repository. Three distinct PNS types were observed: cerebellar degeneration (1 case), Lambert-Eaton myasthenic syndrome (2 cases), and malignancy-associated hyponatremia (5 cases). Moreover, the incidence of severe hyponatremia (serum sodium <125 mmol/L) coincident with MCC was identified among 4.3% (9 of 211) patients with MCC in the Kaiser Permanente Northern California cohort. Limitations: We did not have access to complete medical records on all patients so it was not possible to determine the prevalence of PNS in MCC. Conclusions: MCC can be associated with PNS similar to those found in other neuroendocrine cancers. Clinicians should be aware of these presentations as PNS often precede the identification of the underlying malignancy and usually resolve with appropriate treatment of the cancer. C1 [Iyer, Jayasri G.; Parvathaneni, Kaushik; Tarabadkar, Erica S.; Blom, Astrid; Doumani, Ryan; McKenzie, Jill; Nghiem, Paul] Univ Washington, Div Dermatol, Dept Med, 850 Republican St, Seattle, WA 98109 USA. [Bhatia, Shailender] Univ Washington, Div Med Oncol, Dept Med, Seattle, WA 98195 USA. [Asgari, Maryam M.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Asgari, Maryam M.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. RP Nghiem, P (reprint author), Univ Washington, Div Dermatol, Dept Med, 850 Republican St, Seattle, WA 98109 USA. EM pnghiem@uw.edu RI Nghiem, Paul/A-9210-2011; OI Nghiem, Paul/0000-0003-2784-963X; Parvathaneni, Kaushik/0000-0001-8557-1395 FU American Cancer Society [RSG-08-115-01-CCE, NIH-RC2-CA147820-01, NIH-K24-CA139052-0, NIH-R01-162522]; David and Rosalind Bloom Endowment for Merkel Cell Carcinoma Research; University of Washington Merkel Cell Carcinoma Patient Gift Fund; Michael Piepkorn Endowment FX Supported by the American Cancer Society RSG-08-115-01-CCE, NIH-RC2-CA147820-01, NIH-K24-CA139052-0, NIH-R01-162522, David and Rosalind Bloom Endowment for Merkel Cell Carcinoma Research, Michael Piepkorn Endowment, and University of Washington Merkel Cell Carcinoma Patient Gift Fund. NR 33 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD SEP PY 2016 VL 75 IS 3 BP 541 EP 547 DI 10.1016/j.jaad.2016.04.040 PG 7 WC Dermatology SC Dermatology GA DW0YO UT WOS:000383369700028 PM 27177440 ER PT J AU Lawrence, NF Hammond, MR Frederick, DT Su, YH Dias-Santagata, D Deng, A Selim, MA Mahalingam, M Flaherty, KT Hoang, MP AF Lawrence, Nicholas F. Hammond, Marc R. Frederick, Dennie T. Su, Yuhua Dias-Santagata, Dora Deng, April Selim, M. Angelica Mahalingam, Meera Flaherty, Keith T. Hoang, Mai P. TI Ki-67, p53, and p16 expression, and G691S RET polymorphism in desmoplastic melanoma (DM): A clinicopathologic analysis of predictors of outcome SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE desmoplastic melanoma; immunohistochemistry; Ki-67; p16; p57; RET polymorphism ID CUTANEOUS MALIGNANT-MELANOMA; PROGNOSTIC-FACTORS; PROTEIN; MUTATIONS; BIOMARKER; VARIANTS; PURE; GENE; SKIN AB Background: The prognostic role Ki-67, p53, and p16 immunostains and RET (rearranged during transfection) polymorphism in desmoplastic melanoma has not been evaluated. Objective: We sought to identify potential prognostic markers. Methods: We performed Ki-67, p53, and p16 immunostains on 66 desmoplastic melanomas, and sequenced RET G691 polymorphism and recurrent mutations of 17 cancer genes in 55 and 20 cases, respectively. Results: Recurrence and metastasis were documented in 11 of 66 (17%) and 26 of 66 (39%) patients, respectively. Death was noted in 25 of 55 (45%) patients. Ki-67 expression (>= 10%, 43%) correlated with male gender (P = .009), ulceration (P = .002), and Breslow depth (P = .009). p53 Expression (>= 50%, 28%) correlated with male gender (P = .002) and head and neck location (P = .0228). Using Kaplan-Meier plots, Ki-67 expression (P = .0425) and mitosis (P = .00295) correlated with overall survival, whereas vascular invasion (P = .0292) correlated with disease progression. There was a significant correlation between Ki-67 and p53 expression (P = .003). RET polymorphism was present in 10 of 46 (22%) cases and inversely correlated with Breslow depth (P = .024). Limitation: Our study is small and lacks power to perform a multivariate analysis. Conclusion: Although Ki-67 expression correlated with overall survival, additional studies are needed to determine whether Ki-67 would be an independent prognostic marker in addition to the current routine histopathologic assessment. C1 [Lawrence, Nicholas F.; Su, Yuhua; Dias-Santagata, Dora; Hoang, Mai P.] Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 820, Boston, MA 02114 USA. [Hammond, Marc R.; Frederick, Dennie T.; Flaherty, Keith T.] Massachusetts Gen Hosp, Dept Oncol, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. [Deng, April] Univ Massachusetts, Mem Hosp, Dept Pathol, Worcester, MA 01605 USA. [Selim, M. Angelica] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Mahalingam, Meera] Vet Affairs Consolidated Labs New England, Dept Pathol & Lab Med, Dermatopathol Sect, Boston, MA USA. RP Hoang, MP (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 820, Boston, MA 02114 USA. EM mhoang@mgh.harvard.edu NR 34 TC 2 Z9 2 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD SEP PY 2016 VL 75 IS 3 BP 595 EP 602 DI 10.1016/j.jaad.2016.04.059 PG 8 WC Dermatology SC Dermatology GA DW0YO UT WOS:000383369700036 PM 27543214 ER PT J AU Brink, JA AF Brink, James A. TI Leading the Pack for Cancer Care SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material C1 [Brink, James A.] Massachusetts Gen Hosp, 55 Fruit St,FND 216, Boston, MA 02114 USA. RP Brink, JA (reprint author), Massachusetts Gen Hosp, 55 Fruit St,FND 216, Boston, MA 02114 USA. EM jabrink@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD SEP PY 2016 VL 13 IS 9 BP 1023 EP 1023 DI 10.1016/j.jacr.2016.06.023 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DW0EJ UT WOS:000383313400001 PM 27593090 ER PT J AU Pandharipande, PV Herts, BR Gore, RM Mayo-Smith, WW Harvey, HB Megibow, AJ Berland, LL AF Pandharipande, Pari V. Herts, Brian R. Gore, Richard M. Mayo-Smith, William W. Harvey, H. Benjamin Megibow, Alec J. Berland, Lincoln L. TI Re: "Rethinking Normal: Benefits and Risks of Not Reporting Harmless Incidental Findings" Reply SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Letter C1 [Pandharipande, Pari V.; Harvey, H. Benjamin] Massachusetts Gen Hosp, Dept Radiol, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. [Pandharipande, Pari V.; Harvey, H. Benjamin] Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. [Herts, Brian R.] Cleveland Clin, Dept Radiol, Cleveland, OH 44106 USA. [Gore, Richard M.] NorthShore Univ Hlth Syst, Dept Radiol, Evanston, IL USA. [Mayo-Smith, William W.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Megibow, Alec J.] NYU, Langone Med Ctr, Dept Radiol, New York, NY USA. [Berland, Lincoln L.] Univ Alabama Birmingham, Dept Radiol, Birmingham, AL USA. RP Pandharipande, PV (reprint author), Massachusetts Gen Hosp, Dept Radiol, 101 Merrimac St,10th Floor, Boston, MA 02114 USA.; Pandharipande, PV (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM pari@mgh-ita.org NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD SEP PY 2016 VL 13 IS 9 BP 1025 EP 1027 DI 10.1016/j.jacr.2016.06.045 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DW0EJ UT WOS:000383313400004 PM 27593092 ER PT J AU Patel, ND Broderick, DF Burns, J Deshmukh, TK Fries, IB Harvey, HB Holly, L Hunt, CH Jagadeesan, BD Kennedy, TA O'Toole, JE Perlmutter, JS Policeni, B Rosenow, JM Schroeder, JW Whitehead, MT Cornelius, RS Corey, AS AF Patel, Nandini D. Broderick, Daniel F. Burns, Judah Deshmukh, Tejaswini K. Fries, Ian Blair Harvey, H. Benjamin Holly, Langston Hunt, Christopher H. Jagadeesan, Bharathi D. Kennedy, Tabassum A. O'Toole, John E. Perlmutter, Joel S. Policeni, Bruno Rosenow, Joshua M. Schroeder, Jason W. Whitehead, Matthew T. Cornelius, Rebecca S. Corey, Amanda S. TI ACR Appropriateness Criteria Low Back Pain SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Appropriateness Criteria; low back pain; radiculopathy; red flags ID CAUDA-EQUINA SYNDROME; AMERICAN-COLLEGE; LUMBAR SPINE; CLASSIFICATION; COMPRESSION; PHYSICIANS; DIAGNOSIS; DISEASE; ADULTS; CARE AB Most patients presenting with uncomplicated acute low back pain (LBP) and/or radiculopathy do not require imaging. Imaging is considered in those patients who have had up to 6 weeks of medical management and physical therapy that resulted in little or no improvement in their back pain. It is also considered for those patients presenting with red flags raising suspicion for serious underlying conditions, such as cauda equina syndrome, malignancy, fracture, and infection. Many imaging modalities are available to clinicians and radiologists for evaluating LBP. Application of these modalities depends largely on the working diagnosis, the urgency of the clinical problem, and comorbidities of the patient. When there is concern for fracture of the lumbar spine, multidetector CT is recommended. Those deemed to be interventional candidates, with LBP lasting for > 6 weeks having completed conservative management with persistent radiculopathic symptoms, may seek MRI. Patients with severe or progressive neurologic deficit on presentation and red flags should be evaluated with MRI. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (the RAND/UCLA Appropriateness Method and the Grading of Recommendations Assessment, Development, and Evaluation) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. C1 [Patel, Nandini D.] Fairfax Radiol Consultants PC, 2722 Merrillee Dr,Ste 230, Fairfax, VA 22031 USA. [Broderick, Daniel F.] Mayo Clin Jacksonville, Jacksonville, FL 32224 USA. [Burns, Judah] Montefiore Med Ctr, Bronx, NY USA. [Deshmukh, Tejaswini K.] Childrens Hosp Wisconsin, Milwaukee, WI USA. [Fries, Ian Blair] Chartered, Bone Spine & Hand Surg, Brick, NJ USA. [Fries, Ian Blair] Amer Acad Orthopaed Surg, Washington, DC USA. [Harvey, H. Benjamin] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Holly, Langston] Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA. [Hunt, Christopher H.] Mayo Clin, Rochester, MN USA. [Jagadeesan, Bharathi D.] Univ Minnesota, Minneapolis, MN USA. [Kennedy, Tabassum A.] Univ Wisconsin Hosp & Clin, Madison, WI 53792 USA. [O'Toole, John E.] Rush Univ, Chicago, IL 60612 USA. [Perlmutter, Joel S.] Washington Univ, Sch Med, St Louis, MO USA. [Perlmutter, Joel S.] Amer Acad Neurologists, Minneapolis, MN USA. [Policeni, Bruno] Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. [Rosenow, Joshua M.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Schroeder, Jason W.] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [Whitehead, Matthew T.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Cornelius, Rebecca S.] Univ Cincinnati, Cincinnati, OH USA. [Corey, Amanda S.] Emory Univ, Atlanta, GA 30322 USA. RP Patel, ND (reprint author), Fairfax Radiol Consultants PC, 2722 Merrillee Dr,Ste 230, Fairfax, VA 22031 USA. EM nandini416@gmail.com NR 31 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 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD SEP PY 2016 VL 13 IS 9 BP 1069 EP 1078 DI 10.1016/j.jacr.2016.06.008 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DW0EJ UT WOS:000383313400014 PM 27496288 ER PT J AU Lu, MT Hallett, TR Hemingway, J Hughes, DR Hoffmann, U Duszak, R AF Lu, Michael T. Hallett, Travis R. Hemingway, Jennifer Hughes, Danny R. Hoffmann, Udo Duszak, Richard TI Secondary Interpretation of CT Examinations: Frequency and Payment in the Medicare Fee-for-Service Population SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Secondary interpretation; Medicare reimbursement; utilization ID CANCER CENTER; 2ND-OPINION CONSULTATIONS; RADIOLOGISTS; REINTERPRETATION; COVERAGE; IMPACT; CARE AB Purpose: Secondary interpretation of diagnostic imaging examinations (providing a second formal interpretation for imaging performed at another institution) may reduce repeat imaging after transfer of care. Recently, CMS requested information to guide payment policy. We aimed to study historic trends in submitted claims and payments for secondary interpretation services in the Medicare fee-for-service population. Methods: Applying current procedural terminology codes by body part to Medicare Part B aggregate claims files, we identified all CT interpretation services rendered between 1999 and 2012. Secondary interpretation services were identified using combined code modifiers 26 and 77, in accordance with CMS billing guidelines. The frequencies of billed and denied services were extracted for primary and secondary CT interpretation services. Primary versus secondary interpretation denial rates were calculated and compared. Results: Of all 227 million Medicare Part B claims for CT services, 299,468 (0.13%) were for secondary interpretation services. From 1999 to 2012, growth in secondary interpretation claims outpaced that in primary interpretation claims (+811% versus +56%; compound annual growth rate 17% versus 3.2%). As a percentage of all services, secondary interpretations increased from 0.05% in 1999 to 0.30% in 2012. Denial rates for second interpretations decreased from 1999 to 2012 (12.7% to 7.0%), and now approach those for primary interpretations (5.4% in 2012). Conclusions: Medicare claims for secondary interpretation of Cl examinations are growing but account for less than 1% of all billed CT interpretation services. Denial rates are similar to those of primary interpretation services. C1 [Lu, Michael T.; Hallett, Travis R.; Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Lu, Michael T.; Hoffmann, Udo] Harvard Med Sch, Boston, MA USA. [Hemingway, Jennifer; Hughes, Danny R.; Duszak, Richard] Harvey L Neiman Hlth Policy Inst, Reston, VA USA. [Hughes, Danny R.] George Mason Univ, Dept Hlth Adm & Policy, Fairfax, VA 22030 USA. [Duszak, Richard] Emory Univ, Sch Med, Dept Radiol & Imaging Sci, Atlanta, GA USA. RP Lu, MT (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, 165 Cambridge St,Ste 400, Boston, MA 02114 USA. EM mlu@mgh.harvard.edu FU Harvey L. Neiman Health Policy Institute, Reston, Virginia; American Roentgen Ray Society Scholarship FX Funding for this work was provided by the Harvey L. Neiman Health Policy Institute, Reston, Virginia. Dr. Lu reports research support from the American Roentgen Ray Society Scholarship. NR 22 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD SEP PY 2016 VL 13 IS 9 BP 1096 EP 1101 DI 10.1016/j.jacr.2016.01.020 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DW0EJ UT WOS:000383313400018 PM 27012731 ER PT J AU Krishnaraj, A Gandhi, S Butros, SR Fintelmann, F McDermott, S Shelly, M Patrie, J AF Krishnaraj, Arun Gandhi, Shaan Butros, Selim R. Fintelmann, Florian McDermott, Shaunagh Shelly, Martin Patrie, James TI Augmented Image Interpretation Through the Use of Advanced Health Record Technology SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article ID INFORMATION-TECHNOLOGY; WORKFLOW; ACCESS; IMPACT C1 [Krishnaraj, Arun] Univ Virginia, Sch Med, Div Body Imaging, Dept Radiol & Med Imaging, 1215 Lee St,POB 800170, Charlottesville, VA 22908 USA. [Gandhi, Shaan] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Butros, Selim R.] Minneapolis Vasc Phys, Minneapolis, MN USA. [Fintelmann, Florian; McDermott, Shaunagh] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Shelly, Martin] Univ Limerick, Univ Hosp, Limerick, Ireland. [Patrie, James] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. RP Krishnaraj, A (reprint author), Univ Virginia, Sch Med, Div Body Imaging, Dept Radiol & Med Imaging, 1215 Lee St,POB 800170, Charlottesville, VA 22908 USA. EM arunk@virginia.edu NR 12 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD SEP PY 2016 VL 13 IS 9 BP 1151 EP 1155 DI 10.1016/j.jacr.2016.02.015 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DW0EJ UT WOS:000383313400030 PM 27038998 ER PT J AU Krauss, JC Boonstra, PS Vantsevich, AV Friedman, CP AF Krauss, John C. Boonstra, Philip S. Vantsevich, Anna V. Friedman, Charles P. TI Is the problem list in the eye of the beholder? An exploration of consistency across physicians SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE medical problem list; coordination of patient care; ranked-biased overlap; electronic health record; ranked lists ID ELECTRONIC PROBLEM LIST; PRIMARY-CARE PROVIDERS; ATTITUDES; SPECIALISTS; ACCURACY; RECORDS AB Objective Quantify the variability of patients' problem lists - in terms of the number, type, and ordering of problems - across multiple physicians and assess physicians' criteria for organizing and ranking diagnoses. Materials and Methods In an experimental setting, 32 primary care physicians generated and ordered problem lists for three identical complex internal medicine cases expressed as detailed 2- to 4-page abstracts and subsequently expressed their criteria for ordering items in the list. We studied variability in problem list length. We modified a previously validated rank-based similarity measure, with range of zero to one, to quantify agreement between pairs of lists and calculate a single consensus problem list that maximizes agreement with each physician. Physicians' reasoning for the ordering of the problem lists was recorded. Results Subjects' problem lists were highly variable. The median problem list length was 8 (range: 3-14) for Case A, 10 (range: 4-20) for Case B, and 7 (range: 3-13) for Case C. The median indices of agreement - taking into account the length, content, and order of lists - over all possible physician pairings was 0.479, 0.371, 0.509, for Cases A, B, and C, respectively. The median agreements between the physicians' lists and the consensus list for each case were 0.683, 0.581, and 0.697 (for Cases A, B, and C, respectively). Out of a possible 1488 pairings, 2 lists were identical. Physicians most frequently ranked problem list items based on their acuity and immediate threat to health. Conclusions The problem list is a physician's mental model of a patient's health status. These mental models were found to vary significantly between physicians, raising questions about whether problem lists created by individual physicians can serve their intended purpose to improve care coordination. C1 [Krauss, John C.] Univ Michigan, Sch Med, Dept Internal Med, Div Hematol Oncol, 3-219 Canc Ctr,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. [Boonstra, Philip S.] Univ Michigan, Sch Publ Hlth, Dept Biostat, 2,1415 Washington Hts, Ann Arbor, MI 48109 USA. [Vantsevich, Anna V.] San Francisco VA Med Ctr, Mental Hlth Serv, 4150 Clement St, San Francisco, CA 94121 USA. [Friedman, Charles P.] Univ Michigan, Sch Med, Dept Learning Hlth Sci, Ann Arbor, MI 48109 USA. RP Krauss, JC (reprint author), Univ Michigan, Sch Med, Dept Internal Med, Div Hematol Oncol, 3-219 Canc Ctr,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM jkrauss@med.umich.edu FU National Institutes of Health [P30 CA 046592] FX P.S.B. was supported by the National Institutes of Health (P30 CA 046592). NR 37 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP PY 2016 VL 23 IS 5 BP 859 EP 865 DI 10.1093/jamia/ocv211 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA DW6SU UT WOS:000383782300003 PM 27002075 ER PT J AU Klann, JG Abend, A Raghavan, VA Mandl, KD Murphy, SN AF Klann, Jeffrey G. Abend, Aaron Raghavan, Vijay A. Mandl, Kenneth D. Murphy, Shawn N. TI Data interchange using i2b2 SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE medical informatics; data integration; data models; ontology-driven data representation; patient centered outcomes research institute; PCORnet CDM; informatics for integrating biology and the bedside ID SURVEILLANCE; ARCHITECTURE; SYSTEM; QUERY AB Objective Reinventing data extraction from electronic health records (EHRs) to meet new analytical needs is slow and expensive. However, each new data research network that wishes to support its own analytics tends to develop its own data model. Joining these different networks without new data extraction, transform, and load (ETL) processes can reduce the time and expense needed to participate. The Informatics for Integrating Biology and the Bedside (i2b2) project supports data network interoperability through an ontology-driven approach. We use i2b2 as a hub, to rapidly reconfigure data to meet new analytical requirements without new ETL programming. Materials and Methods Our 12-site National Patient-Centered Clinical Research Network (PCORnet) Clinical Data Research Network (CDRN) uses i2b2 to query data. We developed a process to generate a PCORnet Common Data Model (CDM) physical database directly from existing i2b2 systems, thereby supporting PCORnet analytic queries without new ETL programming. This involved: a formalized process for representing i2b2 information models (the specification of data types and formats); an information model that represents CDM Version 1.0; and a program that generates CDM tables, driven by this information model. This approach is generalizable to any logical information model. Results Eight PCORnet CDRN sites have implemented this approach and generated a CDM database without a new ETL process from the EHR. This enables federated querying within the CDRN and compatibility with the national PCORnet Distributed Research Network. Discussion We have established a way to adapt i2b2 to new information models without requiring changes to the underlying data. Eight Scalable Collaborative Infrastructure for a Learning Health System sites vetted this methodology, resulting in a network that, at present, supports research on 10 million patients' data. Conclusion New analytical requirements can be quickly and cost-effectively supported by i2b2 without creating new data extraction processes from the EHR. C1 [Klann, Jeffrey G.; Murphy, Shawn N.] Partners Healthcare, Boston, MA USA. [Klann, Jeffrey G.; Raghavan, Vijay A.; Mandl, Kenneth D.; Murphy, Shawn N.] Harvard Med Sch, Boston, MA USA. [Klann, Jeffrey G.; Murphy, Shawn N.] Massachusetts Gen Hosp, Boston, MA USA. [Abend, Aaron] Autoimmune Registry, New York, NY USA. [Mandl, Kenneth D.] Boston Childrens Hosp, Boston, MA USA. RP Klann, JG (reprint author), Partners Healthcare Syst Inc, Res Comp, One Constitut Ctr, Charlestown, MA 02129 USA. EM jeff.klann@mgh.harvard.edu FU Patient-Centered Outcomes Research Institute Award [CDRN-1306-04608]; National Institute of General Medical Sciences, NIH [R01GM104303] FX This work was funded through a Patient-Centered Outcomes Research Institute Award (CDRN-1306-04608) for development of the National Patient-Centered Clinical Research Network, known as PCORnet, and by R01GM104303 from the National Institute of General Medical Sciences, NIH. NR 12 TC 0 Z9 0 U1 10 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP PY 2016 VL 23 IS 5 BP 909 EP 915 DI 10.1093/jamia/ocv188 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA DW6SU UT WOS:000383782300009 PM 26911824 ER PT J AU Pevnick, JM Palmer, KA Shane, R Wu, CN Bell, DS Diaz, F Cook-Wiens, G Jackevicius, CA AF Pevnick, Joshua M. Palmer, Katherine A. Shane, Rita Wu, Cindy N. Bell, Douglas S. Diaz, Frank Cook-Wiens, Galen Jackevicius, Cynthia A. TI Potential benefit of electronic pharmacy claims data to prevent medication history errors and resultant inpatient order errors SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE medication reconciliation; adverse drug events; health information exchange ID HOSPITALIZED-PATIENTS; RECONCILIATION; ADMISSION; RECORDS; DISCREPANCIES; METAANALYSIS; ACCURACY; BARRIERS; CARE AB Objective We sought to assess the potential of a widely available source of electronic medication data to prevent medication history errors and resultant inpatient order errors. Methods We used admission medication history (AMH) data from a recent clinical trial that identified 1017 AMH errors and 419 resultant inpatient order errors among 194 hospital admissions of predominantly older adult patients on complex medication regimens. Among the subset of patients for whom we could access current Surescripts electronic pharmacy claims data (SEPCD), two pharmacists independently assessed error severity and our main outcome, which was whether SEPCD (1) was unrelated to the medication error; (2) probably would not have prevented the error; (3) might have prevented the error; or (4) probably would have prevented the error. Results Seventy patients had both AMH errors and current, accessible SEPCD. SEPCD probably would have prevented 110 (35%) of 315 AMH errors and 46 (31%) of 147 resultant inpatient order errors. When we excluded the least severe medication errors, SEPCD probably would have prevented 99 (47%) of 209 AMH errors and 37 (61%) of 61 resultant inpatient order errors. SEPCD probably would have prevented at least one AMH error in 42 (60%) of 70 patients. Conclusion When current SEPCD was available for older adult patients on complex medication regimens, it had substantial potential to prevent AMH errors and resultant inpatient order errors, with greater potential to prevent more severe errors. Further study is needed to measure the benefit of SEPCD in actual use at hospital admission. C1 [Pevnick, Joshua M.] Cedars Sinai Med Ctr, Dept Med, Div Gen Internal Med, 8700 Beverly Blvd, Los Angeles, CA 90048 USA. [Palmer, Katherine A.; Shane, Rita; Wu, Cindy N.; Diaz, Frank] Cedars Sinai Med Ctr, Dept Pharm Serv, 8700 Beverly Blvd, Los Angeles, CA 90048 USA. [Shane, Rita] UCSF Sch Pharm, San Francisco, CA USA. [Bell, Douglas S.] RAND Hlth, Santa Monica, CA USA. [Bell, Douglas S.] Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90095 USA. [Cook-Wiens, Galen] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Biostat Bioinformat & Res Informat Ctr, Los Angeles, CA USA. [Jackevicius, Cynthia A.] Western Univ Hlth Sci, Coll Pharm, Dept Pharm Practice & Adm, Pomona, CA USA. [Jackevicius, Cynthia A.] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Jackevicius, Cynthia A.] Univ Toronto, Fac Med, Dept Hlth Policy Management & Evaluat, Toronto, ON, Canada. [Jackevicius, Cynthia A.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Jackevicius, Cynthia A.] Univ Hlth Network, Toronto, ON, Canada. RP Pevnick, JM (reprint author), Cedars Sinai Hlth Syst, 8700 Beverly Blvd,PACT 400-8G, Los Angeles, CA 90048 USA. EM jpevnick@gmail.com FU NIH/National Center for Advancing Translational Science UCLA CTSI Grant [KL2TR000122, UL1TR000124] FX This research was supported by NIH/National Center for Advancing Translational Science UCLA CTSI Grant Numbers KL2TR000122 (Dr Pevnick) and UL1TR000124 (Dr Bell). The authors have no conflicts of interest to disclose. NR 29 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP PY 2016 VL 23 IS 5 BP 942 EP 950 DI 10.1093/jamia/ocv171 PG 9 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA DW6SU UT WOS:000383782300013 PM 26911817 ER PT J AU Gwathmey, K Burns, T Conaway, M Sadjadi, R Hehir, M Barnett, C Bril, V Ng, E David, W Gable, K Dineen, J Guptill, J Hobson-Webb, L Brannagan, T Byun, E Adler, M AF Gwathmey, K. Burns, T. Conaway, M. Sadjadi, R. Hehir, M. Barnett, C. Bril, V Ng, E. David, W. Gable, K. Dineen, J. Guptill, J. Hobson-Webb, L. Brannagan, T., III Byun, E. Adler, M. TI CONSTRUCTION AND VALIDATION OF THE CHRONIC ACQUIRED POLYNEUROPATHY PATIENT-REPORTED INDEX, "CAP-PRI": A DISEASE-SPECIFIC, HEALTH-RELATED QUALITY OF LIFE INSTRUMENT SO JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM LA English DT Meeting Abstract CT Inflammatory Neuropathy Consortium and GBS 100 Centenary Symposium and Ceilidh CY JUN 21-24, 2016 CL Univ Glasgow, Glasgow, SCOTLAND SP Baxalta, CSL Behring, Grifols, Kedrion S p A, GBS CIDP Fdn Int, Guillain Barre Associated Inflammatory Neuropathies, LFB Biomedicaments, Octapharma, TEVA HO Univ Glasgow C1 [Gwathmey, K.; Burns, T.; Conaway, M.] Univ Virginia, Charlottesville, VA USA. [Sadjadi, R.] Univ Rochester, Rochester, NY USA. [Hehir, M.] Univ Vermont, Burlington, VT USA. [Barnett, C.; Bril, V; Ng, E.] Univ Toronto, Toronto, ON, Canada. [David, W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gable, K.; Guptill, J.; Hobson-Webb, L.] Duke Univ, Durham, NC USA. [Dineen, J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Brannagan, T., III] Columbia Univ, New York, NY USA. [Byun, E.] Jerry L Pettis VA Med Ctr, Loma Linda, CA USA. [Adler, M.] Univ Calif Los Angeles, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1085-9489 EI 1529-8027 J9 J PERIPHER NERV SYST JI J. Peripher. Nerv. Syst. PD SEP PY 2016 VL 21 IS 3 BP 178 EP 178 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DW7TY UT WOS:000383856200063 ER PT J AU Shahrizaila, N Ropper, A AF Shahrizaila, N. Ropper, A. TI FISHER SYNDROME AND OTHER GBS VARIANTS: NORTINA SHAHRIZAILA MEETS ALLAN ROPPER SO JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM LA English DT Meeting Abstract CT Inflammatory Neuropathy Consortium and GBS 100 Centenary Symposium and Ceilidh CY JUN 21-24, 2016 CL Univ Glasgow, Glasgow, SCOTLAND SP Baxalta, CSL Behring, Grifols, Kedrion S p A, GBS CIDP Fdn Int, Guillain Barre Associated Inflammatory Neuropathies, LFB Biomedicaments, Octapharma, TEVA HO Univ Glasgow C1 [Shahrizaila, N.] Univ Malaya, Kuala Lumpur, Malaysia. [Ropper, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1085-9489 EI 1529-8027 J9 J PERIPHER NERV SYST JI J. Peripher. Nerv. Syst. PD SEP PY 2016 VL 21 IS 3 BP 210 EP 210 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DW7TY UT WOS:000383856200151 ER PT J AU Fridman, V AF Fridman, V CA Inherited Neuropathies Consortium TI DISEASE PROGRESSION IN CHARCOT-MARIE-TOOTH DISEASE TYPE 1A: A LONGITUDINAL STUDY USING RASCH ANALYSIS-BASED WEIGHTED CMT NEUROPATHY SCORES SO JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM LA English DT Meeting Abstract CT Inflammatory Neuropathy Consortium and GBS 100 Centenary Symposium and Ceilidh CY JUN 21-24, 2016 CL Univ Glasgow, Glasgow, SCOTLAND SP Baxalta, CSL Behring, Grifols, Kedrion S p A, GBS CIDP Fdn Int, Guillain Barre Associated Inflammatory Neuropathies, LFB Biomedicaments, Octapharma, TEVA HO Univ Glasgow C1 [Fridman, V] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Fridman, V] Univ Colorado Hosp, Dept Neurol, Denver, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1085-9489 EI 1529-8027 J9 J PERIPHER NERV SYST JI J. Peripher. Nerv. Syst. PD SEP PY 2016 VL 21 IS 3 BP 257 EP 258 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DW7TY UT WOS:000383856200275 ER PT J AU Menezes, M Ellis, M Abdel-Salam, G De Carvalho, D De Goede, C Kaymakamzade, B Sawaya, R Swoboda, K Willemsen, M Crow, Y Kennerson, M AF Menezes, M. Ellis, M. Abdel-Salam, G. De Carvalho, D. De Goede, C. Kaymakamzade, B. Sawaya, R. Swoboda, K. Willemsen, M. Crow, Y. Kennerson, M. TI CLINICAL AND NEUROPHYSIOLOGICAL PROFILE OF PERIPHERAL NEUROPATHY IN AICARDI-GOUTIERES SYNDROME SO JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM LA English DT Meeting Abstract CT Inflammatory Neuropathy Consortium and GBS 100 Centenary Symposium and Ceilidh CY JUN 21-24, 2016 CL Univ Glasgow, Glasgow, SCOTLAND SP Baxalta, CSL Behring, Grifols, Kedrion S p A, GBS CIDP Fdn Int, Guillain Barre Associated Inflammatory Neuropathies, LFB Biomedicaments, Octapharma, TEVA HO Univ Glasgow C1 [Menezes, M.] Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Sydney, NSW, Australia. [Ellis, M.; Kennerson, M.] ANZAC Res Inst, Northcott Neurosci Lab, Sydney, NSW, Australia. [Abdel-Salam, G.] Natl Res Ctr, Human Genet & Genome Res Div, Clin Genet Dept, Cairo, Egypt. [De Carvalho, D.] SARAH Network Rehabil Hosp, Genet Unit, Brasilia, DF, Brazil. [De Goede, C.] Royal Preston Hosp, Dept Paediat Neurol, Preston, Lancs, England. [Kaymakamzade, B.] Near East Univ, Fac Med, Dept Neurol, Nicosia, Cyprus. [Sawaya, R.] Amer Univ Beirut, Med Ctr, Dept Neurol, Beirut, Lebanon. [Swoboda, K.] Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Boston, MA 02114 USA. [Willemsen, M.] Radboud Univ Nijmegen, Med Ctr, Dept Pediat Neurol, Nijmegen, Netherlands. [Willemsen, M.] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands. [Crow, Y.] Paris Descartes Univ, Hop Necker, Inst Imagine, INSERM,UMR 1163,Lab Neurogenet & Neuroinflammat, Paris, France. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1085-9489 EI 1529-8027 J9 J PERIPHER NERV SYST JI J. Peripher. Nerv. Syst. PD SEP PY 2016 VL 21 IS 3 BP 280 EP 280 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DW7TY UT WOS:000383856200334 ER PT J AU Rossor, AM Laura, M Feely, S Fridman, V Burns, J Scherer, SS Pareyson, D Shy, ME Reilly, MM AF Rossor, A. M. Laura, M. Feely, S. Fridman, V Burns, J. Scherer, S. S. Pareyson, D. Shy, M. E. Reilly, M. M. CA INC-RDCRC TI GENOTYPE-PHENOTYPE CHARACTERISTICS AND BASELINE NATURAL HISTORY OF CMT2A CAUSED BY MUTATIONS IN THE MFN2 GENE SO JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM LA English DT Meeting Abstract CT Inflammatory Neuropathy Consortium and GBS 100 Centenary Symposium and Ceilidh CY JUN 21-24, 2016 CL Univ Glasgow, Glasgow, SCOTLAND SP Baxalta, CSL Behring, Grifols, Kedrion S p A, GBS CIDP Fdn Int, Guillain Barre Associated Inflammatory Neuropathies, LFB Biomedicaments, Octapharma, TEVA HO Univ Glasgow C1 [Rossor, A. M.; Laura, M.; Reilly, M. M.] UCL, Inst Neurol, Ctr Neuromuscular Dis, London, England. [Feely, S.; Shy, M. E.] Univ Iowa Hosp & Clin, Dept Neurol, Iowa City, IA 52242 USA. [Fridman, V] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Burns, J.] Univ Sydney, Arthrit & Musculoskeletal Res Grp, Sydney Neuromuscular Res Grp,Murdoch Childrens Re, Paediat Gait Anal Serv NSW,Childrens Hosp Westmea, Melbourne, Vic, Australia. [Scherer, S. S.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Pareyson, D.] IRCCS Fdn, Carlo Besta Neurol Inst, Dept Clin Neurosci, Milan, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1085-9489 EI 1529-8027 J9 J PERIPHER NERV SYST JI J. Peripher. Nerv. Syst. PD SEP PY 2016 VL 21 IS 3 BP 294 EP 295 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DW7TY UT WOS:000383856200371 ER PT J AU Shyn, PB Bird, JR Koch, RM Tatli, S Levesque, VM Catalano, PJ Silverman, SG AF Shyn, Paul B. Bird, Jeffery R. Koch, R. Marie Tatli, Servet Levesque, Vincent M. Catalano, Paul J. Silverman, Stuart G. TI Hepatic Microwave Ablation Zone Size: Correlation with Total Energy, Net Energy, and Manufacturer-Provided Chart Predictions SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID LOCAL TUMOR PROGRESSION; EX-VIVO BOVINE; HEPATOCELLULAR-CARCINOMA; RADIOFREQUENCY ABLATION; IN-VIVO; LIVER METASTASES; THERMAL ABLATION; TISSUE SHRINKAGE; PORCINE MODEL; DEVICES AB Purpose: To determine whether total energy (TE) reaching the microwave (MW) applicator or net energy (NE) exiting the applicator (after correcting for reflectivity) correlates better with hepatic MW ablation zone dimensions than manufacturer provided chart predictions. Materials and Methods: Single-applicator, nonoverlapping ablations of 93 liver tumors (0.7-5.9 cm) were performed in 52 adult patients. TE and NE were recorded for each ablation. Long axis diameter (LAD), short axis diameter (SAD), and volume (V) of each ablation zone were measured on magnetic resonance imaging or computed tomography after the procedure and retrospectively compared with TE; NE; and manufacturer-provided chart predictions of LAD, SAD, and V using correlation and regression analyses. Results: For treated tumors, mean (+/- SD) TE and NE were 49.8 kJ (+/- 22.7) and 36.4 kJ (+/- 19.4). Mean LAD, SAD, and V were 5.8 cm (+/- 1.3), 3.7 cm (+/- 0.8), and 44.1 cm(3) (+/- 25.4). Correlation coefficients (95% confidence interval) with LAD, SAD, and V were 0.46 (0.28, 0.61), 0.52 (0.36, 0.66), and 0.52 (0.36, 0.66) for TB; 0.42 (0.24, 0.58), 0.55 (0.39, 0.68), and 0.53 (0.36, 0.66) for NE; and 0.51 (0.34, 0.65), 0.63 (0.49, 0.74), and 0.60 (0.45, 0.73) for chart predictions. Using regression analysis and controlling for TE, SAD was 0.34 cm larger in patients with cirrhosis than in patients without cirrhosis. Conclusions: Correcting for reflectivity did not substantially improve correlation of energy values with MW ablation zone size parameters and did not outperform manufacturer-provided chart predictions. Correlations were moderate and variable using all methods. The results suggest a disproportionate influence of tissue factors on MW ablation results. C1 [Shyn, Paul B.; Bird, Jeffery R.; Koch, R. Marie; Tatli, Servet; Levesque, Vincent M.; Silverman, Stuart G.] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Shyn, Paul B.; Bird, Jeffery R.; Koch, R. Marie; Tatli, Servet; Levesque, Vincent M.; Silverman, Stuart G.] Brigham & Womens Hosp, Abdominal Imaging & Intervent, 75 Francis St, Boston, MA 02115 USA. [Catalano, Paul J.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Shyn, PB (reprint author), Harvard Med Sch, Dept Radiol, Boston, MA USA.; Shyn, PB (reprint author), Brigham & Womens Hosp, Abdominal Imaging & Intervent, 75 Francis St, Boston, MA 02115 USA. EM pshyn@partners.org NR 36 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD SEP PY 2016 VL 27 IS 9 BP 1389 EP 1396 DI 10.1016/j.jvir.2016.05.009 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA DW1OC UT WOS:000383411500017 PM 27425001 ER PT J AU Weng, LD Tessier, SN Smith, K Edd, JF Stott, SL Toner, M AF Weng, Lindong Tessier, Shannon N. Smith, Kyle Edd, Jon F. Stott, Shannon L. Toner, Mehmet TI Bacterial Ice Nucleation in Monodisperse D2O and H2O-in-Oil Emulsions SO LANGMUIR LA English DT Article ID SUPERCOOLED WATER DROPLETS; HETEROGENEOUS NUCLEATION; HOMOGENEOUS NUCLEATION; AQUEOUS-SOLUTIONS; MOUSE OOCYTES; HEAVY-WATER; TEMPERATURE; VOLUME; H2O; CRYOPRESERVATION AB Ice nucleation is of fundamental significance in many areas, including atmospheric science, food technology, and cryobiology, In this study, we investigated the ice-nucleation characteristics of picoliter-sized drops consisting of different D2O and H2O mixtures with and without the ice-nucleating bacteria Pseudomonas syringae. We also studied the effects of commonly used cryoprotectants such as ethylene glycol, propylene glycol, and trehalose on the nucleation characteristics of D2O and H2O mixtures. The results show that the median freezing temperature of the suspension containing 1 mg/mL of a lyophilized preparation of P. syringae is as high as -4.6 degrees C for 100% D2O, compared to -8.9 degrees C for 100% H2O. As the D2O concentration increases every 25% (v/v), the profile of the ice nucleation kinetics of D2O + H2O mixtures containirig 1 mg/mL Snomax shifts by about 1 degrees C, suggesting an ideal mixing-behavior of D2O and H2O. Furthermore, all of the cryoprotectants investigated in this study are found to depress the freezing phenomenon. Both the homogeneous and heterogeneous freezing temperatures of these aqueous solutions depend on the water activity and are independent of the nature of the solute. These findings enrich our fundamental knowledge of D2O-related ice nucleation and suggest that the combination of D2O and ice-nucleating agents could be a potential self-ice-nucleating formulation. The implications of self-nucleation include a higher, precisely controlled ice seeding temperature for slow freezing that would significantly improve the viability of many ice-assisted cryopreservation protocols. C1 [Weng, Lindong; Tessier, Shannon N.; Smith, Kyle; Edd, Jon F.; Stott, Shannon L.; Toner, Mehmet] Harvard Med Sch, BioMEMS Resource Ctr, Ctr Engn Med, Boston, MA 02129 USA. [Stott, Shannon L.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. [Stott, Shannon L.] Harvard Med Sch, Dept Med, Boston, MA 02114 USA. [Weng, Lindong; Tessier, Shannon N.; Toner, Mehmet] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Tessier, Shannon N.; Toner, Mehmet] Shriners Hosp Children, Boston, MA 02114 USA. RP Toner, M (reprint author), Harvard Med Sch, BioMEMS Resource Ctr, Ctr Engn Med, Boston, MA 02129 USA.; Toner, M (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA.; Toner, M (reprint author), Shriners Hosp Children, Boston, MA 02114 USA. EM mehmet.toner@hms.harvard.edu RI Weng, Lindong/A-6041-2017 OI Weng, Lindong/0000-0003-4811-6531 FU Natural Sciences and Engineering Research Council (NSERC) of Canada Postdoctoral Fellowship; NIH [R24OD016985, R01DK046270] FX S. N. T. holds a Natural Sciences and Engineering Research Council (NSERC) of Canada Postdoctoral Fellowship. This work was supported by. NIH grants R24OD016985 and R01DK046270. NR 38 TC 0 Z9 0 U1 20 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD SEP PY 2016 VL 32 IS 36 BP 9229 EP 9236 DI 10.1021/acs.langmuir.6b02212 PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA DW0GE UT WOS:000383318100014 PM 27495973 ER PT J AU Wang, Y Gutierrez-Herrera, E Ortega-Martinez, A Anderson, RR Franco, W AF Wang, Ying Gutierrez-Herrera, Enoch Ortega-Martinez, Antonio Anderson, Richard Rox Franco, Walfre TI UV fluorescence excitation imaging of healing of wounds in skin: Evaluation of wound closure in organ culture model SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE autofluorescence; imaging; skin; wound healing; UV; epithelialization; collagen ID EPIDERMAL PROLIFERATION; SPECTROSCOPY; REEPITHELIALIZATION; EPITHELIALIZATION; AUTOGRAFTS; INHIBITION; OXYGEN AB Background and ObjectiveMolecules native to tissue that fluoresce upon light excitation can serve as reporters of cellular activity and protein structure. In skin, the fluorescence ascribed to tryptophan is a marker of cellular proliferation, whereas the fluorescence ascribed to cross-links of collagen is a structural marker. In this work, we introduce and demonstrate a simple but robust optical method to image the functional process of epithelialization and the exposed dermal collagen in wound healing of human skin in an organ culture model. Materials and MethodsNon-closing non-grafted, partial closing non-grafted, and grafted wounds were created in ex vivo human skin and kept in culture. A wide-field UV fluorescence excitation imaging system was used to visualize epithelialization of the exposed dermis and quantitate wound area, closure, and gap. Histology (H&E staining) was also used to evaluate epithelialization. ResultsThe endogenous fluorescence excitation of cross-links of collagen at 335nm clearly shows the dermis missing epithelium, while the endogenous fluorescence excitation of tryptophan at 295nm shows keratinocytes in higher proliferating state. The size of the non-closing wound was 11.41.8mm and remained constant during the observation period, while the partial-close wound reached 65.5 +/- 4.9% closure by day 16. Evaluations of wound gaps using fluorescence excitation images and histology images are in agreement. ConclusionsWe have established a fluorescence imaging method for studying epithelialization processes, evaluating keratinocyte proliferation, and quantitating closure during wound healing of skin in an organ culture model: the dermal fluorescence of pepsin-digestible collagen cross-links can be used to quantitate wound size, closure extents, and gaps; and, the epidermal fluorescence ascribed to tryptophan can be used to monitor and quantitate functional states of epithelialization. UV fluorescence excitation imaging has the potential to become a valuable tool for research, diagnostic and educational purposes on evaluating the healing of wounds. Lasers Surg. Med. 48:678-685, 2016. (c) 2016 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc. C1 [Wang, Ying; Ortega-Martinez, Antonio; Anderson, Richard Rox; Franco, Walfre] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA USA. [Gutierrez-Herrera, Enoch] Univ Nacl Autonoma Mexico, Ctr Ciencias Aplicadasy Desarrollo Tecnol, Mexico City, DF, Mexico. RP Franco, W (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 50 Blossom St,Thier 209, Boston, MA 02114 USA. EM WFRANCO@mgh.harvard.edu FU ASLMS; Universidad Nacional Autonoma de Mexico [TA100215]; Army, Navy, NIH, Air Force, VA, and Health Affairs [W81XWH-13-2-0054] FX Contract grant sponsor: ASLMS; Contract grant sponsor: Universidad Nacional Autonoma de Mexico; Contract grant number: TA100215; Contract grant sponsor: Army, Navy, NIH, Air Force, VA, and Health Affairs; Contract grant number: W81XWH-13-2-0054. NR 34 TC 1 Z9 1 U1 9 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD SEP PY 2016 VL 48 IS 7 BP 678 EP 685 DI 10.1002/lsm.22523 PG 8 WC Dermatology; Surgery SC Dermatology; Surgery GA DW0YS UT WOS:000383370200006 PM 27075645 ER PT J AU Song, Y Ray, A Li, S Das, DS Tai, Y Carrasco, RD Chauhan, D Anderson, KC AF Song, Y. Ray, A. Li, S. Das, D. S. Tai, Y. T. Carrasco, R. D. Chauhan, D. Anderson, K. C. TI Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma SO LEUKEMIA LA English DT Article ID SMALL-MOLECULE INHIBITOR; OVERCOMES BORTEZOMIB RESISTANCE; SINGLE-AGENT CARFILZOMIB; DEUBIQUITINATING ENZYME; IN-VIVO; PROTEIN-DEGRADATION; KAPPA-B; CELLS; CANCER; APOPTOSIS AB Proteasome inhibitor bortezomib is an effective therapy for relapsed and newly diagnosed multiple myeloma (MM); however, dose-limiting toxicities and the development of resistance can limit its long-term utility. Recent research has focused on targeting ubiquitin receptors upstream of 20S proteasome, with the aim of generating less toxic therapies. Here we show that 19S proteasome-associated ubiquitin receptor Rpn13 is more highly expressed in MM cells than in normal plasma cells. Rpn13-siRNA (small interfering RNA) decreases MM cell viability. A novel agent RA190 targets Rpn13 and inhibits proteasome function, without blocking the proteasome activity or the 19S deubiquitylating activity. CRISPR/Cas9 Rpn13-knockout demonstrates that RA190-induced activity is dependent on Rpn13. RA190 decreases viability in MM cell lines and patient MM cells, inhibits proliferation of MM cells even in the presence of bone marrow stroma and overcomes bortezomib resistance. Anti-MM activity of RA190 is associated with induction of caspase-dependent apoptosis and unfolded protein response-related apoptosis. MM xenograft model studies show that RA190 is well tolerated, inhibits tumor growth and prolongs survival. Combining RA190 with bortezomib, lenalidomide or pomalidomide induces synergistic anti-MM activity. Our preclinical data validates targeting Rpn13 to overcome bortezomib resistance, and provides the framework for clinical evaluation of Rpn13 inhibitors, alone or in combination, to improve patient outcome in MM. C1 [Song, Y.; Ray, A.; Das, D. S.; Tai, Y. T.; Carrasco, R. D.; Chauhan, D.; Anderson, K. C.] Harvard Med Sch, LeBow Inst Myeloma Therapeut, 450 Brookline Ave,M553, Boston, MA 02115 USA. [Song, Y.; Ray, A.; Das, D. S.; Tai, Y. T.; Carrasco, R. D.; Chauhan, D.; Anderson, K. C.] Harvard Med Sch, Jerome Lipper Myeloma Ctr, Dept Med Oncol, Dana Farber Canc Inst, 450 Brookline Ave,M553, Boston, MA 02115 USA. [Li, S.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA USA. RP Chauhan, D; Anderson, KC (reprint author), Harvard Med Sch, LeBow Inst Myeloma Therapeut, 450 Brookline Ave,M553, Boston, MA 02115 USA.; Chauhan, D; Anderson, KC (reprint author), Harvard Med Sch, Jerome Lipper Myeloma Ctr, Dept Med Oncol, Dana Farber Canc Inst, 450 Brookline Ave,M553, Boston, MA 02115 USA. EM Dharminder_Chauhan@dfci.harvard.edu; Kenneth_Anderson@dfci.harvard.edu FU National Institutes of Health Specialized Programs of Research Excellence (SPORE) Grant [P50100707, PO1-CA078378, RO1 CA050947] FX This investigation was supported by National Institutes of Health Specialized Programs of Research Excellence (SPORE) Grant P50100707, PO1-CA078378 and RO1 CA050947. KCA is an American Cancer Society Clinical Research Professor. NR 53 TC 1 Z9 1 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD SEP PY 2016 VL 30 IS 9 BP 1877 EP 1886 DI 10.1038/leu.2016.97 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA DW6UH UT WOS:000383786400026 PM 27118409 ER PT J AU Shin, TH Brynczka, C Dayyani, F Rivera, MN Sweetser, DA AF Shin, Thomas H. Brynczka, Christopher Dayyani, Farshid Rivera, Miguel N. Sweetser, David A. TI TLE4 regulation of wnt-mediated inflammation underlies its role as a tumor suppressor in myeloid leukemia SO LEUKEMIA RESEARCH LA English DT Article DE AML1-ETO; Acute myeloid leukemia; Tumor suppressor; TLE4; Inflammation; Wnt signaling ID BONE-MARROW-TRANSPLANTATION; HEMATOPOIETIC STEM; SIGNALING PATHWAY; SELF-RENEWAL; COLON-CANCER; KAPPA-B; AML1-ETO; CELLS; PROTEIN; DIFFERENTIATION AB The presence of AMU-ET (RUNX1-CBF2T1), a fusion oncoprotein resulting from a t(8;21) chromosomal translocation, has been implicated as a necessary but insufficient event in the development of a subset of acute myeloid leukemias (AML). While AML1-ETO prolongs survival and inhibits differentiation of hematopoietic stem cells (HSC), other contributory events are needed for cell proliferation and leukemogenesis. We have postulated that specific tumor suppressor genes keep the leukemic potential of AML1-ETO in check. In studying del(9q), one of the most common concomitant chromosomal abnormalities with t(8;21), we identified the loss of an apparent tumor suppressor, TLE4, that appears to cooperate with AML1-ETO to confer a leukemic phenotype. This study sought to identify the molecular basis of this cooperation. We show that the loss of TLE4 confers proliferative advantage to leukemic cells, simultaneous with an upregulation of a pro- inflammatory signature mediated through aberrant increases in Wnt signaling activity. We further demonstrate that inhibition of cyclooxygenase (COX) activity partly reverses the pro-leukemic phenotype due to TLE4 knockdown, pointing towards a novel therapeutic approach for myeloid leukemia. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Shin, Thomas H.; Brynczka, Christopher; Dayyani, Farshid; Sweetser, David A.] Massachusetts Gen Hosp, Dept Pediat, Div Pediat Hematol Oncol, 175 Cambridge St, Boston, MA 02114 USA. [Shin, Thomas H.; Brynczka, Christopher; Dayyani, Farshid; Sweetser, David A.] Massachusetts Gen Hosp, Div Med Genet, Dept Pediat, 175 Cambridge St, Boston, MA 02114 USA. [Shin, Thomas H.] Boston Univ, Sch Med, Dept Mol & Translat Med, Boston, MA 02118 USA. [Rivera, Miguel N.] Massachusetts Gen Hosp, Dept Pathol, Mol Pathol Unit, Charlestown, MA 02129 USA. RP Sweetser, DA (reprint author), Massachusetts Gen Hosp, Dept Pediat, Div Pediat Hematol Oncol, 175 Cambridge St, Boston, MA 02114 USA.; Sweetser, DA (reprint author), Massachusetts Gen Hosp, Div Med Genet, Dept Pediat, 175 Cambridge St, Boston, MA 02114 USA. EM dsweetser@partners.org OI Sweetser, David/0000-0002-1621-3284 FU National Institutes of Health Grant [R01 CA115772]; Swim Across America FX This work was supported by National Institutes of Health Grant R01 CA115772 (FD, CB, DAS) and Swim Across America (THS, DAS). NR 50 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 0145-2126 EI 1873-5835 J9 LEUKEMIA RES JI Leuk. Res. PD SEP PY 2016 VL 48 BP 46 EP 56 DI 10.1016/j.leukres.2016.07.002 PG 11 WC Oncology; Hematology SC Oncology; Hematology GA DW7HK UT WOS:000383821600010 PM 27486062 ER PT J AU Halabi, T Lu, HM Bernard, DA Chu, JCH Kirk, MC Hamilton, RJ Lei, Y Driewer, J AF Halabi, Tarek Lu, Hsiao-Ming Bernard, Damian A. Chu, James C. H. Kirk, Michael C. Hamilton, Russell J. Lei, Yu Driewer, Joseph TI Automated survey of 8000 plan checks at eight facilities SO MEDICAL PHYSICS LA English DT Article DE failure mode analysis; error frequencies; plan check automation; chart review; quality assurance ID RADIATION-THERAPY; TREATMENT DELIVERY; QUALITY-ASSURANCE; RADIOTHERAPY; ERROR; IMPACT AB Purpose: To identify policy and system related weaknesses in treatment planning and plan check work-flows. Methods: The authors' web deployed plan check automation solution, PlanCheck, which works with all major planning and record and verify systems (demonstrated here for MOSAIQ only), allows them to compute violation rates for a large number of plan checks across many facilities without requiring the manual data entry involved with incident filings. Workflows and failure modes are heavily influenced by the type of record and verify system used. Rather than tackle multiple record and verify systems at once, the authors restricted the present survey to MOSAIQ facilities. Violations were investigated by sending inquiries to physicists running the program. Results: Frequent violations included inadequate tracking in the record and verify system of total and prescription doses. Infrequent violations included incorrect setting of patient orientation in the record and verify system. Peaks in the distribution, over facilities, of violation frequencies pointed to suboptimal policies at some of these facilities. Correspondence with physicists often revealed incomplete knowledge of settings at their facility necessary to perform thorough plan checks. Conclusions: The survey leads to the identification of specific and important policy and system deficiencies that include: suboptimal timing of initial plan checks, lack of communication or agreement on conventions surrounding prescription definitions, and lack of automation in the transfer of some parameters. (C) 2016 American Association of Physicists in Medicine. C1 [Halabi, Tarek; Lu, Hsiao-Ming] Massachusetts Gen Hosp, Harvard Med Sch, Dept Radiat Oncol, Boston, MA 02114 USA. [Bernard, Damian A.; Chu, James C. H.] Rush Univ, Med Ctr, Dept Radiat Oncol, Chicago, IL 60612 USA. [Kirk, Michael C.] Mass General North Shore Canc Ctr, Dept Radiat Oncol, Danvers, MA 01923 USA. [Hamilton, Russell J.] Univ Arizona, Dept Radiat Oncol, Tucson, AZ 85724 USA. [Lei, Yu] Univ Nebraska Med Ctr, Dept Radiat Oncol, Omaha, NE 68198 USA. [Driewer, Joseph] Nebraska Methodist Hosp, Dept Radiat Oncol, Omaha, NE 68114 USA. RP Halabi, T (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Dept Radiat Oncol, Boston, MA 02114 USA. EM thalabi@mgh.harvard.edu NR 20 TC 0 Z9 0 U1 4 U2 4 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD SEP PY 2016 VL 43 IS 9 BP 4966 EP 4972 DI 10.1118/1.4959999 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DW8BB UT WOS:000383877200002 PM 27587027 ER PT J AU Zaffino, P Raudaschl, P Fritscher, K Sharp, GC Spadea, MF AF Zaffino, Paolo Raudaschl, Patrik Fritscher, Karl Sharp, Gregory C. Spadea, Maria Francesca TI Technical Note: PLASTIMATCH MABS, an open source tool for automatic image segmentation SO MEDICAL PHYSICS LA English DT Article DE automatic segmentation; multiatlas based segmentation; CT; MRI; open source ID ORGAN VOLUME; HUMAN BRAIN; DELINEATION; RADIOTHERAPY; SOFTWARE; FUSION; MODEL AB Purpose: Multiatlas based segmentation is largely used in many clinical and research applications. Due to its good performances, it has recently been included in some commercial platforms for radiotherapy planning and surgery guidance. Anyway, to date, a software with no restrictions about the anatomical district and image modality is still missing. In this paper we introduce PLASTIMATCH MABS, an open source software that can be used with any image modality for automatic segmentation. Methods: PLASTIMATCH MABS workflow consists of two main parts: (1) an offline phase, where optimal registration and voting parameters are tuned and (2) an online phase, where a new patient is labeled from scratch by using the same parameters as identified in the former phase. Several registration strategies, as well as different voting criteria can be selected. A flexible atlas selection scheme is also available. To prove the effectiveness of the proposed software across anatomical districts and image modalities, it was tested on two very different scenarios: head and neck (H&N) CT segmentation for radiotherapy application, and magnetic resonance image brain labeling for neuroscience investigation. Results: For the neurological study, minimum dice was equal to 0.76 (investigated structures: left and right caudate, putamen, thalamus, and hippocampus). For head and neck case, minimum dice was 0.42 for the most challenging structures (optic nerves and submandibular glands) and 0.62 for the other ones (mandible, brainstem, and parotid glands). Time required to obtain the labels was compatible with a real clinical workflow (35 and 120 min). Conclusions: The proposed software fills a gap in the multiatlas based segmentation field, since all currently available tools (both for commercial and for research purposes) are restricted to a well specified application. Furthermore, it can be adopted as a platform for exploring MABS parameters and as a reference implementation for comparing against other segmentation algorithms. (C) 2016 American Association of Physicists in Medicine. C1 [Zaffino, Paolo; Spadea, Maria Francesca] Magna Graecia Univ Catanzaro, Dept Expt & Clin Med, I-88100 Catanzaro, Italy. [Raudaschl, Patrik; Fritscher, Karl] Private Univ Hlth Sci Med Informat & Technol, Inst Biomed Image Anal, A-6060 Hall In Tirol, Austria. [Sharp, Gregory C.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Zaffino, P (reprint author), Magna Graecia Univ Catanzaro, Dept Expt & Clin Med, I-88100 Catanzaro, Italy. EM p.zaffino@unicz.it FU National Institute of Biomedical Imaging and Bioengineering of the National Institute of Health [U54EB005149] FX This work was supported by the National Institute of Biomedical Imaging and Bioengineering of the National Institute of Health under award number U54EB005149. 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 6 U2 6 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD SEP PY 2016 VL 43 IS 9 BP 5155 EP 5160 DI 10.1118/1.4961121 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DW8BB UT WOS:000383877200020 PM 27587045 ER PT J AU Espay, AJ Bonato, P Nahab, FB Maetzler, W Dean, JM Klucken, J Eskofier, BM Merola, A Horak, F Lang, AE Reilmann, R Giuffrida, J Nieuwboer, A Horne, M Little, MA Litvan, I Simuni, T Dorsey, ER Burack, MA Kubota, K Kamondi, A Godinho, C Daneault, JF Mitsi, G Krinke, L Hausdorff, JM Bloem, BR Papapetropoulos, S AF Espay, Alberto J. Bonato, Paolo Nahab, Fatta B. Maetzler, Walter Dean, John M. Klucken, Jochen Eskofier, Bjoern M. Merola, Aristide Horak, Fay Lang, Anthony E. Reilmann, Ralf Giuffrida, Joe Nieuwboer, Alice Horne, Malcolm Little, Max A. Litvan, Irene Simuni, Tanya Dorsey, E. Ray Burack, Michelle A. Kubota, Ken Kamondi, Anita Godinho, Catarina Daneault, Jean-Francois Mitsi, Georgia Krinke, Lothar Hausdorff, Jeffery M. Bloem, Bastiaan R. Papapetropoulos, Spyros CA Movement Disorders Soc Task Force TI Technology in Parkinson's disease: Challenges and opportunities SO MOVEMENT DISORDERS LA English DT Review DE digital health; digital biomarkers; eHealth; Parkinson's disease; precision medicine; remote monitoring; technology; wearable technology ID BODY-WORN SENSORS; QUALITY-OF-LIFE; WEARABLE SENSORS; GAIT; MANAGEMENT; SYMPTOMS; MOVEMENT; BALANCE; FLUCTUATIONS; PROGRESSION AB The miniaturization, sophistication, proliferation, and accessibility of technologies are enabling the capture of more and previously inaccessible phenomena in Parkinson's disease (PD). However, more information has not translated into a greater understanding of disease complexity to satisfy diagnostic and therapeutic needs. Challenges include noncompatible technology platforms, the need for wide-scale and long-term deployment of sensor technology (among vulnerable elderly patients in particular), and the gap between the big data acquired with sensitive measurement technologies and their limited clinical application. Major opportunities could be realized if new technologies are developed as part of open-source and/or open-hardware platforms that enable multichannel data capture sensitive to the broad range of motor and nonmotor problems that characterize PD and are adaptable into self-adjusting, individualized treatment delivery systems. The International Parkinson and Movement Disorders Society Task Force on Technology is entrusted to convene engineers, clinicians, researchers, and patients to promote the development of integrated measurement and closed-loop therapeutic systems with high patient adherence that also serve to (1) encourage the adoption of clinico-pathophysiologic phenotyping and early detection of critical disease milestones, (2) enhance the tailoring of symptomatic therapy, (3) improve subgroup targeting of patients for future testing of disease-modifying treatments, and (4) identify objective biomarkers to improve the longitudinal tracking of impairments in clinical care and research. This article summarizes the work carried out by the task force toward identifying challenges and opportunities in the development of technologies with potential for improving the clinical management and the quality of life of individuals with PD. (c) 2016 International Parkinson and Movement Disorder Society C1 [Espay, Alberto J.] Univ Cincinnati, James J & Joan A Gardner Family Ctr Parkinsons Di, Cincinnati, OH 45267 USA. [Bonato, Paolo; Daneault, Jean-Francois] Harvard Med Sch, Dept Phys Med & Rehabil, Boston, MA USA. [Nahab, Fatta B.; Litvan, Irene] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Maetzler, Walter] Univ Tubingen, Hertie Inst Clin Brain Res HIH, Dept Neurodegenerat, Tubingen, Germany. [Maetzler, Walter] German Ctr Neurodegenerat Dis, DZNE, Tubingen, Germany. [Dean, John M.] Davis Phinney Fdn Parkinsons, Boulder, CO USA. [Klucken, Jochen] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Mol Neurol, Erlangen, Germany. [Eskofier, Bjoern M.] Univ Erlangen Nurnberg, Digital Sports Grp, Erlangen, Germany. [Merola, Aristide] Citta Salute & Sci Torino, Dept Neurosci Rita Levi Montalcini, Turin, Italy. [Horak, Fay] Oregon Hlth & Sci Univ, Dept Neurol, Portland VA Med Syst, Portland, OR 97201 USA. [Horak, Fay] APDM Inc, Portland, OR USA. [Lang, Anthony E.] Toronto Western Hosp, Morton & Gloria Movement Disorders Clin, Toronto, ON, Canada. [Lang, Anthony E.] Toronto Western Hosp, Edmond J Safra Program Parkinsons Dis, Toronto, ON, Canada. [Reilmann, Ralf] George Huntington Inst, Munster, Germany. [Reilmann, Ralf] Univ Munster, Dept Radiol, Munster, Germany. [Reilmann, Ralf] Univ Tubingen, Dept Neurodegenerat Dis, Tubingen, Germany. [Reilmann, Ralf] Univ Tubingen, Hertie Inst Clin Brain Res, Tubingen, Germany. [Giuffrida, Joe] Great Lakes NeuroTechnol, Cleveland, OH USA. [Nieuwboer, Alice] Katholieke Univ Leuven, Neuromotor Rehabil Res Grp, Dept Rehabil Sci, Leuven, Belgium. [Horne, Malcolm] Univ Melbourne, Global Kinet Corp, Parkville, Vic, Australia. [Horne, Malcolm] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic, Australia. [Little, Max A.] Aston Univ, Dept Math, Birmingham, W Midlands, England. [Little, Max A.] MIT, Media Lab, Cambridge, MA 02139 USA. [Simuni, Tanya] Northwestern Univ, Dept Neurol, Feinberg Sch Med, Chicago, IL 60611 USA. [Dorsey, E. Ray; Burack, Michelle A.] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA. [Kubota, Ken] Michael J Fox Fdn Parkinsons Res, New York, NY USA. [Kamondi, Anita] Natl Inst Clin Neurosci, Dept Neurol, Budapest, Hungary. [Godinho, Catarina] Inst Super Ciencias Saude Egas Moniz, Ctr Interdisciplinary Res Egas Moniz CiiEM, Monte De Caparica, Portugal. [Mitsi, Georgia] Apptomics LLC, Wellesley, MA USA. [Krinke, Lothar] Medtron Neuromodulat, Minneapolis, MN USA. [Hausdorff, Jeffery M.] Tel Aviv Univ, Sackler Sch Med, Tel Aviv, Israel. [Hausdorff, Jeffery M.] Tel Aviv Sourasky Med Ctr, Ctr Study Movement Cognit & Mobil, Neurol Inst, Tel Aviv, Israel. [Bloem, Bastiaan R.] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Neurol, Nijmegen, Netherlands. [Papapetropoulos, Spyros] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Espay, AJ (reprint author), Univ Cincinnati, Acad Hlth Ctr, 260 Stetson St,Suite 2300, Cincinnati, OH 45267 USA. EM alberto.espay@uc.edu OI Merola, Aristide/0000-0002-5587-726X FU Great Lakes Neurotechnologies; Michael J Fox Foundation; National Institutes of Health; National Science Foundation; Office of Naval Research; Medtronic Inc.; European Union; Davis Phinney Foundation; Astrum IT; LicherMT; Bosch Sensortec; Medtronic; GE Medical; Prana Biotechnology; Netherlands Organization for Scientific Research; Prinses Beatrix Foundation; Stichting Parkinson Fonds; National Parkinson Foundation; Hersenstichting Nederland; Parkinson Vereniging FX The MDS Technology Task Force assembled a group of experts from the device and biopharmaceutical industry, clinical researchers, and engineers. The authors have taken every effort to minimize the influence of their home institutions and industries on the summarized outcome of the deliberations. A.J.E. has received grant support from Great Lakes Neurotechnologies. He serves as chair of the MDS Technology Task Force. P.B. is supported by the Michael J Fox Foundation, the National Institutes of Health, the National Science Foundation, and the Office of Naval Research. F.N. has received an educational grant from Medtronic Inc. W.M. has received grants from the European Union for FAIR-PARK-II, Moving beyond and SENSE-PARK. J.M.D. is supported by the Davis Phinney Foundation to direct their Healthcare Strategy and Technology division. J.K. has received grant support Astrum IT and LicherMT and is chair of the task force "sensor-based movement analysis" of the German Parkinson Society. B.M.E. has received grant support from Bosch Sensortec and Astrum IT and is co-chair of the task force "sensor-based movement analysis" of the German Parkinson Society. F.H. has research grants from Medtronic and has an equity/interest in APDM, a technology company. A.E.L. has served as an advisor for and received honoraria from Medtronic. R.R. is founding director and owner of the George-Huntington-Institute, a private research institute and QuantiMedis, a clinical research organization providing Q-Motor (quantitative motor) services in clinical trials and research. J.G. is a full-time employee of Great Lakes Neurotechnologies. M.H. has a financial interest in Global Kinetics Corporation, a company that manufactures and supplies the Parkinson's KinetiGraph (PKG), a wearable technology. M.A.L. has nothing to disclose. T.S. has received funding support for educational programming from GE Medical and Medtronic. E.R.D. has filed for a patent related to telemedicine and neurology and has received research funding from Great Lakes Neurotechnologies and Prana Biotechnology. K.K. directs data science and the partnership with Intel on wearable technologies and analytics enacted through the Michael J Fox Foundation for Parkinson's Research full time. G.M. is the founder and chief executive officer of Apptomics LLC. L.K. is a full-time employee of Medtronic and serves as Board Observer at Functional Neuromodulation, Ltd. J.M.H. submitted a patent application on the use of body-fixed sensors in Parkinson disease. The intellectual property rights for this patent application are held by the Tel Aviv Sourasky Medical Center. B.R.B. received research support from the Netherlands Organization for Scientific Research, the Michael J Fox Foundation, the Prinses Beatrix Foundation, the Stichting Parkinson Fonds, the National Parkinson Foundation, the Hersenstichting Nederland and the Parkinson Vereniging. S.P. is a full-time employee of TEVA Pharmaceuticals. He serves as co-chair of the MDS Technology Task Force. All other authors have no financial disclosure to report related to research covered in this article. NR 63 TC 9 Z9 9 U1 11 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2016 VL 31 IS 9 BP 1272 EP 1282 DI 10.1002/mds.26642 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA DW6PO UT WOS:000383773600046 PM 27125836 ER PT J AU Chen, X Chen, H Maguire, M Ya, B Cai, W Zuo, F Logan, R Rahimian, M Robinson, K Vanderburg, CR Yu, Y Wang, Y Fisher, DE Schwarzschild, MA AF Chen, X. Chen, H. Maguire, M. Ya, B. Cai, W. Zuo, F. Logan, R. Rahimian, M. Robinson, K. Vanderburg, C. R. Yu, Y. Wang, Y. Fisher, D. E. Schwarzschild, M. A. TI Melanoma-linked MC1R supports dopaminergic neuron survival SO MOVEMENT DISORDERS LA English DT Meeting Abstract C1 [Chen, X.; Maguire, M.; Ya, B.; Cai, W.; Zuo, F.; Logan, R.; Rahimian, M.; Schwarzschild, M. A.] Harvard Med Sch, MassGen Inst Neurodegenerat Dis, Dept Neurol, Boston, MA USA. [Chen, H.; Robinson, K.; Fisher, D. E.] Harvard Med Sch, Dept Dermatol, Cutaneous Biol Res Ctr, Boston, MA USA. [Vanderburg, C. R.] Harvard Med Sch, Massachusetts Gen Hosp, Harvard Neurodiscovery Ctr, Boston, MA USA. [Yu, Y.; Wang, Y.] Univ Calif Riverside, Dept Chem, Riverside, CA 92521 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2016 VL 31 IS 9 BP E7 EP E7 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA DW6PO UT WOS:000383773600021 ER PT J AU Espay, AJ Coffey, CS Foster, ED Uribe, L Caspell-Garcia, CJ Weintraub, D AF Espay, A. J. Coffey, C. S. Foster, E. D. Uribe, L. Caspell-Garcia, C. J. Weintraub, D. CA Parkinson's Progression Marker TI Dopaminergic medications and mood enhancement in Parkinson disease SO MOVEMENT DISORDERS LA English DT Meeting Abstract C1 Univ Cincinnati, Dept Neurol, James J & Joan A Gardner Family Ctr Parkinsons Di, Cincinnati, OH USA. Univ Iowa, Coll Publ Hlth, Dept Biostat, Iowa City, IA USA. Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA. Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. Philadelphia VA Med Ctr, Dept Vet Affairs, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2016 VL 31 IS 9 BP E11 EP E11 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA DW6PO UT WOS:000383773600034 ER PT J AU Van Laar, AD Webb, K Burton, EA Greenamyre, JT AF Van Laar, A. D. Webb, K. Burton, E. A. Greenamyre, J. T. TI PRESENTATION: A novel, progressive, endogenous synucleinopathy model of PD in rats SO MOVEMENT DISORDERS LA English DT Meeting Abstract C1 [Van Laar, A. D.; Webb, K.; Burton, E. A.; Greenamyre, J. T.] Univ Pittsburgh, Pittsburgh Inst Neurodegenerat Dis, Pittsburgh, PA USA. [Van Laar, A. D.; Burton, E. A.; Greenamyre, J. T.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. [Webb, K.] Univ Pittsburgh, Dept Neurosci, Pittsburgh, PA USA. [Burton, E. A.; Greenamyre, J. T.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Burton, E. A.] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2016 VL 31 IS 9 BP E1 EP E1 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA DW6PO UT WOS:000383773600002 ER PT J AU Weintraub, D Macklin, E Cartaya, A Wesnes, K Eberling, J Kenney, C Cravotto, K Schwarzschild, M Litvan, I Pothier, L Fernandez, H AF Weintraub, Daniel Macklin, Eric Cartaya, Amy Wesnes, Keith Eberling, Jamie Kenney, Christopher Cravotto, Karen Schwarzschild, Michael Litvan, Irene Pothier, Lindsay Fernandez, Hubert TI SYN120, a dual 5-HT6/5-HT2A antagonist, for Parkinson's disease dementia (SYNAPSE): Study design and partial blinded data SO MOVEMENT DISORDERS LA English DT Meeting Abstract C1 [Weintraub, Daniel] Univ Penn, Philadelphia, PA 19104 USA. [Macklin, Eric; Cartaya, Amy; Pothier, Lindsay] Neurol Clin Res Inst, Boston, MA USA. [Wesnes, Keith] Wesnes Cognit Ltd, Streatley On Thames, England. [Eberling, Jamie] Michael J Fox Fdn, New York, NY USA. [Kenney, Christopher; Cravotto, Karen] Biotie Therapies, San Francisco, CA USA. [Litvan, Irene] Univ Calif San Diego, San Diego, CA 92103 USA. [Fernandez, Hubert] Cleveland Clin, Cleveland, OH 44106 USA. [Schwarzschild, Michael] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cartaya, Amy] NCRI, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2016 VL 31 IS 9 BP E11 EP E12 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA DW6PO UT WOS:000383773600036 ER PT J AU Lee, EQ Wen, PY AF Lee, Eudocia Q. Wen, Patrick Y. TI Corticosteroids for peritumoral edema: time to overcome our addiction? SO NEURO-ONCOLOGY LA English DT Editorial Material ID CLINICAL-PRACTICE GUIDELINE; BRAIN METASTASES; DEXAMETHASONE; MANAGEMENT; TUMORS C1 [Lee, Eudocia Q.; Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA 02115 USA. [Lee, Eudocia Q.; Wen, Patrick Y.] Harvard Med Sch, Boston, MA 02115 USA. RP Lee, EQ (reprint author), Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA 02115 USA.; Lee, EQ (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM eqlee@partners.org 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 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD SEP PY 2016 VL 18 IS 9 BP 1191 EP 1192 DI 10.1093/neuonc/now167 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DW9TP UT WOS:000384005900001 PM 27530501 ER PT J AU Oblinger, JL Burns, SS Akhmametyeva, EM Huang, J Pan, L Ren, YL Shen, RL Miles-Markley, B Moberly, AC Kinghorn, AD Welling, DB Chang, LS AF Oblinger, Janet L. Burns, Sarah S. Akhmametyeva, Elena M. Huang, Jie Pan, Li Ren, Yulin Shen, Rulong Miles-Markley, Beth Moberly, Aaron C. Kinghorn, A. Douglas Welling, D. Bradley Chang, Long-Sheng TI Components of the eIF4F complex are potential therapeutic targets for malignant peripheral nerve sheath tumors and vestibular schwannomas SO NEURO-ONCOLOGY LA English DT Article DE eIF4F complex; malignant peripheral nerve sheath tumor (MPNST); orthotopic mouse models; silvestrol; vestibular schwannoma (VS) ID EUKARYOTIC TRANSLATION INITIATION; HISTONE DEACETYLASE INHIBITOR; NEUROFIBROMATOSIS TYPE-2; ANTITUMOR-ACTIVITY; AGLAIA-FOVEOLATA; SILVESTROL; CANCER; GROWTH; CELLS; MECHANISMS AB Background. The eukaryotic initiation factor 4F (eIF4F) complex plays a pivotal role in protein translation initiation; however, its importance in malignant and benign Schwann cell tumors has not been explored, and whether blocking eIF4F function is effective for treating these tumors is not known. Methods. Immunostaining was performed on human malignant peripheral nerve sheath tumors (MPNSTs) and vestibular schwannomas (VSs) for eIF4F components. The role of eIF4A and eIF4E in cell growth was assessed by RNA interference. Various natural compounds were screened for their growth-inhibitory activity. Flow cytometry and Western blotting were performed to characterize the action of silvestrol, and its antitumor activity was verified in orthotopic mouse models. Results. MPNSTs and VSs frequently overexpressed eIF4A, eIF4E, and/or eIF4G. Depletion of eIF4A1, eIF4A2, and eIF4E substantially reduced MPNST cell growth. From screening a panel of plant-derived compounds, the eIF4A inhibitor silvestrol was identified as a leading agent with nanomolar IC50 values in MPNST and VS cells. Silvestrol induced G(2)/M arrest in both NF1-deficient and NF1-expressing MPNST cells and primary VS cells. Silvestrol consistently decreased the levels of multiple cyclins, Aurora A, and mitogenic kinases AKT and ERKs. Silvestrol treatment dramatically suppressed tumor growth in mouse models for NF1(-/-) MPNST and Nf2(-/-) schwannoma. This decreased tumor growth was accompanied by elevated phospho-histone H3 and TUNEL labeling, consistent with G(2)/M arrest and apoptosis in silvestrol-treated tumor cells. Conclusions. The eIF4F complex is a potential therapeutic target in MPNSTs and VS, and silvestrol may be a promising agent for treating these tumors. C1 [Oblinger, Janet L.; Burns, Sarah S.; Akhmametyeva, Elena M.; Huang, Jie; Chang, Long-Sheng] Nationwide Childrens Hosp, Res Inst, Ctr Childhood Canc & Blood Dis, Columbus, OH USA. [Oblinger, Janet L.; Burns, Sarah S.; Akhmametyeva, Elena M.; Huang, Jie; Chang, Long-Sheng] Ohio State Univ, Coll Med, Dept Pediat, Columbus, OH 43210 USA. [Oblinger, Janet L.; Burns, Sarah S.; Miles-Markley, Beth; Moberly, Aaron C.; Kinghorn, A. Douglas; Chang, Long-Sheng] Ohio State Univ, Coll Med, Dept Otolaryngol Head & Neck Surg, Columbus, OH 43210 USA. [Shen, Rulong; Chang, Long-Sheng] Ohio State Univ, Coll Med, Dept Pathol, Columbus, OH 43210 USA. [Pan, Li; Ren, Yulin; Kinghorn, A. Douglas] Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, 500 W 12Th Ave, Columbus, OH 43210 USA. [Welling, D. Bradley] Harvard Med Sch, Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. [Welling, D. Bradley] Massachusetts Gen Hosp, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. RP Chang, LS (reprint author), Nationwide Childrens Hosp, Ctr Childhood Canc & Blood Dis, 700 Childrens Dr, Columbus, OH 43205 USA. EM lchang@chi.osu.edu OI Kinghorn, A. Douglas/0000-0002-6647-8707 FU NCI NIH HHS [P01 CA125066] NR 48 TC 1 Z9 1 U1 4 U2 4 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 SEP PY 2016 VL 18 IS 9 BP 1265 EP 1277 DI 10.1093/neuonc/now032 PG 13 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DW9TP UT WOS:000384005900014 PM 26951381 ER PT J AU Nigim, F Esaki, S Hood, M Lelic, N James, MF Ramesh, V Stemmer-Rachamimov, A Cahill, DP Brastianos, PK Rabkin, SD Martuza, RL Wakimoto, H AF Nigim, Fares Esaki, Shin-ichi Hood, Michael Lelic, Nina James, Marianne F. Ramesh, Vijaya Stemmer-Rachamimov, Anat Cahill, Daniel P. Brastianos, Priscilla K. Rabkin, Samuel D. Martuza, Robert L. Wakimoto, Hiroaki TI A new patient-derived orthotopic malignant meningioma model treated with oncolytic herpes simplex virus SO NEURO-ONCOLOGY LA English DT Article DE higher-grade meningioma; HGM; NF2; orthotopic tumor model; oHSV; patient-derived xenografts ID GLIOBLASTOMA STEM-CELLS; TERT PROMOTER MUTATIONS; MOLECULAR-GENETICS; VECTOR G47-DELTA; NERVOUS-SYSTEM; BREAST-CANCER; HUMAN BRAIN; TUMORS; THERAPY; GROWTH AB Background. Higher-grade meningiomas (HGMs; World Health Organization grades II and III) pose a clinical problem due to high recurrence rates and the absence of effective therapy. Preclinical development of novel therapeutics requires a disease model that recapitulates the genotype and phenotype of patient HGM. Oncolytic herpes simplex virus (oHSV) has shown efficacy and safety in cancers in preclinical and clinical studies, but its utility for HGM has not been well characterized. Methods. Tumorsphere cultures and serial orthotopic xenografting in immunodeficient mice were used to establish a patientderived HGM model. The model was pathologically and molecularly characterized by immunohistochemistry, western blot, and genomic DNA sequencing and compared with the patient tumor. Anti-HGM effects of oHSV G47D were assessed using cell viability and virus replication assays in vitro and animal survival analysis following intralesional injections of G47D. Results. We established a serially transplantable orthotopic malignant meningioma model, MN3, which was lethal within 3 months after tumorsphere implantation. MN3 xenografts exhibited the pathological hallmarks of malignant meningioma such as high Ki67 and vimentin expression. Both the patient tumor and xenografts were negative for neurofibromin 2 (merlin) and had the identical NF2 mutation. Oncolytic HSV G47D efficiently spread and killed MN3 cells, as well as other patient-derived HGM lines in vitro. Treatment with G47D significantly extended the survival of mice bearing subdural MN3 tumors. Conclusions. We established a new patient-derived meningioma model that will enable the study of targeted therapeutic approaches for HGM. Based on these studies, it is reasonable to consider a clinical trial of G47D for HGM. C1 [Nigim, Fares; Esaki, Shin-ichi; Hood, Michael; Lelic, Nina; Cahill, Daniel P.; Rabkin, Samuel D.; Martuza, Robert L.; Wakimoto, Hiroaki] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02115 USA. [James, Marianne F.; Ramesh, Vijaya] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA USA. [Stemmer-Rachamimov, Anat] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neuropathol, Boston, MA USA. [Brastianos, Priscilla K.] Harvard Med Sch, Massachusetts Gen Hosp, Div Neurooncol, Boston, MA USA. RP Wakimoto, H (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02115 USA. EM hwakimoto@mgh.harvard.edu OI Cahill, Daniel/0000-0003-2552-6546 NR 50 TC 0 Z9 0 U1 7 U2 7 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 SEP PY 2016 VL 18 IS 9 BP 1278 EP 1287 DI 10.1093/neuonc/now031 PG 10 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DW9TP UT WOS:000384005900015 PM 26951380 ER PT J AU Harper, DC Moore, RL Cleveland, C Miltner, RS Froelich, K McGuinness, T Waldrop, J Fogger, S Davis, AH Selleck, CS AF Harper, Doreen C. Moore, Randy L. Cleveland, Cynthia Miltner, Rebecca S. Froelich, Kimberly McGuinness, Teena Waldrop, Jessica Fogger, Susanne Davis, Amanda Hood Selleck, Cynthia S. TI Transforming veterans health care through academic-practice partnerships SO NURSING OUTLOOK LA English DT Article DE Academic-practice partnerships; Mental health; Nursing education; Veterans health; Veterans Health Administration AB The Veterans Health Affairs Office of Academic Affiliations (OAA) has invested in the creation of academic-practice partnerships to transform the care of veterans and their families. This article details how a long-standing relationship between the University of Alabama at Birmingham School of Nursing and the Birmingham Veterans Affairs Medical Center grew into such a partnership. The three programs that now exist within the Birmingham Veterans Affairs Nursing Academic Partnership (VANAP) umbrella are described, including an undergraduate VA nurse scholars program that has sustained beyond OAA funding, a VANAP graduate education program for psychiatric mental health nurse practitioners (NPs), and a Mental Health NP Residency. Key features of the programs are noted as are outcomes and lessons learned for building mutual goals and a sustainable academic-practice partnership. With the recent passage of the Veterans Choice Program, the importance of educating all nurses about veterans and veterans' health is stressed. C1 [Harper, Doreen C.; Miltner, Rebecca S.; McGuinness, Teena; Fogger, Susanne; Selleck, Cynthia S.] Univ Alabama Birmingham, Sch Nursing, 1720 2nd Ave South,NB 443A, Birmingham, AL 35294 USA. [Moore, Randy L.; Cleveland, Cynthia; Froelich, Kimberly; Waldrop, Jessica; Davis, Amanda Hood] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Selleck, CS (reprint author), Univ Alabama Birmingham, Sch Nursing, 1720 2nd Ave South,NB 443A, Birmingham, AL 35294 USA. EM cselleck@uab.edu OI Miltner, Rebecca/0000-0002-4653-0328 FU Birmingham Veterans Affairs Medical Center; University of Alabama at Birmingham School of Nursing FX This publication was supported in part by the Veterans Affairs Nursing Academic Partnership between the Birmingham Veterans Affairs Medical Center and the University of Alabama at Birmingham School of Nursing. NR 9 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-6554 EI 1528-3968 J9 NURS OUTLOOK JI Nurs. Outlook PD SEP-OCT PY 2016 VL 64 IS 5 SI SI BP 424 EP 430 DI 10.1016/j.outlook.2016.05.001 PG 7 WC Nursing SC Nursing GA DW6CE UT WOS:000383733200006 PM 27262737 ER PT J AU Coxe, DN Conner, BT Lauerer, J Skipper, J York, J Fraggos, M Stuart, GW AF Coxe, D. Nicole Conner, Brian T. Lauerer, Joy Skipper, Janice York, Janet Fraggos, Mary Stuart, Gail W. TI A prism of excellence: The Charleston Veterans Administration Nursing Academic Partnership SO NURSING OUTLOOK LA English DT Article DE Veterans; Academic; Partnership; Academic-service partnerships; Nursing education; Veteran-centric care ID IMPLEMENTATION AB Background: The Veterans Administration (VA) has been committed to academic affiliate training partnerships for nearly 70 years in efforts to enhance veteran centric health care. One such effort, the VA Nursing Academy (VANA) program, was developed in 2007 in response to the nationwide nursing shortage and began as a five-year pilot with funding competitively awarded to 15 partnerships between local VA medical centers and schools of nursing. The VANA program evolved into the VA Nursing Academic Partnership (VANAP) program following the initial pilot. Purpose: This article describes the development and evolution of the Charleston VANAP, which includes the Ralph H Johnson VA Medical Center (RHJ VAMC) and the Medical University of South Carolina College of Nursing (MUSC CON). Methods: The VA Office of Academic Affiliations (OAA) funded a large portion of the initial five years of the Charleston VANAP. Once the national funding source ceased, the RHJ VAMC and the MUSC CON entered into a Memorandum of Understanding (MOU) to offer in-kind contributions to the partnership. Discussion: The Charleston VANAP is the only program in the nation to offer three different nurse trainee programs and this article highlights some of the more notable achievements from each program. Conclusion: The Charleston VANAP is a comprehensive partnership between the RHJ VAMC and the MUSC CON that truly demonstrates a commitment to assure that the very best care be provided to Veterans, our Nation's heroes. C1 [Coxe, D. Nicole; Skipper, Janice; Fraggos, Mary] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Conner, Brian T.; Lauerer, Joy; York, Janet; Stuart, Gail W.] Med Univ South Carolina, Charleston, SC USA. [Conner, Brian T.; Lauerer, Joy; York, Janet; Stuart, Gail W.] Med Univ South Carolina, Coll Nursing, 99 Jonathan Lucas St, Charleston, SC 29425 USA. [Lauerer, Joy; York, Janet] Ralph H Johnson VA Med Ctr, PMHNP Residency Program, Charleston, SC USA. RP Conner, BT (reprint author), Med Univ South Carolina, Coll Nursing, 99 Jonathan Lucas St, Charleston, SC 29425 USA. EM connerb@musc.edu FU Office of Academic Affiliations; Department of Veterans Affairs FX The Charleston VANAP is supported by the Office of Academic Affiliations and the Department of Veterans Affairs. The authors acknowledge the mentorship of Dr. Mary Doughtery, Ms. Johnnie Guttery, Dr. Carole Hair, and Dr. Jemica Carter (Nursing Education, VA Office of Academic Affiliations) in the implementation of all three Charleston VANAP programs. The authors also wish to acknowledge Dr. Amelia Joseph, Dr. Nancy Duffy, and Dr. Charlene Pope as the authors of the original Charleston VANAP request for proposals; Dr. Donald (Hugh) Myrick, as a co-author of the PHMNP Residency request for proposals; Vanessa Gant-Clark, Erica Grate-Simmons, Steven Lesieur, and Dr. Stacy Gaillard as key VANAP faculty that were instrumental in the development of the VANAP curriculum; the PMHNP residency faculty and preceptors; and Dr. Christopher Pelic, Associate Chief of Staff/Education. NR 23 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-6554 EI 1528-3968 J9 NURS OUTLOOK JI Nurs. Outlook PD SEP-OCT PY 2016 VL 64 IS 5 SI SI BP 431 EP 439 DI 10.1016/j.outlook.2016.05.003 PG 9 WC Nursing SC Nursing GA DW6CE UT WOS:000383733200007 PM 27349633 ER PT J AU Chabner, BA AF Chabner, Bruce A. TI Understanding the Precision in "Precision Medicine" SO ONCOLOGIST LA English DT Editorial Material ID CELL LUNG-CANCER; HETEROGENEITY; RESISTANCE C1 [Chabner, Bruce A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Chabner, BA (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM bchabner@partners.org NR 8 TC 0 Z9 0 U1 2 U2 2 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD SEP PY 2016 VL 21 IS 9 BP 1029 EP 1030 DI 10.1634/theoncologist.2016-0278 PG 2 WC Oncology SC Oncology GA DW1HJ UT WOS:000383393600001 PM 27566249 ER PT J AU Pongas, G Fojo, T AF Pongas, Georgios Fojo, Tito TI BEZ235: When Promising Science Meets Clinical Reality SO ONCOLOGIST LA English DT Editorial Material ID RENAL-CELL CARCINOMA; PHASE-III TRIAL; PANCREATIC NEUROENDOCRINE TUMORS; INTERFERON-ALPHA; DOUBLE-BLIND; TEMSIROLIMUS; MTOR; EVEROLIMUS; THERAPY; CANCER C1 [Fojo, Tito] Columbia Univ, Med Ctr, Div Hematol Oncol, Herbert Irving Pavil,9th Floor, New York, NY 10032 USA. James J Peter VA Med Ctr, Bronx, NY USA. RP Fojo, T (reprint author), Columbia Univ, Med Ctr, Div Hematol Oncol, Herbert Irving Pavil,9th Floor, New York, NY 10032 USA. EM atf2116@columbia.edu NR 32 TC 0 Z9 0 U1 2 U2 2 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD SEP PY 2016 VL 21 IS 9 BP 1033 EP 1034 DI 10.1634/theoncologist.2016-0243 PG 2 WC Oncology SC Oncology GA DW1HJ UT WOS:000383393600003 PM 27566248 ER PT J AU Bardia, A Iafrate, JA Sundaresan, T Younger, J Nardi, V AF Bardia, Aditya Iafrate, John A. Sundaresan, Tilak Younger, Jerry Nardi, Valentina TI Metastatic Breast Cancer With ESR1 Mutation: Clinical Management Considerations From the Molecular and Precision Medicine (MAP) Tumor Board at Massachusetts General Hospital SO ONCOLOGIST LA English DT Article ID ASSAYS AB The last decade in oncology has witnessed impressive response rates with targeted therapies, largely because of collaborative efforts at understanding tumor biology and careful patient selection based on molecular fingerprinting of the tumor. Consequently, there has been a push toward routine molecular genotyping of tumors, and large precision medicine-based clinical trials have been launched to match therapy to the molecular alteration seen in a tumor. However, selecting the "right drug" for an individual patient in clinic is a complex decision-making process, including analytical interpretation of the report, consideration of the importance of the molecular alteration in driving growth of the tumor, tumor heterogeneity, the availability of a matched targeted therapy, efficacy and toxicity considerations of the targeted therapy (compared with standard therapy), and reimbursement issues. In this article, we review the key considerations involved in clinical decision making while reviewing a molecular genotyping report. We present the case of a 67-year-old postmenopausal female with metastatic estrogen receptor-positive (ER+) breast cancer, whose tumor progressed on multiple endocrine therapies. Molecular genotyping of the metastatic lesion revealed the presence of an ESR1 mutation (encoding p.Tyr537Asn), which was absent in the primary tumor. The same ESR1 mutation was also detected in circulating tumor DNA (ctDNA) extracted from her blood. The general approach for interpretation of genotyping results, the clinical significance of the specific mutation in the particular cancer, potential strategies to target the pathway, and implications for clinical practice are reviewed in this article. C1 [Bardia, Aditya; Iafrate, John A.; Sundaresan, Tilak; Younger, Jerry; Nardi, Valentina] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Lawrence House 304,10 North Grove St, Boston, MA 02114 USA. RP Bardia, A (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Lawrence House 304,10 North Grove St, Boston, MA 02114 USA. EM bardia.aditya@mgh.harvard.edu NR 21 TC 2 Z9 2 U1 2 U2 2 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD SEP PY 2016 VL 21 IS 9 BP 1035 EP 1040 DI 10.1634/theoncologist.2016-0240 PG 6 WC Oncology SC Oncology GA DW1HJ UT WOS:000383393600004 PM 27551012 ER PT J AU Tseng, D Mason, XL Neilan, TG Sullivan, RJ AF Tseng, Diane Mason, Xenos L. Neilan, Tomas G. Sullivan, Ryan J. TI Cardiogenic Shock and Respiratory Failure in a Patient With Metastatic Melanoma Receiving Trametinib Therapy SO ONCOLOGIST LA English DT Article ID MEK INHIBITOR; MYOCYTES; HEART C1 [Tseng, Diane] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Tseng, Diane; Mason, Xenos L.; Neilan, Tomas G.; Sullivan, Ryan J.] Harvard Univ, Cambridge, MA 02138 USA. [Mason, Xenos L.; Sullivan, Ryan J.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Neilan, Tomas G.] Massachusetts Gen Hosp, Dept Med, Cardiooncol Program, Dept Cardiol, Boston, MA 02114 USA. RP Tseng, D (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Tseng, D (reprint author), Harvard Univ, Cambridge, MA 02138 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD SEP PY 2016 VL 21 IS 9 BP 1136 EP 1137 DI 10.1634/theoncologist.2016-0080 PG 2 WC Oncology SC Oncology GA DW1HJ UT WOS:000383393600016 PM 27388234 ER PT J AU Plichta, JK Griffin, M Thakuria, J Hughes, KS AF Plichta, Jennifer K. Griffin, Molly Thakuria, Joseph Hughes, Kevin S. TI What's New in Genetic Testing for Cancer Susceptibility? SO ONCOLOGY-NEW YORK LA English DT Review ID BREAST-CANCER; FAMILY-HISTORY; RISK-ASSESSMENT; PRIMARY-CARE; AMERICAN SOCIETY; MUTATIONS; POPULATION; ONCOLOGY; RECOMMENDATIONS; GUIDELINES AB The advent of next-generation sequencing, and its transition further into the clinic with the US Food and Drug Administration approval of a cystic fibrosis assay in 2013, have increased the speed and reduced the cost of DNA sequencing. Coupled with a historic ruling by the Supreme Court of the United States that human genes are not patentable, these events have caused a seismic shift in genetic testing in clinical medicine. More labs are offering genetic testing services; more multigene panels are available for gene testing; more genes and gene mutations are being identified; and more variants of uncertain significance, which may or may not be clinically actionable, have been found. All these factors, taken together, are increasing the complexity of clinical management. While these developments have led to a greater interest in genetic testing, risk assessment, and large-scale population screening, they also present unique challenges. The dilemma for clinicians is how best to understand and manage this rapidly growing body of information to improve patient care. With millions of genetic variants of potential clinical significance and thousands of genes associated with rare but well-established genetic conditions, the complexities of genetic data management clearly will require improved computerized clinical decision support tools, as opposed to continued reliance on traditional rote, memory-based medicine. C1 [Plichta, Jennifer K.; Griffin, Molly; Hughes, Kevin S.] Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. [Thakuria, Joseph] Massachusetts Gen Hosp, Div Med Genet, Boston, MA 02114 USA. [Thakuria, Joseph] Veritas Genet, Danvers, MA USA. [Thakuria, Joseph; Hughes, Kevin S.] Harvard Med Sch, Boston, MA USA. [Hughes, Kevin S.] Massachusetts Gen Hosp, Avon Comprehens Breast Evaluat Ctr, Boston, MA 02114 USA. [Hughes, Kevin S.] Partners HealthCare Int, Bermuda Canc Genet & Risk Assessment Clin, Southampton, Bermuda. RP Hughes, KS (reprint author), 55 Fruit St,Yawkey 7, Boston, MA 02114 USA. EM kshughes@partners.org NR 49 TC 1 Z9 1 U1 2 U2 2 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 SEP PY 2016 VL 30 IS 9 BP 787 EP + PG 12 WC Oncology SC Oncology GA DW1PF UT WOS:000383414400002 ER PT J AU Wahl, AO Gaffney, DK Jhingran, A Yashar, CM Biagioli, M Elshaikh, MA Jolly, S Kidd, E Lee, LJ Li, LN Moore, DH Rao, GG Williams, NL Small, W AF Wahl, Andrew O. Gaffney, David K. Jhingran, Anuja Yashar, Catheryn M. Biagioli, Matthew Elshaikh, Mohamed A. Jolly, Shruti Kidd, Elizabeth Lee, Larissa J. Li, Linna Moore, David H. Rao, Gautam G. Williams, Ned L. Small, William, Jr. TI ACR Appropriateness Criteria (R) Adjuvant Management of Early-Stage Endometrial Cancer SO ONCOLOGY-NEW YORK LA English DT Article ID GYNECOLOGIC-ONCOLOGY-GROUP; PELVIC RADIATION-THERAPY; VAGINAL CUFF BRACHYTHERAPY; PHASE-III TRIAL; HIGH-DOSE-RATE; INTENSITY-MODULATED RADIOTHERAPY; EXTERNAL-BEAM RADIOTHERAPY; INTERMEDIATE-RISK; RANDOMIZED-TRIAL; DEFINITIVE RADIOTHERAPY AB These consensus guidelines on adjuvant radiotherapy for early-stage endometrial cancer were developed from an expert panel convened by the American College of Radiology. The American College of Radiology Appropriateness Criteria (R) are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method; and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. After a review of the published literature, the panel voted on three variants to establish best practices for the utilization of imaging, radiotherapy, and chemotherapy after primary surgery for early-stage endometrial cancer. C1 [Wahl, Andrew O.] Univ Nebraska Med Ctr, Coll Nursing, 985330 Nebraska Med Ctr, Omaha, NE 68198 USA. [Gaffney, David K.] Univ Utah, Med Ctr, Salt Lake City, UT USA. [Jhingran, Anuja] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Yashar, Catheryn M.] Univ Calif San Diego, San Diego, CA 92103 USA. [Biagioli, Matthew] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Elshaikh, Mohamed A.] Henry Ford Hlth Syst, Detroit, MI USA. [Jolly, Shruti] Univ Michigan Hlth Syst, Ann Arbor, MI USA. [Kidd, Elizabeth] Stanford Canc Ctr, Stanford, CA USA. [Lee, Larissa J.] Dana Farber Canc Inst, Brigham & Womens Hosp, Boston, MA 02115 USA. [Li, Linna] Bryn Mawr Hosp, Bryn Mawr, PA USA. [Moore, David H.] Indiana Univ Sch Med, Indianapolis, IN USA. [Moore, David H.] Amer Congress Obstetricians & Gynecologists, Washington, DC USA. [Rao, Gautam G.] Univ Maryland, Sch Med, Baltimore, MD USA. [Rao, Gautam G.] Amer Soc Clin Oncol, Alexandria, VA USA. [Williams, Ned L.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Small, William, Jr.] Loyola Univ Chicago, Stritch Sch Med, Panel Chair, Maywood, IL USA. RP Wahl, AO (reprint author), Amer Coll Radiol, 1891 Preston White Dr, Reston, VA 20191 USA. EM awahl@unmc.edu NR 58 TC 0 Z9 0 U1 1 U2 1 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 SEP PY 2016 VL 30 IS 9 BP 816 EP 822 PG 7 WC Oncology SC Oncology GA DW1PF UT WOS:000383414400005 ER PT J AU Cahana, A Bateman, BT Landau, R AF Cahana, Alex Bateman, Brian T. Landau, Ruth TI The Death of a Prince: Chronicle of a Death Foretold SO PAIN PRACTICE LA English DT Editorial Material C1 [Cahana, Alex] Ctr Lawful Access & Abuse Deterrence, Washington, DC 20007 USA. [Cahana, Alex] Def Vet Ctr Integrat Pain Management, Rockville, MD 20852 USA. [Bateman, Brian T.] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA. [Bateman, Brian T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Landau, Ruth] Columbia Univ, Med Ctr, Dept Anesthesiol, New York, NY USA. [Landau, Ruth] Columbia Univ Coll Phys & Surg, Ctr Precis Med, 630 W 168th St, New York, NY 10032 USA. RP Cahana, A (reprint author), Ctr Lawful Access & Abuse Deterrence, Washington, DC 20007 USA.; Cahana, A (reprint author), Def Vet Ctr Integrat Pain Management, Rockville, MD 20852 USA. NR 4 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1530-7085 EI 1533-2500 J9 PAIN PRACT JI Pain Pract. PD SEP PY 2016 VL 16 IS 7 BP 788 EP 790 DI 10.1111/papr.12487 PG 3 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA DW6PF UT WOS:000383772700006 PM 27600922 ER PT J AU Narayanaswami, P Geisbush, T Tarulli, A Raynor, E Gautam, S Tarsy, D Gronseth, G AF Narayanaswami, Pushpa Geisbush, Thomas Tarulli, Andrew Raynor, Elizabeth Gautam, Shiva Tarsy, Daniel Gronseth, Gary TI Drooling in Parkinson's disease: A randomized controlled trial of incobotulinum toxin A and meta-analysis of Botulinum toxins SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Parkinson's disease; Botulinum toxin; Sialorrhea; Clinical trials randomized controlled; Clinical trials systematic reviews/meta-analysis ID DOUBLE-BLIND; SIALORRHEA; EFFICACY; SAFETY AB Introduction: Botulinum toxins are a therapeutic option for drooling in Parkinson's Disease (PD). The aims of this study were to: 1. evaluate the efficacy of incotiotulinum toxin A for drooling in PD. 2. Perform a meta-analysis of studies of Botulinum toxins for drooling in PD. Methods: 1. Primary study: Randomized, double blind, placebo controlled, cross over trial. Incobotulinum toxin (100 units) or saline was injected into the parotid (20 units) and submandibular (30 units) glands. Subjects returned monthly for three evaluations after each injection. Outcome measures were saliva weight and Drooling Frequency and Severity Scale. 2. Systematic review of literature, followed by inverse variance meta-analyses using random effects models. Results: 1. Primary Study: Nine of 10 subjects completed both arms. There was no significant change in the primary outcome of saliva weight one month after injection in the treatment period compared to placebo period (mean difference, gm +/- SD: -0.194 +/- 0.61, range: -1.28 to 0.97, 95% CI -0.71 to 0.32). Secondary outcomes also did not change. 2. Meta-analysis of six studies demonstrated significant benefit of Botulinum toxin on functional outcomes (effect size, Cohen's d: -1.32, CI -1.86 to -0.78). The other studies used a higher dose of Botulinum toxin A into the parotid glands. Conclusions: This study did not demonstrate efficacy of incobotulinum toxin A for drooling in PD, but lacked precision to exclude moderate benefit. The parotid/submandibular dose-ratio may have influenced results. Studies evaluating higher doses of incobotulinum toxin A into the parotid glands may be useful. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Narayanaswami, Pushpa; Geisbush, Thomas; Tarulli, Andrew; Raynor, Elizabeth; Tarsy, Daniel] Harvard Med Sch, Beth Israel Med Ctr, Dept Neurol, BIDMC, 330 Brookline Ave, Boston, MA 02215 USA. [Gautam, Shiva] Harvard Med Sch, Beth Israel Med Ctr, Dept Med, BIDMC, 330 Brookline Ave, Boston, MA 02215 USA. [Gronseth, Gary] Univ Kansas, Med Ctr, Dept Neurol, 3901 Rainbow Blvd,Mail Stop 1033, Kansas City, KS 66160 USA. [Geisbush, Thomas] Rosalind Franklin Univ Med & Sci, 3333 Green Bay Rd, N Chicago, IL 60064 USA. [Tarulli, Andrew] Overlook Med Ctr, Atlantic Neurosci Inst, 99 Beauvoir Ave, Summit, NJ 07901 USA. RP Narayanaswami, P (reprint author), BIDMC, Neurol TCC 8, 330 Brookline Ave, Boston, MA 02215 USA. EM pnarayan@bidmc.harvard.edu; thomas.geisbush@my.rfums.org; Andrew.Tarulli@atlantichealth.org; eraynor@bidmc.harvard.edu; sgautam@bidmc.harvard.edu; dtarsy@bidmc.harvard.edu; ggronseth@kumc.edu OI Narayanaswami, Pushpa/0000-0002-9412-7349 FU Merz Pharmaceuticals, LLC [CTO-2401] FX The primary study was supported by Merz Pharmaceuticals, LLC (Investigator Initiated Trial, Grant number CTO-2401). NR 13 TC 0 Z9 0 U1 3 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD SEP PY 2016 VL 30 BP 73 EP 77 DI 10.1016/j.parkreldis.2016.07.001 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA DW3FJ UT WOS:000383527200014 PM 27406786 ER PT J AU Holland, CL Nkumsah, MA Morrison, P Tarr, JA Rubio, D Rodriguez, KL Kraemer, KL Day, N Arnold, RM Chang, JC AF Holland, Cynthia L. Nkumsah, Michelle Abena Morrison, Penelope Tarr, Jill A. Rubio, Doris Rodriguez, Keri L. Kraemer, Kevin L. Day, Nancy Arnold, Robert M. Chang, Judy C. TI "Anything above marijuana takes priority": Obstetric providers' attitudes and counseling strategies regarding perinatal marijuana use SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Patient-provider communication; Substance use; Pregnancy; Marijuana ID PRENATAL MARIJUANA; FAMILY PHYSICIANS; SUBSTANCE USE; ILLICIT-DRUG; PREGNANCY; ALCOHOL; DISORDERS; EXPOSURE; OUTCOMES; ABUSE AB Objective: To describe obstetric provider attitudes, beliefs, approaches, concerns, and needs about addressing perinatal marijuana use with their pregnant patients. Methods: We conducted individual semi-structured interviews with obstetric providers and asked them to describe their thoughts and experiences about addressing perinatal marijuana use. Interviews were transcribed verbatim, coded and reviewed to identify themes. Results: Fifty-one providers participated in semi-structured interviews. Providers admitted they were not familiar with identified risks of marijuana use during pregnancy, they perceived marijuana was not as dangerous as other illicit drugs, and they believed patients did not view marijuana as a drug. Most provider counseling strategies focused on marijuana's status as an illegal drug and the risk of child protective services being contacted if patients tested positive at time of delivery. Conclusions: When counseling about perinatal marijuana use, obstetric providers focus more on legal issues than on health risks. They describe needing more information regarding medical consequences of marijuana use during pregnancy. Practice implications: Provider training should include information about potential consequences of perinatal marijuana use and address ways to improve obstetric providers' counseling. Future studies should assess changes in providers' attitudes as more states consider the legalization of marijuana. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Holland, Cynthia L.; Nkumsah, Michelle Abena; Morrison, Penelope; Tarr, Jill A.; Chang, Judy C.] Magee Womens Res Inst, Dept Obstet Gynecol & Reprod Sci, 300 Halket St, Pittsburgh, PA 15213 USA. [Rubio, Doris; Rodriguez, Keri L.; Kraemer, Kevin L.; Arnold, Robert M.; Chang, Judy C.] UPMC Presbyterian Hosp, Dept Med, Div Gen Internal Med, Suite W933, Pittsburgh, PA 15213 USA. [Rubio, Doris; Kraemer, Kevin L.; Arnold, Robert M.; Chang, Judy C.] Univ Pittsburgh, Ctr Res Hlth Care, 230 McKee Pl,Suite 600, Pittsburgh, PA 15213 USA. [Rubio, Doris; Kraemer, Kevin L.] Univ Pittsburgh, Clin & Translat Sci Inst, 200 Meyran Ave, Pittsburgh, PA 15213 USA. [Rodriguez, Keri L.] Vet Affairs Pittsburgh Healthcare Syst, CHERP, Univ Dr 151C, Pittsburgh, PA 15240 USA. [Day, Nancy] Univ Pittsburgh, Dept Psychiat, 3800 OHara St, Pittsburgh, PA 15213 USA. [Arnold, Robert M.] UPMC Montefiore, Sect Palliat Care & Med Eth, Inst Enhance Palliat Care, 932W,200 Lothrop St, Pittsburgh, PA 15213 USA. [Arnold, Robert M.] UPMC Montefiore, Inst Doctor Patient Commun, 932W,200 Lothrop St, Pittsburgh, PA 15213 USA. [Nkumsah, Michelle Abena] Univ Pittsburgh, Dietrich Sch Arts & Sci, 139 Univ Pl, Pittsburgh, PA 15260 USA. RP Chang, JC (reprint author), Univ Pittsburgh, Magee Womens Res Inst, Dept Obstet Gynecol & Reprod Sci, Ctr Res Hlth Care,Div Gen Internal Med,Dept Inter, 3380 Blvd Allies,Suite 328, Pittsburgh, PA 15213 USA. EM chanjc@mail.magee.edu FU National Institute of Drug Abuse (NIDA) [1R01DA026410-01A1]; Pennsylvania Department of Health; Magee Womens Hospital Volunteer Service Board; National Institutes of Health [UL1TR000005] FX Study funded by the National Institute of Drug Abuse (NIDA) 1R01DA026410-01A1 (PI Chang), the Pennsylvania Department of Health, and the Magee Womens Hospital Volunteer Service Board, and supported by the National Institutes of Health through Grant Number UL1TR000005. Funders had no role in study design, collection analysis and interpretation of data; writing the report; and the preparation, review, approval or decision to submit the report for publication. The content does not represent the official views of the National Institute of Drug Abuse, the Pennsylvania Department of Health, Magee-Womens Hospital, or the University of Pittsburgh Medical Center. NR 43 TC 2 Z9 2 U1 4 U2 4 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 SEP PY 2016 VL 99 IS 9 BP 1446 EP 1451 DI 10.1016/j.pec.2016.06.003 PG 6 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA DW0VI UT WOS:000383360700003 PM 27316326 ER PT J AU Bokhour, BG Fix, GM Gordon, HS Long, JA DeLaughter, K Orner, MB Pope, C Houston, TK AF Bokhour, Barbara G. Fix, Gemmae M. Gordon, Howard S. Long, Judith A. DeLaughter, Kathryn Orner, Michelle B. Pope, Charlene Houston, Thomas K. TI Can stories influence African-American patients' intentions to change hypertension management behaviors? A randomized control trial SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Hypertension; Narrative communication; African-American; Disparities; Health literacy; Education ID FUNCTIONAL HEALTH LITERACY; BLOOD-PRESSURE CONTROL; NARRATIVE COMMUNICATION; SELF-MANAGEMENT; PREVENTION; ADHERENCE; EDUCATION; ILLNESS; INTERVENTIONS; PROMOTION AB Objectives: Information-only interventions for hypertension management have limited effectiveness, particularly among disadvantaged populations. We assessed the impact of viewing African-American patients' stories of successfully controlling hypertension on intention to change hypertension management behaviors and engagement with educational materials. Methods: In a three-site randomized trial, 618 African-American Veterans with uncontrolled hypertension viewed an information-only DVD about hypertension (control) or a DVD adding videos of African-American Veterans telling stories about successful hypertension management (intervention). After viewing, patients were asked about their engagement with the DVD, and their intentions to change behavior. Mean scores were compared with two-sided t-tests. Results: Results favored the Stories intervention, with significantly higher emotional engagement versus control (4.3 vs. 2.2 p < 0.0001). Intervention patients reported significantly greater intentions to become more physically active (4.6 vs. 4.4, p = 0.018), use salt substitutes (3.9 vs. 3.4, p = 0.006), talk openly with their doctor about hypertension (4.6 vs. 4.5, p = 0.049), and remember to take hypertension medication (4.8 vs. 4.6, p = 0.04). Conclusion: Patients were more emotionally engaged and reported intentions to change behavior when watching real patient hypertension management success stories. Practice implications: Stories may be more influential than information alone, and represent a scalable approach to modifying behavioral intention. Published by Elsevier Ireland Ltd. C1 [Bokhour, Barbara G.; Fix, Gemmae M.; DeLaughter, Kathryn; Orner, Michelle B.; Houston, Thomas K.] ENRM Vet Affairs Med Ctr, Ctr Healthcare Org & Implementat Res, Bedford, MA 01730 USA. [Bokhour, Barbara G.; Fix, Gemmae M.] Boston Univ, Sch Publ Hlth, Dept Hlth Law Policy & Management, Boston, MA 02215 USA. [Gordon, Howard S.] Jesse Brown Vet Affairs Med Ctr, Ctr Innovat Complex Chron Healthcare, Washington, DC USA. [Gordon, Howard S.] Univ Illinois, Coll Med, Dept Med, Sect Acad Internal Med, Chicago, IL 60680 USA. [Long, Judith A.] Corporal Michael J Crescenz Philadelphia VA Med C, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Long, Judith A.] Univ Penn, Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Pope, Charlene] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Pope, Charlene] Med Univ South Carolina, Coll Nursing, Charleston, SC USA. [Houston, Thomas K.] Univ Massachusetts, Div Hlth Informat & Implementat Sci, Quantitat Hlth Sci, Sch Med, Amherst, MA 01003 USA. RP Bokhour, BG (reprint author), ENRM Vet Affairs Med Ctr, Ctr Healthcare Org & Implementat Res, Bedford, MA 01730 USA. EM Barbara.Bokhour@va.gov; Gemmae.Fix@va.gov; Howard.Gordon@va.gov; jalong@upenn.edu; Kathryn.Delaughter@va.gov; Michelle.Orner@va.gov; Charlene.Pope@va.gov; Thomas.Houston@va.gov RI Gordon, Howard/E-4420-2010; OI Gordon, Howard/0000-0002-6712-5954; Fix, Gemmae/0000-0001-6055-4177 FU US Department of Veterans Affairs, Health Services Research and Development [IIR 10-132]; Quality Enhancement Research Initiative, eHealth QUERI [EHQ10-190]; University of Massachusetts Clinical and Translational Sciences Award [1 UL1 TR001453 01] FX This study was funded by the US Department of Veterans Affairs, Health Services Research and Development, Grant # IIR 10-132 and the Quality Enhancement Research Initiative, eHealth QUERI, grant # EHQ10-190, Dr. Houston was also funded by the University of Massachusetts Clinical and Translational Sciences Award (1 UL1 TR001453 01). We would also like to thank the patients who agreed to tell their stories on camera, and have those stories shared far and wide to other patients. NR 48 TC 1 Z9 1 U1 7 U2 7 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 SEP PY 2016 VL 99 IS 9 BP 1482 EP 1488 DI 10.1016/j.pec.2016.06.024 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA DW0VI UT WOS:000383360700008 PM 27387121 ER PT J AU Maltz, L Matz, EL Gordish-Dressman, H Pillai, DK Teach, SJ Camargo, CA Hubal, MJ Behniwal, S Prosper, GD Certner, N Marwah, R Mansell, DM Nwachukwu, F Lazaroff, R Tsegaye, Y Freishtat, RJ AF Maltz, Lisa Matz, Ethan L. Gordish-Dressman, Heather Pillai, Dinesh K. Teach, Stephen J. Camargo, Carlos A., Jr. Hubal, Monica J. Behniwal, Simran Prosper, Guy D. Certner, Nicole Marwah, Raman Mansell, Douglas M. Nwachukwu, Fisayo Lazaroff, Risa Tsegaye, Yodit Freishtat, Robert J. TI Sex differences in the association between neck circumference and asthma SO PEDIATRIC PULMONOLOGY LA English DT Article DE adiposity; body mass index; pediatric obesity; pediatrics ID BODY-MASS INDEX; QUALITY-OF-LIFE; INSULIN-RESISTANCE; PHENOTYPIC CLUSTERS; CHILDHOOD ASTHMA; LUNG-FUNCTION; OBESITY; CHILDREN; RESPONSIVENESS; INFLAMMATION AB IntroductionThe association between obesity and asthma control/quality of life commonly relies on body mass index (BMI) as the anthropomorphic measure. Due to limitations of BMI and the existence of alternative measures, such as neck circumference (NC), we examined the association between NC and asthma control/quality of life, with particular attention to male-female differences. Materials and MethodsThe AsthMaP-2 Project is an observational study of youth with physician-diagnosed asthma. NC was stratified according to age- and sex-specific cutoffs and associated with asthma control (via Asthma Control Test [ACT]) and quality of life (via Integrated Therapeutics Group [ITG]Asthma Short Form). ResultsThe meanSD age was 11.9 +/- 3.6 years, and 53% were male (N=116). The mean BMI percentile was at the 71 +/- 28 percentile. Thirty-one participants (27%) met criteria for high NC. Males with high NC had significantly worse asthma control (P=0.02) and lower quality of life than those with low NC. No similar association was found for females and the proportion of variability in ACT and ITG was best explained by BMI percentile. Conversely, for males, the proportion of variability in these scores explained by NC was larger than BMI percentile alone (Cohen's f(2)=0.04-0.09, a small to medium effect size). DiscussionAmong male youth with asthma, combined use of NC and BMI percentile explained asthma control and quality of life better than BMI alone. Future studies of asthma should include measurement of NC and other anthropogenic measures of regional adiposity to clarify sex differences in asthma. Pediatr Pulmonol. 2016; 51:893-900. (c) 2016 Wiley Periodicals, Inc. C1 [Maltz, Lisa; Gordish-Dressman, Heather; Pillai, Dinesh K.; Hubal, Monica J.; Behniwal, Simran; Prosper, Guy D.; Certner, Nicole; Marwah, Raman; Mansell, Douglas M.; Nwachukwu, Fisayo; Lazaroff, Risa; Freishtat, Robert J.] Childrens Natl Hlth Syst, Med Genet Res Ctr, Washington, DC USA. [Matz, Ethan L.; Tsegaye, Yodit] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. [Gordish-Dressman, Heather; Pillai, Dinesh K.; Hubal, Monica J.; Freishtat, Robert J.] George Washington Univ, Sch Med & Hlth Sci, Dept Integrat Syst Biol, Washington, DC 20052 USA. [Pillai, Dinesh K.; Teach, Stephen J.; Freishtat, Robert J.] George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20052 USA. [Pillai, Dinesh K.] Childrens Natl Hlth Syst, Div Pulm & Sleep Med, Washington, DC USA. [Teach, Stephen J.; Freishtat, Robert J.] Childrens Natl Hlth Syst, Div Emergency Med, 111 Michigan Ave,NW, Washington, DC 20010 USA. [Camargo, Carlos A., Jr.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA USA. [Mansell, Douglas M.] Howard Univ, Coll Med, Dept Microbiol, Washington, DC USA. RP Freishtat, RJ (reprint author), Childrens Natl Hlth Syst, Div Emergency Med, 111 Michigan Ave,NW, Washington, DC 20010 USA. EM rfreishtat@childrensnational.org OI Freishtat , Robert/0000-0002-7411-2342 FU NIH [R01MD007075, UL1TR000075]; Clark Charitable Foundation FX NIH, Numbers: R01MD007075, UL1TR000075; Clark Charitable 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 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD SEP PY 2016 VL 51 IS 9 BP 893 EP 900 DI 10.1002/ppul.23381 PG 8 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA DW1KI UT WOS:000383401700006 PM 26774073 ER PT J AU McCoy, TH Snapper, L Stern, TA Perlis, RH AF McCoy, Thomas H., Jr. Snapper, Leslie Stern, Theodore A. Perlis, Roy H. TI Underreporting of Delirium in Statewide Claims Data: Implications for Clinical Care and Predictive Modeling SO PSYCHOSOMATICS LA English DT Article DE delirium; claims data; prevalence; predictive modeling ID EMERGENCY-DEPARTMENT PATIENTS; ELECTRONIC HEALTH RECORDS; CRITICALLY-ILL PATIENTS; PREVENT POSTOPERATIVE DELIRIUM; RISK-FACTORS; CARDIAC-SURGERY; CONTROLLED-TRIAL; UNIT PATIENTS; ICU PATIENTS; METAANALYSIS AB Background: Delirium is an acute neuropsychiatric syndrome that portends poor prognosis and represents a significant burden to the health care system. Although detection allows for efficacious treatment, the diagnosis is frequently overlooked This underdiagnosis makes delirium an appealing target for translational predictive algorithmic modeling; however, such approaches require accurate identification in clinical training datasets. Methods: Using the Massachusetts All-Payers Claims Database, encompassing health claims for Massachusetts residents for 2012, we calculated the rate of delirium diagnosis in index hospitalizations by reported ICD-9 diagnosis code. We performed a review of published studies formally assessing delirium to establish an expected rate of delirium when formally assessed Secondarily, we reported a sociodemographic comparison of cases and noncases. Results: Rates of delirium reported in the literature vary widely, from 3.6-73% with a mean of 23.6%. The statewide claims data ( Massachusetts All-Payers Claims Database) identified the rate of delirium among index hospitalizations to be only 2.1%. For Massachusetts All-Payers Claims Database hospitalizations, delirium was coded in 2.8% of patients > 65 years old and for 1.2% of patients <= 65. Conclusion: The lower incidence of delirium in claims data may reflect a failure to diagnose, a failure to code, or a lower rate in community hospitals. The relative absence of the phenotype from large databases may limit the utility of data-driven predictive modeling to the problem of delirium recognition. C1 [McCoy, Thomas H., Jr.; Snapper, Leslie; Perlis, Roy H.] Massachusetts Gen Hosp, Ctr Human Genet Res, Ctr Expt Drugs & Diagnost, Dept Psychiat, Simches Res Bldg MGH,185 Cambridge St,6th Floor, Boston, MA 02114 USA. [McCoy, Thomas H., Jr.; Stern, Theodore A.] Massachusetts Gen Hosp, Avery D Weisman Psychiat Consultat Serv, Boston, MA 02114 USA. RP Perlis, RH (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Ctr Expt Drugs & Diagnost, Dept Psychiat, Simches Res Bldg MGH,185 Cambridge St,6th Floor, Boston, MA 02114 USA. EM rperlis@partners.org OI McCoy, Thomas/0000-0002-5624-0439 NR 67 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 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD SEP-OCT PY 2016 VL 57 IS 5 BP 480 EP 488 PG 9 WC Psychiatry; Psychology SC Psychiatry; Psychology GA DW7GK UT WOS:000383819000004 PM 27480944 ER PT J AU Durante, M Paganetti, H AF Durante, Marco Paganetti, Harald TI Nuclear physics in particle therapy: a review SO REPORTS ON PROGRESS IN PHYSICS LA English DT Review DE particle therapy; radiotherapy; protontherapy; nuclear fragmentation; lateral scattering; dosimetry; imaging ID PROTON-BEAM THERAPY; CARBON-ION THERAPY; MONTE-CARLO SIMULATIONS; RELATIVE BIOLOGICAL EFFECTIVENESS; DOSE CONVERSION COEFFICIENTS; LINEAR-ENERGY-TRANSFER; POSITRON-EMISSION-TOMOGRAPHY; PARTIAL-BREAST IRRADIATION; MAN ANATOMICAL MODEL; LOCAL EFFECT MODEL AB Charged particle therapy has been largely driven and influenced by nuclear physics. The increase in energy deposition density along the ion path in the body allows reducing the dose to normal tissues during radiotherapy compared to photons. Clinical results of particle therapy support the physical rationale for this treatment, but the method remains controversial because of the high cost and of the lack of comparative clinical trials proving the benefit compared to x-rays. Research in applied nuclear physics, including nuclear interactions, dosimetry, image guidance, range verification, novel accelerators and beam delivery technologies, can significantly improve the clinical outcome in particle therapy. Measurements of fragmentation cross-sections, including those for the production of positron-emitting fragments, and attenuation curves are needed for tuning Monte Carlo codes, whose use in clinical environments is rapidly increasing thanks to fast calculation methods. Existing cross sections and codes are indeed not very accurate in the energy and target regions of interest for particle therapy. These measurements are especially urgent for new ions to be used in therapy, such as helium. Furthermore, nuclear physics hardware developments are frequently finding applications in ion therapy due to similar requirements concerning sensors and real-time data processing. In this review we will briefly describe the physics bases, and concentrate on the open issues. C1 [Durante, Marco] Univ Trento, Natl Inst Nucl Phys INFN, Trento Inst Fundamental Phys & Applicat TIFPA, Via Sommar 14, I-38123 Povo, TN, Italy. [Durante, Marco] Univ Naples Federico II, Dept Phys, Naples, Italy. [Paganetti, Harald] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Paganetti, Harald] Harvard Med Sch, Boston, MA USA. RP Durante, M (reprint author), Univ Trento, Natl Inst Nucl Phys INFN, Trento Inst Fundamental Phys & Applicat TIFPA, Via Sommar 14, I-38123 Povo, TN, Italy.; Durante, M (reprint author), Univ Naples Federico II, Dept Phys, Naples, Italy. EM marco.durante@tifpa.infn.it OI Durante, Marco/0000-0002-4615-553X FU Helmholtz Association Portfolio 'Technologie und Medizin' FX We thank Dr Gerhard Kraft for useful discussions and Dr Francesco Tommasino for his contribution to several figures in this paper. Work in nuclear physics applications in MD lab is partly supported by the Helmholtz Association Portfolio 'Technologie und Medizin'. NR 417 TC 5 Z9 5 U1 19 U2 19 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0034-4885 EI 1361-6633 J9 REP PROG PHYS JI Rep. Prog. Phys. PD SEP PY 2016 VL 79 IS 9 AR 096702 DI 10.1088/0034-4885/79/9/096702 PG 59 WC Physics, Multidisciplinary SC Physics GA DW9DV UT WOS:000383957000001 PM 27540827 ER PT J AU Davoudi, S Papavasileiou, E Roohipoor, R Cho, H Kudrimoti, S Hancock, H Hoadley, S Andreoli, C Husain, D James, M Penman, A Chen, CJ Sobrin, L AF Davoudi, Samaneh Papavasileiou, Evangelia Roohipoor, Ramak Cho, Heeyoon Kudrimoti, Shreyas Hancock, Heather Hoadley, Suzanne Andreoli, Christopher Husain, Deeba James, Maurice Penman, Alan Chen, Ching J. Sobrin, Lucia TI OPTICAL COHERENCE TOMOGRAPHY CHARACTERISTICS OF MACULAR EDEMA AND HARD EXUDATES AND THEIR ASSOCIATION WITH LIPID SERUM LEVELS IN TYPE 2 DIABETES SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE hard exudate; hyperreflective foci; optical coherence tomography; diabetic retinopathy; type 2 diabetes ID HYPERREFLECTIVE FOCI; RISK-FACTORS; RETINOPATHY; MACULOPATHY; THICKNESS; RETINA; PEOPLE AB Purpose:To determine whether hyperreflective foci (HF) and macular thickness on spectral domain ocular coherence tomography are associated with lipid levels in patients with Type 2 diabetes.Methods:Two hundred and thirty-eight participants from four sites had fundus photographs and spectral domain ocular coherence tomography images graded for hard exudates and HF, respectively. Regression models were used to determine the association between serum lipid levels and 1) presence of HF and hard exudates and 2) central subfield macular thickness, central subfield macular volume, and total macular volume.Results:All patients with hard exudates on fundus photographs had corresponding HF on spectral domain ocular coherence tomography, but 57% of patients with HF on optical coherence tomography did not have hard exudates detected in their fundus photographs. Presence of HF was associated with higher total cholesterol (odds ratio = 1.13, 95% confidence interval = 1.01-1.27, P = 0.03) and higher low-density lipoprotein levels (odds ratio = 1.17, 95% confidence interval = 1.02-1.35, P = 0.02) in models adjusting for other risk factors. The total macular volume was also associated with higher total cholesterol (P = 0.009) and triglyceride (P = 0.02) levels after adjusting for other risk factors.Conclusion:Higher total and low-density lipoprotein cholesterol were associated with presence of HF on spectral domain ocular coherence tomography. Total macular volume was associated with higher total cholesterol and triglyceride levels. C1 [Davoudi, Samaneh; Papavasileiou, Evangelia; Roohipoor, Ramak; Cho, Heeyoon; Kudrimoti, Shreyas; Husain, Deeba; Sobrin, Lucia] Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Roohipoor, Ramak] Univ Tehran Med Sci, Farabi Eye Hosp, Dept Ophthalmol, Eye Res Ctr, Tehran, Iran. [Cho, Heeyoon] Hanyang Univ, Dept Ophthalmol, Coll Med, Seoul, South Korea. [Hancock, Heather; Hoadley, Suzanne; Penman, Alan; Chen, Ching J.] Univ Mississippi, Med Ctr, Dept Ophthalmol, Jackson, MS 39216 USA. [Andreoli, Christopher] Harvard Vanguard Med Associates, Visual Serv Dept, Boston, MA USA. [James, Maurice] St Dominics Hosp, Ophthalmol, Jackson, MS USA. [Penman, Alan] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA. RP Sobrin, L (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Lucia_sobrin@meei.harvard.edu FU American Diabetes Association Clinical Translational Research Award, Alexandria, VA [1-11-CT-51]; NEI, Bethesda, MD [K12-EY16335]; Research to Prevent Blindness Career Development Award, New York City, NY; William & Mary Greve Special Scholar Award, New York City, NY; Harvard Catalyst \ The Harvard Clinical and Translations Science Center Faculty Fellowship, Boston, MA; Massachusetts Lions Eye Research Fund, Abington, MA; Eleanor and Miles Shore Fellowship, Boston, MA; Sara Elizabeth O'Brien Trust, Boston, MA FX Supported by the American Diabetes Association Clinical Translational Research Award 1-11-CT-51, Alexandria, VA; NEI K12-EY16335, Bethesda, MD; Research to Prevent Blindness Career Development Award and William & Mary Greve Special Scholar Award, New York City, NY; Harvard Catalyst vertical bar The Harvard Clinical and Translations Science Center Faculty Fellowship, Boston, MA; Massachusetts Lions Eye Research Fund, Abington, MA; Eleanor and Miles Shore Fellowship, Boston, MA; Sara Elizabeth O'Brien Trust, Boston, MA. 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 0275-004X EI 1539-2864 J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD SEP PY 2016 VL 36 IS 9 BP 1622 EP 1629 DI 10.1097/IAE.0000000000001022 PG 8 WC Ophthalmology SC Ophthalmology GA DW9KZ UT WOS:000383979500004 PM 26991647 ER PT J AU Singh, K Nandyala, SV Marquez-Lara, A Fineberg, SJ Pelton, M AF Singh, Kern Nandyala, Sreeharsha V. Marquez-Lara, Alejandro Fineberg, Steven J. Pelton, Miguel TI The Effect of Coagulopathies on Perioperative Complications and Clinical Outcomes in Patients Treated With Posterior Lumbar Fusions SO SPINE LA English DT Letter C1 [Singh, Kern] Rush Univ, Med Ctr, Dept Orthopaed Surg, Chicago, IL 60612 USA. [Nandyala, Sreeharsha V.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Marquez-Lara, Alejandro] Wake Forest Baptist Hlth, Dept Orthopaed Surg, Winston Salem, NC USA. [Fineberg, Steven J.] New York Med Coll, Dept Orthopaed Surg, Valhalla, NY 10595 USA. [Pelton, Miguel] Medstar Georgetown Univ Hosp, Dept Orthoped Surg, Washington, DC USA. RP Singh, K (reprint author), Rush Univ, Med Ctr, Dept Orthopaed Surg, Chicago, IL 60612 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD SEP 1 PY 2016 VL 41 IS 17 BP E1069 EP E1070 DI 10.1097/BRS.0000000000001750 PG 2 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA DW7DA UT WOS:000383810200010 PM 27359353 ER PT J AU Jiang, DS Muschhammer, J Qi, Y Kugler, A de Vries, JC Saffarzadeh, M Sindrilaru, A Beken, SV Wlaschek, M Kluth, MA Ganss, C Frank, NY Frank, MH Preissner, KT Scharffetter-Kochanek, K AF Jiang, Dongsheng Muschhammer, Jana Qi, Yu Kuegler, Andrea de Vries, Juliane C. Saffarzadeh, Mona Sindrilaru, Anca Beken, Seppe Vander Wlaschek, Meinhard Kluth, Mark A. Ganss, Christoph Frank, Natasha Y. Frank, Markus H. Preissner, Klaus T. Scharffetter-Kochanek, Karin TI Suppression of Neutrophil-Mediated Tissue Damage-A Novel Skill of Mesenchymal Stem Cells SO STEM CELLS LA English DT Article DE Mesenchymal stem cells; Neutrophils; Neutrophil extracellular traps; Vasculitis; Superoxide dismutase ID EXTRACELLULAR-SUPEROXIDE DISMUTASE; REGULATORY T-CELLS; ENDOTHELIAL DAMAGE; INFLAMMATION; APOPTOSIS; ELASTASE; ACTIVATION; CANCER; INJURY; MICE AB Mesenchymal stem cells (MSCs) are crucial for tissue homeostasis and regeneration. Though of prime interest, their potentially protective role on neutrophil-induced tissue damage, associated with high morbidity and mortality, has not been explored in sufficient detail. Here we report the therapeutic skill of MSCs to suppress unrestrained neutrophil activation and to attenuate severe tissue damage in a murine immune-complex mediated vasculitis model of unbalanced neutrophil activation. MSC-mediated neutrophil suppression was due to intercellular adhesion molecule 1-dependent engulfment of neutrophils by MSCs, decreasing overall neutrophil numbers. Similar to MSCs in their endogenous niche of murine and human vasculitis, therapeutically injected MSCs via upregulation of the extracellular superoxide dismutase (SOD3), reduced superoxide anion concentrations and consequently prevented neutrophil death, neutrophil extracellular trap formation and spillage of matrix degrading neutrophil elastase, gelatinase and myeloperoxidase. SOD3-silenced MSCs did not exert tissue protective effects. Thus, MSCs hold substantial therapeutic promise to counteract tissue damage in conditions with unrestrained neutrophil activation. C1 [Jiang, Dongsheng; Muschhammer, Jana; Qi, Yu; Kuegler, Andrea; de Vries, Juliane C.; Sindrilaru, Anca; Beken, Seppe Vander; Wlaschek, Meinhard; Scharffetter-Kochanek, Karin] Univ Ulm, Dept Dermatol & Allerg Dis, Albert Einstein Allee 23, D-89081 Ulm, Germany. [Saffarzadeh, Mona; Preissner, Klaus T.] Univ Giessen, Sch Med, Dept Biochem, Giessen, Germany. [Kluth, Mark A.; Ganss, Christoph] Ticeba GmbH, Heidelberg, Germany. [Frank, Natasha Y.] Boston VA Healthcare Syst, Dept Med, West Roxbury, MA USA. [Frank, Natasha Y.; Frank, Markus H.] Brigham & Womens Hosp, Div Genet, Dept Dermatol, 75 Francis St, Boston, MA 02115 USA. [Frank, Markus H.] Boston Childrens Hosp, Transplant Res Program, Boston, MA USA. [Frank, Markus H.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Frank, Markus H.] Edith Cowan Univ, Sch Med Sci, Joondalup, WA, Australia. [Saffarzadeh, Mona] Univ Med Ctr Mainz, Ctr Thrombosis & Haemostasis, D-55131 Mainz, Germany. RP Scharffetter-Kochanek, K (reprint author), Univ Ulm, Dept Dermatol & Allerg Dis, Albert Einstein Allee 23, D-89081 Ulm, Germany. EM karin.scharffetter-kocha-nek@uniklinik-ulm.de FU Baden-Wurttemberg Stiftung [P-BWS-ASII/15]; European Commission [CASCADE HEALTH-FP7-223236]; German Research Foundation [SFB1149]; Medical Faculty, University of Ulm [LSBN.0100]; Excellence Cluster Cardio-pulmonary System (ECCPS) FX We thank Carmen Hauser (The Institute for Laser Technology in Medicine and Measurement Technique, University of Ulm) for technical support of confocal microscopy, and Alexander Magnutzki (Institute of Physiological Chemistry, University of Ulm) for technical support for in vivo imaging system. This study was supported in part by research grants from the Baden-Wurttemberg Stiftung (P-BWS-ASII/15), the European Commission (CASCADE HEALTH-FP7-223236) and the German Research Foundation (SFB1149) to K.S.-K., the Baustein Program from the Medical Faculty, University of Ulm (LSBN.0100) to D.J., and from the Excellence Cluster Cardio-pulmonary System (ECCPS) to M.S. and K.T.P. NR 61 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD SEP PY 2016 VL 34 IS 9 BP 2393 EP 2406 DI 10.1002/stem.2417 PG 14 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA DW8NC UT WOS:000383911700011 PM 27299700 ER PT J AU Olson, EJ Lechtenberg, BC Zhao, CX de la Torre, ER Lamberto, I Riedl, SJ Dawson, PE Pasquale, EB AF Olson, Erika J. Lechtenberg, Bernhard C. Zhao, Chunxia de la Torre, Elena Rubio Lamberto, Ilaria Riedl, Stefan J. Dawson, Philip E. Pasquale, Elena B. TI Modifications of a Nanomolar Cyclic Peptide Antagonist for the EphA4 Receptor To Achieve High Plasma Stability SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Peptide inhibitor; SAR; protease resistance; aminopeptidase; ALS; Alzheimer's disease ID SYSTEM; STRATEGIES; DRUGS AB EphA4 is a receptor tyrosine kinase with a critical role in repulsive axon guidance and synaptic function. However, aberrant EphA4 activity can inhibit neural repair after injury and exacerbate neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimers. We previously identified the cyclic peptide APY-d2 (APYCVYR beta ASWSC-NH2, containing a disulfide bond) as a potent and selective EphA4 antagonist. However, APY-d2 lacks sufficient plasma stability to be useful for EphA4 inhibition in vivo through peripheral administration. Using structureactivity relationship studies, we show that protecting the peptide N-terminus from proteolytic degradation dramatically increases the persistence of the active peptide in plasma and that a positively charged peptide N-terminus is essential for high EphA4 binding affinity. Among several improved APY-d2 derivatives, the cyclic peptides APY-d3 (beta APYCVYR beta AEWEC-NH2) and APY-d4 (beta APYCVYR beta AEWEC-NH2) combine high stability in plasma and cerebrospinal fluid with slightly enhanced potency. These properties make them valuable research tools and leads toward development of therapeutics for neurological diseases. C1 [Lechtenberg, Bernhard C.; Zhao, Chunxia; de la Torre, Elena Rubio; Lamberto, Ilaria; Riedl, Stefan J.; Pasquale, Elena B.] Sanford Burnham Prebys Med Discovery Inst, Ctr Canc, La Jolla, CA 92037 USA. [Olson, Erika J.; Dawson, Philip E.] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. [Olson, Erika J.; Dawson, Philip E.] Scripps Res Inst, Dept Cell & Mol Biol, La Jolla, CA 92037 USA. [Pasquale, Elena B.] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Lamberto, Ilaria] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Pasquale, EB (reprint author), Sanford Burnham Prebys Med Discovery Inst, Ctr Canc, La Jolla, CA 92037 USA.; Dawson, PE (reprint author), Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA.; Dawson, PE (reprint author), Scripps Res Inst, Dept Cell & Mol Biol, La Jolla, CA 92037 USA.; Pasquale, EB (reprint author), Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. EM dawson@scripps.edu; elenap@sbpdiscovery.org FU NIH [NS087070]; NCI Cancer Center Support Grant [P30CA030199]; NSF Graduate Research Fellowship Program [DGE-1346837] FX This work was supported by NIH grant NS087070 (to E.B.P., S.J.R., P.E.D.), NCI Cancer Center Support Grant P30CA030199 (to E.B.P., S.J.R), and NSF Graduate Research Fellowship Program DGE-1346837 (E.J.O.). NR 15 TC 0 Z9 0 U1 5 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD SEP PY 2016 VL 7 IS 9 BP 841 EP 846 DI 10.1021/acsmedchemlett.6b00132 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DV6AA UT WOS:000383010600007 PM 27660688 ER PT J AU Wang, YK Wach, JY Sheehan, P Zhong, C Zhan, CY Harris, R Almo, SC Bishop, J Haggarty, SJ Ramek, A Berry, KN O'Herin, C Koehler, AN Hung, AW Young, DW AF Wang, Yikai Wach, Jean-Yves Sheehan, Patrick Zhong, Cheng Zhan, Chenyang Harris, Richard Almo, Steven C. Bishop, Joshua Haggarty, Stephen J. Ramek, Alexander Berry, Kayla N. O'Herin, Conor Koehler, Angela N. Hung, Alvin W. Young, Damian W. TI Diversity-Oriented Synthesis as a Strategy for Fragment Evolution against GSK3 beta SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Diversity oriented synthesis; fragment-based drug discovery; fragment growing GSK3 beta ID DRUG DISCOVERY; STRUCTURAL BIOLOGY; NMR-SPECTROSCOPY; SMALL-MOLECULE; CRYSTALLOGRAPHY; PHOSPHORYLATION; INHIBITORS; DESIGN; POTENT AB Traditional fragment-based drug discovery (FBDD) relies heavily on structural analysis of the hits bound to their targets. Herein, we present a complementary approach based on diversity-oriented synthesis (DOS). A DOS-based fragment collection was able to produce initial hit compounds against the target GSK3 beta allow the systematic synthesis of related fragment analogues to explore fragment-level structure activity relationship, and finally lead to the synthesis of a more potent compound. C1 [Wang, Yikai; Wach, Jean-Yves; Sheehan, Patrick; Zhong, Cheng; Bishop, Joshua; Haggarty, Stephen J.; Ramek, Alexander; Berry, Kayla N.; O'Herin, Conor; Koehler, Angela N.; Hung, Alvin W.; Young, Damian W.] Broad Inst Harvard & MIT, Chem Biol Program, 415 Main St, Cambridge, MA 02142 USA. [Bishop, Joshua; Haggarty, Stephen J.] Harvard Med Sch, Dept Neurol & Psychiat, 185 Cambridge St, Boston, MA 02114 USA. [Bishop, Joshua; Haggarty, Stephen J.] Massachusetts Gen Hosp, 185 Cambridge St, Boston, MA 02114 USA. [Zhan, Chenyang; Harris, Richard; Almo, Steven C.] Albert Einstein Coll Med, Dept Biochem, 1300 Morris Pk Ave, Bronx, NY 10461 USA. [Hung, Alvin W.] Expt Therapeut Ctr A STAR, 11 Biopolis Way 03-10, Singapore 138667, Singapore. [Young, Damian W.] Baylor Coll Med, Ctr Drug Discovery, One Baylor Plaza, Houston, TX 77030 USA. RP Hung, AW; Young, DW (reprint author), Broad Inst Harvard & MIT, Chem Biol Program, 415 Main St, Cambridge, MA 02142 USA.; Hung, AW (reprint author), Expt Therapeut Ctr A STAR, 11 Biopolis Way 03-10, Singapore 138667, Singapore.; Young, DW (reprint author), Baylor Coll Med, Ctr Drug Discovery, One Baylor Plaza, Houston, TX 77030 USA. EM whung@etc.a-star.edu.sg; damiany@bcm.edu OI Haggarty, Stephen J./0000-0002-7872-168X FU Broad Institute SPARC Grant; NIH/NIMH [R01MH091115]; Tau Consortium; Barrus Foundation; NIH/NIGMS [U54 GM094662]; NIH/NCI [P30 CA013330] FX Funding support was provided by Broad Institute SPARC Grant. Additional support for the Haggarty Laboratory was provided by the NIH/NIMH (R01MH091115), the Tau Consortium, and the Barrus Foundation. Additional support for the Almo Laboratory was provided by by NIH/NIGMS U54 GM094662 and NIH/NCI P30 CA013330. NR 33 TC 0 Z9 0 U1 3 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD SEP PY 2016 VL 7 IS 9 BP 852 EP 856 DI 10.1021/acsmedchemlett.6b00230 PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DV6AA UT WOS:000383010600009 PM 27660690 ER PT J AU Conroy, AA Tsai, AC Clark, GM Boum, Y Hatcher, AM Kawuma, A Hunt, PW Martin, JN Bangsberg, DR Weiser, SD AF Conroy, Amy A. Tsai, Alexander C. Clark, Gina M. Boum, Yap Hatcher, Abigail M. Kawuma, Annet Hunt, Peter W. Martin, Jeffrey N. Bangsberg, David R. Weiser, Sheri D. TI Relationship Power and Sexual Violence Among HIV-Positive Women in Rural Uganda SO AIDS AND BEHAVIOR LA English DT Article DE Relationship power; Sexual violence; Transactional sex; HIV/AIDS; Africa ID INTIMATE-PARTNER VIOLENCE; HOUSEHOLD FOOD INSECURITY; GENDER-BASED VIOLENCE; DAR-ES-SALAAM; SOUTH-AFRICA; ALCOHOL-USE; RISK-FACTORS; TRANSACTIONAL SEX; REPRODUCTIVE HEALTH; DOMESTIC VIOLENCE AB Gender-based power imbalances place women at significant risk for sexual violence, however, little research has examined this association among women living with HIV/AIDS. We performed a cross-sectional analysis of relationship power and sexual violence among HIV-positive women on anti-retroviral therapy in rural Uganda. Relationship power was measured using the Sexual Relationship Power Scale (SRPS), a validated measure consisting of two subscales: relationship control (RC) and decision-making dominance. We used multivariable logistic regression to test for associations between the SRPS and two dependent variables: recent forced sex and transactional sex. Higher relationship power (full SRPS) was associated with reduced odds of forced sex (AOR = 0.24; 95 % CI 0.07-0.80; p = 0.020). The association between higher relationship power and transactional sex was strong and in the expected direction, but not statistically significant (AOR = 0.47; 95 % CI 0.18-1.22; p = 0.119). Higher RC was associated with reduced odds of both forced sex (AOR = 0.18; 95 % CI 0.06-0.59; p < 0.01) and transactional sex (AOR = 0.38; 95 % CI 0.15-0.99; p = 0.048). Violence prevention interventions with HIV-positive women should consider approaches that increase women's power in their relationships. C1 [Conroy, Amy A.] Univ Calif San Francisco, Dept Med, Ctr AIDS Prevent Studies, 550 16th St 3rd Floor, San Francisco, CA 94143 USA. [Tsai, Alexander C.; Bangsberg, David R.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Clark, Gina M.] Kaiser Permanente, Dept Psychiat, San Francisco, CA USA. [Boum, Yap; Kawuma, Annet] Mbarara Univ Sci & Technol, Fac Med, Mbarara, Uganda. [Hatcher, Abigail M.] Univ Witwatersrand, Fac Hlth Sci, Johannesburg, South Africa. [Hatcher, Abigail M.; Hunt, Peter W.; Weiser, Sheri D.] Univ Calif San Francisco, Dept Med, Div HIV AIDS, San Francisco, CA USA. [Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Bangsberg, David R.] Harvard Univ, Dept Med, Boston, MA 02115 USA. RP Conroy, AA (reprint author), Univ Calif San Francisco, Dept Med, Ctr AIDS Prevent Studies, 550 16th St 3rd Floor, San Francisco, CA 94143 USA. EM amy.conroy@ucsf.edu OI Tsai, Alexander/0000-0001-6397-7917 FU NIH [K23 MH-079713, MH-079713-03S1, R01 MH-054907, P30 AI27763, K24 MH-87227, K23 MH-096620, T32 MH-019105]; Tim and Jane Meyer Family Foundation; Burke Family Foundation FX We thank the Uganda AIDS Rural Treatment Outcomes (UARTO) participants who made this study possible by sharing their experiences; Annet Kembabazi for providing study coordination and support; Doreen Akello, Marcy Mutumba, Christine Ngabirano, Ruth Ssentongo, and Florence Turyashemererwa for research assistance; and Dr. Jessica Haberer, Dr. Nozmu Mukiibi, Dr. Conrad Muzoora, Dr. Jude Senkungu for invaluable advice and oversight of study design and implementation. While these individuals are acknowledged for their assistance, no endorsement of manuscript contents or conclusions should be inferred. The study was funded by NIH K23 MH-079713, MH-079713-03S1, NIH R01 MH-054907, NIH P30 AI27763, and the Tim and Jane Meyer Family Foundation. Additional sources of salary support came from the Burke Family Foundation, NIH K24 MH-87227, K23 MH-096620, and T32 MH-019105. NR 80 TC 1 Z9 1 U1 17 U2 17 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD SEP PY 2016 VL 20 IS 9 BP 2045 EP 2053 DI 10.1007/s10461-016-1385-y PG 9 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DU1SZ UT WOS:000381990800020 PM 27052844 ER PT J AU Levison, JH Alegria, M AF Levison, Julie H. Alegria, Margarita TI Shifting the HIV Training and Research Paradigm to Address Disparities in HIV Outcomes SO AIDS AND BEHAVIOR LA English DT Article DE HIV/AIDS; Research; Mentorship; Training; Latino/Hispanic; Minority ID LATIN-AMERICA; ANTIRETROVIRAL THERAPY; HEALTH DISPARITIES; UNITED-STATES; RACIAL MICROAGGRESSIONS; TREATMENT ADHERENCE; TREATMENT COHORTS; AFRICAN-AMERICAN; INCOME COUNTRIES; MENTAL-HEALTH AB Tailored programs to diversify the pool of HIV/AIDS investigators and provide sufficient training and support for minority investigators to compete successfully are uncommon in the US and abroad. This paper encourages a shift in the HIV/AIDS training and research paradigm to effectively train and mentor Latino researchers in the US, Latin America and the Caribbean. We suggest three strategies to accomplish this: (1) coaching senior administrative and academic staff of HIV/AIDS training programs on the needs, values, and experiences unique to Latino investigators; (2) encouraging mentors to be receptive to a different set of research questions and approaches that Latino researchers offer due to their life experiences and perspectives; and (3) creating a virtual infrastructure to share resources and tackle challenges faced by minority researchers. Shifts in the research paradigm to include, retain, and promote Latino HIV/AIDS researchers will benefit the scientific process and the patients and communities who await the promise of HIV/AIDS research. C1 [Levison, Julie H.] Massachusetts Gen Hosp, Div Gen Internal Med, Dept Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. [Levison, Julie H.; Alegria, Margarita] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Levison, Julie H.; Alegria, Margarita] Harvard Med Sch, Boston, MA 02115 USA. RP Levison, JH (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, Dept Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA.; Levison, JH (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Levison, JH (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM jlevison@partners.org FU Harvard University Center for AIDS Research [P30 AI060354]; National Institutes of Health [K23 MH100978, R01 DA034952, R01MH098734] FX The work was supported by the Harvard University Center for AIDS Research (P30 AI060354); and the National Institutes of Health (K23 MH100978, R01 DA034952, R01MH098734). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University and its affiliated academic health care centers, or the National Institutes of Health. NR 85 TC 2 Z9 2 U1 3 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD SEP PY 2016 VL 20 SU 2 BP S265 EP S272 DI 10.1007/s10461-016-1489-4 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DU1SL UT WOS:000381989300007 PM 27501811 ER PT J AU Rudinskiy, N Fuerer, C Demurtas, D Zamorano, S De Piano, C Herrmann, AG Spires-Jones, TL Oeckl, P Otto, M Frosch, MP Moniatte, M Hyman, BT Schmid, AW AF Rudinskiy, Nikita Fuerer, Christophe Demurtas, Davide Zamorano, Sebastian De Piano, Cyntia Herrmann, Abigail G. Spires-Jones, Tara L. Oeckl, Patrick Otto, Markus Frosch, Matthew P. Moniatte, Marc Hyman, Bradley T. Schmid, Adrien W. TI Amyloid-beta oligomerization is associated with the generation of a typical peptide fragment fingerprint SO ALZHEIMERS & DEMENTIA LA English DT Article DE Alzheimer's disease; Aggregation; Autocleavage; Oligomers; C-terminal amidation; Mass spectrometry; Selected reaction monitoring ID IMMUNOPRECIPITATION-MASS-SPECTROMETRY; LONG-TERM POTENTIATION; GAMMA-SECRETASE INHIBITION; ALZHEIMERS-DISEASE BRAIN; CEREBROSPINAL-FLUID; A-BETA; TISSUE TRANSGLUTAMINASE; NEURODEGENERATIVE DISEASES; SYNAPTIC PLASTICITY; BIOCHEMICAL MARKER AB Amyloid-beta (A beta) peptide oligomerization plays a central role in the pathogenesis of Alzheimer's disease (AD), and A beta oligomers are collectively considered an appealing therapeutic target for the treatment of AD. However, the molecular mechanisms leading to the pathologic accumulation of oligomers are unclear, and the exact structural composition of oligomers is being debated. Using targeted and quantitative mass spectrometry, we reveal site-specific A beta autocleavage during the early phase of aggregation, producing a typical A beta fragment signature and that truncated A beta peptides can form stable oligomeric complexes with full-length A beta peptide. We show that the use of novel anti-A beta antibodies raised against these truncated A beta isoforms allows for monitoring and targeting the accumulation of truncated A beta. fragments. Antibody-enabled screening of transgenic models of AD as well as human postmortem brain tissue and cerebrospinal fluid revealed that aggregation-associated A beta cleavage is a highly relevant clinical feature of AD. (C) 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved. C1 [Rudinskiy, Nikita; Hyman, Bradley T.] Harvard Med Sch, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Neurol,Alzheimers Dis Res Lab, Charlestown, MA USA. [Fuerer, Christophe; Zamorano, Sebastian; De Piano, Cyntia; Moniatte, Marc; Schmid, Adrien W.] Ecole Polytech Fed Lausanne, Prote Core Facil, Sch Life Sci, Lausanne, Switzerland. [Demurtas, Davide] Ecole Polytech Fed Lausanne, Interdisciplinary Ctr Electron Microscopy CIME, Sch Basic Sci, Lausanne, Switzerland. [Herrmann, Abigail G.; Spires-Jones, Tara L.] Univ Edinburgh, Ctr Cognit & Neural Syst, Edinburgh, Midlothian, Scotland. [Herrmann, Abigail G.; Spires-Jones, Tara L.] Univ Edinburgh, Ctr Dementia Prevent, Edinburgh, Midlothian, Scotland. [Herrmann, Abigail G.; Spires-Jones, Tara L.] Univ Edinburgh, Euan MacDonald Ctr Motorneurone Dis, Edinburgh, Midlothian, Scotland. [Oeckl, Patrick; Otto, Markus] Ulm Univ Hosp, Dept Neurol, Ulm, Germany. [Frosch, Matthew P.] Massachusetts Gen Hosp, Charlestown, MA USA. [Frosch, Matthew P.] Harvard Med Sch, Massachusetts Gen Inst Neurodegenerat Dis, Charlestown, MA USA. RP Schmid, AW (reprint author), Ecole Polytech Fed Lausanne, Prote Core Facil, Sch Life Sci, Lausanne, Switzerland. EM adrien.schmid@epfl.ch RI Otto, Markus/F-4304-2015 OI Otto, Markus/0000-0003-4273-4267 FU "Enable Grant" - Technology Transfer Office (TTO) of the Ecole Polytechnique Federale de Lausanne (EPFL); Biomedizin-Naturwissenschaft-Forschung (BNF) program from the University of Bern, Switzerland; EPFL; Roland Bailly Foundation (Geneva, Switzerland); Massachusetts Alzheimer Disease Research Center [NIHP50 AG005134]; Alzheimer's Research UK [ARUK-SPG2013-1]; Alzheimer's Society [ALZSOC-PhD-2013-020]; Wellcome Trust FX This work was partially funded by the "Enable Grant" kindly awarded by the Technology Transfer Office (TTO) (Dr. Andre Catana) of the Ecole Polytechnique Federale de Lausanne (EPFL), the Biomedizin-Naturwissenschaft-Forschung (BNF) program from the University of Bern, Switzerland, internal funding of the EPFL, and the Roland Bailly Foundation (Geneva, Switzerland). The authors thank Mrs. Maria Anna Lauricella (Eurogentec SA, Liege, Belgium) for the technical expertise and support in antibody development, and Prof. Hilal Lashuel, Laboratory of Molecular Neurobiology and Neuroproteomics (LMNN, EPFL), for kindly providing us with A beta 40/42 peptides. They thank Dr. Adam Swetloff (TTO, EPFL) for constructive discussions on the project. They are grateful to Dr. Bernard Schneider, Neurodegenerative Disease Laboratory (LEN, EPFL), for providing and helping us with APP-Swe/Arc mutant cell cultures and 5xFAD transgenic mouse tissue as well as Mr. Philippe Colin (LEN, EPFL) for his technical support in mouse tissue preparations. Immunohistochemistry and human brain sample preparation was supported by the Massachusetts Alzheimer Disease Research Center (NIHP50 AG005134). Array tomography was partially funded by Alzheimer's Research UK (ARUK-SPG2013-1), the Alzheimer's Society (ALZSOC-PhD-2013-020), and a Wellcome Trust Institutional Strategic Support Fund grant. NR 49 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 1552-5260 EI 1552-5279 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD SEP PY 2016 VL 12 IS 9 BP 996 EP 1013 DI 10.1016/j.jalz.2016.03.011 PG 18 WC Clinical Neurology SC Neurosciences & Neurology GA DV8VT UT WOS:000383215500007 PM 27130892 ER PT J AU Stillman, AE Gatsonis, C Lima, JAC Black, WC Cormack, J Gareen, I Hoffmann, U Liu, T Mavromatis, K Schnall, MD Udelson, JE Woodard, PK AF Stillman, Arthur E. Gatsonis, Constantine Lima, Joao A. C. Black, William C. Cormack, Jean Gareen, Ilana Hoffmann, Udo Liu, Tao Mavromatis, Kreton Schnall, Mitchell D. Udelson, James E. Woodard, Pamela K. TI Rationale and design of the Randomized Evaluation of patients with Stable angina Comparing Utilization of noninvasive Examinations (RESCUE) trial SO AMERICAN HEART JOURNAL LA English DT Article ID CORONARY-ARTERY-DISEASE; QUALITY-OF-LIFE; MYOCARDIAL-PERFUSION; COMPUTED-TOMOGRAPHY; DIAGNOSTIC-ACCURACY; ANGIOGRAPHY; RECLASSIFICATION; QUESTIONNAIRE; PECTORIS; PCI AB RESCUE is a phase III, randomized, controlled, multicenter, comparative efficacy study, designed to compare two diagnostic imaging/treatment paradigms that use coronary computed tomography angiography (CCTA) or single photon emission computed tomography myocardial perfusion imaging (SPECT MPI) for assisting in the diagnosis of ischemic heart disease in patients with stable angina symptoms, and guiding subsequent treatment. The study is based on the hypothesis that CCTA as a diagnostic tool is associated with no increase in cardiac risk, decreased cost, and reduced radiation exposure compared with SPECT MPI. The RESCUE trial was funded by the Agency for Healthcare Research and Quality (AHRQ) and the American College of Radiology Imaging Network (ACRIN) Fund for Imaging Innovation, began in 2011, and completed in 2014. C1 [Stillman, Arthur E.] Emory Univ, Dept Radiol & Imaging Sci, 1365 Clifton Rd NE Atlanta, Atlanta, GA 30322 USA. [Stillman, Arthur E.; Mavromatis, Kreton] Emory Univ, Div Cardiol, Atlanta, GA 30322 USA. [Gatsonis, Constantine; Cormack, Jean; Gareen, Ilana; Liu, Tao] Brown Univ, Ctr Stat Sci, Providence, RI 02912 USA. [Gatsonis, Constantine; Liu, Tao] Brown Univ, Dept Biostat, Sch Publ Hlth, Providence, RI 02912 USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Black, William C.] Dartmouth Hitchcock Med Ctr, Dept Radiol, Lebanon, NH 03766 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Schnall, Mitchell D.] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Udelson, James E.] Tufts Univ New England Med Ctr, Div Cardiol, Boston, MA USA. [Woodard, Pamela K.] Washington Univ, Dept Radiol, Mallinckrodt Inst Radiol, St Louis, MO USA. [Gareen, Ilana] Brown Univ, Sch Publ Health, Dept Epidemiol, Providence, RI 02912 USA. RP Stillman, AE (reprint author), Emory Univ, Dept Radiol & Imaging Sci, 1365 Clifton Rd NE Atlanta, Atlanta, GA 30322 USA. EM aestill@emory.edu NR 27 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD SEP PY 2016 VL 179 BP 19 EP 28 DI 10.1016/j.ahj.2016.06.003 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DV7JL UT WOS:000383112100003 PM 27595676 ER PT J AU Shah, R Hellkamp, A Lokhnygina, Y Becker, RC Berkowitz, SD Breithardt, G Backe, W Halperin, JL Hankey, GJ Fox, KAA Nessel, CC Mahaffey, KW Piccini, JP Singer, DE Patel, MR AF Shah, Rohan Hellkamp, Anne Lokhnygina, Yuliya Becker, Richard C. Berkowitz, Scott D. Breithardt, Guenter Backe, Werner Halperin, Jonathan L. Hankey, Graeme J. Fox, Keith A. A. Nessel, Christopher C. Mahaffey, Kenneth W. Piccini, Jonathan P. Singer, Daniel E. Patel, Manesh R. CA ROCKET AF Steering Comm Investigat TI Use of concomitant aspirin in patients with atrial fibrillation: Findings from the ROCKET AF trial SO AMERICAN HEART JOURNAL LA English DT Article ID STROKE SEVERITY; WARFARIN; RISK; RIVAROXABAN; CLOPIDOGREL; INTENSITY; THERAPY AB Background We aimed to investigate the relationship between aspirin use and clinical outcomes in patients enrolled in Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), in particular, those with known coronary artery disease (CAD). Methods Patients in ROCKET AF, comparing rivaroxaban and warfarin, were analyzed. Aspirin use was assessed at baseline. Stroke and systemic embolism, myocardial infarction, death, and major or nonmajor clinically relevant (NMCR) bleeding were compared between groups. Multivariable modeling was done adjusting for baseline risk factors. Results A total of 5,205 (36.5%) patients were receiving aspirin at baseline (mean dose 99.2 mg); 30.6% of those had known CAD. Patients receiving aspirin were more likely to have prior myocardial infarction (22% vs 14%; P <.001) and heart failure (68% vs 59%; P <.001). Relative efficacy of rivaroxaban versus warfarin was similar with and without aspirin use for both stroke/systemic embolism (P =.95 for interaction), and major or NMCR bleeding (P =.76 for interaction). After adjustment, aspirin use was associated with similar rates of stroke/systemic embolism (hazard ratio [HR] 1.16, 95% CI 0.98-1.37; P =.094) but higher rates of all-cause death (HR 1.27, 95% CI 1.13-1.42; P <.0001) and major or NMCR bleeding (HR 1.32, 95% CI 1.21-1.43; P <.0001). There was a significant interaction between no CAD at baseline and aspirin for all-cause death (P =.009). Conclusions Aspirin use at baseline was associated with an increased risk for bleeding and all-cause death in ROCKET AF, a risk most pronounced in patients without known CAD. Although these findings may reflect unmeasured clinical factors, further investigation is warranted to determine optimal aspirin use in patients with AF. C1 [Shah, Rohan; Hellkamp, Anne; Lokhnygina, Yuliya; Piccini, Jonathan P.; Patel, Manesh R.] Duke Clin Res Inst, Durham, NC USA. [Becker, Richard C.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Berkowitz, Scott D.] Bayer HealthCare Pharmaceut, Whippany, NJ USA. [Breithardt, Guenter] Hosp Univ Munster, Dept Cardiovasc Med, Munster, Germany. [Backe, Werner] Heidelberg Univ, Heidelberg, Germany. [Halperin, Jonathan L.] Mt Sinai Med Ctr, Cardiovasc Inst, New York, NY 10029 USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Crawley, Australia. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. [Nessel, Christopher C.] Janssen Res & Dev LLC, Raritan, NJ USA. [Mahaffey, Kenneth W.] Stanford Univ, Sch Med, Stanford, CA USA. [Piccini, Jonathan P.] Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Med Sch, Boston, MA USA. RP Patel, MR (reprint author), Duke Univ, Duke Clin Res Inst, Med Ctr, POB 17969,2400 Pratt St, Durham, NC 27715 USA. EM manesh.patel@duke.edu RI Hankey, Graeme /H-4968-2014 OI Hankey, Graeme /0000-0002-6044-7328 FU Janssen Research & Development LLC, Raritan, NJ; Bayer HealthCare AG, Leverkusen, Germany FX This work was supported by Janssen Research & Development LLC, Raritan, NJ, and Bayer HealthCare AG, Leverkusen, Germany. NR 11 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD SEP PY 2016 VL 179 BP 77 EP 86 DI 10.1016/j.ahj.2016.05.019 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DV7JL UT WOS:000383112100009 PM 27595682 ER PT J AU Tanguturi, VK Wasfy, JH AF Tanguturi, Varsha K. Wasfy, Jason H. TI Hospital readmissions after percutaneous coronary intervention aredeclining, but caution ahead is needed SO AMERICAN HEART JOURNAL LA English DT Editorial Material ID SHORT-TERM READMISSION; 30-DAY READMISSION; HEALTH; RATES; PREDICTION; THERAPY; PROGRAM; CARE; PCI C1 [Tanguturi, Varsha K.; Wasfy, Jason H.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA USA. RP Wasfy, JH (reprint author), Massachusetts Gen Hosp, Div Cardiol, GRB 8-843,55 Fruit St, Boston, MA 02114 USA. EM jwasfy@mgh.harvard.edu NR 17 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD SEP PY 2016 VL 179 BP 192 EP 194 DI 10.1016/j.ahj.2016.06.022 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DV7JL UT WOS:000383112100023 PM 27595696 ER PT J AU Demirel, D Butler, KL Halic, T Sankaranarayanan, G Spindler, D Cao, C Petrusa, E Molina, M Jones, DB De, S deMoya, MA AF Demirel, Doga Butler, Kathryn L. Halic, Tansel Sankaranarayanan, Ganesh Spindler, David Cao, Caroline Petrusa, Emil Molina, Marcos Jones, Daniel B. De, Suvranu deMoya, Marc A. TI A hierarchical task analysis of cricothyroidotomy procedure for a virtual airway skills trainer simulator SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE Surgical education; Surgical simulator; Cricothyroidotomy; Cricothyroidotomy simulator ID LAPAROSCOPIC SURGERY; REALITY SIMULATION; EMERGENCY; INTUBATION AB BACKGROUND: Despite the critical importance of cricothyroidotomy (CCT) for patient in extremis, clinical experience with CCT is infrequent, and current training tools are inadequate. The long-term goal is to develop a virtual airway skills trainer that requires a thorough task analysis to determine the critical procedural steps, learning metrics, and parameters for assessment. METHODS: Hierarchical task analysis is performed to describe major tasks and subtasks for CCT. A rubric for performance scoring for each task was derived, and possible operative errors were identified. RESULTS: Time series analyses for 7 CCT videos were performed with 3 different observers. According to Pearson's correlation tests, 3 of the 7 major tasks had a strong correlation between their task times and performance scores. CONCLUSIONS: The task analysis forms the core of a proposed virtual CCT simulator, and highlights links between performance time and accuracy when teaching individual surgical steps of the procedure. (C) 2015 Elsevier Inc. All rights reserved. C1 [Demirel, Doga; Halic, Tansel] Univ Cent Arkansas, Dept Comp Sci, 201 Donaghey Ave, Conway, AR 72035 USA. [Butler, Kathryn L.; Petrusa, Emil; deMoya, Marc A.] Harvard Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Sankaranarayanan, Ganesh; De, Suvranu] Rensselaer Polytech Inst, Dept Mech Aerosp & Nucl Engn, Troy, NY USA. [Spindler, David; Cao, Caroline] Wright State Univ, Dept Biomed Ind & Human Factors Engn, Dayton, OH 45435 USA. [Molina, Marcos; Jones, Daniel B.] Harvard Sch Med, Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA USA. RP Halic, T (reprint author), Univ Cent Arkansas, Dept Comp Sci, 201 Donaghey Ave, Conway, AR 72035 USA. EM tanselh@uca.edu OI Sankaranarayanan, Ganesh/0000-0003-1556-2797 FU National Institutes of Health (NIH) [NIH/NHLBI 1R01HL119248-01A1, NIH/NIBIB 2R01EB005807, 5R01EB010037, 1R01EB009362, 1R01EB014305] FX Authors would like to thank Adam Ryason and Alexander Yu for their contributions in the study. This project was supported by National Institutes of Health (NIH) Grant NIH/NHLBI 1R01HL119248-01A1, NIH/NIBIB 2R01EB005807, 5R01EB010037, 1R01EB009362, and 1R01EB014305. NR 19 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 0002-9610 EI 1879-1883 J9 AM J SURG JI Am. J. Surg. PD SEP PY 2016 VL 212 IS 3 BP 475 EP 484 DI 10.1016/j.amjsurg.2015.08.029 PG 10 WC Surgery SC Surgery GA DU5ER UT WOS:000382235500018 PM 26590044 ER PT J AU Hassamal, S Miotto, K Wang, TS Saxon, AJ AF Hassamal, Sameer Miotto, Karen Wang, Tisha Saxon, Andrew J. TI A narrative review: The effects of opioids on sleep disordered breathing in chronic pain patients and methadone maintained patients SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Review ID MAINTENANCE TREATMENT; METABOLIC SYNDROME; HEART HEALTH; RISK-FACTOR; APNEA; THERAPY; SMOKING; PATHOPHYSIOLOGY; BUPRENORPHINE; REVERSAL AB Background and ObjectivesOpioids increase the risk for sleep disordered breathing (SDB), but there are few studies examining the prevalence and risk factors for SDB, specifically central sleep apnea (CSA), and obstructive sleep apnea (OSA) in chronic pain patients on opioids as well as methadone maintained patients (MMPs). MethodsA literature review was conducted in which SDB was confirmed by polysomnography (PSG) in chronic pain patients on opioids as well as patients with a diagnosis of an opioid use disorder or opioid dependence on methadone maintenance treatment (MMT). ResultsAbout 22 reports were included. Six were with MMPs, and 16 were with chronic pain patients on opioids. Among MMPs, the prevalence of SDB ranged from 42.3% to 70%; 0-60% had CSA and 10-35.2% had OSA. In chronic pain patients on opioids, the prevalence of SDB ranged from 71% to 100%; 17-80% had CSA and 20-39% had OSA. In MMPs, studies found a positive association between BMI, weight gain, duration of MMT, non-Caucasian race and the number of obstructive apneas, as well as blood methadone concentrations and the number of central apneas. In chronic pain patients on opioids, older age, higher BMI, male gender, and higher opioid doses predicted more obstructive apneas; older age, lower BMI, male gender, higher pain levels, higher benzodiazepine doses, and higher opioid doses predicted more central apneas. Conclusion and Scientific SignificanceCSA and OSA are common in MMPs and chronic pain patients on opioids. Among chronic pain patients, higher opioid doses appear to be a risk factor for CSA, and to a lesser extent OSA. Therefore, it is important for providers to screen these patient populations for SDB. (Am J Addict 2016;25:452-465) C1 [Hassamal, Sameer] UCLA Kern, Dept Addict Psychiat, 1700 Mt Vernon Ave, Bakersfield, CA 93306 USA. [Miotto, Karen] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Wang, Tisha] Univ Calif Los Angeles, David Geffen Sch Med, Div Pulm Crit Care & Sleep Med, Dept Med, Los Angeles, CA 90095 USA. [Saxon, Andrew J.] Vet Affairs Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, Seattle, WA USA. RP Hassamal, S (reprint author), UCLA Kern, Dept Addict Psychiat, 1700 Mt Vernon Ave, Bakersfield, CA 93306 USA. EM shassama@gmail.com NR 80 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 EI 1521-0391 J9 AM J ADDICTION JI Am. J. Addict. PD SEP PY 2016 VL 25 IS 6 BP 452 EP 465 DI 10.1111/ajad.12424 PG 14 WC Substance Abuse SC Substance Abuse GA DV9TB UT WOS:000383283800002 PM 27554389 ER PT J AU Marcovitz, DE McHugh, RK Volpe, J Votaw, V Connery, HS AF Marcovitz, David E. McHugh, R. Kathryn Volpe, Julie Votaw, Victoria Connery, Hilary S. TI Predictors of early dropout in outpatient buprenorphine/naloxone treatment SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID OPIOID-DEPENDENT YOUTH; QUALITY-OF-LIFE; PRIMARY-CARE; TREATMENT RETENTION; METHADONE-MAINTENANCE; NATIONAL-INSTITUTE; RANDOMIZED-TRIAL; HEROIN USERS; NALOXONE; MULTISITE AB Background and ObjectivesIdentifying predictors of early drop out from outpatient treatment of opioid use disorder (OUD) with buprenorphine/naloxone (BN) may improve care for subgroups requiring more intensive engagement to achieve stabilization. However, previous research on predictors of dropout among this population has yielded mixed results. The aim of the present study was to elucidate these mixed findings by simultaneously evaluating a range of putative risk factors that may predict dropout in BN maintenance treatment. MethodsOutpatient medical records and weekly supervised urine toxicology results were retrospectively reviewed for patients at two community psychiatric clinics (n=202): a private hospital clinic (n=84) and a federally qualified health center (n=118). A forward stepwise logistic regression was utilized to investigate the association between early dropout (i.e., discontinuing treatment or buprenorphine non-adherence within the first 3 months of clinic entry) and extracted sociodemographic, clinical, substance use, and treatment history variables. ResultsOverall, 56 of 202 participants (27.7%) dropped out of treatment. The multivariable analysis indicated that age under 25 (B=1.47, SEB = .52, p<.01) and opioid use in month 1 (B=1.50, SEB=.41, p<.001) were significantly associated with early dropout; those with a history of suicide attempt were significantly less likely to drop out (B=-1.44, SEB=.67, p<.05). Conclusions and Scientific SignificanceConsistent with previous research, younger age and use of opioids during the first month of treatment predicted early dropout. Having a history of prior suicide attempt was associated with 3-month BN treatment retention, which has not been previously reported. (Am J Addict 2016;25:472-477) C1 [Marcovitz, David E.; McHugh, R. Kathryn; Connery, Hilary S.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Marcovitz, David E.] Massachusetts Gen Hosp, McLean Adult Psychiat Residency, Boston, MA 02114 USA. [McHugh, R. Kathryn; Votaw, Victoria; Connery, Hilary S.] McLean Hosp, 115 Mill St, Belmont, MA 02178 USA. [Volpe, Julie] Community Hlth Serv, Hartford, CT USA. RP Marcovitz, DE (reprint author), Massachusetts Gen Hosp, 15 Parkman St,WACC 812, Boston, MA 02114 USA. EM dmarcovitz@partners.org FU Eleanor and Miles Shore Fellowship award (Harvard Medical School) FX In appreciation of support provided by The Eleanor and Miles Shore Fellowship award (Harvard Medical School) to HSC which contributed to the development of this integrated treatment model. NR 35 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 EI 1521-0391 J9 AM J ADDICTION JI Am. J. Addict. PD SEP PY 2016 VL 25 IS 6 BP 472 EP 477 DI 10.1111/ajad.12414 PG 6 WC Substance Abuse SC Substance Abuse GA DV9TB UT WOS:000383283800004 PM 27442456 ER PT J AU Newsome, H Mandapathil, M Koh, YW Duvvuri, U AF Newsome, Hillary Mandapathil, Magis Koh, Yoon Woo Duvvuri, Umamaheswar TI Utility of the Highly Articulated Flex Robotic System for Head and Neck Procedures: A Cadaveric Study SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE TORS; thyroid surgery; neck dissection; salivary gland; head and neck surgery ID TRANSORAL SURGERY; DISSECTION; CARCINOMA; CANCER AB Objective: Robotic head and neck surgery potentially reduces the morbidity associated with traditional open procedures. This study's goal was to employ a novel highly articulated robotic system (Flex Robotic System) for head and neck procedures, including a postauricular facelift approach thyroidectomy, submandibular gland (SMG) removal, and cervical lymphadenectomy. Study Design: It was hypothesized that the Medrobotics Flex Robotic System could be used for transcervical head and neck surgical procedures. Methods: Three fresh upper body human cadavers were used. The Flex Robotic System was used to complete a thyroidectomy, neck dissection, and SMG removal on each cadaver. Results: A postauricular incision and flap was manually raised. The robotic system was positioned on the right side of the cadaver's head. The system's manually controlled flexible instruments and highly shapeable, robot-assisted scope were used to perform a thyroid lobectomy. Neck dissection and SMG removal were also performed. Conclusions: Although a promising technology, the current robotic system (Intuitive Surgical Inc, Sunnyvale, California, USA) has limitations due to its rigid and large configuration, which decreases exposure and access. The new system's shapeable, computer-assisted scope seeks to reduce some of these difficulties and may be better adapted for transcervical approaches to the neck operations. C1 [Newsome, Hillary; Duvvuri, Umamaheswar] Univ Pittsburgh, Med Ctr, Vet Affairs Pittsburgh Hlth Syst, UPMC Dept Otolaryngol Head & Neck Surg, Pittsburgh, PA USA. [Mandapathil, Magis] Univ Marburg, Dept Otorhinolaryngol Head & Neck Surg, Baldingerstr, Marburg, Germany. [Koh, Yoon Woo] Yonsei Univ, Dept Otorhinolaryngol, Severance Hosp, Seoul, South Korea. RP Duvvuri, U (reprint author), Univ Pittsburgh, Med Ctr, Inst Eye & Ear, Vet Affairs Pittsburgh Hlth Syst,Dept Otolaryngol, Suite 500,200 Lothrop St, Pittsburgh, PA 15213 USA. EM duvvuriu@upmc.edu FU BLR&D Career Development Award; PNC Foundation FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded in part by funds from BLR&D Career Development Award and the PNC Foundation (U.D.) NR 16 TC 0 Z9 0 U1 4 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0003-4894 EI 1943-572X J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD SEP PY 2016 VL 125 IS 9 BP 758 EP 763 DI 10.1177/0003489416653409 PG 6 WC Otorhinolaryngology SC Otorhinolaryngology GA DU4XS UT WOS:000382216900010 PM 27287677 ER PT J AU Swanson, EW Miller, DT Susarla, SM Lopez, J Lough, DM May, JW Redett, RJ AF Swanson, Edward W. Miller, Devin T. Susarla, Srinivas M. Lopez, Joseph Lough, Denver M. May, James W., Jr. Redett, Richard J. TI What Effect Does Self-Citation Have on Bibliometric Measures in Academic Plastic Surgery? SO ANNALS OF PLASTIC SURGERY LA English DT Article DE bibliometrics; self-citation; citation; academic plastic surgery; Hirsch index; h-index ID H-INDEX; UNITED-STATES; IMPACT FACTOR; SCHOLARLY PRODUCTIVITY; GENDER DISPARITIES; JOURNALS; OTOLARYNGOLOGY; PUBLICATION; DEPARTMENTS; ANESTHESIA AB Background: Research productivity plays a significant role in academic promotions. Currently, various bibliometric measures utilizing citation counts are used to judge an author's work. With increasing numbers of journals, numbers of open access publications, ease of online submission, and expedited indexing of accepted manuscripts, it is plausible that an author could influence his/her own bibliometric measures through self-citation. The purpose of this study was to determine the impact of self-citation in academic plastic surgery. Methods: A cohort of full-time academic plastic surgeons was identified from 9 U.S. plastic surgery training programs. For all included faculty, academic rank was retrieved from department/division websites, and bibliometric measures were assessed using a subscription bibliographic citation database (Scopus, Reed Elsevier, London, UK). Bibliometric measures included the Hirsch index (h-index, the number of publications h which are cited >= h times), total number of publications, and total number of citations. The h-index and total number of citations were collected with and without self-citations. Percent changes in the h-index and total citations were calculated after removal of self-citations and compared across academic ranks and levels of research productivity (total publications, h-index, and total citations). Results: The study cohort consisted of 169 full-time academic plastic surgeons. The h-index and total citations experienced decreases of 2.8 +/- 5.0% (P < 0.0001) and 4.5 +/- 4.6% (P < 0.0001), respectively, after correction for self-citation. More than half of the cohort (n = 113, 67%) did not experience a change in the h-index after removal of self-citations. These decreases did not vary across academic rank. Surgeons who self-cited at rates greater than 5% were 9.8 times more likely (95% confidence interval, 4.5-21.9; P < 0.001) to have their h-index change as a result of self-citation (after adjusting for academic rank). There were weak correlations between percent decreases in the h-index and total citations and various biblimoteric measures (total publications, h-index, total citations; r < 0.32). Conclusions: Self-citation has a minor impact on common bibliometric measures in academic plastic surgery. The influence of self-citation is consistent across academic ranks and increasing levels of bibliometric measures, suggesting that authors are not manipulating the system with increasing experience. C1 [Swanson, Edward W.; Miller, Devin T.; Susarla, Srinivas M.; Lopez, Joseph; Lough, Denver M.; Redett, Richard J.] Johns Hopkins Univ, Sch Med, Dept Plast & Reconstruct Surg, Baltimore, MD USA. [May, James W., Jr.] Massachusetts Gen Hosp, Dept Surg, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. RP Redett, RJ (reprint author), Johns Hopkins Childrens Ctr, 1800 Orleans St,Bloomberg 7314A, Baltimore, MD 21281 USA. EM rredett@jhu.edu OI Susarla, Srinivas/0000-0003-0155-8260 NR 31 TC 3 Z9 3 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0148-7043 EI 1536-3708 J9 ANN PLAS SURG JI Ann. Plast. Surg. PD SEP PY 2016 VL 77 IS 3 BP 350 EP 353 DI 10.1097/SAP.0000000000000585 PG 4 WC Surgery SC Surgery GA DU5JX UT WOS:000382249100019 PM 26101989 ER PT J AU Gapen, M van der Kolk, BA Hamlin, E Hirshberg, L Suvak, M Spinazzola, J AF Gapen, Mark van der Kolk, Bessel A. Hamlin, Ed. Hirshberg, Laurence Suvak, Michael Spinazzola, Joseph TI A Pilot Study of Neurofeedback for Chronic PTSD SO APPLIED PSYCHOPHYSIOLOGY AND BIOFEEDBACK LA English DT Article DE EEG biofeedback; Neurofeedback; Treatment outcome; Posttraumatic stress disorder; Complex trauma ID POSTTRAUMATIC-STRESS-DISORDER; SCRIPT-DRIVEN IMAGERY; PSYCHOLOGICAL TREATMENTS; DEPRESSIVE SYMPTOMS; MULTILEVEL MODELS; EEG-NEUROFEEDBACK; DOUBLE-BLIND; METAANALYSIS; MEDIATION; CHILDREN AB EEG Biofeedback (also known as neurofeedback) has been in use as a clinical intervention for well over 30 years; however, it has made very little impact on clinical care. One reason for this has been the difficulty in designing research to measure clinical change in the real world. While substantial evidence exists for its efficacy in treating attention deficit/hyperactivity disorder, relatively little evidence exists for its utility in other disorders including posttraumatic stress disorder (PTSD). The current study represents a "proof-of-concept" pilot for the use of neurofeedback with multiply-traumatized individuals with treatment-resistant PTSD. Participants completed 40 sessions of neurofeedback training two times per week with sensors randomly assigned (by the study coordinator, who was not blind to condition) to sensor placements of either T4-P4 or T3-T4. We found that neurofeedback significantly reduced PTSD symptoms (Davidson Trauma Scale scores averaged 69.14 at baseline to 49.26 at termination), and preceded gains in affect regulation (Inventory of Altered Self-Capacities-Affect Dysregulation scores averaged 23.63 at baseline to 17.20 at termination). We discuss a roadmap for future research. C1 [Gapen, Mark; van der Kolk, Bessel A.; Spinazzola, Joseph] JRI, Ctr Trauma, 1269 Beacon St, Brookline, MA 02446 USA. [Gapen, Mark] Community Serv Inst Inc, 1695 Main St, Springfield, MA 01103 USA. [van der Kolk, Bessel A.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [van der Kolk, Bessel A.; Spinazzola, Joseph] Natl Child Traumat Stress Network, Durham, NC USA. [Hamlin, Ed.] Inst Appl Neurosci, Ctr Adv Human Potential, 31 Coll Pl,Bldg B,Suite 218, Asheville, NC 28801 USA. [Hamlin, Ed.] Western Carolina Univ, Dept Psychol, Cullowhee, NC 28723 USA. [Hamlin, Ed.] Univ N Carolina, Dept Psychiat, Sch Med, Chapel Hill, NC USA. [Suvak, Michael] Natl Ctr PTSD, Boston, MA USA. [Suvak, Michael] Suffolk Univ, Dept Psychol, Boston, MA 02114 USA. [Hirshberg, Laurence] NeuroDev Ctr, Providence, RI USA. [Hirshberg, Laurence] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. RP Gapen, M (reprint author), JRI, Ctr Trauma, 1269 Beacon St, Brookline, MA 02446 USA.; Gapen, M (reprint author), Community Serv Inst Inc, 1695 Main St, Springfield, MA 01103 USA. EM mark.gapen@gmail.com OI Gapen, Mark/0000-0002-2562-1108 FU ANS Foundation FX Richard Jacobson, Ilya Yacevich, Regina Musicaro, Marla Zucker Ph.D., Hilary Hogdon Ph.D., Janice Stubblefield. This study was supported by a Grant from the ANS Foundation. NR 47 TC 0 Z9 0 U1 11 U2 11 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-0586 EI 1573-3270 J9 APPL PSYCHOPHYS BIOF JI Appl. Psychophysiol. Biofeedback PD SEP PY 2016 VL 41 IS 3 BP 251 EP 261 DI 10.1007/s10484-015-9326-5 PG 11 WC Psychology, Clinical SC Psychology GA DU2AK UT WOS:000382012400001 PM 26782083 ER PT J AU Waterman, BR Chandler, PJ Teague, E Provencher, MT Tokish, JM Pallis, MP AF Waterman, Brian R. Chandler, Philip J. Teague, Edward Provencher, Matthew T. Tokish, John M. Pallis, Mark P. TI Short-Term Outcomes of Glenoid Bone Block Augmentation for Complex Anterior Shoulder Instability in a High-Risk Population SO ARTHROSCOPY-THE JOURNAL OF ARTHROSCOPIC AND RELATED SURGERY LA English DT Article ID LATARJET PROCEDURE; NEUROLOGIC COMPLICATIONS; SUPRASCAPULAR NERVE; HOSPITAL VOLUME; BANKART REPAIR; UNITED-STATES; BRISTOW; DISLOCATION; STABILIZATION; SURGERY AB Purpose: To describe the short-term clinical outcomes of glenoid bone block augmentation in a high-demand population, as well as to describe its clinical success and complications at greater than 2 years' follow-up in an at-risk military population. Methods: All patients undergoing anterior capsulorrhaphy with coracoid process transfer or anterior bone block augmentation (Current Procedural Terminology code 23662 or 23460) for shoulder instability between 2006 and 2012 were isolated from the Military Health System Management Analysis and Reporting Tool. Demographic and occupational parameters were identified, and multiple surgical factors and clinical outcomes were extracted from the medical record and US Defense Manpower Data Center. Results: A total of 64 service members (65 shoulders) underwent anterior bone block procedures, including coracoid transfer (n = 59, 90.8%), distal tibial allograft (n = 3, 4.6%), and autologous or allograft iliac crest bone graft (n = 3, 4.6%). This group was predominately comprised of men (n = 59), and the mean age was 25.9 years (range, 19 to 45 years). A total of 19 perioperative complications, including 8 neurologic injuries, 6 infections, and 4 hardware failures, occurred in 16 patients (25%). At a mean 2.4-year follow-up, 21 patients (32.8%) reported persistent shoulder pain and 15 patients (23.4%) disclosed subjective apprehension or recurrent instability. Secondary surgical procedures were performed in 12 patients (18.8%), including 4 revisions (6.3%). Ultimately, 20 patients (31.3%) underwent a medical discharge for persistent shoulder disability. Univariate analysis showed that the presence of a perioperative complication (P = .049) and tobacco use (P = .038) were associated with increased risk of subsequent surgical failure. Conclusions: Anterior glenoid bone block procedures for shoulder instability with concomitant bone loss enable a return to high-demand physical function. The short-term complication profile (25%), recurrence rate (23%), and persistence of shoulder pain (33%) should be emphasized during preoperative counseling, particularly in an active military population and revision setting. Although moderately successful in the military, anterior bone block procedures for complex shoulder instability can be associated with significant short-term complications and morbidity. Level of Evidence: Level IV, therapeutic case series. C1 [Waterman, Brian R.; Chandler, Philip J.; Pallis, Mark P.] William Beaumont Army Med Ctr, Dept Orthopaed Surg & Rehabil, El Paso, TX 79920 USA. [Teague, Edward] US Mil Acad, Dept Math, West Point, NY 10996 USA. [Provencher, Matthew T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tokish, John M.] Tripler Army Med Ctr, Honolulu, HI 96859 USA. RP Waterman, BR (reprint author), William Beaumont Army Med Ctr, Orthopaed Surg Serv, 5005 N Piedras St, El Paso, TX 79920 USA. EM brian.r.waterman@gmail.com FU Joint Restoration Foundation; AAOS; AOSSM; ASES; Arthroscopy; AANA; ISAKOS; Knee; Orthopedics; San Diego Shoulder Institute; SLACK; SOMOS; Arthrex; DePuy; Mitek; JSES; Orthopedics Today; Johnson Johnson FX The authors report the following potential conflict of interest or source of funding: M.T.P. receives support from Joint Restoration Foundation (Allo-source), AAOS, AOSSM, ASES, Arthroscopy, AANA, ISAKOS, Knee, Orthopedics, San Diego Shoulder Institute, SLACK, SOMOS, and Arthrex. J.M.T. receives support from DePuy, Mitek, AANA, JSES, Orthopedics Today, and Johnson & Johnson. M.P. receives support from AAOS, AANA, SOMOS, and Johnson & Johnson. NR 37 TC 4 Z9 4 U1 2 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0749-8063 EI 1526-3231 J9 ARTHROSCOPY JI Arthroscopy PD SEP PY 2016 VL 32 IS 9 BP 1784 EP 1790 DI 10.1016/j.arthro.2016.01.051 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DV9PB UT WOS:000383272200011 PM 27132776 ER PT J AU Farvid, MS Cho, EY Eliassen, AH Chen, WY Willett, WC AF Farvid, Maryam S. Cho, Eunyoung Eliassen, A. Heather Chen, Wendy Y. Willett, Walter C. TI Lifetime grain consumption and breast cancer risk SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Whole grain foods; Refined grain foods; Breast cancer ID DOSE-RESPONSE METAANALYSIS; WHOLE-GRAIN; PROSPECTIVE COHORT; ADOLESCENT DIET; CHRONIC DISEASE; EARLY ADULTHOOD; US MEN; WOMEN; FOODS; REPRODUCIBILITY AB We evaluated individual grain-containing foods and whole and refined grain intake during adolescence, early adulthood, and premenopausal years in relation to breast cancer risk in the Nurses' Health Study II. Grain-containing food intakes were reported on a baseline dietary questionnaire (1991) and every 4 years thereafter. Among 90,516 premenopausal women aged 27-44 years, we prospectively identified 3235 invasive breast cancer cases during follow-up to 2013. 44,263 women reported their diet during high school, and from 1998 to 2013, 1347 breast cancer cases were identified among these women. Cox proportional hazards regression was used to estimate relative risks (RR) and 95 % confidence intervals (95 % CI) of breast cancer for individual, whole and refined grain foods. After adjusting for known breast cancer risk factors, adult intake of whole grain foods was associated with lower premenopausal breast cancer risk (highest vs. lowest quintile: RR 0.82; 95 % CI 0.70-0.97; P (trend) = 0.03), but not postmenopausal breast cancer. This association was no longer significant after further adjustment for fiber intake. The average of adolescent and early adulthood whole grain food intake was suggestively associated with lower premenopausal breast cancer risk (highest vs lowest quintile: RR 0.74; 95 % CI 0.56-0.99; P (trend) = 0.09). Total refined grain food intake was not associated with risk of breast cancer. Most individual grain-containing foods were not associated with breast cancer risk. The exceptions were adult brown rice which was associated with lower risk of overall and premenopausal breast cancer (for each 2 servings/week: RR 0.94; 95 % CI 0.89-0.99 and RR 0.91; 95 % CI 0.85-0.99, respectively) and adult white bread intake which was associated with increased overall breast cancer risk (for each 2 servings/week: RR 1.02; 95 % CI 1.01-1.04), as well as breast cancer before and after menopause. Further, pasta intake was inversely associated with overall breast cancer risk. Our results suggest that high whole grain food intake may be associated with lower breast cancer risk before menopause. Fiber in whole grain foods may mediate the association with whole grains. C1 [Farvid, Maryam S.; Willett, Walter C.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Farvid, Maryam S.] Massachusetts Gen Hosp, Harvard MGH Ctr Genom Vulnerable Populat & Hlth D, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Cho, Eunyoung; Eliassen, A. Heather; Chen, Wendy Y.; Willett, Walter C.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Cho, Eunyoung; Eliassen, A. Heather; Chen, Wendy Y.; Willett, Walter C.] Harvard Med Sch, Boston, MA USA. [Cho, Eunyoung] Brown Univ, Warren Alpert Med Sch, Dept Dermatol, Providence, RI 02912 USA. [Cho, Eunyoung] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA. [Eliassen, A. Heather; Willett, Walter C.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Chen, Wendy Y.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Farvid, MS (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.; Farvid, MS (reprint author), Massachusetts Gen Hosp, Harvard MGH Ctr Genom Vulnerable Populat & Hlth D, Mongan Inst Hlth Policy, Boston, MA 02114 USA. EM mfarvid@hsph.harvard.edu FU National Institutes of Health [R01 CA050385, UM1 CA176726]; Breast Cancer Research Foundation FX The study was supported by the National Institutes of Health Grants (R01 CA050385, UM1 CA176726) and a grant from The Breast Cancer Research Foundation. The study sponsors were not involved in the study design and collection, analysis and interpretation of data, or the writing of the article or the decision to submit it for publication. The authors were independent from study sponsors. We would like to thank the participants and staff of the NHSII 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, WY. The authors' responsibility were as follows: MSF, EC, WYC, AHE, and WCW designed the research; MSF performed the analysis and wrote the manuscript; MSF and WCW had primary responsibility for the final content of the manuscript; and all authors provided critical input in the writing of the manuscript and read and approved the final manuscript. The authors assume full responsibility for analyses and interpretation of these data. NR 27 TC 0 Z9 0 U1 8 U2 8 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 SEP PY 2016 VL 159 IS 2 BP 335 EP 345 DI 10.1007/s10549-016-3910-0 PG 11 WC Oncology SC Oncology GA DV5TE UT WOS:000382991500013 PM 27510186 ER PT J AU Tucker-Seeley, RD Bezold, CP James, P Miller, M Wallington, SF AF Tucker-Seeley, Reginald D. Bezold, Carla P. James, Peter Miller, Melecia Wallington, Sherrie F. TI Retail Pharmacy Policy to End the Sale of Tobacco Products: What Is the Impact on Disparity in Neighborhood Density of Tobacco Outlets? SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID UNITED-STATES; CIGARETTE-SMOKING; NEW-YORK; ALCOHOL-CONSUMPTION; US PHARMACIES; LIQUOR STORES; DEMOGRAPHICS; ENVIRONMENT; LEVEL; AVAILABILITY AB Background: Population-level research on the implications of retail pharmacy policies to end the sale of tobacco products is scant, and the impact of such policies on racial/ethnic and socioeconomic disparities across neighborhoods in access to tobacco products remains unexplored. Methods: We investigated the association between neighborhood sociodemographic characteristics and tobacco retail density in Rhode Island (RI; N = 240 census tracts). We also investigated whether the CVS Health (N = 60) policy to end the sale of tobacco products reduces the disparity in the density of tobacco retail across neighborhoods, and we conducted a prospective policy analysis to determine whether a similar policy change in all pharmacies in RI (N = 135) would reduce the disparity in tobacco retail density. Results: The results revealed statistically significant associations between neighborhood sociodemographic characteristics and tobacco retail outlet density across RI neighborhoods. The results when excluding the CVS Health locations, as well as all pharmacies as tobacco retailers, revealed no change in the pattern for this association. Conclusions: The results of this study suggest that while a commendable tobacco control policy, the CVS Health policy appears to have no impact on the neighborhood racial/ethnic and socioeconomic disparities in the density of tobacco retailers in RI. Prospective policy analyses showed no impact on this disparity even if all other pharmacies in the state adopted a similar policy. Impact: Policy efforts aimed at reducing the disparity in access to tobacco products should focus on reducing the density of tobacco outlets in poor and racial/ethnic neighborhoods. (C) 2016 AACR. C1 [Tucker-Seeley, Reginald D.; Miller, Melecia] Dana Farber Canc Inst, Ctr Community Based Res, 450 Brookline Ave,LW 743, Boston, MA 02115 USA. [Tucker-Seeley, Reginald D.] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Bezold, Carla P.; James, Peter] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [James, Peter] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Wallington, Sherrie F.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. RP Tucker-Seeley, RD (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 450 Brookline Ave,LW 743, Boston, MA 02115 USA.; Tucker-Seeley, RD (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. EM retucker@hsph.harvard.edu FU NCI K01 Career Development Grant [K01 CA169041, K01 CA155417]; NIH training grant [T32ES007069]; Harvard NHLBI Cardiovascular Epidemiology Training Grant [T32 HL098048] FX R.D. Tucker-Seeley was supported by an NCI K01 Career Development Grant (K01 CA169041). C.P. Bezold was supported by an NIH training grant (T32ES007069). P. James was supported by the Harvard NHLBI Cardiovascular Epidemiology Training Grant (T32 HL098048). S.F. Wallington was supported by an NCI K01 Career Development Grant (K01 CA155417). NR 57 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2016 VL 25 IS 9 BP 1305 EP 1310 DI 10.1158/1055-9965.EPI-15-1234 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DV6KO UT WOS:000383044500004 PM 27302724 ER PT J AU Calo, WA Gilkey, MB Shah, PD Moss, JL Brewer, NT AF Calo, William A. Gilkey, Melissa B. Shah, Parth D. Moss, Jennifer L. Brewer, Noel T. TI Parents' Support for School-Entry Requirements for Human Papillomavirus Vaccination: A National Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID MANDATORY HPV VACCINATION; UNITED-STATES; ADOLESCENT IMMUNIZATION; NONMEDICAL EXEMPTIONS; ADVISORY-COMMITTEE; PUBLIC-HEALTH; LAWS; POLICY; RECOMMENDATIONS; CONTROVERSY AB Background: The number of states proposing school-entry requirements for human papillomavirus (HPV) vaccination has increased over the last decade. However, data are currently limited regarding parents' support of such laws. We sought to obtain the first national estimates of parents' support of HPV vaccination school-entry requirements. Methods: A national sample of 1,501 parents of 11- to 17-year-old children completed a web-based survey between November 2014 and January 2015. Analyses used multivariable logistic regression to assess correlates of support for school-entry requirements for HPV vaccination. Results: Overall, 21% of parents agreed that laws requiring HPV vaccination for school attendance "are a good idea," and 54% disagreed. If school-entry requirements included opt-out provisions, agreement increased to 57%, and only 21% disagreed. Parents more often agreed with requirements without opt-out provisions if they were Hispanic [OR = 1.53; 95% confidence interval (CI), 1.05-2.22], believed HPV vaccine was as or more important than other adolescent vaccines (OR = 2.76; 95% CI, 1.98-3.83), or believed HPV vaccine was effective for preventing cervical cancer (OR = 2.55; 95% CI, 1.93-3.37). Parents less often agreed if they resided in Midwest states or believed that HPV vaccine was being pushed to make money for drug companies (both P < 0.05). Conclusion: Opt-out provisions almost tripled parents' support for HPV vaccine school-entry requirements. Our findings suggest that race/ethnicity, attitudes about HPV vaccine, and region of residence may influence support for requirements without opt-out provisions. Impact: Opt-out provisions greatly increase parent support of school-entry requirements for HPV vaccination but may make them ineffective. (C) 2016 AACR. C1 [Calo, William A.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Policy & Management, Chapel Hill, NC USA. [Gilkey, Melissa B.] Harvard Med Sch, Dept Populat Med, Boston, MA USA. [Gilkey, Melissa B.] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Gilkey, Melissa B.] Dana Farber Harvard Canc Ctr, Boston, MA USA. [Shah, Parth D.; Moss, Jennifer L.; Brewer, Noel T.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Behav, 325A Rosenau Hall,CB 7440, Chapel Hill, NC 27599 USA. [Moss, Jennifer L.] NCI, Div Canc Prevent, Bethesda, MD 20892 USA. [Brewer, Noel T.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. RP Brewer, NT (reprint author), Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Behav, 325A Rosenau Hall,CB 7440, Chapel Hill, NC 27599 USA. EM ntb@unc.edu FU Merck Sharp & Dohme Investigator Studies Program [50928]; National Cancer Institute [R25 CA116339, K22 CA186979, F31 CA189411] FX This study was funded by Merck Sharp & Dohme Investigator Studies Program, grant #50928 (to N.T. Brewer). This study was also supported by career development or training grants from the National Cancer Institute: R25 CA116339 (to W.A. Calo), K22 CA186979 (to M.B. Gilkey), and F31 CA189411 (to J.L. Moss). NR 52 TC 1 Z9 1 U1 10 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2016 VL 25 IS 9 BP 1317 EP 1325 DI 10.1158/1055-9965.EPI-15-1159 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DV6KO UT WOS:000383044500006 PM 27543621 ER PT J AU Warner, ET Hu, R Collins, LC Beck, AH Schnitt, S Rosner, B Eliassen, AH Michels, KB Willett, WC Tamimi, RM AF Warner, Erica T. Hu, Rong Collins, Laura C. Beck, Andrew H. Schnitt, Stuart Rosner, Bernard Eliassen, A. Heather Michels, Karin B. Willett, Walter C. Tamimi, Rulla M. TI Height and Body Size in Childhood, Adolescence, and Young Adulthood and Breast Cancer Risk According to Molecular Subtype in the Nurses' Health Studies SO CANCER PREVENTION RESEARCH LA English DT Article ID GENOME-WIDE ASSOCIATION; FRENCH E3N COHORT; BINDING-PROTEIN 3; GROWTH-FACTOR 1; COMPETING RISKS; EARLY-LIFE; WOMEN; AGE; PREVENTION; SURVIVAL AB Height and body size in childhood and young adulthood have been consistently associated with breast cancer risk; whether associations differ across molecular subtypes is unclear. In a pooled analysis of the Nurses' Health Studies, we prospectively examined the association of four exposures: height, body mass index (BMI) at the age of 18 years, childhood and adolescent somatotypes, with breast cancer risk according to molecular subtypes defined by immunohistochemical markers. We used multivariable-adjusted Cox proportional hazards regression to estimate HRs and 95% confidence intervals (CI). We identified 2,983 luminal A, 1,281 luminal B, 318 HER2-enriched, 408 basal-like, and 128 unclassified tumors. Height was positively associated with all subtypes (P-heterogeneity = 0.78). BMI at the age of 18 (P-heterogeneity = 0.001), childhood (P-heterogeneity = 0.51), and adolescent somatotype (P-heterogeneity = 0.046) were inversely associated, but with differences in magnitude of association. BMI at the age of 18 of >25 kg/m(2) (compared with 20-21.9 kg/m(2)) was associated with a 52% decreased risk of HER2-enriched (HR, 0.48; 95% CI, 0.26-0.91; P-trend < 0.0001) and 39% reduced risk of basal-like tumors (HR, 0.61; 95% CI, 0.36-1.02; P-trend = 0.008). Compared with the lowest category, women in the highest adolescent body size category were 71% less likely to develop HER2-enriched (HR, 0.29; 95% CI, 0.10-0.85; P-trend = 0.0005) and 60% less likely to develop basal-like (HR, 0.40; 95% CI, 0.17-0.95; P-trend = 0.0008). Height was positively associated with risk of all breast cancer molecular subtypes. BMI at 18 years and childhood and adolescent were inversely associated with risk of most breast cancer molecular subtypes with somewhat stronger associations with HER2-enriched and basal-like subtypes. (C) 2016 AACR. C1 [Warner, Erica T.] Massachusetts Gen Hosp, Clin Translat Epidemiol Unit, Boston, MA 02114 USA. [Warner, Erica T.; Eliassen, A. Heather; Michels, Karin B.; Willett, Walter C.; Tamimi, Rulla M.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Warner, Erica T.; Hu, Rong; Rosner, Bernard; Eliassen, A. Heather; Michels, Karin B.; Willett, Walter C.; Tamimi, Rulla M.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Collins, Laura C.; Beck, Andrew H.; Schnitt, Stuart] Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. [Collins, Laura C.; Beck, Andrew H.; Schnitt, Stuart] Harvard Med Sch, Boston, MA USA. [Rosner, Bernard] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Michels, Karin B.] Harvard Med Sch, Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Dept Obstet Gynecol & Reprod Biol, Boston, MA USA. [Willett, Walter C.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. RP Warner, ET (reprint author), 55 Fruit St, Boston, MA 02114 USA. EM ewarner@mgh.harvard.edu FU National Cancer Institute (NCI) [P01 CA87969, UM1CA186107, UM1CA176726]; National Cancer Institute [K01 CA188075] FX This project was supported National Cancer Institute (NCI) grants P01 CA87969 and UM1CA186107 and UM1CA176726. E.T. Warner was supported by National Cancer Institute grant K01 CA188075. NR 53 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 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD SEP PY 2016 VL 9 IS 9 BP 732 EP 738 DI 10.1158/1940-6207.CAPR-16-0085 PG 7 WC Oncology SC Oncology GA DV7BJ UT WOS:000383090500003 PM 27590596 ER PT J AU Magrangeas, F Kuiper, R Avet-Loiseau, H Gouraud, W Guerin-Charbonnel, C Ferrer, L Aussem, A Elghazel, H Suhard, J Sakissian, HD Attal, M Munshi, NC Sonneveld, P Dumontet, C Moreau, P van Duin, M Campion, L Minvielle, S AF Magrangeas, Florence Kuiper, Rowan Avet-Loiseau, Herve Gouraud, Wilfried Guerin-Charbonnel, Catherine Ferrer, Ludovic Aussem, Alexandre Elghazel, Haytham Suhard, Jerome Sakissian, Henri Der Attal, Michel Munshi, Nikhil C. Sonneveld, Pieter Dumontet, Charles Moreau, Philippe van Duin, Mark Campion, Loic Minvielle, Stephane TI A Genome-Wide Association Study Identifies a Novel Locus for Bortezomib-Induced Peripheral Neuropathy in European Patients with Multiple Myeloma SO CLINICAL CANCER RESEARCH LA English DT Article ID EXPRESSION; CONTRIBUTES; POLYMORPHISM; MCP-1 AB Purpose: Painful peripheral neuropathy is a frequent toxicity associated with bortezomib therapy. This study aimed to identify loci that affect susceptibility to this toxicity. Experimental Design: A genome-wide association study (GWAS) of 370,605 SNPs was performed to identify risk variants for developing severe bortezomib-induced peripheral neuropathy (BiPN) in 469 patients with multiple myeloma who received bortezomib-dexamethasone therapy prior to autologous stem cell in randomized clinical trials of the Inter-groupe Francophone du Myelome (IFM) and findings were replicated in 114 patients with multiple myeloma of the HOVON-65/GMMG-HD4 clinical trial. Results: An SNP in the PKNOX1 gene was associated with BiPN in the exploratory cohort [rs2839629; OR, 1.89, 95% confidence interval (CI), 1.45-2.44; P = 7.6 x 10(-6)] and in the replication cohort (OR, 2.04; 95% CI, = 1.11-3.33; P = 8.3 x 10(-3)). In addition, rs2839629 is in strong linkage disequilibrium(r(2) = 0.87) with rs915854, located in the intergenic region between PKNOX1 and cystathionine-ss-synthetase (CBS). Expression quantitative trait loci mapping showed that both rs2839629 and rs915854 genotypes have an impact on PKNOX1 expression in nerve tissue, whereas rs2839629 affects CBS expression in skin and blood. Conclusions: The use of GWAS in multiple myeloma pharmacogenomics has identified a novel candidate genetic locus mapping to PKNOX1 and in the immediate vicinity of CBS at 21q22.3 associated with the severe bortezomib-induced toxicity. The proximity of these two genes involved in neurologic pain whose tissue-specific expression is modified by the two variants provides new targets for neuroprotective strategies. (C) 2016 AACR. C1 [Magrangeas, Florence; Gouraud, Wilfried; Guerin-Charbonnel, Catherine; Moreau, Philippe; Campion, Loic; Minvielle, Stephane] Univ Nantes, CNRS UMR 6299, INSERM UMR 892, Nantes, France. [Magrangeas, Florence; Moreau, Philippe; Minvielle, Stephane] CHU Nantes, Nantes, France. [Kuiper, Rowan; Sonneveld, Pieter; van Duin, Mark] Erasmus MC, Rotterdam, Netherlands. [Avet-Loiseau, Herve; Attal, Michel] Ctr Hosp Univ, Toulouse, France. [Gouraud, Wilfried; Guerin-Charbonnel, Catherine; Ferrer, Ludovic; Suhard, Jerome; Campion, Loic] Inst Cancerol Ouest, Nantes, France. [Aussem, Alexandre; Elghazel, Haytham] Univ Lyon 1, CNRS, LIRIS UMR 5205, Lyon, France. [Sakissian, Henri Der] LUNAM Univ, IRCCyN, Polytech Nantes, CNRS UMR 6597, Nantes, France. [Munshi, Nikhil C.] Harvard Med Sch, Dana Farber Canc Inst, Lebow Inst Myeloma Therapeut, Boston, MA USA. [Munshi, Nikhil C.] Harvard Med Sch, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA USA. [Munshi, Nikhil C.] Boston Vet Adm Healthcare Syst, W Roxbury, MA USA. [Dumontet, Charles] Ctr Leon Berard, CNRS 5286, INSERM UMR 1052, Lyon, France. RP Campion, L; Minvielle, S (reprint author), Ctr Rech Cancerol, 8 Quai Moncousu, F-44007 Nantes, France. EM m.vanduin@erasmusmc.nl; stephane.minvielle@chu-nantes.fr RI richard, chrystelle/K-8595-2015 FU Intergroupe Francophone du Myelome; French Institute National du Cancer Grant [POBNIMM PROG/08/10]; NIH [PO1CA155258-01] FX This study was supported by Intergroupe Francophone du Myelome; the French Institute National du Cancer Grant POBNIMM PROG/08/10 (to H. Avet-Loiseau, S. Minvielle); and NIH grant PO1CA155258-01 (to S. Minvielle, H. Avet-Loiseau, N.C. Munshi). NR 29 TC 0 Z9 0 U1 3 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 1 PY 2016 VL 22 IS 17 BP 4350 EP 4355 DI 10.1158/1078-0432.CCR-15-3163 PG 6 WC Oncology SC Oncology GA DV6IR UT WOS:000383038200010 PM 27060151 ER PT J AU Bassiouni, R Nemec, KN Iketani, A Flores, O Showalter, A Khaled, AS Vishnubhotla, P Sprung, RW Kaittanis, C Perez, JM Khaled, AR AF Bassiouni, Rania Nemec, Kathleen N. Iketani, Ashley Flores, Orielyz Showalter, Anne Khaled, Amr S. Vishnubhotla, Priya Sprung, Robert W., Jr. Kaittanis, Charalambos Perez, Jesus M. Khaled, Annette R. TI Chaperonin Containing TCP-1 Protein Level in Breast Cancer Cells Predicts Therapeutic Application of a Cytotoxic Peptide SO CLINICAL CANCER RESEARCH LA English DT Article ID T-COMPLEX PROTEINS; CYTOSOLIC CHAPERONIN; MOLECULAR CHAPERONE; IN-VIVO; CARBOXYL-TERMINUS; MAMMALIAN-CELLS; OVER-EXPRESSION; PORE FORMATION; BAX PROTEIN; 8 SUBUNITS AB Purpose: Metastatic disease is a leading cause of death for patients with breast cancer, driving the need for new therapies. CT20p is a peptide previously discovered by our group that displays cancer-specific cytotoxicity. To design the optimal therapeutic use of the peptide, we identified the intracellular target of CT20p in breast cancer cells, correlating expression patterns of the target with susceptibility to CT20p. Experimental Design: Using polymeric nanoparticles to deliver CT20p, we assessed cytoskeletal changes, cell migration, adhesion, and viability in cells treated with the peptide. Protein pull-down experiments, coupled to mass spectrometry, enabled identification of the peptide's intracellular target. Biochemical and histologic techniques validated target identity in human cell lines and breast cancer tissue microarrays and revealed susceptibility patterns to CT20p. Results: Chaperonin containing TCP-1 (CCT) was identified as the intracellular target of CT20p. Cancer cells susceptible to CT20p had increased CCT, and overexpression of CCTb, a subunit of the CCT complex, enhanced susceptibility to CT20p. Susceptible cells displayed reduced tubulin, a substrate of CCT, and inhibition of migration upon CT20p treatment. CCTb levels were higher in invasive ductal carcinomas than in cancer adjacent tissues and increased with breast cancer stage. Decreased breast cancer patient survival correlated with genomic alternations in CCTb and higher levels of the chaperone. Conclusions: Increased CCT protein in breast cancer cells underlies the cytotoxicity of CT20p. CCT is thus a potential target for therapeutic intervention and serves as a companion diagnostic to personalize the therapeutic use of CT20p for breast cancer treatment. (C) 2016 AACR. C1 [Bassiouni, Rania; Nemec, Kathleen N.; Iketani, Ashley; Showalter, Anne; Khaled, Annette R.] Univ Cent Florida, Coll Med, Burnett Sch Biomed Sci, 6900 Lake Nona Blvd, Orlando, FL 32827 USA. [Flores, Orielyz] Univ Cent Florida, Nanosci Technol Ctr, Orlando, FL 32816 USA. [Khaled, Amr S.; Vishnubhotla, Priya] Orlando VA Med Ctr, Orlando, FL USA. [Sprung, Robert W., Jr.] H Lee Moffitt Canc Ctr & Res Inst, Prote, Tampa, FL USA. [Kaittanis, Charalambos] Massachusetts Gen Hosp, Dept Radiol, Gordon Ctr Med Imaging, Boston, MA 02114 USA. [Perez, Jesus M.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RP Khaled, AR (reprint author), Univ Cent Florida, Coll Med, Burnett Sch Biomed Sci, 6900 Lake Nona Blvd, Orlando, FL 32827 USA. EM annette.khaled@ucf.edu FU NIBIB, NIH [1R01EB019288]; Breast Cancer Research Foundation; National Cancer Institute as a Cancer Center Support Grant [P30-CA076292]; Moffitt Foundation FX A.R. Khaled and J.M. Perez are supported by 1R01EB019288, NIBIB, NIH; and A.R. Khaled, Breast Cancer Research Foundation. Proteomics at Moffitt Cancer Center is supported by the National Cancer Institute under Award No. P30-CA076292 as a Cancer Center Support Grant (Principal Investigator: Thomas Sellers) and the Moffitt Foundation. NR 49 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 1 PY 2016 VL 22 IS 17 BP 4366 EP 4379 DI 10.1158/1078-0432.CCR-15-2502 PG 14 WC Oncology SC Oncology GA DV6IR UT WOS:000383038200012 PM 27012814 ER PT J AU Tateishi, K Iafrate, AJ Ho, Q Curry, WT Batchelor, TT Flaherty, KT Onozato, ML Lelic, N Sundaram, S Cahill, DP Chi, AS Wakimoto, H AF Tateishi, Kensuke Iafrate, A. John Ho, Quan Curry, William T. Batchelor, Tracy T. Flaherty, Keith T. Onozato, Maristela L. Lelic, Nina Sundaram, Sudhandra Cahill, Daniel P. Chi, Andrew S. Wakimoto, Hiroaki TI Myc-Driven Glycolysis Is a Therapeutic Target in Glioblastoma SO CLINICAL CANCER RESEARCH LA English DT Article ID NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE NAMPT; IONIZATION MASS-SPECTROMETRY; CANCER STEM-CELLS; C-MYC; PATHWAY MUTATIONS; GENOMIC ANALYSIS; FEEDBACK LOOP; COPY-NUMBER; GLIOMA; INHIBITION AB Purpose: Deregulated Myc drives an oncogenic metabolic state, including pseudohypoxic glycolysis, adapted for the constitutive production of biomolecular precursors to feed rapid tumor cell growth. In glioblastoma, Myc facilitates renewal of the tumor-initiating cell reservoir contributing to tumor maintenance. We investigated whether targeting the Myc-driven metabolic state could be a selectively toxic therapeutic strategy for glioblastoma. Experimental Design: The glycolytic dependency of Myc-driven glioblastoma was tested using C-13 metabolic flux analysis, glucose-limiting culture assays, and glycolysis inhibitors, including inhibitors of the NAD(+) salvage enzyme nicotinamide phosphoribosyl-transferase (NAMPT), in MYC and MYCN shRNA knockdown and lentivirus overexpression systems and in patient-derived glioblastoma tumorspheres with and without MYC/MYCN amplification. The in vivo efficacy of glycolyic inhibition was tested using NAMPT inhibitors in MYCN-amplified patient-derived glioblastoma orthotopic xenograft mouse models. Results: Enforced Myc overexpression increased glucose flux and expression of glycolytic enzymes in glioblastoma cells. Myc and N-Myc knockdown and Myc overexpression systems demonstrated that Myc activity determined sensitivity and resistance to inhibition of glycolysis. Small-molecule inhibitors of glycolysis, particularly NAMPT inhibitors, were selectively toxic to MYC/MYCN-amplified patient-derived glioblastoma tumorspheres. NAMPT inhibitors were potently cytotoxic, inducing apoptosis and significantly extended the survival of mice bearing MYCN-amplified patient-derived glioblastoma orthotopic xenografts. Conclusions: Myc activation in glioblastoma generates a dependency on glycolysis and an addiction to metabolites required for glycolysis. Glycolytic inhibition via NAMPT inhibition represents a novel metabolically targeted therapeutic strategy for MYC or MYCN-amplified glioblastoma and potentially other cancers genetically C1 [Tateishi, Kensuke; Curry, William T.; Lelic, Nina; Cahill, Daniel P.; Wakimoto, Hiroaki] Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Translat Neurooncol Lab, Dept Neurosurg, Boston, MA 02115 USA. [Iafrate, A. John; Ho, Quan; Onozato, Maristela L.] Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Translat Neurooncol Lab, Dept Pathol, Boston, MA USA. [Batchelor, Tracy T.; Flaherty, Keith T.] Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Div Hematol Oncol, Boston, MA USA. [Batchelor, Tracy T.; Sundaram, Sudhandra] Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Translat Neurooncol Lab,Dept Neurol, Stephen E & Catherine Pappas Ctr Neurooncol, Boston, MA USA. [Chi, Andrew S.] NYU, Langone Med Ctr, Laura & Isaac Perlmutter Canc Ctr, New York, NY USA. RP Cahill, DP (reprint author), Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Translat Neurooncol Lab, Dept Neurosurg, Boston, MA 02115 USA.; Chi, AS (reprint author), NYU, Langone Med Ctr, 240 E 38th St,19th Floor, New York, NY 10016 USA.; Wakimoto, H (reprint author), Massachusetts Gen Hosp, 185 Cambridge St, Boston, MA 02114 USA. EM cahill@mgh.harvard.edu; chia01@nyumc.org; hwakimoto@mgh.harvard.edu OI Cahill, Daniel/0000-0003-2552-6546 FU U.S. NIH [P50CA165962-01A1, K24 CA125440-06]; Burroughs Wellcome Fund Career Award; Society of Nuclear Medicine and Molecular Imaging Wagner-Torizuka Fellowship; Japan Brain Foundation; KANAE foundation for the Promotion of Medical Science; Richard B. Simches Scholars Award; MGH Glioblastoma Research Fund FX This work is supported by U.S. NIH P50CA165962-01A1 [to T.T. Batchelor (Principal Investigator), D.P. Cahill, H. Wakimoto, and A.S. Chi] and K24 CA125440-06 (to T.T. Batchelor), a Burroughs Wellcome Fund Career Award (to D.P. Cahill). K. Tateishi is supported by a Society of Nuclear Medicine and Molecular Imaging Wagner-Torizuka Fellowship, the Japan Brain Foundation, and the KANAE foundation for the Promotion of Medical Science. A.S. Chi is supported by a Richard B. Simches Scholars Award and the MGH Glioblastoma Research Fund in memory of David M. King, Kirit N. Patel, Sarah E. Rippetoe, and Eric W. Schwartz. NR 48 TC 3 Z9 3 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 1 PY 2016 VL 22 IS 17 BP 4452 EP 4465 DI 10.1158/1078-0432.CCR-15-2274 PG 14 WC Oncology SC Oncology GA DV6IR UT WOS:000383038200019 PM 27076630 ER PT J AU Shinagare, AB Barysauskas, CM Braschi-Amirfarzan, M O'Neill, AC Catalano, PJ George, S Ramaiya, NH AF Shinagare, Atul B. Barysauskas, Constance M. Braschi-Amirfarzan, Marta O'Neill, Ailbhe C. Catalano, Paul J. George, Suzanne Ramaiya, Nikhil H. TI Comparison of performance of various tumor response criteria in assessment of sunitinib activity in advanced gastrointestinal stromal tumors SO CLINICAL IMAGING LA English DT Article DE Gastrointestinal stromal tumor; Sunitinib; Tumor response criteria; RECIST; Choi ID PHASE-II TRIAL; IMATINIB MESYLATE; SOLID TUMORS; EFFICACY; FAILURE; SAFETY; REGORAFENIB; MULTICENTER; SURVIVAL; THERAPY AB Purpose: To compare the performance of various tumor response criteria (TRC) in the assessment of patients with advanced gastrointestinal stromal tumor (GIST) treated with sunitinib after failure of imatinib. Methods: Sixty-two participants with advanced GIST in two clinical trials received oral sunitinib after prior failure of imatinib (median duration 24 weeks; interquartile range 14-56) and were followed with contrast enhanced computed tomography at baseline and thereafter at median intervals of 6 weeks (IRQ6-9). Tumor response was prospectively determined using Response Evaluation Criteria in Solid Tumors (RECIST) 1.0, and retrospectively reassessed for comparison using RECIST 1.1, Choi criteria, and modified Choi (mChoi) criteria using the original target lesions. For mChoi criteria, progressive disease was defined as 20% increase in sum of the longest dimension, similar to RECIST 1.1. Clinical benefit rate (CBR; complete response, partial response, or stable disease weeks) and progression-free survival were compared between various TRCs using kappa statistics. Results: While partial response as the best response was more frequent by Choi and mChoi criteria (50% each) than RECIST 1.1 (15%) and RECIST 1.0 (13%), CBR was similar between various TRCs (overall CBR 60%-77%, 77%-94% agreement between all TRC pairs). Time to best response was shorter for Choi and mChoi criteria (median 11 weeks each) compared to RECIST 1.1 and RECIST 1.0 (median 25 and 24 weeks, respectively). PFS was similar for RECIST 1.1, RECIST 1.0, and mChoi (median 35 weeks each), and shortest for Choi criteria (median 23 weeks). Conclusions: CBR was similar among the various TRCs, although Choi criteria led to earlier determination of disease progression. Therefore, RECIST 1.1 and mChoi criteria may be preferred for response assessment in patients with advanced GIST. (C) 2016 Elsevier Inc. All rights reserved. C1 [Shinagare, Atul B.; Braschi-Amirfarzan, Marta; O'Neill, Ailbhe C.; Ramaiya, Nikhil H.] Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02215 USA. [Shinagare, Atul B.; Braschi-Amirfarzan, Marta; O'Neill, Ailbhe C.; Ramaiya, Nikhil H.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Barysauskas, Constance M.; Catalano, Paul J.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02215 USA. [Catalano, Paul J.] Harvard Sch Publ Hlth, Dept Biostat, 655 Huntington Ave, Boston, MA 02115 USA. [George, Suzanne] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. RP Shinagare, AB (reprint author), Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02215 USA. EM ashinagare@partners.org FU ARIAD; Pfizer; Novartis; Bayer FX Atul B. Shinagare, Constance M. Barysauskas, Marta Braschi-Amirfarzan, Paul J. Catalano, and Nikhil H. Ramaiya: no conflicts of interest. Suzanne George: research funding from ARIAD, Pfizer, Novartis, Bayer, and consultant/advisory board in ARIAD, Pfizer, Novartis, Bayer, and Blueprint. NR 26 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0899-7071 EI 1873-4499 J9 CLIN IMAG JI Clin. Imaging PD SEP-OCT PY 2016 VL 40 IS 5 BP 880 EP 884 DI 10.1016/j.clinimag.2016.04.007 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DW0BH UT WOS:000383305400011 PM 27179958 ER PT J AU Liu, LCY Voors, AA Teerlink, JR Cotter, G Davison, BA Felker, GM Filippatos, G Chen, YK Greenberg, BH Ponikowski, P Pang, PS Prescott, MF Hua, TA Severin, TM Metra, M AF Liu, Licette C. Y. Voors, Adriaan A. Teerlink, John R. Cotter, Gad Davison, Beth A. Felker, G. Michael Filippatos, Gerasimos Chen, Yakuan Greenberg, Barry H. Ponikowski, Piotr Pang, Peter S. Prescott, Margaret F. Hua, Tsushung A. Severin, Thomas M. Metra, Marco TI Effects of serelaxin in acute heart failure patients with renal impairment: results from RELAX-AHF SO CLINICAL RESEARCH IN CARDIOLOGY LA English DT Article DE Serelaxin; Acute heart failure; Renal function; Renal impairment; Number needed to treat ID GLOMERULAR-FILTRATION-RATE; SERUM CYSTATIN-C; RECOMBINANT HUMAN RELAXIN; PLACEBO-CONTROLLED TRIAL; CHRONIC KIDNEY-DISEASE; RANDOMIZED-TRIALS; HORMONE RELAXIN; CONSCIOUS RATS; DOUBLE-BLIND; CREATININE AB Serelaxin showed beneficial effects on clinical outcome and trajectories of renal markers in patients with acute heart failure. We aimed to study the interaction between renal function and the treatment effect of serelaxin. In the current post hoc analysis of the RELAX-AHF trial, we included all patients with available estimated glomerular filtration rate (eGFR) at baseline (n = 1132). Renal impairment was defined as an eGFR < 60 ml/min/1.73 m(2) estimated by creatinine. 817 (72.2 %) patients had a baseline eGFR < 60 ml/min/1.73 m(2). In placebo-treated patients, baseline renal impairment was related to a higher 180 day cardiovascular (HR 3.12, 95 % CI 1.33-7.30) and all-cause mortality (HR 2.81, 95 % CI 1.34-5.89). However, in serelaxin-treated patients, the risk of cardiovascular and all-cause mortality was less pronounced (HR 1.19, 95 % CI 0.54 -2.64; p for interaction = 0.106, and HR 1.15 95 % CI 0.56-2.34 respectively; p for interaction = 0.088). In patients with renal impairment, treatment with serelaxin resulted in a more pronounced all-cause mortality reduction (HR 0.53, 95 % CI 0.34-0.83), compared with patients without renal impairment (HR 1.30, 95 % CI 0.51-3.29). Renal dysfunction was associated with higher cardiovascular and all-cause mortality in placebo-treated patients, but not in serelaxin-treated patients. The observed reduction in (cardiovascular) mortality in RELAX-AHF was more pronounced in patients with renal dysfunction. These observations need to be confirmed in the ongoing RELAX-AHF-2 trial. C1 [Liu, Licette C. Y.; Voors, Adriaan A.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Hanzepl 1, NL-9713 GZ Groningen, Netherlands. [Teerlink, John R.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [Cotter, Gad; Davison, Beth A.] Momentum Res, Durham, NC USA. [Felker, G. Michael] Duke Univ, Sch Med, Duke Heart Ctr, Durham, NC USA. [Filippatos, Gerasimos] Univ Athens, Attikon Univ Hosp, Sch Med, Athens, Greece. [Chen, Yakuan] Columbia Univ, Med Ctr, New York, NY USA. [Greenberg, Barry H.] Univ Calif San Diego, San Diego, CA 92103 USA. [Ponikowski, Piotr] Med Univ, Clin Mil Hosp, Wroclaw, Poland. [Pang, Peter S.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Prescott, Margaret F.; Hua, Tsushung A.; Severin, Thomas M.] Novartis Pharmaceut, Basel, Switzerland. [Metra, Marco] Univ Brescia, Brescia, Italy. RP Voors, AA (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, 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 Alere; Bayer; Cardio3Biosciences; Celladon; Ceva; European Committee; Dutch Heart Foundation; Novartis; Servier; Torrent; Vifor; Amgen; Corthera; Cardio3 Bioscience; Cytokinetics; Merck; Takeda; Teva; Trevena; Otsuka; Roche Diagnostics; NHLBI; European Union; Abbott; PDL BioPharma; Novartis Pharma FX LCYL, YC have nothing to disclose. AAV has received consultancy fees and/or research grants from Alere, Bayer, Cardio3Biosciences, Celladon, Ceva, European Committee, Dutch Heart Foundation, Novartis, Servier, Torrent, and Vifor. JRT has received research grants or consulting fees from Amgen, Bayer, Corthera, Cardio3 Bioscience, Cytokinetics, Merck, Novartis, Takeda, Teva, and Trevena. GC and BAD are employees of Momentum Research, which has provided consulting and trial management services to NovaCardia, Merck, Corthera, Novartis, Nile Therapeutics, Bioheart, Cardio3 Biosciences, Amgen, Celadon, Targegen, Trevena, Sorbent Therapeutics, and NIH. GMF reports consulting income from Novartis, Medpace, Amgen, Otsuka, Trevena, Roche Diagnostics, Merck, BG Medicine, Medtronic, and St Judes and grant fundings from Amgen, Otsuka, Roche Diagnostics, and NHLBI. GF is an executive committee member and consultant to Corthera (a Novartis company), Bayer, Cardiorentis, and has received research grants from Amgen, European Union. BHG served as a consultant for Corthera and Novartis. PP was a consultant for Astellas, Bayer, EKR Therapeutics, J&J, the Medicines Company, Medtronic, Novartis, Otsuka, Palatin Technologies, PDL BioPharma, Pericor Therapeutics, SigmaTau, Solvay Pharmaceuticals, and Trevena; has received honoraria from Alere, Beckman-Coulter, BiogenIdec, Corthera, Ikaria, Nile Therapeutics, Momentum Research, and Overcome; has received research support from Abbott, Merck and PDL BioPharma; and has received travel support from MyLife and equipment support from Sonosite. PSP, in the last 1 year is or has been a Consultant for: Intersection Medical, INSYS. Janssen, Medtronic, Novartis, Trevena, scPharmaceuticals, Cardioxyl, Roche Diagnostics, Relypsa, Honoraria: Palatin Technologies. MP, TAH and TMS are employees of and receive salary, benefits, and stocks options from Novartis Pharma. MM has received consulting income from Abbott Vascular, Bayer, Corthera, and Novartis, as well as travel support and honoraria from Servier and Novartis. NR 40 TC 0 Z9 0 U1 6 U2 6 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1861-0684 EI 1861-0692 J9 CLIN RES CARDIOL JI Clin. Res. Cardiol. PD SEP PY 2016 VL 105 IS 9 BP 727 EP 737 DI 10.1007/s00392-016-0979-8 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DU2BL UT WOS:000382015600002 PM 27017514 ER PT J AU Scariati, E Schaer, M Karahanoglu, I Schneider, M Richiardi, J Debbane, M Van De Ville, D Eliez, S AF Scariati, Elisa Schaer, Marie Karahanoglu, Isik Schneider, Maude Richiardi, Jonas Debbane, Martin Van De Ville, Dimitri Eliez, Stephan TI Large-scale functional network reorganization in 22q11.2 deletion syndrome revealed by modularity analysis SO CORTEX LA English DT Article DE Brain development; Connectome; Graph theory; Modularity; Resting-state fMRI; Schizophrenia ID CARDIO-FACIAL SYNDROME; DEFAULT MODE NETWORK; STATE BRAIN NETWORKS; WHITE-MATTER; PSYCHOTIC SYMPTOMS; ANTERIOR CINGULATE; VELOCARDIOFACIAL SYNDROME; MICRODELETION SYNDROME; COMMUNITY STRUCTURE; CONNECTIVITY MRI AB The 22q11.2 deletion syndrome (22q11DS) is associated with cognitive impairments and a 41% risk of developing schizophrenia. While several studies performed on patients with 22q11DS showed the presence of abnormal functional connectivity in this syndrome, how these alterations affect large-scale network organization is still unknown. Here we performed a network modularity analysis on whole-brain functional connectomes derived from the resting-state fMRI of 40 patients with 22q11DS and 41 healthy control participants, aged between 9 and 30 years old. We then split the sample at 18 years old to obtain two age subgroups and repeated the modularity analyses. We found alterations of modular communities affecting the visuo-spatial network and the anterior cingulate cortex (ACC) in both age groups. These results corroborate previous structural and functional studies in 22q11DS that showed early impairment of visuo-spatial processing regions. Furthermore, as ACC has been linked to the development of psychotic symptoms in 22q11DS, the early impairment of its functional connectivity provide further support that ACC alterations may provide potential biomarkers for an increased risk of schizophrenia. Finally, we found an abnormal modularity partition of the dorsolateral prefrontal cortex (DLPFC) only in adults with 22q11DS, suggesting the presence of an abnormal development of functional network communities during adolescence in 22q11DS. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Scariati, Elisa; Karahanoglu, Isik; Schneider, Maude; Debbane, Martin; Eliez, Stephan] Univ Geneva, Sch Med, Dept Psychiat, Off Med Pedagog,Res Unit, 1 Rue David Dufour,CP 50, CH-1211 Geneva, Switzerland. [Schaer, Marie] Stanford Univ, Sch Med, Stanford Cognit & Syst Neurosci Lab, Palo Alto, CA 94304 USA. [Karahanoglu, Isik] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Richiardi, Jonas] Univ Geneva, Lab Neurol & Imaging Cognit, Dept Fundamental Neurosci, Geneva, Switzerland. [Debbane, Martin] Univ Geneva, Adolescence Clin Psychol Res Unit, Fac Psychol & Educ Sci, Geneva, Switzerland. [Van De Ville, Dimitri] Univ Geneva, Dept Radiol & Med Informat, Geneva, Switzerland. [Van De Ville, Dimitri] Ecole Polytech Fed Lausanne, Inst Bioengn, Med Image Proc Lab, Lausanne, Switzerland. [Eliez, Stephan] Univ Geneva, Sch Med, Dept Genet Med & Dev, Geneva, Switzerland. RP Scariati, E (reprint author), Univ Geneva, Sch Med, Dept Psychiat, Off Med Pedagog,Res Unit, 1 Rue David Dufour,CP 50, CH-1211 Geneva, Switzerland. EM elisa.scariati@unige.ch RI Centre d'imagerie Biomedicale, CIBM/B-5740-2012; OI Van De Ville, Dimitri/0000-0002-2879-3861 FU Swiss National Science Foundation (SNF) [32473B_121996, 234730_144260, PP00P2_146318]; National Center of Competences in Research "Synapsy-The Synaptic Bases of Mental Diseases" [51AU40_125759]; FNS [145250, 145760]; Marie Curie International Outgoing Fellowship [299500] FX This work was supported by the Swiss National Science Foundation (SNF) to SE (grant numbers 32473B_121996, 234730_144260) and to DVdV (grant number PP00P2_146318) and by the National Center of Competences in Research "Synapsy-The Synaptic Bases of Mental Diseases" to SE (grant number 51AU40_125759). This work was also supported by individual grants of the FNS to ES (grant number #145250) and MS (grant number #145760) and by a Marie Curie International Outgoing Fellowship to JR (grant number #299500). NR 94 TC 1 Z9 1 U1 6 U2 6 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 EI 1973-8102 J9 CORTEX JI Cortex PD SEP PY 2016 VL 82 BP 86 EP 99 DI 10.1016/j.cortex.2016.06.004 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DT5PT UT WOS:000381535800008 PM 27371790 ER PT J AU De Winter, FL Van den Stock, J de Gelder, B Peeters, R Jastorff, J Sunaert, S Vanduffel, W Vandenberghe, R Vandenbulcke, M AF De Winter, Francois-Laurent Van den Stock, Jan de Gelder, Beatrice Peeters, Ronald Jastorff, Jan Sunaert, Stefan Vanduffel, Wim Vandenberghe, Rik Vandenbulcke, Mathieu TI Amygdala atrophy affects emotion-related activity in face-responsive regions in frontotemporal degeneration SO CORTEX LA English DT Article DE Amygdala; Behavioral variant frontotemporal dementia; Dynamic face processing; Emotion processing; fMRI ID VISUAL CORTICAL ACTIVATION; BEHAVIORAL-VARIANT; FACIAL EXPRESSIONS; LOBAR DEGENERATION; ALZHEIMERS-DISEASE; TEMPORAL CORTEX; DEMENTIA; BRAIN; CONNECTIVITY; RECOGNITION AB In the healthy brain, modulatory influences from the amygdala commonly explain enhanced activation in face-responsive areas by emotional facial expressions relative to neutral expressions. In the behavioral variant frontotemporal dementia (bvFTD) facial emotion recognition is impaired and has been associated with atrophy of the amygdala. By combining structural and functional MRI in 19 patients with bvFTD and 20 controls we investigated the neural effects of emotion in face-responsive cortex and its relationship with amygdalar gray matter (GM) volume in neurodegeneration. Voxel-based morphometry revealed decreased GM volume in anterior medio-temporal regions including amygdala in patients compared to controls. During fMRI, we presented dynamic facial expressions (fear and chewing) and their spatiotemporally scrambled versions. We found enhanced activation for fearful compared to neutral faces in ventral temporal cortex and superior temporal sulcus in controls, but not in patients. In the bvFTD group left amygdalar GM volume correlated positively with emotion-related activity in left fusiform face area (FFA). This correlation was amygdala-specific and driven by GM in superficial and basolateral (BLA) subnuclei, consistent with reported amygdalar-cortical networks. The data suggests that anterior medio-temporal atrophy in bvFTD affects emotion processing in distant posterior areas. (C) 2016 Elsevier Ltd. All rights reserved. C1 [De Winter, Francois-Laurent; Van den Stock, Jan; de Gelder, Beatrice; Jastorff, Jan; Vandenbulcke, Mathieu] Katholieke Univ Leuven, Dept Neurosci, Lab Translat Neuropsychiat, Res Grp Psychiat, Leuven, Belgium. [De Winter, Francois-Laurent; Van den Stock, Jan; Vandenbulcke, Mathieu] Univ Hosp Leuven, Dept Old Age Psychiat, Leuven, Belgium. [de Gelder, Beatrice] Maastricht Univ, Dept Cognit Neurosci, Maastricht, Netherlands. [Peeters, Ronald; Sunaert, Stefan] Univ Hosp Leuven, Dept Radiol, Leuven, Belgium. [Peeters, Ronald; Sunaert, Stefan] Katholieke Univ Leuven, Dept Imaging & Pathol, Leuven, Belgium. [Vanduffel, Wim] Katholieke Univ Leuven, Lab Neuro & Psychophysiol, Dept Neurosci, Leuven, Belgium. [Vanduffel, Wim] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Vanduffel, Wim] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Vandenberghe, Rik] Katholieke Univ Leuven, Dept Neurosci, Lab Cognit Neurol, Leuven, Belgium. [Vandenberghe, Rik] Univ Hosp Leuven, Dept Neurol, Leuven, Belgium. RP Vandenbulcke, M (reprint author), UZ Leuven, Univ Hosp Leuven, Dept Old Age Psychiat, Herestr 49, B-3000 Louvain, Belgium. EM mathieu.vandenbulcke@uzleuven.be RI Van den Stock, Jan/F-1906-2014; Vandenberghe, Rik/K-2145-2014 OI Van den Stock, Jan/0000-0001-5756-3195; Vandenberghe, Rik/0000-0001-6237-2502 FU Fonds Wetenschappelijk Onderzoek (FWO)-Vlaanderen [1.5.072.13N, G.0657.15N, 1.2.657.14N]; Foundation for Alzheimer Research (SAO-FRA P) [14013]; European Research Council under the European Union's Seventh Frame-work Programme (FP7) [ERC grant] [295673, 604102]; Odysseus grant [G.0007.12]; Fonds Wetenschappelijk Onderzoek-Vlaanderen [G.0746.09, G0A5613N, G043912N]; Program Financing KU Leuven [PFV/10/008] FX JVdS and JJ are post-doctoral researchers supported by Fonds Wetenschappelijk Onderzoek (FWO)-Vlaanderen [1.5.072.13N (JVdS); G.0657.15N, 1.2.657.14N (JJ)].) JVdS is supported by Foundation for Alzheimer Research (SAO-FRA P#14013). BdG and WV are funded by the European Research Council under the European Union's Seventh Frame-work Programme (FP7/2007-2013) [ERC grant agreement number 295673 (BdG); grant agreement number 604102 (Human Brain Project) (WV)]. WV received funding from Odysseus grant G.0007.12. RV is a senior clinical investigator for FWO-Vlaanderen. MV and WV are supported by Fonds Wetenschappelijk Onderzoek-Vlaanderen [G.0746.09 (MV); G0A5613N and G043912N (WV)]. MV, WV and JJ are supported by Program Financing KU Leuven (PFV/10/008). NR 50 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 EI 1973-8102 J9 CORTEX JI Cortex PD SEP PY 2016 VL 82 BP 179 EP 191 DI 10.1016/j.cortex.2016.06.001 PG 13 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DT5PT UT WOS:000381535800014 PM 27389802 ER PT J AU Essien, UR Shahid, NN Berkowitz, SA AF Essien, Utibe R. Shahid, Naysha N. Berkowitz, Seth A. TI Food Insecurity and Diabetes in Developed Societies SO CURRENT DIABETES REPORTS LA English DT Review DE Food insecurity; Diabetes; CentralAdiposity; Prediabetes; Nutrition ID NUTRITION EXAMINATION SURVEY; LOW-INCOME PATIENTS; US ADULTS; GLYCEMIC CONTROL; METABOLIC SYNDROME; NATIONAL-HEALTH; MEDICATION ADHERENCE; CHRONIC DISEASE; SELF-EFFICACY; OBESITY AB Food insecurity is an important issue in public health even in developed societies, particularly for vulnerable populations. Food insecurity refers to the uncertain or limited access to adequate and safe foods. Emerging evidence shows an association between food insecurity, type 2 diabetes risk factors, and management of type 1 and type 2 diabetes. A review of the current literature describing the association between food insecurity and diabetes reveals possible mechanisms and pathophysiologic pathways. There is less evidence for effective interventions, and much of the current literature is limited to cross-sectional studies. Future work should evaluate longitudinal associations and ways to help vulnerable patients with diabetes access adequate food for effective diabetes management. C1 [Essien, Utibe R.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Essien, Utibe R.; Berkowitz, Seth A.] Harvard Med Sch, 50 Staniford St,9th Floor, Boston, MA 02114 USA. [Shahid, Naysha N.; Berkowitz, Seth A.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Shahid, Naysha N.; Berkowitz, Seth A.] Massachusetts Gen Hosp, Diabet Populat Hlth Res Ctr, Boston, MA 02114 USA. RP Berkowitz, SA (reprint author), Harvard Med Sch, 50 Staniford St,9th Floor, Boston, MA 02114 USA.; Berkowitz, SA (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA.; Berkowitz, SA (reprint author), Massachusetts Gen Hosp, Diabet Populat Hlth Res Ctr, Boston, MA 02114 USA. EM saberkowitz@partners.org OI Berkowitz, Seth/0000-0003-1030-4297 NR 73 TC 0 Z9 0 U1 10 U2 10 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 EI 1539-0829 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD SEP PY 2016 VL 16 IS 9 AR 79 DI 10.1007/s11892-016-0774-y PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU1UV UT WOS:000381996300001 PM 27421977 ER PT J AU McGill, DE Levitsky, LL AF McGill, Dayna E. Levitsky, Lynne L. TI Management of Hypoglycemia in Children and Adolescents with Type 1 Diabetes Mellitus SO CURRENT DIABETES REPORTS LA English DT Review DE Type 1 diabetes; Hypoglycemia; Continuous glucose monitoring; Insulin; Glucagon ID RANDOMIZED CLINICAL-TRIAL; YOUNG-CHILDREN; NOCTURNAL HYPOGLYCEMIA; UNCOOKED CORNSTARCH; EPINEPHRINE RESPONSES; INSULIN SUSPENSION; GLYCEMIC CONTROL; EXERCISE; ASSOCIATION; BRAIN AB Hypoglycemia and fear of hypoglycemia limit appropriate glycemic control in many children and adolescents with type 1 diabetes. Traditional approaches to the prevention of hypoglycemia including patient education about modifiable risk factors for hypoglycemia (changes in insulin, diet, and exercise) and frequency of self glucose monitoring remain important for hypoglycemia prevention. Continuous glucose monitoring systems with or without a partial closed-loop control of insulin infusion have been very useful in the prevention of hypoglycemia. Oral carbohydrate and parenteral glucagon continue to be the mainstays of hypoglycemia treatment. In the future, we can look forward to regulatory approval of closed-loop insulin delivery and glucose monitoring systems to facilitate euglycemia, as well as glucagon administered by the intranasal route to treat hypoglycemia. C1 [McGill, Dayna E.] Harvard Med Sch, MassGen Hosp Children, Joslin Diabet Ctr, Pediat, 5th Floor,175 Cambridge St, Boston, MA 02114 USA. [Levitsky, Lynne L.] Harvard Med Sch, MassGen Hosp Children, Div Pediat Endocrinol, Pediat, 5th Floor,175 Cambridge St, Boston, MA 02114 USA. RP Levitsky, LL (reprint author), Harvard Med Sch, MassGen Hosp Children, Div Pediat Endocrinol, Pediat, 5th Floor,175 Cambridge St, Boston, MA 02114 USA. EM DMcGill@mgh.harvard.edu; LLevitsky@partners.org FU Joslin Diabetes Center NIH Training grant [T32 DK007260-39] FX Dayna McGill is supported by the Joslin Diabetes Center NIH Training grant, T32 DK007260-39. NR 49 TC 1 Z9 2 U1 9 U2 9 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 EI 1539-0829 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD SEP PY 2016 VL 16 IS 9 AR 88 DI 10.1007/s11892-016-0771-1 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU1UV UT WOS:000381996300010 PM 27515311 ER PT J AU Klein, M Berger, S Hoogman, M Dammers, J Makkinje, R Heister, AJGAM Galesloot, TE Kiemeney, LALM Weber, H Kittel-Schneider, S Lesch, KP Reif, A Ribases, M Ramos-Quiroga, JA Cormand, B Zayats, T Hegvik, TA Jacobsen, KK Johansson, S Haavik, J Mota, NR Bau, CHD Grevet, EH Doyle, A Faraone, SV Arias-Vasquez, A Franke, B AF Klein, Marieke Berger, Stefanie Hoogman, Martine Dammers, Janneke Makkinje, Remco Heister, Angelien J. G. A. M. Galesloot, Tessel E. Kiemeney, Lambertus A. L. M. Weber, Heike Kittel-Schneider, Sarah Lesch, Klaus-Peter Reif, Andreas Ribases, Marta Ramos-Quiroga, Josep Antoni Cormand, Bru Zayats, Tetyana Hegvik, Tor-Arne Jacobsen, Kaya K. Johansson, Stefan Haavik, Jan Mota, Nina R. Bau, Claiton H. D. Grevet, Eugenio H. Doyle, Alysa Faraone, Stephen V. Arias-Vasquez, Alejandro Franke, Barbara TI Meta-analysis of the DRD5 VNTR in persistent ADHD SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE DRD5; Attention-Deficit/Hyperactivity Disorder; Candidate gene; Meta-analysis ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEVELOPMENTAL COURSE; ASSOCIATION; GENES AB Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. DRD5, the gene encoding the dopamine receptor D5, was recently confirmed as a candidate gene for ADHD in children through meta-analysis. In this study, we aimed at studying the association of the ADHD-associated variable number tandem repeat (VNTR) polymorphism upstream of DRD5 with adult ADHD. We compiled data from six sites of the International Multicentre persistent ADHD CollaboraTion (IMpACT) and reached N=6979 (3344 cases and 3635 healthy participants), the largest sample investigated so far. We tested the association of the common DRD5 alleles with categorically defined ADHD and with inattentive and hyperactive/impulsive symptom counts. Our findings provide evidence that none of the common DRD5 alleles are associated with ADHD risk or ADHD symptom counts in adults. (C) 2016 Elsevier B.V. and ECNP. All rights reserved. C1 [Klein, Marieke; Berger, Stefanie; Hoogman, Martine; Dammers, Janneke; Makkinje, Remco; Heister, Angelien J. G. A. M.; Arias-Vasquez, Alejandro; Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Human Genet, Nijmegen, Netherlands. [Berger, Stefanie; Weber, Heike; Kittel-Schneider, Sarah; Reif, Andreas] Univ Hosp Frankfurt, Dept Psychiat Psychosomat Med & Psychotherapy, Frankfurt, Germany. [Galesloot, Tessel E.; Kiemeney, Lambertus A. L. M.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands. [Weber, Heike] Univ Hosp Wurzburg, IZKF Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, Wurzburg, Germany. [Lesch, Klaus-Peter] Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, Div Mol Psychiat, ADHD Clin Res Unit, Wurzburg, Germany. [Ribases, Marta; Ramos-Quiroga, Josep Antoni] Inst Salud Carlos III, Biomed Network Res Ctr Mental Hlth CIBERSAM, Madrid, Spain. [Ribases, Marta; Ramos-Quiroga, Josep Antoni] Univ Autonoma Barcelona, Dept Psychiat & Forens Med, Barcelona, Catalonia, Spain. [Ribases, Marta; Ramos-Quiroga, Josep Antoni] Univ Autonoma Barcelona, Univ Hosp Vall dHebron, Dept Psychiat, Barcelona, Catalonia, Spain. [Ribases, Marta; Ramos-Quiroga, Josep Antoni] Univ Hosp Vall dHebron, Psychiat Genet Unit, Barcelona, Catalonia, Spain. [Cormand, Bru] Univ Barcelona, Dept Genet, Fac Biol, Barcelona, Catalonia, Spain. [Cormand, Bru] Univ Barcelona IBUB, Inst Biomed, Barcelona, Catalonia, Spain. [Cormand, Bru] Inst Salud Carlos III, Inst Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain. [Zayats, Tetyana; Hegvik, Tor-Arne; Jacobsen, Kaya K.; Haavik, Jan] Univ Bergen, Dept Biomed, KG Jebsen Ctr Neuropsychiat Disorders, Bergen, Norway. [Hegvik, Tor-Arne; Jacobsen, Kaya K.; Johansson, Stefan] Haukeland Hosp, Ctr Med Genet & Mol Med, Bergen, Norway. [Johansson, Stefan; Faraone, Stephen V.] Univ Bergen, Dept Clin Sci, KG Jebsen Ctr Neuropsychiat Disorders, Bergen, Norway. [Haavik, Jan] Haukeland Hosp, Dept Psychiat, Bergen, Norway. [Mota, Nina R.; Bau, Claiton H. D.] Univ Fed Rio Grande do Sul, Inst Biosci, Dept Genet, Porto Alegre, RS, Brazil. [Mota, Nina R.; Bau, Claiton H. D.; Grevet, Eugenio H.] Hosp Clin Porto Alegre, Adult Div, ADHD Outpatient Program, Porto Alegre, RS, Brazil. [Grevet, Eugenio H.] Univ Fed Rio Grande do Sul, Fac Med, Dept Psychiat, Porto Alegre, RS, Brazil. [Doyle, Alysa] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Doyle, Alysa] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA USA. [Doyle, Alysa] Broad Inst, Stanley Ctr Psychiat Res, Cambridge, 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. [Arias-Vasquez, Alejandro; Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Psychiat, Nijmegen, Netherlands. [Arias-Vasquez, Alejandro] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Cognit Neurosci, Nijmegen, Netherlands. RP Franke, B (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, 855,POB 9101, NL-6500 HB Nijmegen, Netherlands. EM Barbara.franke@radboudumc.nl RI Johansson, Stefan/C-4394-2011; Franke, Barbara/D-4836-2009; Lesch, Klaus-Peter/J-4906-2013; OI Johansson, Stefan/0000-0002-2298-7008; Franke, Barbara/0000-0003-4375-6572; Lesch, Klaus-Peter/0000-0001-8348-153X; Mota, Nina/0000-0003-3504-759X; Kittel-Schneider, Sarah/0000-0003-3057-6150; Cormand, Bru/0000-0001-5318-4382; Ribases, Marta/0000-0003-1039-1116; Haavik, Jan/0000-0001-7865-2808 FU Netherlands Organization for Scientific Research (NWO) [433-09-229, 016-130-669]; Netherlands Brain Foundation [15F07[16]27]; BBMRI-NL [CP2010-33).[2]27, CP2010-33]; DFG [KFO 125, SFB TRR 58, RTG 1252, BMBF 01GV0605]; Instituto de Salud Carlos III [PI11/00571, PI11/01629, PI12/01139, PI14/01700]; European Regional Development Fund (ERDF); Agenda de Gestio d'Ajuts Universitaris i de Recerca-AGAUR; Generalitat de Catalunya [2014SGR1357, 2014SGR0932]; Ministerio de Economia y Competitividad, Spain [SAF2012-33484]; NARSAD Young Investigator Grant from the Brain a Behavior Research Foundation; Miguel de Servet contract from the Instituto de Salud Carlos III, Spain [CP09/00119]; Brazilian National Council for Scientific and Technological Development (CNPq) [476529/2012-3, 306678/2012-8, 466722/2014-1]; European Community [602805, 643051] FX IMpACT-NL: The Dutch IMpACT study is supported by grants from the Netherlands Organization for Scientific Research (NWO), i.e. the NWO Brain Et Cognition Excellence Program (Grant 433-09-229) and a Vici grant to BF (Grant 016-130-669), and by grants from the Netherlands Brain Foundation (Grant 15F07[16]27) and BBMRI-NL (Grant CP2010-33).[2]27) and BBMRI-NL (Grant CP2010-33). The German IMpACT study is supported by grants from the DFG (KFO 125 to AR and KPL; SFB TRR 58 to AR and KPL; RTG 1252, to AR and KPL, BMBF 01GV0605, to KPL).; IMpACT-SPAIN: The Spanish IMpACT study is supported by Instituto de Salud Carlos III (PI11/00571, PI11/01629, PI12/01139, PI14/01700), and cofinanced by the European Regional Development Fund (ERDF), Agenda de Gestio d'Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya (2014SGR1357, 2014SGR0932), Ministerio de Economia y Competitividad, Spain (SAF2012-33484) and a NARSAD Young Investigator Grant from the Brain a Behavior Research Foundation. M Ribases is a recipient of a Miguel de Servet contract from the Instituto de Salud Carlos III, Spain (CP09/00119).; IMpACT-BRA: Claiton H. D. Bau received the following grants from the Brazilian National Council for Scientific and Technological Development (CNPq): 476529/2012-3; 306678/2012-8; 466722/2014-1. The research leading to these results also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under Grant agreement no. 602805 (Aggressotype) and from the European Community's Horizon 2020 Programme (H2020/2014-2020) under Grant agreement no. 643051 (MiND). NR 16 TC 1 Z9 1 U1 6 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2016 VL 26 IS 9 BP 1527 EP 1532 DI 10.1016/j.euroneuro.2016.06.012 PG 6 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DV5ZS UT WOS:000383009800018 PM 27480019 ER PT J AU Cantor, A Woo, A Ghamari, A Pregernig, G Fraenkel, E Patry, C Zheng, KN AF Cantor, Alan Woo, Andrew Ghamari, Alireza Pregernig, Gabriela Fraenkel, Ernest Patry, Chelsea Zheng, Kangni TI ZFP148 (ZBP-89)/ZFP281 (ZBP-99) FAMILY TRANSCRIPTION FACTORS ARE REQUIRED FOR NORMAL ERYTHROID DIFFERENTIATION SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 45th Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 25-28, 2016 CL San Diego, CA SP Int Soc Expt Hematol C1 [Cantor, Alan; Ghamari, Alireza; Patry, Chelsea; Zheng, Kangni] Boston Childrens Hosp, Boston, MA USA. [Cantor, Alan] Dana Farber Canc Inst, Boston, MA 02115 USA. [Cantor, Alan] Harvard Med Sch, Boston, MA USA. [Woo, Andrew] Univ Western Australia, Perth, WA, Australia. [Pregernig, Gabriela; Fraenkel, Ernest] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD SEP PY 2016 VL 44 IS 9 SU 1 MA 3024 BP S63 EP S63 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DU4LR UT WOS:000382184600090 ER PT J AU Dykstra, B Lee, J Mortensen, L Wu, L Lin, C Rossi, D Sackstein, R AF Dykstra, Brad Lee, Jungmin Mortensen, Luke Wu, Leon Lin, Charles Rossi, Derrick Sackstein, Robert TI GLYCOENGINEERING OF E-SELECTIN LIGANDS BY INTRINSIC VERSUS EXTRINSIC FUCOSYLATION DIFFERENTIALLY AFFECTS OSTEOTROPISM OF HUMAN MESENCHYMAL STEM CELLS SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 45th Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 25-28, 2016 CL San Diego, CA SP Int Soc Expt Hematol C1 [Dykstra, Brad; Sackstein, Robert] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Dykstra, Brad] Harvard Med Sch, Boston, MA USA. [Lee, Jungmin] Boston Childrens Hosp, Boston, MA USA. [Mortensen, Luke] Univ Georgia, Athens, GA 30602 USA. [Wu, Leon] Biotechne Com, Minneapolis, MN USA. [Lin, Charles] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rossi, Derrick] Harvard Univ, Boston, MA 02115 USA. NR 0 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 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD SEP PY 2016 VL 44 IS 9 SU 1 MA 3041 BP S68 EP S68 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DU4LR UT WOS:000382184600107 ER PT J AU Mercier, F Sykes, D Scadden, D AF Mercier, Francois Sykes, David Scadden, David TI SINGLE TARGETED EXON MUTATION CREATES A TRUE CONGENIC MOUSE FOR COMPETITIVE HEMATOPOIETIC STEM CELL TRANSPLANTATION: THE C57BL/6-CD45.1STEM MOUSE SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 45th Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 25-28, 2016 CL San Diego, CA SP Int Soc Expt Hematol C1 [Mercier, Francois; Sykes, David; Scadden, David] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD SEP PY 2016 VL 44 IS 9 SU 1 MA 2022 BP S47 EP S47 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DU4LR UT WOS:000382184600049 ER PT J AU Pear, W Yashiro-Ohtani, Y Petrovic, J Yu, SQ Mercado, V Xu, LW Falyabi, R Liu, XS Aster, J Zang, G AF Pear, Warren Yashiro-Ohtani, Yumi Petrovic, Jelena Yu, Shuqian Mercado, Vicki Xu, Lanwei Falyabi, Robert Liu, Xiaolu Shirley Aster, Jon Zang, George TI MODULAR DOMAINS WITHIN A SUPER ENHANCER DETERMINE DRUG RESISTANCE IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 45th Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 25-28, 2016 CL San Diego, CA SP Int Soc Expt Hematol C1 [Pear, Warren; Yashiro-Ohtani, Yumi; Petrovic, Jelena; Mercado, Vicki; Xu, Lanwei; Falyabi, Robert] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Liu, Xiaolu Shirley; Zang, George] Dana Farber Canc Inst, Boston, MA 02115 USA. [Aster, Jon] Brigham & Womens Hosp, Boston, MA 02115 USA. 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 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD SEP PY 2016 VL 44 IS 9 SU 1 MA 1005 BP S25 EP S25 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DU4LR UT WOS:000382184600005 ER PT J AU Rowe, G Wang, L Coma, S Han, A Sousa, P Wagers, A Daley, G AF Rowe, Grant Wang, Leo Coma, Silvia Han, Areum Sousa, Patricia Wagers, Amy Daley, George TI DEVELOPMENTAL REGULATION OF MYELOERYTHROID PROGENITOR FUNCTION BY THE LIN28B-LET-7-HMGA2 AXIS SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 45th Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 25-28, 2016 CL San Diego, CA SP Int Soc Expt Hematol C1 [Rowe, Grant; Wang, Leo] Dana Farber Canc Inst, Boston, MA 02115 USA. [Coma, Silvia; Han, Areum; Sousa, Patricia; Daley, George] Boston Childrens Hosp, Boston, MA USA. [Wagers, Amy] Joslin Diabet Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD SEP PY 2016 VL 44 IS 9 SU 1 MA 2029 BP S50 EP S50 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DU4LR UT WOS:000382184600056 ER PT J AU Sankaran, VG AF Sankaran, Vijay G. TI HEMATOPOIESIS IN NATURA: INSIGHT FROM STUDIES OF BLOOD PRODUCTION IN HUMANS SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 45th Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 25-28, 2016 CL San Diego, CA SP Int Soc Expt Hematol C1 [Sankaran, Vijay G.] Boston Childrens Hosp, Boston, MA USA. [Sankaran, Vijay G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sankaran, Vijay G.] Broad Inst, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD SEP PY 2016 VL 44 IS 9 SU 1 MA 1028 BP S36 EP S36 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DU4LR UT WOS:000382184600028 ER PT J AU Silberstein, L Goncalves, K Kharchenko, P Turcotte, R Kfoury, Y Mercier, F Severe, N Baryawno, N Lin, C Scadden, D AF Silberstein, Lev Goncalves, Kevin Kharchenko, Peter Turcotte, Raphael Kfoury, Youmna Mercier, Francois Severe, Nicolas Baryawno, Ninib Lin, Charles Scadden, David TI PROXIMITY-BASED ANALYSIS OF THE BONE MARROW NICHE IDENTIFIES NOVEL EXTRINSIC REGULATORS OF HEMATOPOIETIC REGENERATION SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 45th Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 25-28, 2016 CL San Diego, CA SP Int Soc Expt Hematol C1 [Silberstein, Lev; Kfoury, Youmna; Mercier, Francois; Severe, Nicolas; Baryawno, Ninib] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Goncalves, Kevin] Tufts Univ, Medford, MA 02155 USA. [Kharchenko, Peter; Lin, Charles] Harvard Univ, Boston, MA 02115 USA. [Turcotte, Raphael] HHMI, Chevy Chase, MD 20815 USA. [Scadden, David] Ctr Regenerat Med, North Miami, FL 33161 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD SEP PY 2016 VL 44 IS 9 SU 1 MA 3139 BP S100 EP S100 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DU4LR UT WOS:000382184600202 ER PT J AU Van Etten, R Hu, YG Zhang, ZH Yoshida, T Jena, N Kashiwagi, M Joshi, I El-Bardeesy, N Somasundaram, R Sigvardsson, M Liu, ZY Tata, P Korber, S Raufi, A Krause, D Paietta, E Georgopoulos, K AF Van Etten, Richard Hu, Yeguang Zhang, Zihong Yoshida, Toshimi Jena, Nilamani Kashiwagi, Mariko Joshi, Ila El-Bardeesy, Nabeel Somasundaram, Rajesh Sigvardsson, Mikael Liu, Zhong-Ying Tata, Prasanthi Korber, Shane Raufi, Alex Krause, Daniela Paietta, Elisabeth Georgopoulos, Katia TI CENTRAL ROLE FOR IKAROS IN PRE-B CELL DIFFERENTIATION AND PATHOGENESIS OF HIGH-RISK B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 45th Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 25-28, 2016 CL San Diego, CA SP Int Soc Expt Hematol C1 [Van Etten, Richard; Jena, Nilamani; Liu, Zhong-Ying; Tata, Prasanthi; Korber, Shane; Raufi, Alex] UC Irvine, Irvine, CA USA. [Van Etten, Richard] Chao Family Comprehens Canc Ctr, Orange, CA USA. [Van Etten, Richard] Div Hematol Oncol, Orange, CA USA. [Hu, Yeguang; Zhang, Zihong; Yoshida, Toshimi; Kashiwagi, Mariko; Joshi, Ila; El-Bardeesy, Nabeel; Georgopoulos, Katia] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Somasundaram, Rajesh; Sigvardsson, Mikael] Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden. [Krause, Daniela] Georg Speyer Haus, Inst Tumor Biol & Expt Therapy, Frankfurt, Germany. [Paietta, Elisabeth] Montifiore Med Ctr, Bronx, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD SEP PY 2016 VL 44 IS 9 SU 1 MA 1018 BP S31 EP S31 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DU4LR UT WOS:000382184600018 ER PT J AU Zon, LI AF Zon, Leonard I. TI PATHWAYS REGULATING STEM CELL INDUCTION, SELF-RENEWAL AND ENGRAFTMENT SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 45th Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 25-28, 2016 CL San Diego, CA SP Int Soc Expt Hematol C1 [Zon, Leonard I.] Boston Childrens Hosp, Boston, MA USA. [Zon, Leonard I.] Harvard Med Sch, Boston, MA USA. [Zon, Leonard I.] HHMI, Boston, MA USA. [Zon, Leonard I.] Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. [Zon, Leonard I.] Childrens Hosp, Hem Onc, Boston, MA 02115 USA. [Zon, Leonard I.] Harvard Univ, Stem Cell & Regenerat Biol Dept, Harvard Med Sch, Dana Farber Canc Inst,HHMI,HSCI, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD SEP PY 2016 VL 44 IS 9 SU 1 MA 1030 BP S37 EP S37 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DU4LR UT WOS:000382184600030 ER PT J AU Manchikanti, L Boswell, MV Hirsch, JA AF Manchikanti, Laxmaiah Boswell, Mark V. Hirsch, Joshua A. TI Innovations in interventional pain management of chronic spinal pain SO EXPERT REVIEW OF NEUROTHERAPEUTICS LA English DT Review DE Neural blockade; epidural injections; spinal cord stimulation; regenerative medicine; minimally invasive lumbar decompression; endoscopic spinal decompression; regenerative medicine; evidence synthesis; methodological quality assessment ID EPIDURAL STEROID INJECTIONS; LUMBAR DISC HERNIATION; PREVENT NEUROLOGIC COMPLICATIONS; DIRECT-CURRENT STIMULATION; PLATELET-RICH PLASMA; CORD STIMULATION; INTERVERTEBRAL DISC; UNITED-STATES; BACK-PAIN; FOLLOW-UP AB Introduction: Interventional pain management dates back to 1901, with significant innovations, which include the definition, literature synthesis, pathophysiology, and technical interventions.Areas covered: Interventional pain management and interventional techniques include neural blockade, neural ablative procedures, spinal cord and peripheral nerve stimulation, intrathecal drug delivery systems, minimally invasive lumbar decompression (MILD (R)), percutaneous endoscopic spinal decompression, and regenerative medicine. In addition, advances are also related to the evidence synthesis of comparative effectiveness research.Expert commentary: Multiple innovations in interventional pain management and potential innovations may reduce costs and improve care and outcomes with proper evidence synthesis and application of principles of evidence-based medicine. Innovations in interventional pain management in managing chronic spinal pain depend on extensive research and appropriate evidence synthesis. Innovations should be developed in conjunction with health care policy based on principles of evidence-based medicine. C1 [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Manchikanti, Laxmaiah; Boswell, Mark V.] Univ Louisville, Anesthesiol & Perioperat Med, Louisville, KY 40292 USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, NeuroIntervent Serv, Boston, MA 02114 USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Neuroendovasc Program, 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 104 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1473-7175 EI 1744-8360 J9 EXPERT REV NEUROTHER JI Expert Rev. Neurother. PD SEP PY 2016 VL 16 IS 9 BP 1033 EP 1042 DI 10.1080/14737175.2016.1194204 PG 10 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DV5AE UT WOS:000382936600006 PM 27224937 ER PT J AU Saghazadeh, A Esfahani, SA Rezaei, N AF Saghazadeh, Amene Esfahani, Shadi A. Rezaei, Nima TI Genetic polymorphisms and the adequacy of brain stimulation: state of the art SO EXPERT REVIEW OF NEUROTHERAPEUTICS LA English DT Review DE Single nucleotide polymorphisms; brain stimulation; pharmacogenetics ID NEUROTROPHIC-FACTOR GENE; TRANSCRANIAL MAGNETIC STIMULATION; TREATMENT-RESISTANT DEPRESSION; BDNF VAL66MET POLYMORPHISM; ONSET ALZHEIMERS-DISEASE; DEFICIT HYPERACTIVITY DISORDER; APOLIPOPROTEIN-E POLYMORPHISM; COMT VAL/MET POLYMORPHISM; FAMILY-BASED ASSOCIATION; GEL-BASED MICROARRAY AB Introduction: Heterogeneity of therapeutic response to brain stimulation techniques has inspired scientists to uncover the secrets to success or failure of these projects. Genetic polymorphisms are one of the major causes of this heterogeneity.Areas covered: More than twenty genetic variants within more than ten genes (e.g. BDNF, COMT, DRD2, TRPV1, 5-HT1A, 5-HHT, P2RX7, VEGF, TPH1, TPH2, ACE, APOE, GNB3, NET, NMDA receptors, and RGS4) have been investigated, among which the BDNF gene and its polymorphism, Val66Met, is the best documented variant. We review the genotypic combinations, which are reported to interact with the work of brain stimulation, of which the DRD2 C957T polymorphism is the most prominent type. Finally, implications of transcranial magnetic stimulation in deciphering the interaction between genetic background (e.g. SCN1A and 5-HTT) and drugs (e.g. carbamazepine and citalopram) at the cortical excitability level is explained.Expert commentary: Studies are ongoing to find missing factors responsible for heterogeneity of response to brain stimulation techniques. Further knowledge about genetic factors affecting the therapeutic response to brain stimulation techniques might provide helpful guidelines for choosing ideal candidates for treatment. C1 [Saghazadeh, Amene; Rezaei, Nima] Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Childrens Med Ctr, Tehran, Iran. [Saghazadeh, Amene] USERN, NeuroImmunol Res Assoc NIRA, Tehran, Iran. [Esfahani, Shadi A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Esfahani, Shadi A.] USERN, NIIMA, Boston, MA USA. [Rezaei, Nima] Univ Tehran Med Sci, Sch Med, Dept Immunol, Tehran, Iran. [Rezaei, Nima] USERN, NIIMA, Tehran, Iran. RP Rezaei, N (reprint author), Childrens Med Ctr Hosp, Dr Qarib St,Keshavarz Blvd, Tehran 14194, Iran. EM rezaei_nima@tums.ac.ir NR 122 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1473-7175 EI 1744-8360 J9 EXPERT REV NEUROTHER JI Expert Rev. Neurother. PD SEP PY 2016 VL 16 IS 9 BP 1043 EP 1054 DI 10.1080/14737175.2016.1194202 PG 12 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DV5AE UT WOS:000382936600007 PM 27228124 ER PT J AU Atri, M Zhang, Z Dehdashti, F Lee, SI Ali, S Marques, H Koh, WJ Moore, K Landrum, L Kim, JW DiSilvestro, P Eisenhauer, E Schnell, F Gold, M AF Atri, Mostafa Zhang, Zheng Dehdashti, Farrokh Lee, Susanna I. Ali, Shamshad Marques, Helga Koh, Wui-Jin Moore, Kathleen Landrum, Lisa Kim, Jae Weon DiSilvestro, Paul Eisenhauer, Eric Schnell, Frederick Gold, Michael TI Utility of PET-CT to evaluate retroperitoneal lymph node metastasis in advanced cervical cancer: Results of ACRIN6671/GOG0233 trial SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Cervical cancer; Lymph node metastasis; PET-CT; CT ID POSITRON-EMISSION-TOMOGRAPHY; UTERINE CERVIX; RADIATION-THERAPY; DIAGNOSTIC-VALUE; CARCINOMA; METAANALYSIS; PRETREATMENT; RADIOTHERAPY; IRRADIATION; MANAGEMENT AB Objective. To assess if FDG PET combined with diagnostic CT improves diagnostic CT accuracy to detect lymph node (LN) metastasis in advanced cervical cancer. Methods. A prospective HIPAA compliant ACRIN/GOG multicenter trial was conducted. Patients underwent concurrent diagnostic contrast-enhanced CT (DCT) and PET and pelvic/abdominal lymphadenectomy. Seven independent blinded readers reviewed PET-DCT and DCT one-month apart Reference standard was surgically removed LN pathology. Accuracy values were calculated at participant level, correlating abdominal (right and left para-aortic/common iliac) and pelvic (right and left external iliac/obturator) LN regions with pathology, respecting laterality. Reader average sensitivities/specificities of PET-DCT vs. DCT were compared with generalized linear mixed models, and AUCs with Obuchowski's method. Results. One hundred fifty-three patients had PET-DCT and pathology. Forty-three of 153 patients had metastasis to abdominal LNs. Sample size calculation required review of the first 40 abdominal positive and 40 randomly selected abdominal negative studies. Patients were 24 to 74 years (48.9 +/- 10.6) old. Mean sensitivities of PET-DCT/DCT for detection of LN metastasis in abdomen were 0.50 (CI: 0.44, 0.56) and 0.42 (CI: 0.36, 0.48) (p = 0.052) and in pelvis 0.83 (CI: 0.78, 0.87) and 0.79 (CI: 0.73, 0.83) (p = 0.15). Corresponding specificities were 0.85 (CI: 0.80, 0.89) and 0.89 (CI: 0.84, 0.92) (p = 0.21) and 0.63 (CI: 0.54, 0.70) and 0.62 (CI: 0.53, 0.69) (p = 0.83). Mean AUC values were 0.70 (CI: 0.61,0.79) and 0.68 (CI: 0.59, 0.77) (p = 0.43) and 0.80 (CI: 0.71, 0.88) and 0.76 (CI: 0.67,0.85) (p = 0.21) respectively. Conclusion. Addition of PET to DCT resulted-in-statistically borderline increase in sensitivity to detect LN metastasis in abdomen in advanced cervical cancer. (C) 2016 Elsevier Inc. All rights reserved. C1 [Atri, Mostafa] Univ Hlth Network, Toronto, ON, Canada. [Zhang, Zheng; Marques, Helga] Brown Univ, Providence, RI 02912 USA. [Dehdashti, Farrokh] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Lee, Susanna I.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ali, Shamshad] Roswell Pk Canc Inst, Buffalo, NY USA. [Koh, Wui-Jin] Washington Univ, St Louis, MO 63130 USA. [Moore, Kathleen; Landrum, Lisa] Univ Oklahoma, Hlth Sci Ctr, Norman, OK 73019 USA. [Kim, Jae Weon] Seoul Natl Univ, Coll Med, Seoul 151, South Korea. [Eisenhauer, Eric] Univ Cincinnati, Cincinnati, OH 45221 USA. [Schnell, Frederick] Cent Georgia Canc Care, Macon, GA USA. [Gold, Michael] Tulsa Canc Inst, Tulsa, OK USA. RP Atri, M (reprint author), Univ Toronto, Dept Med Imaging, Univ Hlth Network, NCSB 1C569 Toronto Gen Hosp,585 Univ Ave, Toronto, ON M5G 2N2, Canada. EM mostafa.atri@uhn.ca OI Landrum, Lisa/0000-0002-4010-6833 FU National Cancer Institute (NCI) grant (ACRIN) [U10 CA80098, U10 CA079778]; National Cancer Institute (NCI) grant (GOG) [U10CA27469, U10 CA37517]; National Cancer Institute (NCI) grant (ECOG-ACRIN) [U01 CA079778, U01 CA080098] FX American College of Radiology Imaging Network [ACRIN], Gynecologic Oncology Group [GOG], and ECOG-ACRIN components of this trial were funded through the National Cancer Institute (NCI) grants (ACRIN: U10 CA80098 and U10 CA079778), (GOG: U10CA27469 and U10 CA37517), (ECOG-ACRIN: U01 CA079778 and U01 CA080098). NR 26 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 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD SEP PY 2016 VL 142 IS 3 BP 413 EP 419 DI 10.1016/j.ygyno.2016.05.002 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DV7KQ UT WOS:000383115200007 PM 27178725 ER PT J AU Soares, RR Maesta, I Colon, J Braga, A Salazar, A Charry, RC Sun, SY Goldstein, DP Berkowitz, RS AF Soares, Renan Rocha Maesta, Izildinha Colon, Jose Braga, Antonio Salazar, Aleydah Charry, Rafael Cortes Sun, Sue Yazaki Goldstein, Donald P. Berkowitz, Ross S. TI Complete molar pregnancy in adolescents from North and South America: Clinical presentation and risk of gestational trophoblastic neoplasia SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Molar pregnancy; Adolescents; Gestational trophoblastic neoplasia ID COMPLETE HYDATIDIFORM MOLE; MATERNAL AGE; DISEASE CENTER; MANAGEMENT; WOMEN; CHEMOTHERAPY; DIAGNOSIS; DECADES AB Objectives. To compare complete hydatidiform mole (CHM) clinical presentation and risk factors associated with GTN development between North American and South American adolescents. Methods. This non-concurrent cohort study was undertaken including adolescents with CHM referred to centers in North America (New England Trophoblastic Disease Center, Harvard University, USA), and South America (Botucatu Trophoblastic Disease Center-Sao Paulo State University, Brazil; Trophoblastic Unit of Central University of Venezuela and Matemidad Concepcion Palacios of Caracas, Venezuela) between 1990 and 2012. Data were obtained from medical records and pathology reports. Study participants were allocated into 2 groups: North America (NA) and South America (SA). Results. In NA and SA, 13.1% and 30.9% of patients with hydatidiform mole were adolescents, respectively. Of these, 77.6% in NA and 86.1% in SA had pathologic diagnosis of CHM (p = 0.121). Vaginal bleeding (SA = 69% vs NA = 51%; p = 0.020), anemia (SA = 48% vs NA = 18%; p<0.001), and elevated serum hCG (SA = 232,860 mIU/mL vs NA = 136,412 mIU/mL; p = 0.039) were more frequent in SA than in NA. Median gestational age at diagnosis (SA = 12 weeks, NA = 11 weeks; p = 0.030) differed whereas GTN development rate (SA = 20%, NA = 27%; p = 0.282) showed no significant difference between groups. Compared to NA, medical complications and clinical factors associated with post-molar GTN were more frequent among SA adolescents. Conclusions. Medical complications and clinical factors associated with GTN development were more frequent in SA than in NA adolescents with CHM, suggesting that, in South America, awareness about the importance of diagnosing molar pregnancy early and considering CHM in the differential diagnosis in adolescents suspected to be pregnant should be raised. (C) 2016 Elsevier Inc. All rights reserved. C1 [Soares, Renan Rocha; Maesta, Izildinha] UNESP Sao Paulo State Univ, Botucatu Med Sch, Dept Gynecol & Obstet, Botucatu, SP, Brazil. [Maesta, Izildinha] UNESP Sao Paulo State Univ, Botucatu Med Sch, Trophoblast Dis Ctr, Botucatu, SP, Brazil. [Colon, Jose] Maternidad Concepc Palacios Caracas, Caracas, Venezuela. [Braga, Antonio] Univ Fed Rio de Janeiro, Matern Sch, Trophoblast Dis Ctr, Rio De Janeiro, Brazil. [Braga, Antonio] Univ Fed Fluminense, Antonio Pedro Univ Hosp, Trophoblast Dis Ctr, Rio De Janeiro, Brazil. [Salazar, Aleydah; Charry, Rafael Cortes] Cent Univ Venezuela, Univ Hosp Caracas, GTD Unit, Dept Obstet & Gynecol, Caracas, Venezuela. [Sun, Sue Yazaki] UNIFESP Sao Paulo Fed Univ, Paulista Sch Med, Dept Obstet, Trophoblast Dis Ctr,Sao Paulo Hosp, Sao Paulo, SP, Brazil. [Goldstein, Donald P.; Berkowitz, Ross S.] Brigham & Womens Hosp, New England Trophoblast Dis Ctr, Donald P Goldstein MD Trophoblast Tumor Registry, Harvard Canc Ctr,Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. [Goldstein, Donald P.; Berkowitz, Ross S.] Harvard Med Sch, Boston, MA USA. RP Maesta, I (reprint author), UNESP Sao Paulo State Univ, Botucatu Med Sch, Dept Gynecol & Obstet, Botucatu, SP, Brazil. EM imaesta@fmb.unesp.br OI Braga, Antonio/0000-0002-2942-6182 FU Sao Paulo Research Foundation-FAPESP [2013/09633-6]; Donald P. Goldstein, MD Trophoblastic Tumor Registry Endowment; Dyett Family Trophoblastic Disease Research and Registry Endowment FX The authors are thankful for the support of the Sao Paulo Research Foundation-FAPESP (grant # 2013/09633-6), the Donald P. Goldstein, MD Trophoblastic Tumor Registry Endowment and the Dyett Family Trophoblastic Disease Research and Registry Endowment. NR 31 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD SEP PY 2016 VL 142 IS 3 BP 496 EP 500 DI 10.1016/j.ygyno.2016.07.002 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DV7KQ UT WOS:000383115200020 PM 27423380 ER PT J AU Wang, D Li, CB Zhang, Y Wang, M Jiang, N Xiang, L Li, T Roberts, TM Zhao, JJ Cheng, HL Liu, PX AF Wang, Dong Li, Chengbo Zhang, Yuan Wang, Min Jiang, Nan Xiang, Lin Li, Ting Roberts, Thomas M. Zhao, Jean J. Cheng, Hailing Liu, Pixu TI Combined inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Ovarian cancer; BKM120; Olaparib; BRCA; Combination therapy ID NEGATIVE BREAST-CANCER; POLY(ADP-RIBOSE) POLYMERASE; COMBINATION; OLAPARIB; PHOSPHORYLATION; ASSOCIATION; NVP-BKM120; RESISTANCE; CARCINOMA; MUTATION AB Objective. Combined inhibition of PI3K and PARP has been shown to be effective in the treatment of preclinical models of breast cancer and prostate cancer independent of BRCA or PIK3CA mutational status. However, the knowledge about this combination treatment in ovarian cancer is limited. The aim of this study was to evaluate the therapeutic effect of PI3K inhibitor BKM1 20 and PARP inhibitor Olaparib on ovarian cancer cell lines bearing wild-type PIK3CA genes. Methods. We exposed three wild-type PIK3CA ovarian cancer cell lines to a PI3K inhibitor BKM120 and/or a PARP inhibitor Olaparib. The effect of BKM120 as a single-agent or in combination with Olaparib was evaluated by Cell Count Kit (CCK8) assay, immunoblotting, comet assay, flow cytometry and immunofluorescence staining assay. The combination indexes for synergistic effect on cell viability were calculated with the Chou-Talalay method. Ex vivo cultured ovarian cancer tissues from patients were analyzed by histological and immunohistochemical analyses. Results. Combined inhibition of PI3K and PARP effectively synergized to block the growth of three wild-type PIK3CA ovarian cancer cell lines and explants of a primary ovarian tumor specimen. Mechanistically, dual blockade of MK and PARP in these ovarian cancer cell lines resulted in substantially attenuated PI3K/AKT/mTOR signaling, impaired DNA damage response and deficient homologous recombination repair, with remarkable BRCA downregulation. Conclusions. The combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib may be effective in ovarian cancers with a broader spectrum of cancer-associated genetic alterations but not limited to those with mutant PIK3CA or BRCA genes. BRCA downregulation may be a potential biomarker for the effective response to the proposed combination treatment. (C) 2016 Published by Elsevier Inc. C1 [Wang, Dong; Zhang, Yuan; Wang, Min; Jiang, Nan; Xiang, Lin; Li, Ting; Cheng, Hailing; Liu, Pixu] Dalian Med Univ, Inst Canc Stem Cell, Hosp 2, Inst Canc, Dalian 116044, Peoples R China. [Wang, Dong] Binzhou Med Univ, Dept Histol & Embryol, Yantai 264000, Peoples R China. [Li, Chengbo] Dalian Med Univ, Hosp 2, Dept Obstet & Gynecol, Dalian 116044, Peoples R China. [Roberts, Thomas M.; Zhao, Jean J.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Cheng, HL; Liu, PX (reprint author), Dalian Med Univ, Inst Canc Stem Cell, Hosp 2, Inst Canc, Dalian 116044, Peoples R China.; Zhao, JJ (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM jean_zhao@dfci.harvard.edu; hailingcheng_dmu@163.com; pixu_liu@dmu.edu.cn FU National Natural Science Foundation of China [81472447, 81372853, 81572586]; Liaoning Provincial Climbing Scholars Supporting Program of China; Program for Changjiang Scholars and Innovative Research Team in University [IRT13049]; Provincial Natural Science Foundation of Liaoning [2014023002] FX This work was supported by the National Natural Science Foundation of China (No. 81472447 to H. Cheng; No. 81372853 and No. 81572586 to P. Liu), Liaoning Provincial Climbing Scholars Supporting Program of China (2012 to P. Liu, 2014 to H. Cheng), Program for Changjiang Scholars and Innovative Research Team in University (No. IRT13049 to P. Liu), and Provincial Natural Science Foundation of Liaoning (No. 2014023002 to P. Liu). NR 32 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 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD SEP PY 2016 VL 142 IS 3 BP 548 EP 556 DI 10.1016/j.ygyno.2016.07.092 PG 9 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DV7KQ UT WOS:000383115200028 PM 27426307 ER PT J AU Poole, EM Konstantinopoulos, PA Terry, KL AF Poole, Elizabeth M. Konstantinopoulos, Panagiotis A. Terry, Kathryn L. TI Prognostic implications of reproductive and lifestyle factors in ovarian cancer SO GYNECOLOGIC ONCOLOGY LA English DT Review DE Ovarian cancer; Prognosis; Survival; Reproductive; Lifestyle ID CLEAR-CELL CARCINOMA; RECREATIONAL PHYSICAL-ACTIVITY; HORMONE REPLACEMENT THERAPY; PROGRESSION-FREE SURVIVAL; ASSOCIATION CONSORTIUM; SOCIOECONOMIC-STATUS; BRCA2 MUTATIONS; MISMATCH-REPAIR; STAGE-III; WOMEN AB Introduction. Despite strides in identifying factors that predict risk of ovarian cancer and improvements in ovarian cancer treatment, little is known about factors that predict ovarian cancer survival. Methods. We reviewed the literature for analyses of factors before, at, or after diagnosis that may predict survival outcomes, including demographics (e.g., age and race), genetics (e.g., inherited BRCA mutations), hormonal factors (e.g., parity and hormone use), and lifestyle (e.g., physical activity and diet). Results. While treatment factors, tumor characteristics and genetic syndromes are predictive of survival, few studies of most hormonal and lifestyle factors have been published; most have evaluated pre-diagnosis factors. For example, we identified eight studies that examined menopausal hormone use prior to diagnosis, reporting a non-significant survival benefit for users compared to non-users, while four studies reported better survival with use after surgery, though only two were significant. Similarly, while increased body size has been extensively studied as potentially associated with reduced survival, other modifiable factors, such as diet and physical activity remain understudied. We identified three studies of pre-diagnosis physical activity and five studies of pre diagnosis diet, with a suggestive benefit of higher vegetable intake and vigorous physical activity. By contrast, large studies of the impact of race/ethnicity and socioeconomic status (SES) confirm that non-white women and women of lower SES fare more poorly than white women and women of higher SES, respectively. Conclusions. Our review of the published literature on predictors of ovarian cancer survival revealed that modifiable lifestyle factors may be related to survival, but that hormonal factors do not strongly predict outcomes in ovarian cancer patients. However, more attention should be paid to women's post-diagnosis survival experience. The dearth of literature on post-diagnosis factors that may improve outcomes makes it difficult to make specific recommendations for survivors. (C) 2016 Elsevier Inc. All rights reserved. C1 [Poole, Elizabeth M.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Poole, Elizabeth M.; Terry, Kathryn L.] Harvard Med Sch, Boston, MA USA. [Poole, Elizabeth M.; Terry, Kathryn L.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Konstantinopoulos, Panagiotis A.] Harvard Med Sch, Dana Farber Canc Inst, Div Med Gynecol Oncol, Boston, MA USA. [Terry, Kathryn L.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA. RP Terry, KL (reprint author), 221 Longwood Ave, Boston, MA 02115 USA. EM kterry@partners.org FU Department of Defense Ovarian Cancer Academy Awards [W81XWH-13-1-0493, W81XWH-10-1-0585, W81XWH-10-1-0280]; Rivkin Center for Ovarian Cancer Skacel Family Scholar Award; Stand Up To Cancer-Ovarian Cancer Research Fund-Ovarian Cancer National Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant [SU2C-AACR-DT16-15]; DOD [W81XWH-14-OCRP-OCACAOC140632] FX Department of Defense Ovarian Cancer Academy Awards W81XWH-13-1-0493 (EMP), W81XWH-10-1-0585 (PAK), and W81XWH-10-1-0280 (KLT); and the Rivkin Center for Ovarian Cancer Skacel Family Scholar Award (EMP).; DOD W81XWH-14-OCRP-OCACAOC140632 (PAK), and the Stand Up To Cancer-Ovarian Cancer Research Fund-Ovarian Cancer National Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant SU2C-AACR-DT16-15 (PAK). NR 64 TC 2 Z9 2 U1 3 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD SEP PY 2016 VL 142 IS 3 BP 574 EP 587 DI 10.1016/j.ygyno.2016.05.014 PG 14 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DV7KQ UT WOS:000383115200031 PM 27189457 ER PT J AU Shaikh, AY Wang, N Yin, XY Larson, MG Vasan, RS Hamburg, NM Magnani, JW Ellinor, PT Lubitz, SA Mitchell, GF Benjamin, EJ McManus, DD AF Shaikh, Amir Y. Wang, Na Yin, Xiaoyan Larson, Martin G. Vasan, Ramachandran S. Hamburg, Naomi M. Magnani, Jared W. Ellinor, Patrick T. Lubitz, Steven A. Mitchell, Gary F. Benjamin, Emelia J. McManus, David D. TI Relations of Arterial Stiffness and Brachial Flow-Mediated Dilation With New-Onset Atrial Fibrillation The Framingham Heart Study SO HYPERTENSION LA English DT Article DE arrhythmia; augmentation index; flow-mediated dilation; pulse wave velocity; tonometry ID INCIDENT CARDIOVASCULAR EVENTS; PULSE PRESSURE; ENDOTHELIAL DYSFUNCTION; RISK-FACTORS; AORTIC STIFFNESS; OLDER-ADULTS; SYSTOLIC HYPERTENSION; INDEPENDENT PREDICTOR; AUGMENTATION INDEX; BLOOD-PRESSURE AB The relations of measures of arterial stiffness, pulsatile hemodynamic load, and endothelial dysfunction to atrial fibrillation (AF) remain poorly understood. To better understand the pathophysiology of AF, we examined associations between noninvasive measures of vascular function and new-onset AF. The study sample included participants aged =45 years from the Framingham Heart Study offspring and third-generation cohorts. Using Cox proportional hazards regression models, we examined relations between incident AF and tonometry measures of arterial stiffness (carotid-femoral pulse wave velocity), wave reflection (augmentation index), pressure pulsatility (central pulse pressure), endothelial function (flow-mediated dilation), resting brachial arterial diameter, and hyperemic flow. AF developed in 407/5797 participants in the tonometry sample and 270/3921 participants in the endothelial function sample during follow-up (median 7.1 years, maximum 10 years). Higher augmentation index (hazard ratio, 1.16; 95% confidence interval, 1.02-1.32; P=0.02), baseline brachial artery diameter (hazard ratio, 1.20; 95% confidence interval, 1.01-1.43; P=0.04), and lower flowmediated dilation (hazard ratio, 0.79; 95% confidence interval, 0.63-0.99; P=0.04) were associated with increased risk of incident AF. Central pulse pressure, when adjusted for age, sex, and hypertension (hazard ratio, 1.14; 95% confidence interval, 1.02-1.28; P=0.02) was associated with incident AF. Higher pulsatile load assessed by central pulse pressure and greater apparent wave reflection measured by augmentation index were associated with increased risk of incident AF. Vascular endothelial dysfunction may precede development of AF. These measures may be additional risk factors or markers of subclinical cardiovascular disease associated with increased risk of incident AF. C1 [Shaikh, Amir Y.] Univ Massachusetts, Sch Med, Dept Med, 55 Lake Ave N, Worcester, MA 01655 USA. [Wang, Na] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA 02215 USA. [Yin, Xiaoyan; Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Yin, Xiaoyan; Larson, Martin G.; Vasan, Ramachandran S.; Benjamin, Emelia J.] NHLBI, Boston, MA USA. [Yin, Xiaoyan; Larson, Martin G.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Sect Cardiovasc Med Prevent Med & Epidemiol, Dept Med, Sch Med, Boston, MA 02215 USA. [Hamburg, Naomi M.; Magnani, Jared W.] Boston Univ, Div Cardiol, Dept Med, Sch Med, Boston, MA 02215 USA. [Ellinor, Patrick T.; Lubitz, Steven A.] Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA 02114 USA. [Ellinor, Patrick T.; Lubitz, Steven A.] Harvard Med Sch, Cambridge, MA USA. [Ellinor, Patrick T.; Lubitz, Steven A.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. [Benjamin, Emelia J.] Boston Univ, Evans Mem Med Dept, Cardiol Sect, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Prevent Med Sect, Sch Med, Boston, MA 02215 USA. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Med, Div Cardiol, Worcester, MA USA. RP Shaikh, AY (reprint author), Univ Massachusetts, Sch Med, Dept Med, 55 Lake Ave N, Worcester, MA 01655 USA. EM Amir.Shaikh@umassmemorial.org FU National Heart Lung and Blood Institute (NHLBI) [N01-HC-25195, HHSN268201500001I, R01-DK-080739, R01-HL-107385, R01-HL-126136, 1R01HL60040, 1RO1-HL-70100, 1R01HL128914, 2R01HL092577, K24HL105780]; American Heart Association [13EIA14220013]; Foundation Leducq [14CVD01]; National Institutes of Health (NIH) [KL2RR031981, 1R15HL121761]; office of Naval Research work unit [N00014-12-1-0171] FX This study was supported, in part, by National Heart Lung and Blood Institute (NHLBI) contracts N01-HC-25195 and HHSN268201500001I (R.S. Vasan), R01-DK-080739 (R.S. Vasan), R01-HL-107385 (R.S. Vasan and G.F. Mitchell), R01-HL-126136 (R.S. Vasan and G.F. Mitchell), and 1R01HL60040 (E.J. Benjamin); 1RO1-HL-70100 (E.J. Benjamin); 1R01HL128914 (E.J. Benjamin and P.T. Ellinor); 2R01HL092577 (E.J. Benjamin and P.T. Ellinor) and K24HL105780 (P.T. Ellinor). P.T. Ellinor is also supported by an Established Investigator Award from the American Heart Association (13EIA14220013) and by the Foundation Leducq (14CVD01). D.D. McManus's time was funded by National Institutes of Health (NIH) grants KL2RR031981 and 1R15HL121761 and office of Naval Research work unit N00014-12-1-0171. NR 53 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 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD SEP PY 2016 VL 68 IS 3 BP 590 EP 596 DI 10.1161/HYPERTENSIONAHA.116.07650 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DT1ZK UT WOS:000381280400015 PM 27456517 ER PT J AU Rahman, F Yin, XY Larson, MG Ellinor, PT Lubitz, SA Vasan, RS McManus, DD Magnani, JW Benjamin, EJ AF Rahman, Faisal Yin, Xiaoyan Larson, Martin G. Ellinor, Patrick T. Lubitz, Steven A. Vasan, Ramachandran S. McManus, David D. Magnani, Jared W. Benjamin, Emelia J. TI Trajectories of Risk Factors and Risk of New-Onset Atrial Fibrillation in the Framingham Heart Study SO HYPERTENSION LA English DT Article DE atrial fibrillation; blood pressure; epidemiology; risk factors; trajectories ID BLOOD-PRESSURE; DEVELOPMENTAL TRAJECTORIES; ATHEROSCLEROSIS RISK; COHORT; COMMUNITY; AMERICANS; DIAMETER; SCORE AB The associations of long-term patterns of risk factors and the risk of incident atrial fibrillation (AF) are incompletely characterized. Among 4351 Framingham Study participants (mean age 50 +/- 11 years at baseline examination, 57% women) from the original and offspring cohorts, we defined longitudinal patterns, referred to as trajectories, of AF risk factors and a composite AF risk score using approximate to 16 years of data. We used Cox proportional hazards models to examine the association of trajectories to 15-year risk of AF. During follow-up, 719 participants developed AF. Five distinct trajectory groups were identified for systolic blood pressure (BP): groups 1 and 2 (normotensive throughout), group 3 (prehypertensive), group 4 (hypertensive initially with decreasing BP), and group 5 (hypertensive and increasing BP). In multivariable-adjusted analyses, compared with group 1, groups 4 (hazard ratio 2.05; 95% confidence interval 1.24-3.37) and 5 (hazard ratio 1.95; 95% confidence interval 1.08-3.49) were associated with incident AF. Three trajectory groups were identified for antihypertensive treatment. Compared with the group with no treatment throughout, the other 2 groups were associated with increased risk of incident AF. Distinct trajectories for diastolic BP, smoking, diabetes mellitus, and the composite risk score were not associated with increased 15-year risk of AF. Longitudinal trajectories may distinguish how exposures related to AF contribute toward prospective AF risk. Distinct trajectory groups with persistently elevated systolic BP and longer antihypertensive treatment are associated with increased risk of incident AF. C1 [Rahman, Faisal] Boston Univ, Med Ctr, Dept Med, Boston, MA 02215 USA. [Yin, Xiaoyan; Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Yin, Xiaoyan; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Sect Cardiovasc Med Prevent Med & Epidemiol, Dept Med, Boston, MA 02215 USA. [Ellinor, Patrick T.; Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Yin, Xiaoyan; Larson, Martin G.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Natl Heart Lung & Blood Inst & Boston Univ Framin, Boston, MA USA. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Med, Div Cardiol, Worcester, MA USA. [Magnani, Jared W.] Univ Pittsburgh, UPMC Heart & Vasc Inst, Div Cardiol, Dept Med, Pittsburgh, PA 15260 USA. RP Benjamin, EJ (reprint author), Boston Univ Sch Med & Publ Hlth Heart Study, Med & Epidemiol, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM emelia@bu.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU National Institutes of Health (NIH) [R03AG045075, K23HL114724, KL2RR031981, 2R01HL092577, 1R01HL128914]; Doris Duke Charitable Foundation [2015084, 2014105]; American Heart Association [13EIA14220013]; Fondation Leducg [14CVD01]; [HHSN268201500001I]; [N01-HC-25195]; [RC1HL101056]; [1P50HL120163]; [R01HL104156]; [K24HL105780] FX This work was supported by HHSN268201500001I; N01-HC-25195; National Institutes of Health (NIH) grants R03AG045075 (J.W. Magnani), K23HL114724 (S.A. Lubitz), KL2RR031981 (D.D. McManus), 2R01HL092577, 1R01HL128914 (P.T. Ellinor and E.J. Benjamin); RC1HL101056, 1P50HL120163 (E.J. Benjamin); R01HL104156, K24HL105780 (P.T. Ellinor); grant 2015084 from the Doris Duke Charitable Foundation (J.W. Magnani); grant 2014105 from the Doris Duke Charitable Foundation (S.A. Lubitz); American Heart Association Award 13EIA14220013 (P.T. Ellinor); and by the Fondation Leducg 14CVD01 (P.T. Ellinor). NR 26 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 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD SEP PY 2016 VL 68 IS 3 BP 597 EP + DI 10.1161/HYPERTENSIONAHA.116.07683 PG 18 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DT1ZK UT WOS:000381280400016 PM 27512109 ER PT J AU Taber, DJ Hunt, KJ Fominaya, CE Payne, EH Gebregziabher, M Srinivas, TR Baliga, PK Egede, LE AF Taber, David J. Hunt, Kelly J. Fominaya, Cory E. Payne, Elizabeth H. Gebregziabher, Mulugeta Srinivas, Titte R. Baliga, Prabhakar K. Egede, Leonard E. TI Impact of Cardiovascular Risk Factors on Graft Outcome Disparities in Black Kidney Transplant Recipients SO HYPERTENSION LA English DT Article DE cardiovascular disease; diabetes mellitus; graft survival; hypertension; prevalence ID RENAL-ALLOGRAFT SURVIVAL; HIGH BLOOD-PRESSURE; AFRICAN-AMERICAN; RACIAL-DIFFERENCES; ETHNIC DISPARITIES; ORGAN TRANSPLANT; PATIENT SURVIVAL; UNITED NETWORK; ADHERENCE; DISEASE AB Although outcome inequalities for non-Hispanic black (NHB) kidney transplant recipients are well documented, there is paucity in data assessing the impact of cardiovascular disease (CVD) risk factors on this disparity in kidney transplantation. This was a longitudinal study of a national cohort of veteran kidney recipients transplanted between January 2001 and December 2007. Data included baseline characteristics acquired through the United States Renal Data System linked to detailed clinical follow-up information acquired through the Veterans Affairs electronic health records. Analyses were conducted using sequential multivariable modeling (Cox regression), incorporating blocks of variables into iterative nested models; 3139 patients were included (2095 non-Hispanic whites [66.7%] and 1044 NHBs [33.3%]). NHBs had a higher prevalence of hypertension (100% versus 99%; P<0.01) and post-transplant diabetes mellitus (59% versus 53%; P<0.01) with reduced control of hypertension (blood pressure <140/90 60% versus 69%; P<0.01), diabetes mellitus (A1c <7%, 35% versus 47%; P<0.01), and low-density lipoprotein (<100 mg/dL, 55% versus 61%; P<0.01). Adherence to medications used to manage CVD risk was significantly lower in NHBs. In the fully adjusted models, the independent risk of graft loss in NHBs was substantially reduced (unadjusted hazard ratio, 2.00 versus adjusted hazard ratio, 1.49). CVD risk factors and control reduced the influence of NHB race by 9% to 18%. Similar trends were noted for mortality, and estimates were robust across in sensitivity analyses. These results demonstrate that NHB kidney transplant recipients have significantly higher rates of CVD risk factors and reduced CVD risk control. These issues are likely partly related to medication nonadherence and meaningfully contribute to racial disparities for graft outcomes. C1 [Taber, David J.; Baliga, Prabhakar K.] Med Univ South Carolina, Div Transplant Surg, Coll Med, Charleston, SC USA. [Srinivas, Titte R.] Med Univ South Carolina, Div Transplant Nephrol, Charleston, SC USA. [Srinivas, Titte R.] Med Univ South Carolina, Div Transplant Nephrol, Charleston, SC USA. [Taber, David J.; Fominaya, Cory E.] Ralph H Johnson VAMC, Dept Pharm Serv, Charleston, SC USA. [Egede, Leonard E.] Ralph H Johnson VAMC, Vet Affairs HSR&D Hlth Equ & Rural Outreach Innov, Charleston, SC USA. RP Taber, DJ (reprint author), Med Univ South Carolina, Div Transplant Surg, 96 Jonathan Lucas St,MSC 611, Charleston, SC 29425 USA. EM taberd@musc.edu OI Gebregziabher, Mulugeta/0000-0002-4826-481X FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [K23DK099440] FX Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number K23DK099440. NR 63 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 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD SEP PY 2016 VL 68 IS 3 BP 715 EP + DI 10.1161/HYPERTENSIONAHA.116.07775 PG 21 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DT1ZK UT WOS:000381280400028 PM 27402921 ER PT J AU Branch-Elliman, W Stanislawski, M Strymish, J Baron, AE Gupta, K Varosy, PD Gold, HS Ho, PM AF Branch-Elliman, Westyn Stanislawski, Maggie Strymish, Judith Baron, Anna E. Gupta, Kalpana Varosy, Paul D. Gold, Howard S. Ho, P. Michael TI Cardiac Electrophysiology Laboratories: A Potential Target for Antimicrobial Stewardship and Quality Improvement? SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID ELECTRONIC DEVICE INFECTIONS; UNITED-STATES; CARDIOVERTER-DEFIBRILLATORS; ANTIBIOTIC-PROPHYLAXIS; PERMANENT PACEMAKER; CLINICAL-ASSESSMENT; HEART-ASSOCIATION; MANAGEMENT; IMPLANTATION; SURGERY AB BACKGROUND. Infections following cardiovascular implantable electronic device (CIED) procedures, including pacemaker and implantable cardioverter-defibrillators, are devastating and costly. Preimplantation prophylactic antimicrobials are effective for reducing postprocedural infections. However, routine postprocedural antimicrobials are not associated with improved outcomes, and they may be harmful. Thus, we sought to characterize antimicrobial use patterns following CIED procedures. DESIGN. All patients who underwent CIED procedures from October 1, 2007 to September 30, 2013 and had procedural information entered into the VA Clinical Assessment Reporting and Tracking (CART) software program were included in this study. All antibiotic prescriptions lasting more than 24 hours following device implantation or revision were identified using pharmacy databases, and postprocedural antibiotic use lasting more than 24 hours was characterized. RESULTS. In total, 3,712 CIED procedures were performed at 34 VA facilities on 3,570 patients with a mean age of 71.7 years (standard deviation [SD], 11.1 years), 98.4% of whom were male. Postprocedural antibiotics >24 hours were prescribed following 1,579 of 3,712 CIED procedures (42.5%). The median duration of therapy was 5 days (interquartile range [IQR], 3-7 days). The most commonly prescribed antibiotic was cephalexin (1,152 of 1,579; 72.9%), followed by doxycycline (118 of 1,579; 7.47%) and ciprofloxacin (93 of 1,579; 5.9%). Vancomycin was used in 73 of 1,579 prescriptions (4.62%). Among the highest quartile of procedural volume, prescribing practices varied considerably, ranging from 3.2% to 77.6%. CONCLUSIONS. Nearly 1 in 2 patients received prolonged postprocedural antimicrobial therapy following CIED procedures, and the rate of postprocedural antimicrobial therapy use varied considerably by facility. Given the lack of demonstrated benefit of routine prolonged antimicrobial therapy following CIED procedures, antimicrobial use following cardiac device interventions may be a potential target for quality improvement programs and antimicrobial stewardship. C1 [Branch-Elliman, Westyn; Varosy, Paul D.; Ho, P. Michael] Eastern Colorado VA Healthcare Syst, Dept Med, Div Infect Dis, Denver, CO USA. [Branch-Elliman, Westyn; Varosy, Paul D.; Ho, P. Michael] Eastern Colorado VA Healthcare Syst, Dept Med, Div Cardiol, Denver, CO USA. [Branch-Elliman, Westyn; Baron, Anna E.; Varosy, Paul D.; Ho, P. Michael] Univ Colorado, Sch Med, Dept Med, Div Infect Dis, Denver, CO USA. [Branch-Elliman, Westyn; Baron, Anna E.; Varosy, Paul D.; Ho, P. Michael] Univ Colorado, Sch Med, Dept Med, Div Cardiol, Denver, CO USA. [Branch-Elliman, Westyn; Stanislawski, Maggie; Baron, Anna E.; Varosy, Paul D.; Ho, P. Michael] Seattle Denver Ctr Innovat Vet Ctr & Value Driven, Seattle, WA USA. [Branch-Elliman, Westyn; Stanislawski, Maggie; Baron, Anna E.; Varosy, Paul D.; Ho, P. Michael] Seattle Denver Ctr Innovat Vet Ctr & Value Driven, Denver, CO USA. [Strymish, Judith; Gupta, Kalpana] Boston VA Healthcare Syst, Dept Med, Div Infect Dis, West Roxbury, MA USA. [Strymish, Judith; Gold, Howard S.] Harvard Med Sch, Boston, MA USA. [Baron, Anna E.] Colorado Sch Publ Hlth, Dept Biostat & Informat, Denver, CO USA. [Gupta, Kalpana] Boston Univ, Sch Med, Boston, MA 02118 USA. [Gold, Howard S.] Beth Israel Deaconess Med Ctr, Dept Med, Div Infect Dis, Boston, MA 02215 USA. RP Branch-Elliman, W (reprint author), Boston VA Healthcare Syst, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM Westyn.Branch-Elliman@VA.gov FU Seattle-Denver Center of Innovation for Veteran-Centered and Value-Driven Care (Seattle, Washington and Denver, Colorado) FX The research was supported by the Seattle-Denver Center of Innovation for Veteran-Centered and Value-Driven Care (Seattle, Washington and Denver, Colorado). NR 28 TC 0 Z9 0 U1 1 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD SEP PY 2016 VL 37 IS 9 BP 1005 EP 1011 DI 10.1017/ice.2016.116 PG 7 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DV4LJ UT WOS:000382896800001 PM 27322021 ER PT J AU Quast, J Knobloch, MJ Patterson, E Purvis, S Shirley, D Safdar, N AF Quast, Joshua Knobloch, Mary Jo Patterson, Erin Purvis, Suzanne Shirley, Daniel Safdar, Nasia TI Understanding Inpatient Perceptions of Indwelling Urinary Catheters Using the Health Belief Model SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article AB Patient interviews using the Health Belief Model framework identified thematic patient perceptions of indwelling urinary catheters and catheter-associated urinary tract infections. Generally, patients perceived catheters as convenient and were unaware of catheter alternatives and risks for infection. Better patient education is needed to reduce urinary catheter use and infections. C1 [Quast, Joshua; Knobloch, Mary Jo; Safdar, Nasia] Univ Wisconsin, Dept Med, Div Infect Dis, Madison, WI USA. [Knobloch, Mary Jo; Patterson, Erin; Safdar, Nasia] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Purvis, Suzanne] Univ Wisconsin, Dept Med, Div Geriatr, Madison, WI USA. [Shirley, Daniel] Univ Wisconsin, Dept Med, Div Hosp Med, Madison, WI USA. RP Safdar, N (reprint author), 1685 Highland Ave, Madison, WI 53705 USA. EM ns2@medicine.wisc.edu FU Agency for Healthcare Research and Quality [R03HS023791] FX Agency for Healthcare Research and Quality (grant R03HS023791). NR 9 TC 0 Z9 0 U1 5 U2 5 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD SEP PY 2016 VL 37 IS 9 BP 1098 EP 1100 DI 10.1017/ice.2016.120 PG 3 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DV4LJ UT WOS:000382896800013 PM 27225225 ER PT J AU Harada, T Hideshima, T Anderson, KC AF Harada, Takeshi Hideshima, Teru Anderson, Kenneth C. TI Histone deacetylase inhibitors in multiple myeloma: from bench to bedside SO INTERNATIONAL JOURNAL OF HEMATOLOGY LA English DT Article DE Multiple myeloma; Histone deacetylase (HDAC); HDAC inhibitor; Proteasome inhibitor; Immunomodulatory drugs ID SUBEROYLANILIDE HYDROXAMIC ACID; PHASE-I TRIAL; CELL-DEATH; MONOCLONAL GAMMOPATHY; MULTIDRUG-RESISTANCE; PANOBINOSTAT LBH589; LYSINE ACETYLATION; HDAC INHIBITORS; P-GLYCOPROTEIN; BORTEZOMIB AB Histone deacetylases (HDACs) deacetylate the lysine residues of both histones and non-histone proteins. Histone acetylation results in a loose local chromatin structure that regulates gene-specific transcription. Non-histone proteins can also be acetylated, leading to dynamic changes in their activity and stability. For these reasons, HDAC inhibition has emerged as a potential approach for the treatment of MM. Specifically, combination treatment with HDAC inhibitors and proteasome inhibitors or immunomodulatory drugs shows remarkable anti-MM activity in both preclinical and clinical settings. However, the clinical studies using non-selective HDAC inhibitors also cause unfavorable side effects in patients, leading us to develop more isoform- and/or class-selective HDAC inhibitors to enhance tolerability without diminishing anti-MM activity, thereby improving patient outcome in MM. C1 [Harada, Takeshi; Hideshima, Teru; Anderson, Kenneth C.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr, 450 Brookline Ave, Boston, MA 02215 USA. RP Hideshima, T (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr, 450 Brookline Ave, Boston, MA 02215 USA. EM teru_hideshima@dfci.harvard.edu NR 71 TC 4 Z9 4 U1 8 U2 8 PU SPRINGER JAPAN KK PI TOKYO PA CHIYODA FIRST BLDG EAST, 3-8-1 NISHI-KANDA, CHIYODA-KU, TOKYO, 101-0065, JAPAN SN 0925-5710 EI 1865-3774 J9 INT J HEMATOL JI Int. J. Hematol. PD SEP PY 2016 VL 104 IS 3 BP 300 EP 309 DI 10.1007/s12185-016-2008-0 PG 10 WC Hematology SC Hematology GA DU3ND UT WOS:000382117300006 PM 27099225 ER PT J AU Park, KK Tsai, TY Dimitriou, D Kwon, YM AF Park, Kwan Kyu Tsai, Tsung-Yuan Dimitriou, Dimitris Kwon, Young-Min TI Three-dimensional in vivo difference between native acetabular version and acetabular component version influences iliopsoas impingement after total hip arthroplasty SO INTERNATIONAL ORTHOPAEDICS LA English DT Article DE Iliopsoas impingement; Total hip arthroplasty; In-vivo 3-dimensional study ID ANTERIOR; REPLACEMENT; ANTEVERSION; PROSTHESIS; DIAGNOSIS AB The potential influence of acetabular component orientation on iliopsoas impingement in total hip arthroplasty (THA) has not been previously quantified. The aim of the present study was to utilize pre- and post-operative CT-based 3D models to quantify iliopsoas impingement on acetabular components, and to identify any potential factors associated with iliopsoas impingement. Iliopsoas muscle was modelled from pre-operative CT scans and transferred to the post-operative 3D models in 19 THAs. The volume and the area of the overlap between iliopsoas muscle and acetabular cup (iliopsoas volume & area) was measured on axial and sagittal images. Most protruded lengths of cup uncovered by acetabular bone were measured on axial sagittal scan of CT scans. Version of acetabulum, acetabular cup, and the difference between the two (version difference) were also measured with cup inclination and size. Linear regression analysis was performed to identify any factor influencing iliopsoas impingement. Iliopsoas impingement volume and area were 100.6 +/- 226.1 (range, 0.0-663.9) mmA(3) and 52.6 +/- 102.0 (0.0-342.3) mmA(3), respectively. The protruded lengths on axial and sagittal view were 6.9 +/- 5.3 (0.0-16.0) and 2.1 +/- 2.7 (0.0-8.0). Linear regression model showed that version difference was significantly related to the iliopsoas impingement volume and area (beta = -0.709, p = 0.041 for volume, and beta = -0.684, p = 0.047 for area). The results of this study demonstrate that iliopsoas impingement on acetabular components was influenced by the version difference between pre-operative acetabular bone and acetabular component rather than the magnitude of post-operative cup version alone. C1 [Park, Kwan Kyu; Tsai, Tsung-Yuan; Dimitriou, Dimitris; Kwon, Young-Min] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab, Boston, MA 02114 USA. [Park, Kwan Kyu] Yonsei Univ, Dept Orthopaed Surg, Coll Med, Seoul, South Korea. [Kwon, Young-Min] Harvard Med Sch, Dept Orthopaed Surg, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kwon, YM (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab, Boston, MA 02114 USA.; Kwon, YM (reprint author), Harvard Med Sch, Dept Orthopaed Surg, Massachusetts Gen Hosp, Boston, MA 02114 USA. EM kkpark@yuhs.ac; ttsai1@partners.org; ddimitriou@partners.org; ymkwon@mgh.harvard.edu OI Tsai, Tsung-Yuan/0000-0003-1522-2987; Dimitriou, Dimitris/0000-0002-9558-7080 FU Mako Surgical Inc. FX The authors would like to acknowledge the technical guidance of Dr. Guoan Li. There was a partial funding from Mako Surgical Inc. NR 20 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0341-2695 EI 1432-5195 J9 INT ORTHOP JI Int. Orthop. PD SEP PY 2016 VL 40 IS 9 BP 1807 EP 1812 DI 10.1007/s00264-015-3055-5 PG 6 WC Orthopedics SC Orthopedics GA DU3DO UT WOS:000382091200004 PM 26611727 ER PT J AU Kwon, YM Liow, MHL Dimitriou, D Tsai, TY Freiberg, AA Rubash, HE AF Kwon, Young-Min Liow, Ming Han Lincoln Dimitriou, Dimitris Tsai, Tsung-Yuan Freiberg, Andrew A. Rubash, Harry E. TI What Is the Natural History of "Asymptomatic" Pseudotumours in Metal-on-Metal Hip Arthroplasty? Minimum 4-Year Metal Artifact Reduction Sequence Magnetic Resonance Imaging Longitudinal Study SO JOURNAL OF ARTHROPLASTY LA English DT Article DE "asymptomatic" pseudotumour; metal-on-metal; hip arthroplasty; MARS MRI; longitudinal study ID TISSUE-REACTIONS; ASSOCIATION; MANAGEMENT; DEBRIS; COHORT AB Background: Metal Artifact Reduction Sequence Magnetic Resonance Imaging (MARS-MRI) is an important cross-sectional imaging modality in detection of metal-on-metal (MoM) hip arthroplasty (HA) pseudotumours. Potential evolution of pseudotumours detected by MARS-MRI in "asymptomatic" patients with MoMHA arthroplasty beyond 2 years remains largely unknown. The aims of this longitudinal study were to (1) determine the natural history of pseudotumours in "asymptomatic" MoMHA patients under MARS-MRI surveillance and (2) characterize MRI feature(s) associated with progressive pseudotumours. Methods: A total of 37 MoMHA (32 patients, mean 56 years old) with pseudotumours on MARS-MRI were evaluated longitudinally using a standardized MARS-MRI protocol. Serum cobalt and chromium levels, pseudotumour size, thickness of the cyst wall, and MRI signal intensity of the abnormality were recorded and analyzed. Results: At minimum of 4-year follow-up (range 49-54 months), 4 Type II pseudotumours (11%) demonstrated MRI evidence of progression. Five Type I pseudotumours (14%) were found to have "regressed." No measurable MRI progression was detected in remaining patients (75%). MRI features associated with progressive pseudotumours included the presence of increased cystic wall thickness and "atypical" mixed fluid signal. MRI pseudotumour progression was not associated with metal ion levels. Conclusion: The natural history of type I cystic pseudotumours continues to be nonprogressive in most "asymptomatic" MoMHA patients at minimum 4 years, suggesting the importance of patient symptoms and MRI characteristic features in the clinical decision-making process. Routine follow-up MARS-MRI evaluation of "asymptomatic" patients with low-grade cystic pseudotumours in the absence of interval clinical changes may not be indicated. (c) 2016 Elsevier Inc. All rights reserved. C1 [Kwon, Young-Min; Liow, Ming Han Lincoln; Dimitriou, Dimitris; Tsai, Tsung-Yuan; Freiberg, Andrew A.; Rubash, Harry E.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St,YAW 3700, Boston, MA 02114 USA. RP Kwon, YM (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St,YAW 3700, Boston, MA 02114 USA. OI Dimitriou, Dimitris/0000-0002-9558-7080 NR 23 TC 0 Z9 0 U1 1 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD SEP PY 2016 VL 31 IS 9 SU S BP S121 EP S126 DI 10.1016/j.arth.2016.02.070 PG 6 WC Orthopedics SC Orthopedics GA DU4UU UT WOS:000382208900026 PM 27094245 ER PT J AU Nebergall, AK Greene, ME Rubash, H Malchau, H Troelsen, A Rolfson, O AF Nebergall, Audrey K. Greene, Meridith E. Rubash, Harry Malchau, Henrik Troelsen, Anders Rolfson, Ola TI Thirteen- Year Evaluation of Highly Cross-Linked Polyethylene Articulating With Either 28-mm or 36-mm Femoral Heads Using Radiostereometric Analysis and Computerized Tomography SO JOURNAL OF ARTHROPLASTY LA English DT Article DE total hip arthroplasty; highly cross-linked polyethylene; radiostereometic analysis; computerized tomography; large femoral head; osteolysis ID MOLECULAR-WEIGHT POLYETHYLENE; TOTAL HIP-ARTHROPLASTY; LOW-FRICTION ARTHROPLASTY; IN-VIVO WEAR; PERIPROSTHETIC OSTEOLYSIS; ACETABULAR COMPONENTS; SIZE; REPLACEMENT; DISLOCATION; LINERS AB Background: The objective of this 13-year prospective evaluation of highly cross-linked ultra high molecular weight polyethylene (HXLPE) was to (1) assess the long-term wear of HXLPE articulating with 2 femoral head sizes using radiostereometric analysis (RSA) and to (2) determine if osteolysis is a concern with this material through the use of plain radiographs and computerized tomography (CT). Methods: All patients received a Longevity HXLPE liner with tantalum beads and either a 28-mm or 36-mm femoral head. Twelve patients (6 in each head size group) agreed to return for 13-year RSA, plain radiograph, and CT follow-up. The 1-year and 13-year plain radiographs as well as the CT scans were analyzed for the presence of osteolysis. Results: The 13-year mean +/- standard error steady-state wear was 0.05 +/- 0.02 mm with no significant increase over time or between the 2 head size groups. Two patients' CT scans showed radiolucent regions in the acetabulum of 4.51 cm(3) and 11.25 cm(3), respectively. In one patient, this area corresponded to a partially healed degenerative cyst treated with autograft during surgery. The second patient had an acetabular protrusio treated with autograft, and the CT scan revealed areas of remodeling of this graft. One patient's 13-year plain radiographs showed evidence of cup loosening and linear radiolucencies in zones 2 and 3. Conclusion: There was no evidence of significant wear over time using RSA. The CT scans did not show evidence of osteolysis due to wear particles. These results suggest that this material has reduced wear compared to conventional polyethylene, irrespective of head size. (C) 2016 Elsevier Inc. All rights reserved. C1 [Nebergall, Audrey K.; Greene, Meridith E.; Rubash, Harry; Malchau, Henrik; Troelsen, Anders; Rolfson, Ola] Massachusetts Gen Hosp, Dept Orthopaed, Harris Orthopaed Lab, Boston, MA 02114 USA. [Troelsen, Anders] Univ Copenhagen, Dept Orthopaed, Hvidovre Hosp, Hvidovre, Denmark. [Rolfson, Ola] Univ Gothenburg, Dept Orthopaed, Inst Clin Sci, Sahlgrenska Acad, Gothenburg, Sweden. RP Nebergall, AK (reprint author), Massachusetts Gen Hosp, Harris Orthopaed Lab, 55 Fruit St, Boston, MA 02114 USA. FU Zimmer (Warsaw, Indiana); Harris Orthopaedic Laboratory FX Zimmer (Warsaw, Indiana) provided funding for the first 5 years of this study. The Harris Orthopaedic Laboratory funded the study from 5-13 years. NR 42 TC 0 Z9 0 U1 3 U2 3 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD SEP PY 2016 VL 31 IS 9 SU S BP S269 EP S276 DI 10.1016/j.arth.2016.02.076 PG 8 WC Orthopedics SC Orthopedics GA DU4UU UT WOS:000382208900056 PM 27436500 ER PT J AU Lopez, MS Dempsey, RJ Vemuganti, R AF Lopez, Mary S. Dempsey, Robert J. Vemuganti, Raghu TI Resveratrol preconditioning induces cerebral ischemic tolerance but has minimal effect on cerebral microRNA profiles SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE Acute stroke; basic science; focal ischemia; genetics; neuroprotection ID TRAUMATIC BRAIN-INJURY; SPINAL-CORD-INJURY; OXIDATIVE STRESS; SUBARACHNOID HEMORRHAGE; BEHAVIORAL IMPAIRMENTS; UP-REGULATION; EXPRESSION; MOUSE; RATS; REPERFUSION AB The health benefits of the plant-derived polyphenol resveratrol were established in multiple disease systems. Notably, pre-treatment with resveratrol was shown to be neuroprotective in several models of cerebral ischemia. Mechanisms of resveratrol-mediated neuroprotection have been explored in the context of canonical resveratrol targets, but epigenetic and non-coding RNA processes have not yet been evaluated. Resveratrol was shown to alter microRNAs in cancer and cardiac ischemia. Previous studies also showed that ischemic preconditioning that induces ischemic tolerance significantly alters cerebral microRNA levels, particularly those that target neuroprotective pathways. Therefore, we tested if resveratrol-mediated ischemic tolerance also alters microRNA expression with a goal to identify microRNAs that are amenable to manipulation to induce neuroprotection after cerebral ischemia. Hence, we tested the microRNA profiles in mouse brain following intraperitoneal administration of resveratrol that induced significant tolerance against transient focal ischemia. We analyzed microRNA profiles using microarrays from both Affymetrix and LC Sciences that contain probes for all known mouse microRNAs. The results show that there is no consistent change in any of the microRNAs tested between resveratrol and vehicle groups indicating that microRNAs play a minimal role in resveratrol-mediated cerebral ischemic tolerance. C1 [Lopez, Mary S.; Dempsey, Robert J.; Vemuganti, Raghu] Univ Wisconsin, Dept Neurol Surg, 600 Highland Ave, Madison, WI 53792 USA. [Lopez, Mary S.; Vemuganti, Raghu] Univ Wisconsin, Cellular & Mol Pathol Training Program, Madison, WI USA. [Dempsey, Robert J.; Vemuganti, Raghu] Univ Wisconsin, Neurosci Training Program, Madison, WI USA. [Vemuganti, Raghu] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Vemuganti, R (reprint author), Univ Wisconsin, Dept Neurol Surg, 600 Highland Ave, Madison, WI 53792 USA. EM vemuganti@neurosurgery.wisc.edu FU UW Cellular & Molecular Pathology Graduate Training Program by the National Institutes of Health [T32GM081061]; Department of Neurological Surgery, University of Wisconsin-Madison FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Mary Lopez received a fellowship from the UW Cellular & Molecular Pathology Graduate Training Program supported by the National Institutes of Health Award T32GM081061. This work was partially supported by the Department of Neurological Surgery, University of Wisconsin-Madison. NR 43 TC 0 Z9 0 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD SEP PY 2016 VL 36 IS 9 BP 1644 EP 1650 DI 10.1177/0271678X16656202 PG 7 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA DV5UU UT WOS:000382996800015 PM 27323784 ER PT J AU Loring, Z Cohen, JK Morgan, J Yang, J Zimmet, J AF Loring, Zak Cohen, Jenny K. Morgan, Juliet Yang, Joseph Zimmet, Jeffrey TI The late presenting STEMI: How ECG scores can be used to estimate event time SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Article DE STEMI; ECG scores; Clinical decision-making ID MYOCARDIAL-INFARCTION; ANGIOPLASTY; ANTERIOR; SALVAGE; TRIALS; SIZE AB Introduction: Patients presenting with ST elevation myocardial infarction (STEMI) derive significant benefit from timely percutaneous coronary intervention (PCI). Electrocardiogram (ECG) scoring systems can complement history to estimate the infarction age and inform clinical decision-making. Case: A 76 year old man presented with eight days of dyspnea on exertion and chest pain. Triage ECG showed ST elevation and Q waves in the anterior leads. The patient was taken for coronary angiography and found to have a 100% occlusion of the left anterior descending artery. Discussion: Determining timing of acute coronary syndromes is challenging. ECG indices aid clinical history by quantifying infarction acuity. (C) 2016 Elsevier Inc. All rights reserved. C1 [Loring, Zak; Cohen, Jenny K.; Morgan, Juliet] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Yang, Joseph; Zimmet, Jeffrey] Univ Calif San Francisco, Dept Med, Div Cardiol, San Francisco, CA 94143 USA. [Zimmet, Jeffrey] San Francisco VA Med Ctr, Dept Med, Div Cardiol, San Francisco, CA 94121 USA. RP Loring, Z (reprint author), Univ Calif San Francisco, 505 Parnassus Ave, San Francisco, CA 94143 USA. EM zak.loring@ucsf.edu NR 8 TC 0 Z9 0 U1 1 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 EI 1532-8430 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD SEP-OCT PY 2016 VL 49 IS 5 BP 740 EP 743 DI 10.1016/j.jelectrocard.2016.06.013 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DV8VS UT WOS:000383215400020 PM 27426204 ER PT J AU Najita, JS Swetter, SM Geller, AC Gershenwald, JE Zelen, M Lee, SJ AF Najita, Julie S. Swetter, Susan M. Geller, Alan C. Gershenwald, Jeffrey E. Zelen, Marvin Lee, Sandra J. TI Sex Differences in Age at Primary Melanoma Diagnosis in a Population-Based Analysis (US Surveillance, Epidemiology, and End Results, 2005-2011) SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Letter ID CUTANEOUS MALIGNANT-MELANOMA; SEEKING MEDICAL ATTENTION; DELAY; AUSTRALIA C1 [Najita, Julie S.; Lee, Sandra J.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Najita, Julie S.; Zelen, Marvin] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Swetter, Susan M.] Stanford Univ, Med Ctr, Pigmented Les & Melanoma Program, Dept Dermatol, Stanford, CA 94305 USA. [Swetter, Susan M.] Inst Canc Res, Stanford, CA 94305 USA. [Swetter, Susan M.] VA Palo Alto Hlth Care Syst, Dermatol Serv, Palo Alto, CA 94550 USA. [Geller, Alan C.] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Gershenwald, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Lee, Sandra J.] Harvard Med Sch, Dept Med Oncol, Boston, MA 02115 USA. RP Najita, JS (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA.; Najita, JS (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. EM jnajita@jimmy.harvard.edu FU NCI NIH HHS [P30 CA016672] NR 18 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 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2016 VL 136 IS 9 BP 1894 EP 1897 DI 10.1016/j.jid.2016.03.044 PG 5 WC Dermatology SC Dermatology GA DV7BP UT WOS:000383091200022 PM 27251792 ER PT J AU Taouli, B Beer, AJ Chenevert, T Collins, D Lehman, C Matos, C Padhani, AR Rosenkrantz, AB Shukla-Dave, A Sigmund, E Tanenbaum, L Thoeny, H Thomassin-Naggara, I Barbieri, S Corcuera-Solano, I Orton, M Partridge, SC Koh, DM AF Taouli, Bachir Beer, Ambros J. Chenevert, Thomas Collins, David Lehman, Constance Matos, Celso Padhani, Anwar R. Rosenkrantz, Andrew B. Shukla-Dave, Amita Sigmund, Eric Tanenbaum, Lawrence Thoeny, Harriet Thomassin-Naggara, Isabelle Barbieri, Sebastiano Corcuera-Solano, Idoia Orton, Matthew Partridge, Savannah C. Koh, Dow-Mu TI Diffusion-weighted imaging outside the brain: Consensus statement from an ISMRM-sponsored workshop SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Review DE diffusion; cancer; liver; kidney; breast; prostate; whole body imaging ID INTRAVOXEL-INCOHERENT-MOTION; EXERTIONAL COMPARTMENT SYNDROME; MAGNETIC-RESONANCE IMAGES; ADVANCED BREAST-CANCER; FOCAL HEPATIC-LESIONS; PROSTATE-CANCER; B-VALUES; WATER DIFFUSION; COEFFICIENT MEASUREMENTS; PREOPERATIVE DETECTION AB The significant advances in magnetic resonance imaging (MRI) hardware and software, sequence design, and postprocessing methods have made diffusion-weighted imaging (DWI) an important part of body MRI protocols and have fueled extensive research on quantitative diffusion outside the brain, particularly in the oncologic setting. In this review, we summarize the most up-to-date information on DWI acquisition and clinical applications outside the brain, as discussed in an ISMRM-sponsored symposium held in April 2015. We first introduce recent advances in acquisition, processing, and quality control; then review scientific evidence in major organ systems; and finally describe future directions. J. Magn. Reson. Imaging 2016;44:521-540. C1 [Taouli, Bachir; Tanenbaum, Lawrence; Corcuera-Solano, Idoia] Icahn Sch Med Mt Sinai, Dept Radiol, 1470 Madison Ave, New York, NY 10029 USA. [Taouli, Bachir; Corcuera-Solano, Idoia] Icahn Sch Med Mt Sinai, Translat & Mol Imaging Inst, New York, NY 10029 USA. [Beer, Ambros J.] Univ Hosp Ulm, Dept Nucl Med, Ulm, Germany. [Chenevert, Thomas] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Collins, David; Orton, Matthew] Royal Marsden Hosp, Inst Canc Res, CR UK Canc Imaging Ctr, London, England. [Collins, David; Orton, Matthew; Koh, Dow-Mu] Royal Marsden Hosp, Dept Radiol, London, England. [Lehman, Constance] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Matos, Celso] Champalimaud Clin Ctr, Dept Radiol, Lisbon, Portugal. [Padhani, Anwar R.] Mt Vernon Canc Ctr, Northwood, Middx, England. [Rosenkrantz, Andrew B.] NYU Langone Med Ctr, Dept Radiol, New York, NY USA. [Shukla-Dave, Amita] Mem Sloan Kettering Canc Ctr, Dept Med Phys, New York, NY 10021 USA. [Shukla-Dave, Amita] Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA. [Sigmund, Eric] NYU Langone Med Ctr, Irene & Bernard Schwartz Ctr Biomed Imaging CBI, New York, NY USA. [Sigmund, Eric] NYU Langone Med Ctr, Dept Radiol, Ctr Adv Imaging & Innovat CAI2R, New York, NY USA. [Thoeny, Harriet; Barbieri, Sebastiano] Inselspital Bern, Dept Diagnost Radiol, Bern, Switzerland. [Thomassin-Naggara, Isabelle] Univ Paris 06, Hop Univ Paris Est, Paris, France. [Partridge, Savannah C.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Koh, Dow-Mu] Royal Marsden Hosp, Inst Canc Res, London, England. RP Taouli, B (reprint author), Icahn Sch Med Mt Sinai, Dept Radiol, 1470 Madison Ave, New York, NY 10029 USA.; Taouli, B (reprint author), Translat & Mol Imaging Inst, 1470 Madison Ave, New York, NY 10029 USA. EM bachir.taouli@mountsinai.org FU Medical Research Council [G0701533]; NIBIB NIH HHS [P41 EB017183] NR 120 TC 5 Z9 5 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD SEP PY 2016 VL 44 IS 3 BP 521 EP 540 DI 10.1002/jmri.25196 PG 20 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DV5AV UT WOS:000382938700002 PM 26892827 ER PT J AU Aspinall, SL Sales, MM Good, CB Calabrese, V Glassman, PA Burk, M Moore, VR Neuhauser, MM Golterman, L Ourth, H Valentino, MA Cunningham, FE AF Aspinall, Sherrie L. Sales, Mariscelle M. Good, Chester B. Calabrese, Vincent Glassman, Peter A. Burk, Muriel Moore, Von R. Neuhauser, Melinda M. Golterman, Lori Ourth, Heather Valentino, Michael A. Cunningham, Francesca E. TI Pharmacy Benefits Management in the Veterans Health Administration Revisited: A Decade of Advancements, 2004-2014 SO JOURNAL OF MANAGED CARE & SPECIALTY PHARMACY LA English DT Article ID CARE-SYSTEM AB Over the past decade, the Department of Veterans Affairs (VA) Pharmacy Benefits Management Services (PBM) has enhanced its formulary management activities and added programs to ensure that the national drug plan continues to meet the pharmacy needs of veterans and to promote safe and appropriate drug therapy in the face of rising medication expenditures. This article describes the broad range of services provided by the VA PBM that work in partnership to deliver a high-quality and sustainable pharmacy benefit for veterans. In support of formulary management, VA PBM pharmacists prepare extensive clinical guidance documents (e.g., drug monographs and criteria for use) that are used by physicians and pharmacists with operational and clinical oversight of the VA national formulary. The VA PBM has utilized various contracting techniques and continually evaluates drug utilization data to identify opportunities for potential savings. Remarkably, since before 2004, the average acquisition cost for a 1-month supply of medication has remained fairly stable at approximately $13-$15. Two new VA PBM programs are the VA Center for Medication Safety (VA MedSAFE) and the Clinical Pharmacy Practice Office (CPPO). VA MedSAFE is a comprehensive pharmacovigilance program focused on the detection, assessment, and prevention of adverse drug events, and CPPO is dedicated to improving safe and appropriate medication use by supporting and expanding clinical pharmacy practice. Moving forward, the VA PBM will consider new initiatives to stay at the forefront of providing quality care while maintaining economic viability. Copyright (C) 2016, Academy of Managed Care Pharmacy. All rights reserved. C1 [Aspinall, Sherrie L.; Sales, Mariscelle M.; Calabrese, Vincent; Burk, Muriel; Moore, Von R.; Neuhauser, Melinda M.; Ourth, Heather; Cunningham, Francesca E.] VA Pharm Benefits Management Serv, Hines, IL USA. [Aspinall, Sherrie L.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Univ Dr 151C,Bldg 30, Pittsburgh, PA 15240 USA. [Aspinall, Sherrie L.] Univ Pittsburgh, Sch Pharm, Pittsburgh, PA USA. [Good, Chester B.] Univ Pittsburgh, Sch Pharm, Ctr Hlth Equ Res & Promot, VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Good, Chester B.] Sch Med, Pittsburgh, PA USA. [Good, Chester B.; Golterman, Lori; Valentino, Michael A.] VA Pharm Benefits Management Serv, Washington, DC USA. [Glassman, Peter A.] VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Glassman, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Aspinall, SL (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Univ Dr 151C,Bldg 30, Pittsburgh, PA 15240 USA. EM shenie.aspinall@va.gov FU VA Pharmacy Benefits Management Services (VA PBM), Hines, Illinois; VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania FX No outside funding supported this research. This work was supported by VA Pharmacy Benefits Management Services (VA PBM), Hines, Illinois, and VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania. Glassman is co-director of the VA Center for Medication Safety, which is part of the VA PBM He is also part of the Medical Advisory Panel for the VA PMB. All other authors are employed by the VA PBM The views expressed in this article are those of the authors, and no official endorsement by the U.S. Department of Veteran Affairs or the U.S. government is intended or should be inferred. NR 11 TC 0 Z9 0 U1 1 U2 1 PU ACAD MANAGED CARE PHARMACY PI ALEXANDRIA PA 100 N PITT ST, 400, ALEXANDRIA, VA 22314-3134 USA SN 2376-0540 EI 2376-1032 J9 J MANAG CARE SPEC PH JI J. Manag. Care Spec. Pharm. PD SEP PY 2016 VL 22 IS 9 BP 1058 EP 1063 PG 6 WC Health Care Sciences & Services; Pharmacology & Pharmacy SC Health Care Sciences & Services; Pharmacology & Pharmacy GA DV4NG UT WOS:000382901700007 PM 27579828 ER PT J AU Boruta, DM Shibley, T AF Boruta, David M. Shibley, Tony TI Power Morcellation of Unsuspected High-grade Leiomyosarcoma Within an Inflated Containment Bag: 2-year Follow-up SO JOURNAL OF MINIMALLY INVASIVE GYNECOLOGY LA English DT Article DE Isolation bag; Laparoscopy; Leiomyosarcoma; Morcellation ID UTERINE LEIOMYOSARCOMA; SURGERY; IMPACT AB The diagnosis of an unsuspected leiomyosarcoma after hysterectomy for the treatment of a presumed benign leiomyoma is a rare but highly clinically significant event. In order to facilitate removal of large uterine specimens using a minimally invasive surgical approach, morcellation with extraction in pieces is often performed. In the event of unsuspected malignancy, this may result in abdominal dispersion of the tumor and contribute to poorer survival. In the present article, we report a case of contained power morcellation of an unsuspected high-grade leiomyosarcoma with 2 years of follow-up. Although further study is necessary, this technique may minimize the risk that women undergoing laparoscopic hysterectomy with morcellation have a worse prognosis when diagnosed with an unexpected malignancy. (C) 2016 AAGL. All rights reserved. C1 [Boruta, David M.] Massachusetts Gen Hosp, Div Gynecol Oncol, Boston, MA 02114 USA. [Shibley, Tony] Fairview Ridges Hosp, Burnsville, MN USA. RP Shibley, T (reprint author), 6565 France Ave South,Suite 200, Edina, MN 55435 USA. EM tshibley3@me.com NR 17 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 1553-4650 EI 1553-4669 J9 J MINIM INVAS GYN JI J. Mimim. Invasive Gynecol. PD SEP-OCT PY 2016 VL 23 IS 6 BP 1009 EP 1011 DI 10.1016/j.jmig.2016.06.017 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DV8VV UT WOS:000383215700027 PM 27393286 ER PT J AU Lennerz, JK McLaughlin, HM Baron, JM Rasmussen, D Shin, MS Berners-Lee, N Batten, JM Swoboda, KJ Gala, MK Winter, HS Schmahmann, JD Sweetser, DA Boswell, M Pacula, M Stenzinger, A Le, LP Hynes, W Rehm, HL Klibanski, A Black-Schaffer, SW Golden, JA Louis, DN Weiss, ST Iafrate, AJ AF Lennerz, Jochen K. McLaughlin, Heather M. Baron, Jason M. Rasmussen, David Shin, Meini Sumbada Berners-Lee, Nancy Batten, Julie Miller Swoboda, Kathryn J. Gala, Manish K. Winter, Harland S. Schmahmann, Jeremy D. Sweetser, David A. Boswell, Marianne Pacula, Maciej Stenzinger, Albrecht Le, Long P. Hynes, William Rehm, Heidi L. Klibanski, Anne Black-Schaffer, Stephen W. Golden, Jeffrey A. Louis, David N. Weiss, Scott T. Iafrate, A. John TI Health Care Infrastructure for Financially Sustainable Clinical Genomics SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID INCIDENTAL FINDINGS; MANAGEMENT; EXOME; MEDICINE; COVERAGE; ACT AB Next-generation sequencing has evolved technically and economically into the method of choice for interrogating the genome in cancer and inherited disorders. The introduction of procedural code sets for whole-exome and genome sequencing is a milestone toward financially sustainable clinical implementation; however, achieving reimbursement is currently a major challenge. As part of a prospective quality-improvement initiative to implement the new code sets, we adopted Agile, a development methodology originally devised in software development. We implemented eight functionally distinct modules (request review, cost estimation, preauthorization, accessioning, prebilling, testing, reporting, and reimbursement consultation) and obtained feedback via an anonymous survey. We managed 50 clinical requests (January to June 2015). The fraction of pursued-to-requested cases (n = 15/50; utilization management fraction, 0.3) aimed for a high rate of preauthorizations. In 13 of 15 patients the insurance plan required preauthorization, which we obtained in 70% and ultimately achieved reimbursement in 50%. InteroperabiLity enabled assessment of 12 different combinations of modules that underline the importance of an adaptive workflow and policy tailoring to achieve higher yields of reimbursement. The survey confirmed a positive attitude toward self-organizing teams. We acknowledge the individuals and their interactions and termed the infrastructure: human pipeline. Nontechnical barriers currently are Limiting the scope and availability of clinical genomic sequencing. The presented human pipeline is one approach toward long-term financial sustainabiLity of clinical genomics. C1 [Lennerz, Jochen K.; Baron, Jason M.; Rasmussen, David; Batten, Julie Miller; Boswell, Marianne; Pacula, Maciej; Le, Long P.; Hynes, William; Black-Schaffer, Stephen W.; Louis, David N.; Iafrate, A. John] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Swoboda, Kathryn J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Gala, Manish K.] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA. [Schmahmann, Jeremy D.] Massachusetts Gen Hosp, Div Gastroenterol, Ataxia Unit, Boston, MA 02114 USA. [Klibanski, Anne] Massachusetts Gen Hosp, Cognit Behav Neurol Unit, Lab Neuroanat & Cerebellar Neurobiol, Neuroendocrine Unit, Boston, MA 02114 USA. [Winter, Harland S.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Winter, Harland S.] Massachusetts Gen Hosp, Pediat Gastroenterol & Nutr Program, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. [McLaughlin, Heather M.; Shin, Meini Sumbada; Rehm, Heidi L.; Weiss, Scott T.] Partners Healthcare Personalized Med, Mol Med Lab, Cambridge, MA USA. [Berners-Lee, Nancy] Int Coach Federat, Lexington, MA USA. [Sweetser, David A.] Massachusetts Gen Hosp, Dept Pediat, Div Med Genet, Boston, MA 02114 USA. [Stenzinger, Albrecht] Univ Heidelberg Hosp, Inst Pathol, Heidelberg, Germany. [Golden, Jeffrey A.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. RP Lennerz, JK (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,WRN503, Boston, MA 02114 USA. EM jlennerz@partners.org FU National Center of Tumor Diseases-Heidelberg School of Oncology, Heidelberg, Germany; NIH grant from MedSeq [U01 HG006500]; American College of Gastroenterology; Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources); Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH) [UL1 TR001102]; Harvard University FX Supported by a fellowship from the National Center of Tumor Diseases-Heidelberg School of Oncology, Heidelberg, Germany (A.S.); NIH grant U01 HG006500 from MedSeq (H.M.M., H.L.R.); and a Junior Faculty Award from the American College of Gastroenterology (M.K.G.). Partly supported by Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH award UL1 TR001102), and financial contributions from Harvard University and its affiliated academic health care centers. NR 41 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD SEP PY 2016 VL 18 IS 5 BP 697 EP 706 DI 10.1016/j.jmoldx.2016.04.003 PG 10 WC Pathology SC Pathology GA DU7VK UT WOS:000382422500010 PM 27471182 ER PT J AU Resnick, CM Inverso, G Wrzosek, M Padwa, BL Kaban, LB Peacock, ZS AF Resnick, Cory M. Inverso, Gino Wrzosek, Mariusz Padwa, Bonnie L. Kaban, Leonard B. Peacock, Zachary S. TI Is There a Difference in Cost Between Standard and Virtual Surgical Planning for Orthognathic Surgery? SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID SIMULATION; RECONSTRUCTION; ACCURACY AB Purpose: Virtual surgical planning (VSP) and 3-dimensional printing of surgical splints are becoming the standard of care for orthognathic surgery, but costs have not been thoroughly evaluated. The purpose of this study was to compare the cost of VSP and 3-dimensional printing of splints ("VSP'') versus that of 2-dimensional cephalometric evaluation, model surgery, and manual splint fabrication ("standard planning''). Materials and Methods: This is a retrospective cohort study including patients planned for bimaxillary surgery from January 2014 to January 2015 at Massachusetts General Hospital. Patients were divided into 3 groups by case type: symmetric, nonsegmental (group 1); asymmetric (group 2); and segmental (group 3). All cases underwent both VSP and standard planning with times for all activities recorded. The primary and secondary predictor variables were method of treatment planning and case type, respectively. Time-driven activity-based micro-costing analysis was used to quantify the differences in cost. Results were analyzed using a paired t test and analysis of variance. Results: The sample included 43 patients (19 in group 1, 17 in group 2, and 7 in group 3). The average times and costs were 194 +/- 14.1 minutes and $ 2,765.94, respectively, for VSP and 540.9 +/- 99.5 minutes and $ 3,519.18, respectively, for standard planning. For the symmetric, nonsegmental group, the average times and costs were 188 +/- 17.8 minutes and $ 2,700.52, respectively, for VSP and 524.4 +/- 86.1 minutes and $ 3,380.17, respectively, for standard planning. For the asymmetric group, the average times and costs were 187.4 +/- 10.9 minutes and $ 2,713.69, respectively, for VSP and 556.1 +/- 94.1 minutes and $ 3,640.00, respectively, for standard planning. For the segmental group, the average times and costs were 208.8 +/- 13.5 minutes and $ 2,883.62, respectively, for VSP and 542.3 +/- 118.4 minutes and $ 3,537.37, respectively, for standard planning. All time and cost differences were statistically significant (P < .001). Conclusions: The results of this study indicate that VSP for bimaxillary orthognathic surgery takes significantly less time and is less expensive than standard planning for the 3 types of cases analyzed. (C) 2016 American Association of Oral and Maxillofacial Surgeons C1 [Resnick, Cory M.; Inverso, Gino; Padwa, Bonnie L.; Kaban, Leonard B.; Peacock, Zachary S.] Harvard Sch Dent Med, Boston, MA USA. [Resnick, Cory M.; Padwa, Bonnie L.] Boston Childrens Hosp, Dept Plast & Oral Surg, 300 Longwood Ave, Boston, MA 02115 USA. [Wrzosek, Mariusz; Kaban, Leonard B.; Peacock, Zachary S.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. RP Resnick, CM (reprint author), Boston Childrens Hosp, Dept Plast & Oral Surg, 300 Longwood Ave, Boston, MA 02115 USA. EM Cory.Resnick@childrens.harvard.edu FU Massachusetts General Hospital, Department of Oral and Maxillofacial Surgery Education and Research Fund FX This study was funded in part by the Massachusetts General Hospital, Department of Oral and Maxillofacial Surgery Education and Research Fund. NR 15 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 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD SEP PY 2016 VL 74 IS 9 BP 1827 EP 1833 DI 10.1016/j.joms.2016.03.035 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DU5GR UT WOS:000382240700021 PM 27181623 ER PT J AU Mellema, JJ Eygendaal, D van Dijk, CN Ring, D Doornberg, JN AF Mellema, Jos J. Eygendaal, Denise van Dijk, C. Niek Ring, David Doornberg, Job N. TI Fracture mapping of displaced partial articular fractures of the radial head SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Article DE Radial head; fracture; traumatic elbow instability; fracture mapping; three-dimensional; computed tomography ID 3-DIMENSIONAL COMPUTED-TOMOGRAPHY; TRAUMATIC ELBOW INSTABILITY; INTERNAL-FIXATION; PATTERNS; BONE; DISLOCATIONS; DENSITY; VOLUME; LINES AB Background: Recognition of patterns of traumatic elbow instability helps anticipate specific fracture characteristics and associated injuries. The objective of this study was to assess the association of fracture line distribution and location of displaced partial articular radial head fractures with specific patterns of traumatic elbow instability using fracture mapping techniques. Methods: Fracture line distribution and location of 66 acute displaced partial articular radial head fractures were identified using quantitative 3-dimensional computed tomography reconstructions that allowed reduction of fracture fragments and a standardized method to divide the radial head into quadrants with forearm in neutral position. Based on qualitative and quantitative assessment of fracture maps, the association between fracture characteristics of displaced partial articular radial head fractures and specific elbow fracture patterns was determined. Results: In partial articular radial head fractures, the highest fracture line intensity was located in the anterolateral quadrant near the center of the radial head. Fracture location corresponded with fracture line distribution; most fractures involved the anterolateral quadrant (n = 65; 98%), whereas parts of the posteromedial quadrant were involved in a minority of the fractures (n = 10; 15%). The association of fracture line distribution and location with overall fracture patterns of the elbow, as depicted on fracture maps, was not statistically significant. Conclusion: Fracture maps demonstrated no association between fracture line distribution and location of displaced partial articular fractures of the radial head and overall specific patterns of traumatic elbow instability, suggesting a common fracture mechanism that involves the anterolateral part of the radial head in most patients. (C) 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved. C1 [Mellema, Jos J.; Ring, David] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthoped Surg, Hand & Upper Extrem Serv, Boston, MA 02114 USA. [Eygendaal, Denise] Amphia Hosp, Dept Orthoped Surg, Upper Limb Unit, Breda, Netherlands. [van Dijk, C. Niek; Doornberg, Job N.] Univ Amsterdam, Acad Med Ctr, Dept Orthoped Surg, Amsterdam, Netherlands. RP Mellema, JJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Yawkey Ctr, Dept Orthoped Surg,Hand & Upper Extrem Serv, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM josjmellema@gmail.com NR 38 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 1058-2746 J9 J SHOULDER ELB SURG JI J. Shoulder Elbow Surg. PD SEP PY 2016 VL 25 IS 9 BP 1509 EP 1516 DI 10.1016/j.jse.2016.01.030 PG 8 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA DU4VA UT WOS:000382209500022 PM 27052270 ER PT J AU Alkaduhimi, H van der Linde, JA Willigenburg, NW Pereira, NRP van Deurzen, DFP van den Bekerom, MPJ AF Alkaduhimi, Hassanin van der Linde, Just A. Willigenburg, Nienke W. Pereira, Nuno Rui Paulino van Deurzen, Derek F. P. van den Bekerom, Michel P. J. TI Redislocation risk after an arthroscopic Bankart procedure in collision athletes: a systematic review SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Review DE Bankart surgery; arthroscopy; redislocation; athletes; shoulder; glenohumeral; instability; collision ID ANTERIOR SHOULDER INSTABILITY; FOLLOW-UP; SUTURE ANCHORS; QUANTITATIVE SYNTHESIS; RUGBY UNION; REPAIR; STABILIZATION; DISLOCATION; LATARJET; 2-YEAR AB Background: The purpose of this review was to determine the redislocation risk for collision athletes after an arthroscopic Bankart repair and to compare the redislocation rate between collision athletes and noncollision athletes after an arthroscopic Bankart repair. Methods: A PubMed and Embase query was performed, screening all relevant literature of arthroscopic Bankart procedures mentioning redislocation rates in collision athletes. Studies with a follow-up <2 years or lacking information on redislocation rates in collision athletes were excluded. We used the modified Coleman Methodology Score to assess the quality of included studies. Finally, the data in all the studies were combined and analyzed. Results: There were 1012 studies screened on title and abstract, of which 111 studies were full-text screened, and finally 20 studies were included. Four studies reported on collision athletes only, whereas 16 compared collision with noncollision athletes. Fourteen studies reported increased redislocation rates for collision athletes in comparison to noncollision athletes (absolute risk difference varying from 0.4% to 28.6%), whereas 2 studies reported decreased rates (absolute risk differences of -6% and -2.4%). A combined analysis revealed that collision athletes have an increased absolute risk of 8.09 with 95% CI from 3.61 to 12.57% for development of postoperative instability in comparison to noncollision athletes (P = .001). Conclusion: Collision athletes have an increased risk for redislocation in comparison to noncollision athletes after an arthroscopic Bankart repair, although there were no differences in return to sport. (C) 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved. C1 [Alkaduhimi, Hassanin; van der Linde, Just A.; Willigenburg, Nienke W.; van Deurzen, Derek F. P.; van den Bekerom, Michel P. J.] Dept Orthopaed Surg OLVG, Shoulder & Elbow Unit, Joint Res, Amsterdam, Netherlands. [Pereira, Nuno Rui Paulino] Massachusetts Gen Hosp, Dept Orthopaed, Boston, MA 02114 USA. RP Alkaduhimi, H (reprint author), Onze Lieve Vrouwe Gasthuis Amsterdam, Shoulder & Elbow Unit, Joint Res, Wijnand Nuijenstr 18, NL-1061 TX Amsterdam, Netherlands. EM hassaninalkaduhimi@gmail.com NR 47 TC 0 Z9 0 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 1058-2746 J9 J SHOULDER ELB SURG JI J. Shoulder Elbow Surg. PD SEP PY 2016 VL 25 IS 9 BP 1549 EP 1558 DI 10.1016/j.jse.2016.05.002 PG 10 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA DU4VA UT WOS:000382209500027 PM 27539545 ER PT J AU von Keudell, A Koh, K Shah, SB Harris, MB Smith, M Rodriguez, EK Dyer, G AF von Keudell, Arvind Koh, Katherine Shah, Sejal B. Harris, Mitchel B. Smith, Malcolm Rodriguez, Edward K. Dyer, George TI Mental health after the Boston marathon bombing SO LANCET PSYCHIATRY LA English DT Editorial Material C1 [von Keudell, Arvind; Harris, Mitchel B.; Smith, Malcolm; Rodriguez, Edward K.; Dyer, George] Harvard Med Sch, Harvard Orthoped Trauma Initiat, Boston, MA 02115 USA. [Koh, Katherine; Shah, Sejal B.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Smith, Malcolm] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA USA. [Harris, Mitchel B.; Dyer, George] Harvard Med Sch, Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA USA. [Rodriguez, Edward K.] Harvard Med Sch, Beth Israel Deaconess Hosp, Dept Orthopaed Surg, Boston, MA USA. RP von Keudell, A (reprint author), Harvard Med Sch, Harvard Orthoped Trauma Initiat, Boston, MA 02115 USA. EM avonkeudell@mgh.harvard.edu NR 11 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2215-0374 J9 LANCET PSYCHIAT JI Lancet Psychiatry PD SEP PY 2016 VL 3 IS 9 BP 802 EP 804 PG 4 WC Psychiatry SC Psychiatry GA DU5TV UT WOS:000382276800010 PM 27568262 ER PT J AU Wang, CY Kundaria, S Fernandez-Miranda, J Duvvuri, U AF Wang, Chengyuan Kundaria, Summit Fernandez-Miranda, Juan Duvvuri, Umamaheswar TI A description of the anatomy of the glossopharyngeal nerve as encountered in transoral surgery SO LARYNGOSCOPE LA English DT Article DE Glossopharyngeal nerve; transoral surgery; parapharyngeal space; anatomy ID SURGICAL ANATOMY; NEURALGIA; TONSILLECTOMY; BLOCK AB Objectives/HypothesisTo illustrate detailed anatomy of the extracranial portion of the glossopharyngeal nerve in the parapharyngeal space as encountered during transoral surgery. Study DesignProspective cadaveric dissection. All dissections were performed transorally and confirmed with transcervical dissection. MethodsEight color-injected cadaveric heads (16 sides) were dissected to demonstrate the course and anatomy of the glossopharyngeal nerve. Conventional external dissections were performed to verify our anatomic measurements. Anatomical measurements of the glossopharyngeal nerve, including segments, branches in each segment, relationship with stylopharyngeus muscle, internal carotid artery, and pharyngeal branch of Vagus were recorded and analyzed. ResultsThe glossopharyngeal nerve was separated into three segments according to the relationship with the stylopharyngeus muscle. Total lengths of the glossopharyngeal nerve are 32.6 3.1 (left side) and 30.6 3.7 (right side) mm, respectively. The average number of branches in the upper, middle, and lower segments is 3 (range 1-3), 4 (range 2-4), and 3 (range 1-3), respectively. The total number of branches is 8 (range 6-9). The average diameter of the main trunk of the glossopharyngeal nerve is 1.2 +/- 0.3 mm, and the average diameter of the lingual branch of the glossopharyngeal nerve is approximately 0.6 +/- 0.2 mm. In 75% of cases, pharyngeal branch of Vagus crosses the glossopharyngeal nerve, whereas in 25% of cases it parallels the course of the glossopharyngeal nerve to form the pharyngeal nerve plexus to innervate the pharyngeal wall. ConclusionUnderstanding the precise and detailed anatomy of the glossopharyngeal nerve in the parapharyngeal space is important in transoral surgery for indications such as transoral robotic surgery or transoral laser microsurgery tumor resection, lingual tonsillectomy, glossopharyngeal neuralgia, glossopharyngeal nerve block, and internal carotid artery dissection. Level of EvidenceN/A. Laryngoscope, 126:2010-2015, 2016 C1 [Wang, Chengyuan] China Japan Friendship Hosp, Dept Otolaryngol Head & Neck Surg, Beijing, Peoples R China. [Wang, Chengyuan] Shenmu Cty Hosp, Dept Head & Neck Surg, Yulin, Shanxi Province, Peoples R China. [Wang, Chengyuan; Kundaria, Summit; Duvvuri, Umamaheswar] Vet Affairs Pittsburgh Hlth Syst, Pittsburgh, PA USA. [Wang, Chengyuan; Kundaria, Summit; Duvvuri, Umamaheswar] Univ Pittsburgh, Inst Eye & Ear, Med Ctr, UPMC Dept Otolaryngol Head & Neck Surg, Pittsburgh, PA 15213 USA. [Wang, Chengyuan; Fernandez-Miranda, Juan] Univ Pittsburgh, Med Ctr, Dept Neurosurg, Pittsburgh, PA USA. RP Duvvuri, U (reprint author), Univ Pittsburgh, Vet Affairs Pittsburgh Hlth Syst, Dept Otolaryngol, Med Ctr,Eye & Ear Inst, Suite 500,200 Lothrop St, Pittsburgh, PA 15213 USA. EM duvuriu@upmc.edu FU Department of Veterans Affairs Bureau of Labor Statistics RD; pittsburgh national corporation (PNC) Foundation FX This work was funded in part by the Department of Veterans Affairs Bureau of Labor Statistics R&D, and the pittsburgh national corporation (PNC) Foundation (U.D.). The authors have no other funding, financial relationships, or conflicts of interest to disclose. NR 15 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD SEP PY 2016 VL 126 IS 9 BP 2010 EP 2015 DI 10.1002/lary.25706 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA DV9VD UT WOS:000383289400021 PM 27312369 ER PT J AU Barber, SR Cheng, YS Owoc, M Lin, BM Remenschneider, AK Kozin, ED Lee, DJ AF Barber, Samuel R. Cheng, Yew Song Owoc, Maryanna Lin, Brian M. Remenschneider, Aaron K. Kozin, Elliott D. Lee, Daniel J. TI Benign paroxysmal positional vertigo commonly occurs following repair of superior canal dehiscence SO LARYNGOSCOPE LA English DT Article DE Benign paroxysmal positional vertigo; superior canal dehiscence; superior canal dehiscence syndrome; plugging; resurfacing; surgery; outcomes; dizziness ID COCHLEAR IMPLANTATION; SURGERY; MANAGEMENT; DIZZINESS; AUTOPHONY; RECOVERY AB Objectives/HypothesisRepair of superior canal dehiscence (SCD) often results in the resolution of preoperative auditory and vestibular symptoms; however, many patients experience dizziness in the postoperative period. Postoperative dizziness may be the result of new-onset benign paroxysmal positional vertigo (BPPV). This study aims to investigate the prevalence of BPPV before and following SCD repair. Study DesignRetrospective chart review at a tertiary care center. MethodsElectronic medical records were reviewed for patients with a diagnosis of SCD syndrome (SCDS) between January 2002 and May 2015. Collected information included demographic data, incidence of BPPV diagnosed by Dix-Hallpike maneuver before and following surgery, operative technique, repair material, and the duration of time to BPPV onset. ResultsA total of 180 patients with a diagnosis of SCDS were identified: 84 patients underwent surgery (operated subjects) and 96 were observed (nonoperated, control group). In operated subjects, 20 of 84 (23.8%) developed BPPV following SCD repair versus 6.2% of nonoperated (P < 0.005). Benign paroxysmal positional vertigo lateralized to the operated side in all but one subject whose laterality was unknown (P < 0.0001). There were no associations of BPPV with surgical approach (P = 0.50) or repair material (P = 0.33). The majority of subjects (58%) were diagnosed with BPPV within 3 months of surgery. ConclusionNew-onset BPPV occurs commonly after SCD repair and may be the result of mobilized otoliths from inner ear pressure changes. Although the exact etiology of post-SCD repair BPPV remains unknown, postoperative dizziness is important to discuss with patients during preoperative counseling. Level of Evidence4. Laryngoscope, 126:2092-2097, 2016 C1 [Barber, Samuel R.; Cheng, Yew Song; Owoc, Maryanna; Lin, Brian M.; Remenschneider, Aaron K.; Kozin, Elliott D.; Lee, Daniel J.] Harvard Med Sch, Dept Otol & Laryngol, Boston, MA USA. [Barber, Samuel R.; Cheng, Yew Song; Owoc, Maryanna; Lin, Brian M.; Remenschneider, Aaron K.; Kozin, Elliott D.; Lee, Daniel J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. RP Lee, DJ (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM daniel_lee@meei.harvard.edu NR 24 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD SEP PY 2016 VL 126 IS 9 BP 2092 EP 2097 DI 10.1002/lary.25797 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA DV9VD UT WOS:000383289400036 PM 26666775 ER PT J AU Al-Qurayshi, Z Randolph, GW Srivastav, S Aslam, R Friedlander, P Kandil, E AF Al-Qurayshi, Zaid Randolph, Gregory W. Srivastav, Sudesh Aslam, Rizwan Friedlander, Paul Kandil, Emad TI Outcomes in thyroid surgery are affected by racial, economic, and healthcare system demographics SO LARYNGOSCOPE LA English DT Article DE Thyroidectomy; surgeon volume; patient environment; patient community; demographic ID UNITED-STATES; SOCIOECONOMIC-STATUS; CANCER INCIDENCE; ASSOCIATION; DISPARITIES; ENVIRONMENT; MORTALITY; RESIDENCE; HISTORY; TRENDS AB Objectives/HypothesisDisparities in economic and social parameters have been identified as underlying factors that influence diseases outcomes. We aim to examine the influence of community-specific measures on outcomes related to thyroid surgery. Study DesignA cross-sectional study utilizing the State Inpatient databases and State Ambulatory Surgery and Services databases, 2010 to 2011. Those databases were merged with the County Health Ranking database. MethodsThe study population included adult (18 years) inpatients and outpatients who underwent thyroidectomy. Access and outcomes of thyroidectomy was assessed in relation to demographics and health-risk status of the patient's community. ResultsA total of 14,220 inpatient and 7,215 outpatient thyroidectomies were included. Low-volume surgeons were more likely to operate on patients living in high-risk communities (P<.05). Patients from these communities of high health risk were more likely to be women, and African Americans (P<.05 each). Compared to low-risk communities, patients from high-risk settings had a higher risk of postoperative complications (odds ratio: 1.58, 95% confidence interval: 1.23, 2.04, P<.001). They also experienced longer hospitalization (P=.003) and higher readmission risk (3.0% vs. 1.5%, P=.03). Interestingly, despite divergent and lower outcome parameters, hospital charges for patients of high-risk communities were in the highest quartile (>$34,535.55) compared to low-health-risk communities (P<.001). ConclusionsPatients from high-health-risk communities and who are undergoing thyroidectomies are more likely to be women and African Americans. Management of those patients is more likely to be performed by low-volume surgeons and more likely to be associated with unfavorable outcomes. Level of Evidence4. Laryngoscope, 126:2194-2199, 2016 C1 [Al-Qurayshi, Zaid; Kandil, Emad] Tulane Univ, Sch Med, Dept Surg, New Orleans, LA 70112 USA. [Randolph, Gregory W.] Massachusetts Eye & Ear Infirm, Div Thyroid & Parathyroid Endocrine Surg, Boston, MA 02114 USA. [Srivastav, Sudesh] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Biostat & Bioinformat, New Orleans, LA USA. [Aslam, Rizwan; Friedlander, Paul] Tulane Univ, Sch Med, Dept Otolaryngol, 1430 Tulane Ave, New Orleans, LA 70112 USA. RP Kandil, E (reprint author), Tulane Sch Med, Dept Surg, 1430 Tulane Ave,SL 22, New Orleans, LA 70112 USA. EM ekandil@tulane.edu OI Al-Qurayshi, Zaid/0000-0002-3534-7253 NR 24 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD SEP PY 2016 VL 126 IS 9 BP 2194 EP 2199 DI 10.1002/lary.25871 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA DV9VD UT WOS:000383289400053 PM 27139800 ER PT J AU Jurczyszyn, A Olszewska-Szopa, M Hungria, V Crusoe, E Pika, T Delforge, M Leleu, X Rasche, L Nooka, AK Druzd-Sitek, A Walewski, J Davila, J Caers, J Maisnar, V Gertz, M Gentile, M Fantl, D Mele, G Vesole, DH Yee, AJ Shustik, C Lentzsch, S Zweegman, S Gozzetti, A Skotnicki, AB Castillo, JJ AF Jurczyszyn, Artur Olszewska-Szopa, Magdalena Hungria, Vania Crusoe, Edvan Pika, Tomas Delforge, Michel Leleu, Xavier Rasche, Leo Nooka, Ajay K. Druzd-Sitek, Agnieszka Walewski, Jan Davila, Julio Caers, Jo Maisnar, Vladimir Gertz, Morie Gentile, Massimo Fantl, Dorotea Mele, Giuseppe Vesole, David H. Yee, Andrew J. Shustik, Chaim Lentzsch, Suzanne Zweegman, Sonja Gozzetti, Alessandro Skotnicki, Aleksander B. Castillo, Jorge J. TI Cutaneous involvement in multiple myeloma: a multi-institutional retrospective study of 53 patients SO LEUKEMIA & LYMPHOMA LA English DT Article DE Cutaneous; diagnosis; myeloma; skin; treatment ID EXTRAMEDULLARY DISEASE; SKIN INVOLVEMENT; POOR SURVIVAL; SINGLE-CENTER; PLASMACYTOMAS; FEATURES AB Skin infiltration in multiple myeloma (skin MM) is a rare clinical problem. Only a few cases of skin involvement have been reported, primarily in single case reports. We analyzed and present the clinical outcomes, immunohistochemistry and cytogenetic features, and relevant laboratory data on 53 biopsy-proven skin MM cases. The median time from MM diagnosis to skin involvement was 2 years. There appears to be an overrepresentation of immunoglobulin class A (IgA) and light chain disease in skin MM. We found no correlation between CD56 negative MM and skin infiltration. We found that skin MM patients presented in all MM stages (i.e. ISS stages I to III), and there was no preferential cytogenetic abnormality. Patients with skin MM carry a very poor prognosis with a median overall survival (OS) of 8.5 months as time from skin involvement. Moreover, patients with IgA disease and plasmablastic morphology appear to have a worse OS. C1 [Jurczyszyn, Artur; Skotnicki, Aleksander B.] Jagiellonian Univ, Coll Med, Krakow, Poland. [Olszewska-Szopa, Magdalena] Wroclaw Med Univ, Wroclaw, Poland. [Hungria, Vania; Crusoe, Edvan] Santa Casa Med Sch, Sao Paulo, Brazil. [Pika, Tomas] Univ Hosp Olomouc, Olomouc, Czech Republic. [Delforge, Michel] Univ Hosp Leuven, Dept Hematol, Leuven, Belgium. [Leleu, Xavier] CHU Poitiers, Hop Mil, Poitiers, France. [Rasche, Leo] Univ Hosp Wuerzburg, Dept Internal Med 2, Wurzburg, Germany. [Nooka, Ajay K.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Druzd-Sitek, Agnieszka; Walewski, Jan] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Warsaw, Poland. [Davila, Julio] Hosp Univ Salamanca, Salamanca, Spain. [Caers, Jo] Ctr Hosp Univ Liege, Liege, Belgium. [Maisnar, Vladimir] Dept Med Haematol, Hradec Kralove, Czech Republic. [Gertz, Morie] Mayo Clin, Div Hematol, Rochester, MN USA. [Gentile, Massimo] AO Cosenza, Dept Oncohematol, Hematol Unit, Cosenza, Italy. [Fantl, Dorotea] Hosp Italiano Buenos Aires, Buenos Aires, DF, Argentina. [Mele, Giuseppe] Osped A Perrino, Haematol, Brindisi, Italy. [Vesole, David H.] Hackensack Univ Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA. [Yee, Andrew J.] Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Boston, MA USA. [Shustik, Chaim] McGill Univ, Royal Victoria Hosp, Montreal, PQ, Canada. [Lentzsch, Suzanne] Columbia Univ Med Ctr, New York, NY USA. [Zweegman, Sonja] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Gozzetti, Alessandro] Azienda Osped Univ Senese, Siena, Italy. [Castillo, Jorge J.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. RP Jurczyszyn, A (reprint author), Jagiellonian Univ, Dept Hematol, Coll Med, 17 Kopernika Str, PL-31501 Krakow, Poland. EM mmjurczy@cyf-kr.edu.pl OI Gozzetti, Alessandro/0000-0003-0769-6891; Castillo, Jorge/0000-0001-9490-7532 NR 25 TC 0 Z9 0 U1 2 U2 2 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 SEP PY 2016 VL 57 IS 9 BP 2071 EP 2076 DI 10.3109/10428194.2015.1128542 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA DT3HX UT WOS:000381372800011 PM 26726867 ER PT J AU Scalea, JR Redfield, RR Foley, DP AF Scalea, Joseph R. Redfield, Robert R. Foley, David P. TI Liver transplant outcomes using ideal donation after circulatory death livers are superior to using older donation after brain death donor livers SO LIVER TRANSPLANTATION LA English DT Article ID CARDIAC DEATH; GRAFT-SURVIVAL; EXPERIENCE; KIDNEY; POOL; ALLOGRAFTS; EXPANSION; VOLUME; AGE AB Multiple reports have demonstrated that liver transplantation following donation after circulatory death (DCD) is associated with poorer outcomes when compared with liver transplantation from donation after brain death (DBD) donors. We hypothesized that carefully selected, underutilized DCD livers recovered from younger donors have excellent outcomes. We performed a retrospective study of the United Network for Organ Sharing database to determine graft survivals for patients who received liver transplants from DBD donors of age60 years, DBD donors<60 years, and DCD donors<50 years of age. Between January 2002 and December 2014, 52,271 liver transplants were performed in the United States. Of these, 41,181 (78.8%) underwent transplantation with livers from DBD donors of age<60 years, 8905 (17.0%) from DBD donors60 years old, and 2195 (4.2%) livers from DCD donors<50 years of age. DCD livers of age<50 years with<6 hours of cold ischemia time (CIT) had superior graft survival when compared with DBD liversage 60 years (P<0.001). In 2014, there were 133 discarded DCD livers; of these, 111 (83.4%) were from donors60 years old. Careful donor organ and recipient selection can lead to excellent results, despite previous reports suggesting otherwise. Increased acceptance of these DCD livers would lead to shorter wait list times and increased national liver transplant rates. Liver Transplantation 22 1197-1204 2016 AASLD C1 [Scalea, Joseph R.; Redfield, Robert R.; Foley, David P.] Univ Wisconsin, Dept Surg, Div Transplantat, Sch Med & Publ Hlth, 600 Highland Ave,Suite H4-7, Madison, WI 53792 USA. [Foley, David P.] William S Middleton Mem Vet Adm Med Ctr, Vet Adm Surg Serv, Madison, WI USA. RP Scalea, JR (reprint author), Univ Wisconsin, Dept Surg, Div Transplantat, Sch Med & Publ Hlth, 600 Highland Ave,Suite H4-7, Madison, WI 53792 USA. EM scalea@surgery.wisc.edu NR 25 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6465 EI 1527-6473 J9 LIVER TRANSPLANT JI Liver Transplant. PD SEP PY 2016 VL 22 IS 9 BP 1197 EP 1204 DI 10.1002/lt.24494 PG 8 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA DV9VI UT WOS:000383289900004 PM 27314220 ER PT J AU Crytzer, TM Hong, EK Dicianno, BE Pearlman, J Schmeler, M Cooper, RA AF Crytzer, Theresa M. Hong, Eun-Kyoung Dicianno, Brad E. Pearlman, Jon Schmeler, Mark Cooper, Rory A. TI Identifying characteristic back shapes from anatomical scans of wheelchair users to improve seating design SO MEDICAL ENGINEERING & PHYSICS LA English DT Article DE Assistive technology; Backrest; Back contour; Back scanning; Back shapes; Pelvic obliquity; Posture; Root mean square error; Seating; Wheelchair; Back support ID SPINAL-CORD-INJURY; SITTING BIOMECHANICS; CEREBRAL-PALSY; SCOLIOSIS; PRESSURE; REQUIREMENTS; PROPULSION; ALIGNMENT; COMFORT; WORK AB Spinal deformities are common in people who require the use of a wheelchair for mobility as a result of spinal cord injuries and other disabilities. Sitting positions vary between individuals with disabilities who use wheelchairs and individuals without disabilities. In individuals with spinal cord injury, spinal deformities can result in the development of back contours that deviate from the shape of standard rigid back support shells. The purpose of this study was to distinguish and classify various back contours of wheelchair users by utilizing digital anatomic scanning technology in order to inform the future development of back supports that would enhance postural support for those with spinal deformities. The three dimensional (3D) locations of bony landmarks were digitized when participants were in position, using a mechanical wand linked to the FastScan(tm) system commonly used to measure surface contours. Raw FastScantm data were transformed according to bony landmarks. A total of 129 individuals participated in this study. A wide range of back contours were identified and categorized. Although participant characteristics (e.g., gender, diagnosis) were similar amongst the contour groups; no one characteristic explained the contours. Participants who were seated in a forward lean position had a higher amount of pelvic obliquity compared to those seated in an upright position; however, participants' back contour was not correlated with pelvic obliquity. In conclusion, an array of different back shapes were classified in our cohort through 3D laser scanning technology. The methods and technology applied in this study could be replicated in future studies to categorize ranges of back shapes in larger populations of people with spinal cord injuries. Preliminary evidence indicates that customized postural support may be warranted to optimize positioning and posture when a standard rigid shell does not align with contours of a person's back. To optimize positioning, a range of contoured rigid backrests as well as height and angle adjustability are likely needed. (C) 2016 IPEM. Published by Elsevier Ltd. All rights reserved. C1 [Crytzer, Theresa M.; Hong, Eun-Kyoung; Dicianno, Brad E.; Pearlman, Jon; Cooper, Rory A.] Vet Affairs Pittsburgh Healthcare Syst, Human Engn Res Labs, 6425 Penn Ave,Suite 400, Pittsburgh, PA 15206 USA. [Crytzer, Theresa M.; Hong, Eun-Kyoung; Dicianno, Brad E.; Pearlman, Jon; Schmeler, Mark; Cooper, Rory A.] Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. [Dicianno, Brad E.] Univ Pittsburgh, Med Ctr, Dept Phys Med & Rehabil, Pittsburgh, PA USA. RP Cooper, RA (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Human Engn Res Labs, 6425 Penn Ave,Suite 400, Pittsburgh, PA 15206 USA. EM rcooper@pitt.edu FU VA Center of Excellence for Wheelchairs and Associated Rehabilitation [B6789C]; Paralyzed Veterans of America FX Supported by The VA Center of Excellence for Wheelchairs and Associated Rehabilitation (Grant B6789C) and Paralyzed Veterans of America. The contents of this paper do not represent the views of the Department of Veterans Affairs or the United States Government. NR 45 TC 1 Z9 1 U1 9 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1350-4533 EI 1873-4030 J9 MED ENG PHYS JI Med. Eng. Phys. PD SEP PY 2016 VL 38 IS 9 SI SI BP 999 EP 1007 DI 10.1016/j.medengphy.2016.06.017 PG 9 WC Engineering, Biomedical SC Engineering GA DV5YN UT WOS:000383006700024 PM 27426985 ER PT J AU Barquilla, A Lamberto, I Noberini, R Heynen-Genel, S Brill, LM Pasquale, EB AF Barquilla, Antonio Lamberto, Ilaria Noberini, Roberta Heynen-Genel, Susanne Brill, Laurence M. Pasquale, Elena B. TI Protein kinase A can block EphA2 receptor-mediated cell repulsion by increasing EphA2 S897 phosphorylation SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID PROSTATE-CANCER CELLS; TYROSINE KINASE; MASS-SPECTROMETRY; CASEIN KINASE; SUBSTRATE DETERMINANTS; VASCULAR-PERMEABILITY; SMALL MOLECULES; EPHRIN SYSTEM; MIGRATION; THERAPY AB The EphA2 receptor tyrosine kinase plays key roles in tissue homeostasis and disease processes such as cancer, pathological angiogenesis, and inflammation through two distinct signaling mechanisms. EphA2 "canonical" signaling involves ephrin-A ligand binding, tyrosine autophosphorylation, and kinase activity; EphA2 "noncanonical" signaling involves phosphorylation of serine 897 (S897) by AKT and RSK kinases. To identify small molecules counteracting EphA2 canonical signaling, we developed a high-content screening platform measuring inhibition of ephrin-A1-induced PC3 prostate cancer cell retraction. Surprisingly, most hits from a screened collection of pharmacologically active compounds are agents that elevate intracellular cAMP by activating G protein-coupled receptors such as the beta 2-adrenoceptor. We found that cAMP promotes phosphorylation of S897 by protein kinase A (PKA) as well as increases the phosphorylation of several nearby serine/threonine residues, which constitute a phosphorylation hotspot. Whereas EphA2 canonical and noncanonical signaling have been viewed as mutually exclusive, we show that S897 phosphorylation by PKA can coexist with EphA2 tyrosine phosphorylation and block cell retraction induced by EphA2 kinase activity. Our findings reveal a novel paradigm in EphA2 function involving the interplay of canonical and noncanonical signaling and highlight the ability of the beta 2-adrenoceptor/cAMP/PKA axis to rewire EphA2 signaling in a subset of cancer cells. C1 [Barquilla, Antonio; Lamberto, Ilaria; Noberini, Roberta; Heynen-Genel, Susanne; Brill, Laurence M.; Pasquale, Elena B.] Sanford Burnham Prebys Med Discovery Inst, Ctr Canc, La Jolla, CA 92037 USA. [Pasquale, Elena B.] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Lamberto, Ilaria] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Noberini, Roberta] Ist Italiano Tecnol, Ctr Genom Sci IIT SEMM, I-20139 Milan, Italy. [Brill, Laurence M.] Intertek Pharmaceut Serv, Bioanalyt LCMS, San Diego, CA 92121 USA. RP Pasquale, EB (reprint author), Sanford Burnham Prebys Med Discovery Inst, Ctr Canc, La Jolla, CA 92037 USA.; Pasquale, EB (reprint author), Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. EM elenap@sbpdiscovery.org FU National Institutes of Health [P01 CA138390, R21 NS066479]; Spanish Ministry of Science and Education; National Cancer Institute Cancer Center Support Grant [P30 CA030199] FX We thank C. Fernandez for generating the EphA2 S897A mutant, R. Elward for help with experiments to characterize the pS901 antibody, S. Taylor for the purified PKA catalytic subunit and the PKA WT and PKA KD constructs, R. Maurer for the pRSV-PKI-v2 construct, C. Comisso for the MIA PaCa2 cell line, J. Reed for the LNCaP cell line, S. Hayward for the BPH1 cell line, P. Itkin-Ansari for the BxPC3 cell line, G. Powis for the Capan2 and PL45 cell lines, F. Levine for the PANC1 cell line, E. Adamson for the DU145 cell line, and A. D'Osualdo for the control pLK0.1 puro lentivirus, VSV-G envelope glycoprotein, and pCMV Delta R8.91 packaging constructs. This work was supported by National Institutes of Health Grants P01 CA138390 and R21 NS066479 and Institutional Funding (E.B.P.), fellowships from the Spanish Ministry of Science and Education (A.B.P.), and National Cancer Institute Cancer Center Support Grant P30 CA030199 (supporting Sanford Burnham Prebys Medical Discovery Institute Core Facilities). NR 99 TC 2 Z9 2 U1 1 U2 1 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 SEP PY 2016 VL 27 IS 17 BP 2757 EP 2770 DI 10.1091/mbc.E16-01-0048 PG 14 WC Cell Biology SC Cell Biology GA DV4IP UT WOS:000382889600012 PM 27385333 ER PT J AU Hogg, SJ Newbold, A Vervoort, SJ Cluse, LA Martin, BP Gregory, GP Lefebure, M Vidacs, E Tothill, RW Bradner, JE Shortt, J Johnstone, RW AF Hogg, Simon J. Newbold, Andrea Vervoort, Stephin J. Cluse, Leonie A. Martin, Benjamin P. Gregory, Gareth P. Lefebure, Marcus Vidacs, Eva Tothill, Richard W. Bradner, James E. Shortt, Jake Johnstone, Ricky W. TI BET Inhibition Induces Apoptosis in Aggressive B-Cell Lymphoma via Epigenetic Regulation of BCL-2 Family Members SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID BROMODOMAIN INHIBITION; C-MYC; SELECTIVE-INHIBITION; GENE-EXPRESSION; RESISTANCE; LEUKEMIA; P53; CHROMATIN; TARGETS; CANCER AB Targeting BET bromodomain proteins using small molecules is an emerging anticancer strategy with clinical evaluation of at least six inhibitors now underway. Although MYC downregulation was initially proposed as a key mechanistic property of BET inhibitors, recent evidence suggests that additional antitumor activities are important. Using the Em-Myc model of B-cell lymphoma, we demonstrate that BET inhibition with JQ1 is a potent inducer of p53-independent apoptosis that occurs in the absence of effects on Myc gene expression. JQ1 skews the expression of proapoptotic (Bim) and antiapoptotic (BCL-2/BCL-xL) BCL-2 family members to directly engage the mitochondrial apoptotic pathway. Consistent with this, Bim knock-out or Bcl-2 overexpression inhibited apoptosis induction by JQ1. We identified lymphomas that were either intrinsically resistant to JQ1-mediated death or acquired resistance following in vivo exposure. Strikingly, in both instances BCL-2 was strongly upregulated and was concomitant with activation of RAS pathways. Em-Myc lymphomas engineered to express activated Nras upregulated BCL-2 and acquired a JQ1 resistance phenotype. These studies provide important information on mechanisms of apoptosis induction and resistance to BET-inhibition, while providing further rationale for the translation of BET inhibitors in aggressive B-cell lymphomas. (C) 2016 AACR. C1 [Hogg, Simon J.; Newbold, Andrea; Vervoort, Stephin J.; Cluse, Leonie A.; Martin, Benjamin P.; Gregory, Gareth P.; Lefebure, Marcus; Vidacs, Eva; Tothill, Richard W.; Shortt, Jake; Johnstone, Ricky W.] Peter MacCallum Canc Ctr, Div Res, Gene Regulat Lab, Melbourne, Vic, Australia. [Hogg, Simon J.; Gregory, Gareth P.; Lefebure, Marcus; Shortt, Jake; Johnstone, Ricky W.] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic, Australia. [Gregory, Gareth P.; Shortt, Jake] Monash Hlth, Monash Hematol, Clayton, Vic, Australia. [Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Shortt, Jake] Monash Univ, Monash Hlth, Sch Clin Sci, Clayton, Vic, Australia. [Bradner, James E.] Novartis Inst BioMed Res, Cambridge, MA USA. RP Shortt, J (reprint author), Peter MacCallum Canc Ctr, Div Res, Gene Regulat Lab, Melbourne, Vic, Australia.; Shortt, J (reprint author), Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic, Australia.; Shortt, J (reprint author), Monash Hlth, Monash Hematol, Clayton, Vic, Australia.; Shortt, J (reprint author), Monash Univ, Monash Hlth, Sch Clin Sci, Clayton, Vic, Australia.; Johnstone, RW (reprint author), Peter MacCallum Canc Ctr, Melbourne, Vic 3000, Australia. EM jake.shortt@monashhealth.org; ricky.johnstone@petermac.org OI Shortt, Jake/0000-0003-3185-6488; Gregory, Gareth/0000-0002-4170-0682; Tothill, Richard/0000-0003-4522-1184 FU Leukemia Foundation of Australia; Cancer Therapeutics CRC; Royal Australasian College of Physicians; Arrow Bone Marrow Transplant Foundation; Eva and Les Erdi/ Snowdome Foundation Victorian Cancer Agency Fellowship; Cancer Council Victoria; NHMRC [APP454569]; Victorian Cancer Agency FX This work was supported by funding from the Leukemia Foundation of Australia (to S.J. Hogg, A. Newbold, G.P. Gregory, and M. Lefebure), the Cancer Therapeutics CRC (to S.J. Hogg and G.P. Gregory), the Royal Australasian College of Physicians (to G.P. Gregory), and the Arrow Bone Marrow Transplant Foundation (to M. Lefebure). J. Shortt is supported by funding from the Eva and Les Erdi/ Snowdome Foundation Victorian Cancer Agency Fellowship, and the Cancer Council Victoria. R.W. Johnstone is a senior principal research fellow (APP1077867) of the National Health and Medical Research Council of Australia (NHMRC) and is supported by an NHMRC program grant (APP454569), the Cancer Council Victoria and the Victorian Cancer Agency. NR 42 TC 3 Z9 3 U1 8 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD SEP 1 PY 2016 VL 15 IS 9 BP 2030 EP 2041 DI 10.1158/1535-7163.MCT-15-0924 PG 12 WC Oncology SC Oncology GA DV6MQ UT WOS:000383050800003 PM 27406984 ER PT J AU Brown, WS Tan, L Smith, A Gray, NS Wendt, MK AF Brown, Wells S. Tan, Li Smith, Andrew Gray, Nathanael S. Wendt, Michael K. TI Covalent Targeting of Fibroblast Growth Factor Receptor Inhibits Metastatic Breast Cancer SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; FOCAL ADHESION KINASE; TGF-BETA; INTEGRIN; OUTGROWTH; CELLS; PROGRESSION; PLASTICITY; PROGRAM AB Therapeutic targeting of late-stage breast cancer is limited by an inadequate understanding of how tumor cell signaling evolves during metastatic progression and by the currently available small molecule inhibitors capable of targeting these processes. Herein, we demonstrate that both beta 3 integrin and fibroblast growth factor receptor-1 (FGFR1) are part of an epithelial-mesenchymal transition (EMT) program that is required to facilitate metastatic outgrowth in response to fibroblast growth factor-2 (FGF2). Mechanistically, beta 3 integrin physically disrupts an interaction between FGFR1 and E-cadherin, leading to a dramatic redistribution of FGFR1 subcellular localization, enhanced FGF2 signaling and increased three-dimensional (3D) outgrowth of metastatic breast cancer cells. This ability of beta 3 integrin to drive FGFR signaling requires the enzymatic activity of focal adhesion kinase (FAK). Consistent with these mechanistic data, we demonstrate that FGFR, beta 3 integrin, and FAK constitute a molecular signature capable of predicting decreased survival of patients with the basal-like subtype of breast cancer. Importantly, covalent targeting of a conserved cysteine in the P-loop of FGFR1-4 with our newly developed small molecule, FIIN-4, more effectively blocks 3D metastatic outgrowth as compared with currently available FGFR inhibitors. In vivo application of FIIN-4 potently inhibited the growth of metastatic, patient-derived breast cancer xenografts and murine-derived metastases growing within the pulmonary microenvironment. Overall, the current studies demonstrate that FGFR1 works in concert with other EMT effector molecules to drive aberrant downstream signaling, and that these events can be effectively targeted using our novel therapeutics for the treatment of the most aggressive forms of breast cancer. (C)2016 AACR. C1 [Brown, Wells S.; Smith, Andrew; Wendt, Michael K.] Purdue Univ, Ctr Canc Res, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. [Tan, Li; Gray, Nathanael S.] Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA USA. RP Wendt, MK (reprint author), Purdue Univ, 201 South Univ St,Hansen Life Sci Bldg, W Lafayette, IN 47907 USA. EM mwendt@purdue.edu FU NIH [R00 CA166140]; Showalter Trust Foundation; Lung SPORE grant [P50 CA090578] FX This research was supported in part by the NIH (R00 CA166140) and the Showalter Trust Foundation (to M.K. Wendt) and by Lung SPORE grant (P50 CA090578; to N.S. Gray). NR 35 TC 2 Z9 2 U1 10 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD SEP 1 PY 2016 VL 15 IS 9 BP 2096 EP 2106 DI 10.1158/1535-7163.MCT-16-0136 PG 11 WC Oncology SC Oncology GA DV6MQ UT WOS:000383050800009 PM 27371729 ER PT J AU Borsook, D Linnman, C Faria, V Strassman, AM Becerra, L Elman, I AF Borsook, D. Linnman, C. Faria, V. Strassman, A. M. Becerra, L. Elman, I. TI Reward deficiency and anti-reward in pain chronification SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Reward; Motivation; Aversion; Analgesia; Amygdala; Habenula; Nucleus accumbens; Dopamine; Addiction; Stress; Pain ID VENTRAL TEGMENTAL AREA; POSTTRAUMATIC-STRESS-DISORDER; LOW-BACK-PAIN; DOPAMINE SYSTEM REGULATION; OPPONENT-PROCESS THEORY; BURNING MOUTH SYNDROME; GRAY-MATTER DENSITY; QUALITY-OF-LIFE; NUCLEUS-ACCUMBENS; LATERAL HABENULA AB Converging lines of evidence suggest that the pathophysiology of pain is mediated to a substantial degree via allostatic neuroadaptations in reward- and stress-related brain circuits. Thus, reward deficiency (RD) represents a within-system neuroadaptation to pain-induced protracted activation of the reward circuits that leads to depletion-like hypodopaminergia, clinically manifested anhedonia, and diminished motivation for natural reinforcers. Anti-reward (AR) conversely pertains to a between-systems neuroadaptation involving over-recruitment of key limbic structures (e.g., the central and basolateral amygdala nuclei, the bed nucleus of the stria terminalis, the lateral tegmental noradrenergic nuclei of the brain stem, the hippocampus and the habenula) responsible for massive outpouring of stressogenic neurochemicals (e.g., norepinephrine, corticotropin releasing factor, vasopressin, hypocretin, and substance P) giving rise to such negative affective states as anxiety, fear and depression. We propose here the Combined Reward deficiency and Anti-reward Model (CReAM), in which biopsychosocial variables modulating brain reward, motivation and stress functions can interact in a 'downward spiral' fashion to exacerbate the intensity, chronicity and comorbidities of chronic pain syndromes (i.e., pain chronification). (C) 2016 The Authors. Published by Elsevier Ltd. C1 [Borsook, D.; Linnman, C.; Faria, V.; Becerra, L.] Boston Childrens Hosp, Ctr Pain & Brain, Boston, MA 02115 USA. [Borsook, D.; Linnman, C.; Faria, V.; Becerra, L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Borsook, D.; Linnman, C.; Faria, V.; Becerra, L.] Boston Childrens Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Borsook, D.; Becerra, L.] Mclean & Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Faria, V.] Uppsala Univ, Dept Psychol, Uppsala, Sweden. [Strassman, A. M.] Beth Israel Deaconess Med Ctr, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Borsook, D.; Linnman, C.; Faria, V.; Strassman, A. M.; Becerra, L.] Harvard Med Sch, Boston, MA USA. [Elman, I.] Wright State Univ, Boonshoft Sch Med, Dept Psychiat, Dayton, OH 45435 USA. [Elman, I.] Dayton VA Med Ctr, Dayton, OH USA. RP Borsook, D (reprint author), Boston Childrens Hosp, Ctr Pain & Brain, Boston, MA 02115 USA. EM david.borsook@childrens.harvard.edu FU NINDS [NINDS K24 NS064050]; Mayday Fund/Louis Herlands Research Endowment FX The work was supported by grants from NINDS (NINDS K24 NS064050) and The Mayday Fund/Louis Herlands Research Endowment (DB). The authors thank Catherine Hubbard for her comments on the earlier versions of the manuscript and Rosanna Veggeberg for her help with the preparation of the manuscript for submission. NR 231 TC 3 Z9 3 U1 5 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 EI 1873-7528 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD SEP PY 2016 VL 68 BP 282 EP 297 DI 10.1016/j.neubiorev.2016.05.033 PG 16 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DV9WS UT WOS:000383293500020 PM 27246519 ER PT J AU Simons, LE Goubert, L Vervoort, T Borsook, D AF Simons, Laura E. Goubert, Liesbet Vervoort, Tine Borsook, David TI Circles of engagement: Childhood pain and parent brain SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Empathy; Chronic pain; Pediatric; Parent-child; Salience network; Stress; Emotional contagion ID VON ECONOMO NEURONS; POSTTRAUMATIC-STRESS-DISORDER; RANDOMIZED CONTROLLED-TRIAL; FUNCTIONAL CONNECTIVITY; MINERALOCORTICOID RECEPTOR; COMMITMENT THERAPY; EMPATHIC RESPONSES; PREFRONTAL CORTEX; REACTIVITY; BEHAVIOR AB Social interaction can have a profound effect on individual behavior, perhaps most salient in interactions between sick suffering children and their parents. Chronic pain is a difficult condition that can produce considerable changes in children's behaviors that can secondarily have profound effects on their parents. It may create a functionally disabling negative feedback loop. Research supports the notion of alterations in the brain of individuals who observe and empathize with loved ones in acute pain. However, neural activity in relation to empathic responses in the context of chronic pain has not been examined. Ongoing suffering with chronic pain in a child can result in child's brain circuit alterations. Moreover, prolonged suffering jointly experienced by the parent may putatively produce maladaptive changes in their neural networks and consequently in parental behaviors. Here we put forth the conceptual framework for 'Chronic pain contagion' (CPC). We review the underlying processes in CPC and discuss implications for devising and implementing treatments for children in chronic pain and their parents. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Simons, Laura E.; Borsook, David] Boston Childrens Hosp, Ctr Pain & Brain, Boston, MA USA. [Simons, Laura E.; Borsook, David] Harvard Med Sch, Dept Anesthesiol Perioperat & Pain Med, Boston, MA USA. [Simons, Laura E.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Goubert, Liesbet; Vervoort, Tine] Univ Ghent, Dept Expt Clin & Hlth Psychol, Ghent, Belgium. [Borsook, David] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. RP Simons, LE (reprint author), Boston Childrens Hopistal, 21 Autumn St, Boston, MA 02115 USA. EM Laura.Simons@childrens.harvard.edu OI Goubert, Liesbet/0000-0002-7657-5148 FU K23 career development award [HD067202, R01HD08327]; K24 Mentoring Grant [NINDS NS064050]; Ghent University Special Research Fund [BOF15/24j/017] FX Supported by a K23 career development award (HD067202) and R01HD08327 to LS, a K24 Mentoring Grant (NINDS NS064050) to DB, and by a Ghent University Special Research Fund grant (BOF15/24j/017) to LG and LS. NR 112 TC 0 Z9 0 U1 6 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 EI 1873-7528 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD SEP PY 2016 VL 68 BP 537 EP 546 DI 10.1016/j.neubiorev.2016.06.020 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DV9WS UT WOS:000383293500036 PM 27320958 ER PT J AU Kovacheva, VP Aglio, LS Boland, TA Mendu, ML Gibbons, FK Christopher, KB AF Kovacheva, Vesela P. Aglio, Linda S. Boland, Torrey A. Mendu, Mallika L. Gibbons, Fiona K. Christopher, Kenneth B. TI Acute Kidney Injury After Craniotomy Is Associated With Increased Mortality: A Cohort Study SO NEUROSURGERY LA English DT Article DE Acute kidney injury; Craniotomy ID ACUTE-RENAL-FAILURE; CRITICALLY-ILL PATIENTS; QUALITY-OF-LIFE; INTENSIVE-CARE-UNIT; HOSPITAL MORTALITY; RIFLE CRITERIA; ISCHEMIA/REPERFUSION INJURY; INTRACEREBRAL HEMORRHAGE; LUNG TRANSPLANTATION; REPLACEMENT THERAPY AB BACKGROUND: Acute kidney injury (AKI) is a serious postoperative complication. OBJECTIVE: To determine whether AKI in patients after craniotomy is associated with heightened 30-day mortality. METHODS: We performed a 2-center, retrospective cohort study of 1656 craniotomy patients who received critical care between 1998 and 2011. The exposure of interest was AKI defined as meeting RIFLE (Risk, Injury, Failure, Loss of Kidney Function, and End-stage Kidney Disease) class risk, injury, and failure criteria, and the primary outcome was 30-day mortality. Adjusted odds ratios were estimated by multivariable logistic regression models with inclusion of covariate terms thought to plausibly interact with both AKI and mortality. Additionally, mortality in craniotomy patients with AKI was analyzed with a risk-adjusted Cox proportional hazards regression model and propensity score matching as a sensitivity analysis. RESULTS: The incidences of RIFLE class risk, injury, and failure were 5.7%, 2.9%, and 1.3%, respectively. The odds of 30-day mortality in patients with RIFLE class risk, injury, or failure fully adjusted were 2.79 (95% confidence interval [CI], 1.76-4.42), 7.65 (95% CI, 4.16-14.07), and 14.41 (95% CI, 5.51-37.64), respectively. Patients with AKI experienced a significantly higher risk of death during follow-up; hazard ratio, 1.82 (95% CI, 1.34-2.46), 3.37 (95% CI, 2.36-4.81), and 5.06 (95% CI, 2.99-8.58), respectively, fully adjusted. In a cohort of propensity score-matched patients, RIFLE class remained a significant predictor of 30-day mortality. CONCLUSION: Craniotomy patients who suffer postoperative AKI are among a high-risk group for mortality. The severity of AKI after craniotomy is predictive of 30-day mortality. C1 [Kovacheva, Vesela P.; Aglio, Linda S.] Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Harvard Med Sch, 75 Francis St, Boston, MA 02115 USA. [Boland, Torrey A.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Mendu, Mallika L.] Brigham & Womens Hosp, Div Renal, Harvard Med Sch, 75 Francis St, Boston, MA 02115 USA. [Gibbons, Fiona K.] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Harvard Med Sch, Dept Med, Boston, MA 02114 USA. [Christopher, Kenneth B.] Brigham & Womens Hosp, Harvard Med Sch, Div Renal, Nathan E Hellman Mem Lab, Boston, MA 02115 USA. RP Christopher, KB (reprint author), Brigham & Womens Hosp, Div Renal, Nathan E Hellman Mem Lab, 75 Francis St,MRB 418, Boston, MA 02115 USA. EM kbchristopher@partners.org FU Department of Anesthesiology, Perioperative and Pain Medicine; Harvard Medical School FX Parts of this work were presented at Anesthesiology 2013, the American Society of the Anesthesiologists Annual Meeting. Funds were received from the Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. NR 69 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD SEP PY 2016 VL 79 IS 3 BP 389 EP 396 DI 10.1227/NEU.0000000000001153 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DV9PX UT WOS:000383274400017 PM 26645967 ER PT J AU Setsompop, K Feinberg, DA Polimeni, JR AF Setsompop, Kawin Feinberg, David A. Polimeni, Jonathan R. TI Rapid brain MRI acquisition techniques at ultra-high fields SO NMR IN BIOMEDICINE LA English DT Review DE CAIPIRINHA; simultaneous multislice; multiband; blipped-CAIPI; 3D imaging; 3D-EPI; wave-CAIPI; simultaneous multislice RF pulse design ID SIMULTANEOUS MULTISLICE EXCITATION; HIGH MAGNETIC-FIELD; PARTIALLY PARALLEL ACQUISITIONS; PINS RADIOFREQUENCY PULSES; OUTER-VOLUME SUPPRESSION; HUMAN CONNECTOME PROJECT; HIGH TEMPORAL RESOLUTION; READOUT-SEGMENTED EPI; CEREBRAL-BLOOD-FLOW; TO-NOISE RATIO AB Ultra-high-field MRI provides large increases in signal-to-noise ratio (SNR) as well as enhancement of several contrast mechanisms in both structural and functional imaging. Combined, these gains result in a substantial boost in contrast-to-noise ratio that can be exploited for higher-spatial-resolution imaging to extract finer-scale information about the brain. With increased spatial resolution, however, there is a concurrent increased image-encoding burden that can cause unacceptably long scan times for structural imaging and slow temporal sampling of the hemodynamic response in functional MRI - particularly when whole-brain imaging is desired. To address this issue, new directions of imaging technology development - such as the move from conventional 2D slice-by-slice imaging to more efficient simultaneous multislice (SMS) or multiband imaging (which can be viewed as pseudo-3D encoding) as well as full 3D imaging - have provided dramatic improvements in acquisition speed. Such imaging paradigms provide higher SNR efficiency as well as improved encoding efficiency. Moreover, SMS and 3D imaging can make better use of coil sensitivity information in multichannel receiver arrays used for parallel imaging acquisitions through controlled aliasing in multiple spatial directions. This has enabled unprecedented acceleration factors of an order of magnitude or higher in these imaging acquisition schemes, with low image artifact levels and high SNR. Here we review the latest developments of SMS and 3D imaging methods and related technologies at ultra-high field for rapid high-resolution functional and structural imaging of the brain. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Setsompop, Kawin; Polimeni, Jonathan R.] Harvard Med Sch, Dept Radiol, Boston, MA 02115 USA. [Setsompop, Kawin; Polimeni, Jonathan R.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Feinberg, David A.] Univ Calif Berkeley, Helen Wills Inst Neurosci, Berkeley, CA 94720 USA. [Feinberg, David A.] Adv MRI Technol, Sebastopol, CA USA. RP Setsompop, K (reprint author), Harvard Med Sch, Dept Radiol, Boston, MA 02115 USA. EM kawin@nmr.mgh.harvard.edu FU NIH National Institute for Biomedical Imaging and Bioengineering [P41-EB015896, R00-EB012107, K01-EB011498, R01-EB019437]; National Institute of Neurological Disease and Stroke (NIH) [R44 NS073417]; NIH Blueprint for Neuroscience Research [U01-MH093765]; multi-institutional Human Connectome Project; BRAIN Initiative project [NIH R24MH106096] FX We would like to thank Dr. Andre van der Kouwe for providing the CAIPI-MEMPRAGE pulse sequence and Dr. Himanshu Bhat for providing the SMS-FLEET ACS pulse sequence. We would also like to thank Drs. Boris Keil and Thomas Witzel for 7T scanning assistance and support, and Dr. Larry Wald for helpful comments. We also thank the anonymous reviewers for their helpful suggestions. This research was provided in part by the NIH National Institute for Biomedical Imaging and Bioengineering (P41-EB015896, R00-EB012107, K01-EB011498, and R01-EB019437) and National Institute of Neurological Disease and Stroke (NIH R44 NS073417). Additional support was provided by the NIH Blueprint for Neuroscience Research (U01-MH093765), part of the multi-institutional Human Connectome Project, and the BRAIN Initiative project (NIH R24MH106096). NR 251 TC 2 Z9 2 U1 7 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 EI 1099-1492 J9 NMR BIOMED JI NMR Biomed. PD SEP PY 2016 VL 29 IS 9 SI SI BP 1198 EP 1221 DI 10.1002/nbm.3478 PG 24 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA DV9OX UT WOS:000383271800007 PM 26835884 ER PT J AU Hogan, CS Freeman, MP AF Hogan, Charlotte S. Freeman, Marlene P. TI Adverse Effects in the Pharmacologic Management of Bipolar Disorder During Pregnancy SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Pregnancy; Bipolar disorder; Adverse effects; Lithium; Anticonvulsant; Antipsychotic ID ATYPICAL ANTIPSYCHOTIC-DRUGS; IN-UTERO EXPOSURE; ANTIEPILEPTIC DRUGS; CONGENITAL-MALFORMATIONS; PSYCHOTROPIC MEDICATION; BIRTH-WEIGHT; POSTPARTUM PSYCHOSIS; PLACENTAL PASSAGE; SPECTRUM DISORDER; MOOD STABILIZERS AB Management of bipolar disorder during pregnancy often involves medications with potential adverse effects, including risks to the mother and fetus. Although some specifics are known, many medications continue to have incompletely characterized reproductive safety profiles. Women with bipolar disorder who are planning pregnancy face challenging decisions about their treatment; careful risk-benefit discussions are necessary. With the goal of further informing these discussions, this article reviews the data currently available regarding medication safety in the management of bipolar disorder during pregnancy, with specific attention to lithium, valproic acid, lamotrigine, carbamazepine, and antipsychotic medications. C1 [Hogan, Charlotte S.] Massachusetts Gen Hosp, Dept Psychiat, Warren 605,55 Fruit St, Boston, MA 02114 USA. [Freeman, Marlene P.] Massachusetts Gen Hosp, Dept Psychiat, Simches 2,185 Cambridge St, Boston, MA 02114 USA. RP Freeman, MP (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Simches 2,185 Cambridge St, Boston, MA 02114 USA. EM mfreeman@mgh.harvard.edu NR 86 TC 0 Z9 0 U1 10 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0193-953X EI 1558-3147 J9 PSYCHIAT CLIN N AM JI Psychiatr. Clin. North Amer. PD SEP PY 2016 VL 39 IS 3 BP 465 EP + DI 10.1016/j.psc.2016.04.007 PG 12 WC Psychiatry SC Psychiatry GA DV5ZD UT WOS:000383008300007 PM 27514299 ER PT J AU Scioli-Salter, ER Johnides, BD Mitchell, KS Smith, BN Resick, PA Rasmusson, AM AF Scioli-Salter, Erica R. Johnides, Benjamin D. Mitchell, Karen S. Smith, Brian N. Resick, Patricia A. Rasmusson, Ann M. TI Depression and Dissociation as Predictors of Physical Health Symptoms Among Female Rape Survivors With Posttraumatic Stress Disorder SO PSYCHOLOGICAL TRAUMA-THEORY RESEARCH PRACTICE AND POLICY LA English DT Article DE depression; dissociation; PTSD; physical health; rape survivors ID CHILDHOOD SEXUAL ABUSE; SELF-REPORTED HEALTH; CHRONIC PAIN; NEUROPEPTIDE-Y; UNDERGRADUATE WOMEN; METABOLIC SYNDROME; MAJOR DEPRESSION; TRAUMA; VETERANS; EXPOSURE AB Objective: To investigate the relative contributions of depression and dissociation, as well as posttraumatic stress disorder (PTSD), to physical health symptoms and to examine the relationships among somatic symptoms, PTSD, depression, and dissociation in relation to childhood and adult trauma exposure. Method: Cross-sectional data are from 132 female rape survivors with PTSD assessed before engaging in a study of trauma-focused cognitive therapy for PTSD. Measures included the Pennebaker Inventory of Limbic Languidness, Clinician Administered PTSD Scale, Beck Depression Inventory, Trauma Symptom Inventory-Dissociation Subscale, Childhood Sexual Abuse Exposure Questionnaire, and Assessing Environments-III-Physical Punishment Scale. Results: Hierarchical regression analyses revealed that only dissociative and depression symptoms contributed significantly to physical health symptoms. Similarly, among the subsample of women with either childhood sexual or physical abuse, depression and dissociation were significant predictors of somatic symptoms. However, among women without childhood abuse, only dissociation significantly predicted somatic symptoms. Conclusion: Understanding the psychological and biological mechanisms that link childhood versus adult trauma exposure, PTSD, and comorbid depression or dissociation to physical health symptoms may aid development of individualized treatments for the physical and psychological consequences of trauma. C1 [Scioli-Salter, Erica R.; Mitchell, Karen S.; Smith, Brian N.; Resick, Patricia A.; Rasmusson, Ann M.] VA Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA USA. [Scioli-Salter, Erica R.; Mitchell, Karen S.; Smith, Brian N.; Rasmusson, Ann M.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Johnides, Benjamin D.] Univ Missouri, Dept Psychol Sci, Columbia, MO 65211 USA. [Resick, Patricia A.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27706 USA. RP Scioli-Salter, ER (reprint author), VA Boston Healthcare Syst, Res Serv, 14D-85A,150 South Huntington Ave, Boston, MA 02130 USA. EM ericarose.scioli@va.gov FU National Institute of Mental Health [2-R01-MH51509]; Department of Veterans Affairs; Veterans Health Administration; Rehabilitation Research and Development Service [1IK2RX000704-01A2]; Women's Health Sciences Division, National Center for PTSD FX This study was funded by the National Institute of Mental Health (2-R01-MH51509), in a grant awarded to PAR entitled "Cognitive Processes in PTSD: Treatment II." Furthermore, the research described here was supported in part by the Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service-Award number 1IK2RX000704-01A2 as well as by the Women's Health Sciences Division, National Center for PTSD. NR 55 TC 0 Z9 0 U1 11 U2 11 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1942-9681 EI 1942-969X J9 PSYCHOL TRAUMA-US JI Psychol. Trauma PD SEP PY 2016 VL 8 IS 5 BP 585 EP 591 DI 10.1037/tra0000135 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DV9IL UT WOS:000383254000006 PM 27149157 ER PT J AU Mullerova, J Hansen, M Contractor, AA Elhai, JD Armour, C AF Mullerova, Jana Hansen, Maj Contractor, Ateka A. Elhai, Jon D. Armour, Cherie TI Dissociative Features in Posttraumatic Stress Disorder: A Latent Profile Analysis SO PSYCHOLOGICAL TRAUMA-THEORY RESEARCH PRACTICE AND POLICY LA English DT Article DE PTSD; dissociation; dissociative PTSD; PTSD Checklist for DSM-5; latent profile analysis ID SYMPTOM CRITERIA; COMMUNITY SAMPLE; PTSD; SUBTYPE; DSM-5; PREVALENCE; ANXIETY; REPLICATION; DEPRESSION; VETERANS AB Objective: The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) characterizes the dissociative subtype of posttraumatic stress disorder (PTSD) in terms of the individual meeting the criteria for PTSD and additionally reporting symptoms of depersonalization and/or derealization. The current study aimed to examine whether a dissociative PTSD profile may include alternative features of dissociation and whether it could be differentiated from a nondissociative PTSD profile on certain psychopathologies and demographics. Method: Data from 309 trauma-exposed participants, collected through Amazon Mechanical Turk, were subjected to latent profile analysis. Regression analyses were used to examine the predictors of latent classes. Results: Three discrete profiles named Baseline, PTSD, and Dissociative profile were uncovered. All examined features of dissociation were significantly elevated in the Dissociative profile. Anxiety, male sex, being employed, and having a minority racial background significantly predicted the Dissociative profile relative to the PTSD profile. Conclusions: The study points to the importance of alternative symptoms of dissociation in the dissociative PTSD subtype beyond the symptoms of depersonalization and derealization. C1 [Mullerova, Jana; Armour, Cherie] Univ Ulster, Sch Psychol, Coleraine BT52 1SA, Londonderry, North Ireland. [Hansen, Maj] Univ Southern Denmark, Dept Psychol, Odense, Denmark. [Contractor, Ateka A.] Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Vet Adm, Boston, MA USA. [Contractor, Ateka A.] Boston Univ, Dept Psychiat, Sch Med, Boston, MA 02215 USA. [Elhai, Jon D.] Univ Toledo, Dept Psychol, 2801 W Bancroft St, Toledo, OH 43606 USA. [Elhai, Jon D.] Univ Toledo, Dept Psychiat, 2801 W Bancroft St, Toledo, OH 43606 USA. RP Armour, C (reprint author), Univ Ulster, Sch Psychol, Coleraine BT52 1SA, Londonderry, North Ireland. EM armour.cherie@gmail.com OI Ross, Jana/0000-0003-2794-1268; Armour, Cherie/0000-0001-7649-3874 NR 43 TC 0 Z9 0 U1 4 U2 5 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1942-9681 EI 1942-969X J9 PSYCHOL TRAUMA-US JI Psychol. Trauma PD SEP PY 2016 VL 8 IS 5 BP 601 EP 608 DI 10.1037/tra0000148 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DV9IL UT WOS:000383254000008 PM 27213680 ER PT J AU Green, JD Bovin, MJ Erb, SE Lachowicz, M Gorman, KR Rosen, RC Keane, TM Marx, BP AF Green, Jonathan D. Bovin, Michelle J. Erb, Sarah E. Lachowicz, Mark Gorman, Kaitlyn R. Rosen, Raymond C. Keane, Terence M. Marx, Brian P. TI The Effect of Enemy Combat Tactics on PTSD Prevalence Rates: A Comparison of Operation Iraqi Freedom Deployment Phases in a Sample of Male and Female Veterans SO PSYCHOLOGICAL TRAUMA-THEORY RESEARCH PRACTICE AND POLICY LA English DT Article DE posttraumatic stress disorder; combat exposure; veterans; sex differences; Operation Iraqi; Freedom ID POSTTRAUMATIC-STRESS-DISORDER; WORLD-WAR-II; MENTAL-HEALTH DIAGNOSES; GENDER-DIFFERENCES; VIETNAM VETERANS; RISK-FACTORS; AFGHANISTAN; SYMPTOMS; CARE; RELIABILITY AB Objective: Research suggests that the nature of combat may affect later development of posttraumatic stress disorder (PTSD) in combat veterans. Studies comparing rates of PTSD across different conflicts indicate that the use of asymmetric or guerilla-style tactics by enemy fighters may result in higher rates of PTSD among U.S. military personnel than the use of symmetric tactics, which mirror tactics used by U.S. forces. Investigations of the association between enemy combat tactics and PTSD across conflicts were limited because of cohort effects and a focus on male veterans. The current study examined rates of PTSD diagnosis in a sample of male and female veterans deployed to Operation Iraqi Freedom (OIF), a conflict with 3 distinct phases marked by varying enemy tactics. Method: Participants were 738 veterans enrolled in Project VALOR (Veterans' After-Discharge Longitudinal Registry) who deployed once to OIF. Participants completed a clinician interview as well as self-report measures. Results: Male veterans deployed during the OIF phase marked by asymmetric tactics were more than twice as likely to be diagnosed with PTSD as those deployed during the other 2 phases, even after controlling for extent of combat exposure, demographic characteristics, and other deployment-related risk factors for PTSD. Differing rates of PTSD across the 3 OIF phases were not observed among female participants. Conclusion: The nature of combat (specifically, asymmetric enemy tactics) may be a risk factor for the development of PTSD among males. Factors other than enemy tactics may be more important to the development of PTSD among females. C1 [Green, Jonathan D.; Erb, Sarah E.; Lachowicz, Mark; Gorman, Kaitlyn R.] Vet Affairs Boston Healthcare Syst, Boston, MA USA. [Green, Jonathan D.; Bovin, Michelle J.; Erb, Sarah E.; Keane, Terence M.; Marx, Brian P.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Bovin, Michelle J.; Keane, Terence M.; Marx, Brian P.] Vet Affairs Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Rosen, Raymond C.] New England Res Inst, 9 Galen St, Watertown, MA 02172 USA. [Lachowicz, Mark] Vanderbilt Univ, Nashville, TN USA. RP Marx, BP (reprint author), Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA.; Marx, BP (reprint author), VA Boston Healthcare Syst 116B 4, Natl Ctr PTSD, 150 South Huntington Ave, Boston, MA 02130 USA. EM brian.marx@va.gov FU U.S. Department of Defense [W81XWH-08-2-0100, W81XWH-08-2-0102] FX This work was funded by the U.S. Department of Defense Awards W81XWH-08-2-0100 and W81XWH-08-2-0102. NR 29 TC 0 Z9 0 U1 4 U2 4 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1942-9681 EI 1942-969X J9 PSYCHOL TRAUMA-US JI Psychol. Trauma PD SEP PY 2016 VL 8 IS 5 BP 634 EP 640 DI 10.1037/tra0000086 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DV9IL UT WOS:000383254000012 PM 26654686 ER PT J AU Carlson, EB Field, NP Ruzek, JI Bryant, RA Dalenberg, CJ Keane, TM Spain, DA AF Carlson, Eve B. Field, Nigel P. Ruzek, Josef I. Bryant, Richard A. Dalenberg, Constance J. Keane, Terence M. Spain, David A. TI Advantages and psychometric validation of proximal intensive assessments of patient-reported outcomes collected in daily life (vol 25, pg 507, 2016) SO QUALITY OF LIFE RESEARCH LA English DT Correction C1 [Carlson, Eve B.; Ruzek, Josef I.] US Dept Vet Affairs, Natl Ctr PTSD, Menlo Pk, CA 94025 USA. [Carlson, Eve B.; Ruzek, Josef I.] US Dept Vet Affairs, VA Palo Alto Hlth Care Syst, Menlo Pk, CA 94025 USA. [Field, Nigel P.] Palo Alto Univ, Pacific Grad Sch Psychol, Palo Alto, CA USA. [Bryant, Richard A.] Univ New South Wales, Sch Psychol, Sydney, NSW, Australia. [Dalenberg, Constance J.] Alliant Int Univ, San Diego, CA USA. [Keane, Terence M.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Keane, Terence M.] Boston Univ, Sch Med, Dept Psychol, Boston, MA 02118 USA. [Keane, Terence M.] US Dept Vet Affairs, Natl Ctr PTSD, Boston, MA USA. [Keane, Terence M.] US Dept Vet Affairs, VA Boston Hlth Care Syst, Boston, MA USA. [Spain, David A.] Stanford Univ, Sch Med, Dept Surg, Stanford, CA 94305 USA. RP Carlson, EB (reprint author), US Dept Vet Affairs, Natl Ctr PTSD, Menlo Pk, CA 94025 USA.; Carlson, EB (reprint author), US Dept Vet Affairs, VA Palo Alto Hlth Care Syst, Menlo Pk, CA 94025 USA. EM eve.carlson@va.gov OI Carlson, Eve/0000-0002-4431-2415 NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD SEP PY 2016 VL 25 IS 9 BP 2399 EP 2399 DI 10.1007/s11136-016-1280-z PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DV5TA UT WOS:000382991000027 ER PT J AU Bhavsar, KV Lin, S Rahimy, E Joseph, A Freund, KB Sarraf, D Cunningham, ET AF Bhavsar, Kavita V. Lin, Sally Rahimy, Ehsan Joseph, Anthony Freund, K. Bailey Sarraf, David Cunningham, Emmett T., Jr. TI Acute macular neuroretinopathy: A comprehensive review of the literature SO SURVEY OF OPHTHALMOLOGY LA English DT Review DE acute macular neuroretinopathy; AMNR; AMN; AMOR; optical coherence tomography; multimodal imaging; paracentral acute middle maculopathy; PAMM; deep capillary ischemia; DCI ID OPTICAL COHERENCE TOMOGRAPHY; ACUTE MIDDLE MACULOPATHY; LASER OPHTHALMOSCOPE FINDINGS; DEEP CAPILLARY ISCHEMIA; WHITE DOT SYNDROME; MULTIFOCAL ELECTRORETINOGRAM; ENHANCED VISUALIZATION; RETINOPATHY; OCT; ABNORMALITIES AB Acute macular neuroretinopathy is a relatively rare condition originally defined by the presence of intraretinal, reddish-brown, wedge-shaped lesions, the apices of which tend to point toward the fovea. Acute onset of paracentral scotomas corresponding to the clinically evident lesions is both common and characteristic. Although the pathogenesis of acute macular neuroretinopathy is complex, recent research suggests a microvascular etiology. Advances in multimodal imaging have enabled better characterization of this retinal disorder and have led to newly proposed diagnostic criteria. We review 101 reported cases in the English and non-English language literature identified from 1975, when acute macular neuroretinopathy was first described, to December, 2014. We discuss common risk factors, demographic and clinical characteristics, and multimodal imaging findings, which together provide insights into pathogenesis and guide areas of future investigation. (C) 2016 Elsevier Inc. All rights reserved. C1 [Bhavsar, Kavita V.; Freund, K. Bailey] Vitreous Retina Macula Consultants New York, Dept Ophthalmol, New York, NY USA. [Bhavsar, Kavita V.; Freund, K. Bailey] Manhattan Eye Ear & Throat Hosp, Dept Ophthalmol, LuEsther T Mertz Retinal Res Ctr, New York, NY 10021 USA. [Bhavsar, Kavita V.; Freund, K. Bailey] NYU, Dept Ophthalmol, Langone Med Ctr, 550 1St Ave, New York, NY 10016 USA. [Bhavsar, Kavita V.; Freund, K. Bailey] Columbia Univ, Dept Ophthalmol, New York, NY 10027 USA. [Lin, Sally; Cunningham, Emmett T., Jr.] Calif Pacific Med Ctr, Dept Ophthalmol, San Francisco, CA USA. [Rahimy, Ehsan] Wills Eye Hosp & Res Inst, Dept Ophthalmol, Philadelphia, PA USA. [Joseph, Anthony; Sarraf, David] Univ Calif Los Angeles, Jules Stein Eye Inst, Dept Ophthalmol, Los Angeles, CA 90024 USA. [Joseph, Anthony; Sarraf, David] Greater Los Angeles VA Healthcare Ctr, Dept Ophthalmol, Los Angeles, CA USA. [Cunningham, Emmett T., Jr.] Stanford Univ, Sch Med, Dept Ophthalmol, Stanford, CA 94305 USA. [Cunningham, Emmett T., Jr.] UCSF Sch Med, Dept Ophthalmol, Francis I Proctor Fdn, San Francisco, CA USA. [Cunningham, Emmett T., Jr.] West Coast Retina Med Grp, Dept Ophthalmol, San Francisco, CA USA. RP Freund, KB (reprint author), Vitreous Retina Macula Consultants New York, 460 Pk Ave, New York, NY 10022 USA. EM kbfnyf@aol.com OI Freund, K. Bailey/0000-0002-7888-9773 FU Portland VA Healthcare System; Pacific Vision Foundation FX Dr. Bhaysar is currently at Casey Eye Institute, Portland, OR. She receives support from the Portland VA Healthcare System. Dr. Lin is currently at the Department of Ophthalmology, Kaiser Permanente Medical Center, Union City, CA. This work was supported in part by the Pacific Vision Foundation (Sally Lin and Ehsan Rahimy). NR 76 TC 3 Z9 3 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6257 EI 1879-3304 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD SEP-OCT PY 2016 VL 61 IS 5 BP 538 EP 565 DI 10.1016/j.survophthal.2016.03.003 PG 28 WC Ophthalmology SC Ophthalmology GA DV8WI UT WOS:000383217000002 PM 26973287 ER PT J AU Jakobiec, FA Stagner, AM Katowitz, WR Eagle, RC AF Jakobiec, Frederick A. Stagner, Anna M. Katowitz, William R. Eagle, Ralph C., Jr. TI A microanatomic abnormality of the lacrimal gland associated with Goldenhar syndrome SO SURVEY OF OPHTHALMOLOGY LA English DT Review DE Goldenhar syndrome; epibulbar or limbal dermoid; lacrimal gland; squamous metaplasia; ducts; acini; cytokeratins; gross cystic disease fluid protein-15 ID AURICULO-VERTEBRAL SPECTRUM; EPITHELIAL TUMORS; SALIVARY-GLANDS; DACRYOMETAPLASIA; MANIFESTATIONS; ANOMALIES; CORNEAL; NEVUS AB A 12-month-old male infant, noted from birth to have a diffuse right temporal epibulbar thickening that encroached on the limbus inferotemporally, was found to manifest stigmata of Goldenhar syndrome, including a limbal dermoid with vellus hairs, esotropia, astigmatism, fullness and ectropion of the lower eyelid, preauricular skin tag, agenesis of the right kidney, and a supernumerary rib. In the excised epibulbar specimen, in addition to a solid dermoid, lobules of lacrimal gland tissue were interpreted as a portion of the palpebral or orbital lobes. This tissue displayed a unique histopathologic finding. Within some of the lobules were cuffs of eosinophilic squamous (epidermoid) cells that surrounded the intralobular ductules and made variable incursions into, with replacement of, the acinar units. Immunohistochemistry disclosed that the normal acinar and lumen forming ductular cells were intermediate weight cytokeratin7-positive. The acinar cells were additionally gross cystic disease fluid protein-15 positive. The cells of the squamous cuffs were heavy weight cytokeratin 5/6-positive. The outermost basal cells of the cuffs were cytokeratin 14-positive, in common with the myoepithelial cells of the acini. The intraacinar squamous cells were negative for smooth muscle actin and gross cystic disease fluid protein-15. These findings suggest, but do not prove, that the source of the periductular and acinar squamous metaplasia was the germinal transitional cells where the acinar myoepithelium interfaces and imperceptibly converts into ductular basal cells. The foregoing findings are evaluated in the context of the panoply of ocular, facial, and visceral anomalies manifested in Goldenhar spectrum. (C) 2016 Elsevier Inc. All rights reserved. C1 [Jakobiec, Frederick A.; Stagner, Anna M.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Dept Ophthalmol, Boston, MA USA. [Katowitz, William R.] Childrens Hosp, Div Ophthalmol, Philadelphia, PA 19104 USA. [Eagle, Ralph C., Jr.] Jefferson Med Coll, Wills Eye Inst, Dept Pathol, Philadelphia, PA USA. RP Jakobiec, FA (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, DG Cogan Pathol Lab, Dept Ophthalmol, 243 Charles St,Suite 328, Boston, MA 02114 USA. EM Fred_Jakobiec@meei.harvard.edu NR 44 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 0039-6257 EI 1879-3304 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD SEP-OCT PY 2016 VL 61 IS 5 BP 654 EP 663 DI 10.1016/j.survophthal.2016.02.002 PG 10 WC Ophthalmology SC Ophthalmology GA DV8WI UT WOS:000383217000008 PM 26892494 ER PT J AU Glass, LRD Freitag, SK AF Glass, Lora R. Dagi Freitag, Suzanne K. TI Orbital inflammation: Corticosteroids first SO SURVEY OF OPHTHALMOLOGY LA English DT Editorial Material DE orbital inflammation; corticosteroid; ancillary testing; biopsy; targeted therapy ID IGG4-RELATED DISEASE; GRAVES ORBITOPATHY; RITUXIMAB; FEATURES; UPDATE; FUTURE AB Orbital inflammation is common, and may affect all ages and both genders. By combining a thorough history and physical examination, targeted ancillary laboratory testing and imaging, a presumptive diagnosis can often be made. Nearly all orbital inflammatory pathology can be empirically treated with corticosteroids, thus obviating the need for histopathologic diagnosis prior to initiation of therapy. In addition, corticosteroids may be effective in treating concurrent systemic disease. Unless orbital inflammation responds atypically or incompletely, patients can be spared biopsy. (C) 2016 Elsevier Inc. All rights reserved. C1 [Glass, Lora R. Dagi; Freitag, Suzanne K.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Ophthalm Plast Surg Serv, 243 Charles St, Boston, MA 02114 USA. RP Freitag, SK (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, Ophthalm Plast Surg Serv, 243 Charles St, Boston, MA 02114 USA. EM suzanne_freitag@meei.harvard.edu NR 48 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6257 EI 1879-3304 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD SEP-OCT PY 2016 VL 61 IS 5 BP 670 EP 673 DI 10.1016/j.survophthal.2016.01.005 PG 4 WC Ophthalmology SC Ophthalmology GA DV8WI UT WOS:000383217000010 ER PT J AU Song, Y Hernandez, N Gee, MS Noble, VE Eisner, BH AF Song, Yan Hernandez, Natalia Gee, Michael S. Noble, Vicki E. Eisner, Brian H. TI Can ureteral stones cause pain without causing hydronephrosis? SO WORLD JOURNAL OF UROLOGY LA English DT Article DE Kidney stone; Imaging; Hydronephrosis ID UNENHANCED HELICAL CT; ACUTE FLANK PAIN; SECONDARY SIGNS; TOMOGRAPHY; CALCULI; US AB While computerized tomography (CT) is the gold standard for diagnosis of ureterolithiasis, ultrasound is a less costly and radiation-free alternative which is commonly used to evaluate patients with ureteral colic. The purpose of this study was to evaluate the frequency with which patients with ureteral stones and renal colic demonstrate hydronephrosis in order to better understand the evaluation of these patients. Two hundred and forty-eight consecutive patients presenting with ureteral colic and diagnosed with a single unilateral ureteral stone on CT scan in an urban tertiary care emergency department were retrospectively reviewed. Radiology reports were reviewed for stone size, diagnosis, and degree of hydronephrosis. Of the 248 patients evaluated for suspected ureteral stone, 221 (89.1 %) demonstrated any hydronephrosis, while 27 (10.9 %) did not. Hydronephrosis grade, available in 194 patients, was as follows: mild-70.6 %, moderate-27.8 %, and severe-1.5 %. Mean patient age was 47.0 years (SD 15.5), gender distribution was 35.9 % female and 64.1 % male, and mean stone axial diameter was 4.1 mm (SD 2.4). Stone location was as follows: ureteropelvic junction-4.1 %, proximal ureter-21 %, distal ureter-24.9 %, and ureterovesical junction-47.1 %. Axial stone diameter and coronal length (craniocaudal) were both significant predictors of degree of hydronephrosis (ANOVA, p < 0.001 for both). Age (ANOVA, p = NS), stone location (Chi square, p = NS), and gender (Chi square, p = NS) were not associated with degree of hydronephrosis. In patients with ureteral stones and colic, nearly 11 % do not demonstrate any hydronephrosis and a majority (nearly 71 %) will demonstrate only mild hydronephrosis. Stone diameter appears to be related to degree of hydronephrosis, whereas age, gender, and stone location are not. The lower incidence of hydronephrosis for small stones causing renal colic may explain the lower diagnostic accuracy of ultrasound when compared to CT for detecting ureteral stones. C1 [Song, Yan] China Med Univ, ShengJing Hosp, Dept Urol, Shenyang, Peoples R China. [Hernandez, Natalia; Eisner, Brian H.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Urol, GRB 1102,55 Fruit St, Boston, MA 02114 USA. [Gee, Michael S.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Noble, Vicki E.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA USA. RP Eisner, BH (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Urol, GRB 1102,55 Fruit St, Boston, MA 02114 USA. EM beisner@partners.org NR 18 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-4983 EI 1433-8726 J9 WORLD J UROL JI World J. Urol. PD SEP PY 2016 VL 34 IS 9 BP 1285 EP 1288 DI 10.1007/s00345-015-1748-4 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA DU4IA UT WOS:000382175100012 PM 26685981 ER PT J AU Perugino, CA Stone, JH AF Perugino, C. A. Stone, J. H. TI Treatment of IgG4-related disease Current and future approaches SO ZEITSCHRIFT FUR RHEUMATOLOGIE LA English DT Article DE B-cells; Antirheumatic agents; Glucocorticoids; Adverse effects; Monoclonal antibodies ID IMMUNOGLOBULIN G4-ASSOCIATED CHOLANGITIS; AUTOIMMUNE PANCREATITIS; RITUXIMAB THERAPY; SYSTEMIC-DISEASE; EXPERIENCE; MANAGEMENT; ANTIBODY; CELLS AB IgG4-related disease (IgG4-RD) is capable of causing great morbidity and even mortality if the condition remains undiagnosed or poorly treated, yet is typically a treatment-responsive disorder. Glucocorticoids have not been studied rigorously and practices with regard to dosing and duration of treatment remain largely empiric. In addition, IgG4-RD patients are often particularly susceptible to and intolerant of the deleterious effects of glucocorticoid therapy. B cell depletion with anti-CD20 monoclonal antibodies appears to be a rapid, effective means of obtaining disease control and limiting patients' glucocorticoid exposure, but this option is frequently not available. Other therapies targeting the B cell lineage may also be efficacious, and one is under study. The means by which depletion or inhibition of B cells and their progeny ameliorate IgG4-RD is coming into focus now through careful mechanistic studies of samples from treated patients. The mechanistic understanding of IgG4-RD will bring an array of specific targets for therapeutic intervention. Plasmablast-directed therapy with a CD19 monoclonal antibody is currently in clinical trials. CD4 + cytotoxic T lymphocytes and fibrosis, both observed nearly universally in the tissue of IgG4-RD patients, present two unexploited vulnerabilities in controlling and even reversing the effects of the disease. Further development of such therapies is a major goal of the next few years. C1 [Perugino, C. A.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Stone, J. H.] Harvard Med Sch, Boston, MA USA. [Stone, J. H.] Massachusetts Gen Hosp, Med, Boston, MA 02114 USA. [Stone, J. H.] Massachusetts Gen Hosp, Rheumatol Clin Yawkey 2, 55 Fruit St, Boston, MA 02114 USA. RP Stone, JH (reprint author), Massachusetts Gen Hosp, Rheumatol Clin Yawkey 2, 55 Fruit St, Boston, MA 02114 USA. EM jhstone@mgh.harvard.edu FU Roche; Xencor FX C.A. Perugino statethat thereare no conflicts of interest. Dr. Stone has received research funding and performed consulting work in the area of IgG4- related disease for both Roche and Xencor. NR 24 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-1855 EI 1435-1250 J9 Z RHEUMATOL JI Z. Rheumatol. PD SEP PY 2016 VL 75 IS 7 BP 681 EP 686 DI 10.1007/s00393-016-0142-y PG 6 WC Rheumatology SC Rheumatology GA DV4UX UT WOS:000382921900006 PM 27431746 ER PT J AU Lo-Ciganic, WH Donohue, JM Jones, BL Perera, S Thorpe, JM Thorpe, CT Marcum, ZA Gellad, WF AF Lo-Ciganic, Wei-Hsuan Donohue, Julie M. Jones, Bobby L. Perera, Subashan Thorpe, Joshua M. Thorpe, Carolyn T. Marcum, Zachary A. Gellad, Walid F. TI Trajectories of Diabetes Medication Adherence and Hospitalization Risk: A Retrospective Cohort Study in a Large State Medicaid Program SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE diabetes; oral hypoglycemics; medication adherence; group-based trajectory models; Medicaid ID BLOOD-PRESSURE CONTROL; COMPLICATIONS SEVERITY INDEX; SELF-REPORTED ADHERENCE; HEALTH-CARE; ADMINISTRATIVE DATA; THERAPY; COSTS; NONADHERENCE; HYPERTENSION; VETERANS AB Numerous interventions are available to boost medication adherence, but the targeting of these interventions often relies on crude measures of poor adherence. Group-based trajectory models identify individuals with similar longitudinal prescription filling patterns. Identifying distinct adherence trajectories may be more useful for targeting interventions, although the association between adherence trajectories and clinical outcomes is unknown. To examine the association between adherence trajectories for oral hypoglycemics and subsequent hospitalizations among diabetes patients. Retrospective cohort study. A total of 16,256 Pennsylvania Medicaid enrollees, non-dually eligible for Medicare, initiating oral hypoglycemics between 2007 and 2009. We used group-based trajectory models to identify trajectories of oral hypoglycemics in the 12 months post-treatment initiation, using monthly proportion of days covered (PDC) as the adherence measure. Multivariable Cox proportional hazard models were used to examine the association between trajectories and time to first diabetes-related hospitalization/emergency department (ED) visits in the following year. We used the C-index to compare prediction performance between adherence trajectories and dichotomous cutpoints (annual PDC < 80 vs. aeyen80 %). The mean annual PDC was 0.58 (SD 0.32). Seven trajectories were identified: perfect adherers (9 % of the cohort), nearly perfect adherers (31.4 %), moderate adherers (21.0 %), low adherers (11.0 %), late discontinuers (6.8 %), early discontinuers (9.7 %), and non-adherers with only one fill (11.1 %). Compared to perfect adherers, trajectories of moderate adherers (HR = 1.48, 95 % CI 1.25, 1.75), low adherers (HR = 1.51, 95 % CI 1.25, 1.83), and non-adherers with only one fill (HR = 1.35, 95 % CI 1.09, 1.67) had greater risk of diabetes-related hospitalizations/ED visits. Predictive accuracy was improved using trajectories compared to dichotomized cutpoints (C-index = 0.714 vs. 0.652). Oral hypoglycemic treatment trajectories were highly variable in this large Medicaid cohort. Low and moderate adherers and those filling only one prescription had a modestly higher risk of hospitalizations/ED visits compared to perfect adherers. Trajectory models may be valuable in identifying specific non-adherence patterns for targeting interventions. C1 [Lo-Ciganic, Wei-Hsuan] Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci, Tucson, AZ 85721 USA. [Donohue, Julie M.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Hlth Policy & Management, Pittsburgh, PA USA. [Donohue, Julie M.; Thorpe, Joshua M.; Thorpe, Carolyn T.; Gellad, Walid F.] Univ Pittsburgh, Ctr Pharmaceut Policy & Prescribing, Pittsburgh, PA USA. [Jones, Bobby L.] Univ Pittsburgh, Dept Psychiat, Med Ctr, Pittsburgh, PA USA. [Perera, Subashan] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Perera, Subashan; Gellad, Walid F.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Thorpe, Joshua M.; Thorpe, Carolyn T.] Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Pittsburgh, PA 15261 USA. [Thorpe, Joshua M.; Thorpe, Carolyn T.; Gellad, Walid F.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. [Marcum, Zachary A.] Univ Washington, Sch Pharm, Dept Pharm, Seattle, WA 98195 USA. RP Lo-Ciganic, WH (reprint author), Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci, Tucson, AZ 85721 USA. EM lociganic@pharmacy.arizona.edu OI Donohue, Julie/0000-0003-2418-6017 FU Pittsburgh Claude D. Pepper Older Americans Independence Center [NIA P30 AGAG024827] FX Dr. Perera is supported by the Pittsburgh Claude D. Pepper Older Americans Independence Center (NIA P30 AGAG024827). NR 58 TC 2 Z9 2 U1 3 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD SEP PY 2016 VL 31 IS 9 BP 1052 EP 1060 DI 10.1007/s11606-016-3747-6 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DT6NJ UT WOS:000381600700014 PM 27229000 ER PT J AU Rendon, P Dhaliwal, G Kim, B Aguayo, A Pierce, JR AF Rendon, Patrick Dhaliwal, Gurpreet Kim, Benjamin Aguayo, Alberto Pierce, J. Rush, Jr. TI Look No Further: An Exercise in Clinical Reasoning SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material DE clinical reasoning; diagnosis; chief complaint ID AUTOIMMUNE HEMOLYTIC-ANEMIA; DIAGNOSIS C1 [Rendon, Patrick; Aguayo, Alberto; Pierce, J. Rush, Jr.] Univ New Mexico, Hlth Sci Ctr, Div Hosp Med, Dept Internal Med, MSC10 5550,1 Univ New Mexico, Albuquerque, NM 87131 USA. [Dhaliwal, Gurpreet; Kim, Benjamin] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Dhaliwal, Gurpreet] San Francisco VA Med Ctr, Med Serv, San Francisco, CA USA. RP Rendon, P (reprint author), Univ New Mexico, Hlth Sci Ctr, Div Hosp Med, Dept Internal Med, MSC10 5550,1 Univ New Mexico, Albuquerque, NM 87131 USA. EM prendon@salud.unm.edu NR 7 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD SEP PY 2016 VL 31 IS 9 BP 1097 EP 1101 DI 10.1007/s11606-016-3635-0 PG 5 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DT6NJ UT WOS:000381600700025 PM 27075183 ER PT J AU Flannick, J Florez, JC AF Flannick, Jason Florez, Jose C. TI Type 2 diabetes: genetic data sharing to advance complex disease research SO NATURE REVIEWS GENETICS LA English DT Review ID GENOME-WIDE ASSOCIATION; LARGE-SCALE ASSOCIATION; HUMAN PANCREATIC-ISLETS; BETA-CELL TRANSCRIPTOME; LOW-FREQUENCY VARIANT; SUSCEPTIBILITY LOCI; MENDELIAN RANDOMIZATION; INSULIN-RESISTANCE; RARE VARIANTS; DNA METHYLATION AB As with other complex diseases, unbiased association studies followed by physiological and experimental characterization have for years formed a paradigm for identifying genes or processes of relevance to type 2 diabetes mellitus (T2D). Recent large-scale common and rare variant genome-wide association studies (GWAS) suggest that substantially larger association studies are needed to identify most T2D loci in the population. To hasten clinical translation of genetic discoveries, new paradigms are also required to aid specialized investigation of nascent hypotheses. We argue for an integrated T2D knowledgebase, designed for a worldwide community to access aggregated large-scale genetic data sets, as one paradigm to catalyse convergence of these efforts. C1 [Flannick, Jason; Florez, Jose C.] Broad Inst MIT & Harvard, Program Metab, 415 Main St, Cambridge, MA 02142 USA. [Flannick, Jason; Florez, Jose C.] Broad Inst MIT & Harvard, Program Med & Populat Genet, 415 Main St, Cambridge, MA 02142 USA. [Flannick, Jason; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Dept Med, 185 Cambridge St, Boston, MA 02062 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Dept Med, 185 Cambridge St, Boston, MA 02062 USA. [Florez, Jose C.] Harvard Med Sch, Dept Med, 25 Shattuck St, Boston, MA 02115 USA. RP Florez, JC (reprint author), Broad Inst MIT & Harvard, Program Metab, 415 Main St, Cambridge, MA 02142 USA.; Florez, JC (reprint author), Broad Inst MIT & Harvard, Program Med & Populat Genet, 415 Main St, Cambridge, MA 02142 USA.; Florez, JC (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Dept Med, 185 Cambridge St, Boston, MA 02062 USA.; Florez, JC (reprint author), Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Dept Med, 185 Cambridge St, Boston, MA 02062 USA.; Florez, JC (reprint author), Harvard Med Sch, Dept Med, 25 Shattuck St, Boston, MA 02115 USA. EM JCFLOREZ@mgh.harvard.edu NR 165 TC 0 Z9 0 U1 16 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 EI 1471-0064 J9 NAT REV GENET JI Nat. Rev. Genet. PD SEP PY 2016 VL 17 IS 9 BP 535 EP 549 DI 10.1038/nrg.2016.56 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA DT5GW UT WOS:000381510700011 PM 27402621 ER PT J AU Lebois, LAM Hertzog, C Slavich, GM Barrett, LF Barsalou, LW AF Lebois, Lauren A. M. Hertzog, Christopher Slavich, George M. Barrett, Lisa Feldman Barsalou, Lawrence W. TI Establishing the situated features associated with perceived stress SO ACTA PSYCHOLOGICA LA English DT Article DE Stress; Perceived stress; Categorization; Stress categorization; Situated cognition; Appraisal ID MINDFUL ATTENTION; LIFE STRESS; EMOTION; NEUROTICISM; COGNITION; EVENTS; HEALTH; CATEGORIES; SIMULATION; STRATEGIES AB We propose that the domain general process of categorization contributes to the perception of stress. When a situation contains features associated with stressful experiences, it is categorized as stressful. From the perspective of situated cognition, the features used to categorize experiences as stressful are the features typically true of stressful situations. To test this hypothesis, we asked participants to evaluate the perceived stress of 572 imagined situations, and to also evaluate each situation for how much it possessed 19 features potentially associated with stressful situations and their processing (e.g., self-threat, familiarity, visual imagery, outcome certainty). Following variable reduction through factor analysis, a core set of 8 features associated with stressful situations expectation violation, self-threat, coping efficacy, bodily experience, arousal, negative valence, positive valence, and perseveration all loaded on a single Core Stress Features factor. In a multilevel model, this factor and an Imagery factor explained 88% of the variance in judgments of perceived stress, with significant random effects reflecting differences in how individual participants categorized stress. These results support the hypothesis that people categorize situations as stressful to the extent that typical features of stressful situations are present. To our knowledge, this is the first attempt to establish a comprehensive set of features that predicts perceived stress. (C) 2016 Elsevier B.V. All rights reserved. C1 [Lebois, Lauren A. M.] Harvard Med Sch, McLean Hosp, Div Depress & Anxiety, Boston, MA USA. [Lebois, Lauren A. M.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Hertzog, Christopher] Georgia Inst Technol, Dept Psychol, Atlanta, GA 30332 USA. [Slavich, George M.] Univ Calif Los Angeles, Cousins Ctr Psychoneuroimmunol, Los Angeles, CA USA. [Slavich, George M.] Univ Calif Los Angeles, Dept Psychiat & Biobehavl Sci, Los Angeles, CA USA. [Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA USA. [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Barrett, Lisa Feldman] Harvard Med Sch, Boston, MA USA. [Barsalou, Lawrence W.] Univ Glasgow, Sch Psychol, Inst Neurosci & Psychol, 58 Hillhead St, Glasgow G12 8QB, Lanark, Scotland. RP Barsalou, LW (reprint author), Univ Glasgow, Sch Psychol, Inst Neurosci & Psychol, 58 Hillhead St, Glasgow G12 8QB, Lanark, Scotland. EM lawrence.barsalou@glasgow.ac.uk FU NIH NRSA award; NIH Director's Pioneer Award [DPI OD003312] FX Work on this article was supported by an NIH NRSA award to Lauren (McDonough) Lebois at Emory University, and by an NIH Director's Pioneer Award DPI OD003312 to Lisa Feldman Barrett at Northeastern University, with a sub-contract to Lawrence Barsalou at Emory University. We are grateful to David Almeida for sharing his stressor database, Taryn Colton, Hailey Friedman, and Bridget Warren for assistance with sampling the stressful life events, and to Christine D. Wilson-Mendenhall for assistance with the valence and arousal instructions. NR 80 TC 2 Z9 2 U1 4 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0001-6918 EI 1873-6297 J9 ACTA PSYCHOL JI Acta Psychol. PD SEP PY 2016 VL 169 BP 119 EP 132 DI 10.1016/j.actpsy.2016.05.012 PG 14 WC Psychology, Experimental SC Psychology GA DV0HX UT WOS:000382599700014 PM 27288834 ER PT J AU Beidas, RS Marcus, S Wolk, CB Powell, B Aarons, GA Evans, AC Hurford, MO Hadley, T Adams, DR Walsh, LM Babbar, S Barg, F Mandell, DS AF Beidas, Rinad S. Marcus, Steven Wolk, Courtney Benjamin Powell, Byron Aarons, Gregory A. Evans, Arthur C. Hurford, Matthew O. Hadley, Trevor Adams, Danielle R. Walsh, Lucia M. Babbar, Shaili Barg, Frances Mandell, David S. TI A Prospective Examination of Clinician and Supervisor Turnover Within the Context of Implementation of Evidence-Based Practices in a Publicly-Funded Mental Health System SO ADMINISTRATION AND POLICY IN MENTAL HEALTH AND MENTAL HEALTH SERVICES RESEARCH LA English DT Article DE Turnover; Implementation; Mental health services ID CHILD-WELFARE SYSTEMS; STAFF TURNOVER; ORGANIZATIONAL-CLIMATE; JOB-SATISFACTION; BURNOUT; SETTINGS; SERVICES; SUPPORT; CULTURE; MODEL AB Staff turnover rates in publicly-funded mental health settings are high. We investigated staff and organizational predictors of turnover in a sample of individuals working in an urban public mental health system that has engaged in a system-level effort to implement evidence-based practices. Additionally, we interviewed staff to understand reasons for turnover. Greater staff burnout predicted increased turnover, more openness toward new practices predicted retention, and more professional recognition predicted increased turnover. Staff reported leaving their organizations because of personal, organizational, and financial reasons; just over half of staff that left their organization stayed in the public mental health sector. Implications include an imperative to focus on turnover, with a particular emphasis on ameliorating staff burnout. C1 [Beidas, Rinad S.; Wolk, Courtney Benjamin; Powell, Byron; Evans, Arthur C.; Hurford, Matthew O.; Hadley, Trevor; Adams, Danielle R.; Walsh, Lucia M.; Babbar, Shaili; Mandell, David S.] Univ Penn, Dept Psychiat, Perelman Sch Med, 3535 Market St,3015, Philadelphia, PA 19104 USA. [Marcus, Steven] Univ Penn, Sch Social Policy & Practice, Philadelphia, PA 19104 USA. [Marcus, Steven] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Aarons, Gregory A.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Evans, Arthur C.; Hurford, Matthew O.] Dept Behav Hlth & Intellectual Disabil Serv, Philadelphia, PA USA. [Hurford, Matthew O.] Community Behav Hlth, Philadelphia, PA USA. [Barg, Frances] Univ Penn, Dept Family Med & Community Hlth, Perelman Sch Med, Philadelphia, PA 19104 USA. [Powell, Byron] Univ North Carolina Chapel Hill, Gillings Sch Global Publ Hlth, Dept Hlth Policy & Management, 1105C McGavran Greenberg Hall,Campus Box 7411, Chapel Hill, NC 27599 USA. [Hurford, Matthew O.] Community Care Behav Hlth Org, Pittsburgh, PA USA. RP Beidas, RS (reprint author), Univ Penn, Dept Psychiat, Perelman Sch Med, 3535 Market St,3015, Philadelphia, PA 19104 USA. EM rbeidas@upenn.edu; bjpowell@unc.edu RI Mandell, David/H-2730-2012; OI Mandell, David/0000-0001-8240-820X; Powell, Byron/0000-0001-5245-1186 FU Department of Behavioral Health and Intellectual disAbility Services; NIMH [K23 MH099179, F32 MH103955]; Implementation Research Institute (IRI), at the George Warren Brown School of Social Work, Washington University in St. Louis; National Institute of Mental Health [R25 MH080916]; Quality Enhancement Research Initiative (QUERI), Department of Veterans Affairs Contract, Veterans Health Administration, Office of Research & Development, Health Services Research & Development Service FX We are especially grateful for the support that the Department of Behavioral Health and Intellectual disAbility Services has provided for this project, and for the Evidence Based Practice and Innovation (EPIC) group. Funding for this research project was supported by the following grants from NIMH: (K23 MH099179, Beidas; F32 MH103955, Benjamin Wolk). Additionally, the preparation of this article was supported in part by the Implementation Research Institute (IRI), at the George Warren Brown School of Social Work, Washington University in St. Louis; through an award from the National Institute of Mental Health (R25 MH080916) and Quality Enhancement Research Initiative (QUERI), Department of Veterans Affairs Contract, Veterans Health Administration, Office of Research & Development, Health Services Research & Development Service. Dr. Beidas was an IRI fellow from 2012 to 2014. We would like to thank for the following experts who provided their time and input on this project: Dr. Marc Atkins, Dr. Ross Brownson, Dr. David Chambers, Dr. Bruce Chorpita, Dr. Charles Glisson, Dr. Nicholas Ialongo, Dr. John Landsverk, Dr. Enola Proctor, Dr. Ronnie Rubin. NR 47 TC 3 Z9 3 U1 6 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0894-587X EI 1573-3289 J9 ADM POLICY MENT HLTH JI Adm. Policy. Ment. Health PD SEP PY 2016 VL 43 IS 5 BP 640 EP 649 DI 10.1007/s10488-015-0673-6 PG 10 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DS9YM UT WOS:000381139400002 PM 26179469 ER PT J AU Cummings, JR Case, BG Ji, X Marcus, SC AF Cummings, Janet R. Case, Brady G. Ji, Xu Marcus, Steven C. TI Availability of Youth Services in US Mental Health Treatment Facilities SO ADMINISTRATION AND POLICY IN MENTAL HEALTH AND MENTAL HEALTH SERVICES RESEARCH LA English DT Article DE Children and adolescents; Access to services; Mental health facilities ID SUPPLEMENT NCS-A; ADOLESCENTS; CHILD; PSYCHIATRISTS; CARE; PEDIATRICIANS; DISORDERS; ACCESS AB Despite concern about access to mental health (MH) services for youth, little is known about the specialty treatment infrastructure serving this population. We used national data to examine which types of MH treatment facilities (hospital- and community-based) were most likely to offer youth services and which types of communities were most likely to have this infrastructure. Larger (p < 0.001) and privately owned (p < 0.001) facilities were more likely to offer youth services. Rural counties, counties in which a majority of residents were nonwhite, and/or counties with a higher percentage of uninsured residents were less likely to have a community-based MH treatment facility that served youth (p < 0.001). C1 [Cummings, Janet R.; Ji, Xu] Emory Univ, Rollins Sch Publ Hlth, Dept Hlth Policy & Management, 1518 Clifton Rd NE, Atlanta, GA 30322 USA. [Case, Brady G.] Bradley Hosp, Hlth Serv Res Program, East Providence, RI USA. [Case, Brady G.] Brown Univ, Dept Psychiat & Human Behav, Alpert Med Sch, Providence, RI 02912 USA. [Case, Brady G.] Brown Sch Publ Hlth, Dept Hlth Serv Policy & Practice, Providence, RI USA. [Marcus, Steven C.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Marcus, Steven C.] Univ Penn, Sch Social Policy & Practice, Philadelphia, PA 19104 USA. RP Cummings, JR (reprint author), Emory Univ, Rollins Sch Publ Hlth, Dept Hlth Policy & Management, 1518 Clifton Rd NE, Atlanta, GA 30322 USA. EM jrcummi@emory.edu OI Case, Brady/0000-0001-9512-0416 FU National Institute of Mental Health [K01MH095823] FX Research reported in this publication was supported by the National Institute of Mental Health (K01MH095823). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 38 TC 2 Z9 2 U1 5 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0894-587X EI 1573-3289 J9 ADM POLICY MENT HLTH JI Adm. Policy. Ment. Health PD SEP PY 2016 VL 43 IS 5 BP 717 EP 727 DI 10.1007/s10488-015-0685-2 PG 11 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DS9YM UT WOS:000381139400008 PM 26467795 ER PT J AU Quinn, GR Singer, DE Chang, YC Go, AS Borowsky, LH Fang, MC AF Quinn, Gene R. Singer, Daniel E. Chang, Yuchiao Go, Alan S. Borowsky, Leila H. Fang, Margaret C. TI How Well Do Stroke Risk Scores Predict Hemorrhage in Patients With Atrial Fibrillation? SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID DOSE WARFARIN; ANTICOAGULATION; PREVENTION; ASSOCIATION; INTENSITY; THERAPY AB The decision to use anticoagulants for atrial fibrillation depends on comparing a patient's estimated risk of stroke to their bleeding risk. Several of the risk factors in the stroke risk schemes overlap with hemorrhage risk. We compared how well 2 stroke risk scores (CHADS(2) and CHA(2)DS(2)-VASc) and 2 hemorrhage risk scores the ATRIA bleeding score and the HAS-BLED score) predicted major hemorrhage on and off warfarin in a cohort of 13,559 community-dwelling adults with AF. Over a cumulative 64,741 person-years of follow-up, we identified a total of 777 incident major hemorrhage events. The ATRIA bleeding score had the highest predictive ability of all the scores in patients on warfarin (c-index of 0.74 [0.72 to 0.76] compared with 0.65 [0.62 to 0.67] for CHADS(2), 0.65 [0.62 to 0.67] for CHA(2)DS(2)-VASc, and 0.64 [0.61 to 0.66] for HAS-BLED) and in those off warfarin (0.77 [0.74 to 0.79] compared with 0.67 [0.64 to 0.711 for CHADS(2), 0.67 [0.64 to 0.70] for CHA(2)DS(2)-VASc, and 0.68 [0.65 to 0.71] for HAS-BLED). In conclusion, although CHADS(2) and CHA(2)DS(2)-VASc stroke scores were better at predicting hemorrhage than chance alone, they were inferior to the ATRIA bleeding score. Our study supports the use of dedicated hemorrhage risk stratification tools to predict major hemorrhage in atrial fibrillation. (C) 2016 Elsevier Inc. All rights reserved. C1 [Quinn, Gene R.] Beth Israel Deaconess Med Ctr, Smith Ctr Outcomes Res, Div Cardiol, Boston, MA 02215 USA. [Singer, Daniel E.; Chang, Yuchiao; Borowsky, Leila H.] Massachusetts Gen Hosp, Clin Epidemiol Unit, Boston, MA 02114 USA. [Go, Alan S.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Go, Alan S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Go, Alan S.; Fang, Margaret C.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Fang, Margaret C.] Univ Calif San Francisco, Div Hosp Med, San Francisco, CA 94143 USA. [Go, Alan S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Palo Alto, CA 94304 USA. RP Fang, MC (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.; Fang, MC (reprint author), Univ Calif San Francisco, Div Hosp Med, San Francisco, CA 94143 USA. EM mfang@medicine.ucsf.edu FU National Institute on Aging [R01 AG15478]; National Heart, Lung, and Blood Institute [U19 HL91179, 5RC2HL101589]; National Center for Research Resources; National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, through UCSF-CTSI Grant [UL1 RR024131]; Eliot B. and Edith C. Shoolman fund of the Massachusetts General Hospital (Boston, Massachusetts) FX This study was supported by the National Institute on Aging (R01 AG15478), the National Heart, Lung, and Blood Institute (U19 HL91179 and 5RC2HL101589), the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, through UCSF-CTSI Grant Number UL1 RR024131, and the Eliot B. and Edith C. Shoolman fund of the Massachusetts General Hospital (Boston, Massachusetts). NR 14 TC 0 Z9 0 U1 4 U2 4 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 1 PY 2016 VL 118 IS 5 BP 697 EP 699 DI 10.1016/j.amjcard.2016.06.014 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DU7UP UT WOS:000382420400013 PM 27394408 ER PT J AU Mi, MY Nelson, SB Weiner, RB AF Mi, Michael Y. Nelson, Sandra B. Weiner, Rory B. TI Clinical and Echocardiographic Factors Associated With In-Hospital Mortality in Patients With Infective Endocarditis Affecting the Native Tricuspid Valve SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID VEGETATION SIZE; RIGHT HEART; DRUG-USERS; GUIDELINES AB Infective endocarditis (IE) is a highly morbid disease, for which most outcomes data come from patients with left-sided valvular lesions. Echocardiographic findings such as vegetation size and prosthetic valve involvement have been identified as important predictors of mortality in left-sided IE, but predictors of outcomes in right-sided IE are less well characterized. Therefore, the aim of this study was to identify clinical and echocardiographic findings predictive of mortality in tricuspid valve (TV) IE. We retrospectively reviewed all echocardiograms showing TV vegetations that were performed at the Massachusetts General Hospital from January 1, 2003, to December 31, 2013. We identified 105 patients who had echocardiographic evidence of TV vegetations and a definite clinical diagnosis of IE based on the modified Duke's criteria but did not have intracardiac device associated vegetations. Of the 105 patients, 88 survived until discharge. Clinical and echocardiographic factors that positively correlated with in-hospital mortality included age (p = 0.002), immunosuppression status (p = 0.016), blood urea nitrogen level (p = 0.029), Candida causative organism (p = 0.025), left ventricular ejection fraction <40% (p = 0.027), right ventricular (RV) systolic dysfunction (p = 0.009), and estimated RV systolic pressure >40 mm Hg (p = 0.040). Of these. factors, immunosuppression status, blood urea nitrogen level, and RV systolic dysfunction were independently associated with increased in-hospital mortality. In conclusion, RV systolic dysfunction may serve as an echocardiographic marker to aid clinicians in identifying high-risk patients with right-sided IE for more aggressive therapy. (C) 2016 Elsevier Inc. All rights reserved. C1 [Mi, Michael Y.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Nelson, Sandra B.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Weiner, Rory B.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Weiner, RB (reprint author), Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. EM rweiner@partners.org NR 11 TC 0 Z9 0 U1 2 U2 5 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 1 PY 2016 VL 118 IS 5 BP 739 EP 743 DI 10.1016/j.amjcard.2016.06.011 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DU7UP UT WOS:000382420400020 PM 27392511 ER PT J AU Iovino, I Stuff, J Liu, Y Brewton, C Dovi, A Kleinman, R Nicklas, T AF Iovino, Isabella Stuff, Janice Liu, Yan Brewton, Christie Dovi, Allison Kleinman, Ronald Nicklas, Theresa TI Breakfast consumption has no effect on neuropsychological functioning in children: a repeated-measures clinical trial SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE breakfast consumption; breakfast skipping; cognition; neuropsychological functioning; children ID COGNITIVE PERFORMANCE; SCHOOL-CHILDREN; ACADEMIC-PERFORMANCE; GLYCEMIC INDEX; BLOOD-GLUCOSE; ADOLESCENTS; MEMORY; SCHOOLCHILDREN; ATTENTION; HABITS AB Background: Although many studies have investigated the relation between breakfast consumption and various domains of cognitive functioning within children, some of the reported findings are. inconsistent. Objective: We sought to determine the short-term effects of a breakfast meal on the neuropsychological functioning of healthy school aged children after an overnight fast. Design: The study was conducted in a clinical research center with the use of a counterbalanced repeated-measures design among children who either consumed breakfast or were fasting. The administered neuropsychological tests included measures of attention, impulsivity, short-term memory, cognitive processing speed, and verbal learning. The sample consisted of children aged 8-10 y (n = 128), of whom 52% were female, 38% were African American, 31% were Hispanic, 28% were white, and 3% were of another race/ethnicity. Results: There were no significant (P >= 0.004) differences between breakfast meal consumption and fasting for any of the neuropsychological measures administered. Conclusion: Breakfast consumption had no short-term effect on neuropsychological functioning in healthy school-aged children. C1 [Iovino, Isabella] Texas Childrens Hosp, Psychol Sect, Dept Pediat, Houston, TX USA. [Stuff, Janice; Liu, Yan; Nicklas, Theresa] Baylor Coll Med, Childrens Nutr Res Ctr, Dept Pediat, Houston, TX 77030 USA. [Brewton, Christie; Dovi, Allison] Univ Houston, Dept Psychol Hlth & Learning Sci, Houston, TX USA. [Kleinman, Ronald] MassGen Hosp Children, Boston, MA USA. RP Nicklas, T (reprint author), Baylor Coll Med, Childrens Nutr Res Ctr, Dept Pediat, Houston, TX 77030 USA. EM tnicklas@bcm.edu FU USDA/Agricultural Research Service; Ferrero USA FX Supported in part by the USDA/Agricultural Research Service and Ferrero USA. NR 35 TC 1 Z9 1 U1 18 U2 18 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2016 VL 104 IS 3 BP 715 EP 721 DI 10.3945/ajcn.116.132043 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7UU UT WOS:000382420900023 PM 27465375 ER PT J AU Yu, Z Malik, VS Keum, N Hu, FB Giovannucci, EL Stampfer, MJ Willett, WC Fuchs, CS Bao, Y AF Yu, Zhi Malik, Vasanti S. Keum, NaNa Hu, Frank B. Giovannucci, Edward L. Stampfer, Meir J. Willett, Walter C. Fuchs, Charles S. Bao, Ying TI Associations between nut consumption and inflammatory biomarkers SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE inflammatory biomarkers; nuts; peanuts; substitution; tree nuts; peanut butter ID C-REACTIVE PROTEIN; POLYUNSATURATED FATTY-ACIDS; CORONARY-HEART-DISEASE; CARDIOVASCULAR RISK-FACTORS; WEIGHT-LOSS; ENDOTHELIAL DYSFUNCTION; INSULIN-RESISTANCE; RANDOMIZED-TRIAL; CROSSOVER TRIAL; DIETARY FIBER AB Background: Increased nut consumption has been associated with reduced risk of cardiovascular disease and type 2 diabetes, as well as a healthy lipid profile. However, the associations between nut consumption and inflammatory biomarkers are unclear. Objective: We investigated habitual nut consumption in relation to inflammatory biomarkers in 2 large cohorts of US men and women. Design: We analyzed cross-sectional data from 5013 participants in the Nurses' Health Study (NHS) and Health Professionals Follow Up Study (HPFS) who were free of diabetes. Nut intake, defined as intake of peanuts and other nuts, was estimated from food frequency questionnaires, and cumulative averages from 1986 and 1990 in the NHS and from 1990 and 1994 in the HPFS were used. Plasma biomarkers were collected in 1989-1990 in the NHS and 1993-1995 in the HPFS. Multivariate linear regression was used to assess the associations of nut consumption with fasting plasma C-reactive protein (CRP, n = 4941), interleukin 6 (IL-6, n = 2859), and tumor necrosis factor receptor 2 (TNFR2, n = 2905). Results: A greater intake of nuts was associated with lower amounts of a subset of inflammatory biomarkers, after adjusting for demographic, medical, dietary, and lifestyle variables. The relative concentrations (ratios) and 95% CIs comparing subjects with nut intake of times/wk and those in the categories of never or almost never were as follows: CRP: 0.80 (0.69, 0.90), P-trend = 0.0003; and IL-6: 0.86 (0.77, 0.97), P-trend = 0.006. These associations remained significant after further adjustment for body mass index. No significant association was observed with TNFR2. Substituting 3 servings of nuts/wk for 3 servings of red meat, processed meat, eggs, or refined grains/wk was associated with significantly lower CRP (all P < 0.0001) and IL-6 (P ranges from 0.001 to 0.017). Conclusion: Frequent nut consumption was associated with a healthy profile of inflammatory biomarkers. C1 [Yu, Zhi] Brigham & Womens Hosp, Clin Sci Sect, Div Rheumatol Allergy & Immunol, 75 Francis St, Boston, MA 02115 USA. [Malik, Vasanti S.; Keum, NaNa; Hu, Frank B.; Giovannucci, Edward L.; Stampfer, Meir J.; Willett, Walter C.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Hu, Frank B.; Giovannucci, Edward L.; Stampfer, Meir J.; Willett, Walter C.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Hu, Frank B.; Giovannucci, Edward L.; Stampfer, Meir J.; Willett, Walter C.; Fuchs, Charles S.; Bao, Ying] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Hu, Frank B.; Giovannucci, Edward L.; Stampfer, Meir J.; Willett, Walter C.; Fuchs, Charles S.; Bao, Ying] Harvard Med Sch, Boston, MA 02115 USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Bao, Y (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.; Bao, Y (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM ying.bao@channing.harvard.edu FU NIH [UM1 CA186107, UM1 CA167552, R01 CA49449, U54CA155626, P30DK046200]; International Tree Nut Council Nutrition Research & Education Foundation; Harvard Catalyst, Harvard Clinical and Translational Science Center (National Center for Research Resources); Harvard Catalyst, Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH) [KL2 TR001100] FX Supported by grants UM1 CA186107, UM1 CA167552, R01 CA49449, U54CA155626, and P30DK046200 from the NIH; by a grant from the International Tree Nut Council Nutrition Research & Education Foundation; and by a KL2/Catalyst Medical Research Investigator Training award (an appointed KL2 award) from Harvard Catalyst, Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH Award KL2 TR001100). NR 54 TC 2 Z9 2 U1 13 U2 13 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2016 VL 104 IS 3 BP 722 EP 728 DI 10.3945/ajcn.116.134205 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7UU UT WOS:000382420900024 PM 27465378 ER PT J AU Abadia, L Gaskins, AJ Chiu, YH Williams, PL Keller, M Wright, DL Souter, I Hauser, R Chavarro, JE AF Abadia, Laura Gaskins, Audrey J. Chiu, Yu-Han Williams, Paige L. Keller, Myra Wright, Diane L. Souter, Irene Hauser, Russ Chavarro, Jorge E. CA Environm Reprod Hlth Study Team TI Serum 25-hydroxyvitamin D concentrations and treatment outcomes of women undergoing assisted reproductiont SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE vitamin D; infertility; assisted reproductive technologies; epidemiology; nutrition ID VITAMIN-D DEFICIENCY; FOLLICULAR-FLUID; PREGNANCY RATE; UNITED-STATES; INFERTILITY; TECHNOLOGY; RATS; FERTILITY AB Background: Vitamin D deficiency impairs fertility in animal models, but the role of vitamin D in human fertility or treatment of infertility is less clear. Objective: We examined the association between circulating 25-hydroxyvitamin D [25(OH)D] concentrations and the outcome in women undergoing assisted reproduction technologies (ARTs). Design: We randomly selected 100 women undergoing infertility treatment with ART enrolled in an ongoing prospective cohort study who underwent 168 treatment cycles. Serum 25(OH)D concentrations were measured in samples collected from women between days 3 and 9 of gonadotropin treatment. Generalized linear mixed models were used to evaluate the association of 25(OH)D concentrations with ART outcomes while adjusting for potential confounders and accounting for repeated treatment cycles per woman. Results: Median (range) serum 25(OH)D concentrations were 86.5 (33.5-155.5) nmol/L. Ninety-one percent of participants consumed multivitamins. Serum 25(OH)D concentrations were positively related to fertilization rate. The adjusted fertilization rate for women in increasing quartiles of serum 25(OH)D were 0.62 (95% CI: 0.51, 0.72), 0.53 (95% CI: 0.43, 0.63), 0.67 (95% CI: 0.56, 0.76), and 0.73 (95% CI: 0.63, 0.80), respectively (P-trend = 0.03). This association persisted when analyses were restricted to women with serum 25(OH)D between 50 and 125 nmol/L when models were further adjusted for season of blood draw and when analyses were restricted to the first treatment cycle. However, 25(OH)D concentrations were unrelated to probability of pregnancy (P-trend = 0.83) or live birth after ART (P-trend = 0.47). Conclusion: Vitamin D may be associated with higher fertilization. rates, but this apparent benefit does not translate into higher probability of pregnancy or live birth. C1 [Abadia, Laura; Gaskins, Audrey J.; Chiu, Yu-Han; Chavarro, Jorge E.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Gaskins, Audrey J.; Chiu, Yu-Han; Williams, Paige L.; Hauser, Russ; Chavarro, Jorge E.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Williams, Paige L.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Keller, Myra; Hauser, Russ] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Keller, Myra; Wright, Diane L.; Souter, Irene; Hauser, Russ] Massachusetts Gen Hosp, Vincent Obstet & Gynecol, Boston, MA 02114 USA. [Keller, Myra; Wright, Diane L.; Souter, Irene; Hauser, Russ; Chavarro, Jorge E.] Harvard Med Sch, Boston, MA 02115 USA. [Chavarro, Jorge E.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. RP Chavarro, JE (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.; Chavarro, JE (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.; Chavarro, JE (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Chavarro, JE (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. EM jchavarr@hsph.harvard.edu FU NIH [ES022955, R01ES009718, R01ES000002, P30DK46200, T32DK007703]; Early Life Nutrition Fund from Danone Nutricia US FX Supported by NIH grants ES022955, R01ES009718, R01ES000002, P30DK46200, and T32DK007703 and the Early Life Nutrition Fund from Danone Nutricia US. NR 35 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 2016 VL 104 IS 3 BP 729 EP 735 DI 10.3945/ajcn.115.126359 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7UU UT WOS:000382420900025 PM 27465382 ER PT J AU Singer, AE Ash, T Ochotorena, C Lorenz, KA Chong, K Shreve, ST Ahluwalia, SC AF Singer, Adam E. Ash, Tayla Ochotorena, Claudia Lorenz, Karl A. Chong, Kelly Shreve, Scott T. Ahluwalia, Sangeeta C. TI A Systematic Review of Family Meeting Tools in Palliative and Intensive Care Settings SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Review DE communication; professional-family relations; interdisciplinary communication; palliative care; psychology; caregivers; review ID OF-LIFE CARE; CRITICALLY-ILL; DECISION-MAKING; MEDICAL-RECORD; END; UNIT; COMMUNICATION; ICU; CONSENSUS; RECOMMENDATIONS AB Purpose: Family meetings can be challenging, requiring a range of skills and participation. We sought to identify tools available to aid the conduct of family meetings in palliative, hospice, and intensive care unit settings. Methods: We systematically reviewed PubMed for articles describing family meeting tools and abstracted information on tool type, usage, and content. Results: We identified 16 articles containing 23 tools in 7 categories: meeting guide (n = 8), meeting planner (n = 5), documentation template (n = 4), meeting strategies (n = 2), decision aid/screener (n = 2), family checklist (n = 1), and training module (n = 1). We found considerable variation across tools in usage and content and a lack of tools supporting family engagement. Conclusion: There is need to standardize family meeting tools and develop tools to help family members effectively engage in the process. C1 [Singer, Adam E.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Singer, Adam E.; Lorenz, Karl A.; Ahluwalia, Sangeeta C.] RAND Corp, Santa Monica, CA USA. [Ash, Tayla] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Ochotorena, Claudia] Drexel Univ, Coll Nursing & Hlth Profess, Philadelphia, PA 19104 USA. [Lorenz, Karl A.; Chong, Kelly; Shreve, Scott T.] Greater Los Angeles VA Hlth Care Syst, Qual Improvement Resource Ctr, Los Angeles, CA USA. [Lorenz, Karl A.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Lorenz, Karl A.] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Shreve, Scott T.] Penn State Coll Med, Lebanon, NH USA. [Ahluwalia, Sangeeta C.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Los Angeles, CA USA. RP Singer, AE (reprint author), 1776 Main St,POB 2138, Santa Monica, CA 90407 USA. EM asinger@rand.org FU Medical Scientist Training Program at the University of California, Los Angeles [T32 GM008042]; National Palliative Care Research Center; VA/NIMH Implementation Research Fellowship [R25 MH080916-01A2]; VA palliative care Quality Improvement Resource Center FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Dr. Singer received support from grant T32 GM008042 as a member of the Medical Scientist Training Program at the University of California, Los Angeles. Dr. Ahluwalia was supported by a career development award from the National Palliative Care Research Center and a VA/NIMH Implementation Research Fellowship (R25 MH080916-01A2). This work was funded by the VA palliative care Quality Improvement Resource Center in order to identify family meeting tools for use in quality improvement. NR 43 TC 0 Z9 0 U1 4 U2 4 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 SEP PY 2016 VL 33 IS 8 BP 797 EP 806 DI 10.1177/1049909115594353 PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DU9EH UT WOS:000382518600012 PM 26213225 ER PT J AU Al-Niaimi, A Rice, LW Shitanshu, U Garvens, B Fitzgerald, M Zerbel, S Safdar, N AF Al-Niaimi, Ahmed Rice, Laurel W. Shitanshu, Uppal Garvens, Bonnie Fitzgerald, Megan Zerbel, Sara Safdar, Nasia TI Safety and tolerability of chlorhexidine gluconate (2%) as a vaginal operative preparation in patients undergoing gynecologic surgery SO AMERICAN JOURNAL OF INFECTION CONTROL LA English DT Article DE Gynecologic surgery; chlorhexidine 2%; vaginal irritation; patient safety ID POVIDONE-IODINE; HYSTERECTOMY; TRIAL; PREVENTION; ANTISEPSIS; INFECTION AB Background: The use of chlorhexidine gluconate (CHG) as an intraoperative vaginal preparation has been shown to be more effective than vaginal povidone-iodine (PI) in decreasing vaginal bacterial colony counts. However, PI remains the standard vaginal preparation because of concerns of CHG's potential for vaginal irritation. The primary outcome of this study is a comparison of the rate of patient-reported vaginal irritation between 2% CHG and PI. Methods: Consecutive patients were enrolled in a pre-post study. Group 1 consisted of consecutive patients who received PI as a vaginal preparation. Group 2 consisted of consecutive patients who received 2% CHG as a vaginal preparation. Patients used a standardized instrument to report irritation to trained nurse practitioners 1 day after surgery. Results: A total of 117 patients received vaginal operative preparation during the course of the study, with 64 patients in group 1 and 53 patients in group 2. Of the patients in group 1, 60 (93.7%) reported no vaginal irritation, 3 (4.69%) reported mild irritation, and 1 (1.56%) reported moderate irritation. In group 2 (2% CHG vaginal preparation), all of the patients (100%) reported no vaginal irritation (P = .38). Conclusions: The use of 2% CHG as a vaginal operative preparation is not associated with increased vaginal irritation compared with PI in gynecologic surgery. It can safely be used, taking advantage of its efficacy in reducing vaginal bacterial colony counts. Published by Elsevier Inc. on behalf of Association for Professionals in Infection Control and Epidemiology, Inc. C1 [Al-Niaimi, Ahmed; Rice, Laurel W.; Garvens, Bonnie; Fitzgerald, Megan; Zerbel, Sara; Safdar, Nasia] Univ Wisconsin Med, Sch & Publ Hlth, Madison, WI USA. [Shitanshu, Uppal] Univ Michigan, Ann Arbor, MI 48109 USA. [Safdar, Nasia] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Safdar, N (reprint author), Univ Wisconsin, Dept Med, Infect Dis Sect, 600 Highland Ave,Box 5158, Madison, WI 53792 USA. EM ns2@medicine.wisc.edu NR 12 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-6553 EI 1527-3296 J9 AM J INFECT CONTROL JI Am. J. Infect. Control PD SEP 1 PY 2016 VL 44 IS 9 BP 996 EP 998 DI 10.1016/j.ajic.2016.02.036 PG 3 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DV0AH UT WOS:000382579100011 PM 27234011 ER PT J AU Sallis, RE Baggish, AL Franklin, BA Whitehead, JR AF Sallis, Robert E. Baggish, Aaron L. Franklin, Barry A. Whitehead, James R. TI The Call for a Physical Activity Vital Sign in Clinical Practice SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material ID AMERICAN-HEART-ASSOCIATION; CARDIORESPIRATORY FITNESS; EXERCISE CAPACITY; CHRONIC DISEASES; UNITED-STATES; INACTIVITY; MORTALITY; RISK; CARE; MEN C1 [Sallis, Robert E.] Kaiser Permanente Med Ctr, Dept Family Med, 9961 Sierra Ave, Fontana, CA 92335 USA. [Baggish, Aaron L.] Massachusetts Gen Hosp, Div Cardiol, Cardiovasc Performance Program, Boston, MA 02114 USA. [Franklin, Barry A.] William Beaumont Hosp, Prevent Cardiol Cardiac Rehabil, Royal Oak, MI 48072 USA. [Franklin, Barry A.] Oakland Univ, William Beaumont Sch Med, Rochester, MI 48063 USA. [Whitehead, James R.] Amer Coll Sports Med, Indianapolis, IN USA. RP Sallis, RE (reprint author), Kaiser Permanente Med Ctr, Dept Family Med, 9961 Sierra Ave, Fontana, CA 92335 USA. EM Robert.E.Sallis@kp.org NR 30 TC 1 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD SEP PY 2016 VL 129 IS 9 BP 903 EP 905 DI 10.1016/j.amjmed.2016.05.005 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DU6FO UT WOS:000382309900027 PM 27235007 ER PT J AU Bennet, CS Dahagam, CR Virani, SS Martin, SS Blumenthal, RS Michos, ED McEvoy, JW AF Bennet, Catherine S. Dahagam, Chanukya R. Virani, Salim S. Martin, Seth S. Blumenthal, Roger S. Michos, Erin D. McEvoy, John W. TI Lipid Management Guidelines from the Departments of Veteran Affairs and Defense: A Critique SO AMERICAN JOURNAL OF MEDICINE LA English DT Review DE Atherosclerotic cardiovascular disease; Coronary artery calcium; Dyslipidemia; Guidelines; Veterans Affairs ID CORONARY-ARTERY CALCIUM; HEART-DISEASE RISK; HEINZ NIXDORF RECALL; STATIN THERAPY; CARDIOVASCULAR-DISEASE; PRIMARY PREVENTION; ASYMPTOMATIC ADULTS; LOWERING THERAPY; REDUCING LIPIDS; FOLLOW-UP AB In December 2014, the US Department of Veterans Affairs and Department of Defense (VA/DoD) published an independent clinical practice guideline for the management of dyslipidemia and cardiovascular disease risk, adding to the myriad of recently published guidelines on this topic. The VA/DoD guidelines differ from major US guidelines published by the American College of Cardiology/American Heart Association in 2013 in the following ways: recommending moderate-intensity statins for the majority of patients with statin indications regardless of atherosclerotic cardiovascular disease risk; advocating for limited on-treatment lipid monitoring; and deemphasizing ancillary data, such as coronary artery calcium testing, to improve atherosclerotic cardiovascular disease risk estimation. In the context of manifold treatment recommendations from numerous guideline committees, the VA/DoD recommendations may generate further confusion and mixed messages among healthcare providers about the optimal treatment of dyslipidemia. In this review, we critically appraise the VA/DoD recommendations with a focus on the evidence base for each area where the VA/DoD guidelines differ from the American College of Cardiology/American Heart Association guidelines. We also call for harmonization of lipid treatment guidelines to ensure high-quality and consistent care for patients with, and at risk for, atherosclerotic cardiovascular disease. (C) 2016 Elsevier Inc. All rights reserved. C1 [Bennet, Catherine S.; Martin, Seth S.; Blumenthal, Roger S.; Michos, Erin D.; McEvoy, John W.] Johns Hopkins Sch Med, Dept Med, Div Cardiol, Baltimore, MD USA. [Dahagam, Chanukya R.] MedStar Franklin Sq Med Ctr, Dept Med, Baltimore, MD USA. [Virani, Salim S.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Virani, Salim S.] Baylor Coll Med, Cardiol Sect, Dept Med, Houston, TX 77030 USA. [Martin, Seth S.; Blumenthal, Roger S.; Michos, Erin D.; McEvoy, John W.] Johns Hopkins Sch Med, Ciccarone Ctr Prevent Heart Dis, Baltimore, MD USA. RP McEvoy, JW (reprint author), Johns Hopkins Univ, Sch Med, Div Cardiol, Dept Med, 600 N Wolfe St,Blalock 524C, Baltimore, MD 21287 USA. EM jmcevoy1@jhmi.edu OI Virani, Salim/0000-0001-9541-6954 NR 51 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD SEP PY 2016 VL 129 IS 9 BP 906 EP 912 DI 10.1016/j.amjmed.2016.04.012 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA DU6FO UT WOS:000382309900028 PM 27154781 ER PT J AU Tapson, VF Platt, DM Xia, F Teal, SA de la Orden, M Divers, CH Satler, CA Joish, VN Channick, RN AF Tapson, Victor F. Platt, David M. Xia, Fang Teal, Simon A. de la Orden, Margarita Divers, Christine H. Satler, Carol A. Joish, Vijay N. Channick, Richard N. TI Monitoring for Pulmonary Hypertension Following Pulmonary Embolism: The INFORM Study SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Chronic thromboembolic pulmonary hypertension; CTEPH; Pulmonary embolism; Pulmonary hypertension; VQ scan ID INTERNATIONAL PROSPECTIVE REGISTRY; TASK-FORCE; MANAGEMENT; DIAGNOSIS; GUIDELINES; RIOCIGUAT; DISEASE AB BACKGROUND: Pulmonary hypertension and chronic thromboembolic pulmonary hypertension may develop after a pulmonary embolism event. A ventilation-perfusion scan is recommended as a first-line modality for suspected chronic thromboembolic pulmonary hypertension. In this study, we determined the prevalence of pulmonary hypertension following incident pulmonary embolism and the disease-monitoring patterns in this population. METHODS: We conducted a retrospective claims database analysis of incident pulmonary embolism cases (July 1, 2010 to September 30, 2011) and extracted data for 1 year prior to and 2 years after the incident pulmonary embolism event. Data were analyzed for diagnoses and symptoms related to pulmonary hypertension, claims consistent with other heart or lung diseases, diagnostic imaging tests, and time to first diagnostic imaging test post pulmonary embolism. RESULTS: Of the 7068 incident pulmonary embolism patients that met eligibility criteria, 87% had a claim for a pulmonary hypertension-related symptom and 7.6% had a claim for pulmonary hypertension during follow-up. Only 55% of all pulmonary embolism patients had diagnostic procedural claim(s) post pulmonary embolism: echocardiogram, 47%; computed tomographic angiography, 20%; ventilation-perfusion scan, 6%; and right heart catheterization or pulmonary angiography, <1%. The mean time from pulmonary embolism diagnosis to first screening test was 131 days. CONCLUSIONS: Despite exhibiting pulmonary hypertension-related symptoms, many pulmonary embolism patients did not undergo imaging tests that could diagnose pulmonary hypertension or chronic thromboembolic pulmonary hypertension. This study suggests that physician education about the risk of pulmonary hypertension and chronic thromboembolic pulmonary hypertension after pulmonary embolism may need to be improved. (C) 2016 Elsevier Inc. All rights reserved. C1 [Tapson, Victor F.] Cedars Sinai Med Ctr, Div Pulm & Crit Care Med, Los Angeles, CA 90048 USA. [Platt, David M.; Xia, Fang; Divers, Christine H.; Satler, Carol A.; Joish, Vijay N.] Bayer HealthCare Pharmaceut, Whippany, NJ USA. [Teal, Simon A.; de la Orden, Margarita] Bayer Pharma AG, Berlin, Germany. [Channick, Richard N.] Massachusetts Gen Hosp, Dept Pulm & Crit Care Med, Boston, MA 02114 USA. RP Tapson, VF (reprint author), Cedars Sinai Med Ctr, Div Pulm Crit Care, Dept Med, Thalians Bldg Room W155,8730 Gracie Allen Dr, Los Angeles, CA 90048 USA. EM victor.tapson@cshs.org FU Bayer HealthCare Pharmaceuticals (Berlin, Germany) FX Bayer HealthCare Pharmaceuticals (Berlin, Germany). NR 31 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 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD SEP PY 2016 VL 129 IS 9 BP 978 EP + DI 10.1016/j.amjmed.2016.03.006 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DU6FO UT WOS:000382309900041 PM 27046247 ER PT J AU Bateman, BT Franklin, JM Bykov, K Avorn, J Shrank, WH Brennan, TA Landon, JE Rathmell, JP Huybrechts, KF Fischer, MA Choudhry, NK AF Bateman, Brian T. Franklin, Jessica M. Bykov, Katsiaryna Avorn, Jerry Shrank, William H. Brennan, Troyen A. Landon, Joan E. Rathmell, James P. Huybrechts, Krista F. Fischer, Michael A. Choudhry, Niteesh K. TI Persistent opioid use following cesarean delivery: patterns and predictors among opioid-naive women SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE cesarean delivery; cohort; opioids; pain; pregnancy studies ID MENTAL-HEALTH DISORDERS; CHRONIC NONCANCER PAIN; ASSOCIATION; SURGERY; ENDOCRINOPATHY; MEDICATIONS; CHILDBIRTH; VETERANS; COHORT AB BACKGROUND: The incidence of opioid-related death in women has increased 5-fold over the past decade. For many women, their initial opioid exposure will occur in the setting of routine medical care. Approximately 1 in 3 deliveries in the United States is by cesarean, and opioids are commonly prescribed for postsurgical pain management. OBJECTIVE: The objective of this study was to determine the risk that opioid-naive women prescribed opioids after cesarean delivery will subsequently become consistent prescription opioid users in the year following delivery and to identify predictors for this behavior. STUDY DESIGN: We identified women in a database of commercial insurance beneficiaries who underwent cesarean delivery and who were opioid naive in the year prior to delivery. To identify persistent users of opioids, we used trajectory models, which group together patients with similar patterns of medication filling during follow-up, based on patterns of opioid dispensing in the year following cesarean delivery. We then constructed a multivariable logistic regression model to identify independent risk factors for membership in the persistent user group. RESULTS: A total of 285 of 80,127 (0.36%, 95% confidence interval, 0.32-0.40), opioid-naive women became persistent opioid users (identified using trajectory models based on monthly patterns of opioid dispensing) following cesarean delivery. Demographics and baseline comorbidity predicted such use with moderate discrimination (c statistic = 0.73). Significant predictors included a history of cocaine abuse (risk, 7.41%; adjusted odds ratio, 6.11, 95% confidence interval, 1.03-36.31) and other illicit substance abuse (2.36%; adjusted odds ratio, 2.78, 95% confidence interval, 1.12-6.91), tobacco use (1.45%; adjusted odds ratio, 3.04, 95% confidence interval, 2.03-4.55), back pain (0.69%; adjusted odds ratio, 1.74, 95% confidence interval, 1.33-2.29), migraines (0.91%; adjusted odds ratio, 2.14, 95% confidence interval, 1.58-2.90), antidepressant use (1.34%; adjusted odds ratio, 3.19, 95% confidence interval, 2.41-4.23), and benzodiazepine use (1.99%; adjusted odds ratio, 3.72, 95% confidence interval, 2.64-5.26) in the year prior to the cesarean delivery. CONCLUSION: A very small proportion of opioid-naive women (approximately 1 in 300) become persistent prescription opioid users following cesarean delivery. Preexisting psychiatric comorbidity, certain pain conditions, and substance use/abuse conditions identifiable at the time of initial opioid prescribing were predictors of persistent use. C1 [Bateman, Brian T.; Franklin, Jessica M.; Bykov, Katsiaryna; Avorn, Jerry; Landon, Joan E.; Huybrechts, Krista F.; Fischer, Michael A.; Choudhry, Niteesh K.] Harvard Med Sch, Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Dept Med, Boston, MA 02115 USA. [Rathmell, James P.] Harvard Med Sch, Brigham & Womens Hosp, Dept Anesthesia, Boston, MA USA. [Rathmell, James P.] Harvard Med Sch, Brigham & Womens Hosp, Dept Perioperat & Pain Med, Boston, MA USA. [Bateman, Brian T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Div Obstet Anesthesia, Boston, MA USA. [Shrank, William H.; Brennan, Troyen A.] CVS Hlth, Woonsocket, RI USA. RP Bateman, BT (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Dept Med, Boston, MA 02115 USA.; Bateman, BT (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Div Obstet Anesthesia, Boston, MA USA. EM bbateman@partners.org OI Franklin, Jessica/0000-0002-8941-4116 FU CVS Caremark; Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health [K08HD075831] FX This study was supported by an unrestricted research grant from CVS Caremark to Brigham and Women's Hospital and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (award number K08HD075831). NR 30 TC 0 Z9 0 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2016 VL 215 IS 3 AR 353.e1-e18 DI 10.1016/j.ajog.2016.03.016 PG 18 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DU8WA UT WOS:000382495100033 PM 26996986 ER PT J AU Shi, P Chen, EY Cs-Szabo, G Chee, A Tannoury, C Qin, L An, S An, S An, HS Zhang, YJ AF Shi, Peng Chen, Er-Yun Cs-Szabo, Gabriella Chee, Ana Tannoury, Chadi Qin, Ling Lin, Han An, Steven An, Howard S. Zhang, Yejia TI Biglycan Inhibits Capsaicin-Induced Substance P Release by Cultured Dorsal Root Ganglion Neurons SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Intervertebral Disc; Pain; Dorsal Root Ganglion (DRG); Biglycan; Capsaicin ID LOW-BACK-PAIN; LUMBAR INTERVERTEBRAL DISCS; ANULUS FIBROSUS; RECEPTOR; NERVE; EXPRESSION; INGROWTH AB Objective: The purpose of this study was to examine the inhibitory effects of biglycan on substance P release from cultured sensory neurons in response to capsaicin. Study Design: In vitro study of cultured primary sensory neurons from the rabbit dorsal root ganglion (DRG). We interrogated the culture system function with capsaicin. Biglycan is an important structural component of the intervertebral disc that may regulate growth factors and inflammatory mediators. We tested the hypothesis that biglycan inhibits substance P release in response to capsaicin. Results: The DRG cultures were shown to contain both neurons and astrocytes by immunostaining using antibodies recognizing neuron and glial cell markers. Cultured DRG cells respond to capsaicin in a dose-and time-dependent manner (capsaicin dose ranges from 5 to 500 mu mol/L; stimulation time ranges from 0 to 60 minutes). The neurons preincubated with biglycan released 27% less substance P compared with neurons without biglycan (n = 4, P = 0.036). Conclusion: We have established a DRG cell culture system, which contains both sensory neurons and the supporting astrocytes. Biglycan, an inhibitor of substance P release by DRG cultures, may serve as an ingredient in intradiscal injectables to reduce back pain. C1 [Shi, Peng; Chee, Ana; An, Steven; An, Howard S.] Rush Univ, Med Ctr, Dept Orthoped Surg, Chicago, IL 60612 USA. [Chen, Er-Yun] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Cs-Szabo, Gabriella] Rush Univ, Med Ctr, Dept Biochem, Chicago, IL 60612 USA. [Tannoury, Chadi] Boston Univ, Med Ctr, Dept Orthoped Surg, Boston, MA USA. [Lin, Han] Drexel Univ, Sch Biomed Engn Sci & Hlth Syst, Philadelphia, PA 19104 USA. [Zhang, Yejia] Univ Penn, Dept Phys Med & Rehabil, Perelman Sch Med, Philadelphia, PA 19104 USA. [Qin, Ling; Zhang, Yejia] Univ Penn, Dept Orthoped Surg, Perelman Sch Med, Philadelphia, PA 19104 USA. [Zhang, Yejia] Philadelphia Vet Affairs Med Ctr, Translat Musculoskeletal Res Ctr, Philadelphia, PA USA. RP Zhang, YJ (reprint author), Philadelphia Vet Affairs Med Ctr, Translat Musculoskeletal Res Ctr, Philadelphia, PA USA.; Zhang, YJ (reprint author), Univ Penn, Dept Phys Med & Rehabil, Dept Orthoped Surg, Perelman Sch Med, Philadelphia, PA 19104 USA. OI Tannoury, Chadi/0000-0002-2369-432X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [1 K08 HD049598] FX Yejia Zhang, MD, PhD has been supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD, 1 K08 HD049598). This work has been presented at the Inaugural ICMRS-ASBMR International Chinese Musculoskeletal Research Conference (ICMRC) in 2013 in Suzhou, PR China as a poster presentation. This work has also been presented at the 2014 Philadelphia Spine Research Society Meeting in Philadelphia, PA as a podium presentation. PS performed rabbit dissections, cell culture, and ELISA; EC performed confocal microscopy; YZ and HSA are responsible for conceptual design, data interpretation, and securing funding. YZ has access to all data collected. All authors critically reviewed and approved the manuscript. Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article. NR 27 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0894-9115 EI 1537-7385 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD SEP PY 2016 VL 95 IS 9 BP 656 EP 662 DI 10.1097/PHM.0000000000000460 PG 7 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA DU5LE UT WOS:000382252400008 PM 26945213 ER PT J AU Klabunde, CN Zheng, YY Quinn, VP Beaber, EF Rutter, CM Halm, EA Chubak, J Doubeni, CA Haas, JS Kamineni, A Schapira, MM Vacek, PM Garcia, MP Corley, DA AF Klabunde, Carrie N. Zheng, Yingye Quinn, Virginia P. Beaber, Elisabeth F. Rutter, Carolyn M. Halm, Ethan A. Chubak, Jessica Doubeni, Chyke A. Haas, Jennifer S. Kamineni, Aruna Schapira, Marilyn M. Vacek, Pamela M. Garcia, Michael P. Corley, Douglas A. CA PROSPR Consortium TI Influence of Age and Comorbidity on Colorectal Cancer Screening in the Elderly SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID COST-EFFECTIVENESS; FOLLOW-UP; AMERICAN-COLLEGE; BREAST; HEALTH; WOMEN; CARE; RECOMMENDATIONS; COLONOSCOPY; STRATEGIES AB Introduction: Expert recommendations differ for colorectal cancer screening in the elderly. Recent studies suggest that healthy adults aged >75 years may benefit from screening. This study examined screening use and follow-up, and how they varied by health status within age strata, among a large cohort of elderly individuals in community settings. Methods: A population-based, longitudinal cohort study was conducted among health plan members aged 65-89 years enrolled during 2011-2012 in three integrated healthcare systems participating in the Population-Based Research Optimizing Screening through Personalized Regimens consortium. Comorbidity measurements used the Charlson index. Analyses, conducted in 2015, comprised descriptive statistics and multivariable modeling that estimated age by comorbidity-specific percentages of patients for two outcomes: colorectal cancer screening uptake and follow-up of abnormal fecal blood tests. Results: Among 846,267 patients, 72% were up-to-date with colorectal cancer screening. Of patients with a positive fecal blood test, 65% received follow-up colonoscopy within 3 months. Likelihood of being up-to-date and receiving timely follow-up was significantly lower for patients aged >= 76 years than their younger counterparts (p < 0.001). Comorbidity was less influential than age and more strongly related to timely follow-up than being up-to-date. In all age groups, considerable numbers of patients with no/low comorbidity were not up-to-date or did not receive timely follow-up. Conclusions: In three integrated healthcare systems, many older, relatively healthy patients were not screening up-to-date, and some relatively young, healthy patients did not receive timely follow-up. Findings suggest a need for re-evaluating age-based screening guidelines and improving screening completion among the elderly. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Klabunde, Carrie N.] NIH, Off Dis Prevent, Off Director, 6100 Execut Blvd,Suite 2B03, Rockville, MD 20852 USA. [Zheng, Yingye; Beaber, Elisabeth F.; Garcia, Michael P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Quinn, Virginia P.] Kaiser Permanente Southern Calif, Res & Evaluat, Pasadena, CA USA. [Rutter, Carolyn M.] RAND Corp, Santa Monica, CA USA. [Halm, Ethan A.] Univ Texas Southwestern Med Ctr, Dept Internal Med & Clin Sci, Dallas, TX USA. [Chubak, Jessica; Kamineni, Aruna] Grp Hlth Res Inst, Seattle, WA USA. [Doubeni, Chyke A.] Univ Penn, Perelman Sch Med, Dept Family Med & Community Hlth, Philadelphia, PA 19104 USA. [Doubeni, Chyke A.] Univ Penn, Perelman Sch Med, Dept Epidemiol, Philadelphia, PA 19104 USA. [Haas, Jennifer S.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Haas, Jennifer S.] Harvard Med Sch, Boston, MA USA. [Schapira, Marilyn M.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Schapira, Marilyn M.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Vacek, Pamela M.] Univ Vermont, Coll Med, Med Biostat Unit, Burlington, VT USA. [Corley, Douglas A.] Kaiser Permanente Div Res, Oakland, CA USA. RP Klabunde, CN (reprint author), NIH, Off Dis Prevent, Off Director, 6100 Execut Blvd,Suite 2B03, Rockville, MD 20852 USA. EM klabundc@od.nih.gov FU National Cancer Institute of NIH PROSPR cooperative agreements [U01CA163304, U54CA163261, U5U54CA163262, U54CA163303, U54CA 163307, U54CA163308, U54CA163313] FX The authors thank the participating Population-Based Research Optimizing Screening through Personalized Regimens (PROSPR) Research Centers for the data they have provided for this study. A list of PROSPR investigators and contributing research staff is provided at: http://healthcaredelivery.cancer.gov/prospr/. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of NIH. The National Cancer Institute of NIH supported the research for this manuscript through the PROSPR cooperative agreements (grant numbers U01CA163304, U54CA163261, U5U54CA163262, U54CA163303, U54CA 163307, U54CA163308, U54CA163313). NR 41 TC 1 Z9 1 U1 4 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2016 VL 51 IS 3 BP E67 EP E75 DI 10.1016/j.amepre.2016.04.018 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DU6CC UT WOS:000382299700002 PM 27344108 ER PT J AU Bartosch, C Pires-Luis, AS Meireles, C Baptista, M Gouveia, A Pinto, C Shannon, KM Jeronimo, C Teixeira, MR Lopes, JM Oliva, E AF Bartosch, Carla Pires-Luis, Ana S. Meireles, Catarina Baptista, Manuela Gouveia, Alfredo Pinto, Carla Shannon, Kristen M. Jeronimo, Carmen Teixeira, Manuel R. Lopes, Jose M. Oliva, Esther TI Pathologic Findings in Prophylactic and Nonprophylactic Hysterectomy Specimens of Patients With Lynch Syndrome SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE Lynch syndrome; endometrial carcinoma; prophylactic hysterectomy ID NONPOLYPOSIS COLORECTAL-CANCER; MISMATCH REPAIR PROTEINS; COST-EFFECTIVENESS ANALYSIS; MSH6 GERMLINE MUTATIONS; LOWER UTERINE SEGMENT; ENDOMETRIAL CANCER; MICROSATELLITE INSTABILITY; OVARIAN-CANCER; SYNDROME FAMILIES; IMMUNOHISTOCHEMICAL ANALYSIS AB Women with Lynch syndrome (LS) have a high risk of developing endometrial carcinoma (EC) and, less frequently, ovarian carcinoma. As EC not uncommonly is the first malignancy, prophylactic hysterectomy (PH) has been increasingly implemented. In this study, we report the clinicopathologic features of a series of 70 LS patients who underwent either PH (n=39) or nonprophylactic hysterectomy (NPH) (n=31) at 3 tertiary referral centers. Among the 39 patients with PH, 2 had endometrial tumors seen grossly, whereas 37 showed no macroscopic lesions. Total inclusion of the endometrium was performed in 24/39 (61.5%). Abnormal histologic findings were identified in 9/39 (23.1%) PHs: 3 endometrial endometrioid carcinomas (EECs), including the 2 macroscopic and 1 microscopic (0.6 cm), and 4 atypical and 6 nonatypical hyperplasias. NPH included those performed for endometrial and ovarian cancer treatment. Tumor sampling followed standard protocols. ECs comprised 26 EECs and 1 clear cell carcinoma, with a median size of 3.7 cm. Hyperplasia was observed in 10 (33.3%) as background in EC, in 4 showing atypia. Eight (29.6%) tumors were centered in the lower uterine segment (all EECs). EECs were predominantly well differentiated (53.8%) and FIGO stage I (77.8%). A papillary architecture was common (51.9%) and associated with microcystic elongated and fragmented foci in 4. Mucinous differentiation was observed in 25.9% of endometrial tumors, typically representing <10%. Most endometrial tumors (81.5%) showed tumor-infiltrating lymphocyte counts >= 42/10 high-power fields. Four tumors showed extensive necrosis. Eight patients had ovarian tumors (4 synchronous), including 2 endometrioid carcinomas, 2 clear cell carcinomas, 1 borderline clear cell adenofibroma, 1 Mullerian carcinoma of mixed cell types, 1 primitive neuroectodermal tumor, and 1 metastatic melanoma. Total inclusion of the endometrium should be done in all LS patients' surgical specimens without macroscopic lesions as some of these patients harbor preneoplastic or neoplastic conditions treatable at an early stage. The phenotype of LS-associated endometrial and ovarian tumors is variable and frequently includes features not commonly observed in sporadic cancers, but in our experience carcinomas were in general low grade and low stage. C1 [Bartosch, Carla; Pires-Luis, Ana S.; Meireles, Catarina] Portuguese Oncol Inst Porto, Dept Pathol, Rua Dr Antonio Bernardino de Almeida, P-4200072 Oporto, Portugal. [Gouveia, Alfredo] Portuguese Oncol Inst Porto, Dept Gynecol, Oporto, Portugal. [Pinto, Carla; Teixeira, Manuel R.] Portuguese Oncol Inst Porto, Dept Genet, Oporto, Portugal. [Bartosch, Carla; Pires-Luis, Ana S.; Jeronimo, Carmen] Portuguese Oncol Inst Porto, Res Ctr, Canc Epigenet & Biol Grp, Oporto, Portugal. [Bartosch, Carla; Lopes, Jose M.] Univ Porto IPATIMUP, Dept Pathol & Oncol, Fac Med, Oporto, Portugal. [Jeronimo, Carmen; Teixeira, Manuel R.] Univ Porto IPATIMUP, Inst Biomed Sci Abel Salazar, Dept Pathol & Mol Immunol, Oporto, Portugal. [Lopes, Jose M.] Univ Porto IPATIMUP, Canc Signaling & Metab Grp, Inst Mol Pathol & Immunol, Oporto, Portugal. Univ Porto, Inst Invest & Inovacao Saude I3S, Rua Campo Alegre 823, P-4100 Oporto, Portugal. [Baptista, Manuela] Ctr Hosp Sao Joao, Dept Surg, Oporto, Portugal. [Lopes, Jose M.] Ctr Hosp Sao Joao, Dept Pathol, Oporto, Portugal. [Shannon, Kristen M.] Massachusetts Gen Hosp, Ctr Canc, Ctr Canc Risk Assessment, Boston, MA USA. [Oliva, Esther] Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Oliva, Esther] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Bartosch, C (reprint author), Portuguese Oncol Inst Porto, Dept Pathol, Rua Dr Antonio Bernardino de Almeida, P-4200072 Oporto, Portugal. EM carlabartosch@med.up.pt OI Lopes, Jose Manuel/0000-0001-8597-3474; Bartosch, Carla/0000-0003-0646-7667 NR 81 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 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD SEP PY 2016 VL 40 IS 9 BP 1177 EP 1191 DI 10.1097/PAS.0000000000000684 PG 15 WC Pathology; Surgery SC Pathology; Surgery GA DU6JO UT WOS:000382321100003 PM 27340747 ER PT J AU Bennett, JA Oliva, E Nardi, V Lindeman, N Ferry, JA Louissaint, A AF Bennett, Jennifer A. Oliva, Esther Nardi, Valentina Lindeman, Neal Ferry, Judith A. Louissaint, Abner, Jr. TI Primary Endometrial Marginal Zone Lymphoma (MALT Lymphoma) A Unique Clinicopathologic Entity SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE endometrial lymphoma; MALT lymphoma; endometrial lymphoid aggregates; endometrial lymphoid proliferations ID B-CELL LYMPHOMA; OF-THE-LITERATURE; FEMALE GENITAL-TRACT; UTERUS; CERVIX; CORPUS; VAGINA AB Primary lymphoma of the endometrium is exceptionally rare. Several cases of distinctly nodular lymphoid proliferations confined to the endometrium have previously been described and reported as lymphomas of mucosa-associated lymphoid tissue (MALT). We report the largest series (n=8) of these lymphomas, further defining their morphologic, immunohistochemical, and molecular spectrum. Patients ranged in age from 50 to 87 (median, 62) years. None had a prior history of lymphoma, and lesions were incidental in all but 1 in which a polyp was noted on macroscopic examination. Nodules ranged from small, round, and uniform with minimal architectural effacement to large, expansile, and coalescing with foci of diffuse growth. In the majority, the nodules were confined to the endometrium; however, 2 cases showed myometrial involvement, 1 of which also had extensive extrauterine disease. The nodules comprised monomorphic populations of mature CD20(+) B lymphocytes with pale scant cytoplasm, CD43, BCL2, and IgM coexpression, and absence of CD10, CD23, and IgD expression. The nodules were associated with CD21/CD23(+) follicular dendritic meshworks. Clonality was detected in 6 lesions, in 4 by polymerase chain reaction for clonal IGH rearrangement and in 3 by in situ hybridization for immunoglobulin light chains. All were negative for IGH and MALT1 rearrangements by fluorescence in situ hybridization. None of the patients received additional therapy after resection, and most (7/8) are alive with no evidence of disease at last follow-up (mean 4.2 y), whereas the remaining patient is alive with stable disease. These findings demonstrate the unique clinical and pathologic features that characterize primary MALT lymphoma of the endometrium. C1 [Bennett, Jennifer A.; Oliva, Esther; Nardi, Valentina; Ferry, Judith A.; Louissaint, Abner, Jr.] Harvard Med Sch Boston, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Lindeman, Neal] Harvard Med Sch Boston, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA. RP Louissaint, A (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 2, Boston, MA 02114 USA. EM alouissaint@partners.org FU Harold Amos Medical Faculty Development Program - American Society of Hematology and Robert Wood Johnson Foundation; 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 A.L. received support from Harold Amos Medical Faculty Development Program (sponsored by American Society of Hematology and Robert Wood Johnson Foundation), as well as Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic healthcare centers. 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 healthcare centers, or the National Institutes of Health. NR 20 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 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD SEP PY 2016 VL 40 IS 9 BP 1217 EP 1223 DI 10.1097/PAS.0000000000000683 PG 7 WC Pathology; Surgery SC Pathology; Surgery GA DU6JO UT WOS:000382321100006 PM 27340748 ER PT J AU Rider, D Furusho, H Xu, S Trachtenberg, AJ Kuo, WP Hirai, K Susa, M Bahammam, L Stashenko, P Fujimura, A Sasaki, H AF Rider, Daniel Furusho, Hisako Xu, Shuang Trachtenberg, Alexander J. Kuo, Winston Patrick Hirai, Kimito Susa, Mako Bahammam, Laila Stashenko, Philip Fujimura, Akira Sasaki, Hajime TI Elevated CD14 (Cluster of Differentiation 14) and Toll-Like Receptor (TLR) 4 Signaling Deteriorate Periapical Inflammation in TLR2 Deficient Mice SO ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY LA English DT Article DE apical periodontitis; innate immunity; toll-like receptor (TLR); CD14; inflammation ID RESORPTION IN-VIVO; NF-KAPPA-B; CUTTING EDGE; BONE DESTRUCTION; PORPHYROMONAS-GINGIVALIS; INNATE IMMUNITY; IFN-GAMMA; INFECTION; ACTIVATION; LIPOPOLYSACCHARIDE AB Apical periodontitis (periapical lesions) is an infection-induced chronic inflammation in the jaw, ultimately resulting in the destruction of apical periodontal tissue. Toll-like receptors (TLRs) are prominent in the initial recognition of pathogens. Our previous study showed that TLR4 signaling is proinflammatory in periapical lesions induced by a polymicrobial endodontic infection. In contrast, the functional role of TLR2 in regulation of periapical tissue destruction is still not fully understood. Using TLR2 deficient (KO), TLR2/TLR4 double deficient (dKO), and wild-type (WT) mice, we demonstrate that TLR2 KO mice are highly responsive to polymicrobial infection-induced periapical lesion caused by over activation of TLR4 signal transduction pathway that resulted in elevation of NF-kB (nuclear factor kappa B) and proinflammatory cytokine production. The altered TLR4 signaling is caused by TLR2 deficiency-dependent elevation of CD14 (cluster of differentiation 14), which is a co-receptor of TLR4. Indeed, neutralization of CD14 strikingly suppresses TLR2 deficiency-dependent inflammation and tissue destruction in vitro and in vivo. Our findings suggest that a network of TLR2, TLR4, and CD14 is a key factor in regulation of polymicrobial dentoalveolar infection and subsequent tissue destruction. Anat Rec, 299:1281-1292, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Rider, Daniel; Xu, Shuang; Hirai, Kimito; Stashenko, Philip; Sasaki, Hajime] Forsyth Inst, Dept Immunol & Infect Dis, 245 First St, Cambridge, MA USA. [Furusho, Hisako] Hiroshima Univ, Dept Oral & Maxillofacial Pathobiol, Hiroshima, Japan. [Trachtenberg, Alexander J.; Kuo, Winston Patrick] Harvard Sch Dent Med, Dept Dev Biol, Boston, MA USA. [Susa, Mako] Tohoku Univ, Grad Sch Dent, Dept Periodontol & Endodontol, Sendai, Miyagi, Japan. [Bahammam, Laila] King Abdulaziz Univ, Dept Endodont, Fac Dent, Jeddah, Saudi Arabia. [Stashenko, Philip; Sasaki, Hajime] Harvard Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA USA. [Fujimura, Akira] Iwate Med Univ, Dept Anat, Div Funct Morphol, Morioka, Iwate 0208505, Japan. [Kuo, Winston Patrick] Predicine Inc, Hayward, CA 94545 USA. RP Sasaki, H (reprint author), Forsyth Inst, Dept Immunol & Infect Dis, 245 First St, Cambridge, MA USA. EM hsasaki@forsyth.org FU JSPS [Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation] [RR027553]; NCRR/NIH [R21DE023178]; NIDCR/NIH [R01DE024796] FX Grant sponsors: JSPS [Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation (H.F.)]; Grant number: RR027553 (H.S.); Grant sponsor: NCRR/NIH; Grant number: R21DE023178 (H.S.); Grant sponsor: NIDCR/NIH; Grant number: R01DE024796 (H.S.). NR 38 TC 0 Z9 0 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-8486 EI 1932-8494 J9 ANAT REC JI Anat. Rec. PD SEP PY 2016 VL 299 IS 9 BP 1281 EP 1292 DI 10.1002/ar.23383 PG 12 WC Anatomy & Morphology SC Anatomy & Morphology GA DV1TI UT WOS:000382703600010 PM 27314637 ER PT J AU Matoba, Y Nonaka, N Takagi, Y Imamura, E Narukawa, M Nakamachi, T Shioda, S Banks, WA Nakamura, M AF Matoba, Yuko Nonaka, Naoko Takagi, Yoshitoki Imamura, Eisaku Narukawa, Masayuki Nakamachi, Tomoya Shioda, Seiji Banks, William A. Nakamura, Masanori TI Pituitary adenylate cyclase-activating polypeptide enhances saliva secretion via direct binding to PACAP receptors of major salivary glands in mice SO ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY LA English DT Article DE salivary gland; PACAP; PAC1R; pillar cell ID EPIDERMAL-GROWTH-FACTOR; RAT SUBMANDIBULAR-GLAND; ISCHEMIA-INDUCED DEATH; BLOOD-BRAIN-BARRIER; IMMUNOHISTOCHEMICAL LOCALIZATION; HIPPOCAMPAL-NEURONS; PEPTIDE; CELLS; INTERNALIZATION; HYPOSALIVATION AB Xerostomia, or dry mouth, is a common syndrome that is generally treated with artificial saliva; however, no other effective methods have yet been established. Saliva secretion is mainly under the control of the autonomic nervous system. Pituitary adenylate cyclase-activating polypeptide (PACAP) is recognized as a multifunctional neuropeptide in various organs. In this study, we examined the effect of PACAP on saliva secretion, and detected the distribution of the PACAP type 1 receptor (PAC1R) in major salivary glands, including the parotid, submandibular, and sublingual glands, in 9-week-old male C57BL/6 mice. Intranasal administration of PACAP 38 increased the amount of saliva secreted, which was not inhibited by atropine pretreatment. Immunohistochemical analysis showed that PAC1R was distributed in the three major salivary glands. In the parotid and sublingual glands, PAC1R was detected in striated duct cells, whereas in the submandibular gland, a strong PAC1R immunoreaction was detected in tall columnar epithelial cells in the granular ducts (i.e., pillar cells), as well as in some striated duct cells. PACAP significantly increased the concentration of epidermal growth factor in saliva. These results suggest that PACAP directly regulates saliva secretion by controlling the absorption activity in the ducts, and that pillar cells regulate the function of granular epithelial cells in the granular duct, such as the secretion of growth factors into the saliva. Collectively, these results suggest the possibility of PACAP as a new effective treatment of xerostomia. Anat Rec, 299:1293-1299, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Matoba, Yuko; Nonaka, Naoko; Takagi, Yoshitoki; Imamura, Eisaku; Narukawa, Masayuki; Nakamura, Masanori] Showa Univ, Dept Oral Anat & Dev Biol, Sch Dent, Shinagawa Ku, 1-5-8 Hatanodai, Tokyo 1428555, Japan. [Matoba, Yuko; Imamura, Eisaku] Yokohama Gen Hosp, Div Oral Surg, Aoba Ku, Yokohama, Kanagawa, Japan. [Nonaka, Naoko; Banks, William A.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Nakamachi, Tomoya] Toyama Univ, Lab Regulatory Biol, Grad Sch Sci & Engn, Toyama, Toyama, Japan. [Shioda, Seiji] Hoshi Univ, Global Res Ctr Innovat Life Sci, Shinagawa Ku, Tokyo, Japan. RP Nakamura, M (reprint author), Showa Univ, Dept Oral Anat & Dev Biol, Sch Dent, Shinagawa Ku, 1-5-8 Hatanodai, Tokyo 1428555, Japan. EM masanaka@dent.showa-u.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan [20592148, 21592342, 15K11022] FX Grant sponsor: Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Grant numbers: 20592148, 21592342, and 15K11022. NR 42 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-8486 EI 1932-8494 J9 ANAT REC JI Anat. Rec. PD SEP PY 2016 VL 299 IS 9 BP 1293 EP 1299 DI 10.1002/ar.23388 PG 7 WC Anatomy & Morphology SC Anatomy & Morphology GA DV1TI UT WOS:000382703600011 PM 27339371 ER PT J AU Herndon, DN Voigt, CD Capek, KD Wurzer, P Guillory, A Kline, A Andersen, CR Klein, GL Tompkins, RG Suman, OE Finnerty, CC Meyer, WJ Sousse, LE AF Herndon, David N. Voigt, Charles D. Capek, Karel D. Wurzer, Paul Guillory, Ashley Kline, Andrea Andersen, Clark R. Klein, Gordon L. Tompkins, Ronald G. Suman, Oscar E. Finnerty, Celeste C. Meyer, Walter J. Sousse, Linda E. TI Reversal of Growth Arrest With the Combined Administration of Oxandrolone and Propranolol in Severely Burned Children SO ANNALS OF SURGERY LA English DT Article DE burns; growth arrest; oxandrolone; pediatric; propranolol; rate of stature increase ID PEDIATRIC-PATIENTS; OVARIECTOMIZED MICE; BONE MASS; EYE DROPS; INJURY; MUSCLE; RATS; HYPERMETABOLISM; DEXAMETHASONE; INFLAMMATION AB Background: The hypercatabolic response in severely burned pediatric patients is associated with increased production of catecholamines and corticosteroids, decreased formation of testosterone, and reduced strength alongside growth arrest for up to 2 years after injury. We have previously shown that, in the pediatric burned population, the administration of the testosterone analog oxandrolone improves lean body mass accretion and bone mineral content and that the administration of the beta 1-, beta 2-adrenoceptor antagonist propranolol decreases cardiac work and resting energy expenditure while increasing peripheral lean mass. Here, we determined whether the combined administration of oxandrolone and propranolol has added benefit. Methods: In this prospective, randomized study of 612 burned children [52% +/- 1% of total body surface area burned, ages 0.5-14 years (boys); ages 0.5-12 years (girls)], we compared controls to the individual administration of these drugs, and the combined administration of oxandrolone and propranolol at the same doses, for 1 year after burn. Data were recorded at discharge, 6 months, and 1 and 2 years after injury. Results: Combined use of oxandrolone and propranolol shortened the period of growth arrest by 84 days (P = 0.0125 vs control) and increased growth rate by 1.7 cm/yr (P = 0.0024 vs control). Conclusions: Combined administration of oxandrolone and propranolol attenuates burn-induced growth arrest in pediatric burn patients. The present study is registered at clinicaltrials.gov: NCT00675714 and NCT00239668. C1 [Herndon, David N.; Voigt, Charles D.; Capek, Karel D.; Wurzer, Paul; Guillory, Ashley; Kline, Andrea; Andersen, Clark R.; Klein, Gordon L.; Suman, Oscar E.; Finnerty, Celeste C.; Sousse, Linda E.] Univ Texas Med Branch, Dept Surg, Galveston, TX 77555 USA. [Herndon, David N.; Finnerty, Celeste C.] Univ Texas Med Branch, Inst Translat Sci, Galveston, TX 77555 USA. [Herndon, David N.; Voigt, Charles D.; Capek, Karel D.; Wurzer, Paul; Guillory, Ashley; Kline, Andrea; Andersen, Clark R.; Klein, Gordon L.; Suman, Oscar E.; Finnerty, Celeste C.; Meyer, Walter J.; Sousse, Linda E.] Shriners Hosp Children, 815 Market St, Galveston, TX 77550 USA. [Wurzer, Paul] Med Univ Graz, Dept Surg, Div Plast Aesthet & Reconstruct Surg, Graz, Austria. [Klein, Gordon L.] Univ Texas Med Branch, Dept Orthoped Surg & Rehabil, Galveston, TX 77555 USA. [Tompkins, Ronald G.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Finnerty, Celeste C.] Univ Texas Med Branch, Sealy Ctr Mol Med, Galveston, TX 77555 USA. [Meyer, Walter J.] Univ Texas Med Branch, Dept Psychiat & Behav Sci, Galveston, TX 77555 USA. RP Herndon, DN (reprint author), Shriners Hosp Children, 815 Market St, Galveston, TX 77550 USA. EM dherndon@utmb.edu FU NIDILRR [90DP0043-02-01]; National Institutes of Health [P50GM060338, R01GM056687, T32GM008256, R01HD049471, R01GM112936]; Shriners Hospitals for Children [84080, 79135, 80100, 71008, 71009, 84291, 79141]; Department of Surgery at UTMB [2014-667]; 15 Research Education Endowment Fund; UTMB's Institute for Translational Sciences; National Center for Advancing Translational Sciences (NIH) [UL1TR001439] FX This work was supported by NIDILRR [90DP0043-02-01 (D.N.H.)], National Institutes of Health [P50GM060338, R01GM056687, and T32GM008256 (D.N.H.); R01HD049471 (O.E.S.); and R01GM112936 (C.C.F.)], Shriners Hospitals for Children [84080, 79135, 80100, and 71008 (D.N.H.); 71009 (O.E.S.); and 84291 and 79141 (C.C.F.)], the Department of Surgery at UTMB [2014-667 (L.E.S.)], and the Remembering the 15 Research Education Endowment Fund. This study was also conducted with the support of UTMB's Institute for Translational Sciences, supported in part by a Clinical and Translational Science Award (UL1TR001439) from the National Center for Advancing Translational Sciences (NIH). The other authors have no conflict of interest to declare. NR 47 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 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD SEP PY 2016 VL 264 IS 3 BP 421 EP 428 DI 10.1097/SLA.0000000000001844 PG 8 WC Surgery SC Surgery GA DU5LP UT WOS:000382253500003 PM 27433905 ER PT J AU Berger, ER Clements, RH Morton, JM Huffman, KM Wolfe, BM Nguyen, NT Ko, CY Hutter, MM AF Berger, Elizabeth R. Clements, Ronald H. Morton, John M. Huffman, Kristopher M. Wolfe, Bruce M. Nguyen, Ninh T. Ko, Clifford Y. Hutter, Matthew M. TI The Impact of Different Surgical Techniques on Outcomes in Laparoscopic Sleeve Gastrectomies The First Report from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) SO ANNALS OF SURGERY LA English DT Article DE bariatric surgery; laparoscopic sleeve gastrectomy; metabolic and bariatric surgery accreditation and quality improvement program (MBSAQIP); process measures ID STAPLE-LINE REINFORCEMENT; BARIATRIC SURGERY; GASTRIC BYPASS; MORBID-OBESITY; PATIENT SAFETY; LEAK; RISK; METAANALYSIS; QUALITY; COMPLICATIONS AB Objective: Questions remain regarding best surgical techniques to use for a laparoscopic sleeve gastrectomy (LSG) including the use of staple line reinforcement (SLR), bougie size (BS), and distance from the pylorus (DP) where the staple line is initiated. Our objectives were to assess the impact of these techniques on 30-day outcomes and to evaluate the impact of these techniques on weight loss and comorbidities at 1 year. Methods: Using the MBSAQIP data registry, univariate analyses and hierarchical logistical regression models were developed to analyze outcomes for techniques of LSG at patient and surgeon-level. Results: A total of 189,477 LSG operations were performed by 1634 surgeons at 720 centers from 2012 to 2014. Eighty percent of surgeons used SLR, 20% did not. SLR cases were associated with higher leak rates (0.96% vs 0.65%, odds ratio [OR] 1.20 95% confidence interval [CI] 1.00-1.43) and lower bleed rates (0.75% vs 1.00%, OR 0.74 95% CI 0.63-0.86) compared to no SLR at patient level. At the surgeon level, leak rates remained significant, but bleeding events became nonsignificant. BS >= 38 was associated with significantly lower leak rates compared to BS <38 at patient and surgeon level (patient level: 0.80% vs 0.96%, OR 0.72, 95% CI 0.62-0.94; surgeon level: 0.84% vs 0.95%, OR 0.90, 95% CI 0.80-0.99). BS >= 40 was associated with increased weight loss. DP had no impact on leaks or bleeds but showed an increase in weight loss with increasing DP. Conclusion: LSG is a safe procedure with a low morbidity rate. SLR is associated with increased leak rates. A surgeon should consider risks, benefits, and costs of these surgical techniques when performing a LSG and selectively utilize those that, in their hands, minimize morbidity while maximizing clinical effectiveness. C1 [Berger, Elizabeth R.] Loyola Univ, Stritch Sch Med, Chicago, IL 60611 USA. [Clements, Ronald H.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Morton, John M.] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Berger, Elizabeth R.; Huffman, Kristopher M.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL USA. [Wolfe, Bruce M.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Nguyen, Ninh T.] Univ Calif Irvine, Sch Med, Irvine, CA 92717 USA. [Ko, Clifford Y.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Hutter, Matthew M.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Hutter, MM (reprint author), Harvard Med Sch, Surg, 15 Parkman St Wang 460, Boston, MA 02114 USA.; Hutter, MM (reprint author), Massachusetts Gen Hosp, Codman Ctr Clin Effectiveness Surg, 15 Parkman St Wang 460, Boston, MA 02114 USA.; Hutter, MM (reprint author), Massachusetts Gen Hosp, MGH Weight Ctr, 15 Parkman St Wang 460, Boston, MA 02114 USA. EM MHutter@mgh.har-vard.edu NR 51 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD SEP PY 2016 VL 264 IS 3 BP 464 EP 473 DI 10.1097/SLA.0000000000001851 PG 10 WC Surgery SC Surgery GA DU5LP UT WOS:000382253500008 PM 27433904 ER PT J AU Balch, CM Klimberg, VS McMasters, KM Pawlik, TM Tanabe, KK Posner, MC Whippen, D Roh, MS AF Balch, Charles M. Klimberg, V. Suzanne McMasters, Kelly M. Pawlik, Timothy M. Tanabe, Kenneth K. Posner, Mitchell C. Whippen, Deborah Roh, Mark S. TI Benchmarking the Scientific and Educational Impact of the Annals of Surgical Oncology SO ANNALS OF SURGICAL ONCOLOGY LA English DT Editorial Material ID JOURNAL RANK INDICATOR C1 [Balch, Charles M.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Balch, Charles M.] Univ Texas Southwestern Med Ctr, Div Surg Oncol, Dept Surg, Dallas, TX 75235 USA. [Klimberg, V. Suzanne] Univ Arkansas Med Sci, Div Breast Surg Oncol, Dept Surg & Pathol, Little Rock, AR 72205 USA. [McMasters, Kelly M.] Univ Louisville, Dept Surg, Louisville, KY 40292 USA. [Pawlik, Timothy M.] Johns Hopkins Univ Hosp, Dept Surg, Div Surg Oncol, Baltimore, MD 21287 USA. [Tanabe, Kenneth K.] Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, Boston, MA USA. [Tanabe, Kenneth K.] Harvard Med Sch, Boston, MA USA. [Posner, Mitchell C.] Univ Chicago, Dept Surg, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Whippen, Deborah] Annals Surg Oncol, Editorial Off, North Ft Myers, FL USA. [Roh, Mark S.] Orlando Hlth, UF Hlth Canc Ctr, Orlando, FL USA. RP Balch, CM (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA.; Balch, CM (reprint author), Univ Texas Southwestern Med Ctr, Div Surg Oncol, Dept Surg, Dallas, TX 75235 USA. EM editor@asoeditorial.org NR 13 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD SEP PY 2016 VL 23 IS 9 BP 2723 EP 2729 DI 10.1245/s10434-016-5270-8 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA DS9ZB UT WOS:000381141000001 PM 27334224 ER PT J AU Bellavance, E Peppercorn, J Kronsberg, S Greenup, R Keune, J Lynch, J Collyar, D Magder, L Tilburt, J Hlubocky, F Yao, K AF Bellavance, Emily Peppercorn, Jeffrey Kronsberg, Shari Greenup, Rachel Keune, Jason Lynch, Julie Collyar, Deborah Magder, Laurence Tilburt, Jon Hlubocky, Fay Yao, Katharine TI Surgeons' Perspectives of Contralateral Prophylactic Mastectomy SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID BREAST-CANCER PATIENTS; BRCA2 MUTATION CARRIERS; BILATERAL MASTECTOMY; DECISION-MAKING; DATA-BASE; UNILATERAL MASTECTOMY; CONSERVING THERAPY; PRACTICE PATTERNS; SELECTION BIAS; WOMEN AB Contralateral prophylactic mastectomy (CPM) is commonly performed for the treatment of breast cancer, despite its limited oncologic benefit. Little is known about surgeons' perceptions of performing CPM. We hypothesized that a proportion of surgeons would report discomfort with performing CPM, particularly when there is discordance between patients' perceived benefit from CPM and the expected oncologic benefit. A survey was sent to members of the American Society of Breast Surgeons seeking self-reports of surgeons' practice patterns, perceptions, and comfort levels with CPM. Of the 2436 members surveyed, 601 responded (response rate = 24.7 %). The median age of respondents was 52 years, and 59 % of responders were women. The majority (58 %) reported that 80 % of their practice was devoted to the treatment of breast disease. Fifty-seven percent (n = 326) of respondents reported discomfort with performing CPM at some point in their practice. While most surgeons (95 %) were comfortable with CPM on a patient with a deleterious BRCA mutation, only 34 % were comfortable performing CPM on an average-risk patient. The most common reasons reported for surgeon discomfort with CPM were a concern for overtreatment, an unfavorable risk/benefit ratio, and inadequate patient understanding of the anticipated risks and benefits of CPM. Despite the increasing use of CPM for the treatment of breast cancer, many surgeons report discomfort with CPM. Concerns with performing CPM predominantly focus on ambiguities surrounding the oncologic benefit and relative risk of this procedure. Further research is needed to define optimal shared decision-making practices in this area. C1 [Bellavance, Emily] Univ Maryland, Dept Surg, Baltimore, MD 21201 USA. [Peppercorn, Jeffrey] Massachusetts Gen Hosp, Dept Med, Ctr Canc, Boston, MA 02114 USA. [Kronsberg, Shari; Magder, Laurence] Univ Maryland, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Greenup, Rachel] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Keune, Jason] St Louis Univ, Sch Med, Dept Surg, St Louis, MO USA. [Lynch, Julie] Vet Hlth Adm, Bedford, MA USA. [Lynch, Julie] RTI Int, Res Triangle Pk, NC USA. [Collyar, Deborah] Patient Advocates Res, Danville, CA USA. [Tilburt, Jon] Mayo Clin, Div Gen Internal Med, Rochester, MN USA. [Tilburt, Jon] Mayo Clin, Biomed Eth Res Unit, Rochester, MN USA. [Tilburt, Jon] Mayo Clin, Knowledge & Evaluat Res Unit, Rochester, MN USA. [Hlubocky, Fay] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Yao, Katharine] NorthShore Univ HealthSyst, Dept Surg, Evanston, IL USA. RP Bellavance, E (reprint author), Univ Maryland, Dept Surg, Baltimore, MD 21201 USA. EM ebellavance@smail.umaryland.edu NR 47 TC 1 Z9 1 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD SEP PY 2016 VL 23 IS 9 BP 2779 EP 2787 DI 10.1245/s10434-016-5253-9 PG 9 WC Oncology; Surgery SC Oncology; Surgery GA DS9ZB UT WOS:000381141000009 PM 27169770 ER PT J AU Decker, MR Trentham-Dietz, A Loconte, NK Neuman, HB Smith, MA Punglia, RS Greenberg, CC Wilke, LG AF Decker, Marquita R. Trentham-Dietz, Amy Loconte, Noelle K. Neuman, Heather B. Smith, Maureen A. Punglia, Rinaa S. Greenberg, Caprice C. Wilke, Lee G. TI The Role of Intraoperative Pathologic Assessment in the Surgical Management of Ductal Carcinoma In Situ SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID BREAST-CONSERVING SURGERY; FROZEN-SECTION ANALYSIS; MARGIN ASSESSMENT; SCREENING MAMMOGRAPHY; CONSERVATION SURGERY; LUMPECTOMY; RATES; IMPACT AB Re-excision surgeries for the treatment of ductal carcinoma in situ (DCIS) put a strain on patients and healthcare resources; however, intraoperative pathologic assessment of DCIS may lead to a reduction in these additional surgeries. This study examined the relationship between intraoperative pathologic assessment and subsequent operations in patients with a diagnosis of DCIS. Surveillance, Epidemiology, and End Results-Medicare patients diagnosed with DCIS from 1999 to 2007 who initially underwent partial mastectomy, without axillary surgery, were included in this study. Use of intraoperative frozen section or touch preparation during the initial surgery was assessed. Multivariable logistic regression was used to describe the relationship between the use of intraoperative pathologic assessment and any subsequent mastectomy or partial mastectomy within 90 days of the initial partial mastectomy. Of 8259 DCIS patients, 3509 (43 %) required a second surgery, and intraoperative pathologic assessment was performed for 2186 (26 %). Intraoperative pathologic assessment had no statistically significant effect on whether or not a subsequent breast surgery occurred (adjusted odds ratio 1.07, 95 % confidence interval 0.95-1.21; p = 0.293). Patient residence in a rural area, tumor size aeyen2 cm, and poorly differentiated tumor grade were associated with a greater likelihood of subsequent surgery, while age 80 years and older was associated with a lower likelihood of subsequent surgery. The use of intraoperative frozen section or touch preparation during partial mastectomy from 1999 to 2007 was not associated with a reduction in subsequent breast operations in women with DCIS. These results highlight the need to identify cost-effective tools and strategies to reduce the need for additional surgery in patients with DCIS. C1 [Decker, Marquita R.; Trentham-Dietz, Amy; Smith, Maureen A.] Univ Wisconsin, Dept Populat Hlth Sci, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Trentham-Dietz, Amy; Loconte, Noelle K.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Neuman, Heather B.; Greenberg, Caprice C.; Wilke, Lee G.] Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, Madison, WI USA. [Punglia, Rinaa S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Decker, MR (reprint author), Univ Wisconsin, Dept Populat Hlth Sci, Sch Med & Publ Hlth, Madison, WI 53706 USA. EM mrdecker@wisc.edu FU University of Wisconsin Carbone Cancer Center (UWCCC) from the National Cancer Institute-National Institutes of Health (NCI-NIH) [P30 CA014520-34]; Health Innovation Program, the University of Wisconsin School of Medicine and Public Health from The Wisconsin Partnership Program; Community-Academic Partnerships core of the University of Wisconsin Institute for Clinical and Translational Research (UW ICTR) through the National Center for Advancing Translational Sciences (NCATS) [UL1TR000427]; California Department of Public Health [103885]; NCI's SEER Program [N01-PC-35136, N01-PC-35139, N02-PC-15105]; Centers for Disease Control and Prevention's National Program of Cancer Registries [U55/CCR921930-02]; NIH Surgical Oncology Training Grant [T32 CA090217] FX This project was supported by the University of Wisconsin Carbone Cancer Center (UWCCC) support grant from the National Cancer Institute-National Institutes of Health (NCI-NIH) [Grant Number P30 CA014520-34]. Additional support was provided by the Health Innovation Program, the University of Wisconsin School of Medicine and Public Health from The Wisconsin Partnership Program, and the Community-Academic Partnerships core of the University of Wisconsin Institute for Clinical and Translational Research (UW ICTR) through the National Center for Advancing Translational Sciences (NCATS) [Grant UL1TR000427]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the Applied Research Program, NCI; the Office of Research, Development and Information, CMS; Information Management Services, Inc. (IMS); and the SEER Program tumor registries in the creation of the SEER-Medicare database. The collection of the California cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Sect. 103885; the NCI's SEER Program under contract N01-PC-35136 awarded to the Northern California Cancer Center, contract N01-PC-35139 awarded to the University of Southern California, and contract N02-PC-15105 awarded to the Public Health Institute; and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement #U55/CCR921930-02 awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the author(s), and endorsement by the State of California, Department of Public Health, the NCI, and the Centers for Disease Control and Prevention or their contractors and subcontractors is not intended nor should be inferred. The work of Marquita R. Decker was supported by the NIH Surgical Oncology Training Grant (T32 CA090217). NR 22 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD SEP PY 2016 VL 23 IS 9 BP 2788 EP 2794 DI 10.1245/s10434-016-5192-5 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA DS9ZB UT WOS:000381141000010 PM 27026436 ER PT J AU Colombo, NH Ribas, LFF Pereira, JA Kreling, PF Kressirer, CA Tanner, ACR Duque, C AF Colombo, Natalia H. Ribas, Lais F. F. Pereira, Jesse A. Kreling, Paula F. Kressirer, Christine A. Tanner, Anne C. R. Duque, Cristiane TI Antimicrobial peptides in saliva of children with severe early childhood caries SO ARCHIVES OF ORAL BIOLOGY LA English DT Article DE Human cathelicidin LL-37; Defensins; Histatin-5; Children; Innate immunity; Dental caries ID DENTAL-CARIES; STREPTOCOCCUS-MUTANS; CANDIDA-ALBICANS; PRESCHOOL-CHILDREN; INNATE IMMUNITY; SOCIAL-FACTORS; ORAL-CAVITY; EXPERIENCE; COLONIZATION; INDIVIDUALS AB Objective: Controversies exist regarding the relationship between the concentrations of antimicrobial peptides (AMPs) and presence of dental caries in children. Thus, the aim of this study was to examine levels of AMPs in saliva of caries-free (CF), early childhood caries (ECC) and severe early childhood caries (S-ECC) children to determine if the levels of these salivary peptides individually or in combinations were related to caries severity and mutans streptococci levels. Design: 36 to 60 month-old children were selected to participate in this study. Children were grouped into CF group (n = 29), ECC group (n = 25) and S-ECC group (n = 29). Saliva was collected from children for microbiological analysis by culture. Salivary concentrations of cathelicidin LL-37, human beta-defensin 2 (hBD-2), human beta-defensin 3 (hBD-3) and histatin-5 (HTN-5) were determined by ELISA. Results: Salivary concentrations of AMPs did not differ among CF, ECC and S-ECC groups. Data showed positive correlations between mutans streptococci levels and salivary hBD-2 or HTN-5. Positive correlations were found between hBD-2, hBD-3, LL-37 and HTN-5. Combinations among AMPs, mainly LL-37, were positively associated with caries levels. Conclusions: Salivary concentrations of AMPs individually were not associated with the severity of early childhood caries. The stimulus of caries appears to trigger a biological response, however, with a combination of these peptides. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Colombo, Natalia H.; Ribas, Lais F. F.; Pereira, Jesse A.; Kreling, Paula F.; Duque, Cristiane] UNESP Univ Estadual Paulista, Dept Pediat Dent & Publ Hlth, Aracatuba Dent Sch, Rua Jose Bonifacio 1193, BR-16015050 Aracatuba, SP, Brazil. [Kressirer, Christine A.; Tanner, Anne C. R.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Tanner, Anne C. R.] Harvard Univ, Harvard Sch Dent Med, Boston, MA 02115 USA. RP Duque, C (reprint author), UNESP Univ Estadual Paulista, Dept Pediat Dent & Publ Hlth, Aracatuba Dent Sch, Rua Jose Bonifacio 1193, BR-16015050 Aracatuba, SP, Brazil. EM cristianeduque@yahoo.com.br FU Sao Paulo Research Foundation (FAPESP), Sao Paulo, SP, Brazil [2012/19235-5, 2013/12167-7]; Coordination for the Improvement of Higher Education Personnel (CAPES) FX This study was supported by grants (2012/19235-5; 2013/12167-7) from Sao Paulo Research Foundation (FAPESP), Sao Paulo, SP, Brazil and Coordination for the Improvement of Higher Education Personnel (CAPES). NR 35 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 0003-9969 EI 1879-1506 J9 ARCH ORAL BIOL JI Arch. Oral Biol. PD SEP PY 2016 VL 69 BP 40 EP 46 DI 10.1016/j.archoralbio.2016.05.009 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DT6KF UT WOS:000381592400007 PM 27232359 ER PT J AU Wen, HM Alshikho, MJ Wang, Y Luo, X Zafonte, R Herbert, MR Wang, QM AF Wen, Hongmei Alshikho, Mohamad J. Wang, Yao Luo, Xun Zafonte, Ross Herbert, Martha R. Wang, Qing Mei TI Correlation of Fractional Anisotropy With Motor Recovery in Patients With Stroke After Postacute Rehabilitation SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article; Proceedings Paper CT Meeting of the American-Academy-of-Physical-Medicine-and-Rehabilitation CY OCT 01-04, 2015 CL Boston, MA SP Amer Acad Phys Med & Rehabil DE Diffusion tensor imaging; Rehabilitation; Stroke ID WATER DIFFUSION; FUNCTIONAL RECOVERY; PYRAMIDAL TRACT; NERVOUS-SYSTEM; TENSOR; BRAIN; MRI; DEGENERATION; DYSMYELINATION; PROFILES AB Objective: To investigate the relation between fractional anisotropy (FA), a suggested biomarker for tissue integrity, and motor recovery in patients with stroke after postacute rehabilitation. Design: Retrospective study. Setting: Acute rehabilitation hospital. Participants: Subjects (N=43) diagnosed with ischemic stroke (n=28) and hemorrhagic stroke (n=15). The average age for subjects was 68 +/- 14 years. Interventions: Magnetic resonance imaging and diffusion tensor imaging were conducted on all patients. Main Outcome Measures: The admission and discharge motor subscores of the FIM were obtained from medical records, and relative gain was calculated using the Montebello Rehabilitation Factor Score (MRFS). K-means cluster analysis (K=3) using both the MRFS and the gain of the FIM motor subscore (Delta FIM) was performed. Analysis of variance was used to determine the difference in FA among the clusters. Spearman analysis was conducted to examine the relation between FA, Delta FIM, and MRFS in each cluster. Results: FA was significantly higher in the clusters of good and moderate recovery in the corticospinal tract (CST), peduncle, and posterior limb of the internal capsule bilaterally (all P<.05) compared with the poor recovery group. Significant positive correlations were observed in multiple regions along the CST between FA, Delta FIM, and MRFS in the clusters of good and moderate recovery, but not in the poor recovery group. Conclusions: Our results showed an association between FA values within the corticospinal tract and motor recovery in patients with stroke undergoing postacute rehabilitation. This finding may help to identify novel targets for new interventions to promote stroke recovery. (C) 2016 by the American Congress of Rehabilitation Medicine C1 [Wen, Hongmei; Wang, Yao; Wang, Qing Mei] Harvard Med Sch, Spaulding Rehabil Hosp, Stroke Biol Recovery Lab, 96 13th St, Charlestown, MA 02129 USA. [Wen, Hongmei] Sun Yat Sen Univ, Affiliated Hosp 3, Dept Rehabil Med, Guangzhou, Guangdong, Peoples R China. [Alshikho, Mohamad J.; Herbert, Martha R.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Transcend Res Lab, Charlestown, MA USA. [Wang, Yao; Luo, Xun] Shenzhen Univ, Nanao Peoples Hosp Shenzhen, Affiliated Hosp 1, Dept Rehabil Med, Shenzhen, Peoples R China. [Luo, Xun] Kerry Rehabil Med Res Inst, Shenzhen, Peoples R China. [Zafonte, Ross] Harvard Med Sch, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Charlestown, MA USA. RP Wang, QM (reprint author), Harvard Med Sch, Spaulding Rehabil Hosp, Stroke Biol Recovery Lab, 96 13th St, Charlestown, MA 02129 USA. EM wang.qingmei@mgh.harvard.edu 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 0003-9993 EI 1532-821X J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD SEP PY 2016 VL 97 IS 9 BP 1487 EP 1495 DI 10.1016/j.apmr.2016.04.010 PG 9 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA DV1VP UT WOS:000382710500012 PM 27178097 ER PT J AU Burgener, SS Baumann, M Basilico, P Remold-O'Donnell, E Touw, IP Benarafa, C AF Burgener, Sabrina S. Baumann, Mathias Basilico, Paola Remold-O'Donnell, Eileen Touw, Ivo P. Benarafa, Charaf TI Myeloid conditional deletion and transgenic models reveal a threshold for the neutrophil survival factor Serpinb1 SO BIOLOGICAL CHEMISTRY LA English DT Article; Proceedings Paper CT 9th General Meeting of the International-Proteolysis-Society (IPS) CY OCT 03-08, 2015 CL Penang, MALAYSIA SP Int Proteolysis Soc DE cell death; cre; serine protease; serpin ID CATHEPSIN-G; ELASTASE; CELLS; INFLAMMATION; INJURY; MOUSE; GRANULOCYTES; INHIBITION; EXPRESSION; ABSENCE AB Serpinb1 is an inhibitor of neutrophil granule serine proteases cathepsin G, proteinase-3 and elastase. One of its core physiological functions is to protect neutrophils from granule protease-mediated cell death. Mice lacking Serpinb1a (Sb1a(-/-)), its mouse ortholog, have reduced bone marrow neutrophil numbers due to cell death mediated by cathepsin G and the mice show increased susceptibility to lung infections. Here, we show that conditional-deletion of Serpinb1a using the Lyz2-cre and Cebpa-cre knock-in mice effectively leads to recombination-mediated deletion in neutrophils but protein-null neutrophils were only obtained using the latter recombinase-expressing strain. Absence of Serpinb1a protein in neutrophils caused neutropenia and increased granule permeabilization-induced cell death. We then generated transgenic mice expressing human Serpinb1 in neutrophils under the human MRP8 (S100A8) promoter. Serpinb1a expression levels in founder lines correlated positively with increased neutrophil survival when crossed with Sb1a(-/-) mice, which had their defective neutrophil phenotype rescued in the higher expressing transgenic line. Using new conditional and transgenic mouse models, our study demonstrates the presence of a relatively low Serpinb1a protein threshold in neutrophils that is required for sustained survival. These models will also be helpful in delineating recently described functions of Serpinb1 in metabolism and cancer. C1 [Burgener, Sabrina S.; Baumann, Mathias; Basilico, Paola; Benarafa, Charaf] Univ Bern, Theodor Kocher Inst, Freiestr 1, CH-3012 Bern, Switzerland. [Burgener, Sabrina S.; Baumann, Mathias; Basilico, Paola] Univ Bern, Grad Sch Cellular & Biomed Sci, CH-3012 Bern, Switzerland. [Remold-O'Donnell, Eileen] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Remold-O'Donnell, Eileen] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Remold-O'Donnell, Eileen] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Touw, Ivo P.] Erasmus MC Canc Inst, Dept Hematol, NL-3015 GE Rotterdam, Netherlands. RP Benarafa, C (reprint author), Univ Bern, Theodor Kocher Inst, Freiestr 1, CH-3012 Bern, Switzerland. EM charaf.benarafa@tki.unibe.ch OI Benarafa, Charaf/0000-0002-2049-7769 FU NHLBI NIH HHS [R01 HL066548] NR 32 TC 1 Z9 1 U1 0 U2 0 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 1431-6730 EI 1437-4315 J9 BIOL CHEM JI Biol. Chem. PD SEP PY 2016 VL 397 IS 9 BP 897 EP 905 DI 10.1515/hsz-2016-0132 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DT3UD UT WOS:000381405700009 PM 27107834 ER PT J AU Offermann, FJ Eagan, A Offermann, AC Subhash, SS Miller, SL Radonovich, LJ AF Offermann, Francis J. Eagan, Aaron Offermann, Aidan C. Subhash, Shobha S. Miller, Shelly L. Radonovich, Lewis J. TI Potential airborne pathogen transmission in a hospital with and without surge control ventilation system modifications SO BUILDING AND ENVIRONMENT LA English DT Article DE Aerosol; Infectious disease; Negative pressure AB To better understand the transport of airborne particulate matter (PM) in hospital environments when surge control strategies are implemented, tests were conducted in a recently decommissioned hospital during a one-week period. An aerosol was released within a patient room and concentrations measured in the room and hallway with and without surge control ventilation system modifications. The average hallway protection efficiencies were high (>98%) both for the baseline ventilation configuration and when the ventilation system was modified for whole floor negative pressure, indicating very little PM reached the hallway. During entry/exit events through the patient room door into the hallway, the average minimum hallway protection efficiencies were lower during the modified ventilation operation (93-94%) than for the baseline operation (98-99%). These lower hallway protection efficiencies may be explained by the 52% reduction in the outdoor air ventilation being supplied to the hallway during the modified operation mode. This suggests that patient room doors should remain closed to control PM movement into the hallway. In addition, if there is concern about airborne infection transmission, an anteroom may be used to further reduce the transport of particles from the patient rooms to the hallways of the ward. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Offermann, Francis J.; Offermann, Aidan C.] Indoor Environm Engn, San Francisco, CA USA. [Miller, Shelly L.] Univ Colorado, Mech Engn, Boulder, CO 80309 USA. [Eagan, Aaron; Subhash, Shobha S.; Radonovich, Lewis J.] US Dept Vet Affairs, Natl Ctr Occupat Hlth & Infect Control, Washington, DC USA. RP Miller, SL (reprint author), Univ Colorado, Mech Engn, Boulder, CO 80309 USA. EM offermann@iee-sf.com; shelly.miller@colorado.edu OI MILLER, SHELLY/0000-0002-1967-7551 FU U.S. Department of Veterans Affairs FX We would like to acknowledge the cooperation of the University of Florida Health for providing the opportunity for this testing in the building before it was torn down. Support for this project was provided by the U.S. Department of Veterans Affairs. NR 14 TC 0 Z9 0 U1 7 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0360-1323 EI 1873-684X J9 BUILD ENVIRON JI Build. Environ. PD SEP PY 2016 VL 106 BP 175 EP 180 DI 10.1016/j.buildenv.2016.06.029 PG 6 WC Construction & Building Technology; Engineering, Environmental; Engineering, Civil SC Construction & Building Technology; Engineering GA DV0IB UT WOS:000382600100015 ER PT J AU Loda, M AF Loda, Massimo TI Challenging Roadblocks to Cancer Cure SO CANCER RESEARCH LA English DT Article ID CELL LUNG-CARCINOMA; PROSTATE-CANCER; MUTANT; RESISTANCE; ANEUPLOIDY; MUTATIONS; THERAPY; (R)-2-HYDROXYGLUTARATE; DIFFERENTIATION; IMMUNOTHERAPY AB The Pezcoller Symposium in Trento, Italy, June 2015, focused entirely on the question of why advanced cancer cure is so uncommon despite the extraordinarily rapid growth of invaluable therapeutic information. Participants were asked to define and to critically evaluate real and potential obstacles to permanent disease eradication. High-level concepts on potential road blocks to cures as well as opportunities for intervention in diverse areas of investigation ranging from genomic alterations to metabolism, microenvironment, immunity, and mechanotransduction were discussed. Provocative concepts and novel therapeutic avenues were proposed. What follows is a critical analysis of the highlights of this meeting. (C) 2016 AACR. C1 [Loda, Massimo] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Oncol Pathol, Boston, MA USA. [Loda, Massimo] Broad Inst, Cambridge, MA USA. [Loda, Massimo] Kings Coll London, Div Canc Studies, London, England. RP Loda, M (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM massimo_loda@dfci.harvard.edu NR 59 TC 0 Z9 0 U1 4 U2 4 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 SEP 1 PY 2016 VL 76 IS 17 BP 4924 EP 4930 DI 10.1158/0008-5472.CAN-16-1443 PG 7 WC Oncology SC Oncology GA DU6BU UT WOS:000382298900004 PM 27520451 ER PT J AU Fehringer, G Kraft, P Pharoah, PD Eeles, RA Chatterjee, N Schumacher, FR Schildkraut, JM Lindstrom, S Brennan, P Bickeboller, H Houlston, RS Landi, MT Caporaso, N Risch, A Al Olama, AA Berndt, SI Giovannucci, EL Gronberg, H Kote-Jarai, Z Ma, J Muir, K Stampfer, MJ Stevens, VL Wiklund, F Willett, WC Goode, EL Permuth, JB Risch, HA Reid, BM Bezieau, S Brenner, H Chan, AT Chang-Claude, J Hudson, TJ Kocarnik, JK Newcomb, PA Schoen, RE Slattery, ML White, E Adank, MA Ahsan, H Aittomaki, K Baglietto, L Blomquist, C Canzian, F Czene, K dos-Santos-Silva, I Eliassen, AH Figueroa, JD Flesch-Janys, D Fletcher, O Garcia-Closas, M Gaudet, MM Johnson, N Hall, P Hazra, A Hein, R Hofman, A Hopper, JL Irwanto, A Johansson, M Kaaks, R Kibriya, MG Lichtner, P Liu, JJ Lund, E Makalic, E Meindl, A Muller-Myhsok, B Muranen, TA Nevanlinna, H Peeters, PH Peto, J Prentice, RL Rahman, N Sanchez, MJ Schmidt, DF Schmutzler, RK Southey, MC Tamimi, R Travis, RC Turnbull, C Uitterlinden, AG Wang, ZM Whittemore, AS Yang, XHR Zheng, W Buchanan, DD Casey, G Conti, DV Edlund, CK Gallinger, S Haile, RW Jenkins, M Le Marchand, L Li, L Lindor, NM Schmit, SL Thibodeau, SN Woods, MO Rafnar, T Gudmundsson, J Stacey, SN Stefansson, K Sulem, P Chen, YA Tyrer, JP Christiani, DC Wei, YY Shen, HB Hu, ZB Shu, XO Shiraishi, K Takahashi, A Bosse, Y Obeidat, M Nickle, D Timens, W Freedman, ML Li, QY Seminara, D Chanock, SJ Gong, J Peters, U Gruber, SB Amos, CI Sellers, TA Easton, DF Hunter, DJ Haiman, CA Henderson, BE Hung, RJ AF Fehringer, Gordon Kraft, Peter Pharoah, Paul D. Eeles, Rosalind A. Chatterjee, Nilanjan Schumacher, Fredrick R. Schildkraut, Joellen M. Lindstrom, Sara Brennan, Paul Bickeboller, Heike Houlston, Richard S. Landi, Maria Teresa Caporaso, Neil Risch, Angela Al Olama, Ali Amin Berndt, Sonja I. Giovannucci, Edward L. Gronberg, Henrik Kote-Jarai, Zsofia Ma, Jing Muir, Kenneth Stampfer, Meir J. Stevens, Victoria L. Wiklund, Fredrik Willett, Walter C. Goode, Ellen L. Permuth, Jennifer B. Risch, Harvey A. Reid, Brett M. Bezieau, Stephane Brenner, Hermann Chan, Andrew T. Chang-Claude, Jenny Hudson, Thomas J. Kocarnik, Jonathan K. Newcomb, Polly A. Schoen, Robert E. Slattery, Martha L. White, Emily Adank, Muriel A. Ahsan, Habibul Aittomaki, Kristiina Baglietto, Laura Blomquist, Carl Canzian, Federico Czene, Kamila dos-Santos-Silva, Isabel Eliassen, A. Heather Figueroa, Jonine D. Flesch-Janys, Dieter Fletcher, Olivia Garcia-Closas, Montserrat Gaudet, Mia M. Johnson, Nichola Hall, Per Hazra, Aditi Hein, Rebecca Hofman, Albert Hopper, John L. Irwanto, Astrid Johansson, Mattias Kaaks, Rudolf Kibriya, Muhammad G. Lichtner, Peter Liu, Jianjun Lund, Eiliv Makalic, Enes Meindl, Alfons Muller-Myhsok, Bertram Muranen, Taru A. Nevanlinna, Heli Peeters, Petra H. Peto, Julian Prentice, Ross L. Rahman, Nazneen Sanchez, Maria Jose Schmidt, Daniel F. Schmutzler, Rita K. Southey, Melissa C. Tamimi, Rulla Travis, Ruth C. Turnbull, Clare Uitterlinden, Andre G. Wang, Zhaoming Whittemore, Alice S. Yang, Xiaohong R. Zheng, Wei Buchanan, Daniel D. Casey, Graham Conti, David V. Edlund, Christopher K. Gallinger, Steven Haile, Robert W. Jenkins, Mark Le Marchand, Loic Li, Li Lindor, Noralene M. Schmit, Stephanie L. Thibodeau, Stephen N. Woods, Michael O. Rafnar, Thorunn Gudmundsson, Julius Stacey, Simon N. Stefansson, Kari Sulem, Patrick Chen, Y. Ann Tyrer, Jonathan P. Christiani, David C. Wei, Yongyue Shen, Hongbing Hu, Zhibin Shu, Xiao-Ou Shiraishi, Kouya Takahashi, Atsushi Bosse, Yohan Obeidat, Ma'en Nickle, David Timens, Wim Freedman, Matthew L. Li, Qiyuan Seminara, Daniela Chanock, Stephen J. Gong, Jian Peters, Ulrike Gruber, Stephen B. Amos, Christopher I. Sellers, Thomas A. Easton, Douglas F. Hunter, David J. Haiman, Christopher A. Henderson, Brian E. Hung, Rayjean J. CA OCAC PRACTICAL Consortium Hereditary Breast Ovarian Canc Res Colorectal Transdisciplinary African Amer Breast Canc African Ancestry Prostate Canc TI Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations SO CANCER RESEARCH LA English DT Article ID SUSCEPTIBILITY LOCI; IDENTIFIES 2; GENETIC POLYMORPHISMS; AGGRESSIVE PROSTATE; AFRICAN ANCESTRY; COMMON VARIANTS; GASTRIC-CANCER; CELL CARCINOMA; RISK LOCI; METAANALYSIS AB Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus atCDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. (C) 2016 AACR. C1 [Fehringer, Gordon; Gallinger, Steven; Hung, Rayjean J.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, 60 Murray St, Toronto, ON M5T 3L9, Canada. [Kraft, Peter; Lindstrom, Sara; Giovannucci, Edward L.; Willett, Walter C.; Eliassen, A. Heather; Christiani, David C.; Wei, Yongyue; Hunter, David J.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Pharoah, Paul D.; Tyrer, Jonathan P.; Easton, Douglas F.] Univ Cambridge, Cambridge, England. [Eeles, Rosalind A.; Houlston, Richard S.; Kote-Jarai, Zsofia] Inst Canc Res, London, England. [Chatterjee, Nilanjan; Landi, Maria Teresa; Caporaso, Neil; Berndt, Sonja I.; Figueroa, Jonine D.; Garcia-Closas, Montserrat; Wang, Zhaoming; Yang, Xiaohong R.; Seminara, Daniela; Chanock, Stephen J.] NCI, Bethesda, MD 20892 USA. [Schumacher, Fredrick R.; Casey, Graham; Conti, David V.; Edlund, Christopher K.; Schmit, Stephanie L.; Gruber, Stephen B.; Haiman, Christopher A.; Henderson, Brian E.] Univ So Calif, Los Angeles, CA USA. [Schildkraut, Joellen M.] Univ Virginia, Charlottesville, VA USA. [Brennan, Paul; Johansson, Mattias] Int Agcy Res Canc, Lyon, France. [Bickeboller, Heike] Univ Gottingen, Sch Med, Gottingen, Germany. [Risch, Angela] Salzburg Univ, Div Canc Genet Epigenet, Dept Mol Biol, Salzburg, Austria. [Risch, Angela] DKFZ German Canc Res Ctr, Div Epigenom & Canc Risk Factors, Heidelberg, Germany. [Risch, Angela] German Ctr Lung Res DZL, Translat Lung Res Ctr Heidelberg TLRCH, Heidelberg, Germany. [Al Olama, Ali Amin] Univ Cambridge, Cambridge, England. [Gronberg, Henrik; Wiklund, Fredrik; Czene, Kamila; Hall, Per] Karolinska Inst, Stockholm, Sweden. [Ma, Jing; Stampfer, Meir J.; Eliassen, A. Heather; Hazra, Aditi; Tamimi, Rulla] Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Muir, Kenneth] Univ Manchester, Manchester, Lancs, England. [Muir, Kenneth] Univ Warwick, Coventry, W Midlands, England. [Stevens, Victoria L.; Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Goode, Ellen L.; Thibodeau, Stephen N.] Mayo Clin, Rochester, MN USA. [Permuth, Jennifer B.; Reid, Brett M.; Chen, Y. Ann; Sellers, Thomas A.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Bezieau, Stephane] Serv Genet Med, Nantes, France. [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Chan, Andrew T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chang-Claude, Jenny; Kaaks, Rudolf] Natl Ctr Tumor Dis, Heidelberg, Germany. [Chang-Claude, Jenny; Kaaks, Rudolf] German Canc Res Ctr, Heidelberg, Germany. [Hudson, Thomas J.] Ontario Inst Canc Res, Toronto, ON, Canada. [Kocarnik, Jonathan K.; Newcomb, Polly A.; White, Emily; Prentice, Ross L.; Gong, Jian; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Slattery, Martha L.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Adank, Muriel A.] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Ahsan, Habibul; Kibriya, Muhammad G.] Univ Chicago, Chicago, IL USA. [Aittomaki, Kristiina; Blomquist, Carl; Muranen, Taru A.; Nevanlinna, Heli] Univ Helsinki, Helsinki, Finland. [Aittomaki, Kristiina; Blomquist, Carl; Muranen, Taru A.; Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Baglietto, Laura; Southey, Melissa C.; Buchanan, Daniel D.; Jenkins, Mark] Univ Melbourne, Melbourne, Vic, Australia. [Canzian, Federico] German Canc Res Ctr, Gen Epidemiol Grp, Heidelberg, Germany. [dos-Santos-Silva, Isabel; Peto, Julian] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England. [Flesch-Janys, Dieter] Univ Med Ctr HamburgEppendorf, Hamburg, Germany. [Fletcher, Olivia; Johnson, Nichola] Breakthrough Res Ctr, Inst Canc Res, London, England. [Hein, Rebecca] German Canc Res Ctr DKFZ Heidelberg, Div Canc Epidemiol, Heidelberg, Germany. [Hein, Rebecca] Univ Cologne, Inst Med Stat Informat & Epidemiol, Cologne, Germany. [Hofman, Albert; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Hopper, John L.; Makalic, Enes; Schmidt, Daniel F.] Univ Melbourne, Melbourne Sch Populat Hlth, Melbourne, Vic, Australia. [Irwanto, Astrid; Liu, Jianjun] Genome Inst Singapore, Singapore, Singapore. [Johansson, Mattias] Umea Univ, Dept Biobank Res, Umea, Sweden. [Lichtner, Peter] German Res Ctr Environm Hlth, Neuherberg, Germany. [Lund, Eiliv] UiT Arctic Univ Norway, Inst Community Med, Tromso, Norway. [Meindl, Alfons] Tech Univ Munich, Munich, Germany. [Muller-Myhsok, Bertram] Max Planck Inst Psychiat, Munich, Germany. [Peeters, Petra H.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, Utrecht, Netherlands. [Rahman, Nazneen; Turnbull, Clare] Inst Canc Res, Sutton, Surrey, England. [Sanchez, Maria Jose] Escuela Andaluza Salud Publ, Inst Invest Biosanitaria Ibs GRANADA, Granada, Spain. [Sanchez, Maria Jose] Univ Granada, Hosp Univ Granada, Granada, Spain. [Sanchez, Maria Jose] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain. [Schmutzler, Rita K.] Univ Cologne, Cologne, Germany. [Travis, Ruth C.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Whittemore, Alice S.; Haile, Robert W.] Stanford Univ, Stanford, CA 94305 USA. [Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Li, Li] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Li, Li] Case Western Reserve Univ, Mary Ann Swetland Ctr Environm Hlth, Cleveland, OH 44106 USA. [Lindor, Noralene M.] Mayo Clin, Scottsdale, AZ USA. [Woods, Michael O.] Mem Univ Newfoundland, St John, NF, Canada. [Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N.; Stefansson, Kari; Sulem, Patrick] Amgen Inc, DeCODE Genet, Reykjavik, Iceland. [Shen, Hongbing; Hu, Zhibin] Nanjing Med Univ, Sch Publ Hlth, Nanjing, Jiangsu, Peoples R China. [Shiraishi, Kouya] Natl Canc Ctr, Div Genome Biol, Tokyo, Japan. [Takahashi, Atsushi] RIKEN Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa, Japan. [Bosse, Yohan] Univ Laval, Inst Univ Cardiol & Pneumol Quebec, Dept Mol Med, Quebec City, PQ, Canada. [Obeidat, Ma'en] Univ British Columbia, St Pauls Hosp, Ctr Heart Lung Innovat, Vancouver, BC, Canada. [Nickle, David] Merck & Co Inc, Merck Res Labs, Seattle, WA USA. [Timens, Wim] Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Groningen, Netherlands. [Freedman, Matthew L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Li, Qiyuan] Xiamen Univ, Xiamen, Peoples R China. [Amos, Christopher I.] Dartmouth Coll, Sch Med, Hanover, NH 03755 USA. RP Hung, RJ (reprint author), Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, 60 Murray St, Toronto, ON M5T 3L9, Canada. EM rayjean.hung@lunenfeld.ca RI Hung, Rayjean/A-7439-2013; Zheng, Wei/O-3351-2013; Brenner, Hermann/B-4627-2017; Risch, Angela/H-2669-2013; OI Zheng, Wei/0000-0003-1226-070X; Brenner, Hermann/0000-0002-6129-1572; Risch, Angela/0000-0002-8026-5505; Muranen, Taru/0000-0002-5895-1808 FU Cancer Research UK [10119, 10124, A10118, A10119, A10124, A12014, A16561, A5660, A8339]; Medical Research Council [G0700491]; NCI NIH HHS [UM1 CA167551, P30 CA023108, R01 CA050385, R01 CA055769, R01 CA074386, R01 CA092824, R01 CA121197, R01 CA127219, R01 CA133996, U01 CA137088, U01 CA164973, U19 CA148065, U19 CA148107, U19 CA148112, U19 CA148127, U19 CA148537, UM1 CA176726]; NIH HHS [S10 OD020069] NR 47 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 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2016 VL 76 IS 17 BP 5103 EP 5114 DI 10.1158/0008-5472.CAN-15-2980 PG 12 WC Oncology SC Oncology GA DU6BU UT WOS:000382298900020 PM 27197191 ER PT J AU Ferraro, GB Kodack, DP Askoxylakis, V Jain, RK AF Ferraro, Gino B. Kodack, David P. Askoxylakis, Vasileios Jain, Rakesh K. TI Closing the gap: astrocytes and brain metastasis SO CELL RESEARCH LA English DT Editorial Material ID BREAST-CANCER; SURVIVAL; GENES; CELLS AB Astrocytes are emerging as essential regulators of brain metastasis progression. In a current issue of Nature, Chen et al. identify a novel mechanism of astrocyte-carcinoma interaction and exploit vulnerabilities therein to slow brain metastatic growth in pre-clinical models. C1 [Ferraro, Gino B.; Kodack, David P.; Askoxylakis, Vasileios; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. [Ferraro, Gino B.; Kodack, David P.; Askoxylakis, Vasileios; Jain, Rakesh K.] Harvard Med Sch, Boston, MA 02114 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA.; Jain, RK (reprint author), Harvard Med Sch, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu NR 12 TC 1 Z9 1 U1 6 U2 6 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYANG ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 EI 1748-7838 J9 CELL RES JI Cell Res. PD SEP PY 2016 VL 26 IS 9 BP 973 EP 974 DI 10.1038/cr.2016.96 PG 2 WC Cell Biology SC Cell Biology GA DU7MK UT WOS:000382398100003 PM 27514701 ER PT J AU Shamsi, MM Mahdavi, M Quinn, LS Gharakhanlou, R Isanegad, A AF Shamsi, M. Molanouri Mahdavi, M. Quinn, L. S. Gharakhanlou, R. Isanegad, A. TI Effect of resistance exercise training on expression of Hsp70 and inflammatory cytokines in skeletal muscle and adipose tissue of STZ-induced diabetic rats SO CELL STRESS & CHAPERONES LA English DT Article DE Hsp70; Inflammatory cytokines; Skeletal muscle; Adipose tissue; Resistance training; Type 1 diabetes ID HEAT-SHOCK PROTEINS; METABOLIC RISK-FACTORS; INSULIN-RESISTANCE; STRESS-RESPONSE; NEONATAL STREPTOZOTOCIN; EXTRACELLULAR HSP70; PLANTARIS MUSCLE; TIME-COURSE; HYPERTROPHY; MECHANISMS AB Impairment of adipose tissue and skeletal muscles accrued following type 1 diabetes is associated with protein misfolding and loss of adipose mass and skeletal muscle atrophy. Resistance training can maintain muscle mass by changing both inflammatory cytokines and stress factors in adipose tissue and skeletal muscle. The purpose of this study was to determine the effects of a 5-week ladder climbing resistance training program on the expression of Hsp70 and inflammatory cytokines in adipose tissue and fast-twitch flexor hallucis longus (FHL) and slow-twitch soleus muscles in healthy and streptozotocin-induced diabetic rats. Induction of diabetes reduced body mass, while resistance training preserved FHL muscle weight in diabetic rats without any changes in body mass. Diabetes increased Hsp70 protein content in skeletal muscles, adipose tissue, and serum. Hsp70 protein levels were decreased in normal and diabetic rats by resistance training in the FHL, but not soleus muscle. Furthermore, resistance training decreased inflammatory cytokines in FHL skeletal muscle. On the other hand, Hsp70 and inflammatory cytokine protein levels were increased by training in adipose tissue. Also, significant positive correlations between inflammatory cytokines in adipose tissue and skeletal muscles with Hsp70 protein levels were observed. In conclusion, we found that in diabetic rats, resistance training decreased inflammatory cytokines and Hsp70 protein levels in fast skeletal muscle, increased adipose tissue inflammatory cytokines and Hsp70, and preserved FHL muscle mass. These results suggest that resistance training can maintain skeletal muscle mass in diabetes by changing inflammatory cytokines and stress factors such as Hsp70 in skeletal muscle and adipose tissue. C1 [Shamsi, M. Molanouri; Gharakhanlou, R.] Tarbiat Modares Univ, Phys Educ & Sport Sci Dept, Fac Humanities, Jala Ale Ahmad Exp, POB 14117-13116, Tehran, Iran. [Mahdavi, M.] Pasteur Inst Iran, Dept Immunol, 69 Pasteur Ave, Tehran, Iran. [Quinn, L. S.] VA Puget Sound Hlth Care Syst, Res Serv, Seattle, WA 98108 USA. [Quinn, L. S.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98108 USA. [Isanegad, A.] Shahed Univ, Fac Humanities, Phys Educ & Sport Sci Dept, POB 14117-13116, Tehran, Iran. [Isanegad, A.] Shahed Univ, Immunoregulat Res Ctr, POB 14117-13116, Tehran, Iran. RP Shamsi, MM (reprint author), Tarbiat Modares Univ, Phys Educ & Sport Sci Dept, Fac Humanities, Jala Ale Ahmad Exp, POB 14117-13116, Tehran, Iran. EM molanouri@modares.ac.ir FU Research Center of Tarbiat Modarres University (TMU), Tehran, Iran FX This work was supported by the Research Center of Tarbiat Modarres University (TMU), Tehran, Iran. We wish to thank Professor Yaghob Fathoallahy for their kind help and sincere cooperation. NR 71 TC 0 Z9 0 U1 6 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1355-8145 EI 1466-1268 J9 CELL STRESS CHAPERON JI Cell Stress Chaperones PD SEP PY 2016 VL 21 IS 5 BP 783 EP 791 DI 10.1007/s12192-016-0703-7 PG 9 WC Cell Biology SC Cell Biology GA DV1BQ UT WOS:000382655300005 ER PT J AU Sievers, CK Kratz, JD Zurbriggen, LD LoConte, NK Lubner, SJ Uboha, N Mulkerin, D Matkowskyj, KA Deming, DA AF Sievers, Chelsie K. Kratz, Jeremy D. Zurbriggen, Luke D. LoConte, Noelle K. Lubner, Sam J. Uboha, Natalya Mulkerin, Daniel Matkowskyj, Kristina A. Deming, Dustin A. TI The Multidisciplinary Management of Colorectal Cancer: Present and Future Paradigms SO CLINICS IN COLON AND RECTAL SURGERY LA English DT Article DE colon cancer; rectal cancer; chemotherapy ID RANDOMIZED CONTROLLED-TRIAL; III COLON-CANCER; ADJUVANT TREATMENT; 1ST-LINE TREATMENT; ANTIBODY THERAPY; PLUS CETUXIMAB; RAS MUTATIONS; POOR SURVIVAL; STAGE-II; PHASE-I AB As treatment strategies for patients with colorectal cancer advance, there has now become an ever-increasing need for multidisciplinary teams to care for these patients. Recent investigations into the timing and duration of perioperative therapy, as well as, the rise of molecular profiling have led to more systemic chemotherapeutic options. The most efficacious use, in terms of timing and patient selection, of these therapies in the setting of modern operative and radiotherapy techniques requires the generation of care teams discussing cases at multidisciplinary conferences. This review highlights the role of multidisciplinary team conferences, advances in perioperative chemotherapy, current clinical biomarkers, and emerging therapeutic agents for molecular subtypes of metastatic colon cancer. As our understanding of relevant molecular subtypes increases and as data becomes available on treatment response, the treatment of colorectal cancer will become more precise and effective. C1 [Sievers, Chelsie K.; Matkowskyj, Kristina A.] Univ Wisconsin, Dept Oncol, Madison, WI USA. [Sievers, Chelsie K.] Univ Wisconsin, Dept Med, Div Gastroenterol & Hepatol, Madison, WI USA. [Kratz, Jeremy D.; Zurbriggen, Luke D.; LoConte, Noelle K.; Lubner, Sam J.; Uboha, Natalya; Mulkerin, Daniel; Deming, Dustin A.] Univ Wisconsin, Dept Med, Div Hematol & Oncol, Madison, WI USA. [LoConte, Noelle K.; Lubner, Sam J.; Uboha, Natalya; Mulkerin, Daniel; Matkowskyj, Kristina A.; Deming, Dustin A.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Matkowskyj, Kristina A.; Deming, Dustin A.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Matkowskyj, Kristina A.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA. RP Deming, DA (reprint author), 600 Highland Ave,K6-544, Madison, WI 53792 USA. EM ddeming@medicine.wisc.edu FU National Institutes of Health [P30 CA014520] FX This project was supported by the National Institutes of Health P30 CA014520 (Core Grant, University of Wisconsin Carbone Cancer Center, Madison, WI). NR 60 TC 1 Z9 1 U1 4 U2 4 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1531-0043 EI 1530-9681 J9 CLIN COLON RECT SURG JI Clin. Colon Rectal Surg. PD SEP PY 2016 VL 29 IS 3 BP 232 EP 238 DI 10.1055/s-0036-1584292 PG 7 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA DT1LA UT WOS:000381243000008 PM 27582648 ER PT J AU Zhu, H Alt, C Webb, RH Melki, S Kochevar, IE AF Zhu, Hong Alt, Clemens Webb, Robert H. Melki, Samir Kochevar, Irene E. TI Corneal Crosslinking With Rose Bengal and Green Light: Efficacy and Safety Evaluation SO CORNEA LA English DT Article DE corneal crosslinks; collagen crosslinks; Rose Bengal; keratoconus; crosslinking ID OPTICAL COHERENCE TOMOGRAPHY; PHOTOCHEMICAL KERATODESMOS; BIOMECHANICAL PROPERTIES; RIBOFLAVIN/UVA-TREATMENT; ELECTRON-TRANSFER; SINGLET OXYGEN; BOVINE CORNEA; ULTRAVIOLET-A; INCISIONS; PHOTOCOAGULATION AB Purpose: To evaluate crosslinking of cornea in vivo using green light activation of Rose Bengal (RGX) and assess potential damaging effects of the green light on retina and iris. Methods: Corneas of Dutch belted rabbits were de-epithelialized, then stained with Rose Bengal and exposed to green light, or not further treated. Corneal stiffness was measured by uniaxial tensiometry. Re-epithelialization was assessed by fluorescein fluorescence. Keratocytes were counted on hematoxylin and eosin (H&E)-stained sections, and iris cell damage was assessed by lactate dehydrogenase staining. Thermal effects on the blood-retinal barrier (BRB) were assessed by fluorescein angiography and those on photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris by light microscopy and transmission electron microscopy. Results: RGX (10-min irradiation; 150 J/cm(2)) increased corneal stiffness 1.9-fold on day 1 (1.25 +/- 0.21 vs. 2.38 +/- 0.59 N/mm; P = 0.036) and 2.8-fold compared with controls on day 28 (1.70 +/- 0.74 vs. 4.95 +/- 1.86 N/mm; P = 0.003). Keratocytes decreased only in the anterior stroma on day 1 (24.0 +/- 3.0 vs. 3.67 +/- 4.73, P = 0.003) and recovered by day 28 (37.7 +/- 8.9 vs. 34.5 +/- 2.4, P = 0.51). Iris cells were not thermally damaged. No evidence of BRB breakdown was detected on days 1 or 28. Retina from RGX-treated eyes seemed normal with RPE cells showing intact nuclei shielded apically by melanosomes, morphologically intact photoreceptor outer segments, normal outer nuclear layer thickness, and choriocapillaris containing intact erythrocytes. Conclusions: The substantial corneal stiffening produced by RGX together with the lack of significant effects on keratocytes and no evidence for retina or iris damage suggest that RGX-initiated corneal crosslinking may be a safe, rapid, and effective treatment. C1 [Zhu, Hong; Alt, Clemens; Webb, Robert H.; Kochevar, Irene E.] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, 50 Blossom St, Boston, MA 02114 USA. [Zhu, Hong] Shanghai Jiao Tong Univ, Sch Med, Shanghai Peoples Hosp 1, Dept Ophthalmol, Shanghai, Peoples R China. [Melki, Samir] Boston Eye Grp, Boston, MA USA. RP Kochevar, IE (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, 50 Blossom St, Boston, MA 02114 USA. EM kochevar@helix.mgh.harvard.edu FU United States Department of Defense, Air Force Office of Scientific Research [FA9550-13-1-0068] FX Supported by United States Department of Defense, Air Force Office of Scientific Research under agreement number FA9550-13-1-0068. NR 33 TC 2 Z9 2 U1 5 U2 5 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 SEP PY 2016 VL 35 IS 9 BP 1234 EP 1241 PG 8 WC Ophthalmology SC Ophthalmology GA DT4GA UT WOS:000381437000023 PM 27362877 ER PT J AU Gukovskaya, AS Pandol, SJ Gukovsky, I AF Gukovskaya, Anna S. Pandol, Stephen J. Gukovsky, Ilya TI New insights into the pathways initiating and driving pancreatitis SO CURRENT OPINION IN GASTROENTEROLOGY LA English DT Review DE acute pancreatitis; autophagy; calcium; chronic pancreatitis; lysosomes; mitochondrial permeability transition pore ID NEUTROPHIL EXTRACELLULAR TRAPS; SENSITIVE CALCIUM POOL; ACINAR-CELL; TRYPSIN ACTIVATION; PROTEIN-SYNTHESIS; CA2+ RELEASE; MOUSE MODELS; INFLAMMATION; AUTOPHAGY; MICE AB Purpose of review In this article, we discuss recent studies that advance our understanding of molecular and cellular factors initiating and driving pancreatitis, with the emphasis on the role of acinar cell organelle disorders. Recent findings The central physiologic function of the pancreatic acinar cell to synthesize, store, and secrete digestive enzymes critically relies on coordinated actions of the endoplasmic reticulum (ER), the endolysosomal system, mitochondria, and autophagy. Recent studies begin to unravel the roles of these organelles' disordering in the mechanism of pancreatitis. Mice deficient in key autophagy mediators Atg5 or Atg7, or lysosome-associated membrane protein-2, exhibit dysregulation of multiple signaling and metabolic pathways in pancreatic acinar cells and develop spontaneous pancreatitis. Mitochondria! dysfunction caused by sustained opening of the permeability transition pore is shown to mediate pancreatitis in several clinically relevant experimental models, and its inhibition by pharmacologic or genetic means greatly reduces local and systemic pathologic responses. Experimental pancreatitis is also alleviated with inhibitors of ORAI1, a key component of the plasma membrane channel mediating pathologic rise in acinar cell cytosolic Ca2+. Pancreatitis-promoting mutations are increasingly associated with the ER stress. These findings suggest novel pathways and drug targets for pancreatitis treatment. In addition, the recent studies identify new mediators (e.g., neutrophil extracellular traps) of the inflammatory and other responses of pancreatitis. Summary The recent findings illuminate a critical role of organelles regulating the autophagic, endolysosomal, mitochondrial, and ER pathways in maintaining pancreatic acinar cell homeostasis and secretory function; provide compelling evidence that organelle disordering is a key pathogenic mechanism initiating and driving pancreatitis; and identify molecular and cellular factors that could be targeted to restore organellar functions and thus alleviate or treat pancreatitis. C1 [Gukovskaya, Anna S.; Gukovsky, Ilya] Univ Calif Los Angeles, Los Angeles, CA USA. [Gukovskaya, Anna S.; Gukovsky, Ilya] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Pandol, Stephen J.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RP Gukovskaya, AS (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, 11301 Wilshire Blvd,Bldg 258-340, Los Angeles, CA 90073 USA.; Gukovskaya, AS (reprint author), West Los Angeles Healthcare Ctr, Pancreat Res Grp, 11301 Wilshire Blvd,Bldg 258-340, Los Angeles, CA 90073 USA. EM agukovsk@ucla.edu FU NIH [R01DK59936, R01AA19730, P01 DK98108, P50 AA11999, DoD PR140717P2, U01 DK108314, NWU2014-04-01]; Veterans Administration Merit Review FX The work was supported in part by the NIH grants R01DK59936, R01AA19730, P01 DK98108, P50 AA11999, DoD PR140717P2, U01 DK108314, NWU2014-04-01; and by Veterans Administration Merit Review. NR 63 TC 1 Z9 1 U1 9 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0267-1379 EI 1531-7056 J9 CURR OPIN GASTROEN JI Curr. Opin. Gastroenterol. PD SEP PY 2016 VL 32 IS 5 BP 429 EP 435 DI 10.1097/MOG.0000000000000301 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DU7XS UT WOS:000382428500013 ER PT J AU Gregg, T Poudel, C Schmidt, BA Dhillon, RS Sdao, SM Truchan, NA Baar, EL Fernandez, LA Denu, JM Eliceiri, KW Rogers, JD Kimple, ME Lamming, DW Merrins, MJ AF Gregg, Trillian Poudel, Chetan Schmidt, Brian A. Dhillon, Rashpal S. Sdao, Sophia M. Truchan, Nathan A. Baar, Emma L. Fernandez, Luis A. Denu, John M. Eliceiri, Kevin W. Rogers, Jeremy D. Kimple, Michelle E. Lamming, Dudley W. Merrins, Matthew J. TI Pancreatic beta-Cells From Mice Offset Age-Associated Mitochondrial Deficiency With Reduced K-ATP Channel Activity SO DIABETES LA English DT Article ID INSULIN-SECRETION; METABOLIC OSCILLATIONS; CYTOCHROME-C; ISLETS; GLUCOSE; FLUORESCENCE; CA2+; MECHANISMS; NADH; GLYCOLYSIS AB Aging is accompanied by impaired glucose homeostasis and an increased risk of type 2 diabetes, culminating in the failure of insulin secretion from pancreatic beta-cells. To investigate the effects of age on beta-cell metabolism, we established a novel assay to directly image islet metabolism with NAD(P)H fluorescence lifetime imaging (FLIM). We determined that impaired mitochondrial activity underlies an age-dependent loss of insulin secretion in human islets. NAD(P)H FLIM revealed a comparable decline in mitochondrial function in the pancreatic islets of aged mice (W24 months), the result of 52% and 57% defects in flux through complex I and II, respectively, of the electron transport chain. However, insulin secretion and glucose tolerance are preserved in aged mouse islets by the heightened metabolic sensitivity of the beta-cell triggering pathway, an adaptation clearly encoded in the metabolic and Ca2+ oscillations that trigger insulin release (Ca2+ plateau fraction: young 0.211 +/- 0.006, aged 0.380 +/- 0.007, P < 0.0001). This enhanced sensitivity is driven by a reduction in K-ATP channel conductance (diazoxide: young 5.1 +/- 0.2 nS; aged 3.5 +/- 0.5 nS, P < 0.01), resulting in an similar to 2.8 mmol/L left shift in the beta-cell glucose threshold. The results demonstrate how mice but not humans are able to successfully compensate for age-associated metabolic dysfunction by adjusting beta-cell glucose sensitivity and highlight an essential mechanism for ensuring the maintenance of insulin secretion. C1 [Gregg, Trillian; Poudel, Chetan; Schmidt, Brian A.; Truchan, Nathan A.; Baar, Emma L.; Kimple, Michelle E.; Lamming, Dudley W.; Merrins, Matthew J.] Univ Wisconsin Madison, Dept Med, Div Endocrinol Diabet & Metab, Madison, WI 53706 USA. [Gregg, Trillian] Univ Wisconsin Madison, Biophys Grad Training Program, Madison, WI USA. [Gregg, Trillian; Poudel, Chetan; Eliceiri, Kevin W.; Rogers, Jeremy D.; Merrins, Matthew J.] Univ Wisconsin Madison, Lab Opt & Computat Instrumentat, Madison, WI 53706 USA. [Dhillon, Rashpal S.; Denu, John M.; Merrins, Matthew J.] Univ Wisconsin Madison, Dept Biomol Chem, Madison, WI 53706 USA. [Sdao, Sophia M.] Univ Wisconsin Madison, Integrated Program Biochem, Madison, WI USA. [Fernandez, Luis A.] Univ Wisconsin Madison, Div Transplantat, Dept Surg, Madison, WI USA. [Eliceiri, Kevin W.; Rogers, Jeremy D.] Univ Wisconsin Madison, Dept Biomed Engn, Madison, WI USA. [Kimple, Michelle E.; Lamming, Dudley W.; Merrins, Matthew J.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. RP Lamming, DW; Merrins, MJ (reprint author), Univ Wisconsin Madison, Dept Med, Div Endocrinol Diabet & Metab, Madison, WI 53706 USA.; Merrins, MJ (reprint author), Univ Wisconsin Madison, Lab Opt & Computat Instrumentat, Madison, WI 53706 USA.; Merrins, MJ (reprint author), Univ Wisconsin Madison, Dept Biomol Chem, Madison, WI 53706 USA.; Lamming, DW; Merrins, MJ (reprint author), William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. EM dlamming@medicine.wisc.edu; merrins@wisc.edu FU National Institutes of Health (NIH) Molecular Biophysics Training Grant [T32-GM-08293]; Laboratory for Optical and Computational Instrumentation; Wisconsin Alumni Research Foundation Dissertation Fellowship; American Diabetes Association [1-14-BS-115, 1-16-IBS-212]; NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01-DK-102598]; NIH NIA [R00-AG-041765, R21-AG-050135]; Glenn Foundation Award; American Federation for Aging Research; NIH NIDDK [K01-DK-101683]; University of Wisconsin-Madison School of Medicine and Public Health and Department of Medicine FX T.G. received support from a National Institutes of Health (NIH) Molecular Biophysics Training Grant (T32-GM-08293), the Laboratory for Optical and Computational Instrumentation, and a Wisconsin Alumni Research Foundation Dissertation Fellowship. The Kimple laboratory was supported by grants to M.E.K. from the American Diabetes Association (1-14-BS-115) and the NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01-DK-102598). The Lamming laboratory is supported by a grant to D.W.L. from the NIH NIA (R00-AG-041765) and a Glenn Foundation Award for research in the biological mechanisms of aging. This research was conducted while D.W.L. was a research grant recipient from the American Federation for Aging Research. The Merrins laboratory is supported by grants to M.J.M. from the NIH NIDDK (K01-DK-101683) and the American Diabetes Association (1-16-IBS-212). The Merrins and Lamming laboratories are jointly supported by a grant from the NIH NIA (R21-AG-050135), and both laboratories are supported by startup funds from the University of Wisconsin-Madison School of Medicine and Public Health and Department of Medicine. NR 51 TC 0 Z9 0 U1 5 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD SEP PY 2016 VL 65 IS 9 BP 2700 EP 2710 DI 10.2337/db16-0432 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU3GW UT WOS:000382099800024 PM 27284112 ER PT J AU Katagiri, S Park, K Maeda, Y Rao, TN Khamaisi, M Li, Q Yokomizo, H Mima, A Lancerotto, L Wagers, A Orgill, DP King, GL AF Katagiri, Sayaka Park, Kyoungmin Maeda, Yasutaka Rao, Tata Nageswara Khamaisi, Mogher Li, Qian Yokomizo, Hisashi Mima, Akira Lancerotto, Luca Wagers, Amy Orgill, Dennis P. King, George L. TI Overexpressing IRS1 in Endothelial Cells Enhances Angioblast Differentiation and Wound Healing in Diabetes and Insulin Resistance SO DIABETES LA English DT Article ID PROTEIN-KINASE-C; TOPICAL INSULIN; MOLECULAR-BASIS; EXPRESSION; REPAIR; COMPLICATIONS; MICE; ATHEROSCLEROSIS; FIBROBLAST; ACTIVATION AB The effect of enhancing insulin's actions in endothelial cells (ECs) to improve angiogenesis and wound healing was studied in obesity and diabetes. Insulin receptor substrate 1 (IRS1) was overexpressed in ECs using the VE-cadherin promoter to create ECIRS1 TG mice, which elevated pAkt activation and expressions of vascular endothelial growth factor (VEGF), Flk1, and VE-cadherin in ECs and granulation tissues (GTs) of full-thickness wounds. Open wound and epithelialization rates and angiogenesis significantly improved in normal mice and high fat (HF) diet-induced diabetic mice with hyperinsulinemia in ECIRS1 TG versus wild type (WT), but not in insulin deficient diabetic mice. Increased angioblasts and EC numbers in GT of ECIRS1 mice were due to proliferation in situ rather than uptake. GT in HF-fed diabetic mice exhibited parallel decreases in insulin and VEGF-induced pAkt and EC numbers by >50% without changes in angioblasts versus WT mice, which were improved in ECIRS1 TG mice on normal chow or HF diet. Thus, HF-induced diabetes impaired angiogenesis by inhibiting insulin signaling in GT to decrease the differentiation of angioblasts to EC, which was normalized by enhancing insulin's action targeted to EC, a potential target to improve wound healing in diabetes and obesity. C1 [Katagiri, Sayaka; Park, Kyoungmin; Maeda, Yasutaka; Khamaisi, Mogher; Li, Qian; Yokomizo, Hisashi; Mima, Akira; King, George L.] Harvard Med Sch, Joslin Diabet Ctr, Sect Vasc Cell Biol, Boston, MA 02115 USA. [Rao, Tata Nageswara; Wagers, Amy] Havard Med Sch, Joslin Diabet Ctr, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Boston, MA USA. [Lancerotto, Luca; Orgill, Dennis P.] Harvard Med Sch, Brigham & Womens Hosp, Div Plast Surg, Boston, MA USA. RP King, GL (reprint author), Harvard Med Sch, Joslin Diabet Ctr, Sect Vasc Cell Biol, Boston, MA 02115 USA. EM george.king@joslin.harvard.edu FU Hiroo Kaneda Scholarship, Sunstar Foundation, Japan; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Diabetes Research Center [P30DK036836]; Japan Society for the Promotion of Science [26463128]; NIH/NIDDK [R01 DK053105-13] FX S.K. is the recipient of a research fellowship (Hiroo Kaneda Scholarship, Sunstar Foundation, Japan). Support was also provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Diabetes Research Center grant P30DK036836 and Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (26463128). This work was also supported by NIH/NIDDK grant R01 DK053105-13 to G.L.K. NR 44 TC 0 Z9 0 U1 5 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD SEP PY 2016 VL 65 IS 9 BP 2760 EP 2771 DI 10.2337/db15-1721 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU3GW UT WOS:000382099800030 PM 27217486 ER PT J AU Afrogheh, AH Meserve, E Sadow, PM Stephen, AE Nose, V Berlin, S Faquin, WC AF Afrogheh, Amir H. Meserve, Emily Sadow, Peter M. Stephen, Antonia E. Nose, Vania Berlin, Suzanne Faquin, William C. TI Molecular Characterization of an Endometrial Endometrioid Adenocarcinoma Metastatic to a Thyroid Hurthle Cell Adenoma Showing Cancerization of Follicles SO ENDOCRINE PATHOLOGY LA English DT Article DE Tumor-to-tumor metastasis; Cancerization of follicles; Endometrial endometrioid adenocarcinoma; Hurthle cell adenoma; Columnar cell variant of papillary thyroid carcinoma; Fine-needle aspiration biopsy; Thyroid ID TO-TUMOR METASTASIS; DNA-SEQUENCING DATA; OF-THE-LITERATURE; INITIAL PRESENTATION; MALIGNANT-MELANOMA; FOLLICULAR ADENOMA; CARCINOMA; CANCER; GLAND; FRAMEWORK AB Tumor-to-tumor metastasis is rare. Herein, we present a unique case of endometrial endometrioid adenocarcinoma metastatic to a thyroid Hurthle cell adenoma 9 years after initial diagnosis. On histologic examination of the thyroid, the malignant endometrioid glands and single cells (donor tumor) were dispersed within the Hurthle cell adenoma (recipient tumor). In several sections of the adenoma with still preserved microfollicular architecture, malignant endometrial adenocarcinoma cells were admixed within oncocytic adenomatous epithelium (so-called "cancerization of the follicles"). This unusual phenomenon, to our knowledge, is a novel finding in the thyroid gland. Immunohistochemistry, subsequently elicited clinical history, and morphologic comparison of the tumor in the thyroid to the primary endometrial tumor confirmed the origin of the donor tumor cells. Molecular analysis of both the metastatic and primary endometrial tumors demonstrated PIK3CA and PTEN mutations in both tumors, as is characteristic of well-differentiated endometrioid tumors of the endometrium. Amplification of chromosome 1q was detected in both sites; however, only the metastatic tumor showed loss of chromosomes 2, 9, and 22. The morphologic differential diagnosis of metastatic endometrioid adenocarcinoma in the thyroid includes columnar cell variant of papillary thyroid carcinoma (CCVPTC) arising in a preexisting adenoma, endocrine glandular atypia within an adenoma, and metastasis from other anatomic sites. Histomorphologic differences among these entities may be subtle; therefore, knowledge of and morphologic comparison with prior malignancies and immunohistochemistry can be helpful in rendering the correct diagnosis. C1 [Afrogheh, Amir H.; Sadow, Peter M.; Nose, Vania; Faquin, William C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Meserve, Emily] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Berlin, Suzanne] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Stephen, Antonia E.] Massachusetts Gen Hosp, Dept Surg Oncol, Boston, MA 02114 USA. [Afrogheh, Amir H.; Meserve, Emily; Sadow, Peter M.; Stephen, Antonia E.; Nose, Vania; Berlin, Suzanne; Faquin, William C.] Harvard Med Sch, Boston, MA 02114 USA. [Faquin, William C.] Massachusetts Gen Hosp, Pathol Serv, WRN219,55 Fruit St, Boston, MA 02114 USA. RP Faquin, WC (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.; Faquin, WC (reprint author), Harvard Med Sch, Boston, MA 02114 USA.; Faquin, WC (reprint author), Massachusetts Gen Hosp, Pathol Serv, WRN219,55 Fruit St, Boston, MA 02114 USA. EM wfaquin@partners.org NR 40 TC 0 Z9 0 U1 1 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1046-3976 EI 1559-0097 J9 ENDOCR PATHOL JI Endocr. Pathol. PD SEP PY 2016 VL 27 IS 3 BP 213 EP 219 DI 10.1007/s12022-015-9412-5 PG 7 WC Endocrinology & Metabolism; Pathology SC Endocrinology & Metabolism; Pathology GA DT6LD UT WOS:000381594800005 PM 26687112 ER PT J AU Lai, PS Hang, JQ Zhang, FY Sun, J Zheng, BY Su, L Washko, GR Christiani, DC AF Lai, Peggy S. Hang, Jing-qing Zhang, Feng-ying Sun, J. Zheng, Bu-Yong Su, Li Washko, George R. Christiani, David C. TI Imaging Phenotype of Occupational Endotoxin-Related Lung Function Decline SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; COTTON TEXTILE WORKERS; COMPUTED-TOMOGRAPHY; DUST EXPOSURE; RESPIRATORY HEALTH; EMPHYSEMA; SMOKING; DENSITY; HOMES; COPD AB BACKGROUND: Although occupational exposures contribute to a significant proportion of obstructive lung disease, the phenotype of obstructive lung disease associated with work-related organic dust exposure independent of smoking remains poorly defined. OBJECTIVE: We identified the relative contributions of smoking and occupational endotoxin exposure to parenchymal and airway remodeling as defined by quantitative computed tomography (CT). METHODS: The Shanghai Textile Worker Study is a longitudinal study of endotoxin-exposed cotton workers and endotoxin-unexposed silk workers that was initiated in 1981. Spirometry, occupational endotoxin exposure, and smoking habits were assessed at 5-year intervals. High-resolution computed tomography (CT) was performed in 464 retired workers in 2011, along with quantitative lung densitometric and airway analysis. RESULTS: Significant differences in all CT measures were noted across exposure groups. Occupational endotoxin exposure was associated with a decrease (-1.3%) in percent emphysema (LAA(1.950)), a 3.3-Hounsfield unit increase in 15th percentile density, an 18.1-g increase in lung mass, and a 2.3% increase in wall area percent. Current but not former smoking was associated with a similar CT phenotype. Changes in LAA(1.950) were highly correlated with 15th percentile density (correlation -1.0). Lung mass was the only measure associated with forced expiratory volume in 1 sec (FEV1) decline, with each 10-g increase in lung mass associated with an additional loss (-6.1mL) of FEV1 (p = 0.001) between 1981 and 2011. CONCLUSIONS: There are many similarities between the effects of occupational endotoxin exposure and those of tobacco smoke exposure on lung parenchyma and airway remodeling. The effects of occupational endotoxin exposure appear to persist even after the cessation of exposure. LAA(1.950) may not be a reliable indicator of emphysema in subjects without spirometric impairment. Lung mass is a CT-based biomarker of accelerated lung function decline. C1 [Lai, Peggy S.; Christiani, David C.] Massachusetts Gen Hosp, Div Pulm & Crit Care, Boston, MA 02114 USA. [Lai, Peggy S.; Su, Li; Christiani, David C.] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Lai, Peggy S.; Washko, George R.; Christiani, David C.] Harvard Med Sch, Boston, MA USA. [Hang, Jing-qing; Zhang, Feng-ying; Sun, J.; Zheng, Bu-Yong] Shanghai Putuo Dist Peoples Hosp, Shanghai, Peoples R China. [Washko, George R.] Brigham & Womens Hosp, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA. RP Lai, PS (reprint author), Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Bulfinch 148,55 Fruit St, Boston, MA 02114 USA. EM pslai@hsph.harvard.edu FU National Institute for Occupational Safety and Health (NIOSH) [R01 OH002421]; National Insititutes of Health, National Insititute of Environmental Health Sciences [NIH-NIEHS] [K23ES023700, F32ES020082, P30 ES00002] FX Support for this work was provided by the National Institute for Occupational Safety and Health (NIOSH; R01 OH002421) to D.C.C. and by the National Insititutes of Health, National Insititute of Environmental Health Sciences [NIH-NIEHS; K23ES023700, F32ES020082 (to P.S.L.), and P30 ES00002 (to D. Dockery)]. NR 39 TC 0 Z9 0 U1 6 U2 6 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 2016 VL 124 IS 9 BP 1436 EP 1442 DI 10.1289/EHP195 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DU9IM UT WOS:000382530200024 PM 27138294 ER PT J AU Willems, SM Cornes, BK Brody, JA Morrison, AC Lipovich, L Dauriz, M Chen, YN Liu, CT Rybin, DV Gibbs, RA Muzny, D Pankow, JS Psaty, BM Boerwinkle, E Rotter, JI Siscovick, DS Vasan, RS Kaplan, RC Isaacs, A Dupuis, J van Duijn, CM Meigs, JB AF Willems, Sara M. Cornes, Belinda K. Brody, Jennifer A. Morrison, Alanna C. Lipovich, Leonard Dauriz, Marco Chen, Yuning Liu, Ching-Ti Rybin, Denis V. Gibbs, Richard A. Muzny, Donna Pankow, James S. Psaty, Bruce M. Boerwinkle, Eric Rotter, Jerome I. Siscovick, David S. Vasan, Ramachandran S. Kaplan, Robert C. Isaacs, Aaron Dupuis, Josee van Duijn, Cornelia M. Meigs, James B. TI Association of the IGF1 gene with fasting insulin levels SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID RARE-VARIANT ASSOCIATION; GROWTH-FACTOR-I; SEQUENCING DATA; POPULATION-GROWTH; WIDE ASSOCIATION; AGING RESEARCH; LOW-FREQUENCY; OLDER-ADULTS; DISEASE; MUTATIONS AB Insulin-like growth factor 1 (IGF-I) has been associated with insulin resistance. Genome-wide association studies (GWASs) of fasting insulin (FI) identified single-nucleotide variants (SNVs) near the IGF1 gene, raising two hypotheses: (1) these associations are mediated by IGF-I levels and (2) these noncoding variants either tag other functional variants in the region or are directly functional. In our study, analyses including 5141 individuals from population-based cohorts suggest that FI associations near IGF1 are not mediated by IGF-I. Analyses of targeted sequencing data in 3539 individuals reveal a large number of novel rare variants at the IGF1 locus and show a FI association with a subset of rare nonsynonymous variants (P-SKAT=5.7 x 10(-4)). Conditional analyses suggest that this association is partly explained by the GWAS signal and the presence of a residual independent rare variant effect (P-conditional=0.019). Annotation using ENCODE data suggests that the GWAS variants may have a direct functional role in insulin biology. In conclusion, our study provides insight into variation present at the IGF1 locus and into the genetic architecture underlying FI levels, suggesting that FI associations of SNVs near IGF1 are not mediated by IGF-I and suggesting a role for both rare nonsynonymous and common functional variants in insulin biology. C1 [Willems, Sara M.; Isaacs, Aaron; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Cornes, Belinda K.; Dauriz, Marco; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. [Cornes, Belinda K.; Dauriz, Marco; Meigs, James B.] Harvard Med Sch, Dept Med, Boston, MA USA. [Brody, Jennifer A.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Morrison, Alanna C.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Houston, TX 77030 USA. [Lipovich, Leonard] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Lipovich, Leonard] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48201 USA. [Dauriz, Marco] Univ Verona, Dept Med, Div Endocrinol Diabet & Metab, Sch Med, Verona, Italy. [Dauriz, Marco] Hosp Trust Verona, Verona, Italy. [Chen, Yuning; Liu, Ching-Ti; Dupuis, Josee] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA USA. [Rybin, Denis V.] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA. [Gibbs, Richard A.; Muzny, Donna] Univ Texas Hlth Sci Ctr Houston, Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth JSP, Minneapolis, MN 55455 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Siscovick, David S.] New York Acad Med, New York, NY USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Prevent Med & Epidemiol, Cardiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. [Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM jmeigs@mgh.harvard.edu RI Dauriz, Marco/S-5843-2016; OI Dauriz, Marco/0000-0002-5542-5941; Ramachandran, Vasan/0000-0001-7357-5970 FU U.S. CHARGE Consortium by the NIH through the American Recovery and Reinvestment Act (ARRA) [5RC2HL102419]; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; NHLBI; Boston University [N01 HC 25195]; Affymetrix, Inc. [N02-HL-6-4278]; NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA) [1R01AG031890, R01AG023629]; National Center for Advancing Translational Sciences, CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; Netherlands Organization for 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 Organization for Scientific Research (NWO) [050-060-810, 242244]; Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; [R01 DK078616]; [K24 DK080140] FX Funding support for 'Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium' was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). Data for 'Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium' were provided by Eric Boerwinkle on behalf of the Atherosclerosis Risk in Communities (ARIC) Study, L Adrienne Cupples, principal investigator for the Framingham Heart Study, and Bruce Psaty, principal investigator for the Cardiovascular Health Study. Sequencing was carried out at the Baylor Genome Center (U54 HG003273). The ARIC Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. N01 HC 25195), and its contract with Affymetrix, Inc., for genome-wide genotyping services (Contract No. N02-HL-6-4278), for quality control by Framingham Heart Study investigators using genotypes in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Clusters for Genetic Analysis (LinGA) computing resources at Boston University Medical Campus. Also supported by R01 DK078616 (Dr Meigs) and K24 DK080140 (Dr Meigs). This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through 1R01AG031890 and R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI Grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) Grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organization for 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 Organization for Scientific Research (NWO) project nr. 050-060-810, CHANCES (nr 242244). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 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 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD SEP PY 2016 VL 24 IS 9 BP 1337 EP 1343 DI 10.1038/ejhg.2016.4 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DU6FV UT WOS:000382310600016 PM 26860063 ER PT J AU Clark, AM Ma, B Taylor, DL Griffith, L Wells, A AF Clark, Amanda M. Ma, Bo Taylor, D. Lansing Griffith, Linda Wells, Alan TI Liver metastases: Microenvironments and ex-vivo models SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article DE Liver metastasis; metastatic models; tumor microenvironment; hepatic niche; microphysiological ID HEPATIC STELLATE CELLS; COLON-CARCINOMA CELLS; MACROPHAGE-MEDIATED CYTOTOXICITY; EXPERIMENTAL MELANOMA METASTASIS; STIMULATED KUPFFER CELLS; E-CADHERIN EXPRESSION; TUMOR-NECROSIS-FACTOR; BREAST-CANCER; HEPATOCELLULAR-CARCINOMA; ENDOTHELIAL-CELLS AB The liver is a highly metastasis-permissive organ, tumor seeding of which usually portends mortality. Its unique and diverse architectural and cellular composition enable the liver to undertake numerous specialized functions, however, this distinctive biology, notably its hemodynamic features and unique microenvironment, renders the liver intrinsically hospitable to disseminated tumor cells. The particular focus for this perspective is the bidirectional interactions between the disseminated tumor cells and the unique resident cell populations of the liver; notably, parenchymal hepatocytes and non-parenchymal liver sinusoidal endothelial, Kupffer, and hepatic stellate cells. Understanding the early steps in the metastatic seeding, including the decision to undergo dormancy versus outgrowth, has been difficult to study in 2D culture systems and animals due to numerous limitations. In response, tissue-engineered biomimetic systems have emerged. At the cutting-edge of these developments are ex vivo 'microphysiological systems' (MPS) which are cellular constructs designed to faithfully recapitulate the structure and function of a human organ or organ regions on a milli-to micro-scale level and can be made all human to maintain species-specific interactions. Hepatic MPSs are particularly attractive for studying metastases as in addition to the liver being a main site of metastatic seeding, it is also the principal site of drug metabolism and therapy-limiting toxicities. Thus, using these hepatic MPSs will enable not only an enhanced understanding of the fundamental aspects of metastasis but also allow for therapeutic agents to be fully studied for efficacy while also monitoring pharmacologic aspects and predicting toxicities. The review discusses some of the hepatic MPS models currently available and although only one MPS has been validated to relevantly modeling metastasis, it is anticipated that the adaptation of the other hepatic models to include tumors will not be long in coming. C1 [Clark, Amanda M.; Ma, Bo; Wells, Alan] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. [Taylor, D. Lansing; Wells, Alan] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15213 USA. [Taylor, D. Lansing; Wells, Alan] Univ Pittsburgh, Dept Computat & Syst Biol, Pittsburgh, PA 15213 USA. [Taylor, D. Lansing; Wells, Alan] Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA 15213 USA. [Taylor, D. Lansing] Univ Pittsburgh, Drug Discovery Inst, Pittsburgh, PA 15213 USA. [Taylor, D. Lansing] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. [Griffith, Linda] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Wells, Alan] VA Pittsburgh Healthcare Syst, Pittsburgh VA Med Ctr, Pittsburgh, PA 15240 USA. RP Wells, A (reprint author), Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA.; Wells, A (reprint author), Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15213 USA.; Wells, A (reprint author), Univ Pittsburgh, Dept Computat & Syst Biol, Pittsburgh, PA 15213 USA.; Wells, A (reprint author), Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA 15213 USA.; Wells, A (reprint author), VA Pittsburgh Healthcare Syst, Pittsburgh VA Med Ctr, Pittsburgh, PA 15240 USA. EM wellsa@upmc.edu OI Wells, Alan/0000-0002-1637-8150 FU NIH [UH3TR000496, UH3TR000503]; VA Merit Award FX We thank the members of the Wells, Taylor and Griffith groups and the UPitt Drug Discovery Institute for helpful discussions and feedback. We also thank our collaborators Donna Stolz, Raman Venkataramanan at UPitt, Doug Lauffenburger, and Dave Trumper at MIT. Concepts herein were funded through NIH grants UH3TR000496 (Griffith) and UH3TR000503 (Taylor), and a VA Merit Award (Wells). NR 126 TC 2 Z9 2 U1 6 U2 6 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1535-3702 EI 1535-3699 J9 EXP BIOL MED JI Exp. Biol. Med. PD SEP PY 2016 VL 241 IS 15 BP 1639 EP 1652 DI 10.1177/1535370216658144 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DU6FU UT WOS:000382310500002 PM 27390264 ER PT J AU Salameh, TS Rhea, EM Banks, WA Hanson, AJ AF Salameh, Therese S. Rhea, Elizabeth M. Banks, William A. Hanson, Angela J. TI Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article DE Alzheimer's disease; apolipoprotein E; dyslipidemia; insulin resistance; cognition ID BLOOD-BRAIN-BARRIER; CENTRAL-NERVOUS-SYSTEM; GROWTH-FACTOR EXPRESSION; GALANIN-LIKE PEPTIDE; INTRANASAL INSULIN; AMYLOID-BETA; E GENOTYPE; APOE GENOTYPE; GLUCOSE-METABOLISM; DIABETES-MELLITUS AB An increased risk for Alzheimer's disease is associated with dyslipidemia and insulin resistance. A separate literature shows the genetic risk for developing Alzheimer's disease is strongly correlated to the presence of the E4 isoform of the apolipoprotein E carrier protein. Understanding how apolipoprotein E carrier protein, lipids, amyloid beta peptides, glucose, central nervous system insulin, and peripheral insulin interact with one another in Alzheimer's disease is an area of increasing interest. Here, we will review the evidence relating apolipoprotein E carrier protein, lipids, and insulin action to Alzheimer's disease and Ab peptides and then propose mechanisms as to how these factors might interact with one another to impair cognition and promote Alzheimer's disease. C1 [Salameh, Therese S.; Rhea, Elizabeth M.; Banks, William A.; Hanson, Angela J.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Salameh, Therese S.; Rhea, Elizabeth M.; Banks, William A.; Hanson, Angela J.] Univ Washington, Sch Med, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. RP Banks, WA (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA.; Banks, WA (reprint author), Univ Washington, Sch Med, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. EM wabanks1@uw.edu FU National Institutes of Health National Institute on Aging [RO1 - AG046619, K23 AG047978-01]; AFAR Hartford Center of Excellence Award; Veterans Affairs Puget Sound Health Care System, Seattle, Washington; [T32 - AG000057] FX This research was supported by the National Institutes of Health National Institute on Aging RO1 - AG046619 for Salameh and Banks, K23 AG047978-01 and AFAR Hartford Center of Excellence Award to Hanson, and T32 - AG000057 for Rhea. This article results from work supported by resources from the Veterans Affairs Puget Sound Health Care System, Seattle, Washington. NR 105 TC 1 Z9 1 U1 5 U2 5 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1535-3702 EI 1535-3699 J9 EXP BIOL MED JI Exp. Biol. Med. PD SEP PY 2016 VL 241 IS 15 BP 1676 EP 1683 DI 10.1177/1535370216660770 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DU6FU UT WOS:000382310500006 PM 27470930 ER PT J AU Drel, VR Tan, CY Barnes, JL Gorin, Y Lee, DY Wagner, B AF Drel, Viktor R. Tan, Chunyan Barnes, Jeffrey L. Gorin, Yves Lee, Doug-Yoon Wagner, Brent TI Centrality of bone marrow in the severity of gadolinium-based contrast-induced systemic fibrosis SO FASEB JOURNAL LA English DT Article DE nephrogenic fibrosing dermopathy; skin diseases; NADPH oxidase; chemokine CCL2; CCR2 ID ACTIVATION; BIODISTRIBUTION; MACROPHAGES; FIBROCYTES; OXIDASE; INJURY; AGENTS; CELLS; MICE AB Systemic fibrosis can be induced in humans with gadolinium-based contrast, and cumulative doses correlate with severity. Bone marrow-derived fibrocytes accumulate in the dermis. Whether target organs liberate chemokines to recruit these fibrocytes or whether fibrocytes are stimulated to home to the affected tissue is unknown. Transgenic (tagged) donor rats were treated with gadolinium-based contrast. Bone marrow was obtained from diseased animals and age-matched controls. Rats with subtotal nephrectomies were lethally irradiated and underwent salvage transplantation with either the contrast-naive or contrast-exposed bone marrow. Groups were randomly assigned to control or contrast treatment. Contrast treatment led to dermal fibrosis, and this was exacerbated in recipients of contrast-exposed marrow. Fibronectin, C-C chemokine receptors (CCRs)2 and 7, and oxidative stress were all increased in skin from contrast-treated animalsall parameters more severe in recipients of contrast-treated animals. The respective ligands, monocyte chemoattractant protein and C-C motif ligand 19, were both elevated in skin from contrast-treated animals. Coadministration of gadolinium-based contrast and a CCR2 inhibitor reduced the severity of skin disease as well as dermal cellularity. The functional role of chemokines in the effects of gadolinium-based contrast was further confirmed in in situ coculture studies using neutralizing CCR2 antibodies. These data implicate dermal liberation of specific chemokines in the recruitment of circulating bone marrow-derived cells. The disease is augmented by bone marrow exposure to contrast, which explains why multiple exposures correlate with severity.Drel, V. R., Tan, C., Barnes, J. L., Gorin, Y., Lee, D.-Y., Wagner, B. Centrality of bone marrow in the severity of gadolinium-based contrast-induced systemic fibrosis. C1 [Drel, Viktor R.; Tan, Chunyan; Barnes, Jeffrey L.; Gorin, Yves; Lee, Doug-Yoon; Wagner, Brent] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Barnes, Jeffrey L.; Wagner, Brent] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Wagner, B (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Nephrol, Dept Med, 7703 Floyd Curl Dr,MC 7882, San Antonio, TX 78229 USA. EM wagnerb@uthscsa.edu FU Veterans Administration Merit [I01 BX001958]; U.S. National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK102085, R01-DK080106, R01-DK079996, R01-DK78971]; NIH National Center for Advancing Translational Sciences/Linked Specialized Center Cooperative Agreement [UL1-TR001120]; Qatar National Research Fund, National Priorities Research Program [NPRP8-1750-3-360] FX This work was funded by Veterans Administration Merit Award I01 BX001958 (to B.W.), U.S. National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases Grants R01-DK102085 (to B.W.), R01-DK080106 (to J.L.B.), R01-DK079996 (to Y.G.), and R01-DK78971 (to Y.G.), NIH National Center for Advancing Translational Sciences/Linked Specialized Center Cooperative Agreement Grant UL1-TR001120 (to Y.G.), and an award from the Qatar National Research Fund, National Priorities Research Program (NPRP8-1750-3-360) (to Y.G.). Author contributions: B. Wagner and Y. Gorin designed the research, analyzed the data, and wrote the paper; J. L. Barnes provided the hPAP donor animals; and C. Tan, D.-Y. Lee, and V. R. Drel performed the experiments. The authors declare no conflicts of interest. NR 23 TC 0 Z9 0 U1 1 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD SEP PY 2016 VL 30 IS 9 BP 3026 EP 3038 DI 10.1096/fj.201500188R PG 13 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA DV3JD UT WOS:000382816300004 PM 27221979 ER PT J AU Becattini, B Zani, F Breasson, L Sardi, C D'Agostino, VG Choo, MK Provenzani, A Park, JM Solinas, G AF Becattini, Barbara Zani, Fabio Breasson, Ludovic Sardi, Claudia D'Agostino, Vito Giuseppe Choo, Min-Kyung Provenzani, Alessandro Park, Jin Mo Solinas, Giovanni TI JNK1 ablation in mice confers long-term metabolic protection from diet-induced obesity at the cost of moderate skin oxidative damage SO FASEB JOURNAL LA English DT Article DE type-2 diabetes; insulin resistance; metabolic inflammation; antioxidants; oxidative stress tolerance ID EXTENDS LIFE-SPAN; INSULIN-RECEPTOR SUBSTRATE-1; HEME OXYGENASE-1 GENE; PROMOTES OBESITY; PROTEIN-KINASE; IN-VIVO; RESISTANCE; INFLAMMATION; PHOSPHORYLATION; ACTIVATION AB Obesity and insulin resistance are associated with oxidative stress, which may be implicated in the progression of obesity-related diseases. The kinase JNK1 has emerged as a promising drug target for the treatment of obesity and type 2 diabetes. JNK1 is also a key mediator of the oxidative stress response, which can promote cell death or survival, depending on the magnitude and context of its activation. In this article, we describe a study in which the long-term effects of JNK1 inactivation on glucose homeostasis and oxidative stress in obese mice were investigated for the first time. Mice lacking JNK1 (JNK1(-/-)) were fed an obesogenic high-fat diet (HFD) for a long period. JNK1(-/-) mice fed an HFD for the long term had reduced expression of antioxidant genes in their skin, more skin oxidative damage, and increased epidermal thickness and inflammation compared with the effects in control wild-type mice. However, we also observed that the protection from obesity, adipose tissue inflammation, steatosis, and insulin resistance, conferred by JNK1 ablation, was sustained over a long period and was paralleled by decreased oxidative damage in fat and liver. We conclude that compounds targeting JNK1 activity in brain and adipose tissue, which do not accumulate in the skin, may be safer and most effective.Becattini, B., Zani, F., Breasson, L., Sardi, C., D'Agostino, V. G., Choo, M.-K., Provenzani, A., Park, J. M., Solinas, G. JNK1 ablation in mice confers long-term metabolic protection from diet-induced obesity at the cost of moderate skin oxidative damage. C1 [Becattini, Barbara; Zani, Fabio; Breasson, Ludovic; Sardi, Claudia; Solinas, Giovanni] Univ Fribourg, Dept Med, Lab Metab Stress Biol, Fribourg, Switzerland. [D'Agostino, Vito Giuseppe; Provenzani, Alessandro] Univ Trento, Ctr Integrat Biol, Trento, Italy. [Choo, Min-Kyung; Park, Jin Mo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. [Choo, Min-Kyung; Park, Jin Mo] Harvard Med Sch, Charlestown, MA USA. [Becattini, Barbara; Breasson, Ludovic; Sardi, Claudia; Solinas, Giovanni] Univ Gothenburg, Dept Mol & Clin Med, Wallenberg Lab, S-41345 Gothenburg, Sweden. RP Solinas, G (reprint author), Univ Gothenburg, Dept Mol & Clin Med, Wallenberg Lab, S-41345 Gothenburg, Sweden. EM giovanni.solinas@wlab.gu.se OI Provenzani, Alessandro/0000-0003-1652-3415 FU Swiss National Science Foundation; Swedish Diabetes Foundation; Swedish Research Council; University of Gothenburg FX This work was supported by grants from the Swiss National Science Foundation, the Swedish Diabetes Foundation, the Swedish Research Council, and a startup package from the University of Gothenburg (to G.S.). Author contributions: B. Becattini and F. Zani performed most of the experiments, analyzed data, and contributed to the discussion; L. Breasson and C. Sardi performed experiments; V. G. D'Agostino and A. Provenzani performed the DNA microarray analysis; M.-K. Choo and J. M. Park performed the skin histopathological analysis and discussed the skin data; G. Solinas conceived the project, the experimental design, and wrote the manuscript; B. Becattini, F. Zani, A. Provenzani, M.-K. Choo and J. M. Park, significantly contributed to the writing of the manuscript with their comments; and all authors approved the paper. The authors declare no conflicts of interest. NR 44 TC 1 Z9 1 U1 1 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD SEP PY 2016 VL 30 IS 9 BP 3124 EP 3132 DI 10.1096/fj.201600393R PG 9 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA DV3JD UT WOS:000382816300013 PM 27230858 ER PT J AU Tang, SJ Vilmann, AS Saftoiu, A Wang, WM Streba, CT Fink, PP Griswold, M Wu, RN Dietrich, CF Jenssen, C Hocke, M Kantowski, M Pohl, J Fockens, P Annema, JT van der Heijden, EHFM Havre, RF Pham, KDC Kunda, R Deprez, PH Mariana, J Vazquez-Sequeiros, E Larghi, A Buscarini, E Fusaroli, P Lahav, M Puri, R Garg, PK Sharma, M Maluf, F Sahai, A Brugge, WR Lee, LS Aslanian, HR Wang, AY Shami, VM Markowitz, A Siddiqui, AA Mishra, G Scheiman, JM Isenberg, G Siddiqui, UD Shah, RJ Buxbaum, J Watson, RR Willingham, FF Bhutani, MS Levy, MJ Harris, C Wallace, MB Nolsoe, CP Lorentzen, T Bang, N Sorensen, SM Gilja, OH D'Onofrio, M Piscaglia, F Gritzmann, N Radzina, M Sparchez, ZA Sidhu, PS Freeman, S McCowan, TC de Araujo, CR Patel, A Ali, MA Campbell, G Chen, E Vilmann, P AF Tang, Shou-jiang Vilmann, Andreas S. Saftoiu, Adrian Wang, Wanmei Streba, Costin Teodor Fink, Peter P. Griswold, Michael Wu, Ruonan Dietrich, Christoph F. Jenssen, Christian Hocke, Michael Kantowski, Marcus Pohl, Juergen Fockens, Paul Annema, Jouke T. van der Heijden, Erik H. F. M. Havre, Roald Flesland Pham, Khanh Do-Cong Kunda, Rastislav Deprez, Pierre H. Mariana, Jinga Vazquez-Sequeiros, Enrique Larghi, Alberto Buscarini, Elisabetta Fusaroli, Pietro Lahav, Maor Puri, Rajesh Garg, Pramod Kumar Sharma, Malay Maluf-Filho, Fauze Sahai, Anand Brugge, William R. Lee, Linda S. Aslanian, Harry R. Wang, Andrew Y. Shami, Vanessa M. Markowitz, Arnold Siddiqui, Ali A. Mishra, Girish Scheiman, James M. Isenberg, Gerard Siddiqui, Uzma D. Shah, Raj J. Buxbaum, James Watson, Rabindra R. Willingham, Field F. Bhutani, Manoop S. Levy, Michael J. Harris, Cynthia Wallace, Michael B. Nolsoe, Christian Pallson Lorentzen, Torben Bang, Niels Sorensen, Sten Mellerup Gilja, Odd Helge D'Onofrio, Mirko Piscaglia, Fabio Gritzmann, Norbert Radzina, Maija Sparchez, Zeno Adrian Sidhu, Paul S. Freeman, Simon McCowan, Timothy C. de Araujo, Cyrillo Rodrigues, Jr. Patel, Akash Ali, Mohammad Adel Campbell, Garth Chen, Edward Vilmann, Peter TI EUS Needle Identification Comparison and Evaluation study (with videos) SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID ASPIRATION BIOPSY; ULTRASONOGRAPHIC ECHOGENICITY; BREAST SONOGRAPHY; IN-VITRO; ULTRASOUND; VISIBILITY; TECHNOLOGY; STANDARD AB Background and Aims: EUS-guided FNA or biopsy sampling is widely practiced. Optimal sonographic visualization of the needle is critical for image-guided interventions. Of the several commercially available needles, bench-top testing and direct comparison of these needles have not been done to reveal their inherent echogenicity. The aims are to provide bench-top data that can be used to guide clinical applications and to promote future device research and development. Methods: Descriptive bench-top testing and comparison of 8 commonly used EUS-FNA needles (all size 22 gauge): SonoTip Pro Control (Medi-Globe); Expect Slimline (Boston Scientific); EchoTip, EchoTip Ultra, EchoTip ProCore High Definition (Cook Medical); ClearView (Conmed); EZ Shot 2 (Olympus); and BNX (Beacon Endoscopic), and 2 new prototype needles, SonoCoat (Medi-Globe), coated by echogenic polymers made by Encapson. Blinded evaluation of standardized and unedited videos by 43 EUS endoscopists and 17 radiologists specialized in GI US examination who were unfamiliar with EUS needle devices. Results: There was no significant difference in the ratings and rankings of these needles between endosonographers and radiologists. Overall, 1 prototype needle was rated as the best, ranking 10% to 40% higher than all other needles (P < .01). Among the commercially available needles, the EchoTip Ultra needle and the ClearView needle were top choices. The EZ Shot 2 needle was ranked statistically lower than other needles (30%-75% worse, P < .001). Conclusions: All FNA needles have their inherent and different echogenicities, and these differences are similarly recognized by EUS endoscopists and radiologists. Needles with polymeric coating from the entire shaft to the needle tip may offer better echogenicity. C1 [Wu, Ruonan] Univ Mississippi, Med Ctr, Dept Med, Div Digest Dis, Jackson, MS 39216 USA. [Wang, Wanmei; Griswold, Michael] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA. [Vilmann, Andreas S.; Saftoiu, Adrian; Nolsoe, Christian Pallson; Lorentzen, Torben; Vilmann, Peter] Copenhagen Univ Hosp Herlev, GastroUnit, Copenhagen, Denmark. [Tang, Shou-jiang; Saftoiu, Adrian; Streba, Costin Teodor] Res Ctr Gastroenterol & Hepatol Craiova, Dept Gastroenterol, Craiova, Romania. [Fink, Peter P.] Medi Globe GmbH, Rosenheim, Germany. [Dietrich, Christoph F.] Caritas Krankenhaus Bad Mergentheim, Bad Mergentheim, Germany. [Jenssen, Christian] Krankenhaus Markisch Oderland GmbH, Strausberg, Germany. [Hocke, Michael] Helios Hosp Meiningen, Meiningen, Germany. [Kantowski, Marcus] Univ Hosp Hamburg Eppendorf, Hamburg, Germany. [Pohl, Juergen] Vivantes Klinikum Friedrichshain, Berlin, Germany. [Fockens, Paul; Annema, Jouke T.] Univ Amsterdam, Amsterdam, Netherlands. [van der Heijden, Erik H. F. M.] Radboud Univ Nijmegen, Med Ctr, Nijmegen, Netherlands. [Havre, Roald Flesland; Pham, Khanh Do-Cong] Haukeland Hosp, Bergen, Norway. [Kunda, Rastislav; Bang, Niels; Sorensen, Sten Mellerup] Aarhus Univ Hosp, Aarhus, Denmark. [Deprez, Pierre H.] Catholic Univ Louvain, Brussels, Belgium. [Mariana, Jinga] Univ Med & Pharm, Bucharest, Romania. [Vazquez-Sequeiros, Enrique] Univ Hosp Ramon y Cajal, Madrid, Spain. [Larghi, Alberto] Catholic Univ, Rome, Italy. [Buscarini, Elisabetta] Maggiore Hosp, Crema, Italy. [Fusaroli, Pietro; Piscaglia, Fabio] Univ Bologna, Dept Med & Surg Sci, Hosp Imola, Bologna, Italy. [Lahav, Maor] Tel Aviv Univ, Tel Aviv, Israel. [Puri, Rajesh] Inst Digest & Hepatobiliary Sci, Gurgaon, India. [Garg, Pramod Kumar] All India Inst Med Sci, New Delhi, India. [Sharma, Malay] Jaswant Rai Special Hosp, Uttar Pradersh, India. [Maluf-Filho, Fauze] Univ Sao Paulo, Inst Canc, Sao Paulo, Brazil. [Sahai, Anand] Ctr Hosp Univ Montreal, Montreal, PQ, Canada. [Brugge, William R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lee, Linda S.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Aslanian, Harry R.] Yale Univ, Sch Med, New Haven, CT USA. [Wang, Andrew Y.; Shami, Vanessa M.] Univ Virginia Hlth Syst, Div Gastroenterol & Hepatol, Charlottesville, VA USA. [Markowitz, Arnold] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Siddiqui, Ali A.] Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. [Mishra, Girish] Wake Forest Univ Hosp, Winston Salem, NC USA. [Scheiman, James M.] Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. [Isenberg, Gerard] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Siddiqui, Uzma D.] Univ Chicago, Chicago, IL 60637 USA. [Shah, Raj J.] Univ Colorado Hosp, Denver, CO USA. [Buxbaum, James] Univ South Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Watson, Rabindra R.] Univ Calif Los Angeles, Los Angeles, CA USA. [Willingham, Field F.] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Bhutani, Manoop S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Levy, Michael J.] Mayo Clin, Rochester, MN USA. [Harris, Cynthia] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Wallace, Michael B.] Mayo Clin Florida, Jacksonville, FL USA. [Gilja, Odd Helge] Haukeland Hosp, Natl Ctr Ultrasound Gastroenterol, Bergen, Norway. [Gilja, Odd Helge] Univ Bergen, Dept Clin Med, Bergen, Norway. [D'Onofrio, Mirko] GB Rossi Univ Hosp, Verona, Italy. [Gritzmann, Norbert] Ctr Radiol Esslinger, Vienna, Austria. [Radzina, Maija] Paula Stradina Clin Univ Hosp, Riga, Latvia. [Sparchez, Zeno Adrian] Univ Med & Pharm, Inst Gastroenterol & Hepatol, Dept Med 3, Cluj Napoca, Romania. [Sidhu, Paul S.] Kings Coll Hosp London, London, England. [Freeman, Simon] Derriford Hosp, Plymouth, Devon, England. [McCowan, Timothy C.; de Araujo, Cyrillo Rodrigues, Jr.; Patel, Akash; Ali, Mohammad Adel; Campbell, Garth] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Chen, Edward] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. RP Vilmann, P (reprint author), Copenhagen Univ Hosp Herlev, GastroUnit, Copenhagen, Denmark. RI D'Onofrio, Mirko/S-6828-2016; van der Heijden, H.F.M. (Erik)/D-3774-2009; OI D'Onofrio, Mirko/0000-0003-3229-9329; van der Heijden, H.F.M. (Erik)/0000-0003-3596-518X; Willingham, Field/0000-0002-7071-3001; Nolsoe, Christian Pallson/0000-0003-0168-6131; Sidhu, Paul/0000-0003-1928-4077 NR 17 TC 1 Z9 1 U1 4 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD SEP PY 2016 VL 84 IS 3 BP 424 EP + DI 10.1016/j.gie.2016.01.068 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DU5DY UT WOS:000382233600006 ER PT J AU Basar, O Brugge, WR AF Basar, Omer Brugge, William R. TI Which guidelines should be used for branch-duct intraductal papillary mucinous neoplasms? SO GASTROINTESTINAL ENDOSCOPY LA English DT Editorial Material ID INTERNATIONAL CONSENSUS GUIDELINES; CYSTIC NEOPLASMS; PANCREATIC CYSTS; MANAGEMENT C1 [Basar, Omer; Brugge, William R.] Massachusetts Gen Hosp, Gastrointestinal Unit, Pancreas Biliary Ctr, Boston, MA 02114 USA. [Basar, Omer] Hacettepe Med Sch, Dept Gastroenterol, Ankara, Turkey. RP Basar, O (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Pancreas Biliary Ctr, Boston, MA 02114 USA.; Basar, O (reprint author), Hacettepe Med Sch, Dept Gastroenterol, Ankara, Turkey. NR 11 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD SEP PY 2016 VL 84 IS 3 BP 446 EP 449 DI 10.1016/j.gie.2016.04.044 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DU5DY UT WOS:000382233600009 PM 27530478 ER PT J AU Yuen, EK Gros, K Welsh, KE McCauley, J Resnick, HS Danielson, CK Price, M Ruggiero, KJ AF Yuen, Erica K. Gros, Kirstin Welsh, Kyleen E. McCauley, Jenna Resnick, Heidi S. Danielson, Carla K. Price, Matthew Ruggiero, Kenneth J. TI Development and preliminary testing of a web-based, self-help application for disaster-affected families SO HEALTH INFORMATICS JOURNAL LA English DT Article DE ehealth; evidence-based practice; healthcare service innovation and IT; IT design and development methodologies; telecare ID RANDOMIZED CONTROLLED-TRIAL; POSTTRAUMATIC-STRESS-DISORDER; DEPRESSION; ANXIETY; INTERVENTION; ADOLESCENTS; PROGRAM AB Technology-based self-help interventions have the potential to increase access to evidence-based mental healthcare, especially for families affected by natural disasters. However, development of these interventions is a complex process and poses unique challenges. Usability testing, which assesses the ability of individuals to use an application successfully, can have a significant impact on the quality of a self-help intervention. This article describes (a) the development of a novel web-based multi-module self-help intervention for disaster-affected adolescents and their parents and (b) a mixed-methods formal usability study to evaluate user response. A total of 24 adolescents were observed, videotaped, and interviewed as they used the depressed mood component of the self-help intervention. Quantitative results indicated an above-average user experience, and qualitative analysis identified 120 unique usability issues. We discuss the challenges of developing self-help applications, including design considerations and the value of usability testing in technology-based interventions, as well as our plan for widespread dissemination. C1 [Yuen, Erica K.] Univ Tampa, Tampa, FL 33606 USA. [Gros, Kirstin; Ruggiero, Kenneth J.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Gros, Kirstin; Welsh, Kyleen E.; McCauley, Jenna; Resnick, Heidi S.; Danielson, Carla K.; Ruggiero, Kenneth J.] Med Univ South Carolina, Charleston, SC USA. [Price, Matthew] Univ Vermont, Burlington, VT 05405 USA. RP Yuen, EK (reprint author), Univ Tampa, Dept Psychol, 401 W Kennedy Blvd,Box Q, Tampa, FL 33606 USA. EM eyuen@ut.edu FU National Institute of Mental Health (NIMH) [R01 MH081056]; NIMH [T32 MH018869] 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 National Institute of Mental Health (NIMH) Grant #R01 MH081056 (PI: Ruggiero). Dr. Price was supported by NIMH Grant T32 MH018869 (PI: Kilpatrick). Views presented in this article do not necessarily reflect those of the funding agency. NR 43 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1460-4582 EI 1741-2811 J9 HEALTH INFORM J JI Health Inform. J. PD SEP PY 2016 VL 22 IS 3 BP 659 EP 675 DI 10.1177/1460458215579292 PG 17 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA DU9NC UT WOS:000382543400018 PM 25933798 ER PT J AU Justo, F Fuller, H Nearing, BD Rajamani, S Belardinelli, L Verrier, RL AF Justo, Fernanda Fuller, Henrique Nearing, Bruce D. Rajamani, Sridharan Belardinelli, Luiz Verrier, Richard L. TI Inhibition of the cardiac late sodium current with eleclazine protects against ischemia-induced vulnerability to atrial fibrillation and reduces atrial and ventricular repolarization abnormalities in the absence and presence of concurrent adrenergic stimulation SO HEART RHYTHM LA English DT Article DE Atrial fibrillation; Repolarization; Alternans; Heterogeneity; Epinephrine; Late sodium current ID T-WAVE ALTERNANS; AUTONOMIC NERVOUS-SYSTEM; LATE NA+ CURRENT; ARRHYTHMIAS; RANOLAZINE; GS-458967; POTENT; HETEROGENEITY; TACHYCARDIA; DEATH AB BACKGROUND Myocardial ischemia carries dual risk for initiating atrial and ventricular arrhythmias that can be exacerbated by adrenergic stimulation. OBJECTIVE The purpose of this study was to investigate whether selective inhibition of the cardiac late sodium current (I-Na) with eleclazine decreases susceptibility to ischemia-induced atrial fibrillation (AF) and atrial and ventricular repolarization abnormalities before and after epinephrine infusion. METHODS In chloralose-anesthetized, open-chest, male Yorkshire pigs (n = 12), atrial and ventricular ischemia was induced by partial occlusion of the left circumflex coronary artery proximal segment to reduce flow by 75%. Epinephrine (0.5 mu g/kg IV bolus over 1 minute; n = 6) was infused before and at 2 hours after eleclazine (0.9 mg/ kg IV bolus over 15 minutes). RESULTS Left circumflex coronary artery occlusion significantly increased ventricular dispersion of repolarization (T-wave alternans [TWA] by 861%, T-wave heterogeneity by 286%, T-peak-T-end interval by 74%) and atrial repolarization alternans (TWA(a)) by 2850% and lowered AF threshold by 65%. Eleclazine reduced the ischemia-induced surge in TWA by 81% (P =.007), T-wave heterogeneity by 23% (P=.035), and T-peak-T-end by 28% (P=.014), suppressed the ischemia-induced surge in atrial TWA(a) by 64% (P=.002), and reduced the ischemia-induced fall in AF threshold to 20%. It shortened baseline QT interval by 6% (P<.001), JT interval by 8% (P<.001), and atrial action potential duration (PTa) by 8% (P=.002). Similar beneficial effects of eleclazine were observed after epinephrine infusion without reducing contractility (P=.054). CONCLUSION Selective inhibition of cardiac late INa with eleclazine confers dual protection against vulnerability to ischemia-induced AF and reduces atrial and ventricular repolarization abnormalities before and during adrenergic stimulation without negative inotropic effects. C1 [Justo, Fernanda; Fuller, Henrique; Nearing, Bruce D.; Verrier, Richard L.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Justo, Fernanda; Fuller, Henrique] Univ Sao Paulo, Fac Med, Sao Paulo, Brazil. [Nearing, Bruce D.; Verrier, Richard L.] Harvard Med Sch, Boston, MA USA. [Rajamani, Sridharan; Belardinelli, Luiz] Gilead Sci Inc, Fremont, CA USA. [Rajamani, Sridharan; Belardinelli, Luiz] Gilead Sci Inc, Foster City, CA USA. RP Verrier, RL (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, Harvard Thorndike Electrophysiol Inst, 99 Brookline Ave,RN 301, Boston, MA 02215 USA. EM rverrier@bidmc.harvard.edu FU Gilead Sciences; Science without Borders Program of Brazil FX This study was funded by a grant from Gilead Sciences to Beth Israel Deaconess Medical Center (Dr. Verrier, Principal Investigator). Ms. Justo and Mr. Fuller received support from the Science without Borders Program of Brazil administered by CAPES, the Brazilian Coordinating Office for the Advancement of Higher Education. Dr. Belardinelli and Dr. Rajamani were employees of Gilead Sciences, the company that supported this study. Drs. Verrier and Nearing received royalties from Georgetown University and Beth Israel Deaconess Medical Center for intellectual property on the Modified Moving Average method for TWA analysis, which was licensed to GE Healthcare and was used in this study. NR 34 TC 4 Z9 4 U1 3 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 EI 1556-3871 J9 HEART RHYTHM JI Heart Rhythm PD SEP PY 2016 VL 13 IS 9 BP 1860 EP 1867 DI 10.1016/j.hrthm.2016.06.020 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DU6ER UT WOS:000382307400021 PM 27317981 ER PT J AU van den Heuvel, MP Scholtens, LH Turk, E Mantini, D Vanduffel, W Barrett, LF AF van den Heuvel, Martijn P. Scholtens, Lianne H. Turk, Elise Mantini, Dante Vanduffel, Wim Barrett, Lisa Feldman TI Multimodal Analysis of Cortical Chemoarchitecture and Macroscale fMRI Resting-State Functional Connectivity SO HUMAN BRAIN MAPPING LA English DT Article DE fMRI; functional connectivity; chemoarchitecture; receptor; excitatory; inhibitory; connectome; resting-state fMRI ID HUMAN CEREBRAL-CORTEX; RICH CLUB ORGANIZATION; HUMAN BRAIN; SPONTANEOUS FLUCTUATIONS; RECEPTOR FINGERPRINTS; MACAQUE CONNECTOME; GENETIC-CONTROL; DEFAULT MODE; NETWORKS; SCHIZOPHRENIA AB The cerebral cortex is well known to display a large variation in excitatory and inhibitory chemoarchitecture, but the effect of this variation on global scale functional neural communication and synchronization patterns remains less well understood. Here, we provide evidence of the chemoarchitecture of cortical regions to be associated with large-scale region-to-region resting-state functional connectivity. We assessed the excitatory versus inhibitory chemoarchitecture of cortical areas as an ExIn ratio between receptor density mappings of excitatory ( AMPA, M-1) and inhibitory ( GABA(A), M-2) receptors, computed on the basis of data collated from pioneering studies of autoradiography mappings as present in literature of the human ( 2 datasets) and macaque ( 1 dataset) cortex. Cortical variation in ExIn ratio significantly correlated with total level of functional connectivity as derived from restingstate functional connectivity recordings of cortical areas across all three datasets ( human I: P50.0004; human II: P=0.0008; macaque: P=0.0007), suggesting cortical areas with an overall more excitatory character to show higher levels of intrinsic functional connectivity during resting-state. Our findings are indicative of the microscale chemoarchitecture of cortical regions to be related to resting-state fMRI connectivity patterns at the global system's level of connectome organization. (C) 2016 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc. C1 [van den Heuvel, Martijn P.; Scholtens, Lianne H.; Turk, Elise] Univ Med Ctr Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Heidelberglaan 100,POB 85500,Room A01-126, NL-3508 GA Utrecht, Netherlands. [Mantini, Dante; Vanduffel, Wim] Katholieke Univ Leuven, Lab Neuro & Psychophysiol, Leuven, Belgium. [Mantini, Dante] Katholieke Univ Leuven, Movement Control & Neuroplast Res Grp, Leuven, Belgium. [Mantini, Dante] Swiss Fed Inst Technol, Dept Hlth Sci & Technol, Zurich, Switzerland. [Vanduffel, Wim] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Dept Psychiat, Psychiat Neuroimaging Program, Charlestown, MA USA. [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP van den Heuvel, MP (reprint author), Univ Med Ctr Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Heidelberglaan 100,POB 85500,Room A01-126, NL-3508 GA Utrecht, Netherlands. EM M.P.vandenheuvel@umcutrecht.nl OI Mantini, Dante/0000-0001-6485-5559 FU Human Connectome Project, WU-Minn Consortium; NIH; McDonnell Center for Systems Neuroscience at Washington University [1U54MH091657]; Netherlands Organisation for Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek) Innovational Research Incentives Scheme VENI [451-12-001] FX Contract grant sponsor: Human Connectome Project, WU-Minn Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil; 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University); Contract grant number: 1U54MH091657; Contract grant sponsor: Netherlands Organisation for Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek) Innovational Research Incentives Scheme VENI; Contract grant number: 451-12-001 NR 81 TC 2 Z9 2 U1 9 U2 12 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 SEP PY 2016 VL 37 IS 9 BP 3103 EP 3113 DI 10.1002/hbm.23229 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DU8SL UT WOS:000382484600003 PM 27207489 ER PT J AU Lerma-Usabiaga, G Iglesias, JE Insausti, R Greve, DN Paz-Alonso, PM AF Lerma-Usabiaga, Garikoitz Eugenio Iglesias, Juan Insausti, Ricardo Greve, Douglas N. Paz-Alonso, Pedro M. TI Automated Segmentation of the Human Hippocampus Along Its Longitudinal Axis SO HUMAN BRAIN MAPPING LA English DT Article DE hippocampus; magnetic resonance imaging; neuroanatomy; principal component analysis; reproducibility of results; segmentation ID MILD COGNITIVE IMPAIRMENT; TEMPORAL-LOBE REGIONS; HIGH-RESOLUTION MRI; IN-VIVO MRI; ALZHEIMERS-DISEASE; VOLUME MEASUREMENTS; ENTORHINAL CORTEX; VERBAL MEMORY; AMYGDALA; RELIABILITY AB The human hippocampal formation is a crucial brain structure for memory and cognitive function that is closely related to other subcortical and cortical brain regions. Recent neuroimaging studies have revealed differences along the hippocampal longitudinal axis in terms of structure, connectivity, and function, stressing the importance of improving the reliability of the available segmentation methods that are typically used to divide the hippocampus into its anterior and posterior parts. However, current segmentation conventions present two main sources of variability related to manual operations intended to correct in-scanner head position across subjects and the selection of dividing planes along the longitudinal axis. Here, our aim was twofold: ( 1) to characterize inter-and intra-rater variability associated with these manual operations and compare manual ( landmark based) and automatic ( percentage based) hippocampal anterior-posterior segmentation procedures; and ( 2) to propose and test automated rotation methods based on approximating the hippocampal longitudinal axis to a straight line ( estimated with principal component analysis, PCA) or a quadratic Bezier curve ( fitted with numerical methods); as well as an automated anterior-posterior hippocampal segmentation procedure based on the percentage-based method. Our results reveal that automated rotation and segmentation procedures, used in combination or independently, minimize inconsistencies generated by the accumulation of manual operations while providing higher statistical power to detect well-known effects. A Matlab-based implementation of these procedures is made publicly available to the research community. (C) 2016 Wiley Periodicals, Inc. C1 [Lerma-Usabiaga, Garikoitz; Eugenio Iglesias, Juan; Paz-Alonso, Pedro M.] BCBL Basque Ctr Cognit Brain & Language, Donostia San Sebastian, Spain. [Insausti, Ricardo] Univ Castilla La Mancha, Dept Hlth Sci, Human Neuroanat Lab, Albacete, Spain. [Insausti, Ricardo] Univ Castilla La Mancha, Sch Med, Reg Ctr Biomed Res, Albacete, Spain. [Greve, Douglas N.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Greve, Douglas N.] Harvard Med Sch, Charlestown, MA USA. RP Lerma-Usabiaga, G (reprint author), Basque Ctr Cognit Brain & Language, Paseo Mikeletegi 69,2nd Floor, Donostia San Sebastian 20009, Gipuzkoa, Spain. EM g.lerma@bcbl.eu OI Lerma-Usabiaga, Garikoitz/0000-0001-9800-4816 FU EMBO [158-2015]; Spanish Ministry of Economy and Competitiveness (MINECO) [TEC2014-51882-P]; European Union [654911]; "Ramon y Cajal" Fellowship [PSI2012-32093, PSI2015-65696, RYC-2014-15440]; MINECO [SEV-2015-049] FX Contract grant sponsor: EMBO Short-Term Fellowship (158-2015) to G.L-U.; Contract grant sponsor: Spanish Ministry of Economy and Competitiveness (MINECO; to J.E.I. and G.L-U.); Contract grant number: TEC2014-51882-P; Contract grant sponsor: European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 654911 (project "THALAMODEL"; to J.E.I.); Contract grant sponsor: "Ramon y Cajal" Fellowship; Contract grant numbers: PSI2012-32093, PSI2015-65696, and RYC-2014-15440; Contract grant sponsor: MINECO (Severo Ochoa programe to P.M.P-A.; SEV-2015-049) NR 43 TC 0 Z9 0 U1 9 U2 9 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 SEP PY 2016 VL 37 IS 9 BP 3353 EP 3367 DI 10.1002/hbm.23245 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DU8SL UT WOS:000382484600020 PM 27159325 ER PT J AU Fan, J Yang, MX Ouyang, Q Fu, DL Xu, ZD Liu, XP Mino-Kenudson, M Geng, J Tang, F AF Fan, Jie Yang, Michelle X. Ouyang, Qi Fu, Deliang Xu, Zude Liu, Xiuping Mino-Kenudson, Mari Geng, Jiang Tang, Feng TI Phosphatase PPM1A is a novel prognostic marker in pancreatic ductal adenocarcinoma SO HUMAN PATHOLOGY LA English DT Article DE Phosphatase; PPM1A; Pancreatic ductal adenocarcinoma; Prognosis, marker; Smad4; TGF-beta; Immunohistochemistry ID CANCER-CELL-LINES; TGF-BETA; SIGNALING PATHWAY; SMAD4 PROTEIN; EXPRESSION; INVASION; GROWTH; PROGRESSION; METASTASIS; SURVIVAL AB Pancreatic ductal adenocarcinoma (PDAC) harbors complex molecular alterations and remains a lethal disease. Aberrant TGF-beta/Smads signaling is a well-known mechanism involved in the progression of PDACs. However, loss of Smad4 expression is reported in only 50% of PDACs and is generally associated with worse prognosis. Investigating additional prognostic markers is warranted. PPM1A is a phosphatase that dephosphorylates TGF-beta activated Smad2/3 and inactivates the TGF-beta signaling. Little is known about the clinical significance of PPM1A in PDACs and its functional relationship to Smad4. In this study, PPM1A and Smad4 immunohistochemistry was assessed in 180 R0 resected human PDACs. PPM1A was lost in 41.7% cases, whereas Smad4 was lost in 45.7% cases. The median survival rate with negative and positive PPM1A was 10.9 and 16.8 months, respectively. Loss of PPM1A was significantly associated with larger tumor size and higher stage and was an independent predictor of unfavorable outcomes. Intriguingly, the overall survival of this cohort was divided into 3 groups based on the expression pattern of PPM1A and Smad4, with the Smad4+/PPM1A+ pattern associated with favorable survival, the Smad4+/PPM1A- or Smad4-/PPM1A- pattern associated with unfavorable, and the PPM1A+/Smad4- pattern fell between these 2 groups. In 82 cases with negative Smad4, PPM1A or P-Smad2/3 expression was retained. Using a SMAD4-deficient human PDAC cell line, BxPC3, we further demonstrated that TGF-beta 1 treatment induced PPM1A and P-Smad2/3 expression in this cell line. PPM1A and Smad4 immunohistochemistry in surgical specimens may provide more accurate prognostic stratification for patients with PDAC. (C) 2016 Elsevier Inc. All rights reserved. C1 [Fan, Jie; Xu, Zude; Tang, Feng] Fudan Univ, Huashan Hosp, Dept Pathol, 12 Wulumuqi Rd, Shanghai 200040, Peoples R China. [Yang, Michelle X.] Univ Vermont, Med Ctr, Dept Pathol, Burlington, VT 05401 USA. [Ouyang, Qi] Fudan Univ, Huadong Hosp, Dept Pathol, Shanghai 200040, Peoples R China. [Fu, Deliang] Fudan Univ, Huashan Hosp, Dept Pancreat Surg, Shanghai 200040, Peoples R China. [Liu, Xiuping] Fudan Univ, Sch Basic Med Sci, Dept Pathol, Shanghai 200032, Peoples R China. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Geng, Jiang] Tongji Univ, Shanghai Peoples Hosp 10th, Dept Urol, 301 Yan Chang Rd, Shanghai 200072, Peoples R China. RP Tang, F (reprint author), Fudan Univ, Huashan Hosp, Dept Pathol, 12 Wulumuqi Rd, Shanghai 200040, Peoples R China.; Geng, J (reprint author), Tongji Univ, Shanghai Peoples Hosp 10th, Dept Urol, 301 Yan Chang Rd, Shanghai 200072, Peoples R China. EM gengjiangsn@sina.com; tangfeng1996@sina.com FU National Natural Science Foundation of China [81001134, 81101803, 81272387] FX This work was supported by National Natural Science Foundation of China (81001134, to J. F.). Portions of this study were funded by National Natural Science Foundation of China (81101803, to J. G., and 81272387, to X. P. L.). NR 33 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 0046-8177 EI 1532-8392 J9 HUM PATHOL JI Hum. Pathol. PD SEP PY 2016 VL 55 BP 151 EP 158 DI 10.1016/j.humpath.2016.05.002 PG 8 WC Pathology SC Pathology GA DT5RW UT WOS:000381541300020 PM 27195906 ER PT J AU Wrzosek, MK Peacock, ZS Laviv, A Goldwaser, BR Ortiz, R Resnick, CM Troulis, MJ Kaban, LB AF Wrzosek, M. K. Peacock, Z. S. Laviv, A. Goldwaser, B. R. Ortiz, R. Resnick, C. M. Troulis, M. J. Kaban, L. B. TI Comparison of time required for traditional versus virtual orthognathic surgery treatment planning SO INTERNATIONAL JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Association-of-Oral-and-Maxillofacial-Surgeons CY 2015 CL Washington, DC SP Amer Assoc Oral & Maxillofacial Surg DE model surgery; splint construction; virtual surgical planning; orthognathic surgery; resident work-hours ID AIDED SURGICAL SIMULATION; RESIDENTS; REGULATIONS; EFFICIENCY; EDUCATION AB Virtual surgical planning (VSP) is a tool for predicting complex surgical movements in three dimensions and it may reduce preoperative laboratory time. A prospective study to compare the time required for standard preoperative planning versus VSP was conducted at Massachusetts General Hospital from January 2014 through January 2015. Workflow data for bimaxillary cases planned by both standard techniques and VSP were recorded in real time. Time spent was divided into three parts: (1) obtaining impressions, face-bow mounting, and model preparation; (2) occlusal analysis and modification, model surgery, and splint fabrication; (3) online VSP session. Average times were compared between standard treatment planning (sum of parts 1 and 2) and VSP (sum of parts 1 and 3). Of 41 bimaxillary cases included, 20 were simple (symmetric) and 21 were complex (asymmetry and segmental osteotomies). Average times for parts 1, 2, and 3 were 4.43, 3.01, and 0.67 h, respectively. The average time required for standard treatment planning was 7.45 h and for VSP was 5.10 h, a 31% time reduction (P < 0.001). By eliminating all or some components of part 1, time savings may increase to as much as 91%. This study indicates that in an academic setting, VSP reduces the time required for treatment planning of bimaxillary orthognathic surgery cases. C1 [Wrzosek, M. K.; Peacock, Z. S.; Laviv, A.; Goldwaser, B. R.; Ortiz, R.; Resnick, C. M.; Troulis, M. J.; Kaban, L. B.] Harvard Sch Dent Med, Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA USA. RP Peacock, ZS (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Warren 1201,55 Fruit St, Boston, MA 02114 USA. EM zpeacock@partners.org NR 22 TC 0 Z9 0 U1 2 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0901-5027 EI 1399-0020 J9 INT J ORAL MAX SURG JI Int. J. Oral Maxillofac. Surg. PD SEP PY 2016 VL 45 IS 9 BP 1065 EP 1069 DI 10.1016/j.ijom.2016.03.012 PG 5 WC Dentistry, Oral Surgery & Medicine; Surgery SC Dentistry, Oral Surgery & Medicine; Surgery GA DV3CM UT WOS:000382798600002 PM 27102289 ER PT J AU Xia, CJ Dickerson, BC AF Xia, Chenjie Dickerson, Bradford C. TI Tau PET: the next frontier in molecular imaging of dementia SO INTERNATIONAL PSYCHOGERIATRICS LA English DT Editorial Material ID ALZHEIMERS-DISEASE; PATHOLOGY; TRACER; BRAIN AB We have arrived at an exciting juncture in dementia research: the second major pathological hallmark of Alzheimer's disease (AD)-tau-can now be seen for the first time in the living human brain. The major proteinopathies in AD include amyloid- plaques and neurofibrillary tangles (NFTs) made of hyperphosphorylated paired helical filament (PHF) tau. Since its advent more than a decade ago, amyloid PET imaging has revolutionized the field of dementia research, enabling more confident diagnosis of the likely pathology in patients with a variety of clinical dementia syndromes, paving the way for the identification of people with preclinical or prodromal AD pathology, and serving as a minimally invasive molecular readout in clinical trials of putative disease-modifying interventions. Now that we are on the brink of a second revolution in molecular imaging in dementia, it is worth considering the likely potential impact of this development on the field. C1 [Xia, Chenjie; Dickerson, Bradford C.] Massachusetts Gen Hosp, Frontotemporal Disorders Unit, Dept Neurol, Charlestown, MA 02129 USA. [Xia, Chenjie; Dickerson, Bradford C.] Harvard Med Sch, Charlestown, MA 02129 USA. [Dickerson, Bradford C.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Dickerson, BC (reprint author), Massachusetts Gen Hosp, Frontotemporal Disorders Unit, Dept Neurol, Charlestown, MA 02129 USA.; Dickerson, BC (reprint author), Harvard Med Sch, Charlestown, MA 02129 USA.; Dickerson, BC (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM brad.dickerson@mgh.harvard.edu FU [R01 AG046396]; [R21 NS084156] FX R01 AG046396 & R21 NS084156. NR 15 TC 0 Z9 0 U1 5 U2 5 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1041-6102 EI 1741-203X J9 INT PSYCHOGERIATR JI Int. Psychogeriatr. PD SEP PY 2016 VL 28 IS 9 BP 1403 EP 1406 DI 10.1017/S1041610216000880 PG 4 WC Psychology, Clinical; Geriatrics & Gerontology; Gerontology; Psychiatry; Psychology SC Psychology; Geriatrics & Gerontology; Psychiatry GA DU7HP UT WOS:000382385000001 PM 27334648 ER PT J AU Deutsch, MB Liang, LJ Jimenez, EE Mather, MJ Mendez, MF AF Deutsch, Mariel B. Liang, Li-Jung Jimenez, Elvira E. Mather, Michelle J. Mendez, Mario F. TI Are we comparing frontotemporal dementia and Alzheimer disease patients with the right measures? SO INTERNATIONAL PSYCHOGERIATRICS LA English DT Article DE Alzheimer disease; behavioral and psychological symptoms of dementia; frontotemporal dementia; neuropsychiatric symptoms; research design and methodology ID COGNITIVE IMPAIRMENT; VARIANT AB Background: Clinical research studies of behavioral variant frontotemporal dementia (bvFTD) often use Alzheimer disease (AD) as a comparison group for control of dementia variables, using tests of cognitive function to match the groups. These two dementia syndromes, however, are very different in clinical manifestations, and the comparable severity of these dementias may not be reflected by commonly used cognitive scales such as the Mini-Mental State Examination (MMSE). Methods: We evaluated different measures of dementia severity and symptoms among 20 people with bvFTD compared to 24 with early-onset AD. Results: Despite similar ages, disease-duration, education, and cognitive performance on two tests of cognitive function, the MMSE and the Montreal Cognitive Assessment (MoCA), the bvFTD participants, compared to the AD participants, were significantly more impaired on other measures of disease severity, including function (Functional Assessment Questionnaire (FAQ)), neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI)), and global dementia stage (Clinical Dementia Rating Scales (CDRs)). However, when we adjusted for the frontotemporal lobar degeneration-CDR (FTLD-CDR) in the analyses, the two dementia groups were comparable across all measures despite significant differences on the cognitive scales. Conclusion: We found tests of cognitive functions (MMSE and MoCA) to be insufficient measures for ensuring comparability between bvFTD and AD groups. In clinical studies, the FTLD-CDR, which includes additional language and behavior items, may be a better overall way to match bvFTD and AD groups on dementia severity. C1 [Deutsch, Mariel B.; Jimenez, Elvira E.; Mather, Michelle J.; Mendez, Mario F.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Deutsch, Mariel B.; Jimenez, Elvira E.; Mendez, Mario F.] Vet Affairs Greater Los Angeles Healthcare Syst, Neurobehav Unit, Los Angeles, CA USA. [Liang, Li-Jung] Univ Calif Los Angeles, David Geffen Sch Med, Med Stat Core, Los Angeles, CA 90095 USA. [Mendez, Mario F.] Univ Calif Los Angeles, David Geffen Sch Med, Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. RP Deutsch, MB (reprint author), Icahn Sch Med Mt Sinai, Dept Neurol, 1 Gustave L Levy Pl,Box 1139, New York, NY 10029 USA. EM mariel.deutsch@mssm.edu OI Deutsch, Mariel/0000-0003-1228-8868 FU NIH [R01AG034499-05] FX Dr. Mendez has previously received a grant (#R01AG034499-05) from the NIH, and receives royalties from Oxford University Press, Cambridge for book publications. The remaining authors have reported no conflicts of interest. NR 16 TC 1 Z9 1 U1 2 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1041-6102 EI 1741-203X J9 INT PSYCHOGERIATR JI Int. Psychogeriatr. PD SEP PY 2016 VL 28 IS 9 BP 1481 EP 1485 DI 10.1017/S1041610216000582 PG 5 WC Psychology, Clinical; Geriatrics & Gerontology; Gerontology; Psychiatry; Psychology SC Psychology; Geriatrics & Gerontology; Psychiatry GA DU7HP UT WOS:000382385000008 PM 27079571 ER PT J AU Mallick, A Gandhi, PU Gaggin, HK Ibrahim, N Januzzi, JL AF Mallick, Aditi Gandhi, Parul U. Gaggin, Hanna K. Ibrahim, Nasrien Januzzi, James L. TI The Importance of Worsening Heart Failure in Ambulatory Patients Definition, Characteristics, and Effects of Amino-Terminal Pro-B-Type Natriuretic Peptide Guided Therapy SO JACC-HEART FAILURE LA English DT Article DE biomarkers; chronic heart failure; worsening heart failure ID PROTECT; TRIAL; ST2 AB OBJECTIVES The goal of this study was to define and assess the significance of worsening heart failure (WHF) in patients with chronic ambulatory heart failure with reduced ejection fraction (HFrEF). may BACKGROUND WHF has been identified as a potentially relevant clinical event in patients with acute heart failure (HF) and is increasingly used as an endpoint in clinical trials. No standardized definition of WHF exists. It remains uncertain how WHF relates to risk for other HF events or how treatment may affect WHF. METHODS A total of 151 symptomatic patients with chronic HFrEF were randomized to standard of care HF management or a goal to lower N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations <= 1,000 pg/ml in addition to standard of care. WHF was prospectively defined as: 1) new or progressive symptoms and/or signs of decompensated HF; and 2) unplanned intensification of diuretic therapy. RESULTS Over a mean follow-up of 10 months, 45 subjects developed WHF. At baseline, patients developing incident WHF had higher ejection fraction (31% vs. 25%; p = 0.03), were more likely to have jugular venous distension and edema (p < 0.02), were less likely to receive angiotensin-converting enzyme inhibitors or received these agents at Lower doses (p < 0.04), and also received higher loop diuretic doses (p < 0.001). Occurrence of WHF was strongly associated with subsequent HF hospitalization/cardiovascular death (hazard ratio, landmark analysis: 18.8; 95% confidence interval: 5.7 to 62.5; p < 0.001). NT-proBNP-guided care reduced the incidence of WHF in adjusted analyses (hazard ratio: 0.52; p = 0.06) and improved event-free survival (log-rank test p = 0.04). CONCLUSIONS In chronic HFrEF, WHF was associated with substantial risk for morbidity and mortality. NT-proBNP-guided care reduced risk for WHF. (C) 2016 by the American College of Cardiology Foundation. C1 [Mallick, Aditi; Gaggin, Hanna K.; Ibrahim, Nasrien; Januzzi, James L.] Massachusetts Gen Hosp, Div Cardiol, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. [Gandhi, Parul U.] VA Connecticut Hlthcare Syst, Cardiol Div, West Haven, CT USA. [Gandhi, Parul U.] Yale Sch Med, New Haven, CT USA. [Gaggin, Hanna K.; Januzzi, James L.] Harvard Clin Res Inst, Boston, MA USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. EM jjanuzzi@mgh.harvard.edu NR 15 TC 2 Z9 2 U1 4 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD SEP PY 2016 VL 4 IS 9 BP 749 EP 755 DI 10.1016/j.jchf.2016.03.012 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DV4OV UT WOS:000382905800009 PM 27179830 ER PT J AU Ahonkhai, AA Banigbe, B Adeola, J Adegoke, AB Regan, S Bassett, IV Idigbe, I Losina, E Okonkwo, P Freedberg, KA AF Ahonkhai, Aimalohi A. Banigbe, Bolanle Adeola, Juliet Adegoke, Abdulkabir B. Regan, Susan Bassett, Ingrid V. Idigbe, Ifeoma Losina, Elena Okonkwo, Prosper Freedberg, Kenneth A. TI Age Matters: Increased Risk of Inconsistent HIV Care and Viremia Among Adolescents and Young Adults on Antiretroviral Therapy in Nigeria SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Adolescents; HIV; Young adults; Older adults; Inconsistent care; Retention; Viremia; ART; Resource-limited setting ID SUB-SAHARAN AFRICA; INFECTED ADOLESCENTS; MEDICATION ADHERENCE; TREATMENT OUTCOMES; SOUTH-AFRICA; YOUTH; CHALLENGES; PROGRAM; INTERRUPTIONS; EPIDEMIOLOGY AB Purpose: Interruptions in HIV care are a major cause of morbidity and mortality, particularly in resource-limited settings. We compared engagement in care and virologic outcomes between HIV-infected adolescents and young adults (AYA) and older adults (OA) one year after starting anti-retroviral therapy (ART) in Nigeria. Methods: We conducted a retrospective cohort study of AYA (15-24 years) and OA (>24 years) who initiated ART from 2009-2011. We used negative binomial regression to model the risk of inconsistent care and viremia (HIV RNA >1,000 copies/mL) among AYA and OA in the first year on ART. Regular care included monthly ART pickup and 3-monthly clinical visits. Patients with <= 3 months between consecutive visits were considered in care. Those with inconsistent care had >3 months between consecutive visits. Results: The cohort included 354 AYA and 2,140 OA. More AYA than OA were female (89% vs. 65%, p < .001). Median baseline CD4 was 252/mu L in AYA and 204/mu L in OA (p = .002). More AYA had inconsistent care than OA (55% vs. 47%, p = .001). Adjusting for sex, baseline CD4, and education, AYA had a greater risk of inconsistent care than OA (Relative Risk [RR]: 1.15, p = .008). Among those in care after one year on ART, viremia was more common in AYA than OA (40% vs. 26% p = .003, RR: 1.53, p = .002). Conclusions: In a Nigerian cohort, AYA were at increased risk for inconsistent HIV care. Of patients remaining in care, youth was the only independent predictor of viremia at 1 year. Youth-friendly models of HIV care are needed to optimize health outcomes. (C) 2016 Society for Adolescent Health and Medicine. All rights reserved. C1 [Ahonkhai, Aimalohi A.; Bassett, Ingrid V.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Ahonkhai, Aimalohi A.; Adegoke, Abdulkabir B.; Regan, Susan; Bassett, Ingrid V.; Losina, Elena; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Ahonkhai, Aimalohi A.; Bassett, Ingrid V.; Losina, Elena; Okonkwo, Prosper; Freedberg, Kenneth A.] Harvard Med Sch, Boston, MA USA. [Banigbe, Bolanle; Adeola, Juliet] AIDS Prevent Initiat Nigeria, Abuja, Nigeria. [Regan, Susan; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Regan, Susan; Bassett, Ingrid V.; Losina, Elena; Freedberg, Kenneth A.] Harvard Univ, Ctr AIDS Res, Boston, MA 02115 USA. [Idigbe, Ifeoma] Nigerian Inst Med Res, Lagos, Nigeria. [Losina, Elena] Brigham & Womens Hosp, Dept Orthoped Surg, 75 Francis St, Boston, MA 02115 USA. [Losina, Elena] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA USA. [Freedberg, Kenneth A.] Boston Univ, Dept Epidemiol, Sch Publ Hlth, Boston, MA USA. [Freedberg, Kenneth A.] Harvard TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. RP Ahonkhai, AA (reprint author), 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM aahonkhai@mgh.harvard.edu FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [K23 AI106406, R01 AI058736-09S1, R01 MH090326, P30AI060354]; Centers for Disease Control and Prevention [5U2GPS001058] FX Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers: K23 AI106406, R01 AI058736-09S1, R01 MH090326, and P30AI060354. This study was also supported in part by cooperative agreement number 5U2GPS001058 from the Centers for Disease Control and Prevention, and by the President and fellows of Harvard College. NR 44 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 1054-139X EI 1879-1972 J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD SEP PY 2016 VL 59 IS 3 BP 298 EP 304 DI 10.1016/j.jadohealth.2016.05.002 PG 7 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA DU6GM UT WOS:000382312300011 PM 27329680 ER PT J AU Oreskovic, NM Winickoff, JP Perrin, JM Robinson, AI Goodman, E AF Oreskovic, Nicolas M. Winickoff, Jonathan P. Perrin, James M. Robinson, Alyssa I. Goodman, Elizabeth TI A Multimodal Counseling-Based Adolescent Physical Activity Intervention SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Physical activity; Built environment; Adolescents; Overweight; Obesity; Intervention; Counseling ID BUILT ENVIRONMENT; UNITED-STATES; CHILDREN; OBESITY; ACCELEROMETER; CHILDHOOD; SCHOOL AB Purpose: National guidelines recommend adolescents achieve 60 minutes of moderate-to-vigorous physical activity (MVPA)/day, yet few adolescents meet these guidelines. Methods: We piloted a novel quasi-randomized physical activity intervention to promote adolescent's use of their surrounding built environment among 30 intervention and 30 control overweight/obese adolescents aged 10-16 years living in greater Boston from 2013 to 2015. Location-specific MPVA was measured by accelerometry and global positioning system for three one-week periods (Time 1 [T1], Time 2 [T2], and Time 3 [T3]). One month after T1, intervention participants received individualized counseling on how to use their surrounding built environment to increase MVPA, and control participants received standard-of-care lifestyle modification counseling; both groups received their T1 physical activity data. T2 assessment occurred the week after the counseling visit and T3 assessment 3-4 months later. The main outcome was change in average daily minutes of MVPA; the secondary outcome was meeting national MVPA guidelines. Multivariable modeling accounted for covariates (baseline MVPA, body mass index, age, sex, race/ethnicity) and clustering by study group and town. Results: Among the 60 adolescents recruited, 55 (92%) completed data collection. Short-term (T2) intervention effects included increased average MVPA of +13.9 minutes intervention versus -.6 minutes control (p < .0001). Differential increase in mean daily MVPA was sustained at T3 (9.3 minutes more in intervention group; p = .0006). The proportion of adolescents in the intervention group who achieved 60 minutes/day of MVPA increased from 11% (T1) to 21% (T2), whereas declining (7%-0%) among controls. Conclusions: Individualized counseling about the built environment can help increase MVPA among overweight and obese adolescents. (C) 2016 Society for Adolescent Health and Medicine. All rights reserved. C1 [Oreskovic, Nicolas M.; Winickoff, Jonathan P.; Perrin, James M.; Robinson, Alyssa I.; Goodman, Elizabeth] MassGen Hosp Children, Div Gen Acad Pediat, Dept Pediat, Boston, MA USA. [Oreskovic, Nicolas M.; Winickoff, Jonathan P.; Perrin, James M.; Goodman, Elizabeth] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Oreskovic, Nicolas M.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Oreskovic, Nicolas M.; Winickoff, Jonathan P.; Perrin, James M.; Goodman, Elizabeth] Harvard Med Sch, Dept Pediat, Boston, MA USA. RP Oreskovic, NM (reprint author), Massachusetts Gen Hosp, Div Gen Acad Pediat, 125 Nashua St,8th Floor, Boston, MA 02114 USA. EM noreskovic@mgh.harvard.edu FU National Institutes of Health [5K23HL103841, P30DK046200] FX This study was sponsored by the National Institutes of Health grants 5K23HL103841 and P30DK046200. The funding sources had no involvement in study design, data collection, data interpretation, writing of the report, or decision to submit the article for publication. NR 21 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X EI 1879-1972 J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD SEP PY 2016 VL 59 IS 3 BP 332 EP 337 DI 10.1016/j.jadohealth.2016.03.012 PG 6 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA DU6GM UT WOS:000382312300016 PM 27235377 ER PT J AU Gaggar, A Weathington, N AF Gaggar, Amit Weathington, Nathaniel TI Bioactive extracellular matrix fragments in lung health and disease SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Review ID BRONCHIOLITIS OBLITERANS SYNDROME; OBSTRUCTIVE PULMONARY-DISEASE; NEUTROPHIL ELASTASE CLEAVES; EPITHELIAL-CELL MIGRATION; PROLINE-GLYCINE-PROLINE; TOLL-LIKE RECEPTORS; LAMININ-5 GAMMA-2-CHAIN; PROLYL ENDOPEPTIDASE; CHEMOTACTIC ACTIVITY; POTENTIAL ROLE AB The extracellular matrix (ECM) is the noncellular component critical in the maintenance of organ structure and the regulation of tissue development, organ structure, and cellular signaling. The ECM is a dynamic entity that undergoes continuous degradation and resynthesis. In addition to compromising structure, degradation of the ECM can liberate bioactive fragments that cause cellular activation and chemotaxis of a variety of cells. These fragments are termed matrikines, and their cellular activities are sentinel in the development and progression of tissue injury seen in chronic lung disease. Here, we discuss the matrikines that are known to be active in lung biology and their roles in lung disease. We also consider the use of matrikines as disease markers and potential therapeutic targets in lung disease. C1 [Gaggar, Amit] Univ Alabama Birmingham, Dept Med, Div Pulm & Crit Care Med, Birmingham, AL USA. [Gaggar, Amit] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Gaggar, Amit] Program Protease & Matrix Biol, Birmingham, AL USA. [Weathington, Nathaniel] Univ Pittsburgh, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. RP Weathington, N (reprint author), 3459 Fifth Ave,MUH NW 628, Pittsburgh, PA 15213 USA.; Gaggar, A (reprint author), 1900 Univ Ave THT 422, Birmingham, AL 35294 USA. EM agaggar@uabmc.edu; weathingtonnm@upmc.edu FU NIH [HL102371, HL126135]; Veterans Administration [1 I01 BX001756]; American Lung Association; Ismail Moustapha Scholar Fund FX We thank J.E. Blalock for his thoughtful reading of this manuscript. These studies were funded in part by grants from the NIH (HL102371 to A. Gaggar; HL126135 to N. Weathington), the Veterans Administration (1 I01 BX001756 to A. Gaggar), the American Lung Association (to N. Weathington), and the Ismail Moustapha Scholar Fund (to A. Gaggar). NR 115 TC 0 Z9 0 U1 10 U2 10 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD SEP PY 2016 VL 126 IS 9 BP 3176 EP 3184 DI 10.1172/JCI83147 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DU9CI UT WOS:000382513400004 PM 27584731 ER PT J AU Boyraz, B Moon, DH Segal, M Muosieyiri, MZ Aykanat, A Tai, AK Cahan, P Agarwal, S AF Boyraz, Baris Moon, Diane H. Segal, Matthew Muosieyiri, Maud Z. Aykanat, Asli Tai, Albert K. Cahan, Patrick Agarwal, Suneet TI Posttranscriptional manipulation of TERC reverses molecular hallmarks of telomere disease SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID POLY(A)-SPECIFIC RIBONUCLEASE PARN; DYSKERATOSIS-CONGENITA; PULMONARY-FIBROSIS; RNA COMPONENT; MUTATIONS; MATURATION; LENGTH; DEGRADATION; ADENYLATION; CANCER AB The telomerase RNA component (TERC) is a critical determinant of cellular self-renewal. Poly(A)-specific ribonuclease (PARN) is required for posttranscriptional maturation of TERC. PARN mutations lead to incomplete 3' end processing and increased destruction of nascent TERC RNA transcripts, resulting in telomerase deficiency and telomere diseases. Here, we determined that overexpression of TERC increased telomere length in PARN-deficient cells and hypothesized that decreasing posttranscriptional 3' oligo-adenylation of TERC would counteract the deleterious effects of PARN mutations. Inhibition of the noncanonical poly(A) polymerase PAP-associated domain-containing 5 (PAPD5) increased TERC levels in PARN-mutant patient cells. PAPD5 inhibition was also associated with increases in TERC stability, telomerase activity, and telomere elongation. Our results demonstrate that manipulating posttranscriptional regulatory pathways may be a potential strategy to reverse the molecular hallmarks of telomere disease. C1 [Boyraz, Baris; Moon, Diane H.; Segal, Matthew; Muosieyiri, Maud Z.; Aykanat, Asli; Agarwal, Suneet] Boston Childrens Hosp, Hematol Oncol & Stem Cell Program, Boston, MA 02115 USA. [Boyraz, Baris; Moon, Diane H.; Segal, Matthew; Muosieyiri, Maud Z.; Aykanat, Asli; Agarwal, Suneet] Dana Farber Canc Inst, Pediat Oncol, Boston, MA USA. [Boyraz, Baris; Moon, Diane H.; Segal, Matthew; Muosieyiri, Maud Z.; Aykanat, Asli; Agarwal, Suneet] Harvard Stem Cell Inst, Boston, MA USA. [Boyraz, Baris; Moon, Diane H.; Segal, Matthew; Muosieyiri, Maud Z.; Aykanat, Asli; Agarwal, Suneet] Harvard Med Sch, Pediat, Boston, MA USA. [Boyraz, Baris] Hacettepe Univ, Inst Canc, Basic Oncol, Ankara, Turkey. [Tai, Albert K.] Tufts Univ, Sch Med, Integrat Physiol & Pathobiol, Boston, MA 02111 USA. [Cahan, Patrick] Johns Hopkins Univ, Sch Med, Biomed Engn & Cell Engn, Baltimore, MD USA. RP Agarwal, S (reprint author), Boston Childrens Hosp, 3 Blackfan Circle,CLS 3002, Boston, MA 02115 USA. EM suneet.agarwal@chil-drens.harvard.edu FU NIH [R01 DK107716-01]; Pedals for Pediatrics; Dana-Farber Cancer Institute; Scientific and Technological Council of Turkey; [T32 HL007574] FX We thank the patients and families for participation in research. The work was funded by NIH R01 DK107716-01 and Pedals for Pediatrics, Dana-Farber Cancer Institute (to SA); T32 HL007574 (to DHM); and the Scientific and Technological Council of Turkey (to BB). NR 26 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD SEP PY 2016 VL 126 IS 9 BP 3377 EP 3382 DI 10.1172/JCI87547 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DU9CI UT WOS:000382513400019 PM 27482890 ER PT J AU O'Neill, BT Lee, KY Klaus, K Softic, S Krumpoch, MT Fentz, J Stanford, KI Robinson, MM Cai, WK Kleinridders, A Pereira, RO Hirshman, MF Abel, ED Accili, D Goodyear, LJ Nair, KS Kahn, CR AF O'Neill, Brian T. Lee, Kevin Y. Klaus, Katherine Softic, Samir Krumpoch, Megan T. Fentz, Joachim Stanford, Kristin I. Robinson, Matthew M. Cai, Weikang Kleinridders, Andre Pereira, Renata O. Hirshman, Michael F. Abel, E. Dale Accili, Domenico Goodyear, Laurie J. Nair, K. Sreekumaran Kahn, C. Ronald TI Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID SKELETAL-MUSCLE; BODY-COMPOSITION; POSTTRANSLATIONAL MODIFICATIONS; MITOCHONDRIAL-FUNCTION; PROTEIN DYNAMICS; OLDER-ADULTS; IN-VIVO; AUTOPHAGY; GROWTH; HEALTH AB Diabetes strongly impacts protein metabolism, particularly in skeletal muscle. Insulin and IGF-1 enhance muscle protein synthesis through their receptors, but the relative roles of each in muscle proteostasis have not been fully elucidated. Using mice with muscle-specific deletion of the insulin receptor (M-IR-/- mice), the IGF-1 receptor (M-IGF1R(-/-) mice), or both (MIGIRKO mice), we assessed the relative contributions of IR and IGF1R signaling to muscle proteostasis. In differentiated muscle, IR expression predominated over IGF1R expression, and correspondingly, M-IR-/- mice displayed a moderate reduction in muscle mass whereas M-IGF1R(-/-) mice did not. However, these receptors serve complementary roles, such that double-knockout MIGIRKO mice displayed a marked reduction in muscle mass that was linked to increases in proteasomal and autophagy-lysosomal degradation, accompanied by a high-protein-turnover state. Combined muscle-specific deletion of Fox01, Fox03, and Fox04 in MIGIRKO mice reversed increased autophagy and completely rescued muscle mass without changing proteasomal activity. These data indicate that signaling via IR is more important than IGF1R in controlling proteostasis in differentiated muscle. Nonetheless, the overlap of IR and IGF1R signaling is critical to the regulation of muscle protein turnover, and this regulation depends on suppression of FoxO-regulated, autophagy-mediated protein degradation. C1 [O'Neill, Brian T.; Lee, Kevin Y.; Softic, Samir; Krumpoch, Megan T.; Fentz, Joachim; Stanford, Kristin I.; Cai, Weikang; Kleinridders, Andre; Hirshman, Michael F.; Goodyear, Laurie J.; Kahn, C. Ronald] Harvard Med Sch, Sect Integrat Physiol & Metab, Joslin Diabet Ctr, Boston, MA USA. [Klaus, Katherine; Robinson, Matthew M.; Nair, K. Sreekumaran] Mayo Clin, Coll Med, Div Endocrinol & Metab, Rochester, MN USA. [Pereira, Renata O.; Abel, E. Dale] Univ Iowa, Fraternal Order Eagles Diabet Res Ctr, Roy J & Lucille A Carver Coll Med, Iowa City, IA USA. [Pereira, Renata O.; Abel, E. Dale] Univ Iowa, Div Endocrinol & Metab, Roy J & Lucille A Carver Coll Med, Iowa City, IA USA. [Accili, Domenico] Columbia Univ, Med Ctr, Dept Med, New York, NY USA. [Accili, Domenico] Columbia Univ, Med Ctr, Naomi Berrie Diabet Ctr, New York, NY USA. [Lee, Kevin Y.] Ohio Univ, Dept Biomed Sci, Athens, OH 45701 USA. [Fentz, Joachim] Univ Copenhagen, Sect Mol Physiol, August Krogh Ctr, Dept Nutr Exercise & Sports, Copenhagen, Denmark. [Stanford, Kristin I.] Ohio State Univ, Dorothy M Davis Heart & Lung Res Inst, Wexner Med Ctr, Dept Physiol & Cell Biol, Columbus, OH 43210 USA. [Kleinridders, Andre] German Inst Human Nutr Potsdam Rehbrucke, Nuthetal, Germany. [Kleinridders, Andre] Natl Ctr Diabet Res DZD, Neuherberg, Germany. RP Kahn, CR (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM C.Ronald.Kahn@joslin.harvard.edu FU NIH [R0l DK031036, R01AR42238, R01 DK41973, U24 DK100469]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the NIH [K08 DK100543]; Mayo Clinic Metabolomics Resource Core grant from the NIDDK [U24 DK100469]; Mayo Clinic Clinical and Translational Science Awards from the National Center for Advancing Translational Sciences of the NIH [UL1 TR000135]; K01 award from the NIDDK of the NIH [K01 DK105109]; German Research Foundation (DFG) [K12399-1/1] FX This work was supported by NIH grants R0l DK031036 (to CRK), R01AR42238 (to LJG), and R01 DK41973 and U24 DK100469 (to KSN). BTO was funded by a K08 training award from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the NIH (K08 DK100543), Mayo Clinic Metabolomics Resource Core grant U24 DK100469 from the NIDDK, which originates from the NIH Director's Common Fund, and Mayo Clinic Clinical and Translational Science Awards grant UL1 TR000135 from the National Center for Advancing Translational Sciences of the NIH. KIS was funded by a K01 award from the NIDDK of the NIH (K01 DK105109). AK was supported by a German Research Foundation (DFG) fellowship K12399-1/1 grant. The Joslin Diabetes Research Center core facility was used for part of this work (P30 DK36836). NR 47 TC 4 Z9 4 U1 4 U2 4 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD SEP PY 2016 VL 126 IS 9 BP 3433 EP 3446 DI 10.1172/JCI86522 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DU9CI UT WOS:000382513400024 PM 27525440 ER PT J AU Bluteau, D Masliah-Planchon, J Clairmont, C Rousseau, A Ceccaldi, R d'Enghien, CD Bluteau, O Cuccuini, W Gachet, S de Latour, RP Leblanc, T Socie, G Baruchel, A Stoppa-Lyonnet, D D'Andrea, AD Soulier, J AF Bluteau, Dominique Masliah-Planchon, Julien Clairmont, Connor Rousseau, Alix Ceccaldi, Raphael d'Enghien, Catherine Dubois Bluteau, Olivier Cuccuini, Wendy Gachet, Stephanie de Latour, Regis Peffault Leblanc, Thierry Socie, Gerard Baruchel, Andre Stoppa-Lyonnet, Dominique D'Andrea, Alan D. Soulier, Jean TI Biallelic inactivation of REV7 is associated with Fanconi anemia SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID DNA-POLYMERASE-ZETA; HEMATOPOIETIC STEM; CORE COMPLEX; POL-ZETA; REPAIR; PATHWAY; CELLS; MOUSE; RECOMBINATION; RESECTION AB Fanconi anemia (FA) is a recessive genetic disease characterized by congenital abnormalities, chromosome instability, progressive bone marrow failure (BMF), and a strong predisposition to cancer. Twenty FA genes have been identified, and the FANC proteins they encode cooperate in a common pathway that regulates DNA crosslink repair and replication fork stability. We identified a child with severe BMF who harbored biallelic inactivating mutations of the translesion DNA synthesis (TLS) gene REV7 (also known as MAD2L2), which encodes the mutant REV7 protein REV7-V85E. Patient-derived cells demonstrated an extended FA phenotype, which included increased chromosome breaks and G(2)/M accumulation upon exposure to DNA crosslinking agents, gamma H2AX and 53BP1 foci accumulation, and enhanced p53/p21 activation relative to cells derived from healthy patients. Expression of WT REV7 restored normal cellular and functional phenotypes in the patient's cells, and CRISPR/Cas9 inactivation of REV7 in a non-FA human cell line produced an FA phenotype. Finally, silencing Rev7 in primary hematopoietic cells impaired progenitor function, suggesting that the DNA repair defect underlies the development of BMF in FA. Taken together, our genetic and functional analyses identified REV7 as a previously undescribed FA gene, which we term FANCY. C1 [Bluteau, Dominique; Masliah-Planchon, Julien; Rousseau, Alix; Bluteau, Olivier; Gachet, Stephanie; Soulier, Jean] St Louis Hosp, CNRS, INSERM, U944,UMR7212, F-75010 Paris, France. [Bluteau, Dominique; Masliah-Planchon, Julien; Rousseau, Alix; Bluteau, Olivier; Gachet, Stephanie; de Latour, Regis Peffault; Socie, Gerard; Baruchel, Andre; Soulier, Jean] Univ Paris Diderot, Sorbonne Paris Cite, Inst Hematol IUH, F-75010 Paris, France. [Clairmont, Connor; Ceccaldi, Raphael; D'Andrea, Alan D.] Harvard Med Sch, Dana Farber Canc Inst, Dept Radiat Oncol, Ctr DNA Damage & Repair, Mayer 640,450 Brookline Ave, Boston, MA 02215 USA. [d'Enghien, Catherine Dubois; Stoppa-Lyonnet, Dominique] Inst Curie, Oncogenet Lab, Paris, France. [Bluteau, Olivier; Cuccuini, Wendy; Soulier, Jean] St Louis Hosp, AP HP, Hematol Lab, F-75010 Paris, France. [de Latour, Regis Peffault; Socie, Gerard] St Louis Hosp, AP HP, Hematol Transplantat, F-75010 Paris, France. [Leblanc, Thierry; Baruchel, Andre] Robert Debre Hosp, Dept Pediat Hematol, Paris, France. RP D'Andrea, AD (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Radiat Oncol, Ctr DNA Damage & Repair, Mayer 640,450 Brookline Ave, Boston, MA 02215 USA.; Soulier, J (reprint author), St Louis Hosp, INSERM, U944, Batiment Jean Bernard,1 Ave Claude Vellefaux, F-75010 Paris, France.; Soulier, J (reprint author), Univ Paris Diderot, INSERM, U944, Batiment Jean Bernard,1 Ave Claude Vellefaux, F-75010 Paris, France. EM Alan_dandrea@dfci.harvard.edu; jean.soulier@sls.aphp.fr FU European Research Council (ERC) [311660]; INCa grant [TRANSLA-12-011]; Saint-Louis Institute program [ANR-10-IBHU-0002]; French Government (Direction de l'Hospitalisation et de l'Organisation des Soins) as Centre de Reference Maladies Rares "Aplasies Medullaires Constitutionnelles"; Fondation ARC; NIH [DK43889]; Association Francaise de la Maladie de Fanconi (AFMF); FA patients and their families FX This work was supported by the European Research Council (ERC) Grant Consolidator 311660, an INCa grant (TRANSLA-12-011), and the Saint-Louis Institute program (ANR-10-IBHU-0002) (to JS). Saint-Louis/Robert Debre Hospital is supported by the French Government (Direction de l'Hospitalisation et de l'Organisation des Soins) as Centre de Reference Maladies Rares "Aplasies Medullaires Constitutionnelles" (to TL, GS, AB, JS). AR was supported by a fellowship from the Fondation ARC. ADD was supported by NIH grant DK43889. We thank the FA patients and their families, the Association Francaise de la Maladie de Fanconi (AFMF) for their support, and the physicians and nurses from French pediatric, genetic, and/or hematological centers who have taken care of the patients. NR 32 TC 8 Z9 8 U1 5 U2 5 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD SEP PY 2016 VL 126 IS 9 BP 3580 EP 3584 DI 10.1172/JCI88010 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DU9CI UT WOS:000382513400035 PM 27500492 ER PT J AU Gainor, JF AF Gainor, Justin F. TI Moving Programmed Death-1 Inhibitors to the Front Lines in Non-Small-Cell Lung Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; SUPPORTIVE CARE; PD-1 BLOCKADE; OPEN-LABEL; DOCETAXEL; CISPLATIN; NIVOLUMAB; ANTIBODY; THERAPY; PHASE-3 C1 [Gainor, Justin F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Gainor, JF (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 20 TC 2 Z9 2 U1 3 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 1 PY 2016 VL 34 IS 25 BP 2953 EP + DI 10.1200/JCO.2016.68.1205 PG 4 WC Oncology SC Oncology GA DU8NJ UT WOS:000382470100003 PM 27382094 ER PT J AU Smith, M De Bono, J Sternberg, C Le Moulec, S Oudard, S De Giorgi, U Krainer, M Bergman, A Hoelzer, W De Wit, R Bogemann, M Saad, F Cruciani, G Thiery-Vuillemin, A Feyerabend, S Miller, K Houede, N Hussain, S Lam, E Polikoff, J Stenzl, A Mainwaring, P Ramies, D Hessel, C Weitzman, A Fizazi, K AF Smith, Matthew De Bono, Johann Sternberg, Cora Le Moulec, Sylvestre Oudard, Stephane De Giorgi, Ugo Krainer, Michael Bergman, Andries Hoelzer, Wolfgang De Wit, Ronald Boegemann, Martin Saad, Fred Cruciani, Giorgio Thiery-Vuillemin, Antoine Feyerabend, Susan Miller, Kurt Houede, Nadine Hussain, Syed Lam, Elaine Polikoff, Jonathan Stenzl, Arnulf Mainwaring, Paul Ramies, David Hessel, Colin Weitzman, Aaron Fizazi, Karim TI Phase III Study of Cabozantinib in Previously Treated Metastatic Castration-Resistant Prostate Cancer: COMET-1 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MITOXANTRONE PLUS PREDNISONE; GROWTH FACTOR/SCATTER FACTOR; PLACEBO-CONTROLLED PHASE-3; DOUBLE-BLIND; INCREASED SURVIVAL; END-POINTS; C-MET; DOCETAXEL; TRIAL; CHEMOTHERAPY AB Purpose Cabozantinib is an inhibitor of kinases, including MET and vascular endothelial growth factor receptors, and has shown activity in men with previously treated metastatic castration-resistant prostate cancer (mCRPC). This blinded phase III trial compared cabozantinib with prednisone in patients with mCRPC. Patients and Methods Men with progressive mCRPC after docetaxel and abiraterone and/or enzalutamide were randomly assigned at a two-to-one ratio to cabozantinib 60 mg once per day or prednisone 5 mg twice per day. The primary end point was overall survival (OS). Bone scan response (BSR) at week 12 as assessed by independent review committee was the secondary end point; radiographic progression-free survival (rPFS) and effects on circulating tumor cells (CTCs), bone biomarkers, serum prostate-specific antigen (PSA), and symptomatic skeletal events (SSEs) were exploratory assessments. Results A total of 1,028 patients were randomly assigned to cabozantinib (n = 682) or prednisone (n = 346). Median OS was 11.0 months with cabozantinib and 9.8 months with prednisone (hazard ratio, 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = .213). BSR at week 12 favored cabozantinib (42% v 3%; stratified Cochran-Mantel-Haenszel P < .001). rPFS was improved in the cabozantinib group (median, 5.6 v 2.8 months; hazard ratio, 0.48; 95% CI, 0.40 to 0.57; stratified log-rank P < 001). Cabozantinib was associated with improvements in CTC conversion, bone biomarkers, and post-random assignment incidence of SSEs but not PSA outcomes. Grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone (71% v 56% and 33% v 12%, respectively). Conclusion Cabozantinib did not significantly improve OS compared with prednisone in heavily treated patients with mCRPC and progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving BSR, rPFS, SSEs, CTC conversions, and bone biomarkers but not PSA outcomes. (C) 2016 by American Society of Clinical Oncology C1 [Smith, Matthew] Massachusetts Gen Hosp, Boston, MA 02114 USA. [De Bono, Johann] Royal Marsden Hosp, Sutton, Surrey, England. [Hussain, Syed] Univ Liverpool, Liverpool, Merseyside, England. [Sternberg, Cora] San Camillo & Forlanini Hosp, Rome, Italy. [De Giorgi, Ugo] Ist Sci Romagnolo Studio & Cura Tumori, Ist Ricovero & Cura Carattere Sci, Meldola, Italy. [Cruciani, Giorgio] Ist Tumori Romagna, Lugo Di Romagna, Italy. [Le Moulec, Sylvestre] Hop Instruct Armees Val De Grace, Paris, France. [Oudard, Stephane] Hop Europeen Georges Pompidou, Paris, France. [Oudard, Stephane] Paris Descartes Univ, Paris, France. [Thiery-Vuillemin, Antoine] Jean Minjoz Hosp, Besancon, France. [Houede, Nadine] CHU Caremeau, Inst Canc Gard, Nimes, France. [Fizazi, Karim] Univ Paris Sud, Inst Gustave Roussy, Villejuif, France. [Krainer, Michael] Med Univ Vienna, Vienna, Austria. [Bergman, Andries] Netherlands Canc Inst, Amsterdam, Netherlands. [De Wit, Ronald] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [De Wit, Ronald] Erasmus Univ, Inst Canc, Rotterdam, Netherlands. [Hoelzer, Wolfgang] Praxis Urol, Burgdorf, Switzerland. [Miller, Kurt] Charite Univ Med Berlin, Berlin, Germany. [Boegemann, Martin] Univ Munster, Med Ctr, Munster, Germany. [Feyerabend, Susan] Studienpraxis Urol, Nurtingen, Germany. [Stenzl, Arnulf] Univ Hosp, Tubingen, Germany. [Saad, Fred] Ctr Hosp Univ Montreal, Montreal, PQ, Canada. [Lam, Elaine] Univ Colorado, Anschutz Med Campus, Aurora, CO USA. [Polikoff, Jonathan] Kaiser Permanente Med Grp, San Diego, CA USA. [Ramies, David; Hessel, Colin; Weitzman, Aaron] Exelixis, San Francisco, CA USA. [Mainwaring, Paul] Hematol & Oncol Clin Australia, Brisbane, Qld, Australia. RP Smith, M (reprint author), Massachusetts Gen Hosp, Ctr Canc, Yawkey 7030,55 Fruit St, Boston, MA 02114 USA. EM smith.matthew@mgh.harvard.edu OI Krainer, Michael/0000-0002-7011-4957 FU Exelixis FX Supported by Exelixis. NR 46 TC 8 Z9 8 U1 4 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 1 PY 2016 VL 34 IS 25 BP 3005 EP + DI 10.1200/JCO.2015.65.5597 PG 16 WC Oncology SC Oncology GA DU8NJ UT WOS:000382470100011 PM 27400947 ER PT J AU Lagmay, JP Krailo, MD Dang, H Kim, A Hawkins, DS Beaty, O Widemann, BC Zwerdling, T Bomgaars, L Langevin, AM Grier, HE Weigel, B Blaney, SM Gorlick, R Janeway, KA AF Lagmay, Joanne P. Krailo, Mark D. Dang, Ha Kim, AeRang Hawkins, Douglas S. Beaty, Orren, III Widemann, Brigitte C. Zwerdling, Theodore Bomgaars, Lisa Langevin, Anne-Marie Grier, Holcombe E. Weigel, Brenda Blaney, Susan M. Gorlick, Richard Janeway, Katherine A. TI Outcome of Patients With Recurrent Osteosarcoma Enrolled in Seven Phase II Trials Through Children's Cancer Group, Pediatric Oncology Group, and Children's Oncology Group: Learning From the Past to Move Forward SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID REFRACTORY SOLID TUMORS; RESPONSE EVALUATION CRITERIA; FREE SURVIVAL; MURAMYL TRIPEPTIDE; OSTEOGENIC-SARCOMA; PROGNOSTIC-FACTORS; PROGRESSION-FREE; RECIST CRITERIA; CLINICAL-TRIALS; CHEMOTHERAPY AB Purpose The use of radiographic response as the primary end point in phase II osteosarcoma trials may limit optimal detection of treatment response because of the calcified tumor matrix. We performed this study to determine if time to progression could be used as an end point for subsequent studies. Patients and Methods We performed a retrospective analysis of outcome for patients with recurrent/refractory osteosarcoma enrolled in one of seven phase II trials conducted by the Children's Oncology Group and predecessor groups from 1997 to 2007. All trials used RECIST or WHO radiographic response criteria and the primary end point of response rate. The following potential prognostic factors-age, trial, number of prior chemotherapy regimens, sex, and race/ethnicity-were evaluated for their impact on event-free survival (EFS). We used data from a phase II study (AOST0221) of patients with osteosarcoma who were given inhaled granulocyte-macrophage colony-stimulating factor with first pulmonary recurrence who had an EFS as well as biologic end point to determine the historical disease control rate for patients with fully resected disease. Results In each included trial, the drugs tested were determined to be inactive on the basis of radiographic response rates. The EFS for 96 patients with osteosarcoma and measurable disease was 12% at 4 months (95% CI, 6% to 19%). There was no significant difference in EFS across trials according to number of prior treatment regimens or patient age, sex, and ethnicity. The 12-month EFS for the 42 evaluable patients enrolled in AOST0221 was 20% (95% CI, 10% to 34%). Conclusion The EFS was uniformly poor for children with recurrent/refractory osteosarcoma in these single-arm phase II trials. We have now constructed baseline EFS outcomes that can be used as a comparison for future phase II trials for recurrent osteosarcoma. (C) 2016 by American Society of Clinical Oncology C1 [Lagmay, Joanne P.] Univ Florida, Shands Hosp Children, Gainesville, FL USA. [Krailo, Mark D.; Dang, Ha] Univ Southern Calif, Los Angeles, CA USA. [Krailo, Mark D.; Dang, Ha] Childrens Oncol Grp, Monrovia, CA USA. [Zwerdling, Theodore] Miller Childrens & Womens Hosp, Jonathan Jaques Childrens Canc Ctr, Long Beach, CA USA. [Kim, AeRang] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Hawkins, Douglas S.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle Childrens Hosp, Seattle, WA 98195 USA. [Beaty, Orren, III] Mission Hosp, Zeiss Childrens Canc Ctr, Asheville, NC USA. [Widemann, Brigitte C.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Bomgaars, Lisa; Blaney, Susan M.] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. [Langevin, Anne-Marie] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Grier, Holcombe E.; Janeway, Katherine A.] Boston Childrens Canc & Blood Disorders Ctr, Dana Farber Canc Inst, Boston, MA USA. [Weigel, Brenda] Univ Minnesota, Minneapolis, MN USA. [Gorlick, Richard] Yeshiva Univ, Albert Einstein Coll Med, Childrens Hosp Montefiore, New York, NY 10033 USA. RP Lagmay, JP (reprint author), Univ Florida, Shands Hosp Children, Div Pediat Hematol Oncol, 1600 SW Archer Rd,HD 204, Gainesville, FL 32610 USA. EM jplagmay@peds.ufl.edu FU National Clinical Trials Network (NCTN) Operations Center, from the National Cancer Institute [U10CA180886]; NCTN Statistics and Data Center, from the National Cancer Institute [U10CA180899, U10CA98543, U10CA98413]; QuadW Foundation FX Supported by National Clinical Trials Network (NCTN) Operations Center Grant No. U10CA180886, NCTN Statistics and Data Center Grant No. U10CA180899, Chair Grant No. U10CA98543, and Statistics and Data Center Grant No. U10CA98413, all from the National Cancer Institute. Additional research support was provided by a grant from the QuadW Foundation to the Children's Oncology Group. NR 32 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 SEP 1 PY 2016 VL 34 IS 25 BP 3031 EP + DI 10.1200/JCO.2015.65.5381 PG 9 WC Oncology SC Oncology GA DU8NJ UT WOS:000382470100014 PM 27400942 ER PT J AU Niedzwiecki, D Frankel, WL Venook, AP Ye, X Friedman, PN Goldberg, RM Mayer, RJ Colacchio, TA Mulligan, JM Davison, TS O'Brien, E Kerr, P Johnston, PG Kennedy, RD Harkin, DP Schilsky, RL Bertagnolli, MM Warren, RS Innocenti, F AF Niedzwiecki, Donna Frankel, Wendy L. Venook, Alan P. Ye, Xing Friedman, Paula N. Goldberg, Richard M. Mayer, Robert J. Colacchio, Thomas Anthony Mulligan, Jude Marie Davison, Timothy S. O'Brien, Eamonn Kerr, Peter Johnston, Patrick G. Kennedy, Richard D. Harkin, D. Paul Schilsky, Richard L. Bertagnolli, Monica M. Warren, Robert S. Innocenti, Federico TI Association Between Results of a Gene Expression Signature Assay and Recurrence-Free Interval in Patients With Stage II Colon Cancer in Cancer and Leukemia Group B 9581 (Alliance) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PARAFFIN-EMBEDDED TISSUE; CASE-COHORT DESIGNS; ADJUVANT CHEMOTHERAPY; PROGNOSTIC ASSAY; RECOMMENDATIONS; VALIDATION AB Purpose Conventional staging methods are inadequate to identify patients with stage II colon cancer (CC) who are at high risk of recurrence after surgery with curative intent. ColDx is a gene expression, microarray-based assay shown to be independently prognostic for recurrence-free interval (RFI) and overall survival in CC. The objective of this study was to further validate ColDx using formalin-fixed, paraffin-embedded specimens collected as part of the Alliance phase III trial, C9581. Patients and Methods C9581 evaluated edrecolomab versus observation in patients with stage II CC and reported no survival benefit. Under an initial case-cohort sampling design, a randomly selected subcohort (RS) comprised 514 patients from 901 eligible patients with available tissue. Forty-nine additional patients with recurrence events were included in the analysis. Final analysis comprised 393 patients: 360 RS (58 events) and 33 non-RS events. Risk status was determined for each patient by ColDx. The Self-Prentice method was used to test the association between the resulting ColDx risk score and RFI adjusting for standard prognostic variables. Results Fifty-five percent of patients (216 of 393) were classified as high risk. After adjustment for prognostic variables that included mismatch repair (MMR) deficiency, ColDx high-risk patients exhibited significantly worse RFI (multivariable hazard ratio, 2.13; 95% CI, 1.3 to 3.5; P < .01). Age and MMR status were marginally significant. RFI at 5 years for patients classified as high risk was 82% (95% CI, 79% to 85%), compared with 91% (95% CI, 89% to 93%) for patients classified as low risk. Conclusion ColDx is associated with RFI in the C9581 subsample in the presence of other prognostic factors, including MMR deficiency. ColDx could be incorporated with the traditional clinical markers of risk to refine patient prognosis. (C) 2016 by American Society of Clinical Oncology C1 [Niedzwiecki, Donna; Ye, Xing] Duke Univ, Durham, NC USA. [Innocenti, Federico] Univ N Carolina, Chapel Hill, NC USA. [Frankel, Wendy L.; Goldberg, Richard M.] Ohio State Univ, Columbus, OH 43210 USA. [Venook, Alan P.; Warren, Robert S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Friedman, Paula N.] Univ Chicago, Chicago, IL 60637 USA. [Mayer, Robert J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bertagnolli, Monica M.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Colacchio, Thomas Anthony] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Mulligan, Jude Marie; Davison, Timothy S.; O'Brien, Eamonn; Kerr, Peter; Kennedy, Richard D.; Harkin, D. Paul] Almac Diagnost, Craigavon, North Ireland. [Johnston, Patrick G.] Queens Univ, Belfast, Antrim, North Ireland. [Schilsky, Richard L.] Amer Soc Clin Oncol, Alexandria, VA USA. RP Niedzwiecki, D (reprint author), Duke Univ, Alliance Stat & Data Ctr, Med Ctr, Hock Plaza,2424 Erwin Rd,Room 8040, Durham, NC 27705 USA. EM donna.niedzwiecki@duke.edu FU National Cancer Institute to the Alliance for Clinical Trials in Oncology (Alliance) [U10 CA180821-01]; National Cancer Institute to the Alliance Statistics and Data Center [U10 CA180882-01] FX The research for CALGB 150705, B3 was supported, in part, by Grant No. U10 CA180821-01 from the National Cancer Institute to the Alliance for Clinical Trials in Oncology (Alliance; M.M.B., Chair) and Grant No. U10 CA180882-01 from the National Cancer Institute to the Alliance Statistics and Data Center (D.J. Sargent). NR 23 TC 12 Z9 12 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 1 PY 2016 VL 34 IS 25 BP 3047 EP + DI 10.1200/JCO.2015.65.4699 PG 10 WC Oncology SC Oncology GA DU8NJ UT WOS:000382470100016 PM 27432924 ER PT J AU Rugo, HS Rumble, RB Macrae, E Barton, DL Connolly, HK Dickler, MN Fallowfield, L Fowble, B Ingle, JN Jahanzeb, M Johnston, SRD Korde, LA Khatcheressian, JL Mehta, RS Muss, HB Burstein, HJ AF Rugo, Hope S. Rumble, R. Bryan Macrae, Erin Barton, Debra L. Connolly, Hannah Klein Dickler, Maura N. Fallowfield, Lesley Fowble, Barbara Ingle, James N. Jahanzeb, Mohammad Johnston, Stephen R. D. Korde, Larissa A. Khatcheressian, James L. Mehta, Rita S. Muss, Hyman B. Burstein, Harold J. TI Endocrine Therapy for Hormone Receptor-Positive Metastatic Breast Cancer: American Society of Clinical Oncology Guideline SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; FULVESTRANT 500 MG; FIRST-LINE THERAPY; PHASE-III TRIAL; NONSTEROIDAL AROMATASE INHIBITOR; POSTMENOPAUSAL JAPANESE WOMEN; EVEROLIMUS PLUS EXEMESTANE; PROGRESSION-FREE SURVIVAL; PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND AB Purpose To develop recommendations about endocrine therapy for women with hormone receptor (HR) -positive metastatic breast cancer (MBC). Methods The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of evidence from 2008 through 2015 to create recommendations informed by that evidence. Outcomes of interest included sequencing of hormonal agents, hormonal agents compared with chemotherapy, targeted biologic therapy, and treatment of premenopausal women. This guideline puts forth recommendations for endocrine therapy as treatment for women with HR-positive MBC. Recommendations Sequential hormone therapy is the preferential treatment for most women with HR-positive MBC. Except in cases of immediately life-threatening disease, hormone therapy, alone or in combination, should be used as initial treatment. Patients whose tumors express any level of hormone receptors should be offered hormone therapy. Treatment recommendations should be based on type of adjuvant treatment, disease-free interval, and organ function. Tumor markers should not be the sole criteria for determining tumor progression; use of additional biomarkers remains experimental. Assessment of menopausal status is critical; ovarian suppression or ablation should be included in premenopausal women. For postmenopausal women, aromatase inhibitors (AIs) are the preferred first-line endocrine therapy, with or without the cyclin-dependent kinase inhibitor palbociclib. As second-line therapy, fulvestrant should be administered at 500 mg with a loading schedule and may be administered with palbociclib. The mammalian target of rapamycin inhibitor everolimus may be administered with exemestane to postmenopausal women with MBC whose disease progresses while receiving nonsteroidal AIs. Among patients with HR-positive, human epidermal growth factor receptor 2-positive MBC, human epidermal growth factor receptor 2-targeted therapy plus an AI can be effective for those who are not chemotherapy candidates. (C) 2016 by American Society of Clinical Oncology C1 [Rumble, R. Bryan] Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. [Rugo, Hope S.] Univ Calif San Francisco, Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Fowble, Barbara] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Mehta, Rita S.] Univ Calif Irvine, Orange, CA 92668 USA. [Khatcheressian, James L.] Virginia Canc Inst, Richmond, VA USA. [Macrae, Erin] Columbus Oncol & Hematol Associates, Columbus, OH USA. [Barton, Debra L.] Univ Michigan, Sch Nursing, Ann Arbor, MI USA. [Dickler, Maura N.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Dickler, Maura N.] Weill Cornell Med Coll, New York, NY USA. [Fallowfield, Lesley] Sussex Hlth Outcomes Res & Educ Canc, Brighton, E Sussex, England. [Fallowfield, Lesley] Univ Sussex, Sussex Med Sch, Brighton, Sussex, England. [Johnston, Stephen R. D.] Royal Marsden Hosp, London, England. [Ingle, James N.] Mayo Clin, Rochester, MN USA. [Jahanzeb, Mohammad] Univ Miami, Sylvester Comprehens Canc Ctr, Deerfield Beach, FL USA. [Korde, Larissa A.] Univ Washington, Seattle, WA 98195 USA. [Muss, Hyman B.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Burstein, Harold J.] Dana Farber Canc Ctr, Boston, MA USA. RP Rugo, HS (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org NR 97 TC 7 Z9 7 U1 4 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 1 PY 2016 VL 34 IS 25 BP 3069 EP + DI 10.1200/JCO.2016.67.1487 PG 37 WC Oncology SC Oncology GA DU8NJ UT WOS:000382470100019 PM 27217461 ER PT J AU Happold, C Gorlia, T Chinot, O Gilbert, MR Nabors, LB Wick, W Pugh, SL Hegi, M Cloughesy, T Roth, P Reardon, DA Perry, JR Mehta, MP Stupp, R Weller, M AF Happold, Caroline Gorlia, Thierry Chinot, Oliver Gilbert, Mark R. Nabors, L. Burt Wick, Wolfgang Pugh, Stephanie L. Hegi, Monika Cloughesy, Timothy Roth, Patrick Reardon, David A. Perry, James R. Mehta, Minesh P. Stupp, Roger Weller, Michael TI Valproate in Adjuvant Glioblastoma Treatment Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID ACID; SURVIVAL C1 [Happold, Caroline; Roth, Patrick; Stupp, Roger; Weller, Michael] Univ Zurich Hosp, Zurich, Switzerland. [Gorlia, Thierry] European Org Res & Treatment Canc Data Ctr, Brussels, Belgium. [Chinot, Oliver] Aix Marseille Univ, Marseille, France. [Gilbert, Mark R.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Nabors, L. Burt] Univ Alabama Birmingham, Birmingham, AL USA. [Wick, Wolfgang] Heidelberg Univ, German Canc Res Ctr, Heidelberg, Germany. [Pugh, Stephanie L.] NRG Oncol Stat & Data Management Ctr, Philadelphia, PA USA. [Hegi, Monika] Univ Lausanne Hosp, Lausanne, Switzerland. [Cloughesy, Timothy] Univ Calif Los Angeles, Los Angeles, CA USA. [Reardon, David A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Perry, James R.] Univ Toronto, Toronto, ON, Canada. [Mehta, Minesh P.] Univ Maryland, Baltimore, MD 21201 USA. RP Happold, C (reprint author), Univ Zurich Hosp, Zurich, Switzerland. FU NCI NIH HHS [U10 CA180822, U10 CA180868, U10 CA021661] NR 5 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 SEP 1 PY 2016 VL 34 IS 25 BP 3107 EP + DI 10.1200/JCO.2016.68.0926 PG 3 WC Oncology SC Oncology GA DU8NJ UT WOS:000382470100022 PM 27298403 ER PT J AU Asdourian, MS Skolny, MN Brunelle, C Seward, CE Salama, L Taghian, AG AF Asdourian, Maria S. Skolny, Melissa N. Brunelle, Cheryl Seward, Cara E. Salama, Laura Taghian, Alphonse G. TI Do No Harm: Lymphedema Risk Reduction Behaviors Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID BREAST-CANCER; IMPACT C1 [Asdourian, Maria S.; Skolny, Melissa N.; Brunelle, Cheryl; Seward, Cara E.; Salama, Laura; Taghian, Alphonse G.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Asdourian, MS (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, 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 SEP 1 PY 2016 VL 34 IS 25 BP 3111 EP + DI 10.1200/JCO.2016.68.0967 PG 3 WC Oncology SC Oncology GA DU8NJ UT WOS:000382470100026 PM 27298408 ER PT J AU Rosness, TA Engedal, K Chemali, Z AF Rosness, Tor Atle Engedal, Knut Chemali, Zeina TI Frontotemporal Dementia: An Updated Clinician's Guide SO JOURNAL OF GERIATRIC PSYCHIATRY AND NEUROLOGY LA English DT Article DE frontotemporal dementia; dementia; early-onset dementia ID PRIMARY PROGRESSIVE APHASIA; EARLY-ONSET DEMENTIA; OF-LIFE ISSUES; ALZHEIMERS-DISEASE; LOBAR DEGENERATION; BEHAVIORAL-VARIANT; SEMANTIC DEMENTIA; CAREGIVER BURDEN; DECISION-MAKING; FAMILY CARERS AB Today, frontotemporal dementia (FTD) remains one of the most common forms of early-onset dementia, that is, before the age of 65, thus posing several diagnostic challenges to clinicians since symptoms are often mistaken for psychiatric or neurological diseases causing a delay in correct diagnosis, and the majority of patients with FTD present with symptoms at ages between 50 and 60. Genetic components are established risk factors for FTD, but the influence of lifestyle, comorbidity, and environmental factors on the risk of FTD is still unclear. Approximately 40% of individuals with FTD have a family history of dementia but less than 10% have a clear autosomal dominant pattern of inheritance. Lack of insight is often an early clue to FTD. A tailored treatment option at an early phase can mitigate suffering and improve patients' and caregivers' quality of life. C1 [Rosness, Tor Atle] Lovisenberg Diaconal Univ Coll, Lovisenberggt 15b, N-0456 Oslo, Norway. [Engedal, Knut] Norwegian Natl Advisory Unit Ageing & Hlth, Tonsberg, Norway. [Chemali, Zeina] Massachusetts Gen Hosp, Dept Neurol & Psychiat, Neuropsychiat Clin, Boston, MA 02114 USA. [Chemali, Zeina] Massachusetts Gen Hosp, Dept Psychiat, Neuropsychiat Clin, Boston, MA 02114 USA. [Chemali, Zeina] Harvard Med Sch, Boston, MA USA. RP Rosness, TA (reprint author), Lovisenberg Diaconal Univ Coll, Lovisenberggt 15b, N-0456 Oslo, Norway. EM rosness@gmail.com NR 119 TC 0 Z9 0 U1 11 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0891-9887 EI 1552-5708 J9 J GERIATR PSYCH NEUR JI J. Geriatr. Psychiatry Neurol. PD SEP PY 2016 VL 29 IS 5 SI SI BP 271 EP 280 DI 10.1177/0891988716654986 PG 10 WC Geriatrics & Gerontology; Clinical Neurology; Psychiatry SC Geriatrics & Gerontology; Neurosciences & Neurology; Psychiatry GA DV1GV UT WOS:000382669700005 PM 27502302 ER PT J AU Li, X Cullere, X Nishi, H Saggu, G Durand, E Mansour, MK Tam, JM Song, XY Lin, X Vyas, JM Mayadas, T AF Li, Xun Cullere, Xavier Nishi, Hiroshi Saggu, Gurpanna Durand, Enrique Mansour, Michael K. Tam, Jenny M. Song, Xiu-yu Lin, Xin Vyas, Jatin M. Mayadas, Tanya TI PKC- activation in neutrophils promotes fungal clearance SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE dectin-1; Mac-1; C; albicans; reactive oxygen species; host defense; signaling ID KINASE-C-DELTA; INNATE ANTIFUNGAL IMMUNITY; BETA-GLUCAN RECEPTOR; CANDIDA-ALBICANS; ASPERGILLUS-FUMIGATUS; ALVEOLAR MACROPHAGES; NADPH OXIDASE; HOST-DEFENSE; DENDRITIC CELLS; DECTIN-1 AB PKC is essential for neutrophil, but not macrophage functions required for host defense against fungal pathogens. The C-type lectin receptor dectin-1 and the integrin Mac-1 have key roles in controlling fungal infection. Here, we demonstrate that dectin-1- and Mac-1-induced activation of protein kinase C in neutrophils, independent of the Card9 adaptor, is required for reactive oxygen species production and for intracellular killing upon Candida albicans uptake. Protein kinase C was also required for zymosan-induced cytokine generation in neutrophils. In macrophages, protein kinase C deficiency prevented fungi-induced reactive oxygen species generation but had no effect on activation of TGF--activated kinase-1, an effector of Card9, or nuclear factor B activation, nor did it affect phagolysosomal maturation, autophagy, or intracellular C. albicans killing. In vivo, protein kinase C-deficient mice were highly susceptible to C. albicans and Aspergillus fumigatus infection, which was partially rescued with adoptively transferred wild-type neutrophils. Thus, protein kinase C activation downstream of dectin-1 and Mac-1 has an important role in neutrophil, but not macrophage, functions required for host defense against fungal pathogens. C1 [Li, Xun; Cullere, Xavier; Nishi, Hiroshi; Saggu, Gurpanna; Durand, Enrique; Mayadas, Tanya] Brigham & Womens Hosp, Dept Pathol, Ctr Excellence Vasc Biol, 75 Francis St, Boston, MA 02115 USA. [Li, Xun; Cullere, Xavier; Nishi, Hiroshi; Saggu, Gurpanna; Durand, Enrique; Mayadas, Tanya] Harvard Med Sch, 77 Ave Louis Pasteur,NRB Rm 752O, Boston, MA 02115 USA. [Li, Xun; Song, Xiu-yu] Xiamen Univ, Coll Med, Affiliated Hosp 1, Dept Lab Med, Xiamen, Fujian, Peoples R China. [Mansour, Michael K.; Tam, Jenny M.; Vyas, Jatin M.] Harvard Med Sch, Massachusetts Gen Hosp, Div Infect Dis, Dept Med, Boston, MA USA. [Lin, Xin] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. RP Mayadas, T (reprint author), Harvard Med Sch, 77 Ave Louis Pasteur,NRB Rm 752O, Boston, MA 02115 USA.; Mayadas, T (reprint author), Brigham & Womens Hosp, Dept Pathol, 77 Ave Louis Pasteur,NRB Rm 752O, Boston, MA 02115 USA. EM tmayadas@rics.bwh.harvard.edu FU U.S. National Institutes of Health (NIH) National Heart, Lung, and Blood Institute [R01HL065095]; NIH National Institute of Allergy and Infectious Diseases [5R01AI092084, 5R01AI097519, 1K08AI110655]; National Natural Science Foundation of China [81302529]; Natural Science Foundation of Fujian, China [2014D007] FX This work was supported by the U.S. National Institutes of Health (NIH) National Heart, Lung, and Blood Institute Grant R01HL065095 (to T.M.); NIH National Institute of Allergy and Infectious Diseases Grants 5R01AI092084, 5R01AI097519 (to J.M.V.), and 1K08AI110655 (to M.K.M); the National Natural Science Foundation of China Grant 81302529 (to X. Li); and the Natural Science Foundation of Fujian, China Grant 2014D007 (to X. Li). NR 56 TC 0 Z9 0 U1 5 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD SEP PY 2016 VL 100 IS 3 BP 581 EP 588 DI 10.1189/jlb.4A0915-405R PG 8 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA DV3GT UT WOS:000382809700016 PM 26965632 ER PT J AU Hamilton, BE Woltjer, RL Prola-Netto, J Nesbit, GM Gahramanov, S Pham, T Wagner, J Neuwelt, EA AF Hamilton, Bronwyn E. Woltjer, Randall L. Prola-Netto, Joao Nesbit, Gary M. Gahramanov, Seymur Thao Pham Wagner, Jaime Neuwelt, Edward A. TI Ferumoxytol-enhanced MRI differentiation of meningioma from dural metastases: a pilot study with immunohistochemical observations SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Blood-brain barrier; Contrast agents; Extraaxial masses; Ferumoxytol; Immunohistochemistry; MRI ID BRAIN-TUMORS; ULTRASTRUCTURE; JUNCTIONS; CELLS AB Malignant dural neoplasms are not reliably distinguished from benign dural neoplasms with contrast-enhanced magnetic resonance imaging (MRI). MRI enhancement in central nervous system (CNS) diseases imaged with ferumoxytol has been attributed to intracellular uptake in macrophages rather than vascular leakage. We compared imaging to histopathology and immunohistochemistry in meningiomas and dural metastases having ferumoxytol-enhanced MRI (FeMRI) and gadolinium-enhanced MRI (GdMRI) in order to correlate enhancement patterns to macrophage presence and vascular state. All patients having extraaxial CNS tumors were retrospectively selected from one of two ongoing FeMRI studies. Enhancement was compared between GdMRI and FeMRI. Diagnoses were confirmed histologically and/or by characteristic imaging. Tumor and vascular histology was reviewed. Immunohistochemical staining for CD68 (a macrophage marker), Connexin-43 (Cx43) (a marker of normal gap junctions), and smooth muscle actin (SMA) as a marker of vascularity, was performed in seven study cases with available tissue. Immunohistochemistry was performed on archival material from 33 subjects outside of the current study as controls: 20 WHO grade I cases of meningioma and 13 metastatic tumors. Metastases displayed marked delayed enhancement on FeMRI, similar to GdMRI. Four patients with dural metastases and one patient with meningioma showed similar enhancement on FeMRI and GdMRI. Five meningiomas with typical enhancement on GdMRI lacked enhancement on FeMRI. Enhancement on FeMRI was better associated with decreased Cx43 expression than intralesional macrophages. These pilot data suggest that FeMRI may better differentiate metastatic disease from meningiomas than GdMRI, and that differences in tumor vasculature rather than macrophage presence could underlie differences in contrast enhancement. C1 [Hamilton, Bronwyn E.; Prola-Netto, Joao; Nesbit, Gary M.] Oregon Hlth & Sci Univ, Dept Neuroradiol, Portland, OR 97201 USA. [Woltjer, Randall L.; Thao Pham] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. [Nesbit, Gary M.] Oregon Hlth & Sci Univ, Dotter Intervent Inst, Portland, OR 97201 USA. [Gahramanov, Seymur] Univ New Mexico, Dept Neurosurg, Albuquerque, NM 87131 USA. [Wagner, Jaime] Miami Cardiac & Vasc Inst, Miami, FL USA. [Neuwelt, Edward A.] Oregon Hlth & Sci Univ, Dept Neurol, 3181 SW Sam Jackson Pk Rd,L603, Portland, OR 97239 USA. [Neuwelt, Edward A.] Oregon Hlth & Sci Univ, Dept Neurosurg, Portland, OR 97201 USA. [Neuwelt, Edward A.] Portland VA Med Ctr, Portland, OR 97239 USA. RP Neuwelt, EA (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, 3181 SW Sam Jackson Pk Rd,L603, Portland, OR 97239 USA.; Neuwelt, EA (reprint author), Oregon Hlth & Sci Univ, Dept Neurosurg, Portland, OR 97201 USA.; Neuwelt, EA (reprint author), Portland VA Med Ctr, Portland, OR 97239 USA. EM neuwelte@ohsu.edu FU Veterans Administration merit review Grant; National Institute of Health [NS44687, CA137488]; Walter S. and Lucienne Driskill Foundation FX This work was supported by a Veterans Administration merit review Grant and by National Institute of Health Grants NS44687, and CA137488, and by the Walter S. and Lucienne Driskill Foundation to EAN. The authors thank Samantha Rolph and Emily Hochhalter Youngers for their help with manuscript preparation. NR 11 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD SEP PY 2016 VL 129 IS 2 BP 301 EP 309 DI 10.1007/s11060-016-2175-0 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DU3CC UT WOS:000382087400012 PM 27393348 ER PT J AU Sands, KA Shahripour, RB Kumar, G Barlinn, K Lyerly, MJ Harsany, M Cure, J Yakov, YL Alexandrov, AW Alexandrov, AV AF Sands, Kara A. Shahripour, Reza Bavarsad Kumar, Gyanendra Barlinn, Kristian Lyerly, Michael J. Harsany, Michal Cure, Joel Yakov, Yuri L. Alexandrov, Anne W. Alexandrov, Andrei V. TI Acute Isolated Central Facial Palsy as Manifestation of Middle Cerebral Artery Ischemia SO JOURNAL OF NEUROIMAGING LA English DT Article DE Stroke; isolated central facial palsy; middle cerebral artery ischemia ID LACUNAR SYNDROME; STROKE; THROMBOLYSIS; INFARCTION AB BACKGROUNDIsolated central facial palsy (I-CFP) is attributed to a lacunar syndrome affecting the corona radiata region or pons. We examined our acute stroke registry for patients presenting with I-CFP and localized their symptoms to a vascular lesion. SUBJECT & METHODSOur database of consecutive patients with symptoms of acute cerebral ischemia admitted from January 2008 to December 2012 was reviewed for NIH Stroke Scale (NIHSS) scores and subcomponents. All patients with I-CFP dysarthria (total NIHSS 3) had contrast-enhanced MR-angiography and transcranial Doppler as standard of care. All ischemic lesions were localized by MRI within 72 hours from symptom onset. RESULTSOf 2,202 patients with acute cerebral ischemia, 879 patients (35%) had NIHSS score 3 points (mean age 63 + 15 years, 46 % women). Nine patients (.4%) presented with I-CFP +/- dysarthria. Of these, only 1 had a lesion in the corona radiata and patent MCA, 1 had a pontine lesion without proximal vessel occlusion (2/9, or 22%). Remaining 7 patients (78%) had flow-limiting thromboembolic mid-to-distal M1/proximal M2 MCA disease. Of these, 6 (86%) patients had a prominent early anterior temporal artery on MRA and nonlacunar ischemic lesions on MRI. CONCLUSIONSContrary to current teaching of lesion localization for an I-CFP, our study revealed the majority of acute patients presenting with this symptom had evidence of flow-limiting thromboembolic MCA disease rather than a lacunar lesion. Our findings underscore the essential role of comprehensive vascular imaging in patients presenting with I-CFP, which is commonly associated with acute flow-limiting thromboembolic MCA disease. C1 [Sands, Kara A.; Shahripour, Reza Bavarsad; Kumar, Gyanendra; Lyerly, Michael J.; Yakov, Yuri L.; Alexandrov, Anne W.; Alexandrov, Andrei V.] Univ Alabama Birmingham, Dept Neurol, Comprehens Stroke Ctr, UAB Stn, Birmingham, AL 35294 USA. [Barlinn, Kristian] Tech Univ Dresden, Dresden Univ Stroke Ctr, Dresden, Germany. [Lyerly, Michael J.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Harsany, Michal] St Annes Univ Hosp, Int Clin Res Ctr, Brno, Czech Republic. [Harsany, Michal] Masaryk Univ, Fac Med, Brno, Czech Republic. [Harsany, Michal] St Annes Univ Hosp, Dept Neurol, Brno, Czech Republic. [Cure, Joel] Univ Alabama Birmingham, Dept Neuroradiol, Birmingham, AL USA. [Yakov, Yuri L.; Alexandrov, Anne W.; Alexandrov, Andrei V.] Univ Tennessee, Med Ctr, Dept Neurol, Memphis, TN USA. RP Alexandrov, AV (reprint author), Univ Tennessee, Hlth Sci Ctr, Dept Neurol, 855 Monroe Ave,Suite 415, Memphis, TN 38163 USA. EM aalexa30@uthsc.edu OI Lyerly, Michael/0000-0003-4236-1018 NR 20 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1051-2284 EI 1552-6569 J9 J NEUROIMAGING JI J. Neuroimaging PD SEP-OCT PY 2016 VL 26 IS 5 BP 499 EP 502 DI 10.1111/jon.12338 PG 4 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DV4AW UT WOS:000382868200006 PM 27061014 ER PT J AU Prakkamakul, S Witzel, T Huang, S Boulter, D Borja, MJ Schaefer, P Rosen, B Heberlein, K Ratai, E Gonzalez, G Rapalino, O AF Prakkamakul, Supada Witzel, Thomas Huang, Susie Boulter, Daniel Borja, Maria J. Schaefer, Pamela Rosen, Bruce Heberlein, Keith Ratai, Eva Gonzalez, Gilberto Rapalino, Otto TI Ultrafast Brain MRI: Clinical Deployment and Comparison to Conventional Brain MRI at 3T SO JOURNAL OF NEUROIMAGING LA English DT Article DE MRI; brain; image quality; fast imaging ID RESONANCE-IMAGING PROTOCOL; SPATIAL HARMONICS SMASH; SIMULTANEOUS ACQUISITION; STROKE; AGREEMENT; SEQUENCE; KAPPA; SENSE; FLAIR; EPI AB BACKGROUND AND PURPOSETo compare an ultrafast brain magnetic resonance imaging (MRI) protocol to the conventional protocol in motion-prone inpatient clinical settings. METHODSThis retrospective study was HIPAA compliant and approved by the Institutional Review Board with waived inform consent. Fifty-nine inpatients (30 males, 29 females; mean age 55.1, range 23-93 years)who underwent 3-Tesla brain MRI using ultrafast and conventional protocols, both including five sequences, were included in the study. The total scan time for five ultrafast sequences was 4 minutes 59 seconds. The ideal conventional acquisition time was 10 minutes 32 seconds but the actual acquisition took 15-20 minutes. The average scan times for ultrafast localizers, T1-weighted, T2-weighted, fluid-attenuated inversion recovery (FLAIR), diffusion-weighted, T2*-weighted sequences were 14, 41, 62, 96, 80, 6 seconds, respectively. Two blinded neuroradiologists independently assessed three aspects: (1) image quality, (2) gray-white matter (GM-WM) differentiation, and (3) diagnostic concordance for the detection of six clinically relevant imaging findings. Wilcoxon signed-rank test was used to compare image quality and GM-WM scores. Interobserver reproducibility was calculated. RESULTSThe ultrafast T1-weighted sequence demonstrated significantly better image quality (P = .005) and GM-WM differentiation (P < .001) compared to the conventional sequence. There was high agreement (>85%) between both protocols for the detection of mass-like lesion, hemorrhage, diffusion restriction, WM FLAIR hyperintensities, subarachnoid FLAIR hyperintensities, and hydrocephalus. CONCLUSIONSThe ultrafast protocol achieved at least comparable image quality and high diagnostic concordance compared to the conventional protocol. This fast protocol can be a viable option to replace the conventional protocol in motion-prone inpatient clinical settings. C1 [Prakkamakul, Supada; Huang, Susie; Schaefer, Pamela; Ratai, Eva; Gonzalez, Gilberto; Rapalino, Otto] Massachusetts Gen Hosp, Dept Radiol, Neuroradiol Div, Boston, MA USA. [Witzel, Thomas; Huang, Susie; Rosen, Bruce; Ratai, Eva; Gonzalez, Gilberto] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Boulter, Daniel] Ohio State Univ, Dept Radiol, Neuroradiol Div, Columbus, OH 43210 USA. [Borja, Maria J.] NYU, Sch Med, Dept Radiol, Neuroradiol Div, New York, NY USA. [Heberlein, Keith] Siemens Med Solut USA, Charlestown, MA USA. [Prakkamakul, Supada] King Chulalongkorn Mem Hosp, Thai Red Cross Soc, Dept Radiol, Bangkok, Thailand. RP Rapalino, O (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM orapalino@mgh.harvard.edu NR 29 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1051-2284 EI 1552-6569 J9 J NEUROIMAGING JI J. Neuroimaging PD SEP-OCT PY 2016 VL 26 IS 5 BP 503 EP 510 DI 10.1111/jon.12365 PG 8 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DV4AW UT WOS:000382868200007 PM 27273370 ER PT J AU Wehrenberg-Klee, E Turker, NS Heidari, P Larimer, B Juric, D Baselga, J Scaltriti, M Mahmood, U AF Wehrenberg-Klee, Eric Turker, N. Selcan Heidari, Pedram Larimer, Benjamin Juric, Dejan Baselga, Jose Scaltriti, Maurizio Mahmood, Umar TI Differential Receptor Tyrosine Kinase PET Imaging for Therapeutic Guidance SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE imaging; receptor tyrosine kinase; breast cancer; PI3K; AKT ID ADVANCED BREAST-CANCER; INHIBITION; PATHWAY; TRASTUZUMAB; HER3; AKT; EVEROLIMUS; FRAGMENTS; PROSTATE; TARGET AB Inhibitors of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway hold promise for the treatment of breast cancer, but resistance to these treatments can arise via feedback loops that increase surface expression of the receptor tyrosine kinases (RTK) epidermal growth factor receptor 1 (EGFR) and human epidermal growth factor receptor 3 (HER3), leading to persistent growth pathway signaling. We developed PET probes that provide a method of imaging this response in vivo, determining which tumors may use this escape pathway while avoiding the need for repeated biopsies. Methods: Anti-EGFR-F(ab')(2) and anti-HER3-F(ab')(2) were generated from monoclonal antibodies by enzymatic digestion, conjugated to DOTA, and labeled with Cu-64. A panel of breast cancer cell lines was treated with increasing concentrations of the AKT inhibitor GDC-0068 or the PI3K inhibitor GDC-0941. Pre- and posttreatment expression of EGFR and HER3 was compared using Western blot and correlated to probe accumulation with binding studies. Nude mice xenografts of HCC-70 or MDA-MB-468 were treated with either AKT inhibitor or PI3K inhibitor and imaged with either EGFR or HER3 PET probe. Results: Changes in HER3 and EGFR PET probe accumulation correlate to RTK expression change as assessed by Western blot (R-2 of 0.85-0.98). EGFR PET probe PET/CT imaging of HCC70 tumors shows an SUV of 0.32 +/- 0.03 for vehicle-, 0.50 +/- 0.01 for GDC-0941-, and 0.62 +/- 0.01 for GDC-0068-treated tumors, respectively (P < 0.01 for both comparisons to vehicle). HER3 PET probe PET/CT imaging of MDAMB468 tumors shows an SUV of 0.35 +/- 0.02 for vehicle- and 0.73 +/- 0.05 for GDC-0068-treated tumors (P < 0.01). Conclusion: Our imaging studies, using PET probes specific to EGFR and HER3, show that changes in RTK expression indicative of resistance to PI3K and AKT inhibitors can be seen within days of therapy initiation and are of sufficient magnitude as to allow reliable clinical interpretation. Noninvasive PET monitoring of these RTK feedback loops should help to rapidly assess resistance to PI3K and AKT inhibitors and guide selection of an appropriate combinatorial therapeutic regimen on an individual patient basis. C1 [Wehrenberg-Klee, Eric; Turker, N. Selcan; Heidari, Pedram; Larimer, Benjamin; Mahmood, Umar] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Juric, Dejan] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. [Baselga, Jose; Scaltriti, Maurizio] Mem Sloan Kettering Canc Ctr, HOPP, 1275 York Ave, New York, NY 10021 USA. RP Mahmood, U (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. EM umahmood@mgh.harvard.edu FU NIH [U01CA084301, P50CA127003, U01CA143056]; "Stand Up to Cancer" Dream Team Translational Research Grant; Program of the Entertainment Industry Foundation [SU2C-AACR-DT0209]; Breast Cancer Research Foundation; Dubai Harvard Foundation for Medical Research (DHFMR) [223439] FX The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. This research was supported by NIH U01CA084301, P50CA127003, and U01CA143056; by a "Stand Up to Cancer" Dream Team Translational Research Grant, a Program of the Entertainment Industry Foundation (SU2C-AACR-DT0209) and the Breast Cancer Research Foundation; and by the Dubai Harvard Foundation for Medical Research (DHFMR, grant number 223439). Dr. Jose Baselga has consulting and advisory positions at Genentech. No other potential conflict of interest relevant to this article was reported. NR 24 TC 1 Z9 1 U1 2 U2 2 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD SEP PY 2016 VL 57 IS 9 BP 1413 EP 1419 DI 10.2967/jnumed.115.169417 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DU7UK UT WOS:000382419900030 PM 27081168 ER PT J AU Singh, P Gonzalez-Ramos, S Mojena, M Rosales-Mendoza, CE Emami, H Swanson, J Morss, A Fayad, ZA Rudd, JHF Gelfand, J Paz-Garcia, M Martin-Sanz, P Bosca, L Tawakol, A AF Singh, Parmanand Gonzalez-Ramos, Silvia Mojena, Marina Eduardo Rosales-Mendoza, Cesar Emami, Hamed Swanson, Jeffiey Morss, Alex Fayad, Zahi A. Rudd, James H. F. Gelfand, Jeffrey Paz-Garcia, Marta Martin-Sanz, Paloma Bosca, Lisardo Tawakol, Ahmed TI GM-CSF Enhances Macrophage Glycolytic Activity In Vitro and Improves Detection of Inflammation In Vivo SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE F-18-FDG-PET; glycolysis; GM-CSF; inflammation; macrophage ID COLONY-STIMULATING FACTOR; POSITRON-EMISSION-TOMOGRAPHY; MYOCARDIAL-INFARCTION; CARDIAC SARCOIDOSIS; COMPUTED-TOMOGRAPHY; UNKNOWN ORIGIN; CLINICAL-VALUE; FACTOR SIGNALS; ATHEROSCLEROSIS; DISEASE AB F-18-FDG accumulates in glycolytically active tissues and is known to concentrate in tissues that are rich in activated macrophages. In this study, we tested the hypotheses that human granulocyte-macrophage colony-stimulating factor (GM-CSF), a clinically used cytokine, increases macrophage glycolysis and deoxyglucose uptake in vitro and acutely enhances 18F-FDG uptake within inflamed tissues such as atherosclerotic plaques in vivo. Methods: In vitro experiments were conducted on human macrophages whereby inflammatory activation and uptake of radiolabeled 2-deoxyglucose was assessed before and after GM-CSF exposure. In vivo studies were performed on mice and New Zealand White rabbits to assess the effect of GM-CSF on F-18-FDG uptake in normal versus inflamed arteries, using PET. Results: Incubation of human macrophages with GM-CSF resulted in increased glycolysis and increased 2-deoxyglucose uptake (P < 0.05). This effect was attenuated by neutralizing antibodies against tumor necrosis factor a or after silencing or inhibition of 6-phosphofructo-2-kinase. In vivo, in mice and in rabbits, intravenous GM-CSF administration resulted in a 70% and 73% increase (P < 0.01 for both), respectively, in arterial F-18-FDG uptake in atherosclerotic animals but not in nonatherosclerotic controls. Histopathologic analysis demonstrated a significant correlation between in vivo 18F-FDG uptake and macrophage staining (R = 0.75, P < 0.01). Conclusion: GM-CSF substantially augments glycolytic flux in vitro (via a mechanism dependent on ubiquitous type 6-phosphofructo-2-kinase and tumor necrosis factor-alpha) and increases F-18-FDG uptake within inflamed atheroma in vivo. These findings demonstrate that GM-CSF can be used to enhance detection of inflammation. Further studies should explore the role of GM-CSF stimulation to enhance the detection of inflammatory foci in other disease states. C1 [Singh, Parmanand] Weill Cornell Med Coll, New York Presbyterian Hosp, Div Cardiol, New York, NY USA. [Gonzalez-Ramos, Silvia; Mojena, Marina; Eduardo Rosales-Mendoza, Cesar; Paz-Garcia, Marta; Martin-Sanz, Paloma; Bosca, Lisardo] UAM, CSIC, Inst Invest Biomed Alberto Sols, Arturo Duperier 4, Madrid 28029, Spain. [Eduardo Rosales-Mendoza, Cesar] Univ Autonoma Nuevo Leon, Dept Bioquim & Med Mol, Monterrey, Nuevo Leon, Mexico. [Emami, Hamed; Swanson, Jeffiey; Morss, Alex; Tawakol, Ahmed] Massachusetts Gen Hosp, Div Cardiol, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Emami, Hamed; Swanson, Jeffiey; Morss, Alex; Gelfand, Jeffrey; Tawakol, Ahmed] Harvard Med Sch, Boston, MA USA. [Fayad, Zahi A.] Icahn Sch Med Mt Sinai, Translat & Mol Imaging Inst, New York, NY USA. [Rudd, James H. F.] Univ Cambridge, Div Cardiovasc Med, Cambridge, England. [Gelfand, Jeffrey] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Martin-Sanz, Paloma; Bosca, Lisardo] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain. RP Bosca, L (reprint author), UAM, CSIC, Inst Invest Biomed Alberto Sols, Arturo Duperier 4, Madrid 28029, Spain. EM lbosca@iib.uam.es FU NIHR Cambridge Biomedical Research Centre; British Heart Foundation; HEFCE; NIH/NHLBI [R01 HL071021, R01 HL078667, R01 HL122177]; NIH/NBIB [R01 EB009638]; NIH/NHLBI Program of Excellence in Nano technology (PEN) Award [HHSN268201000045C]; NHLBI - Marfan Foundation [5T32 HL076136]; MINECO [SAF2014-52492R, RTC2015-3741]; Institute de Salud Carlos III; Comunidad de Madrid [S2010/BMD-2378]; [RD12/0042/0019] FX The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. James H.F. Rudd is in part supported by the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation, and HEFCE. Zahi A. Fayad is supported by NIH/NHLBI R01 HL071021, R01 HL078667, NIH/NBIB R01 EB009638, and the NIH/NHLBI Program of Excellence in Nano technology (PEN) Award, contract HHSN268201000045C. Parmanand Singh was supported by a grant from the NHLBI (5T32 HL076136) and is funded by the Marfan Foundation. Lisardo Bosca was supported by SAF2014-52492R, RTC2015-3741 from MINECO, and RD12/0042/0019. Centro de Investigation Biomedica en Red de Enfermedades Hepaticas y Digestivas is funded by the Institute de Salud Carlos III and S2010/BMD-2378 from Comunidad de Madrid. Ahmed Tawakol is supported by NIH/NHLBI R01 HL122177. No other potential conflict of interest relevant to this article was reported. NR 39 TC 1 Z9 1 U1 3 U2 3 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD SEP PY 2016 VL 57 IS 9 BP 1428 EP 1435 DI 10.2967/jnumed.115.167387 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DU7UK UT WOS:000382419900032 PM 27081166 ER PT J AU Ting, BL Heng, M Vrahas, MS Rodriguez, EK Harris, MB Weaver, MJ AF Ting, Beverlie L. Heng, Marilyn Vrahas, Mark S. Rodriguez, Edward K. Harris, Mitchel B. Weaver, Michael J. TI Is Disuse Osteopenia a Favorable Prognostic Sign After Femoral Neck Fracture? SO JOURNAL OF ORTHOPAEDIC TRAUMA LA English DT Article DE femoral neck fracture; hip fracture; fracture; avascular necrosis; osteonecrosis; AVN ID SUBCAPITAL HIP-FRACTURES; AVASCULAR NECROSIS; INTERNAL-FIXATION; YOUNG-ADULTS; OPEN REDUCTION; HEAD; OSTEONECROSIS; COMPLICATIONS; OUTCOMES; FAILURE AB Objectives: Avascular necrosis (AVN) of the femoral head is a devastating complication following fixation of femoral neck fractures in younger adults. In this study, we investigate the prognostic utility of disuse osteopenia. Design: Retrospective study. Setting: Three academic Level 1 trauma centers. Patients: One hundred twenty patients younger than 60 years treated for a femoral neck fracture. Intervention: N/A. Main Outcome Measures: The presence of sclerosis or osteopenia, compared to the contralateral femoral head, was measured 6 weeks from injury both subjectively and using a novel radiographic measure, the relative density ratio (RDR). The outcome measure was radiographic development of AVN. Results: The presence of relative sclerosis was associated with AVN and overall treatment failure. Patients with subjective relative sclerosis had a 12.6 (95% confidence interval, 2.9-61.3; P < 0.001) times higher odds of developing AVN. Multiple logistic regression showed that for every 0.10 increase in the RDR, there was a 5.2 increase in the odds (95% confidence interval, 2.1-26.9; P = 0.009) of developing AVN. Patients with an RDR of >= 1.2 have an 80% probability of AVN, whereas those with an RDR <0.8 have a <1% probability of developing AVN. Conclusions: Disuse osteopenia detected on 6-week radiographs is a favorable prognostic sign following fixation of femoral neck fractures. Patients who have relative sclerosis of the femoral head at 6-week follow-up are at a higher risk of developing AVN. C1 [Ting, Beverlie L.; Harris, Mitchel B.; Weaver, Michael J.] Harvard Med Sch, Dept Orthoped Surg, Orthoped Trauma Initiat, Brigham & Womens Hosp, Boston, MA 02115 USA. [Heng, Marilyn; Vrahas, Mark S.] Harvard Med Sch, Orthoped Trauma Initiat, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA USA. [Rodriguez, Edward K.] Harvard Med Sch, Orthoped Trauma Initiat, Dept Orthoped, Beth Israel Deaconess Med Ctr, Boston, MA USA. RP Weaver, MJ (reprint author), Harvard Med Sch, Dept Orthoped Surg, Orthoped Trauma Initiat, Brigham & Womens Hosp, Boston, MA 02115 USA. EM mjweaver@partners.org NR 45 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 0890-5339 EI 1531-2291 J9 J ORTHOP TRAUMA JI J. Orthop. Trauma PD SEP PY 2016 VL 30 IS 9 BP 496 EP 502 DI 10.1097/BOT.0000000000000635 PG 7 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA DU6LX UT WOS:000382327500014 PM 27243346 ER PT J AU Busch, RA Heneghan, AF Pierre, JF Neuman, JC Reimer, CA Wang, XY Kimple, ME Kudsk, KA AF Busch, Rebecca A. Heneghan, Aaron F. Pierre, Joseph F. Neuman, Joshua C. Reimer, Claire A. Wang, Xinying Kimple, Michelle E. Kudsk, Kenneth A. TI Bombesin Preserves Goblet Cell Resistin-Like Molecule During Parenteral Nutrition but Not Other Goblet Cell Products SO JOURNAL OF PARENTERAL AND ENTERAL NUTRITION LA English DT Article DE parenteral nutrition; enteric nervous system; small intestine; innate immunity; goblet cells; mucin 2; trefoil factor 3; resistin-like molecule; bombesin ID PENETRATING ABDOMINAL-TRAUMA; RESPIRATORY-TRACT IMMUNITY; LYMPHOID-TISSUE; MUCOSAL IMMUNITY; BARRIER FUNCTION; FED MICE; GASTROINTESTINAL-TRACT; BACTERIAL PNEUMONIA; ENTERAL NUTRITION; SEPTIC MORBIDITY AB Introduction: Parenteral nutrition (PN) increases the risk of infection in critically ill patients and is associated with defects in gastrointestinal innate immunity. Goblet cells produce mucosal defense compounds, including mucin (principally MUC2), trefoil factor 3 (TFF3), and resistin-like molecule (RELM). Bombesin (BBS), a gastrin-releasing peptide analogue, experimentally reverses PN-induced defects in Paneth cell innate immunity. We hypothesized that PN reduces goblet cell product expression and PN+BBS would reverse these PN-induced defects. Methods: Two days after intravenous cannulation, male Institute of Cancer Research mice were randomized to chow (n = 15), PN (n = 13), or PN+BBS (15 mu g tid) (n = 12) diets for 5 days. Defined segments of ileum and luminal fluid were analyzed for MUC2, TFF3, and RELM by quantitative reverse transcriptase polymerase chain reaction and Western blot. Th2 cytokines interleukin (IL)-4 and IL-13 were measured by enzyme-linked immunosorbent assay. Results: Compared with chow, PN significantly reduced MUC2 in ileum (P < .01) and luminal fluid (P = .01). BBS supplementation did not improve ileal or luminal MUC2 compared with PN (P > .3). Compared with chow, PN significantly reduced TFF3 in ileum (P < .02) and luminal fluid (P < .01). BBS addition did not improve ileal or luminal TFF3 compared with PN (P > .3). Compared with chow, PN significantly reduced ileal RELM (P < .01). BBS supplementation significantly increased ileal RELM to levels similar to chow (P < .03 vs PN; P > .6 vs chow). Th2 cytokines were decreased with PN and returned to chow levels with BBS. Conclusion: PN significantly impairs the goblet cell component of innate mucosal immunity. BBS only preserves goblet cell RELM during PN but not other goblet cell products measured. C1 [Heneghan, Aaron F.; Kudsk, Kenneth A.] William S Middleton Mem Vet Adm Med Ctr, Vet Adm Surg Serv, Madison, WI USA. [Busch, Rebecca A.; Heneghan, Aaron F.; Pierre, Joseph F.; Reimer, Claire A.; Wang, Xinying; Kudsk, Kenneth A.] Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, Madison, WI USA. [Pierre, Joseph F.] Univ Chicago, Dept Med, Div Gastroenterol, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Neuman, Joshua C.] Univ Wisconsin, Dept Nutr Sci, Sch Med & Publ Hlth, 1415 Linden Dr, Madison, WI 53706 USA. [Wang, Xinying] Nanjing Univ, Sch Med, Jinling Hosp, Dept Surg, Nanjing, Jiangsu, Peoples R China. [Kimple, Michelle E.] Univ Wisconsin, Dept Med, Div Endocrinol Diabet & Metab, Sch Med & Publ Hlth, Madison, WI USA. RP Kudsk, KA (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, 600 Highland Ave,Clin Sci Ctr H4-736, Madison, WI 53792 USA. EM kudsk@surgery.wisc.edu FU Biomedical Laboratory Research & Development Service of the VA Office of Research and Development [I01BX001672]; National Institute of Health (NIH) [R01 DK102598]; NIH [T32 CA090217, T32 DK007074, T32 AG000213] FX The project described was supported by award number I01BX001672 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development. The contents of this article do not represent the views of the Veterans Affairs or the United States government. This material is also based upon work supported by the National Institute of Health (NIH) grant R01 DK102598 (MEK) and NIH training grants T32 CA090217 (RAB), T32 DK007074 (JFP), and T32 AG000213 (JCN). NR 49 TC 1 Z9 1 U1 3 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0148-6071 EI 1941-2444 J9 JPEN-PARENTER ENTER JI J. Parenter. Enter. Nutr. PD SEP PY 2016 VL 40 IS 7 BP 1042 EP 1049 DI 10.1177/0148607115585353 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DV1VA UT WOS:000382708700018 PM 25934045 ER PT J AU Cox, KS Mouilso, ER Venners, MR Defever, ME Duviviere, L Rauch, SAM Strom, TQ Joiner, TE Tuerk, PW AF Cox, Keith S. Mouilso, Emily R. Venners, Margaret R. Defever, Mahrie E. Duviviere, Leticia Rauch, Sheila A. M. Strom, Thad Q. Joiner, Thomas E. Tuerk, Peter W. TI Reducing suicidal ideation through evidence-based treatment for posttraumatic stress disorder SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Suicide; Suicidal ideation; Suicide prevention; Posttraumatic stress disorder (PTSD); Evidence-based treatments (EBTs); Effectiveness research ID VETERANS; RISK; PTSD; HEALTH; CARE; THERAPY; IRAQ AB Background: Suicide is a major public health concern in military and civilian contexts. Veteran populations are at increased risk for suicide, especially veterans with mental health disorders such as Posttraumatic Stress Disorder (PTSD). Suicidal ideation (SI) is a primary risk factor for suicide. Methods: We investigated changes in SI in a multi-site sample of treatment seeking veterans from three separate Veterans Health Administration (VA) medical centers (n = 289) who received Prolonged Exposure (PE) therapy, an evidence-based treatment (EBT) for PTSD. SI and PTSD symptoms were assessed, using self-report instruments, throughout routine clinical care. Results: Both PTSD and SI symptoms reduced over the course of treatment (d-type effect sizes of 1.47 and 0.27, respectively). While SI was associated with PTSD symptoms at all time points, appropriately specified, time lagged models indicated that changes in PTSD symptoms were predictive of future declines in SI, while the converse was not true. Conclusions: Results indicate that treating PTSD symptoms with an EBT for PTSD can be an effective way to reduce SI, at least partially, and for some patients. These data are significant in light of the resources and programming devoted to addressing SI in the VA relative to available empirical evidence regarding the effectiveness of developed strategies. The findings demonstrate the importance of facilitating EBT referrals for specific disorders as a component of broad-based suicide outreach and preventions strategies. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Cox, Keith S.] Univ North Carolina Asheville, Dept Psychol, One Univ Hts, Asheville, NC 28803 USA. [Mouilso, Emily R.] Univ Georgia, Dept Psychol, 125 Baldwin St, Athens, GA 30602 USA. [Venners, Margaret R.; Defever, Mahrie E.] VA Ann Arbor Hlth Care Syst, 2215 Fuller Rd, Ann Arbor, MI 48105 USA. [Venners, Margaret R.; Defever, Mahrie E.] Univ Michigan, Sch Med, Dept Psychiat, 4250 Plymouth Rd, Ann Arbor, MI 48109 USA. [Duviviere, Leticia] Evidence Based Practice Inst, 3303 South Irving St, Seattle, WA 98144 USA. [Rauch, Sheila A. M.] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, 12 Execut Pk Dr NE 200, Atlanta, GA 30329 USA. [Strom, Thad Q.] Minneapolis VA Hlth Care Syst, 1 Vet Dr, Minneapolis, MN 55417 USA. [Strom, Thad Q.] Univ Minnesota, Sch Med, Dept Psychiat, Minneapolis, MN 55454 USA. [Joiner, Thomas E.] Florida State Univ, Dept Psychol, 1107 West Call St, Tallahassee, FL 32304 USA. [Tuerk, Peter W.] Ralph H Johnson VA Med Ctr, 109 Bee St, Charleston, SC 29401 USA. [Tuerk, Peter W.] Med Univ South Carolina, Dept Psychiat & Behav Sci, 67 President St,MSC 861, Charleston, SC 29425 USA. RP Cox, KS (reprint author), Univ North Carolina Asheville, Dept Psychol, One Univ Hts, Asheville, NC 28803 USA. EM kcox2@unca.edu FU Department of Veteran Affairs, Veterans Health Administration, Office of Research and Development, Clinical Sciences Research and Development [CDA-2] FX Dr. Tuerk's contribution to this work was supported by a Career Development Award (CDA-2) from the Department of Veteran Affairs, Veterans Health Administration, Office of Research and Development, Clinical Sciences Research and Development (PI: Peter W. Tuerk). NR 38 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 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD SEP PY 2016 VL 80 BP 59 EP 63 DI 10.1016/j.jpsychires.2016.05.011 PG 5 WC Psychiatry SC Psychiatry GA DU6TI UT WOS:000382347100010 PM 27295122 ER PT J AU Steffel, J Giugliano, RP Braunwald, E Murphy, SA Mercuri, M Choi, Y Aylward, P White, H Zamorano, JL Antman, EM Ruff, CT AF Steffel, Jan Giugliano, Robert P. Braunwald, Eugene Murphy, Sabina A. Mercuri, Michele Choi, Youngsook Aylward, Phil White, Harvey Luis Zamorano, Jose Antman, Elliott M. Ruff, Christian T. TI Edoxaban Versus Warfarin in Atrial Fibrillation Patients at Risk of Falling ENGAGE AF-TIMI 48 Analysis SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE anticoagulation; atrial fibrillation; edoxaban; falls; frailty; NOACs ID DIALYSIS PATIENTS; ELDERLY-PATIENTS; CO-MORBIDITY; ADULTS; ANTICOAGULATION; PREVENTION; PREDICTION; COMMUNITY; INJURIES; OUTCOMES AB BACKGROUND Anticoagulation is often avoided in patients with atrial fibrillation who are at an increased risk of falling. OBJECTIVES This study assessed the relative efficacy and safety of edoxaban versus warfarin in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial in patients with atrial fibrillation judged to be at increased risk of falling. METHODS We performed a pre-specified analysis of the ENGAGE AF-TIMI 48, comparing patients with versus without increased risk of falling. RESULTS Nine hundred patients (4.3%) were judged to be at increased risk of falling. These patients were older (median, 77 vs. 72 years; p < 0.001), and had a higher prevalence of comorbidities including prior stroke/transient ischemic attack, diabetes, and coronary artery disease. After multivariable adjustment, patients at increased risk of falling experienced more bone fractures caused by falling (adjusted hazard ratio [HRadj]: 1.88; 95% confidence interval [CI]: 1.49 to 2.38; p < 0.001), major bleeding (HRadj: 1.30; 95% CI: 1.04 to 1.64; p = 0.023), life-threatening bleeding (HRadj: 1.67; 95% CI: 1.11 to 2.50; p = 0.013), and all-cause death (HRadj: 1.45; 95% CI: 1.23 to 1.70; p < 0.001), but not ischemic events including stroke/systemic embolic event (HRadj: 1.16; 95% CI: 0.89 to 1.51; p = 0.27). No treatment interaction was observed between either dosing regimens of edoxaban and warfarin for the efficacy and safety outcomes. Treatment with edoxaban resulted in a greater absolute risk reduction in severe bleeding events and all-cause mortality compared with warfarin. CONCLUSIONS Edoxaban is an attractive alternative to warfarin in patients at increased risk of falling, because it is associated with an even greater absolute reduction in severe bleeding events and mortality. (C) 2016 by the American College of Cardiology Foundation. C1 [Steffel, Jan] Univ Heart Ctr Zurich, Dept Cardiol, Zurich, Switzerland. [Giugliano, Robert P.; Braunwald, Eugene; Murphy, Sabina A.; Antman, Elliott M.; Ruff, Christian T.] Brigham & Womens Hosp, Cardiovasc Div, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. [Mercuri, Michele; Choi, Youngsook] Daiichi Sankyo Pharma Dev, Edison, NJ USA. [Aylward, Phil] Flinders Med Ctr, Adelaide, SA, Australia. [White, Harvey] Auckland City Hosp, Auckland, New Zealand. [Luis Zamorano, Jose] Ramon & Cajal Univ Hosp, Madrid, Spain. RP Ruff, CT (reprint author), TIMI Study Grp, 350 Longwood Ave,1st Floor Off, Boston, MA 02115 USA. EM cruff@partners.org FU Daiichi-Sankyo Pharma Development; Amgen; AstraZeneca; Atricure; Bayer; Biotronik; Biosense Webster; Boehringer-Ingelheim; Boston Scientific; Bristol-Myers Squibb; Daiichi-Sankyo; Cook Medical; Medtronic; Novartis; Pfizer; Roche; Sanofi; Sorin; St. Jude Medical; Zoll; Bayer Healthcare; American College of Cardiology; Janssen; Merck; Portola; Johnson Johnson; The Medicines Company; Theravance; Menarini; Medscape; Merck Co.; GlaxoSmithKline; Eli Lilly and Company; National Institutes of Health; Merck Sharpe Dohme; George Institute; Omthera Pharmaceuticals; Pfizer New Zealand; Intarcia Therapeutics Inc.; Elsai Inc.; DalGen Products and Services; Boehringer Ingelheim; Eisai; Intarcia FX The ENGAGE AF-TIMI 48 study was supported by Daiichi-Sankyo Pharma Development. Dr. Steffel has received consultant and/or speaker fees from Amgen, AstraZeneca, Atricure, Bayer, Biotronik, Biosense Webster, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi-Sankyo, Cook Medical, Medtronic, Novartis, Pfizer, Roche, Sanofi, Sorin, St. Jude Medical, and Zoll; grant support through his institution from Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, Daiichi-Sankyo, Medtronic, and St. Jude Medical; and is codirector of CorXL. Dr. Giugliano has received consulting fees from the American College of Cardiology, Boehringer-Ingelheim, Bristol-Myers Squibb, Janssen, Daiichi-Sankyo, Merck, Pfizer, Portola, and Sanofi; and grant support to his institution from Daiichi-Sankyo, Merck, Johnson & Johnson, Sanofi, and AstraZeneca. Dr. Braunwald has received consulting fees from The Medicines Company and Theravance; lecture fees from Menarini and Medscape; grant support through his institution from Daiichi-Sankyo, AstraZeneca, Merck & Co., Novartis, and GlaxoSmithKline; served as an unpaid consultant for Merck and Novartis; and provided uncompensated lectures for Merck & Co. Ms. Murphy has received grant support through her institution from Daiichi-Sankyo. Dr. Mercuri is an employee of Daiichi-Sankyo; and has a pending patent related to the clinical properties of edoxaban. Dr. Choi is an employee of Daiichi-Sankyo. Dr. Aylward has received research support from Daiicho-Sankyo. Dr. White has received a research grant from Sanofi, Eli Lilly and Company, National Institutes of Health, Merck Sharpe & Dohme, AstraZeneca, GlaxoSmithKline, George Institute, Omthera Pharmaceuticals, Pfizer New Zealand, Intarcia Therapeutics Inc., Elsai Inc., DalGen Products and Services, and Daiichi-Sankyo Pharma Development; and consulting fees from AstraZeneca. Dr. Zamorano is an investigator on the Daiichi-Sankyo Engage trial. Dr. Antman has received grant support through his institution from Daiichi Sankyo. Dr. Ruff has received consulting fees from Bayer, Daiichi-Sankyo, Portola, and Boehringer Ingelheim; and grant support through his institution from Daiichi-Sankyo, AstraZeneca, Eisai, and Intarcia. Parts of this paper were presented as a poster at the American Heart Association Scientific Sessions 2015 in Orlando, Florida. NR 39 TC 5 Z9 5 U1 6 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP PY 2016 VL 68 IS 11 BP 1169 EP 1178 DI 10.1016/j.jacc.2016.06.034 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DU7MU UT WOS:000382399200003 PM 27609678 ER PT J AU Kim, JB Spotnitz, M Lindsay, ME MacGillivray, TE Isselbacher, EM Sundt, TM AF Kim, Joon Bum Spotnitz, Matthew Lindsay, Mark E. MacGillivray, Thomas E. Isselbacher, Eric M. Sundt, Thoralf M., III TI Risk of Aortic Dissection in the Moderately Dilated Ascending Aorta SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE aneurysm; aorta; aortic dissection; prognosis; risk factors ID NATURAL-HISTORY; INTERNATIONAL REGISTRY; COMPUTED-TOMOGRAPHY; VALVE-REPLACEMENT; COMPETING RISK; ANEURYSMS; MANAGEMENT; RUPTURE; DISEASE; SURGERY AB BACKGROUND Recent studies have demonstrated that many patients with acute type A aortic dissection (AD) have aortic diameters of <55 mm at presentation, prompting discussion of lowering the prophylactic surgical guidelines. However, risk of dissection at these smaller diameters is poorly defined. OBJECTIVES The purpose of this study is to understand the risk of AD in moderately dilated ascending aortas using a large echocardiographic data set. METHODS Using an institutional echocardiography database, we identified 4,654 nonsyndromic adults (age: 68.6 +/- 13.1 years; 1,003 women) with maximal ascending aortic diameters of 40 to 55 mm. We performed competing risk analysis to determine the independent risk factors of AD or aortic rupture. RESULTS Five hundred eighty-six individuals (12.6%) had bicuspid aortic valves (BAVs). During follow-up (14,431.5 patient-years), AD and rupture occurred in 13 and 1 patients, respectively, which demonstrated a linearized incidence of AD and/or rupture of 0.1% per patient-year. Elective ascending aortic repair was performed in 176 individuals. On multivariable analyses, independent predictors of AD and/or rupture were age (hazard ratio [HR]: 1.06; 95% confidence interval [CI]: 1.01 to 1.12; p = 0.024) and baseline aortic diameters (HR: 1.20; 95% CI: 1.05 to 1.36; p = 0.006). The presence of a BAV was not a significant factor (HR: 0.94; 95% CI: 0.10 to 8.40; p = 0.95). Estimated risks of AD and/or rupture within 5 years were 0.4%, 1.1%, and 2.9% at baseline aortic diameters of 45, 50, and 55 mm, respectively. CONCLUSIONS Risks of AD and/or rupture were significantly correlated with the aortic diameter and age in patients with moderately dilated ascending aortas. However, the risks were low for diameters < 5.0 cm when timely elective aortic repair was performed, regardless of the morphology of the aortic valve. (C) 2016 by the American College of Cardiology Foundation. C1 [Kim, Joon Bum] Univ Ulsan, Coll Med, Dept Thorac & Cardiovasc Surg, Asan Med Ctr, Seoul, South Korea. [Spotnitz, Matthew; MacGillivray, Thomas E.; Sundt, Thoralf M., III] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiac Surg, Boston, MA USA. [Lindsay, Mark E.; Isselbacher, Eric M.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiol Div, Boston, MA USA. [Lindsay, Mark E.] Harvard Med Sch, Massachusetts Gen Hosp, Pediat Cardiol, Boston, MA USA. [Lindsay, Mark E.; MacGillivray, Thomas E.; Isselbacher, Eric M.; Sundt, Thoralf M., III] Harvard Med Sch, Massachusetts Gen Hosp, Thorac Aort Ctr, Boston, MA USA. [Spotnitz, Matthew] Harvard TH Chan Sch Publ Hlth, Cambridge, MA USA. RP Sundt, TM (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Cox 652, Boston, MA 02114 USA. EM tsundt@partners.org OI Kim, Joon Bum/0000-0001-5801-2395 FU American Association for Thoracic Surgery's Evarts A. Graham Foundation; American Association for Thoracic Surgery's Evarts A. Graham Memorial Traveling Fellowship FX This study was funded by the American Association for Thoracic Surgery's Evarts A. Graham Foundation. Dr. Kim is sponsored by the American Association for Thoracic Surgery's Evarts A. Graham Memorial Traveling Fellowship. Presented at the American Association for Thoracic Surgery Aortic Symposium Workshop 2015, Kobe, Japan, October 16, 2015. Dr. Sundt has served as a consultant for Thrasos. The other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 33 TC 0 Z9 0 U1 5 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP PY 2016 VL 68 IS 11 BP 1209 EP 1219 DI 10.1016/j.jacc.2016.06.025 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DU7MU UT WOS:000382399200009 ER PT J AU de Boer, IH Zelnick, L Afkarian, M Ayers, E Curtin, L Himmelfarb, J Ikizler, TA Kahn, SE Kestenbaum, B Utzschneider, K AF de Boer, Ian H. Zelnick, Leila Afkarian, Maryam Ayers, Ernest Curtin, Laura Himmelfarb, Jonathan Ikizler, T. Alp Kahn, Steven E. Kestenbaum, Bryan Utzschneider, Kristina TI Impaired Glucose and Insulin Homeostasis in Moderate-Severe CKD SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; RENAL-DISEASE; ORAL GLUCOSE; RESISTANCE; METABOLISM; CLEARANCE; SENSITIVITY; SECRETION; INTOLERANCE AB Kidney disease leads to clinically relevant disturbances in glucose and insulin homeostasis, but the pathophysiology in moderate-severe CKD remains incompletely defined. In a cross-sectional study of 59 participants with nondiabetic CKD (mean eGFR =37.6 ml/min per 1.73 m(2)) and 39 healthy control subjects, we quantified insulin sensitivity, clearance, and secretion and glucose tolerance using hyperinsulinemic-euglycemic clamp and intravenous and oral glucose tolerance tests. Participants with CKD had lower insulin sensitivity than participants without CKD (mean[SD] 3.9[2.0] versus 5.0 [2.0] mg/min per mu U/ml; P<0.01). Insulin clearance correlated with insulin sensitivity (r=0.72; P<0.001) and was also lower in participants with CKD than controls (876 [226] versus 998 [212] ml/min; P<0.01). Adjustment for physical activity, diet, fat mass, and fatfree mass in addition to demographics and smoking partially attenuated associations of CKD with insulin sensitivity (adjusted difference, -0.7; 95% confidence interval, -1.4 to 0.0 mg/min per mu U/ml) and insulin clearance (adjusted difference, -85; 95% confidence interval, -160 to -10 ml/min). Among participants with CKD, eGFR did not significantly correlate with insulin sensitivity or clearance. Insulin secretion and glucose tolerance did not differ significantly between groups, but 65% of participants with CKD had impaired glucose tolerance. In conclusion, moderate-severe CKD associated with reductions in insulin sensitivity and clearance that are explained, in part, by differences in lifestyle and body composition. We did not observe a CKD-specific deficit in insulin secretion, but the combination of insulin resistance and inadequate augmentation of insulin secretion led to a high prevalence of impaired glucose tolerance. C1 [de Boer, Ian H.; Zelnick, Leila; Afkarian, Maryam; Ayers, Ernest; Curtin, Laura; Himmelfarb, Jonathan; Kestenbaum, Bryan] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. [de Boer, Ian H.; Zelnick, Leila; Afkarian, Maryam; Ayers, Ernest; Curtin, Laura; Himmelfarb, Jonathan; Kestenbaum, Bryan] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA. [Kahn, Steven E.; Utzschneider, Kristina] Univ Washington, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. [de Boer, Ian H.; Kahn, Steven E.; Utzschneider, Kristina] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Ikizler, T. Alp] Vanderbilt Univ, Med Ctr, Div Nephrol, Nashville, TN USA. [Ikizler, T. Alp] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Kidney Dis, Nashville, TN USA. RP de Boer, IH (reprint author), Box 359606,325 9th Ave, Seattle, WA 98104 USA. EM deboer@u.washington.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01DK087726]; NIDDK [UL1TR000423, P01DK017047, P30DK035816, R01DK088762, R01DK099199] FX The Study of Glucose and Insulin in Renal Disease was funded by Grant R01DK087726 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Additional support came from NIDDK Grants UL1TR000423, P01DK017047, P30DK035816, R01DK088762, and R01DK099199. NR 40 TC 4 Z9 4 U1 1 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD SEP PY 2016 VL 27 IS 9 BP 2861 EP 2871 DI 10.1681/ASN.2015070756 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA DU5SB UT WOS:000382270500030 PM 26823551 ER PT J AU Horwitz, SM Zelenetz, AD Gordon, LI Wierda, WG Abramson, JS Advani, RH Andreadis, CB Bartlett, N Byrd, JC Fayad, LE Fisher, RI Glenn, MJ Habermann, TM Harris, NL Hernandez-Ilizaliturri, F Hoppe, RT Kaminski, MS Kelsey, CR Kim, YH Krivacic, S LaCasce, AS Lunning, M Nademanee, A Press, O Rabinovitch, R Reddy, N Reid, E Roberts, K Saad, AA Sokol, L Swinnen, LJ Vose, JM Yahalom, J Zafar, N Dwyer, M Sundar, H Porcu, P AF Horwitz, Steven M. Zelenetz, Andrew D. Gordon, Leo I. Wierda, William G. Abramson, Jeremy S. Advani, Ranjana H. Andreadis, C. Babis Bartlett, Nancy Byrd, John C. Fayad, Luis E. Fisher, Richard I. Glenn, Martha J. Habermann, Thomas M. Harris, Nancy Lee Hernandez-Ilizaliturri, Francisco Hoppe, Richard T. Kaminski, Mark S. Kelsey, Christopher R. Kim, Youn H. Krivacic, Susan LaCasce, Ann S. Lunning, Matthew Nademanee, Auayporn Press, Oliver Rabinovitch, Rachel Reddy, Nishitha Reid, Erin Roberts, Kenneth Saad, Ayman A. Sokol, Lubomir Swinnen, Lode J. Vose, Julie M. Yahalom, Joachim Zafar, Nadeem Dwyer, Mary Sundar, Hema Porcu, Pierluigi TI Non-Hodgkin's Lymphomas, Version 3.2016 Featured Updates to the NCCN Guidelines SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article ID T-CELL LYMPHOMA; PHASE-II TRIAL; LONG-TERM REMISSIONS; BREAST IMPLANTS; SINGLE-AGENT; OPEN-LABEL; ALLOGENEIC TRANSPLANTATION; PROGNOSTIC-SIGNIFICANCE; BRENTUXIMAB VEDOTIN; CHEMOTHERAPY AB Peripheral T-cell lymphomas (PTCLs) represent a relatively uncommon heterogeneous group of non-Hodgkin's lymphomas (NHLs) with an aggressive clinical course and poor prognosis. Anthracycline-based multiagent chemotherapy with or without radiation therapy followed by first-line consolidation with high-dose therapy followed by autologous stem cell rescue (HDT/ASCR) is the standard approach to most of the patients with newly diagnosed PTCL. Relapsed or refractory disease is managed with second-line systemic therapy followed by HDT/ASCR or allogeneic stem cell transplant, based on the patient's eligibility for transplant. In recent years, several newer agents have shown significant activity in patients with relapsed or refractory disease across all 4 subtypes of PTCL. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for NHL, specific to the management of patients with relapsed or refractory PTCL. C1 [Horwitz, Steven M.; Zelenetz, Andrew D.; Yahalom, Joachim] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Gordon, Leo I.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Wierda, William G.; Fayad, Luis E.] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Abramson, Jeremy S.; Harris, Nancy Lee] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Advani, Ranjana H.; Kim, Youn H.] Stanford Canc Inst, Stanford, CA USA. [Andreadis, C. Babis] UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Bartlett, Nancy] Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO 63110 USA. [Bartlett, Nancy] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Byrd, John C.; Porcu, Pierluigi] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp & Solove Res Inst, Columbus, OH 43210 USA. [Fisher, Richard I.] Fox Chase Canc Ctr, Philadelphia, PA USA. [Glenn, Martha J.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Habermann, Thomas M.] Mayo Clin, Ctr Canc, Rochester, MN USA. [Hernandez-Ilizaliturri, Francisco] Roswell Pk Canc Inst, Buffalo, NY USA. [Kaminski, Mark S.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Kelsey, Christopher R.] Duke Canc Inst, Durham, NC USA. [LaCasce, Ann S.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Lunning, Matthew; Vose, Julie M.] Fred & Pamela Buffett Canc Ctr, Omaha, NE USA. [Nademanee, Auayporn] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Press, Oliver] Fred Hutchinson Canc Res Ctr, Seattle Canc Care Alliance, Seattle, WA USA. [Rabinovitch, Rachel] Univ Colorado, Ctr Canc, Boulder, CO 80309 USA. [Reddy, Nishitha] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Reid, Erin] UC San Diego Moores Canc Ctr, La Jolla, CA USA. [Roberts, Kenneth] Yale Canc Ctr, Smilow Canc Hosp, New Haven, CT USA. [Saad, Ayman A.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL USA. [Sokol, Lubomir] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Swinnen, Lode J.] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Zafar, Nadeem] Univ Tennessee, Hlth Sci Ctr, St Jude Childrens Res Hosp, Knoxville, TN 37996 USA. [Dwyer, Mary; Sundar, Hema] Natl Comprehens Canc Network, Ft Washington, MD USA. RP Horwitz, SM (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. FU AstraZeneca; Bayer Healthcare Pharmaceuticals Inc.; Bristol-Myers Squibb; Clovis Oncology; Foundation Medicine; Genentech; Novartis Oncology; Otsuka America Pharmaceutical, Inc.; Seattle Genetics, Inc.; Takeda Oncology; Actelion Pharmaceuticals US, Inc.; Astellas; Medivation, Inc. FX This activity is supported by educational grants from AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Bristol-Myers Squibb, Clovis Oncology, Foundation Medicine, Genentech, Novartis Oncology, Otsuka America Pharmaceutical, Inc., Seattle Genetics, Inc., and Takeda Oncology; support provided by Actelion Pharmaceuticals US, Inc.; and by an independent educational grant from Astellas and Medivation, Inc. NR 60 TC 1 Z9 1 U1 1 U2 1 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD SEP PY 2016 VL 14 IS 9 BP 1067 EP 1079 PG 13 WC Oncology SC Oncology GA DV4OC UT WOS:000382903900004 PM 27587620 ER PT J AU Olszewski, AJ Mantripragada, KC Castillo, JJ AF Olszewski, Adam J. Mantripragada, Kalyan C. Castillo, Jorge J. TI Risk Factors for Early Death After Rituximab-Based Immunochemotherapy in Older Patients With Diffuse Large B-Cell Lymphoma SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article ID COMPREHENSIVE GERIATRIC ASSESSMENT; NON-HODGKINS-LYMPHOMA; ELDERLY-PATIENTS; CANCER-TREATMENT; CHEMOTHERAPY TOXICITY; CHOP CHEMOTHERAPY; THERAPY; TRIAL; DOXORUBICIN; OUTCOMES AB Background: Older patients with diffuse large B-cell lymphoma (DLBCL) are at risk of severe chemotherapy-related morbidity and mortality. Our objective was to quantify the risk and identify factors associated with death during the first cycle of immunochemotherapy in this population. Patients and Methods: Using Medicare claims linked to the population-based SEER registry (SEER-Medicare), we studied patients with DLBCL aged 65 years and older who received immunochemotherapy containing rituximab, cyclophosphamide, and vincristine, in combination with doxorubicin, mitoxantrone, or etoposide in 2003-2012. Risk factors for death and hospitalization within the first 30 days of treatment were studied in multivariable logistic regression models. Results: We identified 5,530 patients with a median age of 76 years, of whom 94% received doxorubicin-containing immunochemotherapy. Granulocyte colony-stimulating factor (G-CSF) was administered to 66% of patients during the first treatment cycle. Cumulative incidence of death at day 30 was 2.2%. The risk was significantly higher in patients aged 75 years and older and those who had B symptoms, chronic kidney disease, poor functional status, use of walking aids or wheelchairs, and prior hospitalization or upper endoscopy. The group with 0 to 1 risk factors (56% of patients) had a very low (0.6%) risk of early death, whereas the group with 4 or more risk factors (6% of patients) had a risk of 8.3%. Receipt of G-CSF was associated with a lower probability of early death in the high-risk group. The incidence of hospitalization within the first 30 days was 23.5%, peaking at day 8 of the cycle. Conclusions: Among older patients with DLBCL who receive contemporary immunochemotherapy, 1 in 45 die during the first month of treatment, and 1 in 4 are hospitalized. Factors identifiable from administrative/electronic records can stratify this risk and could be incorporated into decision support tools. Prophylactic G-CSF is not administered to more than one-third of patients, indicating an opportunity for improved preventive interventions. C1 [Olszewski, Adam J.; Mantripragada, Kalyan C.] Brown Univ, Alpert Med Sch, Dept Med, Providence, RI 02903 USA. [Olszewski, Adam J.; Mantripragada, Kalyan C.] Rhode Isl Hosp, Div Hematol Oncol, Providence, RI USA. [Castillo, Jorge J.] Harvard Med Sch, Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA USA. RP Olszewski, AJ (reprint author), Brown Univ, Alpert Med Sch, Ctr Comprehens Canc, Rhode Isl Hosp, 593 Eddy St,George 301, Providence, RI 02903 USA. EM adam_olszewski@brown.edu OI Castillo, Jorge/0000-0001-9490-7532 FU Bristol-Myers Squibb; Genentech; TG Therapeutics; ASH Research scholar award; Otsuka; Millennium; Pharmacyclics; Gilead Sciences; Alpert Medical School of Brown University FX Dr. Olszewski has disclosed that he receives consulting fees from Bristol-Myers Squibb and institutional research support from Genentech and TG Therapeutics, and is supported by the ASH Research scholar award. Dr. Mantripragada has disclosed that he has no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Dr. Castillo has disclosed that he receives consulting fees from Otsuka and research funding from Millennium, Pharmacyclics, and Gilead Sciences. This research was funded by Alpert Medical School of Brown University. NR 42 TC 1 Z9 1 U1 0 U2 1 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD SEP PY 2016 VL 14 IS 9 BP 1121 EP 1129 PG 9 WC Oncology SC Oncology GA DV4OC UT WOS:000382903900008 PM 27587624 ER PT J AU Morgan, RJ Armstrong, DK Alvarez, RD Bakkum-Gamez, JN Behbakht, K Chen, LM Copeland, L Crispens, MA DeRosa, M Dorigo, O Gershenson, DM Gray, HJ Hakam, A Havrilesky, LJ Johnston, C Lele, S Martin, L Matulonis, UA O'Malley, DM Penson, RT Percac-Lima, S Pineda, M Plaxe, SC Powell, MA Ratner, E Remmenga, SW Rose, PG Sabbatini, P Santoso, JT Werner, TL Burns, J Hughes, M AF Morgan, Robert J., Jr. Armstrong, Deborah K. Alvarez, Ronald D. Bakkum-Gamez, Jamie N. Behbakht, Kian Chen, Lee-May Copeland, Larry Crispens, Marta Ann DeRosa, Maria Dorigo, Oliver Gershenson, David M. Gray, Heidi J. Hakam, Ardeshir Havrilesky, Laura J. Johnston, Carolyn Lele, Shashikant Martin, Lainie Matulonis, Ursula A. O'Malley, David M. Penson, Richard T. Percac-Lima, Sanja Pineda, Mario Plaxe, Steven C. Powell, Matthew A. Ratner, Elena Remmenga, Steven W. Rose, Peter G. Sabbatini, Paul Santoso, Joseph T. Werner, Theresa L. Burns, Jennifer Hughes, Miranda TI Ovarian Cancer, Version 1.2016 SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Review ID GERM-CELL TUMORS; GYNECOLOGIC-ONCOLOGY-GROUP; REDUCING SALPINGO-OOPHORECTOMY; TERM-FOLLOW-UP; PLATINUM-BASED CHEMOTHERAPY; FERTILITY-SPARING SURGERY; PRIMARY PERITONEAL CANCER; CORD-STROMAL TUMORS; OF-THE-LITERATURE; CISPLATIN COMBINATION THERAPY AB This selection from the NCCN Guidelines for Ovarian Cancer focuses on the less common ovarian histopathologies (LCOHs), because new algorithms were added for LCOHs and current algorithms were revised for the 2016 update. The new LCOHs algorithms include clear cell carcinomas, mucinous carcinomas, and grade 1 (low-grade) serous carcinomas/endometrioid epithelial carcinomas. The LCOHs also include carcinosarcomas (malignant mixed Mullerian tumors of the ovary), borderline epithelial tumors (also known as low malignant potential tumors), malignant sex cord-stromal tumors, and malignant germ cell tumors. C1 [Morgan, Robert J., Jr.] City Hope Comprehens Canc Ctr, Duarte, CA 91010 USA. [Armstrong, Deborah K.] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Alvarez, Ronald D.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL USA. [Bakkum-Gamez, Jamie N.] Mayo Clin, Ctr Canc, Rochester, MN USA. [Behbakht, Kian] Univ Colorado, Ctr Canc, Boulder, CO 80309 USA. [Chen, Lee-May] UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Copeland, Larry; O'Malley, David M.] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Copeland, Larry; O'Malley, David M.] Solove Res Inst, Columbus, OH USA. [Crispens, Marta Ann] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [DeRosa, Maria; Dorigo, Oliver] Stanford Canc Inst, Stanford, CA USA. [Gershenson, David M.] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Gray, Heidi J.] Univ Washington, Med Ctr, Seattle Canc Care Alliance, Seattle, WA 98195 USA. [Hakam, Ardeshir] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Havrilesky, Laura J.] Duke Canc Inst, Durham, NC USA. [Johnston, Carolyn] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Lele, Shashikant] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Martin, Lainie] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Matulonis, Ursula A.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Penson, Richard T.; Percac-Lima, Sanja] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Pineda, Mario] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Plaxe, Steven C.] UC San Diego Moores Canc Ctr, La Jolla, CA USA. [Powell, Matthew A.] Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO 63110 USA. [Powell, Matthew A.] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Ratner, Elena] Yale Canc Ctr, Smilow Canc Hosp, New Haven, CT USA. [Remmenga, Steven W.] Fred & Pamela Buffett Canc Ctr, Omaha, NE USA. [Rose, Peter G.] Case Comprehens Canc Ctr, Univ Hosp Seidman Canc Ctr, Cleveland, OH USA. [Rose, Peter G.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Sabbatini, Paul] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Santoso, Joseph T.] Univ Tennessee, Hlth Sci Ctr, St Jude Childrens Res Hosp, Knoxville, TN 37996 USA. [Werner, Theresa L.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. RP Morgan, RJ (reprint author), City Hope Comprehens Canc Ctr, Duarte, CA 91010 USA. FU Astellas LLC; AstraZeneca Pharmaceuticals LP; Clovis Oncology; GOG Foundation; NRG Oncology; TESARO, Inc.; Janssen Pharmaceutica Products, LP; NCI; Novartis Pharmaceuticals Corporation; Synta Pharmaceuticals Corp.; Amgen Inc.; Endocyte, Inc.; Genentech, Inc.; Vascular Biogenics Ltd; Azaya Therapeutics, Inc.; BIND Therapeutics, Inc.; Millennium Pharmaceuticals, Inc.; Navidea Biopharmaceuticals; Pfizer Inc.; PharmaMar; Bristol-Myers Squibb Company; Eisai Inc. FX Deborah K. Armstrong, MD Astellas LLC; AstraZeneca Pharmaceuticals LP; and Clovis Oncology None None 10/27/15; Larry Copeland, MD GOG Foundation; NRG Oncology; and TESARO, Inc. Advaxis, Inc.; Bayer HealthCare; Cerulean Pharma Inc.; Endocyte, Inc; Helomics, Inc.; and Johnson & Johnson None 9/30/15; Marta Ann Crispens, MD AstraZeneca Pharmaceuticals LP; and Janssen Pharmaceutica Products, LP None None 5/8/16; David M. Gershenson, MDa NCI None None 8/7/15; Lainie Martin, MD Novartis Pharmaceuticals Corporation; and Synta Pharmaceuticals Corp. None None 9/29/15; Richard T. Penson, MD, MRCP Amgen Inc.; AstraZeneca Pharmaceuticals LP; Endocyte, Inc.; Genentech, Inc.; and Vascular Biogenics Ltd AstraZeneca Pharmaceuticals LP; Genentech, Inc; and Vascular Biogenics, Ltd None 3/9/16; Steven C. Plaxe, MDa Amgen Inc.; AstraZeneca Pharmaceuticals LP; Azaya Therapeutics, Inc.; BIND Therapeutics, Inc.; Endocyte, Inc.; Janssen Pharmaceutica Products, LP; Millennium Pharmaceuticals, Inc.; Navidea Biopharmaceuticals; Novartis Pharmaceuticals Corporation; Pfizer Inc.; PharmaMar; and TESARO, Inc. Ambrx, Inc.; and Insys Therapeutics, Inc. Insys Therapeutics, Inc. 11/6/15; Matthew A. Powell, MD Bristol-Myers Squibb Company; and Eisai Inc. AnorMED Inc.; and Genentech, Inc. Genentech, Inc. 7/13/15; Paul Sabbatini, MD Bristol-Myers Squibb Company None None 10/5/15 NR 249 TC 5 Z9 5 U1 6 U2 6 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD SEP PY 2016 VL 14 IS 9 BP 1134 EP 1163 PG 30 WC Oncology SC Oncology GA DV4OC UT WOS:000382903900009 PM 27587625 ER PT J AU Evans, T Matulonis, U AF Evans, Tarra Matulonis, Ursula TI Next-Generation Sequencing: Role in Gynecologic Cancers SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Review ID GRADE SEROUS CARCINOMA; OLAPARIB MAINTENANCE THERAPY; CLEAR-CELL CARCINOMA; OVARIAN-CANCER; CERVICAL-CANCER; HYPERCALCEMIC TYPE; RISK ASSESSMENT; MUTATIONS; HPV; VALIDATION AB Next-generation sequencing (NGS) has risen to the forefront of tumor analysis and has enabled unprecedented advances in the molecular profiling of solid tumors. Through massively parallel sequencing, previously unrecognized genomic alterations have been unveiled in many malignancies, including gynecologic cancers, thus expanding the potential repertoire for the use of targeted therapies. NGS has expanded the understanding of the genomic foundation of gynecologic malignancies and has allowed identification of germline and somatic mutations associated with cancer development, enabled tumor reclassification, and helped determine mechanisms of treatment resistance. NGS has also facilitated rationale therapeutic strategies based on actionable molecular aberrations. However, issues remain regarding cost and clinical utility. This review covers NGS analysis of and its impact thus far on gynecologic cancers, specifically ovarian, endometrial, cervical, and vulvar cancers. C1 [Evans, Tarra] Brigham & Womens Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, 75 Francis St, Boston, MA 02115 USA. [Matulonis, Ursula] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. RP Matulonis, U (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM umatulonis@partners.org FU AstraZeneca Pharmaceuticals LP FX The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Dr. Matulonis has disclosed that she is a scientific advisor for Genentech, Inc./Roche, ImmunoGen, Merck & Co, Inc., and Pfizer Inc.; receives consulting fees from AstraZeneca Pharmaceuticals LP; and is an unpaid consultant for AstraZeneca Pharmaceuticals LP. NR 74 TC 2 Z9 2 U1 6 U2 6 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD SEP PY 2016 VL 14 IS 9 BP 1165 EP 1173 PG 9 WC Oncology SC Oncology GA DV4OC UT WOS:000382903900010 PM 27587626 ER PT J AU Helsel, LTCBS David, MEA Antevil, CDRJL AF Helsel, L. T. C. Bryan S. David, Maj Elizabeth A. Antevil, C. D. R. Jared L. TI Special considerations of military cardiothoracic surgeons SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material ID OPERATION-IRAQI-FREEDOM; COMBAT CASUALTY CARE C1 [Helsel, L. T. C. Bryan S.] San Antonio Mil Med Ctr, Dept Cardiothorac Surg, 3551 Roger Brooke Dr, San Antonio, TX 78234 USA. [Helsel, L. T. C. Bryan S.] Audie L Murphy Vet Affairs Med Ctr, Dept Cardiothorac Surg, San Antonio, TX USA. [David, Maj Elizabeth A.] David Grant Med Ctr, Heart Lung Vasc Ctr, Travis Air Force Base, CA USA. [David, Maj Elizabeth A.] Univ Calif Davis, Med Ctr, Sect Gen Thorac Surg, Sacramento, CA 95817 USA. [Antevil, C. D. R. Jared L.] Walter Reed Natl Mil Med Ctr, Dept Cardiothorac Surg, Bethesda, MD USA. RP Helsel, LTCBS (reprint author), San Antonio Mil Med Ctr, Dept Cardiothorac Surg, 3551 Roger Brooke Dr, San Antonio, TX 78234 USA. EM deltaguns@aol.com NR 13 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2016 VL 152 IS 3 BP 664 EP 666 DI 10.1016/j.jtcvs.2016.04.089 PG 3 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DU5HB UT WOS:000382241700015 ER PT J AU Kim, JB Ejiofor, JI Yammine, M Ando, M Camuso, JM Youngster, I Nelson, SB Kim, AY Melnitchouk, SI Rawn, JD MacGillivray, TE Cohn, LH Byrne, JG Sundt, TM AF Kim, Joon Bum Ejiofor, Julius I. Yammine, Maroun Ando, Masahiko Camuso, Janice M. Youngster, Ilan Nelson, Sandra B. Kim, Arthur Y. Melnitchouk, Serguei I. Rawn, James D. MacGillivray, Thomas E. Cohn, Lawrence H. Byrne, John G. Sundt, Thoralf M., III TI Surgical outcomes of infective endocarditis among intravenous drug users SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article; Proceedings Paper CT 95th Annual Meeting of the American-Association-for-Thoracic-Surgery CY APR 25-29, 2015 CL Seattle, WA SP Amer Assoc Thorac Surg DE intravenous drug use; infective endocarditis; valvular heart disease; operative risk ID PROSTHETIC VALVE ENDOCARDITIS; ADDICTS 33 YEARS; MORTALITY; ASSOCIATION; REPLACEMENT; POPULATION; GUIDELINES; MANAGEMENT; OPERATIONS; FEATURES AB Background: With increasing prevalence of injected drug use in the United States, a growing number of intravenous drug users (IVDUs) are at risk for infective endocarditis (IE) that may require surgical intervention; however, few data exist about clinical outcomes of these individuals. Methods: We evaluated consecutive adult patients undergoing surgery for active IE between 2002 and 2014 pooled from 2 prospective institutional databases. Death and valve-related events, including reinfection or heart valve reoperation, thromboembolism, and anticoagulation-related hemorrhage were evaluated. Results: Of the 436 patients identified, 78 (17.9%) were current IVDUs. The proportion of IVDUs increased from 14.8% in 2002 to 2004 to 26.1% in 2012 to 2014. IVDUs were younger (aged 35.9 +/- 9.9 years vs 59.3 +/- 14.1 years) and had fewer cardiovascular risk factors than non-IVDUs. During follow-up (median, 29.4 months; quartile 1-3, 4.7-72.6 months), adverse events among all patients included death in 92, reinfection in 42, valve-reoperation in 35, thromboembolism in 17, and hemorrhage in 16. Operative mortality was lower among IVDUs (odds ratio, 0.25; 95% confidence interval [CI], 0.06-0.71), but overall mortality was not significantly different (hazard ratio [HR], 0.78; 95% CI, 0.44-1.37). When baseline profiles were adjusted by propensity score, IVDUs had higher risk of valve-related complications (HR, 3.82; 95% CI, 1.95-7.49; P < .001) principally attributable to higher rates of reinfection (HR, 6.20; 95% CI, 2.56-15.00; P < .001). Conclusions: The proportion of IVDUs among surgically treated IE patients is increasing. Although IVDUs have lower operative risk, long-term outcomes are compromised by reinfection. C1 [Kim, Joon Bum; Ando, Masahiko; Camuso, Janice M.; Melnitchouk, Serguei I.; MacGillivray, Thomas E.; Sundt, Thoralf M., III] Massachusetts Gen Hosp, Div Cardiac Surg, Cox 652,55 Fruit St, Boston, MA 02114 USA. [Youngster, Ilan; Nelson, Sandra B.; Kim, Arthur Y.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Ejiofor, Julius I.; Yammine, Maroun; Rawn, James D.; Cohn, Lawrence H.; Byrne, John G.] Harvard Med Sch, Brigham & Womens Hosp, Div Cardiac Surg, Boston, MA USA. [Kim, Joon Bum] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Thorac & Cardiovasc Surg, Seoul, South Korea. RP Sundt, TM (reprint author), Massachusetts Gen Hosp, Div Cardiac Surg, Cox 652,55 Fruit St, Boston, MA 02114 USA. EM tsundt@partners.org OI Youngster, Ilan/0000-0001-5233-1213; Kim, Joon Bum/0000-0001-5801-2395 NR 36 TC 2 Z9 2 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2016 VL 152 IS 3 BP 832 EP 839 DI 10.1016/j.jtcvs.2016.02.072 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DU5HB UT WOS:000382241700051 PM 27068439 ER PT J AU Wijdh-den Hamer, IJ Bouma, W Lai, EK Levack, MM Shang, EK Pouch, AM Eperjesi, TJ Plappert, TJ Yushkevich, PA Hung, J Mariani, MA Khabbaz, KR Gleason, TG Mahmood, F Acker, MA Woo, YJ Cheung, AT Gillespie, MJ Jackson, BM Gorman, JH Gorman, RC AF Wijdh-den Hamer, Inez J. Bouma, Wobbe Lai, Eric K. Levack, Melissa M. Shang, Eric K. Pouch, Alison M. Eperjesi, Thomas J. Plappert, Theodore J. Yushkevich, Paul A. Hung, Judy Mariani, Massimo A. Khabbaz, Kamal R. Gleason, Thomas G. Mahmood, Feroze Acker, Michael A. Woo, Y. Joseph Cheung, Albert T. Gillespie, Matthew J. Jackson, Benjamin M. Gorman, Joseph H., III Gorman, Robert C. TI The value of preoperative 3-dimensional over 2-dimensional valve analysis in predicting recurrent ischemic mitral regurgitation after mitral annuloplasty SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article DE ischemia; mitral regurgitation; mitral valve repair; echocardiography ID RESTRICTIVE ANNULOPLASTY; RING ANNULOPLASTY; HEART-FAILURE; REPAIR; REPLACEMENT; DYSSYNCHRONY; MECHANISM; SEVERITY; SURVIVAL AB Objectives: Repair for ischemic mitral regurgitation with undersized annuloplasty is characterized by high recurrence rates. We sought to determine the value of pre-repair 3-dimensional echocardiography over 2-dimensional echocardiography in predicting recurrence at 6 months. Methods: Intraoperative transesophageal 2-dimensional echocardiography and 3-dimensional echocardiography were performed in 50 patients undergoing undersized annuloplasty for ischemic mitral regurgitation. Two-dimensional echocardiography annular diameter and tethering parameters were measured in the apical 2-and 4-chamber views. A customized protocol was used to assess 3-dimensional annular geometry and regional leaflet tethering. Recurrence (grade >= 2) was assessed with 2-dimensional transthoracic echocardiography at 6 months. Results: Preoperative 2- and 3-dimensional annular geometry were similar in all patients with ischemic mitral regurgitation. Preoperative 2- and 3-dimensional leaflet tethering were significantly higher in patients with recurrence (n = 13) when compared with patients without recurrence (n = 37). Multivariate logistic regression revealed preoperative 2-dimensional echocardiography posterior tethering angle as an independent predictor of recurrence with an optimal cutoff value of 32.0 degrees (area under the curve, 0.81; 95% confidence interval, 0.68-0.95; P = .002) and preoperative 3-dimensional echocardiography P3 tethering angle as an independent predictor of recurrence with an optimal cutoff value of 29.9 degrees (area under the curve, 0.92; 95% confidence interval, 0.84-1.00; P < .001). The predictive value of the 3-dimensional geometric multivariate model can be augmented by adding basal aneurysm/dyskinesis (area under the curve, 0.94; 95% confidence interval, 0.87-1.00; P < .001). Conclusions: Preoperative 3-dimensional echocardiography P3 tethering angle is a stronger predictor of ischemic mitral regurgitation recurrence after annuloplasty than preoperative 2-dimensional echocardiography posterior tethering angle, which is highly influenced by viewing plane. In patients with a preoperative P3 tethering angle of 29.9 degrees or larger (especially when combined with basal aneurysm/dyskinesis), chordal-sparing valve replacement should be strongly considered. C1 [Wijdh-den Hamer, Inez J.; Bouma, Wobbe; Lai, Eric K.; Levack, Melissa M.; Pouch, Alison M.; Eperjesi, Thomas J.; Plappert, Theodore J.; Gorman, Joseph H., III; Gorman, Robert C.] Univ Penn, Childrens Hosp Philadelphia, Gorman Cardiovasc Res Grp, Philadelphia, PA 19104 USA. [Shang, Eric K.; Acker, Michael A.; Jackson, Benjamin M.; Gorman, Joseph H., III; Gorman, Robert C.] Univ Penn, Childrens Hosp Philadelphia, Dept Surg, Philadelphia, PA 19104 USA. [Yushkevich, Paul A.] Univ Penn, Childrens Hosp Philadelphia, Dept Radiol, Philadelphia, PA 19104 USA. [Gillespie, Matthew J.] Univ Penn, Childrens Hosp Philadelphia, Dept Cardiol, Philadelphia, PA 19104 USA. [Wijdh-den Hamer, Inez J.; Bouma, Wobbe; Mariani, Massimo A.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiothorac Surg, Groningen, Netherlands. [Hung, Judy] Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. [Khabbaz, Kamal R.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Cardiothorac Surg, Boston, MA USA. [Mahmood, Feroze] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Anesthesia, Boston, MA USA. [Gleason, Thomas G.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. [Woo, Y. Joseph] Stanford Univ, Dept Cardiothorac Surg, Stanford, CA 94305 USA. [Cheung, Albert T.] Stanford Univ, Dept Anesthesia, Stanford, CA 94305 USA. RP Gorman, RC (reprint author), Smilow Ctr Translat Res, Gorman Cardiovasc Res Grp, 3400 Civ Ctr Blvd,Bldg 421,11th Floor,Room 114, Philadelphia, PA 19104 USA. EM gormanr@uphs.upenn.edu FU National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, Maryland [HL 103723, HL73021, HL063954] FX Funding was provided by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, Maryland (HL 103723, HL73021, and HL063954). NR 35 TC 1 Z9 1 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2016 VL 152 IS 3 BP 847 EP 859 DI 10.1016/j.jtcvs.2016.06.040 PG 13 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DU5HB UT WOS:000382241700054 PM 27530639 ER PT J AU Brown, SC Wang, KF Dong, CH Farrell, MB Heller, GV Gornik, HL Hutchisson, M Needleman, L Benenati, JF Jaff, MR Meier, GH Perese, S Bendick, P Hamburg, NM Lohr, JM LaPerna, L Leers, SA Lilly, MP Tegeler, C Katanick, SL Alexandrov, AV Siddiqui, AH Rundek, T AF Brown, Scott C. Wang, Kefeng Dong, Chuanhui Farrell, Mary Beth Heller, Gary V. Gornik, Heather L. Hutchisson, Marge Needleman, Laurence Benenati, James F. Jaff, Michael R. Meier, George H. Perese, Susana Bendick, Phillip Hamburg, Naomi M. Lohr, Joann M. LaPerna, Lucy Leers, Steven A. Lilly, Michael P. Tegeler, Charles Katanick, Sandra L. Alexandrov, Andrei V. Siddiqui, Adnan H. Rundek, Tatjana TI Intersocietal Accreditation Commission Accreditation Status of Outpatient Cerebrovascular Testing Facilities Among Medicare Beneficiaries The VALUE Study SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE carotid duplex ultrasound; cerebrovascular disorders; cerebrovascular testing; geographic disparities; health services research; Intersocietal Accreditation Commission; Medicare beneficiaries; public policy; sonography; transcranial Doppler ultrasound; ultrasound; vascular laboratory testing accreditation ID UNITED-STATES; STROKE; CARE AB Objectives-Accreditation of cerebrovascular ultrasound laboratories by the Intersocietal Accreditation Commission (IAC) and equivalent organizations is supported by the Joint Commission certification of stroke centers. Limited information exists on the accreditation status and geographic distribution of cerebrovascular testing facilities in the United States. Our study objectives were to identify the proportion of IAC-accredited outpatient cerebrovascular testing facilities used by Medicare beneficiaries, describe their geographic distribution, and identify variations in cerebrovascular testing procedure types and volumes by accreditation status. Methods-As part of the VALUE (Vascular Accreditation, Location, and Utilization Evaluation) Study, we examined the proportion of IAC-accredited facilities that conducted cerebrovascular testing in a 5% Centers for Medicare and Medicaid Services random Outpatient Limited Data Set in 2011 and investigated their geographic distribution using geocoding. Results-Among 7327 outpatient facilities billing Medicare for cerebrovascular testing, only 22% (1640) were IAC accredited. The proportion of IAC-accredited cerebrovascular testing facilities varied by region (chi(2)[3] = 177.1; P < .0001), with 29%, 15%, 13%, and 10% located in the Northeast, South, Midwest, and West, respectively. However, of the total number of cerebrovascular outpatient procedures conducted in 2011 (38,555), 40% (15,410) were conducted in IAC-accredited facilities. Most cerebrovascular testing procedures were carotid duplex, with 40% of them conducted in IAC-accredited facilities. Conclusions-The proportion of facilities conducting outpatient cerebrovascular testing accredited by the IAC is low and varies by region. The growing number of certified stroke centers should be accompanied by more accredited outpatient vascular testing facilities, which could potentially improve the quality of stroke care. C1 [Brown, Scott C.; Wang, Kefeng; Rundek, Tatjana] Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, 1120 NW 14th St,Clin Res Bldg,Room 1065, Miami, FL 33136 USA. [Wang, Kefeng; Dong, Chuanhui; Rundek, Tatjana] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Farrell, Mary Beth; Heller, Gary V.; Hutchisson, Marge; Katanick, Sandra L.] Intersocietal Accreditat Commiss, Ellicott City, MD USA. [Gornik, Heather L.] Cleveland Clin, Dept Vasc Med, Cleveland, OH 44106 USA. [Needleman, Laurence] Thomas Jefferson Univ, Jefferson Med Coll, Dept Radiol, Philadelphia, PA 19107 USA. [Benenati, James F.] Baptist Hosp Miami, Baptist Cardiac & Vasc Inst, Miami, FL USA. [Jaff, Michael R.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Meier, George H.] Univ Cincinnati, Acad Hlth Ctr, Dept Vasc Surg, Cincinnati, OH USA. [Perese, Susana] Univ Southern Calif, Keck Sch Med, Dept Vasc Surg, Los Angeles, CA USA. [Bendick, Phillip] William Beaumont Hosp, Vasc Lab, Royal Oak, MI 48072 USA. [Hamburg, Naomi M.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Lohr, Joann M.] Good Samaritan Outpatient Ctr, Cincinnati, OH USA. [LaPerna, Lucy] Riverside Radiol Associates, Columbus, OH USA. [Leers, Steven A.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Lilly, Michael P.] Univ Maryland, Sch Med, Vasc Lab, Baltimore, MD 21201 USA. [Tegeler, Charles] Wake Forest Baptist Hlth, Winston Salem, NC USA. [Alexandrov, Andrei V.] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. [Siddiqui, Adnan H.] SUNY Buffalo, Dept Neurosurg, Buffalo, NY USA. RP Brown, SC (reprint author), Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, 1120 NW 14th St,Clin Res Bldg,Room 1065, Miami, FL 33136 USA. EM sbrown@med.miami.edu FU Intersocietal Accreditation Commission (IAC); National Institutes of Health [NINDS K24 NS 062737]; IAC grant FX This work was funded by an Intersocietal Accreditation Commission (IAC) grant, "Utilization of Vascular Testing in Medicare Beneficiaries: The Role of Ultrasound Laboratory Accreditation" (principal investigator: T. Rundek). Its contents are solely the responsibility of the authors and do not necessarily represent the views of the IAC. Additional funding came from National Institutes of Health grant NINDS K24 NS 062737, awarded to T. Rundek, which allowed protected time for this research. Portions of this work were presented at a poster session at the International Stroke Conference; February 12, 2015; Nashville, Tennessee. S. C. Brown, K. Wang, C. Dong, and T. Rundek received partial salary support from an IAC grant (principal investigator: T. Rundek). M. B. Farrell, G. V. Heller, M. Hutchisson, and S. L. Katanick are paid employees of the IAC. H. L. Gornik, J. F. Benenati, M. R. Jaff, N. M. Hamburg, M. P. Lilly, L. Needleman, A. H. Siddiqui, and T. Rundek are members of the IAC Vascular Testing Board of Directors. M. R. Jaff is a member of the Board of Trustees of VIVA Physicians, a 501(c)(3) not-for-profit education and research organization. M. P. Lilly is a member of the Board of Directors of the American Registry for Diagnostic Medical Sonography. NR 20 TC 0 Z9 0 U1 0 U2 0 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 EI 1550-9613 J9 J ULTRAS MED JI J. Ultrasound Med. PD SEP 1 PY 2016 VL 35 IS 9 BP 1957 EP 1965 DI 10.7863/ultra.15.08021 PG 9 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA DU9JH UT WOS:000382532400015 PM 27466261 ER PT J AU DeMartino, R Brooke, B Neal, D Beck, AW Conrad, M Arya, S Desai, S Aziz, F Ryan, P Kraiss, L AF DeMartino, Randall Brooke, Benjamin Neal, Dan Beck, Adam W. Conrad, Mark Arya, Shipra Desai, Sapan Aziz, Faisal Ryan, Patrick Kraiss, Larry TI Development of a Validated Model to Predict 30-Day Stroke and One-Year Survival After Carotid Endarterectomy for Asymptomatic Stenosis Using the Vascular Quality Initiative SO JOURNAL OF VASCULAR SURGERY LA English DT Meeting Abstract CT 30th Annual Meeting of the Eastern-Vascular-Society CY SEP 15-17, 2016 CL Philadelphia, PA SP Eastern Vasc Soc C1 [DeMartino, Randall] Mayo Clin, Div Vasc & Endovasc Surg, Rochester, MN USA. [Brooke, Benjamin; Kraiss, Larry] Univ Utah, Salt Lake City, UT USA. [Neal, Dan; Beck, Adam W.] Univ Florida, Gainesville, FL USA. [Conrad, Mark] Massachussetts Gen Hosp, Boston, MA USA. [Arya, Shipra] Emory Univ, Atlanta, GA 30322 USA. [Desai, Sapan] Southern Illinois Univ, Springfield, IL USA. [Aziz, Faisal] Penn State Heart & Vasc Inst, Hershey, PA USA. [Ryan, Patrick] Nashville Vasc & Vein Inst, Nashville, TN USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD SEP PY 2016 VL 64 IS 3 BP 877 EP 878 PG 3 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA DU5AS UT WOS:000382224900144 ER PT J AU Zhuang, YH Berens-Norman, HM Leser, JS Clarke, P Tyler, KL AF Zhuang, Yonghua Berens-Norman, Heather M. Leser, J. Smith Clarke, Penny Tyler, Kenneth L. TI Mitochondrial p53 Contributes to Reovirus-Induced Neuronal Apoptosis and Central Nervous System Injury in a Mouse Model of Viral Encephalitis SO JOURNAL OF VIROLOGY LA English DT Article ID INDEPENDENT CELL-DEATH; TISSUE-INJURY; BAK; ACTIVATION; MEMBRANE; PATHWAY; PROTEIN; BRAIN; PHOSPHORYLATION; ANTAGONIZES AB The tumor suppressor p53 plays a critical part in determining cell fate both as a regulator of the transcription of several proapoptotic genes and through its binding interactions with Bcl-2 family proteins at mitochondria. We now demonstrate that p53 protein levels are increased in infected brains during reovirus encephalitis. This increase occurs in the cytoplasm of reovirus-infected neurons and is associated with the activation of caspase 3. Increased levels of p53 in reovirus-infected brains are not associated with increased expression levels of p53 mRNA, suggesting that p53 regulation occurs at the protein level. Increased levels of p53 are also not associated with the increased expression levels of p53-regulated, proapoptotic genes. In contrast, upregulated p53 accumulates in mitochondria. Previous reports demonstrated that the binding of p53 to Bak at mitochondria causes Bak activation and results in apoptosis. We now show that Bak is activated and that activated Bak is bound to p53 during reovirus encephalitis. In addition, survival is enhanced in reovirus-infected Bak(-/-) mice compared to controls, demonstrating a role for Bak in reovirus pathogenesis. Inhibition of the mitochondrial translocation of p53 with pifithrin mu prevents the formation of p53/Bak complexes following reovirus infection of ex vivo brain slice cultures and results in decreased apoptosis and tissue injury. These results suggest that the mitochondrial localization of p53 regulates reovirus-induced pathogenesis in the central nervous system (CNS) through its interactions with Bak. IMPORTANCE There are virtually no specific treatments of proven efficacy for virus-induced neuroinvasive diseases. A better understanding of the pathogenesis of virus-induced CNS injury is crucial for the rational development of novel therapies. Our studies demonstrate that p53 is activated in the brain following reovirus infection and may provide a therapeutic target for virus-induced CNS disease. C1 [Zhuang, Yonghua; Leser, J. Smith; Clarke, Penny; Tyler, Kenneth L.] Univ Colorado Denver, Dept Neurol, Aurora, CO 80045 USA. [Berens-Norman, Heather M.] Univ Colorado Denver, Internal Med Residency Program, Aurora, CO USA. [Berens-Norman, Heather M.] Univ Colorado Denver, Phys Scientist Training Program, Aurora, CO USA. [Tyler, Kenneth L.] Univ Colorado Denver, Dept Immunol & Microbiol, Aurora, CO USA. [Tyler, Kenneth L.] Univ Colorado Denver, Dept Med, Aurora, CO USA. [Tyler, Kenneth L.] Denver VA Med Ctr, Denver, CO USA. RP Clarke, P (reprint author), Univ Colorado Denver, Dept Neurol, Aurora, CO 80045 USA. EM Penny.Clarke@ucdenver.edu FU HHS \ National Institutes of Health (NIH) [R33AI101064, RO1NS076512, T32AI052066]; U.S. Department of Veterans Affairs (VA) [BX000963] FX This work, including the efforts of Kenneth L. Tyler, was funded by HHS vertical bar National Institutes of Health (NIH) (R33AI101064 and RO1NS076512). This work, including the efforts of Heather M. Berens-Norman, was funded by HHS vertical bar National Institutes of Health (NIH) (T32AI052066). This work, including the efforts of Kenneth L. Tyler, was funded by U.S. Department of Veterans Affairs (VA) (BX000963). NR 37 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2016 VL 90 IS 17 BP 7684 EP 7691 DI 10.1128/JVI.00583-16 PG 8 WC Virology SC Virology GA DU6EM UT WOS:000382306800009 PM 27307572 ER PT J AU Zerbato, JM Serrao, E Lenzi, G Kim, B Ambrose, Z Watkins, SC Engelman, AN Sluis-Cremer, N AF Zerbato, Jennifer M. Serrao, Erik Lenzi, Gina Kim, Baek Ambrose, Zandrea Watkins, Simon C. Engelman, Alan N. Sluis-Cremer, Nicolas TI Establishment and Reversal of HIV-1 Latency in Naive and Central Memory CD4(+) T Cells In Vitro SO JOURNAL OF VIROLOGY LA English DT Article ID SUPPRESSIVE ANTIRETROVIRAL THERAPY; IMMUNODEFICIENCY-VIRUS HIV; LONG-TERM NONPROGRESSORS; CCR7 LIGANDS CCL19; HOMEOSTATIC CHEMOKINES; TISSUE RESERVOIRS; VIRAL REPLICATION; ENHANCED LEVELS; CORTICAL ACTIN; PCR ASSAY AB The latent HIV-1 reservoir primarily resides in resting CD4(+) T cells which are a heterogeneous population composed of both naive (T-N) and memory cells. In HIV-1-infected individuals, viral DNA has been detected in both naive and memory CD4(+) T cell subsets although the frequency of HIV-1 DNA is typically higher in memory cells, particularly in the central memory (T-CM) cell subset. T-N and T-CM cells are distinct cell populations distinguished by many phenotypic and physiological differences. In this study, we used a primary cell model of HIV-1 latency that utilizes direct infection of highly purified T-N and T-CM cells to address differences in the establishment and reversal of HIV-1 latency. Consistent with what is seen in vivo, we found that HIV-1 infected T-N cells less efficiently than T-CM cells. However, when the infected T-N cells were treated with latency-reversing agents, including anti-CD3/CD28 antibodies, phorbol myristate acetate/phytohemagglutinin, and prostratin, as much (if not more) extracellular virion-associated HIV-1 RNA was produced per infected T-N cell as per infected T-CM cell. There were no major differences in the genomic distribution of HIV-1 integration sites between T-N and T-CM cells that accounted for these observed differences. We observed decay of the latent HIV-1 cells in both T cell subsets after exposure to each of the latency-reversing agents. Collectively, these data highlight significant differences in the establishment and reversal of HIV-1 latency in T-N and T-CM CD4(+) T cells and suggest that each subset should be independently studied in preclinical and clinical studies. IMPORTANCE The latent HIV-1 reservoir is frequently described as residing within resting memory CD4(+) T cells. This is largely due to the consistent finding that memory CD4(+) T cells, specifically the central (T-CM) and transitional memory compartments, harbor the highest levels of HIV-1 DNA in individuals on suppressive therapy. This has yielded little research into the contribution of CD4(+) naive T (T-N) cells to the latent reservoir. In this study, we show that although T-N cells harbor significantly lower levels of HIV-1 DNA, following latency reversal, they produced as many virions as did the T-CM cells (if not more virions). This suggests that latently infected T-N cells may be a major source of virus following treatment interruption or failure. These findings highlight the need for a better understanding of the establishment and reversal of HIV-1 latency in T-N cells in evaluating therapeutic approaches to eliminate the latent reservoir. C1 [Zerbato, Jennifer M.; Ambrose, Zandrea; Sluis-Cremer, Nicolas] Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA 15213 USA. [Serrao, Erik; Engelman, Alan N.] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA USA. [Lenzi, Gina; Kim, Baek] Emory Univ, Dept Pediat, Childrens Healthcare Atlanta, Ctr Drug Discovery, Atlanta, GA 30322 USA. [Watkins, Simon C.] Univ Pittsburgh, Sch Med, Dept Cell Biol & Physiol, Pittsburgh, PA USA. RP Sluis-Cremer, N (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA 15213 USA. EM nps2@pitt.edu FU HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [AI049781, AI065380, AI007386, AI119117]; HHS \ NIH \ National Institute of General Medical Sciences (NIGMS) [GM082251, GM104198] FX This work, including the efforts of Baek Kim, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI049781). This work, including the efforts of Jennifer Zerbato, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI065380). This work, including the efforts of Erik Serrao, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI007386). This work, including the efforts of Nicolas Sluis-Cremer, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI119117). This work, including the efforts of Zandrea Ambrose, Simon Watkins, Alan Engelman, and Nicolas Sluis-Cremer, was funded by HHS vertical bar NIH vertical bar National Institute of General Medical Sciences (NIGMS) (GM082251). This work, including the efforts of Baek Kim, was funded by HHS vertical bar NIH vertical bar National Institute of General Medical Sciences (NIGMS) (GM104198). NR 79 TC 3 Z9 3 U1 5 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP PY 2016 VL 90 IS 18 BP 8059 EP 8073 DI 10.1128/JVI.00553-16 PG 15 WC Virology SC Virology GA DU6HD UT WOS:000382314100004 PM 27356901 ER PT J AU Cortazar, FB Marrone, KA Troxell, ML Ralto, KM Hoenig, MP Brahmer, JR Le, DT Lipson, EJ Glezerman, IG Wolchok, J Cornell, LD Feldman, P Stokes, MB Zapata, SA Hodi, FS Ott, PA Yamashita, M Leaf, DE AF Cortazar, Frank B. Marrone, Kristen A. Troxell, Megan L. Ralto, Kenneth M. Hoenig, Melanie P. Brahmer, Julie R. Le, Dung T. Lipson, Evan J. Glezerman, Ilya G. Wolchok, Jedd Cornell, Lynn D. Feldman, Paul Stokes, Michael B. Zapata, Sarah A. Hodi, F. Stephen Ott, Patrick A. Yamashita, Michifumi Leaf, David E. TI Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors SO KIDNEY INTERNATIONAL LA English DT Article DE acute kidney injury; ipilimumab; nivolumab; pembrolizumab ID ACUTE INTERSTITIAL NEPHRITIS; CELL LUNG-CANCER; ADVERSE EVENTS; T-CELLS; IPILIMUMAB; NIVOLUMAB; MELANOMA; PD-1; INVOLVEMENT; RECOVERY AB Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory receptors expressed on T cells, represent an emerging class of immunotherapy used in treating solid organ and hematologic malignancies. We describe the clinical and histologic features of 13 patients with CPI-induced acute kidney injury (AKI) who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91 (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal immune related adverse event occurred prior to the onset of AKI in 7 patients. Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4 patients requiring hemodialysis. The prevalent pathologic lesion was acute tubulointerstitial nephritis in 12 patients, with 3 having granulomatous features, and 1 thrombotic microangiopathy. Among the 12 patients with acute tubulointerstitial nephritis, 10 received treatment with glucocorticoids, resulting in complete or partial improvement in renal function in 2 and 7 patients, respectively. However, the 2 patients with acute tubulointerstitial nephritis not given glucocorticoids had no improvement in renal function. Thus, CPI-induced AKI is a new entity that presents with clinical and histologic features similar to other causes of drug-induced acute tubulointerstitial nephritis, though with a longer latency period. Glucocorticoids appear to be a potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by a unique mechanism of action linked to reprogramming of the immune system, leading to loss of tolerance. C1 [Cortazar, Frank B.] Massachusetts Gen Hosp, Div Renal, Boston, MA 02114 USA. [Marrone, Kristen A.; Brahmer, Julie R.; Le, Dung T.; Lipson, Evan J.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Troxell, Megan L.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. [Ralto, Kenneth M.; Hoenig, Melanie P.] Beth Israel Deaconess Med Ctr, Div Nephrol, Boston, MA 02215 USA. [Glezerman, Ilya G.; Wolchok, Jedd] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Cornell, Lynn D.] Mayo Clin, Dept Pathol, Rochester, MN USA. [Feldman, Paul] Adv Kidney Care Hudson Valley, Poughkeepsie, NY USA. [Stokes, Michael B.] Columbia Univ, Med Ctr, Dept Pathol, New York, NY USA. [Zapata, Sarah A.] Kaiser Permanente, Div Nephrol, Portland, OR USA. [Hodi, F. Stephen; Ott, Patrick A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Yamashita, Michifumi] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Leaf, David E.] Brigham & Womens Hosp, Div Renal Med, 75 Francis St, Boston, MA 02115 USA. RP Leaf, DE (reprint author), Brigham & Womens Hosp, Div Renal Med, 75 Francis St, Boston, MA 02115 USA. EM DELEAF@partners.org FU National Institute of Diabetes and Digestive Kidney Diseases [K23DK106448]; Bristol-Myers Squibb (BMS); BMS; Merck; Medimmune; Genentech FX DEL is supported by K23DK106448 from the National Institute of Diabetes and Digestive Kidney Diseases. JRB received grant support from Bristol-Myers Squibb (BMS) and consulted for Merck. DTL received research funding from BMS and Merck and speaking honorarium from Merck. IGG served on an advisory committee for Otsuka and has stock ownership in Pfizer. JW served as a consultant and has received research support from BMS, Merck, Medimmune, and Genentech. EJP consulted for BMS, Merck, Amgen, and Castle Biosciences. PAO received research support to the institution from BMS and Merck and consulted for BMS, Amgen, and Alexion. FSH received research support from BMS and consulted for Merck and Genentech. NR 33 TC 9 Z9 9 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD SEP PY 2016 VL 90 IS 3 BP 638 EP 647 DI 10.1016/j.kint.2016.04.008 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA DU7SQ UT WOS:000382415300022 PM 27282937 ER PT J AU Scott, JW Rose, JA Tsai, TC Zogg, CK Shrime, MG Sommers, BD Salim, A Haider, AH AF Scott, John W. Rose, John A. Tsai, Thomas C. Zogg, Cheryl K. Shrime, Mark G. Sommers, Benjamin D. Salim, Ali Haider, Adil H. TI Impact of ACA Insurance Coverage Expansion on Perforated Appendix Rates Among Young Adults SO MEDICAL CARE LA English DT Article DE health policy; Affordable Care Act; insurance disparities; surgery; appendectomy; emergency general; surgery; access ID AFFORDABLE CARE ACT; PEDIATRIC APPENDICITIS; RUPTURED APPENDICITIS; UNINSURED ADULTS; HEALTH-INSURANCE; TRAUMA PATIENTS; RISK; DISPARITIES; ACCESS; PROVISION AB Background: The 2010 Dependent Coverage Provision (DCP) of the Affordable Care Act allowed young adults to remain on their parents' health insurance plans until age 26 years. Although the provision improved coverage and survey-reported access to care, little is known regarding its impact on timely access for acute conditions. This study aims to assess changes in insurance coverage and perforation rates among young adults with acute appendicitis-an established metric for population-level health care access-after the DCP. Methods: The National Inpatient Sample and difference-in-differences linear regression were used to assess prepolicy/postpolicy changes for policy-eligible young adults (aged 19-25 y) compared with a slightly older, policy-ineligible comparator group (aged 26-34 y). Results: After adjustment for covariates, 19-25 year olds experienced a 3.6-percentage point decline in the uninsured rate after the DCP (baseline 22.5%), compared with 26-34 year olds (P < 0.001). This coincided with a 1.4-percentage point relative decline in perforated appendix rate for 19-25 year olds (baseline 17.5%), compared with 26-34 year olds (P = 0.023). All subgroups showed significant reductions in uninsured rates; however, statistically significant reductions in perforation rates were limited to racial/ethnic minorities, patients from lower-income communities, and patients presenting to urban teaching hospitals. Conclusions: Reductions in uninsured rates among young adults after the DCP were associated with significant reductions in perforated appendix rates relative to a comparator group, suggesting that insurance expansion could lead to fewer delays in seeking and accessing care for acute conditions. Greater relative declines in perforation rates among the most at-risk subpopulations hold important implications for the use of coverage expansion to mitigate existing disparities in access to care. C1 [Scott, John W.; Rose, John A.; Tsai, Thomas C.; Zogg, Cheryl K.; Salim, Ali; Haider, Adil H.] Harvard TH Chan Sch Publ Hlth, Ctr Surg & Publ Hlth, Dept Surg, Brigham & Womens Hosp,Harvard Med Sch, Boston, MA USA. [Scott, John W.; Shrime, Mark G.] Harvard Med Sch, Program Global Surg & Social Change, Boston, MA USA. [Tsai, Thomas C.; Sommers, Benjamin D.] Harvard TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Shrime, Mark G.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. [Shrime, Mark G.] Massachusetts Eye & Ear Infirm, Off Global Surg, Boston, MA 02114 USA. [Sommers, Benjamin D.] Brigham & Womens Hosp, Dept Med, Boston, MA 02120 USA. [Salim, Ali; Haider, Adil H.] Brigham & Womens Hosp, Dept Surg, Div Trauma, Boston, MA 02120 USA. RP Scott, JW (reprint author), Brigham & Womens Hosp, Ctr Surg & Publ Hlth, One Brigham Circle,1620 Tremont St,Suite 4-020, Boston, MA 02120 USA. EM jwscott@partners.org FU Ethicon; Harvard Surgery Affinity Research Collaborative (ARC); [AD-1306-03980] FX M.G.S. received speaking fees from Ethicon in 2014 for work unrelated to this project. B.D.S. and T.C.T. serve part-time as advisors to the Office of the Assistant Secretary for Planning and Evaluation at the Department of Health & Human Services. This work does not represent the official views of the US Department of Health and Human Services. A.H.H. is the PI of a contract (AD-1306-03980) with the Patient-Centered Outcomes Research Institute entitled "Patient-Centered Approaches to Collect Sexual Orientation/Gender Identity in the ED" and a Harvard Surgery Affinity Research Collaborative (ARC) Program Grant entitled "Mitigating Disparities Through Enhancing Surgeons' Ability To Provide Culturally Relevant Care." A.H.H. is also the cofounder and an equity holder in Patient Doctor Technologies Inc., which owns and operates the website http://www.doctella.com. The remaining authors declare no conflict of interest. NR 39 TC 2 Z9 2 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD SEP PY 2016 VL 54 IS 9 BP 818 EP 826 DI 10.1097/MLR.0000000000000586 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DU5JJ UT WOS:000382247700003 PM 27367865 ER PT J AU Lasser, KE Hanchate, AD McCormick, D Chu, C Xuan, ZM Kressin, NR AF Lasser, Karen E. Hanchate, Amresh D. McCormick, Danny Chu, Chieh Xuan, Ziming Kressin, Nancy R. TI Massachusetts Health Reform's Effect on Hospitals' Racial Mix of Patients and on Patients' Use of Safety-net Hospitals SO MEDICAL CARE LA English DT Article DE vulnerable populations; safety-net hospitals; disparities ID CARE; DISPARITIES; ACCESS; SEGREGATION; PROVIDERS; SEPARATE; QUALITY; FUTURE; ADULTS AB Background: Because of residential segregation and a lack of health insurance, minorities often receive care in different facilities than whites. Massachusetts (MA) health reform provided insurance to previously uninsured patients, which enabled them to potentially shift inpatient care to nonminority-serving or nonsafety-net hospitals. Objectives: Examine whether MA health reform affected hospitals' racial mix of patients, and individual patients' use of safety-net hospitals. Research Design: Difference-in-differences analysis of 2004-2009 inpatient discharge data from MA, compared with New York (NY), and New Jersey (NJ), to identify postreform changes, adjusting for secular changes. Subjects: (1) Hospital-level analysis (discharges): 345 MA, NY, and NJ hospitals; (2) patient-level analysis (patients): 39,921 patients with >= 2 hospitalizations at a safety-net hospital in the prereform period. Measures: Prereform to postreform changes in percentage of discharges that are minority (black and Hispanic) at minority-serving hospitals; adjusted odds of patient movement from safety-net hospitals (prereform) to nonsafety-net hospitals (postreform) by age group and state. Results: Treating NJ as the comparison state, MA reform was associated with an increase of 5.8% (95% CI, 1.4%-10.3%) in the percentage of minority discharges at MA minority-serving hospitals; with NY as the comparison state, the change was 2.1% (95% CI, -0.04% to 4.3%). Patient movement from safety-net to non-safety-net hospitals was greater in MA than comparison states (difference-in-differences adjusted OR = 1.3; 95% CI, 1.0-1.7; P = 0.04). Conclusions: Following MA health reform, the safety-net remains an important component of the health care system. C1 [Lasser, Karen E.; Hanchate, Amresh D.; Chu, Chieh; Kressin, Nancy R.] Boston Univ, Sch Med, Gen Internal Med Sect, Boston Med Ctr, Boston, MA 02118 USA. [Lasser, Karen E.; Xuan, Ziming] Boston Univ, Sch Publ Hlth, Dept Community Hlth Sci, Boston, MA 02118 USA. [Hanchate, Amresh D.; Kressin, Nancy R.] VA Boston Healthcare Syst, Boston, MA USA. [McCormick, Danny] Harvard Med Sch, Dept Med, Cambridge Hlth Alliance, Cambridge, MA USA. RP Lasser, KE (reprint author), Boston Univ, Sch Med, Gen Internal Med Sect, Boston Med Ctr, Boston, MA 02118 USA. EM karen.lasser@bmc.org FU NIH [1U01HL105342-01]; Rx foundation; Department of Veterans Affairs, Health Services Research & Development Service [RCS 02-066-1] FX Supported by NIH grants (1U01HL105342-01, N.R.K., PI) and a grant from the Rx foundation. N.R.K. is supported in part by a Research Career Scientist award from the Department of Veterans Affairs, Health Services Research & Development Service (RCS 02-066-1). 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 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD SEP PY 2016 VL 54 IS 9 BP 827 EP 836 DI 10.1097/MLR.0000000000000575 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DU5JJ UT WOS:000382247700004 PM 27261638 ER PT J AU Chen, C Cheng, X Li, J Chen, H Zhang, S Dong, YL Gan, L Liu, J Zhu, T AF Chen, Chan Cheng, Xu Li, Ji Chen, Hai Zhang, Shu Dong, Yuanlin Gan, Lu Liu, Jin Zhu, Tao TI Extracellular RNAs as a chemical initiator for postoperative cognitive dysfunction SO MEDICAL HYPOTHESES LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; AGED RATS; SURGERY; POPULATION; BIOMARKERS; NECROSIS; OUTCOMES; DECLINE; DISEASE AB Postoperative cognitive dysfunction (POCD) is a common complication that presents in the postoperative stage, especially in elderly patients. Despite years of considerable progress, the detailed molecular mechanisms of POCD remain largely unknown. Neuroinflammation has been increasingly pointed out as one of the core mechanisms for the pathogenesis of POCD. However, application of anti-inflammatory drugs failed to show consistent beneficial effect in patients with cognitive decline. Hence, it might be of great importance to identify the inflammatory initiators that are involved in the mediation, amplification and perpetuation of postoperative neuroinflammatory reactions. Extracellular RNAs (exRNAs), released from necrotic cells, were demonstrated to initiate the inflammatory responses in various pathological conditions. Recent study has suggested neuroprotective and edema protective effects of ribonuclease (RNase), the counterpart of RNA, in acute stroke. It was theorized that RNase acted against endogenous RNA that was released from tissue damage. Similarly, we have observed significant attenuation of cognitive impairment by RNase in aged mice after unilateral nephrectomy. Damping the systemic initiators at early stages may help to prevent the chain reaction that triggers the central inflammatory or apoptotic response. Therefore, we propose the hypothesis that exRNAs released upon stress, through acting on the peripheral and/or central receptors, may trigger a damaging cascade leading to the development of POCD. Undoubtedly, further study is urgently needed to elucidated the exact signaling mechanisms and confirm the proposed hypothesis. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Chen, Chan; Cheng, Xu; Chen, Hai; Gan, Lu; Liu, Jin; Zhu, Tao] Sichuan Univ, West China Hosp, Dept Anesthesiol, Chengdu, Sichuan, Peoples R China. [Chen, Chan; Cheng, Xu; Chen, Hai; Gan, Lu; Liu, Jin; Zhu, Tao] Sichuan Univ, West China Hosp, Translat Neurosci Ctr, Chengdu, Sichuan, Peoples R China. [Li, Ji] Sichuan Univ, West China Hosp, Dept Surg Operating Room, Chengdu, Sichuan, Peoples R China. [Zhang, Shu] Sichuan Univ, West China Hosp, Dept Emergency Med, Chengdu, Sichuan, Peoples R China. [Dong, Yuanlin] Massachusetts Gen Hosp, Geriatr Anesthesia Res Unit, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Dong, Yuanlin] Harvard Med Sch, Boston, MA USA. RP Zhu, T (reprint author), 37 Guoxue Xiang, Chengdu, Sichuan, Peoples R China. EM xwtao_zhu@yahoo.com FU National Natural Science Foundation of China [81500937]; Science and Technology Pillar Program of Sichuan Province Research Grant [2014sz0056]; Distinguished Professorships Awards from the China Medical Board [0082827601157] FX This work was supported by the National Natural Science Foundation of China (No. 81500937, to Dr. Chan Chen), the Science and Technology Pillar Program of Sichuan Province Research Grant (No. 2014sz0056, to Dr. Chan Chen), and the Distinguished Professorships Awards from the China Medical Board (No. 0082827601157, to Dr. Jin Liu). We sincerely thank Dr. David B. Auyong from Virginia Mason Medical Center, Seattle, WA, USA for his help with language use, spelling, and grammar. NR 36 TC 0 Z9 0 U1 4 U2 4 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0306-9877 EI 1532-2777 J9 MED HYPOTHESES JI Med. Hypotheses PD SEP PY 2016 VL 94 BP 47 EP 50 DI 10.1016/j.mehy.2016.06.014 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DU6RC UT WOS:000382341300012 PM 27515198 ER PT J AU Conceicao, MS Chacon-Mikahil, MPT Telles, GD Libardi, CA Mendes, EM Vechin, FC De Andrade, ALL Gaspari, AF Brum, PC Cavaglieri, CR Serag, S Spiegelman, BM Hawley, JA Camera, DM AF Conceicao, Miguel Soares Traina Chacon-Mikahil, Mara Patricia Telles, Guilherme Defante Libardi, Cleiton Augusto Mendes Junior, Edson Manoel Vechin, Felipe Cassaro Lugnani De Andrade, Andre Luis Gaspari, Arthur Fernandes Brum, Patricia Chakur Cavaglieri, Claudia Regina Serag, Sara Spiegelman, Bruce M. Hawley, John A. Camera, Donny M. TI Attenuated PGC-1 alpha Isoforms following Endurance Exercise with Blood Flow Restriction SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE MITOCHONDRIAL BIOGENESIS; CELL SIGNALING; SKELETAL MUSCLE; ADAPTATION; ANGIOGENESIS; HIGH-INTENSITY EXERCISE ID HUMAN SKELETAL-MUSCLE; HIGH-INTENSITY INTERVAL; RESISTANCE EXERCISE; PROTEIN-SYNTHESIS; GENE-EXPRESSION; MESSENGER-RNA; MITOCHONDRIAL BIOGENESIS; P53 PHOSPHORYLATION; YOUNG MEN; INCREASES AB Introduction: Exercise performed with blood flow restriction simultaneously enhances the acute responses to both myogenic and mitochondrial pathways with roles in training adaptation. We investigated isoform-specific gene expression of the peroxisome proliferator-activated receptor gamma coactivator 1 and selected target genes and proteins regulating skeletal muscle training adaptation. Methods: Nine healthy, untrained males participated in a randomized, counterbalanced, crossover design in which each subject completed a bout of low-intensity endurance exercise performed with blood flow restriction (15 min cycling at 40% of (v) over dot O-2peak, BFR-EE), endurance exercise (30min cycling at 70% of (v) over dot O-2peak, EE), or resistance exercise (4 x 10 repetitions of leg press at 70% of one-repetition maximum) separated by at least 1 wk of recovery. A single resting muscle biopsy (vastus lateralis) was obtained 2 wk before the first exercise trial (rest) and 3 h after each bout. Results: Total PGC-1 alpha mRNA abundance, along with all four isoforms, increased above rest with EE only (P < 0.05) being higher than BFR-EE (P < 0.05). PGC-1 alpha 1, 2, and 4 were higher after EE compared with resistance exercise (P < 0.05). EE also increased vascular endothelial growth factor, Hif-1 alpha, and MuRF-1 mRNA abundance above rest (P < 0.05), whereas COXIV mRNA expression increased with EE compared with BFR-EE (P < 0.05). Conclusion: The attenuated expression of all four PGC-1 alpha isoforms when EE is performed with blood flow restriction suggests this type of exercise provides an insufficient stimulus to activate the signaling pathways governing mitochondrial and angiogenesis responses observed with moderate-to high-intensity EE. C1 [Conceicao, Miguel Soares; Traina Chacon-Mikahil, Mara Patricia; Telles, Guilherme Defante; Mendes Junior, Edson Manoel; Lugnani De Andrade, Andre Luis; Gaspari, Arthur Fernandes; Cavaglieri, Claudia Regina] Univ Estadual Campinas, Fac Phys Educ, Ave Erico Verissimo 701, BR-13083851 Campinas, SP, Brazil. [Libardi, Cleiton Augusto] Univ Fed Sao Carlos, Dept Phys Educ, Lab Neuromuscular Adaptat Resistance Training, Sao Carlos, SP, Brazil. [Vechin, Felipe Cassaro; Brum, Patricia Chakur] Univ Sao Paulo, Sch Phys Educ & Sport, Sao Paulo, Brazil. [Serag, Sara; Spiegelman, Bruce M.] Harvard Med Sch, Dana Farber Canc Inst, Dept Cell Biol, Boston, MA USA. [Hawley, John A.; Camera, Donny M.] Australian Catholic Univ, Ctr Exercise & Nutr, Mary MacKillop Inst Hlth Res, Melbourne, Vic, Australia. [Hawley, John A.] Liverpool John Moores Univ, Res Inst Sport & Exercise Sci, Liverpool, Merseyside, England. RP Conceicao, MS (reprint author), Univ Estadual Campinas, Fac Phys Educ, Ave Erico Verissimo 701, BR-13083851 Campinas, SP, Brazil. EM conceicao.miguel0106@gmail.com RI Vechin, Felipe/G-9439-2012; Cavaglieri, Claudia/C-4291-2012 OI Cavaglieri, Claudia/0000-0002-7795-6575 FU FAPESP [2014/00985-0]; FAEPEX; Collaborative Research Networks [2013000443] FX The authors would like to express gratitude for the FAPESP (2014/00985-0) and FAEPEX for financial support. The writing of this publication was also supported by a Collaborative Research Networks grant awarded to J. A. Hawley (2013000443). NR 40 TC 1 Z9 1 U1 7 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD SEP PY 2016 VL 48 IS 9 BP 1699 EP 1707 DI 10.1249/MSS.0000000000000970 PG 9 WC Sport Sciences SC Sport Sciences GA DU5NX UT WOS:000382259600008 PM 27128665 ER PT J AU Pennock, S Kim, LA Kazlauskas, A AF Pennock, Steven Kim, Leo A. Kazlauskas, Andrius TI Vascular Endothelial Cell Growth Factor A Acts via Platelet-Derived Growth Factor Receptor alpha To Promote Viability of Cells Enduring Hypoxia SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SMOOTH-MUSCLE-CELLS; PREVENT PROLIFERATIVE VITREORETINOPATHY; FACTOR-BETA RECEPTOR; PDGF RECEPTOR; SIGNAL-TRANSDUCTION; FAMILY KINASES; ANGIOTENSIN-II; TRANSACTIVATION; ACTIVATION; PATHWAY AB Vascular endothelial cell growth factor A ( VEGF) is a biologically and therapeutically important growth factor because it promotes angiogenesis in response to hypoxia, which underlies a wide variety of both physiological and pathological settings. We report here that both VEGF receptor 2 (VEGFR2)-positive and -negative cells depended on VEGF to endure hypoxia. VEGF enhanced the viability of platelet-derived growth factor receptor alpha (PDGFR alpha)-positive and VEGFR2-negative cells by enabling indirect activation of PDGFR alpha, thereby reducing the level of p53. We conclude that the breadth of VEGF's influence extends beyond VEGFR-positive cells and propose a plausible mechanistic explanation of this phenomenon. C1 [Pennock, Steven; Kim, Leo A.; Kazlauskas, Andrius] Harvard Med Sch, Schepens Eye Res Inst, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. [Pennock, Steven] Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA. RP Kazlauskas, A (reprint author), Harvard Med Sch, Schepens Eye Res Inst, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. EM andrius_kazlauskas@meei.harvard.edu FU Harvard Vision Clinical Scientist Development Program Research [5K12EY016335]; HHS \ National Institutes of Health (NIH) [EY012509, EY022979]; Gouvernement du Canada \ Canadian Institutes of Health Research (CIHR) FX This work, including the efforts of Leo Kim, was funded by Harvard Vision Clinical Scientist Development Program Research (5K12EY016335). This work, including the efforts of Andrius Kazlauskas, was funded by HHS vertical bar National Institutes of Health (NIH) (EY012509 and EY022979). This work, including the efforts of Steven Pennock, was funded by Gouvernement du Canada vertical bar Canadian Institutes of Health Research (CIHR). NR 44 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2016 VL 36 IS 18 BP 2314 EP 2327 DI 10.1128/MCB.01019-15 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DU6JL UT WOS:000382320800001 PM 27325673 ER PT J AU Apelo, SIA Lamming, DW AF Apelo, Sebastian I. Arriola Lamming, Dudley W. TI mTORC2 Puts Its Shoulder to Krebs' Wheel SO MOLECULAR CELL LA English DT Editorial Material ID GLUTAMINE-METABOLISM; MECHANISTIC TARGET; RAPAMYCIN; PATHWAY AB In this issue of Molecular Cell, Moloughney et al. (2016) find that mTORC2 responds to falling levels of glucose and glutamine catabolites, promoting glutaminolysis and preserving the TCA cycle and hexosamine biosynthesis. C1 [Apelo, Sebastian I. Arriola; Lamming, Dudley W.] Univ Wisconsin, Dept Med, Madison, WI 53705 USA. [Apelo, Sebastian I. Arriola; Lamming, Dudley W.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. RP Lamming, DW (reprint author), Univ Wisconsin, Dept Med, Madison, WI 53705 USA.; Lamming, DW (reprint author), William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. EM dlamming@medicine.wisc.edu OI Lamming, Dudley/0000-0002-0079-4467 NR 10 TC 0 Z9 0 U1 5 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD SEP 1 PY 2016 VL 63 IS 5 BP 723 EP 725 DI 10.1016/j.molcel.2016.08.016 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DU9MO UT WOS:000382542000002 ER PT J AU Thapar, A Martin, J Mick, E Vasquez, AA Langley, K Scherer, SW Schachar, R Crosbie, J Williams, N Franke, B Elia, J Glessner, J Hakonarson, H Owen, MJ Faraone, SV O'Donovan, MC Holmans, P AF Thapar, A. Martin, J. Mick, E. Vasquez, A. Arias Langley, K. Scherer, S. W. Schachar, R. Crosbie, J. Williams, N. Franke, B. Elia, J. Glessner, J. Hakonarson, H. Owen, M. J. Faraone, S. V. O'Donovan, M. C. Holmans, P. CA IMAGE 2 Consortium TI Psychiatric gene discoveries shape evidence on ADHD's biology SO MOLECULAR PSYCHIATRY LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; GENOME-WIDE ASSOCIATION; AUTISM SPECTRUM DISORDER; COPY NUMBER VARIANTS; POLYGENIC RISK; RARE VARIANTS; SCHIZOPHRENIA; MUTATIONS; PATHWAYS AB A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P = 5.4 x 10(-4)) and targets of the Fragile X mental retardation protein (P = 0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P = 0.23) or N-methyl-D-aspartate receptor (P = 0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P = 0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders. C1 [Thapar, A.; Martin, J.; Langley, K.; Williams, N.; Owen, M. J.; O'Donovan, M. C.; Holmans, P.] Cardiff Univ, Sch Med, Inst Psychol Med & Clin Neurosci, Cardiff, S Glam, Wales. [Thapar, A.; Martin, J.; Langley, K.; Williams, N.; Owen, M. J.; O'Donovan, M. C.; Holmans, P.] Cardiff Univ, Sch Med, MRC, Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales. [Mick, E.] Univ Massachusetts, Sch Med, Dept Psychiat, Dept Quantitat Hlth Sci, Worcester, MA 01655 USA. [Mick, E.] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. [Vasquez, A. Arias; Franke, B.] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Psychiat, Nijmegen, Netherlands. [Vasquez, A. Arias; Franke, B.] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Human Genet, Nijmegen, Netherlands. [Vasquez, A. Arias] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Cognit Neurosci, Nijmegen, Netherlands. [Langley, K.] Cardiff Univ, Sch Psychol, Cardiff, S Glam, Wales. [Scherer, S. W.] Hosp Sick Children, Ctr Appl Genom, Toronto, ON, Canada. [Schachar, R.; Crosbie, J.] Univ Toronto, Hosp Sick Children, Dept Psychiat Neurosci & Mental Hlth, Toronto, ON, Canada. [Elia, J.] Thomas Jefferson Univ, Dept Pediat & Psychiat, Sidney Kimmel Coll Med, Philadelphia, PA USA. [Elia, J.] Nemours Neurosci Ctr, Wilmington, DE USA. [Elia, J.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Glessner, J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Hakonarson, H.] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Faraone, S. V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Faraone, S. V.] SUNY Upstate Med Univ, Dept Neurosci, Syracuse, NY 13210 USA. [Faraone, S. V.] Univ Bergen, KG Jebsen Ctr Res Neuropsychiat Disorders, Bergen, Norway. RP Thapar, A; Holmans, P (reprint author), Cardiff Univ, Sch Med, Inst Psychol Med & Clin Neurosci, MRC,Ctr Neuropsychiat Genet & Genom, Hadyn Ellis Bldg,Maindy Rd, Cardiff CF24 4HQ, S Glam, Wales. EM thapar@cf.ac.uk; holmanspa@cf.ac.uk RI Franke, Barbara/D-4836-2009; Scherer, Stephen /B-3785-2013; OI Franke, Barbara/0000-0003-4375-6572; Scherer, Stephen /0000-0002-8326-1999; Martin, Joanna/0000-0002-8911-3479 FU Wellcome Trust; MRC; Action Medical Research; NIH [R1 3MH059126, R0 1MH62873, R0 1MH081803]; UMass Center for Clinical and Translational Science - NIH [P30HD004147] FX We thank the patients and the family members who provided data for this project and research staff who helped collect and manage the data. They also thank Benjamin Neale for the original data retrieval. The Wellcome Trust, MRC and Action Medical Research have provided ADHD research support for AT, PH, JM, NW, MJO, MCO; we also acknowledge support from NIH grants R1 3MH059126, R0 1MH62873 and R0 1MH081803 to Dr SV Faraone. Dr E Mick received funding through the UMass Center for Clinical and Translational Science (P30HD004147) supported by the NIH. NR 44 TC 2 Z9 2 U1 8 U2 8 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 SEP PY 2016 VL 21 IS 9 BP 1202 EP 1207 DI 10.1038/mp.2015.163 PG 6 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DU6MK UT WOS:000382328900007 PM 26573769 ER PT J AU Song, J Bergen, SE Di Florio, A Karlsson, R Charney, A Ruderfer, DM Stahl, EA Chambert, KD Moran, JL Gordon-Smith, K Forty, L Green, EK Jones, I Jones, L Scolnick, EM Sklar, P Smoller, JW Lichtenstein, P Hultman, C Craddock, N Landen, M AF Song, J. Bergen, S. E. Di Florio, A. Karlsson, R. Charney, A. Ruderfer, D. M. Stahl, E. A. Chambert, K. D. Moran, J. L. Gordon-Smith, K. Forty, L. Green, E. K. Jones, I. Jones, L. Scolnick, E. M. Sklar, P. Smoller, J. W. Lichtenstein, P. Hultman, C. Craddock, N. Landen, M. CA ICCBD TI Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder SO MOLECULAR PSYCHIATRY LA English DT Article ID RECEPTOR POTENTIAL CHANNELS; NEUROTROPHIC FACTOR GENE; PROPHYLACTIC LITHIUM; MAINTENANCE TREATMENT; JAPANESE PATIENTS; TRPC5 CHANNELS; BRAIN; MECHANISM; POLYMORPHISM; SCHIZOPHRENIA AB Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P = 2.74 x 10(-8)). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD. C1 [Song, J.; Bergen, S. E.; Karlsson, R.; Lichtenstein, P.; Hultman, C.; Landen, M.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Bergen, S. E.; Chambert, K. D.; Moran, J. L.; Scolnick, E. M.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Di Florio, A.; Forty, L.; Jones, I.; Craddock, N.] Cardiff Univ, Natl Ctr Mental Hlth, MRC, Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales. [Charney, A.; Ruderfer, D. M.; Stahl, E. A.; Sklar, P.] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA. [Gordon-Smith, K.; Jones, L.] Univ Birmingham, Sch Clin & Expt Med, Dept Psychiat, Birmingham, W Midlands, England. [Green, E. K.] Univ Plymouth, Peninsula Sch Med, Sch Biomed & Healthcare Sci, Plymouth, Devon, England. [Green, E. K.] Univ Plymouth, Peninsula Sch Dent, Sch Biomed & Healthcare Sci, Plymouth, Devon, England. [Sklar, P.] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Sklar, P.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Smoller, J. W.] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Landen, M.] Gothenburg Univ, Sahlgrenska Acad, Inst Neurosci & Physiol, S-41345 Gothenburg, Sweden. RP Landen, M (reprint author), Gothenburg Univ, Sahlgrenska Acad, Inst Neurosci & Physiol, S-41345 Gothenburg, Sweden. EM Mikael.landen@neuro.gu.se OI Moran, Jennifer/0000-0002-5664-4716 FU Stanley Center for Psychiatric Research, Broad Institute from Stanley Medical Research Institute; Swedish Medical Research Council [K2014-62X-14647-12-51, K2010-61P-21568-01-4]; Soderstrom-Konigska Foundation [SLS-472751]; Swedish foundation for Strategic Research [KF10-0039]; China Scholarship Council; Wellcome Trust; Stanley Medical Research Institute; NIMH [RO1MH085542] FX We would like to thank all of the participants who have kindly given their time and DNA to participate in our research, the Swedish quality register for bipolar disorders (BipolaR), data collectors at the Department of Medical Epidemiology and Biostatistics (MEB) at Karolinska Institutet, Bipolar UK, BDRN clinical collaborators and facilitators, and the Mental Health Research Network (MHRN) for help with recruitment of participants. The Swedish part was funded by the Stanley Center for Psychiatric Research, Broad Institute from a grant from Stanley Medical Research Institute, the Swedish Medical Research Council (K2014-62X-14647-12-51 and K2010-61P-21568-01-4), the Soderstrom-Konigska Foundation (SLS-472751), the Swedish foundation for Strategic Research (KF10-0039) and the China Scholarship Council. The UK collection was supported by grants from the Wellcome Trust and the Stanley Medical Research Institute. The International Cohort Collection for Bipolar Disorder (ICCBD) was funded by NIMH grant RO1MH085542. NR 75 TC 3 Z9 3 U1 8 U2 8 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 SEP PY 2016 VL 21 IS 9 BP 1290 EP 1297 DI 10.1038/mp.2015.165 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DU6MK UT WOS:000382328900018 PM 26503763 ER PT J AU Carreno, FR Donegan, JJ Boley, AM Shah, A DeGuzman, M Frazer, A Lodge, DJ AF Carreno, F. R. Donegan, J. J. Boley, A. M. Shah, A. DeGuzman, M. Frazer, A. Lodge, D. J. TI Activation of a ventral hippocampus-medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine SO MOLECULAR PSYCHIATRY LA English DT Article ID RESISTANT MAJOR DEPRESSION; NMDA RECEPTOR BLOCKADE; D-ASPARTATE ANTAGONIST; NUCLEUS-ACCUMBENS; BASOLATERAL AMYGDALA; DENDRITIC MORPHOLOGY; NEUROTROPHIC FACTOR; NEURONS; RAT; STRESS AB A single sub-anesthetic dose of ketamine exerts rapid and sustained antidepressant effects. Here, we examined the role of the ventral hippocampus (vHipp)-medial prefrontal cortex (mPFC) pathway in ketamine's antidepressant response. Inactivation of the vHipp with lidocaine prevented the sustained, but not acute, antidepressant-like effect of ketamine as measured by the forced swim test (FST). Moreover, optogenetic as well as pharmacogenetic specific activation of the vHipp-mPFC pathway using DREADDs (designer receptors exclusively activated by designer drugs) mimicked the antidepressant-like response to ketamine; importantly, this was pathway specific, in that activation of a vHipp to nucleus accumbens circuit did not do this. Furthermore, optogenetic inactivation of the vHipp/mPFC pathway at the time of FST completely reversed ketamine's antidepressant response. In addition, we found that a transient increase in TrkB receptor phosphorylation in the vHipp contributes to ketamine's sustained antidepressant response. These data demonstrate that activity in the vHipp-mPFC pathway is both necessary and sufficient for the antidepressant-like effect of ketamine. C1 [Carreno, F. R.; Donegan, J. J.; Boley, A. M.; Shah, A.; DeGuzman, M.; Frazer, A.; Lodge, D. J.] Univ Texas Hlth Sci Ctr San Antonio, Ctr Biomed Neurosci, Dept Pharmacol, 7703 Floyd Curl Dr,Mail Code 7764, San Antonio, TX 78229 USA. [Frazer, A.] South Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. RP Carreno, FR (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Ctr Biomed Neurosci, Dept Pharmacol, 7703 Floyd Curl Dr,Mail Code 7764, San Antonio, TX 78229 USA. EM Carrenof@uthscsa.edu FU NIMH [MH082933, MH090067]; NARSAD award from the Maltz Family Foundation FX This work was supported by NIMH grants MH082933 (AF) and MH090067 (DJL) and a NARSAD award from the Maltz Family Foundation (DJL). NR 44 TC 7 Z9 7 U1 7 U2 8 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 SEP PY 2016 VL 21 IS 9 BP 1298 EP 1308 DI 10.1038/mp.2015.176 PG 11 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DU6MK UT WOS:000382328900019 PM 26619811 ER PT J AU Dror, S Sander, L Schwartz, H Sheinboim, D Barzilai, A Dishon, Y Apcher, S Golan, T Greenberger, S Barshack, I Malcov, H Zilberberg, A Levin, L Nessling, M Friedmann, Y Igras, V Barzilay, O Vaknine, H Brenner, R Zinger, A Schroeder, A Gonen, P Khaled, M Erez, N Hoheisel, JD Levy, C AF Dror, Shani Sander, Laureen Schwartz, Hila Sheinboim, Danna Barzilai, Aviv Dishon, Yuval Apcher, Sebastien Golan, Tamar Greenberger, Shoshana Barshack, Iris Malcov, Hagar Zilberberg, Alona Levin, Lotan Nessling, Michelle Friedmann, Yael Igras, Vivien Barzilay, Ohad Vaknine, Hananya Brenner, Ronen Zinger, Assaf Schroeder, Avi Gonen, Pinchas Khaled, Mehdi Erez, Neta Hoheisel, Joerg D. Levy, Carmit TI Melanoma miRNA trafficking controls tumour primary niche formation SO NATURE CELL BIOLOGY LA English DT Article ID CANCER-ASSOCIATED FIBROBLASTS; STROMAL FIBROBLASTS; MALIGNANT-MELANOMA; BREAST CARCINOMAS; SUPPRESSOR GENE; GROWTH; CELLS; MELANOSOMES; METASTASIS; CONTRIBUTE AB Melanoma originates in the epidermis and becomes metastatic after invasion into the dermis. Prior interactions between melanoma cells and dermis are poorly studied. Here, we show that melanoma cells directly affect the formation of the dermal tumour niche by microRNA trafficking before invasion. Melanocytes, cells of melanoma origin, are specialized in releasing pigment vesicles, termed melanosomes. In melanoma in situ, we found melanosome markers in distal fibroblasts before melanoma invasion. The melanosomes carry microRNAs into primary fibroblasts triggering changes, including increased proliferation, migration and pro-inflammatory gene expression, all known features of cancer-associated fibroblasts (CAFs). Specifically, melanosomal microRNA-211 directly targets IGF2R and leads to MAPK signalling activation, which reciprocally encourages melanoma growth. Melanosome release inhibitor prevented CAF formation. Since the first interaction of melanoma cells with blood vessels occurs in the dermis, our data suggest an opportunity to block melanoma invasion by preventing the formation of the dermal tumour niche. C1 [Dror, Shani; Sheinboim, Danna; Dishon, Yuval; Golan, Tamar; Malcov, Hagar; Zilberberg, Alona; Levin, Lotan; Gonen, Pinchas; Levy, Carmit] Tel Aviv Univ, Dept Human Genet & Biochem, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Sander, Laureen; Hoheisel, Joerg D.] Deutsch Krebsforschungszentrum DKFZ, Funct Genome Anal, D-69120 Heidelberg, Germany. [Schwartz, Hila; Erez, Neta] Tel Aviv Univ, Dept Pathol, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Barzilai, Aviv; Greenberger, Shoshana; Barshack, Iris] Sheba Med Ctr, Inst Pathol, IL-52621 Tel Hashomer, Israel. [Apcher, Sebastien] Univ Paris, Inst Gustave Roussy, Dept Immunol, F-94805 Villejuif, France. [Nessling, Michelle] Deutsch Krebsforschungszentrum DKFZ, Unit Electron Microscopy, Imaging & Cytometry Core Facil, D-69120 Heidelberg, Germany. [Friedmann, Yael] Hebrew Univ Jerusalem, Bioimaging Unit, IL-91904 Jerusalem, Israel. [Igras, Vivien] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Dept Dermatol, Boston, MA 02114 USA. [Igras, Vivien] Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA 02114 USA. [Barzilay, Ohad] Tel Aviv Univ, Coller Sch Management, IL-69978 Tel Aviv, Israel. [Vaknine, Hananya; Brenner, Ronen] E Wolfson Med Ctr, Inst Pathol, IL-58100 Holon, Israel. [Zinger, Assaf; Schroeder, Avi] Technion Israel Inst Technol, Dept Chem Engn, IL-32000 Haifa, Israel. [Khaled, Mehdi] Univ Paris Saclay, INSERM 1186, F-94805 Villejuif, France. RP Levy, C (reprint author), Tel Aviv Univ, Dept Human Genet & Biochem, Sackler Fac Med, IL-69978 Tel Aviv, Israel. EM carmitlevy@post.tau.ac.il RI khaled, mehdi/C-4854-2012; OI Schroeder, Avi/0000-0003-2571-5937 FU Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ); Israel's Ministry of Science, Technology and Space (MOST); Israel Science Foundation (ISF) FX This work was supported in part by the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israel's Ministry of Science, Technology and Space (MOST) and by the Israel Science Foundation (ISF). We thank the microarray unit of the DKFZ Genomics and Proteomics Core Facility for performing microarray analyses on the Illumina Human Sentrix-12 BeadChip array and the Agilent Human miRNA Microarray. NR 56 TC 4 Z9 4 U1 14 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD SEP PY 2016 VL 18 IS 9 BP 1006 EP 1017 DI 10.1038/ncb3399 PG 12 WC Cell Biology SC Cell Biology GA DU7TF UT WOS:000382416800010 PM 27548915 ER PT J AU Hyde, CL Nagle, MW Tian, C Chen, X Paciga, SA Wendland, JR Tung, JY Hinds, DA Perlis, RH Winslow, AR AF Hyde, Craig L. Nagle, Michael W. Tian, Chao Chen, Xing Paciga, Sara A. Wendland, Jens R. Tung, Joyce Y. Hinds, David A. Perlis, Roy H. Winslow, Ashley R. TI Identification of 15 genetic loci associated with risk of major depression in individuals of European descent SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MOOD DISORDERS; SCHIZOPHRENIA; MEF2C; EPILEPSY; BURDEN; DORSAL; BRAIN; TRIAL; MEIS2 AB Despite strong evidence supporting the heritability of major depressive disorder (MDD), previous genome-wide studies were unable to identify risk loci among individuals of European descent. We used self-report data from 75,607 individuals reporting clinical diagnosis of depression and 231,747 individuals reporting no history of depression through 23andMe and carried out meta-analysis of these results with published MDD genome-wide association study results. We identified five independent variants from four regions associated with self-report of clinical diagnosis or treatment for depression. Loci with a P value <1.0 x 10(-5) in the meta-analysis were further analyzed in a replication data set (45,773 cases and 106,354 controls) from 23andMe. A total of 17 independent SNPs from 15 regions reached genome-wide significance after joint analysis over all three data sets. Some of these loci were also implicated in genome-wide association studies of related psychiatric traits. These studies provide evidence for large-scale consumer genomic data as a powerful and efficient complement to data collected from traditional means of ascertainment for neuropsychiatric disease genomics. C1 [Hyde, Craig L.; Chen, Xing] Pfizer Inc, Pfizer Global Res & Dev, Stat, Cambridge, MA USA. [Nagle, Michael W.; Paciga, Sara A.; Wendland, Jens R.; Winslow, Ashley R.] Pfizer Inc, Pfizer Global Res & Dev, Human Genet & Computat Biomed, Cambridge, MA USA. [Tian, Chao; Tung, Joyce Y.; Hinds, David A.] 23andMe Inc, Mountain View, CA 94041 USA. [Perlis, Roy H.] Massachusetts Gen Hosp, Ctr Human Genet Res, Ct Expt Drugs & Diagnost, Boston, MA 02114 USA. [Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Winslow, Ashley R.] Univ Penn, Perelman Sch Med, Orphan Dis Ctr, Philadelphia, PA 19104 USA. RP Hinds, DA (reprint author), 23andMe Inc, Mountain View, CA 94041 USA.; Perlis, RH (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Ct Expt Drugs & Diagnost, Boston, MA 02114 USA.; Perlis, RH (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM dhinds@23andme.com; rperlis@mgh.harvard.edu FU Pfizer, Inc.; National Institute of Mental Health; National Human Genome Research Institute [P50 MH106933] FX This study was supported in part by Pfizer, Inc. R.H.P. is supported in part by the National Institute of Mental Health and the National Human Genome Research Institute (P50 MH106933). We also thank the Social Science Genetics Association Consortium (SSGAC) for sharing results for subjective well-being, depressive symptoms, and neuroticism. NR 36 TC 20 Z9 20 U1 18 U2 20 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD SEP PY 2016 VL 48 IS 9 BP 1031 EP + DI 10.1038/ng.3623 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DU7MQ UT WOS:000382398800013 PM 27479909 ER PT J AU Zhou, KX Yee, SW Seiser, EL van Leeuwen, N Tavendalel, R Bennett, AJ Groves, CJ Coleman, RL van der Heijden, AA Beulens, JW de Keyser, CE Zaharenkoll, L Rotroff', DM Out, M Jablonski, KA Chen, L Javorsky, M Zidzik, J Levin, AM Williams, LK Dujic, T Semiz, S Kubo, M Chien, HC Maeda, S Witte, JS Wu, LY Tkac, I Kooy, A van Schaik, RHN Stehouwer, CDA Logie, L Sutherland, C Klovins, J Pirags, V Hofman, A Stricker, BH Motsinger-Reif, AA Wagner, MJ Innocenti, F Hart, LM'T Holman, RR McCarthy, MI Hedderson, MM Palmer, CNA Florez, JC Giacomini, KM Pearson, ER AF Zhou, Kaixin Yee, Sook Wah Seiser, Eric L. van Leeuwen, Nienke Tavendalel, Roger Bennett, Amanda J. Groves, Christopher J. Coleman, Ruth L. van der Heijden, Amber A. Beulens, Joline W. de Keyser, Catherine E. Zaharenkoll, Linda Rotroff', Daniel M. Out, Mattijs Jablonski, Kathleen A. Chen, Ling Javorsky, Martin Zidzik, Jozef Levin, Albert M. Williams, L. Keoki Dujic, Tanja Semiz, Sabina Kubo, Michiaki Chien, Huan-Chieh Maeda, Shiro Witte, John S. Wu, Longyang Tkac, Ivan Kooy, Adriaan van Schaik, Ron H. N. Stehouwer, Coen D. A. Logie, Lisa Sutherland, Calum Klovins, Janis Pirags, Valdis Hofman, Albert Stricker, Bruno H. Motsinger-Reif, Alison A. Wagner, Michael J. Innocenti, Federico Hart, Leen M. 't Holman, Rory R. McCarthy, Mark I. Hedderson, Monique M. Palmer, Colin N. A. Florez, Jose C. Giacomini, Kathleen M. Pearson, Ewan R. CA MetGen Investigators DPP Investigators ACCORD Investigators TI Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; DIABETES PREVENTION PROGRAM; COMMON VARIANTS; WEIGHT-LOSS; EXPRESSION; PHARMACOKINETICS; METAANALYSIS; PATHWAYS; PHARMACODYNAMICS; COMPLICATIONS AB Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear(1). Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 x 10(-14)) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine. C1 [Zhou, Kaixin; Tavendalel, Roger; Dujic, Tanja; Logie, Lisa; Sutherland, Calum; Palmer, Colin N. A.; Pearson, Ewan R.] Univ Dundee, Sch Med, Dundee, Scotland. [Yee, Sook Wah; Chien, Huan-Chieh; Giacomini, Kathleen M.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Seiser, Eric L.; Innocenti, Federico] Univ N Carolina, Eshelman Sch Pharm, Ctr Pharmacogen & Individualized Therapy, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA. [van Leeuwen, Nienke; Hart, Leen M. 't] Leiden Univ, Med Ctr, Dept Mol Cell Biol, Leiden, Netherlands. [Bennett, Amanda J.; Groves, Christopher J.; McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Coleman, Ruth L.; Holman, Rory R.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Diabetes Trials Unit, Oxford, England. [van der Heijden, Amber A.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Dept Gen Practice, Amsterdam, Netherlands. [Beulens, Joline W.; Hart, Leen M. 't] Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Dept Epidemiol & Biostat, Amsterdam, Netherlands. [Beulens, Joline W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [de Keyser, Catherine E.; Hofman, Albert; Stricker, Bruno H.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Zaharenkoll, Linda; Klovins, Janis] LGDB, Riga, Latvia. [Zaharenkoll, Linda; Klovins, Janis; Pirags, Valdis] Latvian Biomed Res & Study Ctr, Riga, Latvia. [Rotroff', Daniel M.; Motsinger-Reif, Alison A.] N Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC 27695 USA. [Rotroff', Daniel M.] North Carolina State Univ, Dept Stat, Raleigh, NC 27695 USA. [Out, Mattijs; Kooy, Adriaan] Locat Bethesda, Treant Zorggrp, Hoogeveen, Netherlands. [Out, Mattijs; Kooy, Adriaan] Bethesda Diabet Res Ctr, Hoogeveen, Netherlands. [Jablonski, Kathleen A.] George Washington Univ, Biostat Ctr, Rockville, MD USA. [Chen, Ling; Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Chen, Ling; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Javorsky, Martin; Zidzik, Jozef; Tkac, Ivan] Safarik Univ, Fac Med, Kosice, Slovakia. [Levin, Albert M.] Henry Ford Hlth Syst, Dept Publ Hlth Sci, Detroit, MI USA. [Williams, L. Keoki] Henry Ford Hlth Syst, Ctr Hlth Policy arid Hlth Serv Res, Detroit, MI USA. [Williams, L. Keoki] Henry Ford Hlth Syst, Dept Internal Med, Detroit, MI USA. [Dujic, Tanja; Semiz, Sabina] Univ Sarajevo, Fac Pharm, Sarajevo, Bosnia & Herceg. [Semiz, Sabina] Int Univ Sarajevo, Fac Engn & Nat Sci, Sarajevo, Bosnia & Herceg. [Kubo, Michiaki] RIKEN, Ctr Integrat Med Sci IMS, Yokohama, Kanagawa, Japan. [Maeda, Shiro] Univ Ryukyus, Grad Sch Med, Dept Adv Genom & Lab Med, Nishihara, Okinawa, Japan. [Maeda, Shiro] Univ Ryukyus Hosp, Div Clin Lab & Blood Transfus, Nishihara, Okinawa, Japan. [Witte, John S.; Wu, Longyang] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Witte, John S.; Giacomini, Kathleen M.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Witte, John S.] Univ Calif San Francisco, Dept Urol, San Francisco, CA USA. [Witte, John S.] Univ Calif San Francisco, UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [van Schaik, Ron H. N.] Erasmus Univ, Med Ctr, Dept Clin C;hernistry, Rotterdam, Netherlands. [Stehouwer, Coen D. A.] Maastricht Univ, Med Ctr, Res Inst Maastricht, Dept Internal Med & Cardiovasc, Maastricht, Netherlands. [Pirags, Valdis] Univ Latvia, Fac Med, Riga, Latvia. [Pirags, Valdis] Pauls Stradins Clin Univ Hosp, Dept Endocrinol, Riga, Latvia. [Stricker, Bruno H.] Inspeceorate Healthcare, Heerlen, Netherlands. [Wagner, Michael J.] Univ North Carolina Chapel Hill, Ctr Pharrnacogen & Individualized Therapy, Chapel Hill, NC USA. [Hart, Leen M. 't] Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands. [McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [McCarthy, Mark I.] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford, England. [Hedderson, Monique M.] Kaiser Permanente Nothern Calif, Div Res, Oakland, CA USA. [Florez, Jose C.] Broad Inst, Program Metab, Cambridge, MA USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Florez, Jose C.] Harvard Med Sch, Dept Med, Boston, MA USA. RP Pearson, ER (reprint author), Univ Dundee, Sch Med, Dundee, Scotland.; Giacomini, KM (reprint author), Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA.; Giacomini, KM (reprint author), Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. EM kaliriv.giacomini@ucsl.edu; e.z.pearson@dundee.ac.uk RI Out, Mattijs/P-6963-2016; Palmer, Colin/C-7053-2008; OI Palmer, Colin/0000-0002-6415-6560; Coleman, Ruth/0000-0002-5194-8550; Zidzik, Jozef/0000-0002-9863-4217 FU Diabetes UK [10/0004063]; NIDDK NIH HHS [U01 DK048380, P30 DK017047, U01 DK048349, U01 DK048375, U01 DK048377, U01 DK048381, U01 DK048387, U01 DK048397, U01 DK048400, U01 DK048404, U01 DK048406, U01 DK048407, U01 DK048411, U01 DK048412, U01 DK048413, U01 DK048434, U01 DK048437, U01 DK048443, U01 DK048468, U01 DK048485, U01 DK048489, U01 DK048514]; NIGMS NIH HHS [R01 GM117163, U19 GM061390]; Wellcome Trust [092272, 102820] NR 51 TC 3 Z9 4 U1 13 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD SEP PY 2016 VL 48 IS 9 BP 1055 EP + DI 10.1038/ng.3632 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA DU7MQ UT WOS:000382398800017 PM 27500523 ER PT J AU Shen, CH Kim, SH Trousil, S Frederick, DT Piris, A Yuan, P Cai, L Gu, L Li, M Lee, JH Mitra, D Fisher, DE Sullivan, RJ Flaherty, KT Zheng, B AF Shen, Che-Hung Kim, Sun Hye Trousil, Sebastian Frederick, Dennie T. Piris, Adriano Yuan, Ping Cai, Li Gu, Lei Li, Man Lee, Jung Hyun Mitra, Devarati Fisher, David E. Sullivan, Ryan J. Flaherty, Keith T. Zheng, Bin TI Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma SO NATURE MEDICINE LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACQUIRED-RESISTANCE; BLADDER-CANCER; METASTATIC MELANOMA; CELL-PROLIFERATION; GENOMIC LANDSCAPE; EWING SARCOMA; BINDING SITES; B-RAF; MUTATIONS AB The protein kinase B-Raf proto-oncogene, serine/threonine kinase (BRAF) is an oncogenic driver and therapeutic target in melanoma. Inhibitors of BRAF (BRAFi) have shown high response rates and extended survival in patients with melanoma who bear tumors that express mutations encoding BRAF proteins mutant at Val600, but a vast majority of these patients develop drug resistance(1,2). Here we show that loss of stromal antigen 2 (STAG2) or STAG3, which encode subunits of the cohesin complex, in melanoma cells results in resistance to BRAFi. We identified loss-of-function mutations in STAG2, as well as decreased expression of STAG2 or STAG3 proteins in several tumor samples from patients with acquired resistance to BRAFi and in BRAFi-resistant melanoma cell lines. Knockdown of STAG2 or STAG3 expression decreased sensitivity of BRAF(Val600Glu)-mutant melanoma cells and xenograft tumors to BRAFi. Loss of STAG2 inhibited CCCTCbinding- factor-mediated expression of dual specificity phosphatase 6 (DUSP6), leading to reactivation of mitogenactivated protein kinase (MAPK) signaling (via the MAPKs ERK1 and ERK2; hereafter referred to as ERK). Our studies unveil a previously unknown genetic mechanism of BRAFi resistance and provide new insights into the tumor suppressor function of STAG2 and STAG3. C1 [Shen, Che-Hung; Kim, Sun Hye; Trousil, Sebastian; Yuan, Ping; Cai, Li; Li, Man; Lee, Jung Hyun; Mitra, Devarati; Fisher, David E.; Zheng, Bin] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Shen, Che-Hung; Kim, Sun Hye; Trousil, Sebastian; Yuan, Ping; Cai, Li; Li, Man; Lee, Jung Hyun; Mitra, Devarati; Fisher, David E.; Zheng, Bin] Harvard Med Sch, Charlestown, MA 02129 USA. [Frederick, Dennie T.; Fisher, David E.; Sullivan, Ryan J.; Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Dept Med Oncol, Boston, MA 02114 USA. [Piris, Adriano] Brigham & Womens Hosp, Dept Dermatol, 75 Francis St, Boston, MA 02115 USA. [Piris, Adriano] Harvard Med Sch, Boston, MA USA. [Gu, Lei] Harvard Med Sch, Boston Childrens Hosp, Div Newborn Med, Boston, MA USA. [Shen, Che-Hung] China Med Univ, China Med Univ Hosp, Dept Dermatol, Taichung, Taiwan. RP Zheng, B (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA.; Zheng, B (reprint author), Harvard Med Sch, Charlestown, MA 02129 USA. EM bin.zheng@cbrc2.mgh.harvard.edu FU Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; V Foundation; Harry J. Lloyd Charitable Trust; Melanoma Research Alliance; US National Institutes of Health (NIH) [P01 CA163222, R01 AR043369, R21 CA175907, R01 CA166717] FX We thank K. Swanson, Y. Zhang and G. Zhao for critical comments on the manuscript. We also thank L. Chin (MD Anderson Cancer Center), M. Herlyn (Wistar Institute), C. Pritchard (University of Leicester) and J. Zippin (Weill Cornell Medical College) for providing cell lines. This work is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (D.E.F.), the V Foundation (B.Z.), the Harry J. Lloyd Charitable Trust (B.Z.), the Melanoma Research Alliance (B.Z.) and the US National Institutes of Health (NIH) grants P01 CA163222 (D.E.F.), R01 AR043369 (D.E.F.), R21 CA175907 (D.E.F.) and R01 CA166717 (B.Z.). NR 39 TC 1 Z9 1 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD SEP PY 2016 VL 22 IS 9 BP 1056 EP + DI 10.1038/nm.4155 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DU9MW UT WOS:000382542800017 PM 27500726 ER PT J AU Tung, N Domchek, SM Stadler, Z Nathanson, KL Couch, F Garber, JE Offit, K Robson, ME AF Tung, Nadine Domchek, Susan M. Stadler, Zsofia Nathanson, Katherine L. Couch, Fergus Garber, Judy E. Offit, Kenneth Robson, Mark E. TI Counselling framework for moderate-penetrance cancer-susceptibility mutations SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Article ID CONTRALATERAL BREAST-CANCER; OVARIAN-CANCER; GERMLINE MUTATIONS; BRCA2 MUTATION; HIGH-RISK; ATM GENE; CONFER SUSCEPTIBILITY; PREDISPOSITION GENES; COLORECTAL-CANCER; PANCREATIC-CANCER AB The use of multigene panels for the assessment of cancer susceptibility is expanding rapidly in clinical practice, particularly in the USA, despite concerns regarding the uncertain clinical validity for some gene variants and the uncertain clinical utility of most multigene panels. So-called 'moderate-penetrance' gene mutations associated with cancer susceptibility are identified in approximately 2-5% of individuals referred for clinical testing; some of these mutations are potentially actionable. Nevertheless, the appropriate management of individuals harbouring such moderate-penetrance genetic variants is unclear. The cancer risks associated with mutations in moderate-penetrance genes are lower and different than those reported for high-penetrance gene mutations (such as mutations in BRCA1 and BRCA2, and those associated with Lynch syndrome). The extrapolation of guide-lines for the management of individuals with high-penetrance variants of cancer-susceptibility genes to the clinical care of patients with moderate-penetrance gene mutations could result in substantial harm. Thus, we provide a framework for clinical decision-making pending the development of a sufficient evidence base to document the clinical utility of the interventions for individuals with inherited moderate-penetrance gene mutations associated with an increased risk of cancer. C1 [Tung, Nadine] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, 330 Brookline Ave, Boston, MA 02215 USA. [Domchek, Susan M.; Nathanson, Katherine L.] Abramson Canc Ctr, 3400 Spruce St, Philadelphia, PA 19104 USA. [Domchek, Susan M.; Nathanson, Katherine L.] Univ Penn, Perelman Sch Med, Dept Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. [Stadler, Zsofia; Offit, Kenneth; Robson, Mark E.] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, 1275 York Ave, New York, NY 10065 USA. [Stadler, Zsofia; Offit, Kenneth; Robson, Mark E.] Weill Cornell Med Coll, 1300 York Ave, New York, NY 10065 USA. [Couch, Fergus] Mayo Clin, Dept Lab Med & Pathol, 200 First St South West, Rochester, MN 55905 USA. [Garber, Judy E.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. RP Robson, ME (reprint author), Mem Sloan Kettering Canc Ctr, Clin Genet Serv, 1275 York Ave, New York, NY 10065 USA.; Robson, ME (reprint author), Weill Cornell Med Coll, 1300 York Ave, New York, NY 10065 USA. EM robsonm@mskcc.org FU Myriad Genetics FX M.E.R. and J.G. receive research support from Myriad Genetics. The other authors declare no competing interests. NR 69 TC 5 Z9 5 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD SEP PY 2016 VL 13 IS 9 BP 581 EP 588 DI 10.1038/nrclinonc.2016.90 PG 8 WC Oncology SC Oncology GA DU4HS UT WOS:000382174300008 PM 27296296 ER PT J AU Outterson, K Rex, JH Jinks, T Jackson, P Hallinan, J Karp, S Hung, DT Franceschi, F Merkeley, T Houchens, C Dixon, DM Kurilla, MG Aurigemma, R Larsen, J AF Outterson, Kevin Rex, John H. Jinks, Tim Jackson, Peter Hallinan, John Karp, Steve Hung, Deborah T. Franceschi, Francois Merkeley, Tyler Houchens, Christopher Dixon, Dennis M. Kurilla, Michael G. Aurigemma, Rosemarie Larsen, Joseph TI Accelerating global innovation to address antibacterial resistance: introducing CARB-X SO NATURE REVIEWS DRUG DISCOVERY LA English DT Editorial Material AB A global response to the chronic shortfall in antibiotic innovation is urgently needed to combat antimicrobial resistance. Here, we introduce CARB-X, a new global public-private partnership that will invest more than US$350 million in the next 5 years to accelerate the progression of a diverse portfolio of innovative antibacterial products into clinical trials. C1 [Outterson, Kevin] Boston Univ, Sch Law, Boston, MA 02215 USA. [Outterson, Kevin] Chatham House, London SW1Y 4LE, England. [Rex, John H.] AstraZeneca, Waltham, MA 02451 USA. [Rex, John H.] Univ Texas Houston, Sch Med, Houston, TX 77225 USA. [Jinks, Tim] Wellcome Trust Res Labs, London NW1 2BE, England. [Jackson, Peter] AMR Ctr, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England. [Hallinan, John] Mass Bio, Cambridge, MA 02139 USA. [Karp, Steve] Calif Life Sci Inst, San Francisco, CA 94080 USA. [Hung, Deborah T.] Broad Inst, Cambridge, MA 02142 USA. [Hung, Deborah T.] Harvard Med Sch, Boston, MA 02215 USA. [Hung, Deborah T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Franceschi, Francois; Dixon, Dennis M.; Kurilla, Michael G.; Aurigemma, Rosemarie] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Merkeley, Tyler; Houchens, Christopher; Larsen, Joseph] Biomed Adv Res & Dev Author, Washington, DC 20201 USA. RP Outterson, K (reprint author), Boston Univ, Sch Law, Boston, MA 02215 USA.; Outterson, K (reprint author), Chatham House, London SW1Y 4LE, England. EM mko@bu.edu NR 4 TC 3 Z9 3 U1 5 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD SEP PY 2016 VL 15 IS 9 BP 589 EP 590 DI 10.1038/nrd.2016.155 PG 2 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA DU9JI UT WOS:000382532500001 PM 27469032 ER PT J AU Ayata, C AF Ayata, Cenk TI Treasure hunt in a minefield - exploring migraine with GWAS SO NATURE REVIEWS NEUROLOGY LA English DT Editorial Material ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; METAANALYSIS; AURA AB In a powerful display of international collaboration, a new genome-wide association study has mapped susceptibility loci for migraine on the basis of genetic data from 375,000 individuals. The study implicates several new loci in migraine - many of them suggestive of vascular pathophysiology - but the functional relevance of many now-detected risk alleles remains elusive. C1 [Ayata, Cenk] Massachusetts Gen Hosp, Dept Radiol, 149 13th St, Charlestown, MA 02129 USA. [Ayata, Cenk] Massachusetts Gen Hosp, Dept Neurol, 149 13th St, Charlestown, MA 02129 USA. [Ayata, Cenk] Harvard Med Sch, 149 13th St, Charlestown, MA 02129 USA. RP Ayata, C (reprint author), Massachusetts Gen Hosp, Dept Radiol, 149 13th St, Charlestown, MA 02129 USA.; Ayata, C (reprint author), Massachusetts Gen Hosp, Dept Neurol, 149 13th St, Charlestown, MA 02129 USA.; Ayata, C (reprint author), Harvard Med Sch, 149 13th St, Charlestown, MA 02129 USA. EM cayata@mgh.harvard.edu NR 10 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4758 EI 1759-4766 J9 NAT REV NEUROL JI Nat. Rev. Neurol. PD SEP PY 2016 VL 12 IS 9 BP 497 EP 498 DI 10.1038/nrneurol.2016.118 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA DU2BW UT WOS:000382017000002 PM 27539559 ER PT J AU Lampson, BL Gray, SW Cibas, ES Levy, BD Loscalzo, J AF Lampson, Benjamin L. Gray, Stacy W. Cibas, Edmund S. Levy, Bruce D. Loscalzo, Joseph TI Tip of the Tongue SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID LUNG-CANCER PATIENTS; CEREBROSPINAL-FLUID CYTOLOGY; LEPTOMENINGEAL METASTASES; ANTIRETROVIRAL THERAPY; HIV-INFECTION; SOLID TUMORS; CARCINOMATOSIS; ERA C1 [Lampson, Benjamin L.; Levy, Bruce D.; Loscalzo, Joseph] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Cibas, Edmund S.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Gray, Stacy W.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lampson, Benjamin L.; Gray, Stacy W.; Cibas, Edmund S.; Levy, Bruce D.; Loscalzo, Joseph] Harvard Med Sch, Boston, MA USA. RP Levy, BD (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM blevy@partners.org NR 16 TC 0 Z9 0 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 1 PY 2016 VL 375 IS 9 BP 880 EP 886 DI 10.1056/NEJMcps1414168 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA DU9HA UT WOS:000382526000013 PM 27579639 ER PT J AU Delichatsios, H Fasano, A AF Delichatsios, Helen Fasano, Alessio TI Case 14-2016: A Woman with a Thyroid Nodule and Psychosis REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Delichatsios, Helen; Fasano, Alessio] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Delichatsios, H (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 1 PY 2016 VL 375 IS 9 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DU9HA UT WOS:000382526000038 ER PT J AU Sacks, CA Malina, D Morrissey, S Campion, EW Hamel, MB Drazen, JM AF Sacks, Chana A. Malina, Debra Morrissey, Stephen Campion, Edward W. Hamel, Mary Beth Drazen, Jeffrey M. TI In the Wake of Orlando - Taking Steps against Gun Violence SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Sacks, Chana A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Sacks, CA (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 SEP 1 PY 2016 VL 375 IS 9 DI 10.1056/NEJMe1608173 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DU9HA UT WOS:000382526000016 PM 27376581 ER PT J AU Buswell, L Umuhizi, DG Hategekimana, V Muhayimana, C Kennell-Heiling, S AF Buswell, Lori Umuhizi, Denis Gilbert Hategekimana, Vedaste Muhayimana, Clemence Kennell-Heiling, Stephanie TI Voices of Hope From Rural Rwanda: Three Oncology Nurse Leaders Emerge SO ONCOLOGY NURSING FORUM LA English DT Editorial Material DE Africa; cancer care; nursing education; sustainability; low-income countries; twinning ID CANCER; BURDEN AB Committed, longitudinal, and respectful partnerships between low- and high-income countries can significantly strengthen cancer care capacity and oncology nursing. This article describes a partnership between the United States and Rwanda and the impact the program has had on three Rwandan oncology nurses. C1 [Buswell, Lori] Dana Farber Canc Inst, Nursing Serv, Boston, MA 02115 USA. [Buswell, Lori] Dana Farber Canc Inst, Clin Serv, Boston, MA 02115 USA. [Umuhizi, Denis Gilbert; Hategekimana, Vedaste; Muhayimana, Clemence] Hlth Butaro Hosp, Rwandan Minist, Burera, Rwanda. [Kennell-Heiling, Stephanie] Partners Hlth, Boston, MA USA. RP Buswell, L (reprint author), Dana Farber Canc Inst, Nursing Serv, Boston, MA 02115 USA.; Buswell, L (reprint author), Dana Farber Canc Inst, Clin Serv, Boston, MA 02115 USA. EM lori_buswell@dfci.harvard.edu NR 10 TC 0 Z9 0 U1 2 U2 2 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X EI 1538-0688 J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD SEP PY 2016 VL 43 IS 5 BP 661 EP 664 DI 10.1188/16.ONF.661-664 PG 4 WC Oncology; Nursing SC Oncology; Nursing GA DU6BL UT WOS:000382298000019 PM 27541559 ER PT J AU Albergotti, WG Davis, KS Abberbock, S Bauman, JE Ohr, J Clump, DA Heron, DE Duvvuri, U Kim, S Johnson, JT Ferris, RL AF Albergotti, William G. Davis, Kara S. Abberbock, Shira Bauman, Julie E. Ohr, James Clump, David A. Heron, Dwight E. Duvvuri, Umamaheswar Kim, Seungwon Johnson, Jonas T. Ferris, Robert L. TI Association of pretreatment body mass index and survival in human papillomavirus positive oropharyngeal squamous cell carcinoma SO ORAL ONCOLOGY LA English DT Article DE Body mass index; Survival; Oropharyngeal squamous cell carcinoma; Human papillomavirus ID NECK-CANCER; WEIGHT-LOSS; HEAD; OBESITY; IMPACT; OUTCOMES; CHEMORADIATION; CHEMORADIOTHERAPY; PREDICTORS; RADIATION AB Background: Pretreatment body mass index (BMI) > 25 kg/m(2) is a positive prognostic factor in patients with head and neck cancer. Previous studies have not been adequately stratified by human papilloma virus (HPV) status or subsite. Our objective is to determine prognostic significance of pretreatment BMI on overall survival in HPV+ oropharyngeal squamous cell carcinoma (OPSCC). Methods: This is a retrospective review of patients with HPV+ OPSCC treated between 8/1/2006 and 8/31/2014. Patients were stratified by BMI status (>/< 25 kg/m(2)). Univariate and multivariate analyses of survival were performed. Results: 300 patients met our inclusion/exclusion criteria. Patients with a BMI > 25 kg/m(2) had a longer overall survival (HR = 0.49, P = 0.01) as well as a longer disease-specific survival (HR = 0.43, P = 0.02). Overall survival remained significantly associated with high BMI on multivariate analysis (HR = 0.54, P = 0.04). Conclusions: Pre-treatment normal or underweight BMI status is associated with worse overall survival in HPV+ OPSCC. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Albergotti, William G.; Davis, Kara S.; Heron, Dwight E.; Duvvuri, Umamaheswar; Kim, Seungwon; Johnson, Jonas T.; Ferris, Robert L.] Univ Pittsburgh, Med Ctr, Dept Otolaryngol Head & Neck Surg, Pittsburgh, PA USA. [Abberbock, Shira] Univ Pittsburgh, Inst Canc, Biostat Facil, Pittsburgh, PA USA. [Bauman, Julie E.; Ohr, James] Univ Pittsburgh, Dept Med, Div Med Oncol, Pittsburgh, PA USA. [Clump, David A.; Heron, Dwight E.] Univ Pittsburgh, Inst Canc, Dept Radiat Oncol, Pittsburgh, PA USA. [Duvvuri, Umamaheswar] Vet Affairs Pittsburgh Hlth Syst, Pittsburgh, PA USA. RP Albergotti, WG (reprint author), Univ Pittsburgh, Med Ctr, Dept Otolaryngol, Inst Eye & Ear, 200 Lothrop St,Suite 500, Pittsburgh, PA 15213 USA. EM albergottiwg@upmc.edu FU University of Pittsburgh Cancer Institute Biostatistics Facility [P30CA047904]; Career Development Award from Department of Veterans Affairs; BLRD; PNC Foundation FX Contract grant sponsor: This project was conducted using the University of Pittsburgh Cancer Institute Biostatistics Facility that is supported in part by award P30CA047904.; This works was supported in part by a Career Development Award from the Department of Veterans Affairs, BLR&D and a Grant from the PNC Foundation (U.D.). NR 29 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 EI 1879-0593 J9 ORAL ONCOL JI Oral Oncol. PD SEP PY 2016 VL 60 BP 55 EP 60 DI 10.1016/j.oraloncology.2016.07.003 PG 6 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA DU5DP UT WOS:000382232700009 PM 27531873 ER PT J AU Lin, Y Mallen-St Clair, J Wang, GY Luo, J Palma-Diaz, F Lai, C Elashoff, DA Sharma, S Dubinett, SM St John, M AF Lin, Yuan Mallen-St Clair, Jon Wang, Guanyu Luo, Jie Palma-Diaz, Fernando Lai, Chi Elashoff, David A. Sharma, Sherven Dubinett, Steven M. St John, Maie TI p38 MAPK mediates epithelial-mesenchymal transition by regulating p38IP and Snail in head and neck squamous cell carcinoma SO ORAL ONCOLOGY LA English DT Article DE EMT; p38; p38IP; Snail; HNSCC ID TRANSCRIPTION FACTOR SNAIL; E-CADHERIN; P38-INTERACTING PROTEIN; KAPPA-B; EXPRESSION; CANCER; CYCLOOXYGENASE-2; PROGRESSION; REPRESSOR; RECEPTOR AB Background: In the present study, we investigated the role of p38-p38IP signaling in the inflammation-induced promotion of epithelial-to-mesenchymal transition (EMT) in Head and Neck Squamous Cell Carcinoma (HNSCC). Methods: Quantitative RT-PCR, western blot analysis, spheroid modeling and immunohistochemical staining of human HNSCC tissue sections were used. Results: p38 inhibitor treated and p38 shRNA HNSCC cell lines demonstrate a significant upregulation in E-cadherin mRNA and a decrease in the mRNA expression of Snail. p38 binds to and stabilizes p38IP, a subunit of histone SPT3-TAF9-GCN5 acetyltransferase (STAGA), resulting in enhanced transcription of Snail. p38 shRNA HNSCC cell lines show a less invasive phenotype in a spheroid model. In clinical HNSCC samples, p38 interacting protein (p38IP) is significantly increased compared to adjacent normal tissue. An inverse relationship between p38, p38IP and E-cadherin is demonstrated. Conclusions: Herein we provide the first report that p38-p38IP is required for the Snail-induced E-cadherin down-regulation and cell invasion in HNSCC. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Lin, Yuan; Wang, Guanyu; Luo, Jie; Sharma, Sherven; Dubinett, Steven M.] Jonsson Comprehens Canc Ctr, Lung Canc Res Program, Los Angeles, CA 90034 USA. [Lin, Yuan; Wang, Guanyu; Luo, Jie; Sharma, Sherven; Dubinett, Steven M.] Dept Med, Div Pulm & Crit Care Med, Los Angeles, CA USA. [Mallen-St Clair, Jon; St John, Maie] Dept Head & Neck Surg, Los Angeles, CA USA. [Palma-Diaz, Fernando; Lai, Chi; Sharma, Sherven; Dubinett, Steven M.] Dept Pathol & Lab Med, Los Angeles, CA USA. [Sharma, Sherven; Dubinett, Steven M.; St John, Maie] Jonsson Comprehens Canc Ctr, Los Angeles, CA 90034 USA. [Elashoff, David A.; St John, Maie] UCLA Head & Neck Canc Program, Los Angeles, CA USA. [Sharma, Sherven; Dubinett, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biostat, Los Angeles, CA 90095 USA. [Sharma, Sherven; Dubinett, Steven M.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP St John, M (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, 37-131 CHS,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM mstjohn@mednet.ucla.edu FU American Academy of Otolaryngology-American Head & Neck Society Surgeon Scientist Career Development Award; Tobacco-Related Disease Research Program of the University of California; STOP Cancer Foundation; Jonsson Cancer Center, NIDCR [DE021193]; VA Merit Review Research Funds; NCI [RO1 CA111851] FX This study was supported by the American Academy of Otolaryngology-American Head & Neck Society Surgeon Scientist Career Development Award (MSJ), the Tobacco-Related Disease Research Program of the University of California (MSJ), the STOP Cancer Foundation (MSJ), The Jonsson Cancer Center, NIDCR DE021193 (MSJ), the VA Merit Review Research Funds (SD), and NCI RO1 CA111851 (SD). 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 1368-8375 EI 1879-0593 J9 ORAL ONCOL JI Oral Oncol. PD SEP PY 2016 VL 60 BP 81 EP 89 DI 10.1016/j.oraloncology.2016.06.010 PG 9 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA DU5DP UT WOS:000382232700013 PM 27531877 ER PT J AU Abram, TJ Floriano, PN Christodoulides, N James, R Kerr, AR Thornhill, MH Redding, SW Vigneswaran, N Speight, PM Vick, J Murdoch, C Freeman, C Hegarty, AM D'Apice, K Phelan, JA Corby, PM Khouly, I Bouquot, J Demian, NM Weinstock, YE Rowan, S Yeh, CK McGuff, HS Miller, FR Gaur, S Karthikeyan, K Taylor, L Le, C Nguyen, M Talavera, H Raja, R Wong, J McDevitt, JT AF Abram, Timothy J. Floriano, Pierre N. Christodoulides, Nicolaos James, Robert Kerr, A. Ross Thornhill, Martin H. Redding, Spencer W. Vigneswaran, Nadarajah Speight, Paul M. Vick, Julie Murdoch, Craig Freeman, Christine Hegarty, Anne M. D'Apice, Katy Phelan, Joan A. Corby, Patricia M. Khouly, Ismael Bouquot, Jerry Demian, Nagi M. Weinstock, Y. Etan Rowan, Stephanie Yeh, Chih-Ko McGuff, H. Stan Miller, Frank R. Gaur, Surabhi Karthikeyan, Kailash Taylor, Leander Le, Cathy Nguyen, Michael Talavera, Humberto Raja, Rameez Wong, Jorge McDevitt, John T. TI 'Cytology-on-a-chip' based sensors for monitoring of potentially malignant oral lesions SO ORAL ONCOLOGY LA English DT Article DE Cytology; Oral cancer; Oral epithelial dysplasia; Microfluidic; High content analysis; Machine learning; Random forest; LASSO ID DYSPLASIA CLASSIFICATION; EXFOLIATIVE CYTOLOGY; SYSTEM; CANCER; ENUMERATION; PLATFORM AB Despite significant advances in surgical procedures and treatment, long-term prognosis for patients with oral cancer remains poor, with survival rates among the lowest of major cancers. Better methods are desperately needed to identify potential malignancies early when treatments are more effective. Objective: To develop robust classification models from cytology-on-a-chip measurements that mirror diagnostic performance of gold standard approach involving tissue biopsy. Materials and methods: Measurements were recorded from 714 prospectively recruited patients with suspicious lesions across 6 diagnostic categories (each confirmed by tissue biopsy -histopathology) using a powerful new 'cytology-on-a-chip' approach capable of executing high content analysis at a single cell level. Over 200 cellular features related to biomarker expression, nuclear parameters and cellular morphology were recorded per cell. By cataloging an average of 2000 cells per patient, these efforts resulted in nearly 13 million indexed objects. Results: Binary "low-risk"/"high-risk" models yielded AUC values of 0.88 and 0.84 for training and validation models, respectively, with an accompanying difference in sensitivity + specificity of 6.2%. In terms of accuracy, this model accurately predicted the correct diagnosis approximately 70% of the time, compared to the 69% initial agreement rate of the pool of expert pathologists. Key parameters identified in these models included cell circularity, Ki67 and EGFR expression, nuclear-cytoplasmic ratio, nuclear area, and cell area. Conclusions: This chip-based approach yields objective data that can be leveraged for diagnosis and management of patients with PMOL as well as uncovering new molecular-level insights behind cytological differences across the OED spectrum. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Abram, Timothy J.; Christodoulides, Nicolaos; Gaur, Surabhi; Karthikeyan, Kailash; Taylor, Leander; Le, Cathy; Nguyen, Michael; Talavera, Humberto; Raja, Rameez; Wong, Jorge; McDevitt, John T.] Rice Univ, Dept Bioengn, Houston, TX USA. [Floriano, Pierre N.] NeoTherma Oncol, Houston, TX USA. [James, Robert; Vick, Julie] Rho Inc, Chapel Hill, NC USA. [Kerr, A. Ross; Phelan, Joan A.] NYU, Coll Dent, Dept Oral & Maxillofacial Pathol, Radiol & Med, New York, NY USA. [Thornhill, Martin H.; Murdoch, Craig; Freeman, Christine] Univ Sheffield, Sch Clin Dent, Acad Unit Oral & Maxillofacial Med & Surg, Sheffield, S Yorkshire, England. [Redding, Spencer W.; Rowan, Stephanie; Yeh, Chih-Ko] Univ Texas Hlth Sci Ctr San Antonio, Dept Comprehens Dent, San Antonio, TX 78229 USA. [Redding, Spencer W.; Rowan, Stephanie; Yeh, Chih-Ko; Miller, Frank R.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Vigneswaran, Nadarajah; Bouquot, Jerry] Univ Texas Hlth Sci Ctr San Antonio, Dept Diagnost & Biomed Sci, San Antonio, TX 78229 USA. [Speight, Paul M.] Univ Sheffield, Sch Clin Dent, Acad Unit Oral & Maxillofacial Pathol, Sheffield, S Yorkshire, England. [Hegarty, Anne M.; D'Apice, Katy] Sheffield Teaching Hosp Natl Hlth Serv Fdn Trust, Charles Clifford Dent Hosp, Unit Oral Med, Sheffield, S Yorkshire, England. [Corby, Patricia M.] NYU, Sch Med, Dept Populat Hlth & Radiat Oncol, New York, NY USA. [Khouly, Ismael] NYU, Coll Dent, Bluestone Ctr Clin Res, New York, NY USA. [Demian, Nagi M.] Univ Texas Hlth Sci Ctr Houston, Dept Oral & Maxillofacial Surg, Houston, TX 77030 USA. [Weinstock, Y. Etan] Univ Texas Hlth Sci Ctr Houston, Dept Otolaryngol Head & Neck Surg, Houston, TX 77030 USA. [Yeh, Chih-Ko] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX USA. [McGuff, H. Stan] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Miller, Frank R.] Univ Texas Hlth Sci Ctr San Antonio, Dept Otolaryngol Head & Neck Surg, San Antonio, TX 78229 USA. [McDevitt, John T.] Rice Univ, Dept Chem, Houston, TX USA. [McDevitt, John T.] NYU, Dept Biomat, New York, NY USA. RP McDevitt, JT (reprint author), NYU, Bioengn Inst, Dept Biomat, 433 First Ave,Room 820, New York, NY 10010 USA. EM mcdevitt@nyu.edu OI McDevitt, John T/0000-0001-8789-9351; Murdoch, Craig/0000-0001-9724-122X FU National Institutes of Health (NIH) through the National Institute of Dental and Craniofacial Research [1RC2DE020785-01, 5RC2DE020785-02, 3RC2DE020785-02S1, 3RC2DE020785-02S2]; Renaissance Health Service Corporation; Delta Dental of Michigan FX Funding for this work was provided by the National Institutes of Health (NIH) through the National Institute of Dental and Craniofacial Research (Award Number 1RC2DE020785-01, 5RC2DE020785-02, 3RC2DE020785-02S1, 3RC2DE020785-02S2). The content of this paper is solely the responsibility of the authors and does not necessarily represent or reflect the official views of the NIH or the US government. Segments of this work are supported by Renaissance Health Service Corporation and Delta Dental of Michigan. NR 36 TC 0 Z9 0 U1 6 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 EI 1879-0593 J9 ORAL ONCOL JI Oral Oncol. PD SEP PY 2016 VL 60 BP 103 EP 111 DI 10.1016/j.oraloncology.2016.07.002 PG 9 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA DU5DP UT WOS:000382232700016 PM 27531880 ER PT J AU Meneses, SRF Goode, AP Nelson, AE Lin, J Jordan, JM Allen, KD Bennell, KL Lohmander, LS Fernandes, L Hochberg, MC Underwood, M Conaghan, PG Liu, S McAlindon, TE Golightly, YM Hunter, DJ AF Meneses, S. R. F. Goode, A. P. Nelson, A. E. Lin, J. Jordan, J. M. Allen, K. D. Bennell, K. L. Lohmander, L. S. Fernandes, L. Hochberg, M. C. Underwood, M. Conaghan, P. G. Liu, S. McAlindon, T. E. Golightly, Y. M. Hunter, D. J. TI Clinical algorithms to aid osteoarthritis guideline dissemination SO OSTEOARTHRITIS AND CARTILAGE LA English DT Review DE Osteoarthritis; Management; Guidelines ID EVIDENCE-BASED RECOMMENDATIONS; EULAR-STANDING-COMMITTEE; KNEE OSTEOARTHRITIS; TASK-FORCE; HIP OSTEOARTHRITIS; MANAGEMENT; PAIN; CONSENSUS; QUALITY; ESCISIT AB Background: Numerous scientific organisations have developed evidence-based recommendations aiming to optimise the management of osteoarthritis (OA). Uptake, however, has been suboptimal. The purpose of this exercise was to harmonize the recent recommendations and develop a user-friendly treatment algorithm to facilitate translation of evidence into practice. Methods: We updated a previous systematic review on clinical practice guidelines (CPGs) for OA management. The guidelines were assessed using the Appraisal of Guidelines for Research and Evaluation for quality and the standards for developing trustworthy CPGs as established by the National Academy of Medicine (NAM). Four case scenarios and algorithms were developed by consensus of a multidisciplinary panel. Results: Sixteen guidelines were included in the systematic review. Most recommendations were directed toward physicians and allied health professionals, and most had multi-disciplinary input. Analysis for trustworthiness suggests that many guidelines still present a lack of transparency. A treatment algorithm was developed for each case scenario advised by recommendations from guidelines and based on panel consensus. Conclusion: Strategies to facilitate the implementation of guidelines in clinical practice are necessary. The algorithms proposed are examples of how to apply recommendations in the clinical context, helping the clinician to visualise the patient flow and timing of different treatment modalities. (C) 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 [Meneses, S. R. F.] Univ Sao Paulo, Sch Med, Dept Physiotherapy Occupat Therapy & Speech Thera, Sao Paulo, Brazil. [Meneses, S. R. F.; Liu, S.; Hunter, D. J.] Univ Sydney, Royal North Shore Hosp, Dept Rheumatol, Sydney, NSW, Australia. [Meneses, S. R. F.; Liu, S.; Hunter, D. J.] Univ Sydney, Inst Bone & Joint Res, Kolling Inst, Sydney, NSW, Australia. [Goode, A. P.] Duke Univ, Dept Orthoped Surg, Durham, NC USA. [Nelson, A. E.; Jordan, J. M.; Allen, K. D.; Golightly, Y. M.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Nelson, A. E.; Jordan, J. M.; Allen, K. D.; Golightly, Y. M.] Univ N Carolina, Thurston Arthrit Res Ctr, Chapel Hill, NC USA. [Lin, J.] Peking Univ, Peoples Hosp, Inst Bone & Joint, Beijing, Peoples R China. [Jordan, J. M.] Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Jordan, J. M.] Univ N Carolina, Dept Orthopaed, Chapel Hill, NC USA. [Allen, K. D.] US Dept Vet Affairs, Med Ctr, Hlth Serv Res & Dev Serv, Durham, NC USA. [Bennell, K. L.] Univ Melbourne, Ctr Hlth Exercise & Sports Med, Dept Physiotherapy, Melbourne, Vic 3010, Australia. [Lohmander, L. S.] Lund Univ, Dept Clin Sci, Orthopaed, S-22100 Lund, Sweden. [Fernandes, L.] Odense Univ Hosp, Dept Rehabil, Odense C, Denmark. [Hochberg, M. C.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Hochberg, M. C.] Vet Affairs Maryland Hlth Care Syst, Med Care Clin Ctr, Baltimore, MD USA. [Underwood, M.] Warwick Med Sch, Warwick Clin Trials Unit, Warwick, England. [Conaghan, P. G.] Univ Leeds, Leeds Inst Rheumat & Musculoskeletal Med, Leeds, W Yorkshire, England. [Conaghan, P. G.] NIHR Leeds Musculoskeletal Biomed Res Unit, Leeds, W Yorkshire, England. [McAlindon, T. E.] Tufts Med Ctr, Dept Rheumatol, Boston, MA USA. [Golightly, Y. M.] Univ N Carolina, Injury Prevent Res Ctr, Chapel Hill, NC USA. RP Meneses, SRF (reprint author), Royal North Shore Hosp, Dept Rheumatol, Clin Adm, 7C,Level 7,Reserve Rd, St Leonards, NSW 2065, Australia. EM sarah.meneses@usp.br RI Underwood, Martin/D-6364-2015 OI Meneses, Sarah/0000-0003-2587-1649; Underwood, Martin/0000-0002-0309-1708 NR 36 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD SEP PY 2016 VL 24 IS 9 BP 1487 EP 1499 DI 10.1016/j.joca.2016.04.004 PG 13 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA DU5PY UT WOS:000382265000001 PM 27095418 ER PT J AU Fujita, T Shin, JE Cunnane, M Fujita, K Henein, S Psaltis, D Stankovic, KM AF Fujita, Takeshi Shin, Jung Eun Cunnane, MaryBeth Fujita, Kyoko Henein, Simon Psaltis, Demetri Stankovic, Konstantina M. TI Surgical Anatomy of the Human Round Window Region: Implication for Cochlear Endoscopy Through the External Auditory Canal SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Endoscopy; Human temporal bones; Round window; Sensorineural hearing loss ID DRUG-DELIVERY; COMPUTED-TOMOGRAPHY; IMPLANT; NERVE; DIAGNOSIS; SURGERY; TYMPANI; NICHE AB Objective: To enable development of an endoscope for cellular-level optical imaging of the inner ear. Study Design: A prospective study of 50 cadaveric human temporal bones to define detailed surgical anatomy of the round window (RW) region and the range of angles necessary to reach the RW membrane perpendicularly via the external ear canal. Main Outcome Measure: The transcanal angle to the RW membrane was surgically measured in 3D intact specimens, and correlated with the angle calculated from temporal bone computed tomography (CT) scans of the same specimens obtained before and after measurements in situ. Results: Surgically measured transcanal angles to the RW membrane correlated well with the radiographically measured angles. The angles ranged from 110 to 127 degrees, with the median of 115 degrees and the middle 50% ranging from 109 to 119 degrees. Four temporal bones were excluded because of pathology. The opening of the RW niche was located posteriorly in six bones (13%), inferiorly in 18 bones (39%), and postero-inferiorly in 22 bones (48%). The angles were not statistically different among the three orientations of the RW niche. Conclusions: By correlating measurement from cadaveric human temporal bones and their CT scans, we defined key parameters necessary for designing an endoscope for intracochlear imaging using a minimally invasive approach through the external auditory canal. The excellent correlation between the measurement on the CT scan and the actual shape of the probe that was able to reach the RW through the ear canal enables selection of the probe using the CT data. C1 [Fujita, Takeshi; Shin, Jung Eun; Fujita, Kyoko; Stankovic, Konstantina M.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Eaton Peabody Labs, 243 Charles St, Boston, MA 02114 USA. [Fujita, Takeshi; Shin, Jung Eun; Fujita, Kyoko; Stankovic, Konstantina M.] Harvard Med Sch, Dept Otol & Laryngol, Boston, MA USA. [Cunnane, MaryBeth] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Shin, Jung Eun] Konkuk Univ, Med Ctr, Dept Otorhinolaryngol Head & Neck Surg, Seoul, South Korea. [Henein, Simon; Psaltis, Demetri] Ecole Polytech Fed Lausanne, Sch Engn, Lausanne, Switzerland. RP Stankovic, KM (reprint author), 243 Charles St, Boston, MA 02114 USA. EM konstantina_stankovic@meei.harvard.edu FU Bertarelli Foundation; Wyss Center for Bio and Neuroengineering; Lauer Tinnitus Research Center; Nancy Sayles Day Foundation FX Authors Takeshi Fujita and Jung Eun Shin contributed equally. This project was supported by the Bertarelli Foundation (DP, KMS), Wyss Center for Bio and Neuroengineering (DP, KMS), Lauer Tinnitus Research Center (KMS), and Nancy Sayles Day Foundation (KMS). NR 25 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD SEP PY 2016 VL 37 IS 8 BP 1189 EP 1194 DI 10.1097/MAO.0000000000001074 PG 6 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA DU5FE UT WOS:000382236800044 PM 27228017 ER PT J AU Miller, MS Allen, P Brentnall, TA Goggins, M Hruban, RH Petersen, GM Rao, CV Whitcomb, DC Brand, RE Chari, ST Klein, AP Lubman, DM Rhim, AD Simeone, DM Wolpin, BM Umar, A Srivastava, S Steele, VE Rinaudo, JAS AF Miller, Mark Steven Allen, Peter Brentnall, Teresa A. Goggins, Michael Hruban, Ralph H. Petersen, Gloria M. Rao, Chinthalapally V. Whitcomb, David C. Brand, Randall E. Chari, Suresh T. Klein, Alison P. Lubman, David M. Rhim, Andrew D. Simeone, Diane M. Wolpin, Brian M. Umar, Asad Srivastava, Sudhir Steele, Vernon E. Rinaudo, Jo Ann S. TI Pancreatic Cancer Chemoprevention Translational Workshop Meeting Report SO PANCREAS LA English DT Article DE pancreatic cancer; chemoprevention; biomarkers; early detection; high-risk patient cohorts; clinical trials ID PAPILLARY MUCINOUS NEOPLASMS; ENGINEERED MOUSE MODELS; INTRAEPITHELIAL NEOPLASIA; DUCTAL ADENOCARCINOMA; HIGH-RISK; HEREDITARY PANCREATITIS; INVASIVE-CARCINOMA; DELAY PROGRESSION; WHOLE-EXOME; STEM-CELLS AB Pancreatic cancer is the fourth leading cause of cancer related deaths in the United Stateswith a 5-year survival rate of less than 10%. The Division of Cancer Prevention of the National Cancer Institute sponsored the Pancreatic Cancer Chemoprevention Translational Workshop on September 10 to 11, 2015. The goal of the workshop was to obtain information regarding the current state of the science and future scientific areas that should be prioritized for pancreatic cancer prevention research, including early detection and intervention for high-risk precancerous lesions. The workshop addressed the molecular/genetic landscape of pancreatic cancer and precursor lesions, high-risk populations and criteria to identify a high-risk population for potential chemoprevention trials, identification of chemopreventative/immunopreventative agents, and use of potential biomarkers and imaging for assessing short-term efficacy of a preventative agent. The field of chemoprevention for pancreatic cancer is emerging, and this workshop was organized to begin to address these important issues and promotemulti-institutional efforts in this area. The meeting participants recommended the development of an National Cancer Institute working group to coordinate efforts, provide a framework, and identify opportunities for chemoprevention of pancreatic cancer. C1 [Miller, Mark Steven; Umar, Asad; Srivastava, Sudhir; Steele, Vernon E.; Rinaudo, Jo Ann S.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Allen, Peter] Mem Sloan Kettering Canc Ctr, Dept Surg, David M Rubenstein Ctr Pancreat Canc Res, 1275 York Ave, New York, NY 10021 USA. [Brentnall, Teresa A.] Univ Washington, Div Gastroenterol, Seattle, WA 98195 USA. [Goggins, Michael; Hruban, Ralph H.] Johns Hopkins Univ, Dept Pathol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD USA. [Petersen, Gloria M.] Mayo Clin, Dept Epidemiol, Hlth Sci Res, Rochester, MN USA. [Rao, Chinthalapally V.] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Ctr Canc Prevent, Oklahoma City, OK USA. [Rao, Chinthalapally V.] Univ Oklahoma, Hlth Sci Ctr, Drug Dev Program, PC Stephenson Oklahoma Canc Ctr, Oklahoma City, OK USA. [Whitcomb, David C.; Brand, Randall E.] Univ Pittsburgh, Med Ctr, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA. [Chari, Suresh T.] Mayo Clin, Dept Med, Rochester, MN USA. [Klein, Alison P.] Johns Hopkins Univ, Dept Oncol, Natl Familial Pancreas Tumor Registry, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD USA. [Lubman, David M.] Univ Michigan, Dept Surg, Pancreat Canc Ctr, Ann Arbor, MI 48109 USA. [Rhim, Andrew D.] Univ Michigan, Dept Internal Med, Pancreat Canc Ctr, Ann Arbor, MI 48109 USA. [Simeone, Diane M.] Univ Michigan, Dept Surg, Translat Oncol Program, Pancreat Canc Ctr, Ann Arbor, MI 48109 USA. [Wolpin, Brian M.] Harvard Med Sch, Dana Farber Canc Inst, Pancreat Tumor Ctr, Dept Med, Cambridge, MA USA. RP Miller, MS (reprint author), Canc Prevent Div, Chemoprevent Agent Dev Res Grp, 9609 Med Ctr Dr,MSC9787,Room 5E546, Bethesda, MD 20892 USA. EM mark.miller5@nih.gov FU Division of Cancer Prevention, National Cancer Institute; Office of Disease Prevention, National Institutes of Health FX The Pancreatic Cancer Chemoprevention Translational Workshop was jointly funded by the Division of Cancer Prevention, National Cancer Institute and the Office of Disease Prevention, National Institutes of Health. NR 108 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 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD SEP PY 2016 VL 45 IS 8 BP 1080 EP 1091 DI 10.1097/MPA.0000000000000705 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DU6JZ UT WOS:000382322200005 PM 27518363 ER PT J AU Chinman, M McCarthy, S Mitchell-Miland, C Daniels, K Youk, A Edelen, M AF Chinman, Matthew McCarthy, Sharon Mitchell-Miland, Chantele Daniels, Karin Youk, Ada Edelen, Maria TI Early Stages of Development of a Peer Specialist Fidelity Measure SO PSYCHIATRIC REHABILITATION JOURNAL LA English DT Article DE peer specialists; serious mental illness; fidelity ID SEVERE MENTAL-ILLNESS; HEALTH-SERVICES; SUPPORT; IMPLEMENTATION; METAANALYSIS; INDIVIDUALS; PROVIDERS; MODEL AB Objective: Research on peer specialists (individuals with serious mental illness supporting others with serious mental illness in clinical and other settings) has not yet included the measurement of fidelity. Without measuring fidelity, it is unclear whether the absence of impact in some studies is attributable to ineffective peer specialist services or because the services were not true to the intended role. This article describes the initial development of a peer specialist fidelity measure for 2 content areas: services provided by peer specialists and factors that either support or hamper the performance of those services. Method: A literature search identified 40 domains; an expert panel narrowed the number of domains and helped generate and then review survey items to operationalize those domains. Twelve peer specialists, individuals with whom they work, and their supervisors participated in a pilot test and cognitive interviews regarding item content. Results: Peer specialists tended to rate themselves as having engaged in various peer service activities more than did the supervisors and individuals with whom they work. A subset of items tapping peer specialist services "core" to the role regardless of setting had higher ratings. Participants stated the measure was clear, appropriate, and could be useful in improving performance. Conclusions and Implications for Practice: Although preliminary, findings were consistent with organizational research on performance ratings of supervisors and employees made in the workplace. Several changes in survey content and administration were identified. With continued work, the measure could crystalize the role of peer specialists and aid in research and clinical administration. C1 [Chinman, Matthew; McCarthy, Sharon; Mitchell-Miland, Chantele; Daniels, Karin; Youk, Ada] VA Pittsburgh Healthcare Syst, Res Off Bldg,151R,Univ Dr C, Pittsburgh, PA 15240 USA. [Edelen, Maria] RAND Corp, Boston, MA USA. RP Chinman, M (reprint author), VA Pittsburgh Healthcare Syst, Res Off Bldg,151R,Univ Dr C, Pittsburgh, PA 15240 USA. EM chinman@rand.org FU Department of Veterans Affairs FX Financial support for the article was provided by the Department of Veterans Affairs. The contents do not represent the views of the Department of Veterans Affairs or the U.S. government. We thank the peer specialists, veterans, and supervisors who participated in the pilot test and cognitive interviews. We would also like to thank Daniel O'Brien-Mazza for providing support for this project. NR 33 TC 2 Z9 2 U1 2 U2 2 PU CENTER PSYCHIATRIC REHABILITATION PI BOSTON PA BOSTON UNIV, 930 COMMONWEALTH AVE, BOSTON, MA 02215 USA SN 1095-158X EI 1559-3126 J9 PSYCHIATR REHABIL J JI Psychiatr. Rehabil. J. PD SEP PY 2016 VL 39 IS 3 SI SI BP 256 EP 265 DI 10.1037/prj0000209 PG 10 WC Psychiatry; Rehabilitation SC Psychiatry; Rehabilitation GA DV4LL UT WOS:000382897000009 PM 27618462 ER PT J AU Bowers, ME Flory, JD Abu-Amara, D Marmara, CD Yehuda, R AF Bowers, Mallory E. Flory, Janine D. Abu-Amara, Duna Marmara, Charles D. Yehuda, Rachel TI Association between estradiol and posttraumatic stress disorder in men and women military veterans SO PSYCHONEUROENDOCRINOLOGY LA English DT Meeting Abstract CT 46th Annual Conference of the International-Society-of-Psychoneuroendocrinology - Personalized Medicine in the Neurosciences - Genetics, Imaging, and Hormones CY SEP 08-11, 2016 CL Miami, FL SP Int Soc Psychoneuroendocrinol C1 [Bowers, Mallory E.; Flory, Janine D.; Yehuda, Rachel] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Bowers, Mallory E.; Flory, Janine D.; Yehuda, Rachel] James J Peters Bronx Vet Affairs Med Ctr, Bronx, NY USA. [Abu-Amara, Duna; Marmara, Charles D.] NYU, Langone Sch Med, New York, NY 10003 USA. EM mallory.bowers@mssm.edu NR 0 TC 0 Z9 0 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD SEP PY 2016 VL 71 SU S BP 4 EP 5 DI 10.1016/j.psyneuen.2016.07.020 PG 2 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA DV0FX UT WOS:000382594500010 ER PT J AU Daskalakis, NP AF Daskalakis, Nikolaos P. TI Epigenetic regulation in association with treatment response in PTSD SO PSYCHONEUROENDOCRINOLOGY LA English DT Meeting Abstract CT 46th Annual Conference of the International-Society-of-Psychoneuroendocrinology - Personalized Medicine in the Neurosciences - Genetics, Imaging, and Hormones CY SEP 08-11, 2016 CL Miami, FL SP Int Soc Psychoneuroendocrinol C1 [Daskalakis, Nikolaos P.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Daskalakis, Nikolaos P.] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. EM nikolaos.daskalakis@mssm.edu NR 0 TC 0 Z9 0 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD SEP PY 2016 VL 71 SU S BP 10 EP 11 DI 10.1016/j.psyneuen.2016.07.037 PG 2 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA DV0FX UT WOS:000382594500027 ER PT J AU Daskalakis, NP AF Daskalakis, Nikolaos P. TI Integrative systems biology approach to identify novel glucocorticoid-based biomarkers and treatment targets for PTSD SO PSYCHONEUROENDOCRINOLOGY LA English DT Meeting Abstract CT 46th Annual Conference of the International-Society-of-Psychoneuroendocrinology - Personalized Medicine in the Neurosciences - Genetics, Imaging, and Hormones CY SEP 08-11, 2016 CL Miami, FL SP Int Soc Psychoneuroendocrinol C1 [Daskalakis, Nikolaos P.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Daskalakis, Nikolaos P.] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. EM nikolaos.daskalakis@mssm.edu NR 0 TC 0 Z9 0 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD SEP PY 2016 VL 71 SU S BP 71 EP 71 DI 10.1016/j.psyneuen.2016.07.185 PG 1 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA DV0FX UT WOS:000382594500173 ER PT J AU Brody, AL Hubert, R Mamoun, MS Enoki, R Garcia, LY Abraham, P Young, P Mandelkern, MA AF Brody, Arthur L. Hubert, Robert Mamoun, Michael S. Enoki, Ryutaro Garcia, Lizette Y. Abraham, Paul Young, Paulina Mandelkern, Mark A. TI Nicotinic acetylcholine receptor availability in cigarette smokers: effect of heavy caffeine or marijuana use SO PSYCHOPHARMACOLOGY LA English DT Article DE Positron emission tomography; Tobacco dependence; Nicotinic acetylcholine receptors; Caffeine; Marijuana; Cannabis; Brain imaging; Neuroimaging; Human; Cigarette smoking ID LATERAL PREFRONTAL CORTEX; TOBACCO SMOKING; HUMAN-BRAIN; COMMUNITY SAMPLE; MENTAL-ILLNESS; UNITED-STATES; UP-REGULATION; CANNABIS USE; CESSATION; BINDING AB Upregulation of alpha(4)beta(2)* nicotinic acetylcholine receptors (nAChRs) is one of the most well-established effects of chronic cigarette smoking on the brain. Prior research by our group gave a preliminary indication that cigarette smokers with concomitant use of caffeine or marijuana have altered nAChR availability. We sought to determine if smokers with heavy caffeine or marijuana use have different levels of alpha(4)beta(2)* nAChRs than smokers without these drug usages. One hundred and one positron emission tomography (PET) scans, using the radiotracer 2-FA (a ligand for beta(2)*-containing nAChRs), were obtained from four groups of males: non-smokers without heavy caffeine or marijuana use, smokers without heavy caffeine or marijuana use, smokers with heavy caffeine use (mean four coffee cups per day), and smokers with heavy marijuana use (mean 22 days of use per month). Total distribution volume (Vt/fp) was determined for the brainstem, prefrontal cortex, and thalamus, as a measure of nAChR availability. A significant between-group effect was found, resulting from the heavy caffeine and marijuana groups having the highest Vt/fp values (especially for the brainstem and prefrontal cortex), followed by smokers without such use, followed by non-smokers. Direct between-group comparisons revealed significant differences for Vt/fp values between the smoker groups with and without heavy caffeine or marijuana use. Smokers with heavy caffeine or marijuana use have higher alpha(4)beta(2)* nAChR availability than smokers without these drug usages. These findings are likely due to increased nicotine exposure but could also be due to an interaction on a cellular/molecular level. C1 [Brody, Arthur L.; Hubert, Robert; Mamoun, Michael S.; Enoki, Ryutaro; Garcia, Lizette Y.; Abraham, Paul; Young, Paulina; Mandelkern, Mark A.] VA Greater Los Angeles Healthcare Syst, Dept Psychiat, Los Angeles, CA 90073 USA. [Brody, Arthur L.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90095 USA. [Mandelkern, Mark A.] Univ Calif Irvine, Dept Phys, Irvine, CA 92717 USA. [Brody, Arthur L.] 300 UCLA Med Plaza,Suite 2200, Los Angeles, CA 90095 USA. RP Brody, AL (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Psychiat, Los Angeles, CA 90073 USA.; Brody, AL (reprint author), Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90095 USA.; Brody, AL (reprint author), 300 UCLA Med Plaza,Suite 2200, Los Angeles, CA 90095 USA. EM abrody@ucla.edu FU National Institute on Drug Abuse [R01 DA20872]; Department of Veterans Affairs, Office of Research and Development (CSR&D Merit Review Award) [I01 CX000412]; Tobacco-Related Disease Research Program [23XT-0002] FX This work was supported by the National Institute on Drug Abuse (R01 DA20872), the Department of Veterans Affairs, Office of Research and Development (CSR&D Merit Review Award I01 CX000412), and the Tobacco-Related Disease Research Program (#23XT-0002) to ALB. The authors report no biomedical financial interests or potential conflicts of interest. NR 65 TC 0 Z9 0 U1 8 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2016 VL 233 IS 17 BP 3249 EP 3257 DI 10.1007/s00213-016-4367-x PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DT6HY UT WOS:000381586500016 PM 27370018 ER PT J AU Fricchione, J Greenberg, MS Spring, J Wood, N Mueller-Pfeiffer, C Milad, MR Pitman, RK Orr, SP AF Fricchione, Jon Greenberg, Mark S. Spring, Justin Wood, Nellie Mueller-Pfeiffer, Christoph Milad, Mohammed R. Pitman, Roger K. Orr, Scott P. TI Delayed extinction fails to reduce skin conductance reactivity to fear-conditioned stimuli SO PSYCHOPHYSIOLOGY LA English DT Article DE Fear conditioning; Reconsolidation; Skin conductance; Extinction; Posttraumatic stress disorder (PTSD) ID POSTTRAUMATIC-STRESS-DISORDER; MEMORY RECONSOLIDATION; PUBLICATION RECOMMENDATIONS; ELECTRODERMAL MEASUREMENTS; PTSD SYMPTOMS; AMYGDALA; PROPRANOLOL; HUMANS; CONSOLIDATION; ATTENUATION AB A brief 10-min time delay between an initial and subsequent exposure to extinction trials has been found to impair memory reconsolidation in fear-conditioned rodents and humans, providing a potential means to reduce fearfulness in anxiety disorders and posttraumatic stress disorder (PTSD). The present study used videos of biologically prepared, conditioned stimuli (tarantulas) to test the efficacy of delayed extinction in blocking reconsolidation of conditioned fear in healthy young adults. Strong differential conditioning, measured by skin conductance, was observed among a screened subset of participants during acquisition. However, the delayed-extinction intervention failed to reduce reactivity to the conditioned stimulus paired with the extinction delay. These results are partially consistent with other recent, mixed findings and point to a need for testing other candidate interventions designed to interfere with the reconsolidation process. C1 [Fricchione, Jon; Greenberg, Mark S.; Spring, Justin; Wood, Nellie; Milad, Mohammed R.; Pitman, Roger K.; Orr, Scott P.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Fricchione, Jon; Greenberg, Mark S.; Spring, Justin; Wood, Nellie; Milad, Mohammed R.; Pitman, Roger K.; Orr, Scott P.] Harvard Med Sch, Boston, MA USA. [Mueller-Pfeiffer, Christoph] Univ Zurich, Dept Psychiat & Psychotherapy, Univ Zurich Hosp, Zurich, Switzerland. RP Orr, SP (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 120 Second Ave, Charlestown, MA 02129 USA. EM scott_orr@hms.harvard.edu FU United States Army Medical Research and Materiel Command [W81XWH-11-2-0092 {DM102744}] FX This work was supported by a grant from the United States Army Medical Research and Materiel Command (award number W81XWH-11-2-0092 {DM102744}). 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 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2016 VL 53 IS 9 BP 1343 EP 1351 DI 10.1111/psyp.12687 PG 9 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA DV2AR UT WOS:000382723700005 PM 27314560 ER PT J AU Pineles, SL Blumenthal, TD Curreri, AJ Nillni, YI Putnam, KM Resick, PA Rasmusson, AM Orr, SP AF Pineles, Suzanne L. Blumenthal, Terry D. Curreri, Andrew J. Nillni, Yael I. Putnam, Katherine M. Resick, Patricia A. Rasmusson, Ann M. Orr, Scott P. TI Prepulse inhibition deficits in women with PTSD SO PSYCHOPHYSIOLOGY LA English DT Article DE Posttraumatic stress disorder; Prepulse inhibition; PTSD; Menstrual cycle; Startle ID POSTTRAUMATIC-STRESS-DISORDER; ACOUSTIC STARTLE; VIETNAM VETERANS; MENSTRUAL-CYCLE; COMBAT VETERANS; BASE-LINE; SMOKING; PSYCHOPHYSIOLOGY; SCHIZOPHRENIA; DEPRESSION AB Prepulse inhibition (PPI) is an automatic and preattentive process, whereby a weak stimulus attenuates responding to a sudden and intense startle stimulus. PPI is a measure of sensorimotor filtering, which is conceptualized as a mechanism that facilitates processing of an initial stimulus and is protective from interruption by a later response. Impaired PPI has been found in (a) healthy women during the luteal phase of the menstrual cycle, and (b) individuals with types of psychopathology characterized by difficulty suppressing and filtering sensory, motor, or cognitive information. In the current study, 47 trauma-exposed women with or without posttraumatic stress disorder (PTSD) completed a PPI session during two different phases of the menstrual cycle: the early follicular phase, when estradiol and progesterone are both low, and the midluteal phase, when estradiol and progesterone are both high. Startle stimuli were 100 dB white noise bursts presented for 50 ms, and prepulses were 70 dB white noise bursts presented for 20 ms that preceded the startle stimuli by 120 ms. Women with PTSD showed deficits in PPI relative to the healthy trauma-exposed participants. Menstrual phase had no effect on PPI. These results provide empirical support for individuals with PTSD having difficulty with sensorimotor filtering. The potential utility of PPI as a Research Domain Criteria (RDoC) phenotype is discussed. C1 [Pineles, Suzanne L.; Curreri, Andrew J.; Nillni, Yael I.; Rasmusson, Ann M.] VA Boston Healthcare Syst, Womens Hlth Sci Div, Natl Ctr PTSD, Boston, MA USA. [Pineles, Suzanne L.; Nillni, Yael I.; Rasmusson, Ann M.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Blumenthal, Terry D.] Wake Forest Univ, Dept Psychol, Winston Salem, NC 27109 USA. [Putnam, Katherine M.] VA Cent Western Massachusetts Healthcare Syst, Dept Psychol, Leeds, MA USA. [Resick, Patricia A.] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. [Orr, Scott P.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Orr, Scott P.] Harvard Med Sch, Boston, MA USA. RP Pineles, SL (reprint author), VA Boston Healthcare Syst 116B 3, 150 South Huntington Ave, Boston, MA 02130 USA. EM Suzanne.Pineles@va.gov FU VA Career Development Award (PI: SLP) from the Clinical Sciences R&D Service, Department of Veterans Affairs FX Support for this work was provided by a VA Career Development Award (PI: SLP) from the Clinical Sciences R&D Service, Department of Veterans Affairs. NR 48 TC 0 Z9 0 U1 13 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2016 VL 53 IS 9 BP 1377 EP 1385 DI 10.1111/psyp.12679 PG 9 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA DV2AR UT WOS:000382723700008 PM 27237725 ER PT J AU Familoni, BO Gregor, KL Dodson, TS Krzywicki, AT Lowery, BN Orr, SP Suvak, MK Rasmusson, AM AF Familoni, Babajide O. Gregor, Kristin L. Dodson, Thomas S. Krzywicki, Alan T. Lowery, Bobby N., Jr. Orr, Scott P. Suvak, Michael K. Rasmusson, Ann M. TI Sweat pore reactivity as a surrogate measure of sympathetic nervous system activity in trauma-exposed individuals with and without posttraumatic stress disorder SO PSYCHOPHYSIOLOGY LA English DT Article DE Trauma; PTSD; Thermal imaging; Skin conductance; Sweat pore; Sympathetic nervous system; Loud noise test ID PHYSIOLOGICAL-RESPONSES; NICOTINE DEPENDENCE; LOUD TONES; VIETNAM VETERANS; STARTLING TONES; GLAND ACTIVITY; SMOKING; PTSD; QUESTIONNAIRE; NONCONTACT AB Stress analysis by FLIR (forward-looking infrared) evaluation (SAFE) has been demonstrated to monitor sweat pore activation (SPA) as a novel surrogate measure of sympathetic nervous system (SNS) activity in a normal population. SNS responses to a series of 15 1-s, 82 dB, white noise bursts were measured by skin conductance (SC) and SAFE monitoring of SPA on the fingers (FiP) and face (FaP) in 10 participants with posttraumatic stress disorder (PTSD) and 16 trauma-exposed participants without PTSD (M-age=48.92 +/- 12.00 years; 26.9% female). Within participants, SC and FiP responses across trials were strongly correlated (r=.92, p<.001). Correlations between SC and FaP (r=.76, p=.001) and between FiP and FaP (r=.47, p=.005) were smaller. The habituation of SNS responses across the 15 trials was substantial (SC: d=-2.97; FiP: d=-2.34; FaP: d=-1.02). There was a strong correlation between habituation effects for SC and FiP (r=.76, p<.001), but not for SC and FaP (r=.15, p=.45) or FiP and FaP (r=.29, p=.16). Participants with PTSD showed larger SNS responses to the first loud noise than those without PTSD. PTSD reexperiencing symptoms assessed by the PTSD Checklist on the day of testing were associated with the SNS responses to the first loud noise measured by SC (d=1.19) and FiP (d=.99), but not FaP (d=.10). This study confirms convergence of SAFE and SC as valid measures of SNS activity. SAFE FiP and SC responses were highly predictive of self-rated PTSD reexperiencing symptoms. SAFE may offer an attractive alternative for applications in PTSD and similar populations. C1 [Familoni, Babajide O.; Krzywicki, Alan T.] US Army RDECOM CERDEC, Night Vis & Elect Sensors Directorate, Div Modeling & Simulat, Ft Belvoir, VA 22060 USA. [Gregor, Kristin L.; Dodson, Thomas S.; Rasmusson, Ann M.] VA Boston Healthcare Syst, Womens Hlth Sci Div, Natl Ctr PTSD, Boston, MA USA. [Gregor, Kristin L.; Rasmusson, Ann M.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Lowery, Bobby N., Jr.] EOIR Technol Inc, Fredericksburg, VA USA. [Orr, Scott P.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Orr, Scott P.] Harvard Med Sch, Boston, MA USA. [Suvak, Michael K.] Suffolk Univ, Dept Psychol, Boston, MA 02114 USA. RP Familoni, BO (reprint author), US Army RDECOM CERDEC, Night Vis & Elect Sensors Directorate, Ft Belvoir, VA 22060 USA. EM info@nvl.army.mil FU U.S. Army Medical Research and Materiel Command [MIPR2BDATM2043, MIPR2BDATM2046]; VA Boston Healthcare System, National Center for PTSD, Department of Veterans Affairs (Women's Health Science Division; Night Vision and Electronic Sensors Directorate FX This document is cleared for public release by the Night Vision & Electronic Sensors Directorate, Fort Belvoir, VA. This research was supported in part by U.S. Army Medical Research and Materiel Command award number MIPR2BDATM2043 and MIPR2BDATM2046; VA Boston Healthcare System, National Center for PTSD, Department of Veterans Affairs (Women's Health Science Division); and the Night Vision and Electronic Sensors Directorate. Portions of the findings have been previously presented in poster formats at Military Health System Research Symposium and International Society for Traumatic Stress Studies (ISTSS) conferences. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. NR 44 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2016 VL 53 IS 9 BP 1417 EP 1428 DI 10.1111/psyp.12681 PG 12 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA DV2AR UT WOS:000382723700012 PM 27286885 ER PT J AU Sampson, S Smith, J Vincent, H Aufiero, D Zall, M Botto-van-Bemden, A AF Sampson, Steven Smith, Jay Vincent, Hunter Aufiero, Danielle Zall, Mona Botto-van-Bemden, Angie TI Intra-articular bone marrow concentrate injection protocol: short-term efficacy in osteoarthritis SO REGENERATIVE MEDICINE LA English DT Article DE bone marrow concentrate; orthobiologics; osteoarthritis; platelet-rich plasma ID PLATELET-RICH PLASMA; MESENCHYMAL STEM-CELLS; KNEE OSTEOARTHRITIS; CARTILAGE REPAIR; DOUBLE-BLIND; PAIN; BIOPSY; MICROFRACTURE; REGENERATION; ASPIRATION AB Aim: Evaluate intra-articular injection of bone marrow concentrate (BMC), followed by platelet-rich plasma (PRP) injection at 8 weeks follow-up in moderate/severe osteoarthritis. Design: Single center, retrospective Case Series (n = 125). Methods: Bone marrow was aspirated/concentrated using a standardized technique. Patients received a single intra-articular injection of BMC, with follow-up injection of PRP at 8 weeks. Results: Median absolute pain reduction in all joints was five points (71.4%) on visual analog scale. Median patient satisfaction was 9.0/10, while 91.7% indicated that they would repeat the procedure and 94% said that they would recommend the procedure to a friend. Conclusion: Intra-articular injection of BMC, followed by a PRP injection, can provide short-term benefits in moderate-to-severe osteoarthritis. C1 [Sampson, Steven; Aufiero, Danielle] Univ Calif Los Angeles, David Geffen Sch Med, 10833 Le Conte Ave, Los Angeles, CA 90095 USA. [Sampson, Steven; Aufiero, Danielle] Western Univ Hlth Sci, 309 E 2nd St, Pomona, CA 91766 USA. [Sampson, Steven; Aufiero, Danielle] Touro Coll Osteopath Med, 230 W 125th St 1, New York, NY 10027 USA. [Sampson, Steven; Aufiero, Danielle] Orthobiol Inst TOBI, Woodland Hills, CA 91365 USA. [Smith, Jay] Mayo Clin, Coll Med, Ctr Sports Med, Dept PM&R, 200 1st St SW, Rochester, MN 55905 USA. [Smith, Jay] Mayo Clin, Coll Med, Ctr Sports Med, Dept Radiol, 200 1st St SW, Rochester, MN 55905 USA. [Smith, Jay] Mayo Clin, Coll Med, Ctr Sports Med, Dept Anat, 200 1st St SW, Rochester, MN 55905 USA. [Vincent, Hunter] Univ Calif Davis, Med Ctr, Dept Phys Med & Rehabil, 4860 Y St, Sacramento, CA 95817 USA. [Zall, Mona] Greater Los Angeles VA Med Ctr, Dept Phys Med & Rehabil, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. [Botto-van-Bemden, Angie] Musculoskeletal Res Int, Clin Res Experts, 1004 Avocado Isle, Ft Lauderdale, FL 33315 USA. RP Vincent, H (reprint author), Univ Calif Davis, Med Ctr, Dept Phys Med & Rehabil, 4860 Y St, Sacramento, CA 95817 USA. EM huntervincent35@gmail.com NR 45 TC 0 Z9 0 U1 1 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0751 EI 1746-076X J9 REGEN MED JI Regen. Med. PD SEP PY 2016 VL 11 IS 6 BP 511 EP 520 DI 10.2217/rme-2016-0081 PG 10 WC Cell & Tissue Engineering; Engineering, Biomedical SC Cell Biology; Engineering GA DU6EA UT WOS:000382305600004 PM 27527808 ER PT J AU Pastore, LM Manichaikul, A Wang, XQ Finkelstein, JS AF Pastore, Lisa M. Manichaikul, Ani Wang, Xin Q. Finkelstein, Joel S. TI FMR1 CGG Repeats: Reference Levels and Race-Ethnic Variation in Women With Normal Fertility (Study of Women's Health Across the Nation) SO REPRODUCTIVE SCIENCES LA English DT Article DE race-ethnicity; genetic variation; FMR1; diminished ovarian reserve; women; primary ovarian insufficiency; reference population ID FRAGILE-X-SYNDROME; PRIMARY OVARIAN INSUFFICIENCY; COST-EFFECTIVENESS ANALYSIS; MENTAL-RETARDATION; AFRICAN-AMERICANS; BLOOD SPOTS; POPULATION; CARRIER; PREVALENCE; ALLELES AB FMR1 premutation carriers (55-199 CGG repeats), and potentially women with high normal (35-44) or low normal (<28) CGG repeats, are at risk of premature ovarian aging. The scarcity of population data on CGG repeats <45 CGG, and variation in race-ethnicity, makes it difficult to determine true associations. DNA was analyzed for FMR1 CGG repeat lengths from 803 women (386 caucasians, 219 African Americans, 102 Japanese, and 96 Chinese) from the US-based Study of Women's Health Across the Nation (SWAN). Participants had 1 menses in the 3 months before enrollment, 1 pregnancy, no history of infertility or hormonal therapy, and menopause 46 years. Statistical analyses used Fisher exact tests. Among these women with normal reproductive histories, significant FMR1 repeat length differences were found across race-ethnicity for both the longer (P = .0002) and the shorter (P < .0001) alleles. The trinucleotide length variance was greater for non-Asian than Asian women (P < .0001), despite identical median values. Our data indicate that short allele lengths <25 CGG on one or both alleles are more common in non-Asian than Asian women. We confirm the minor allele in the 35 to 39 CGG range among Asians as reported previously. Only 2 (0.3%) premutation carriers were identified. These data demonstrate that FMR1 distributions do vary by race-ethnicity, even within the normal range. This study indicates the need to control for race-ethnicity in FMR1 ovarian aging research and provides race-ethnic population data for females separated by allele. C1 [Pastore, Lisa M.] SUNY Stony Brook, Dept Obstet Gynecol & Reprod Med, Stony Brook, NY 11794 USA. [Manichaikul, Ani] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Manichaikul, Ani; Wang, Xin Q.] Univ Virginia, Div Biostat & Epidemiol, Dept Publ Hlth Sci, Charlottesville, VA USA. [Finkelstein, Joel S.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Pastore, LM (reprint author), SUNY Stony Brook, Dept Obstet Gynecol & Reprod Med, Stony Brook, NY 11794 USA. EM pastorestudies@gmail.com FU National Center for Child Health and Human Development at the National Institutes of Health (NIH) [R01HD068440]; National Institutes of Health (NIH), DHHS, 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]; NIH [U01AG017719]; National Center for Research Resources; National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI [UL1 RR024131] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Center for Child Health and Human Development at the National Institutes of Health (NIH, Grant R01HD068440 to L.M.P.). The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), DHHS, 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, U01AG012495). The SWAN Repository is funded by NIH grant U01AG017719. This publication was also supported in part by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number UL1 RR024131. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, ORWH, or the NIH. NR 41 TC 3 Z9 3 U1 5 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD SEP PY 2016 VL 23 IS 9 BP 1225 EP 1233 DI 10.1177/1933719116632927 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA DU9NH UT WOS:000382544000013 PM 26905421 ER PT J AU Walsh, BK Smallwood, CD Rettig, JS Thompson, JE Kacmarek, RM Arnold, JH AF Walsh, Brian K. Smallwood, Craig D. Rettig, Jordan S. Thompson, John E. Kacmarek, Robert M. Arnold, John H. TI Categorization in Mechanically Ventilated Pediatric Subjects: A Proposed Method to Improve Quality SO RESPIRATORY CARE LA English DT Article DE computer decision support; mechanical ventilation; ventilator-induced lung injury; quality; protocols; evidence-based practice; data ID LOWER TIDAL VOLUMES; ACUTE LUNG INJURY; RESPIRATORY-DISTRESS-SYNDROME; RANDOMIZED CONTROLLED-TRIAL; INTENSIVE-CARE-UNIT; WEANING PROTOCOL; PROTECTIVE VENTILATION; CLINICAL-OUTCOMES; EXTUBATION; CHILDREN AB BACKGROUND: Thousands of children require mechanical ventilation each year. Although mechanical ventilation is lifesaving, it is also associated with adverse events if not properly managed. The systematic implementation of evidence-based practice through the use of guidelines and protocols has been shown to mitigate risk, yet variation in care remains prevalent. Advances in health-care technology provided the ability to stream data about mechanical ventilation and therapeutic response. Through these advances, a computer system was developed to enable the coupling of physiologic and ventilation data for real-time interpretation. Our aim was to assess the feasibility and utility of a newly developed patient categorization and scoring system to objectively measure compliance with standards of care. METHODS: We retrospectively categorized the ventilation and oxygenation statuses of subjects within our pediatric ICU utilizing 15 rules-based algorithms. Targets were predetermined based on generally accepted practices. All patient categories were calculated and presented as a percent score (0-100%) of acceptable ventilation, acceptable oxygenation, barotrauma-free, and volutrauma-free states. RESULTS: Two hundred twenty-two subjects were identified and analyzed encompassing 1,578 d of mechanical ventilation. Median age was 3 y, median ideal body weight was 14.7 kg, and 63% were male. The median acceptable ventilation score was 84.6%, and the median acceptable oxygenation score was 70.1% (100% being maximally acceptable). Potential for ventilator-induced lung injury was broken into 2 components: barotrauma and volutrauma. There was very little potential for barotrauma, with a median barotrauma-free state of 100%. Median potential for a volutrauma-free state was 56.1%. CONCLUSIONS: We demonstrate the first patient categorization system utilizing a coordinated data-banking system and analytics to determine patient status and a surveillance of mechanical ventilation quality. Further research is needed to determine whether interventions such as visual display of variance from goal and patient categorization summaries can improve outcomes. C1 [Walsh, Brian K.; Smallwood, Craig D.; Rettig, Jordan S.; Thompson, John E.; Arnold, John H.] Harvard Med Sch, Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Div Crit Care Med, Boston, MA USA. [Walsh, Brian K.; Smallwood, Craig D.; Rettig, Jordan S.; Thompson, John E.; Arnold, John H.] Harvard Med Sch, Pediat Anesthesia, Boston, MA USA. [Smallwood, Craig D.] Boston Childrens Hosp, Div Crit Care Med, Dept Anesthesiol Perioperat & Pain Med, 300 Longwood Ave,Bader 634, Boston, MA 02115 USA. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. RP Walsh, BK (reprint author), Boston Childrens Hosp, Div Crit Care Med, Dept Anesthesiol Perioperat & Pain Med, 300 Longwood Ave,Bader 634, Boston, MA 02115 USA. EM briankwalsh@me.com FU Draeger Medical; GE Healthcare FX Dr Walsh, Mr Smallwood, Dr Rettig, Mr Thompson, and Dr Arnold are on staff at Boston Children's Hospital, which owns the intellectual property and receives royalties on the sale of the T3 system. Dr Rettig, Mr Walsh, Mr Smallwood, and Dr Arnold have intellectual property surrounding the computer-aided mechanical ventilation project and have received research support from Draeger Medical. Mr Walsh has received research support from GE Healthcare. Dr Kacmarek discloses relationships with Covidien, OrangeMed, and Venner Medical. NR 25 TC 3 Z9 3 U1 1 U2 1 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD SEP PY 2016 VL 61 IS 9 BP 1168 EP 1178 DI 10.4187/respcare.04723 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DU7GR UT WOS:000382382400006 PM 27303050 ER PT J AU Mirelea-Cabodevila, E Kacmarek, RM AF Mirelea-Cabodevila, Eduardo Kacmarek, Robert M. TI We Agree!! SO RESPIRATORY CARE LA English DT Letter C1 [Mirelea-Cabodevila, Eduardo] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. [Kacmarek, Robert M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesiol, Dept Resp Care, Boston, MA USA. RP Mirelea-Cabodevila, E (reprint author), Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD SEP PY 2016 VL 61 IS 9 BP 1280 EP 1281 DI 10.4187/respcare.05141 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DU7GR UT WOS:000382382400023 PM 27587874 ER PT J AU Branson, RD Kacmarek, RM AF Branson, Richard D. Kacmarek, Robert M. TI Intermittent Mandatory Ventilation: What's in a Name? SO RESPIRATORY CARE LA English DT Letter ID MECHANICAL VENTILATION; WEANING PATIENTS C1 [Branson, Richard D.] Univ Cincinnati, Dept Surg, 231 Bethesda Ave, Cincinnati, OH 45267 USA. [Kacmarek, Robert M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesiol, Dept Resp Care, Boston, MA USA. RP Branson, RD (reprint author), Univ Cincinnati, Dept Surg, 231 Bethesda Ave, Cincinnati, OH 45267 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD SEP PY 2016 VL 61 IS 9 BP 1282 EP 1283 DI 10.4187/respcare.05155 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DU7GR UT WOS:000382382400025 PM 27587876 ER PT J AU Zitek, EM Jordan, AH AF Zitek, Emily M. Jordan, Alexander H. TI Narcissism Predicts Support for Hierarchy (At Least When Narcissists Think They Can Rise to the Top) SO SOCIAL PSYCHOLOGICAL AND PERSONALITY SCIENCE LA English DT Article DE narcissism; social hierarchy; social rank; self-enhancement ID PERSONALITY-INVENTORY; SOCIAL HIERARCHY; SELF-ESTEEM; DOMINANCE; PERFORMANCE; TENDENCIES; EMERGENCE; ATTITUDES; VALIDITY; LEADER AB Five studies tested the relationship between narcissism and support for hierarchy. Narcissism was associated with endorsing group-based hierarchy, income inequality, and hierarchy in business (Studies 1a-1b) and with liking organizations with a hierarchical structure (Studies 2a-2b). Analyses suggested that more narcissistic participants' preference for a hierarchy may have been due at least partly to their current high standing in that hierarchy (Studies 1a-1b) or their expectation that they will rise in rank (Studies 2a-2b). When participants learned about an organization where it was possible or impossible to rise in rank, there was a positive relationship between narcissism and support for hierarchy if it was possible to rise in rank, whereas the same relationship was negative if it was not possible to rise in rank (Study 3). These studies provide evidence consistent with the idea that narcissistic individuals prefer hierarchies because they are or think they will be on the top. C1 [Zitek, Emily M.] Cornell Univ, Sch Ind & Labor Relat, Org Behav, Ithaca, NY 14853 USA. [Jordan, Alexander H.] VA Boston Healthcare Syst, Boston, MA USA. [Jordan, Alexander H.] Boston Univ, Sch Med, Psychiat, Boston, MA 02118 USA. RP Zitek, EM (reprint author), Cornell Univ, Sch Ind & Labor Relat, Ithaca, NY 14853 USA. EM emily.zitek@cornell.edu OI Zitek, Emily/0000-0002-0535-5260 NR 41 TC 0 Z9 0 U1 18 U2 18 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1948-5506 EI 1948-5514 J9 SOC PSYCHOL PERS SCI JI Soc. Psychol. Personal Sci. PD SEP PY 2016 VL 7 IS 7 BP 707 EP 716 DI 10.1177/1948550616649241 PG 10 WC Psychology, Social SC Psychology GA DV1UE UT WOS:000382705900011 ER PT J AU Bierer, BE Li, R Seltzer, J Sleeper, LA Frank, E Knirsch, C Aldinger, CE Levine, RJ Massaro, J Shah, A Barnes, M Snapinn, S Wittes, J AF Bierer, Barbara E. Li, Rebecca Seltzer, Jonathan Sleeper, Lynn A. Frank, Elizabeth Knirsch, Charles Aldinger, Carmen E. Levine, Robert J. Massaro, Joe Shah, Amish Barnes, Mark Snapinn, Steven Wittes, Janet TI Responsibilities of Data Monitoring Committees: Consensus Recommendations SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE safety data; clinical trials; oversight of clinical trials; human subject safety; multi-site clinical trials; Data Monitoring Committees AB Background: A data monitoring committee (DMC) has special responsibilities for protecting the safety of clinical trial participants. Few guidance documents are available that address the operations and mechanics of establishing, serving on, or reporting to a DMC. This article provides a practical guide to sponsors, institutions, and individuals responsible for, or serving on, a DMC. Methods: A workgroup of professionals from academia and not-for-profit and commercial organizations that included investigators, statisticians, patient advocates, and ethicists met to define the essential elements of planning, coordinating, and populating a DMC. All members of the group have formed, served on, advised, or worked with DMCs. Results: The group outlined the objectives and mechanics of running a DMC, including operational and practical considerations, membership characteristics, roles, members' liability, and indemnification. Further, it delineated the roles and responsibilities of each DMC member. Conclusions: The group recommended practices for each phase of the DMC process from inception through execution of a clinical trial, with appropriate considerations for confidentiality. The group's practical guidance should assist in comprehensive oversight of appropriate clinical trials and should help DMC members execute their obligations with greater assurance. C1 [Bierer, Barbara E.; Li, Rebecca] Brigham & Womens Hosp, Dept Med, Div Global Hlth Equ, 75 Francis St, Boston, MA 02115 USA. [Bierer, Barbara E.; Li, Rebecca] Harvard Med Sch, Boston, MA USA. [Bierer, Barbara E.; Li, Rebecca; Aldinger, Carmen E.; Barnes, Mark] Brigham & Womens Hosp, Multireg Clin Trials Ctr, 14 Story St,4th Floor, Cambridge, MA 02138 USA. [Bierer, Barbara E.; Li, Rebecca; Aldinger, Carmen E.; Barnes, Mark] Harvard, 14 Story St,4th Floor, Cambridge, MA 02138 USA. [Seltzer, Jonathan] ACI Clin, Bala Cynwyd, PA USA. [Sleeper, Lynn A.] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [Frank, Elizabeth] Dana Farber Canc Inst, Boston, MA 02115 USA. [Knirsch, Charles] Pfizer, New York, NY USA. [Levine, Robert J.] Yale Univ, New Haven, CT USA. [Massaro, Joe] Boston Univ, Boston, MA 02215 USA. [Shah, Amish; Barnes, Mark] Ropes & Gray, Boston, MA USA. [Snapinn, Steven] Amgen Inc, Thousand Oaks, CA USA. [Wittes, Janet] Stat Collaborat Inc, Washington, DC USA. RP Li, R (reprint author), Brigham & Womens Hosp, Multireg Clin Trials Ctr, 14 Story St,4th Floor, Cambridge, MA 02138 USA.; Li, R (reprint author), Harvard, 14 Story St,4th Floor, Cambridge, MA 02138 USA. EM rli@bwh.harvard.edu NR 8 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 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD SEP PY 2016 VL 50 IS 5 BP 648 EP 659 DI 10.1177/2168479016646812 PG 12 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA DV1VU UT WOS:000382711000017 ER PT J AU Lubberts, B Pereira, NRP Kabrhel, C Kuter, DJ DiGiovanni, CW AF Lubberts, Bart Pereira, Nuno Rui Paulino Kabrhel, Christopher Kuter, David J. DiGiovanni, Christopher W. TI What is the effect of venous thromboembolism and related complications on patient reported health-related quality of life? SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Quality of life; meta-analysis; chronic thromboembolic pulmonary hypertension; post-thrombotic syndrome; venous thromboembolism ID DEEP-VEIN THROMBOSIS; CATHETER-DIRECTED THROMBOLYSIS; INTERVENTIONALLY TREATED PATIENTS; SUBMASSIVE PULMONARY-EMBOLISM; PEMB-QOL QUESTIONNAIRE; POSTTHROMBOTIC SYNDROME; PHYSICAL-ACTIVITY; RANDOMIZED-TRIAL; FOLLOW-UP; HYPERTENSION AB We conducted a meta-analysis of the literature to 1) assess the health related quality of life for patients with a minimum follow-up of one year after an episode of pulmonary embolism (PE) or deep-vein thrombosis (DVT), and 2) to assess the HRQOL for patients who develop chronic thromboembolic pulmonary hypertension (CTEPH) and post thrombotic syndrome (PTS). PubMed, EMBASE, and the Cochrane Library were searched from inception to March 30, 2016. Data were pooled using random-effects meta-analysis, and heterogeneity was assessed with 12 and Tau tests. SF-12, SF-36, and VEINES-QOL were evaluated with pooled standardised mean difference (SMD) and 95 % confidence intervals (CI). Fourteen studies were included for meta analysis. In patients who sustain a PE, physical health becomes impaired (p<0.001, 2 studies) but mental health appears to remain similar to population norms (p=0.069, 2 studies) after at least one year. Patients who develop CTEPH report worse physical (p<0.001,1 study) and mental health (p=0.009, 1 study). In patients who suffer from a DVT, physical health (p=0.19, 9 studies), mental health (p=0.67, 9 studies), and disease specific quality of life (p=0.61, 8 studies) remain similar to population norms after at least one year. Patients who develop PTS, however, report worse physical health (p<0.001, 7 studies), mental health (p<0.001, 7 studies), and disease specific quality of life (p<0.001,10 studies). These data can be used to educate patients during the shared decision making process that increasingly governs medical care today. Level of Evidence: II. C1 [Lubberts, Bart; DiGiovanni, Christopher W.] Harvard Med Sch, Massachusetts Gen Hosp, Orthopaed Foot & Ankle Serv, 55 Fruit St, Boston, MA 02114 USA. [Pereira, Nuno Rui Paulino] Harvard Med Sch, Massachusetts Gen Hosp, Orthopaed Spine & Oncol Serv, Boston, MA USA. [Kabrhel, Christopher] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA USA. [Kuter, David J.] Harvard Med Sch, Massachusetts Gen Hosp, Clin Hematol, Boston, MA USA. RP Lubberts, B (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Orthopaed Foot & Ankle Serv, 55 Fruit St, Boston, MA 02114 USA. EM blubberts@partners.org FU Extremity Medical Inc; Wright Medical Technologies; Elsevier; Lippincott Williams Wilkins; Saunders; Gallagher FX Dr. C. Kabrhel reported receiving expert testimony fees from Fain and Anderson, Gallagher, and Evelius and Jones. Dr. C.W. DiGiovanni reported receiving personal fees from Extremity Medical Inc, Wright Medical Technologies, Elsevier, Lippincott Williams Wilkins, and Saunders. No other disclosures were reported. NR 83 TC 0 Z9 0 U1 3 U2 3 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD SEP PY 2016 VL 116 IS 3 BP 417 EP 431 DI 10.1160/TH16-02-0152 PG 15 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DV0HQ UT WOS:000382599000006 PM 27362694 ER PT J AU Garcia, BJ Loxton, AG Dolganov, GM Van, TT Davis, JL de Jong, BC Voskuil, MI Leach, SM Schoolnik, GK Walzl, G Strong, M Walter, ND AF Garcia, Benjamin J. Loxton, Andre G. Dolganov, Gregory M. Van, Tran T. Davis, J. Lucian de Jong, Bouke C. Voskuil, Martin I. Leach, Sonia M. Schoolnik, Gary K. Walzl, Gerhard Strong, Michael Walter, Nicholas D. TI Sputum is a surrogate for bronchoalveolar lavage for monitoring Mycobacterium tuberculosis transcriptional profiles in TB patients SO TUBERCULOSIS LA English DT Article DE Mycobacterium tuberculosis/genetics; Mycobacterium tuberculosis/physiology; Sputum/microbiology; Bronchoalveolar lavage/microbiology; Computational biology/methods; * Gene expression profiling; Tuberculosis; pulmonary/epidemiology/*microbiology ID GENE-EXPRESSION; ADAPTATION; PERSISTENCE AB Pathogen-targeted transcriptional profiling in human sputum may elucidate the physiologic state of Mycobacterium tuberculosis (M. tuberculosis) during infection and treatment. However, whether M. tuberculosis transcription in sputum recapitulates transcription in the lung is uncertain. We therefore compared M. tuberculosis transcription in human sputum and bronchoalveolar lavage (BAL) samples from 11 HIV-negative South African patients with pulmonary tuberculosis. We additionally compared these clinical samples with in vitro log phase aerobic growth and hypoxic non-replicating persistence (NRP-2). Of 2179 M. tuberculosis transcripts assayed in sputum and BAL via multiplex RT-PCR, 194 (8.9%) had a p-value <0.05, but none were significant after correction for multiple testing. Categorical enrichment analysis indicated that expression of the hypoxia-responsive DosR regulon was higher in BAL than in sputum. M. tuberculosis transcription in BAL and sputum was distinct from both aerobic growth and NRP-2, with a range of 396-1020 transcripts significantly differentially expressed after multiple testing correction. Collectively, our results indicate that M. tuberculosis transcription in sputum approximates M. tuberculosis transcription in the lung. Minor differences between M. tuberculosis transcription in BAL and sputum suggested lower oxygen concentrations or higher nitric oxide concentrations in BAL. M. tuber-culosis-targeted transcriptional profiling of sputa may be a powerful tool for understanding M. tuberculosis pathogenesis and monitoring treatment responses in vivo. Published by Elsevier Ltd. C1 [Garcia, Benjamin J.; Leach, Sonia M.; Strong, Michael; Walter, Nicholas D.] Natl Jewish Hlth, Ctr Genes Environm & Hlth, Denver, CO USA. [Garcia, Benjamin J.; Leach, Sonia M.; Strong, Michael] Univ Colorado Denver, Computat Biosci Program, Anschutz Med Campus,Mailstop 8303, Aurora, CO 80045 USA. [Loxton, Andre G.; Walzl, Gerhard] Univ Stellenbosch, DST NRF Ctr Excellence Biomed TB Res, Cape Town, South Africa. [Loxton, Andre G.; Walzl, Gerhard] Univ Stellenbosch, SAMRC Ctr TB Res, Div Mol Biol & Human Genet, Dept Biomed Sci, Cape Town, South Africa. [Dolganov, Gregory M.; Van, Tran T.; Schoolnik, Gary K.] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Davis, J. Lucian] Yale Sch Publ Hlth, Epidemiol Microbial Dis, New Haven, CT USA. [Davis, J. Lucian] Yale Sch Med, Pulm Crit Care & Sleep Med, New Haven, CT USA. [de Jong, Bouke C.] Inst Trop Med, Antwerp, Belgium. [Voskuil, Martin I.] Univ Colorado, Sch Med, Dept Immunol & Microbiol, Aurora, CO USA. [Walter, Nicholas D.] Denver Vet Affairs Med Ctr, Pulm Sect, Denver, CO USA. [Walter, Nicholas D.] Univ Colorado Denver, Div Pulm Sci & Crit Care Med, Anschutz Med Campus, Aurora, CO USA. RP Garcia, BJ (reprint author), Univ Colorado Denver, Computat Biosci Program, Anschutz Med Campus,Mailstop 8303, Aurora, CO 80045 USA. EM benjamin.garcia@ucdenver.edu OI Garcia, Benjamin/0000-0001-5524-6946 FU National Institutes of Health [UL1 RR025780, 2T15LM009451-06]; European Research Council-INTERRUPTB [311725]; Veteran's Administration [CDA1IK2CX000914-01A1]; Boettcher Foundation Webb-Waring Award FX This work was supported by National Institutes of Health [grant numbers UL1 RR025780, 2T15LM009451-06 (to BJG), European Research Council-INTERRUPTB starting grant nr. 311725 (to BdJ), and Veteran's Administration [CDA1IK2CX000914-01A1 (to NDW)], and a Boettcher Foundation Webb-Waring Award (to MS). NR 18 TC 0 Z9 0 U1 3 U2 3 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1472-9792 J9 TUBERCULOSIS JI Tuberculosis PD SEP PY 2016 VL 100 BP 89 EP 94 DI 10.1016/j.tube.2016.07.004 PG 6 WC Immunology; Microbiology; Respiratory System SC Immunology; Microbiology; Respiratory System GA DU4RX UT WOS:000382201400012 PM 27553415 ER PT J AU Im, HY Zhong, SH Halberda, J AF Im, Hee Yeon Zhong, Sheng-hua Halberda, Justin TI Grouping by proximity and the visual impression of approximate number in random dot arrays SO VISION RESEARCH LA English DT Article DE Perceptual grouping; Numerosity estimation ID TEXTURE DENSITY ADAPTATION; PERCEIVED NUMEROSITY; OBJECT RECOGNITION; MENTAL NUMBER; ENUMERATION; MODEL; ATTENTION; PSYCHOPHYSICS; JUDGMENT; VISION AB We address the challenges of how to model human perceptual grouping in random dot arrays and how perceptual grouping affects human number estimation in these arrays. We introduce a modeling approach relying on a modified k-means clustering algorithm to formally describe human observers' grouping behavior. We found that a default grouping window size of approximately 4 of visual angle describes human grouping judgments across a range of random dot arrays (i.e., items within 4 are grouped together). This window size was highly consistent across observers and images, and was also stable across stimulus durations, suggesting that the k-means model captured a robust signature of perceptual grouping. Further, the k-means model outperformed other models (e.g., CODE) at describing human grouping behavior. Next, we found that the more the dots in a display are clustered together, the more human observers tend to underestimate the numerosity of the dots. We demonstrate that this effect is independent of density, and the modified k-means model can predict human observers' numerosity judgments and underestimation. Finally, we explored the robustness of the relationship between clustering and dot number underestimation and found that the effects of clustering remain, but are greatly reduced, when participants receive feedback on every trial. Together, this work suggests some promising avenues for formal models of human grouping behavior, and it highlights the importance of a 4 window of perceptual grouping. Lastly, it reveals a robust, somewhat plastic, relationship between perceptual grouping and number estimation. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Im, Hee Yeon] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Cambridge, MA 02138 USA. [Zhong, Sheng-hua] Shen Zhen Univ, Coll Comp Sci & Software Engn, Shenzhen, Guangdong, Peoples R China. [Im, Hee Yeon; Zhong, Sheng-hua; Halberda, Justin] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD 21218 USA. RP Im, HY (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Cambridge, MA 02138 USA. EM him3@mgh.harvard.ediu NR 82 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 0042-6989 EI 1878-5646 J9 VISION RES JI Vision Res. PD SEP PY 2016 VL 126 SI SI BP 291 EP 307 DI 10.1016/j.visres.2015.08.013 PG 17 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA DV1WK UT WOS:000382712600026 PM 26386344 ER PT J AU Li, Z Scott, MJ Fan, EK Li, Y Liu, J Xiao, G Li, S Billiar, TR Wilson, MA Jiang, Y Fan, J AF Li, Z. Scott, M. J. Fan, E. K. Li, Y. Liu, J. Xiao, G. Li, S. Billiar, T. R. Wilson, M. A. Jiang, Y. Fan, J. TI Tissue damage negatively regulates LPS-induced macrophage necroptosis SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID HEMORRHAGIC-SHOCK; PROGRAMMED NECROSIS; LUNG INFLAMMATION; NLRP3 INFLAMMASOME; ENDOTHELIAL-CELLS; TLR4 ENDOCYTOSIS; BONE-MARROW; IN-VIVO; ACTIVATION; RECEPTOR AB Infection is a common clinical complication following tissue damage resulting from surgery and severe trauma. Studies have suggested that cell pre-activation by antecedent trauma/tissue damage profoundly impacts the response of innate immune cells to a secondary infectious stimulus. Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that control cell release of inflammatory mediators from important innate immune executive cells such as macrophages (M.), which critically regulate the progress of inflammation. In this study, we investigated the mechanism and role of trauma/tissue damage in the regulation of LPS-induced M. necroptosis using a mouse model simulating long-bone fracture. We demonstrate that LPS acting through Toll-like receptor (TLR) 4 promotes M. necroptosis. However, necroptosis is ameliorated by high-mobility group box 1 (HMGB1) release from damaged tissue. We show that HMGB1 acting through cell surface receptor for advanced glycation end products (RAGE) upregulates caveolin-1 expression, which in turn induces caveolae-mediated TLR4 internalization and desensitization to decrease M. necroptosis. We further show that RAGE-MyD88 activation of Cdc42 and subsequent activation of transcription factor Sp1 serves as a mechanism underlying caveolin-1 transcriptional upregulation. These results reveal a previous unidentified protective role of damage-associated molecular pattern (DAMP) molecules in restricting inflammation in response to exogenous pathogen-associated molecular pattern molecules. C1 [Li, Z.; Scott, M. J.; Li, Y.; Billiar, T. R.; Wilson, M. A.; Fan, J.] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA. [Li, Z.; Li, Y.; Wilson, M. A.; Fan, J.] Vet Affairs Pittsburgh Healthcare Syst, Res & Dev, Pittsburgh, PA 15240 USA. [Li, Z.; Liu, J.; Jiang, Y.] Southern Med Univ, Dept Pathophysiol, Guangzhou 510515, Guangdong, Peoples R China. [Fan, E. K.] Univ Pittsburgh, Sch Arts & Sci, Pittsburgh, PA 15213 USA. [Xiao, G.] South Univ Sci & Technol China, Dept Biol, Shenzhen 518055, Peoples R China. [Xiao, G.] South Univ Sci & Technol China, Shenzhen Key Lab Cell Microenvironm, Shenzhen 518055, Peoples R China. [Xiao, G.] Rush Univ, Med Ctr, Dept Biochem, Chicago, IL 60612 USA. [Li, S.] Univ Pittsburgh, Sch Pharm, Ctr Pharmacogenet, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Billiar, T. R.; Fan, J.] Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA 15219 USA. RP Jiang, Y; Fan, J (reprint author), Univ Pittsburgh, Sch Med, Dept Surg, Bldg 1,2W109,151U-L,Univ Dr,VAPHS, Pittsburgh, PA 15240 USA. EM jiang48231@163.com; jif7@pitt.edu FU National Institutes of Health [R01-HL-079669, R56-HL-123882]; National Institutes of Health Center Grant [P50-GM-53789]; VA Merit Award [1I01BX002729]; National Key Basic Research Program (China) [2010CB529704]; PCSIRT [IRT0731]; National Natural Science Foundation of China [30670828] FX This work was supported by the National Institutes of Health Grant R01-HL-079669 (JF and MAW), National Institutes of Health Center Grant P50-GM-53789 (TRB and JF), National Institutes of Health Grant R56-HL-123882 (JF), VA Merit Award 1I01BX002729 (JF), National Key Basic Research Program 2010CB529704 (JY China), PCSIRT IRT0731 (JY), and National Natural Science Foundation of China 30670828 (JY). NR 60 TC 1 Z9 1 U1 12 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD SEP PY 2016 VL 23 IS 9 BP 1428 EP 1447 DI 10.1038/cdd.2016.21 PG 20 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DS8ZY UT WOS:000381072800002 PM 26943325 ER PT J AU Farhat, MR Sultana, R Iartchouk, O Bozeman, S Galagan, J Sisk, P Stolte, C Nebenzahl-Guimaraes, H Jacobson, K Sloutsky, A Kaur, D Posey, J Kreiswirth, BN Kurepina, N Rigouts, L Streicher, EM Victor, TC Warren, RM van Soolingen, D Murray, M AF Farhat, Maha R. Sultana, Razvan Iartchouk, Oleg Bozeman, Sam Galagan, James Sisk, Peter Stolte, Christian Nebenzahl-Guimaraes, Hanna Jacobson, Karen Sloutsky, Alexander Kaur, Devinder Posey, James Kreiswirth, Barry N. Kurepina, Natalia Rigouts, Leen Streicher, Elizabeth M. Victor, Tommie C. Warren, Robin M. van Soolingen, Dick Murray, Megan TI Genetic Determinants of Drug Resistance in Mycobacterium tuberculosis and Their Diagnostic Value SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE multidrug-resistant tuberculosis; molecular diagnostics; sensitivity and specificity ID GENOTYPE MTBDRSL TEST; ANTIBIOTIC-RESISTANCE; COMPLEX STRAINS; EPIDEMIOLOGY; PYRAZINAMIDE; MUTATIONS; 2ND-LINE; TOOL; FLUOROQUINOLONES; CLASSIFICATION AB Rationale: The development of molecular diagnostics that detect both the presence of Mycobacterium tuberculosis in clinical samples and drug resistance-conferring mutations promises to revolutionize patient care and interrupt transmission by ensuring early diagnosis. However, these tools require the identification of genetic determinants of resistance to the full range of antituberculosis drugs. Objectives: To determine the optimal molecular approach needed, we sought to create a comprehensive catalog of resistance mutations and assess their sensitivity and specificity in diagnosing drug resistance. Methods: We developed and validated molecular inversion probes for DNA capture and deep sequencing of 28 drug-resistance loci in M. tuberculosis. We used the probes for targeted sequencing of a geographically diverse set of 1,397 clinical M. tuberculosis isolates with known drug resistance phenotypes. We identified a minimal set of mutations to predict resistance to first- and second-line antituberculosis drugs and validated our predictions in an independent dataset. We constructed and piloted a web-based database that provides public access to the sequence data and predidtion tool. Measurements and Main Results: The predicted resistance to rifampicin and isoniazid exceeded 90% sensitivity and specificity but was lower for other drugs. The number of mutations needed to diagnose resistance is large, and for the 13 drugs studied it was 238 across 18 genetic loci. Conclusions: These data suggest that a comprehensive M. tuberculosis drug resistance diagnostic will need to allow for a high dimension of mutation detection. They also support the hypothesis that currently unknown genetic determinants, potentially discoverable by whole-genome sequencing, encode resistance to second-line tuberculosis drugs. C1 [Farhat, Maha R.] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Farhat, Maha R.; Sloutsky, Alexander; Murray, Megan] Harvard Med Sch, Dept Global Hlth & Social Med, Boston, MA USA. [Sultana, Razvan] Queen Mary Univ, Genom England, London, England. [Iartchouk, Oleg] Novartis Inst Biomed Res, Cambridge, MA USA. [Bozeman, Sam] Abt Associates Inc, Boston, MA USA. [Galagan, James] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Galagan, James] Boston Univ, Dept Microbiol, Boston, MA 02215 USA. [Galagan, James] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. [Sisk, Peter] Gen9 Inc, Cambridge, MA USA. [Stolte, Christian] CSIRO, N Ryde, NSW, Australia. [Nebenzahl-Guimaraes, Hanna] Natl Inst Publ Hlth & Environm, Bilthoven, Netherlands. [Nebenzahl-Guimaraes, Hanna; van Soolingen, Dick] Radboud Univ Nijmegen, Med Ctr, Dept Pulm Dis, Nijmegen, Netherlands. [Nebenzahl-Guimaraes, Hanna; van Soolingen, Dick] Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Nijmegen, Netherlands. [Nebenzahl-Guimaraes, Hanna; van Soolingen, Dick] Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst, Braga, Portugal. [Nebenzahl-Guimaraes, Hanna] PT Govt Associate Lab, Life & Hlth Sci Res Inst 3Bs, Braga, Portugal. [Jacobson, Karen] Boston Univ, Sch Med, Sect Infect Dis, Boston, MA 02118 USA. [Jacobson, Karen; Streicher, Elizabeth M.; Victor, Tommie C.; Warren, Robin M.] Univ Stellenbosch, Fac Med & Hlth Sci, SAMRC Ctr TB Res, DST NRF Ctr Excellence Biomed TB Res,Div Mol Biol, Tygerberg, South Africa. [Sloutsky, Alexander; Kaur, Devinder] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Posey, James] Ctr Dis Control & Prevent, Div TB Eliminat, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Atlanta, GA USA. [Kreiswirth, Barry N.; Kurepina, Natalia] Rutgers State Univ, Publ Hlth Res Inst, TB Ctr, Newark, NJ USA. [Rigouts, Leen] Inst Trop Med, Mycobacteriol, Antwerp, Belgium. [Rigouts, Leen] Univ Antwerp, Biomed Sci, Antwerp, Belgium. [Murray, Megan] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Farhat, MR (reprint author), 55 Fruit St,Bldg 148, Boston, MA 02114 USA. EM mrfarhat@partners.org OI Jacobson, Karen/0000-0003-4239-3685 FU NIAID NIH HHS [U19 AI076217, U19 AI109755]; NIEHS NIH HHS [K01 ES026835] NR 49 TC 11 Z9 11 U1 5 U2 12 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD SEP 1 PY 2016 VL 194 IS 5 BP 621 EP 630 DI 10.1164/rccm.201510-2091OC PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DU7SY UT WOS:000382416100018 PM 26910495 ER PT J AU Jacobs, ML Jacobs, JP Pasquali, SK Hill, KD Hornik, C O'Brien, SM Shahian, DM Habib, RH Edwards, FH AF Jacobs, Marshall L. Jacobs, Jeffrey P. Pasquali, Sara K. Hill, Kevin D. Hornik, Christoph O'Brien, Sean M. Shahian, David M. Habib, Robert H. Edwards, Fred H. TI The Society of Thoracic Surgeons Congenital Heart Surgery Database: 2016 Update on Research SO ANNALS OF THORACIC SURGERY LA English DT Article ID MORTALITY RISK; OUTCOMES ASSESSMENT; CLINICAL REGISTRY; DISEASE; QUALITY; IMPACT AB The Society of Thoracic Surgeons Congenital Heart Surgery Database (STS CHSD) is the largest congenital and pediatric cardiac surgical clinical data registry in the world. With more than 400,000 total operations from nearly all centers performing pediatric and congenital heart operations in North America, the STS CHSD is an unparalleled platform for clinical investigation, outcomes research, and quality improvement activities in this subspecialty. In 2015, several major original publications reported analyses of data in the CHSD pertaining to specific diagnostic and procedural groups, age-defined cohorts, or the entire population of patients in the database. Additional publications reported the most recent development, evaluation, and application of metrics for quality measurement and reporting of pediatric and congenital heart operation outcomes. This use of the STS CHSD for outcomes research and for quality measurement continues to expand as database participation and the available wealth of data in it continue to grow. This article reviews outcomes research and quality improvement articles published in 2015 based on STS CHSD data. (C) 2016 by The Society of Thoracic Surgeons C1 Johns Hopkins Med Inst, Div Cardiac Surg, Baltimore, MD 21205 USA. Johns Hopkins All Childrens Hosp, Johns Hopkins All Childrens Heart Inst, St Petersburg, FL USA. Florida Hosp Children, St Petersburg, FL USA. Johns Hopkins All Childrens Hosp, Johns Hopkins All Childrens Heart Inst, Tampa, FL USA. Florida Hosp Children, Tampa, FL USA. Johns Hopkins All Childrens Hosp, Johns Hopkins All Childrens Heart Inst, Orlando, FL USA. Florida Hosp Children, Orlando, FL USA. Univ Michigan, CS Mott Childrens Hosp, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. Duke Univ, Sch Med, Durham, NC USA. Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. Harvard Med Sch, Massachusetts Gen Hosp, Ctr Qual & Safety, Boston, MA USA. Soc Thorac Surg Res Ctr, Chicago, IL USA. Univ Florida, Div Cardiothorac Surg, Jacksonville, FL USA. RP Jacobs, ML (reprint author), Johns Hopkins Univ Hosp, 1800 Orleans St,Sheikh Zayed Tower,Ste 7107, Baltimore, MD 21287 USA. EM marshall.jacobs@comcast.net FU National Heart, Lung, and Blood Institute [K08-HL-103631, R01-HL-122261] FX Dr Pasquali received support from the National Heart, Lung, and Blood Institute (K08-HL-103631 and R01-HL-122261). NR 16 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD SEP PY 2016 VL 102 IS 3 BP 688 EP 695 DI 10.1016/j.athoracsur.2016.07.015 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DU6EG UT WOS:000382306200034 PM 27492669 ER PT J AU Salmon, AB AF Salmon, Adam B. TI Beyond Diabetes: Does Obesity-Induced Oxidative Stress Drive the Aging Process? SO ANTIOXIDANTS LA English DT Review DE reactive oxygen species; mitochondria; inflammation; adipose; fatty acid oxidation; longevity; health span ID HIGH-FAT DIET; MUSCLE INSULIN-RESISTANCE; METHIONINE SULFOXIDE REDUCTASE; MN-SUPEROXIDE-DISMUTASE; LIFE-SPAN; ADIPOSE-TISSUE; MITOCHONDRIAL DYSFUNCTION; DROSOPHILA-MELANOGASTER; CARDIOVASCULAR-DISEASE; COGNITIVE IMPAIRMENT AB Despite numerous correlative data, a causative role for oxidative stress in mammalian longevity has remained elusive. However, there is strong evidence that increased oxidative stress is associated with exacerbation of many diseases and pathologies that are also strongly related to advanced age. Obesity, or increased fat accumulation, is one of the most common chronic conditions worldwide and is associated with not only metabolic dysfunction but also increased levels of oxidative stress in vivo. Moreover, obesity is also associated with significantly increased risks of cardiovascular disease, neurological decline and cancer among many other diseases as well as a significantly increased risk of mortality. In this review, we investigate the possible interpretation that the increased incidence of these diseases in obesity may be due to chronic oxidative stress mediating segmental acceleration of the aging process. Understanding how obesity can alter cellular physiology beyond that directly related to metabolic function could open new therapeutic areas of approach to extend the period of healthy aging among people of all body composition. C1 [Salmon, Adam B.] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78245 USA. [Salmon, Adam B.] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78245 USA. RP Salmon, AB (reprint author), South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78245 USA.; Salmon, AB (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78245 USA. EM salmona@uthscsa.edu OI Salmon, Adam/0000-0002-1475-7843 NR 123 TC 1 Z9 1 U1 6 U2 12 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2076-3921 J9 ANTIOXIDANTS JI Antioxidants PD SEP PY 2016 VL 5 IS 3 AR 24 DI 10.3390/antiox5030024 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DU9AT UT WOS:000382509300004 ER PT J AU Loscertales, M Nicolaou, F Jeanne, M Longoni, M Gould, DB Sun, YW Maalouf, FI Nagy, N Donahoe, PK AF Loscertales, Maria Nicolaou, Fotini Jeanne, Marion Longoni, Mauro Gould, Douglas B. Sun, Yunwei Maalouf, Faouzi I. Nagy, Nandor Donahoe, Patricia K. TI Type IV collagen drives alveolar epithelial-endothelial association and the morphogenetic movements of septation (vol 14, 59, 2016) SO BMC BIOLOGY LA English DT Correction C1 [Loscertales, Maria; Nicolaou, Fotini; Longoni, Mauro; Sun, Yunwei; Maalouf, Faouzi I.; Nagy, Nandor; Donahoe, Patricia K.] Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. [Loscertales, Maria; Longoni, Mauro; Nagy, Nandor; Donahoe, Patricia K.] Harvard Med Sch, Dept Surg, Boston, MA 02115 USA. [Jeanne, Marion; Gould, Douglas B.] Univ Calif San Francisco, Sch Med, Inst Human Genet, Dept Ophthalmol, San Francisco, CA 94143 USA. [Jeanne, Marion; Gould, Douglas B.] Univ Calif San Francisco, Sch Med, Inst Human Genet, Dept Anat, San Francisco, CA 94143 USA. [Nagy, Nandor] Semmelweis Univ, Fac Med, Dept Human Anat Histol & Embryol, H-1094 Budapest, Hungary. [Donahoe, Patricia K.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Loscertales, M (reprint author), Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA.; Loscertales, M (reprint author), Harvard Med Sch, Dept Surg, Boston, MA 02115 USA. EM MLOSCERTALES@mgh.harvard.edu NR 1 TC 0 Z9 0 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD SEP 1 PY 2016 VL 14 AR 73 DI 10.1186/s12915-016-0297-7 PG 3 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DU8JH UT WOS:000382458600001 ER PT J AU Napoli, N Schafer, AL Lui, LY Cauley, JA Strotmeyer, ES Le Blanc, ES Hoffman, AR Lee, CG Black, DM Schwartz, AV AF Napoli, Nicola Schafer, Anne L. Lui, Li-Yung Cauley, Jane A. Strotmeyer, Elsa S. Le Blanc, Erin S. Hoffman, Andrew R. Lee, Christine G. Black, Dennis M. Schwartz, Ann V. TI Serum 25-hydroxyvitamin D level and incident type 2 diabetes in older men, the Osteoporotic Fractures in Men (MrOS) study SO BONE LA English DT Article DE Type 2 diabetes; Vitamin D; Older men ID VITAMIN-D DEFICIENCY; MENDELIAN RANDOMIZATION; RISK; METAANALYSIS; OBESITY; CALCIUM AB The association between vitamin D status and diabetes risk is inconsistent among observational studies, and most of the available studies have been with women. In the present study we investigated the association between serum 25-hydroxyvitamin D (25(OH)D) levels and incident type 2 diabetes (T2D) in older men (>= 65 years old) who participated in the multisite Osteoporotic Fractures in Men (MrOS) study enrolled from March 2000 to April 2002. Baseline 25(OH)D levels were available in 1939 subjects without prevalent T2D. Clinical information, body mass index (BMI) and other factors related to T2D were assessed at the baseline visit. Incident diabetes, defined by self report and medication use, was determined over an average follow-up of 6.4 years. At baseline, participants were, on average, 73.3 (+/- 5.7) years old, had a mean BMI in the overweight range (272 kg/m(2) +/- 3.6) and had total serum 25(OH)D of 26.1 ng/ml (+/- 8.3). Incident diabetes was diagnosed in 139 subjects. Cox regression analysis showed a trend toward a protective effect of higher 25 (OH)D levels with a lower risk of T2D (HR 0.87, 95% CI: 0.73-1.04 per 1 SD increase of 25(OH)D). After adjusted for BMI and other potential confounders, the relationship between 25(OH)D levels and incident diabetes was further attenuated (HR 1.03, 95% Cl 0.85-1.25). No significant difference in the incidence of diabetes emerged after analyzing study subjects according to baseline 25(OH)D quartiles. In conclusion, 25(OH)D levels were not associated with incident T2D in older men. (C) 2016 Published by Elsevier Inc. C1 [Napoli, Nicola] Univ Campus Biomed Roma, Rome, Italy. [Napoli, Nicola] Washington Univ, Div Bone & Mineral Dis, St Louis, MO 63130 USA. [Schafer, Anne L.; Black, Dennis M.; Schwartz, Ann V.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Schafer, Anne L.] San Francisco VA Med Ctr, San Francisco, CA USA. [Lui, Li-Yung] Calif Pacific Med Ctr, San Francisco, CA USA. [Cauley, Jane A.; Strotmeyer, Elsa S.] Ctr Aging & Populat Hlth, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Le Blanc, Erin S.] Kaiser Permanente, Ctr Hlth Res NW, Rockville, MD USA. [Hoffman, Andrew R.] Stanford Univ, Stanford, CA 94305 USA. [Lee, Christine G.] Vet Affairs Hlth Care Syst, Portland, OR USA. RP Napoli, N (reprint author), Univ Campus Biomed Roma, Unit Endocrinol & Diabet, Dept Med, Via Alvaro del Portillo 21, I-00128 Rome, Italy. EM n.napoli@unicampus.it FU National Institutes of Health; National Institute on Aging (NIA); National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Center for Advancing Translational Sciences (NCATS); NIH Roadmap for Medical Research [U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01 AG027810, UL1 TR000128]; Ministero della Salute [GR09-277]; American Diabetes Association [1-04-JF-46]; VA Clinical Science Research and Development Career Development Award [5IK2CW000729-02, 5IK2CX000549-05] FX The Osteoporotic Fractures in Men (MrOS) study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01 AG027810, and UL1 TR000128.; NN is supported by research grant provided by Ministero della Salute GR09-277.; The American Diabetes Association provided funding for Elsa Strotmeyer's grant "Longitudinal changes in BMD with diabetes mellitus" (1-04-JF-46, Strotmeyer ES).; CGL receives support from a VA Clinical Science Research and Development Career Development Award, project number 5IK2CW000729-02. ALS receives support from a VA Clinical Science Research and Development Career Development Award, project number 5IK2CX000549-05. NR 23 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD SEP PY 2016 VL 90 BP 181 EP 184 DI 10.1016/j.bone.2016.07.001 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT1MK UT WOS:000381246600022 PM 27393241 ER PT J AU Koerte, IK Willems, A Muehlmann, M Moll, K Cornell, S Pixner, S Steffinger, D Keeser, D Heinen, F Kubicki, M Shenton, ME Ertl-Wagner, B Schulte-Korne, G AF Koerte, Inga K. Willems, Anna Muehlmann, Marc Moll, Kristina Cornell, Sonia Pixner, Silvia Steffinger, Denise Keeser, Daniel Heinen, Florian Kubicki, Marek Shenton, Martha E. Ertl-Wagner, Birgit Schulte-Koerne, Gerd TI Mathematical abilities in dyslexic children: a diffusion tensor imaging study SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Dyslexia; Diffusion tensor imaging; Mathematical ability; Mathematics disorder; Learning disorder ID WHITE-MATTER ARCHITECTURE; DEVELOPMENTAL DYSLEXIA; READING-ABILITY; BRAIN; REPRESENTATIONS; DISABILITIES; DYSCALCULIA AB Dyslexia is characterized by a deficit in language processing which mainly affects word decoding and spelling skills. In addition, children with dyslexia also show problems in mathematics. However, for the latter, the underlying structural correlates have not been investigated. Sixteen children with dyslexia (mean age 9.8 years [0.39]) and 24 typically developing children (mean age 9.9 years [0.29]) group matched for age, gender, IQ, and handedness underwent 3 T MR diffusion tensor imaging as well as cognitive testing. Tract-Based Spatial Statistics were performed to correlate behavioral data with diffusion data. Children with dyslexia performed worse than controls in standardized verbal number tasks, such as arithmetic efficiency tests (addition, subtraction, multiplication, division). In contrast, the two groups did not differ in the nonverbal number line task. Arithmetic efficiency, representing the total score of the four arithmetic tasks, multiplication, and division, correlated with diffusion measures in widespread areas of the white matter, including bilateral superior and inferior longitudinal fasciculi in children with dyslexia compared to controls. Children with dyslexia demonstrated lower performance in verbal number tasks but performed similarly to controls in a nonverbal number task. Further, an association between verbal arithmetic efficiency and diffusion measures was demonstrated in widespread areas of the white matter suggesting compensatory mechanisms in children with dyslexia compared to controls. Taken together, poor fact retrieval in children with dyslexia is likely a consequence of deficits in the language system, which not only affects literacy skills but also impacts on arithmetic skills. C1 [Koerte, Inga K.; Willems, Anna; Muehlmann, Marc; Moll, Kristina; Schulte-Koerne, Gerd] Univ Munich, Dept Child & Adolescent Psychiat Psychosomat & Ps, Munich, Germany. [Koerte, Inga K.; Willems, Anna; Muehlmann, Marc; Kubicki, Marek; Shenton, Martha E.] Harvard Med Sch, Brigham & Womens Hosp, Dept Psychiat, Psychiat Neuroimaging Lab, Boston, MA 02115 USA. [Koerte, Inga K.; Steffinger, Denise; Keeser, Daniel; Ertl-Wagner, Birgit] Univ Munich, Inst Clin Radiol, Munich, Germany. [Cornell, Sonia; Heinen, Florian] Univ Munich, Dept Pediat Neurol & Dev Med, Dr von Hauner Childrens Hosp, Munich, Germany. [Pixner, Silvia] Univ Hlth Sci Med Informat & Technol, Inst Appl Psychol, Hall In Tirol, Austria. [Keeser, Daniel] Univ Munich, Dept Psychiat & Psychotherapy, Munich, Germany. [Kubicki, Marek; Shenton, Martha E.] Harvard Med Sch, Brigham & Womens Hosp, Dept Psychiat, Boston, MA USA. [Kubicki, Marek; Shenton, Martha E.] Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, Boston, MA USA. [Shenton, Martha E.] VA Boston Healthcare Syst, Boston, MA USA. RP Koerte, IK (reprint author), Univ Munich, Dept Child & Adolescent Psychiat Psychosomat & Ps, Munich, Germany.; Koerte, IK (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Psychiat, Psychiat Neuroimaging Lab, Boston, MA 02115 USA.; Koerte, IK (reprint author), Univ Munich, Inst Clin Radiol, Munich, Germany. EM ikoerte@med.lmu.de FU Else Kroner-Fresenius Foundation; Cusanuswerk FX This study was partly funded by the Else Kroner-Fresenius Foundation (IK) and the Cusanuswerk (AW). This study was part of the doctoral thesis of Anna Willems. NR 44 TC 0 Z9 0 U1 15 U2 19 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 EI 1931-7565 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD SEP PY 2016 VL 10 IS 3 BP 781 EP 791 DI 10.1007/s11682-015-9436-y PG 11 WC Neuroimaging SC Neurosciences & Neurology GA DU7IL UT WOS:000382387300017 PM 26286825 ER PT J AU Koerte, IK Mayinger, M Muehlmann, M Kaufmann, D Lin, AP Steffinger, D Fisch, B Rauchmann, BS Immler, S Karch, S Heinen, FR Ertl-Wagner, B Reiser, M Stern, RA Zafonte, R Shenton, ME AF Koerte, Inga K. Mayinger, Michael Muehlmann, Marc Kaufmann, David Lin, Alexander P. Steffinger, Denise Fisch, Barbara Rauchmann, Boris-Stephan Immler, Stefanie Karch, Susanne Heinen, Florian R. Ertl-Wagner, Birgit Reiser, Maximilian Stern, Robert A. Zafonte, Ross Shenton, Martha E. TI Cortical thinning in former professional soccer players SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Repetitive subconcussive head impact; Soccer; Cortical thickness; Aging; Traumatic brain injury ID CONCUSSION; THICKNESS AB Soccer is the most popular sport in the world. Soccer players are at high risk for repetitive subconcussive head impact when heading the ball. Whether this leads to long-term alterations of the brain's structure associated with cognitive decline remains unknown. The aim of this study was to evaluate cortical thickness in former professional soccer players using high-resolution structural MR imaging. Fifteen former male professional soccer players (mean age 49.3 [SD 5.1] years) underwent high-resolution structural 3 T MR imaging, as well as cognitive testing. Fifteen male, age-matched former professional non-contact sport athletes (mean age 49.6 [SD 6.4] years) served as controls. Group analyses of cortical thickness were performed using voxel-based statistics. Soccer players demonstrated greater cortical thinning with increasing age compared to controls in the right inferolateral-parietal, temporal, and occipital cortex. Cortical thinning was associated with lower cognitive performance as well as with estimated exposure to repetitive subconcussive head impact. Neurocognitive evaluation revealed decreased memory performance in the soccer players compared to controls. The association of cortical thinning and decreased cognitive performance, as well as exposure to repetitive subconcussive head impact, further supports the hypothesis that repetitive subconcussive head impact may play a role in early cognitive decline in soccer players. Future studies are needed to elucidate the time course of changes in cortical thickness as well as their association with impaired cognitive function and possible underlying neurodegenerative process. C1 [Koerte, Inga K.; Mayinger, Michael; Muehlmann, Marc; Lin, Alexander P.; Rauchmann, Boris-Stephan; Shenton, Martha E.] Harvard Med Sch, Brigham & Womens Hosp, Psychiat Neuroimaging Lab, Boston, MA 02115 USA. [Koerte, Inga K.; Mayinger, Michael; Muehlmann, Marc; Kaufmann, David; Steffinger, Denise; Fisch, Barbara; Rauchmann, Boris-Stephan; Ertl-Wagner, Birgit; Reiser, Maximilian] Univ Munich, Inst Clin Radiol, Munich, Germany. [Koerte, Inga K.; Muehlmann, Marc] Univ Munich, Dept Child & Adolescent Psychiat Psychosomat & Ps, Munich, Germany. [Kaufmann, David] Charite, Dept Radiol, Berlin, Germany. [Lin, Alexander P.; Shenton, Martha E.] Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, Boston, MA USA. [Immler, Stefanie; Heinen, Florian R.] Univ Munich, Dept Pediat Neurol & Dev Med, Dr von Hauner Childrens Hosp, Munich, Germany. [Karch, Susanne] Univ Munich, Dept Psychiat, Munich, Germany. [Stern, Robert A.] Boston Univ, Sch Med, Dept Neurol, Alzheimers Dis Ctr, Boston, MA 02118 USA. [Stern, Robert A.] Boston Univ, Sch Med, Dept Neurosurg, Alzheimers Dis Ctr, Boston, MA 02118 USA. [Stern, Robert A.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Alzheimers Dis Ctr, Boston, MA 02118 USA. [Zafonte, Ross] Harvard Med Sch, Brigham & Womens Hosp, Dept Phys Med & Rehabil, Spaulding Rehabil Hosp,Massachusetts Gen Hosp, Boston, MA USA. [Shenton, Martha E.] VA Boston Healthcare Syst, Boston, MA USA. RP Koerte, IK (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Psychiat Neuroimaging Lab, Boston, MA 02115 USA.; Koerte, IK (reprint author), Univ Munich, Inst Clin Radiol, Munich, Germany.; Koerte, IK (reprint author), Univ Munich, Dept Child & Adolescent Psychiat Psychosomat & Ps, Munich, Germany. EM ikoerte@bwh.harvard.edu FU Else Kroner-Fresenius Stiftung, Germany; Department of Defense [X81XWH-07-CC-CSDoD]; VA Merit Award; Petraeic Legate foundation, Germany FX This study was supported by the Else Kroner-Fresenius Stiftung, Germany (IK). This work was also partially funded by grants from The Department of Defense (X81XWH-07-CC-CSDoD; RZ, MES) and a VA Merit Award (MES). Michael Mayinger was supported by the Petraeic Legate foundation, Germany. NR 22 TC 5 Z9 5 U1 11 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 EI 1931-7565 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD SEP PY 2016 VL 10 IS 3 BP 792 EP 798 DI 10.1007/s11682-015-9442-0 PG 7 WC Neuroimaging SC Neurosciences & Neurology GA DU7IL UT WOS:000382387300018 PM 26286826 ER PT J AU Norvell, DC Williams, RM Turner, AP Czerniecki, JM AF Norvell, Daniel C. Williams, Rhonda M. Turner, Aaron P. Czerniecki, Joseph M. TI The development and validation of a novel outcome measure to quantify mobility in the dysvascular lower extremity amputee: the amputee single item mobility measure SO CLINICAL REHABILITATION LA English DT Article DE Amputation; diabetes; peripheral arterial disease; patient-reported outcome; mobility; validity ID LOWER-LIMB AMPUTATION; QUALITY-OF-LIFE; HEALTH-STATUS; PROSTHETIC PROFILE; PEOPLE; QUESTIONNAIRE; SCALES; REHABILITATION; RESPONSIVENESS; RELIABILITY AB Objective: This study describes the development and psychometric evaluation of a novel patient-reported single-item mobility measure. Design: Prospective cohort study. Setting: Four Veteran's Administration Medical Centers. Subjects: Individuals undergoing their first major unilateral lower extremity amputation; 198 met inclusion criteria; of these, 113 (57%) enrolled. Interventions: None. Main measures: The Amputee Single Item Mobility Measure, a single item measure with scores ranging from 0 to 6, was developed by an expert panel, and concurrently administered with the Locomotor Capabilities Index-5 (LCI-5) and other outcome measures at six weeks, four months, and 12 months post-amputation. Criterion and construct validity, responsiveness, and floor/ceiling effects were evaluated. Responsiveness was assessed using the standardized response mean. Results: The overall mean 12-month Amputee Single Item Mobility Measure score was 3.391.4. Scores for transmetatarsal, transtibial, and transfemoral amputees were 4.2 (+/- 1.3), 3.2 (+/- 1.5), and 2.9 (+/- 1.1), respectively. Amputee Single Item Mobility Measure scores demonstrated large and statistically significant correlations with the LCI-5 scores at six weeks (r=0.72), four months (r=0.81), and 12 months (r=0.86). At four months and 12months, the correlation between Amputee Single Item Mobility Measure scores and hours of prosthetic use were r=0.69 and r=0.66, respectively, and between Amputee Single Item Mobility Measure scores and Trinity Amputation and Prosthesis Experience Scales functional restriction scores were r=0.45 and r=0.67, respectively. Amputee Single Item Mobility Measure scores increased significantly from six weeks to 12months post-amputation. Minimal floor/ceiling effects were demonstrated. Conclusions: In the unilateral dysvascular amputee, the Amputee Single Item Mobility Measure has strong criterion and construct validity, excellent responsiveness, and does not exhibit floor/ceiling effects. C1 [Norvell, Daniel C.] Spectrum Res Inc, 705 S 9th St,Suite 203, Tacoma, WA 98407 USA. [Williams, Rhonda M.; Turner, Aaron P.; Czerniecki, Joseph M.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Williams, Rhonda M.; Turner, Aaron P.; Czerniecki, Joseph M.] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. RP Norvell, DC (reprint author), Spectrum Res Inc, 705 S 9th St,Suite 203, Tacoma, WA 98407 USA. EM dan@specri.com FU US Department of Veterans Affairs, Office of Research and Development, Rehabilitation Research and Development [A41241, B4927W] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This material is based upon work supported by the US Department of Veterans Affairs, Office of Research and Development, Rehabilitation Research and Development (Merit Review A41241 Joseph Czerniecki, PI and Career Development Award B4927W Aaron Turner, PI). NR 38 TC 0 Z9 0 U1 6 U2 6 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-2155 EI 1477-0873 J9 CLIN REHABIL JI Clin. Rehabil. PD SEP PY 2016 VL 30 IS 9 BP 878 EP 889 DI 10.1177/0269215516644308 PG 12 WC Rehabilitation SC Rehabilitation GA DU8FK UT WOS:000382448500005 PM 27496697 ER PT J AU Lenzi, R Bleier, BS Felisati, G Muscatello, L AF Lenzi, Riccardo Bleier, Benjamin S. Felisati, Giovanni Muscatello, Luca TI Purely endoscopic trans-nasal management of orbital intraconal cavernous haemangiomas: a systematic review of the literature SO EUROPEAN ARCHIVES OF OTO-RHINO-LARYNGOLOGY LA English DT Review DE Cavernous hemangioma; Endoscopy; Endoscopic endonasal approach; Orbit; Orbitotomy ID RESECTION; REMOVAL; SPACE; APEX AB The surgical management of medial and inferior orbital lesions is demanding via traditional external approach, since the conic-shaped surgical field is narrow and damage to neural, muscular or vascular structures of the orbit can have serious consequences. In recent years, the evolution of endoscopic endonasal approaches for lesions that goes beyond the nose brought the orbit to the attention of rhinosurgeons. If procedures such as transnasal orbital decompression and lacrimal pathways surgery have been described some decades ago, the last frontier of transnasal orbital surgery, namely intraconal tumor surgery, is a new and rapidly expanding field. Papers describing endoscopic endonasal approaches to the orbit appeared in the international literature, but most of them contain a small number of cases, also because the relatively rarity of intraorbital lesions. We herein report the results of a systematic review of the literature regarding the endoscopic endonasal approach to intraconal cavernous haemangiomas, the most common benign orbital lesion. The endoscopic management of intraconal cavernous haemangiomas results feasible and safe. A critical step of this kind of surgery is the management of the medial rectus muscle, mandatory to expose the intraconal space. C1 [Lenzi, Riccardo; Muscatello, Luca] Ss Giacomo Cristoforo Gen Hosp, Div Otorhinolaryngol, Via Sottomonte 1, I-54100 Massa, Italy. [Bleier, Benjamin S.] Harvard Med Sch, Div Otorhinolaryngol, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Felisati, Giovanni] Univ Milan, San Paolo Hosp, Div Otorhinolaryngol, Milan, Italy. RP Lenzi, R (reprint author), Ss Giacomo Cristoforo Gen Hosp, Div Otorhinolaryngol, Via Sottomonte 1, I-54100 Massa, Italy. EM riclenzi@gmail.com NR 15 TC 0 Z9 1 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0937-4477 EI 1434-4726 J9 EUR ARCH OTO-RHINO-L JI Eur. Arch. Oto-Rhino-Laryn. PD SEP PY 2016 VL 273 IS 9 BP 2319 EP 2322 DI 10.1007/s00405-015-3733-3 PG 4 WC Otorhinolaryngology SC Otorhinolaryngology GA DT1TD UT WOS:000381264100006 PM 26210157 ER PT J AU Hathout, L Patel, V Wen, P AF Hathout, Leith Patel, Vishal Wen, Patrick TI A 3-dimensional DTI MRI-based model of GBM growth and response to radiation therapy SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE GBM; modeling; diffusion tensor imaging; anisotropy ID CENTRAL-NERVOUS-SYSTEM; BRAIN-TUMOR RESPONSE; MATHEMATICAL-MODEL; GLIOBLASTOMA PATIENTS; MALIGNANT GLIOMAS; WHITE-MATTER; RADIOTHERAPY; INVASION; CHEMOTHERAPY; MIGRATION AB Glioblastoma (GBM) is both the most common and the most aggressive intra-axial brain tumor, with a notoriously poor prognosis. To improve this prognosis, it is necessary to understand the dynamics of GBM growth, response to treatment and recurrence. The present study presents a mathematical diffusion-proliferation model of GBM growth and response to radiation therapy based on diffusion tensor (DTI) MRI imaging. This represents an important advance because it allows 3-dimensional tumor modeling in the anatomical context of the brain. Specifically, tumor infiltration is guided by the direction of the white matter tracts along which glioma cells infiltrate. This provides the potential to model different tumor growth patterns based on location within the brain, and to simulate the tumor's response to different radiation therapy regimens. Tumor infiltration across the corpus callosum is simulated in biologically accurate time frames. The response to radiation therapy, including changes in cell density gradients and how these compare across different radiation fractionation protocols, can be rendered. Also, the model can estimate the amount of subthreshold tumor which has extended beyond the visible MR imaging margins. When combined with the ability of being able to estimate the biological parameters of invasiveness and proliferation of a particular GBM from serial MRI scans, it is shown that the model has potential to simulate realistic tumor growth, response and recurrence patterns in individual patients. To the best of our knowledge, this is the first presentation of a DTI-based GBM growth and radiation therapy treatment model. C1 [Hathout, Leith; Wen, Patrick] Harvard Med Sch, 107 Ave Louis Pasteur, Boston, MA 02115 USA. [Patel, Vishal] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol Sci, Los Angeles, CA 90024 USA. [Wen, Patrick] Harvard Univ, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Hathout, L (reprint author), Harvard Med Sch, 107 Ave Louis Pasteur, Boston, MA 02115 USA. EM leith_hathout@hms.harvard.edu NR 31 TC 0 Z9 0 U1 3 U2 3 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 EI 1791-2423 J9 INT J ONCOL JI Int. J. Oncol. PD SEP PY 2016 VL 49 IS 3 BP 1081 EP 1087 DI 10.3892/ijo.2016.3595 PG 7 WC Oncology SC Oncology GA DU8EY UT WOS:000382447300023 PM 27572745 ER PT J AU Gorissen, BL Unkelbach, J Bortfeld, TR AF Gorissen, Bram L. Unkelbach, Jan Bortfeld, Thomas R. TI Mathematical Optimization of Treatment Schedules SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material ID RADIOTHERAPY C1 [Bortfeld, Thomas R.] Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 362, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Bortfeld, TR (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 362, Boston, MA 02114 USA. EM tbortfeld@mgh.harvard.edu NR 8 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD SEP 1 PY 2016 VL 96 IS 1 BP 6 EP 8 DI 10.1016/j.ijrobp.2016.04.012 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DS9FD UT WOS:000381087300002 PM 27511841 ER PT J AU Baumann, BC Bosch, WR Bahl, A Birtle, AJ Breau, RH Challapalli, A Chang, AJ Choudhury, A Daneshmand, S El-Gayed, A Feldman, A Finkelstein, SE Guzzo, TJ Hilman, S Jani, A Malkowicz, SB Mantz, CA Master, V Mitra, AV Murthy, V Porten, SP Richaud, PM Efstathiou, JA Eapen, LJ Christodouleas, JP AF Baumann, Brian C. Bosch, Walter R. Bahl, Amit Birtle, Alison J. Breau, Rodney H. Challapalli, Amarnath Chang, Albert J. Choudhury, Ananya Daneshmand, Sia El-Gayed, Ali Feldman, Adam Finkelstein, Steven E. Guzzo, Thomas J. Hilman, Serena Jani, Ashesh Malkowicz, S. Bruce Mantz, Constantine A. Master, Viraj Mitra, Anita V. Murthy, Vedang Porten, Sima P. Richaud, Pierre M. Efstathiou, Jason A. Eapen, Libni J. Christodouleas, John P. TI Development and Validation of Consensus Contouring Guidelines for Adjuvant Radiation Therapy for Bladder Cancer After Radical Cystectomy SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID FAILURE RISK STRATIFICATION; LOCOREGIONAL FAILURE; EXTERNAL VALIDATION; PROSTATE-CANCER; RADIOTHERAPY; CARCINOMA AB Purpose: To develop multi-institutional consensus clinical target volumes (CTVs) and organs at risk (OARs) for male and female bladder cancer patients undergoing adjuvant radiation therapy (RT) in clinical trials. Methods and Materials: We convened a multidisciplinary group of bladder cancer specialists from 15 centers and 5 countries. Six radiation oncologists and 7 urologists participated in the development of the initial contours. The group proposed initial language for the CTVs and OARs, and each radiation oncologist contoured them on computed tomography scans of a male and female cystectomy patient with input from >= 1 urologist. On the basis of the initial contouring, the group updated its CTV and OAR descriptions. The cystectomy bed, the area of greatest controversy, was contoured by another 6 radiation oncologists, and the cystectomy bed contouring language was again updated. To determine whether the revised language produced consistent contours, CTVs and OARs were redrawn by 6 additional radiation oncologists. We evaluated their contours for level of agreement using the Landis-Koch interpretation of the k statistic. Results: The group proposed that patients at elevated risk for local-regional failure with negative margins should be treated to the pelvic nodes alone (internal/external iliac, distal common iliac, obturator, and presacral), whereas patients with positive margins should be treated to the pelvic nodes and cystectomy bed. Proposed OARs included the rectum, bowel space, bone marrow, and urinary diversion. Consensus language describing the CTVs and OARs was developed and externally validated. The revised instructions were found to produce consistent contours. Conclusions: Consensus descriptions of CTVs and OARs were successfully developed and can be used in clinical trials of adjuvant radiation therapy for bladder cancer. (C) 2016 Elsevier Inc. All rights reserved. C1 [Baumann, Brian C.; Guzzo, Thomas J.; Malkowicz, S. Bruce; Christodouleas, John P.] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Bosch, Walter R.] Washington Univ, St Louis, MO USA. [Bahl, Amit; Challapalli, Amarnath; Hilman, Serena] Univ Hosp Bristol NHS Fdn Trust, Bristol, Avon, England. [Birtle, Alison J.] Royal Preston Hosp, Preston, Lancs, England. [Breau, Rodney H.; Eapen, Libni J.] Univ Ottawa, Ottawa, ON, Canada. [Chang, Albert J.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Choudhury, Ananya] Christie NHS Fdn Trust, Dept Clin Oncol, Manchester, Lancs, England. [Choudhury, Ananya] Univ Manchester, Manchester Acad Heath Sci Ctr, Manchester, Lancs, England. [Daneshmand, Sia] Univ Southern Calif, Los Angeles, CA USA. [El-Gayed, Ali] Saskatoon Canc Ctr, Saskatoon, SK, Canada. [Feldman, Adam; Efstathiou, Jason A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Finkelstein, Steven E.] Canc Treatment Ctr Amer, Tulsa, OK USA. [Jani, Ashesh; Master, Viraj] Emory Univ, Atlanta, GA 30322 USA. [Mantz, Constantine A.] 21st Century Oncol, Scottsdale, AZ USA. [Mantz, Constantine A.] 21st Century Oncol, Ft Myers, FL USA. [Mitra, Anita V.] Univ Coll London Hosp, London, England. [Murthy, Vedang] Tata Mem Hosp, Bombay, Maharashtra, India. [Richaud, Pierre M.; Efstathiou, Jason A.] Inst Bergonie, Bordeaux, France. RP Christodouleas, JP (reprint author), Univ Penn, Dept Radiat Oncol, 3400 Civ Ctr Blvd,PCAM 2, Philadelphia, PA 19103 USA. EM christojo@uphs.upenn.edu FU NCI NIH HHS [U10 CA180868, U24 CA081647, U24 CA180803] NR 13 TC 4 Z9 4 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD SEP 1 PY 2016 VL 96 IS 1 BP 78 EP 86 DI 10.1016/j.ijrobp.2016.04.032 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DS9FD UT WOS:000381087300012 PM 27511849 ER PT J AU Stapleton, CJ Torok, CM Rabinov, JD Walcott, BP Mascitelli, JR Leslie-Mazwi, TM Hirsch, JA Yoo, AJ Ogilvy, CS Patel, AB AF Stapleton, Christopher J. Torok, Collin M. Rabinov, James D. Walcott, Brian P. Mascitelli, Justin R. Leslie-Mazwi, Thabele M. Hirsch, Joshua A. Yoo, Albert J. Ogilvy, Christopher S. Patel, Aman B. TI Validation of the Modified Raymond-Roy classification for intracranial aneurysms treated with coil embolization SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article AB Background The Raymond-Roy Occlusion Classification (RROC) qualitatively assesses intracranial aneurysm occlusion following endovascular coil embolization. The Modified Raymond-Roy Classification (MRRC) was developed as a refinement of this classification scheme, and dichotomizes RROC III occlusions into IIIa (opacification within the interstices of the coil mass) and IIIb (opacification between the coil mass and aneurysm wall) closures. Methods To demonstrate in an external cohort the predictive accuracy of the MRRC, the records of 326 patients with 345 intracranial aneurysms treated with endovascular coil embolization from January 2007 to December 2013 were retrospectively analyzed. Results Within this cohort, 84 (24.3%) and 83 aneurysms (24.1%) had MRRC IIIa and IIIb closures, respectively, during initial coil embolization. Progression to complete occlusion was more likely with IIIa than IIIb closures (53.6% vs 19.2%, p <= 0.01), while recanalization was more likely with IIIb than IIIa closures (65.1% vs 27.4%, p<0.01). Kaplan-Meier estimates demonstrated a significant difference in the test of equality for progression to complete occlusion (p=0.02) and recurrence (p<0.01) between class IIIa and IIIb distributions. For the entire cohort, male gender (p<0.01), ruptured aneurysm (p=0.04), intraluminal thrombus (p<0.01), and MRRC IIIb closure (p<0.01) were identified as predictors of recanalization. For aneurysms with an initial RROC III occlusion, MRRC IIIa closure was found to be an independent predictor of progression to complete occlusion (p=0.02). Conclusions This study confirms that the MRRC enhances the predictive accuracy of the RROC. C1 [Stapleton, Christopher J.; Walcott, Brian P.; Patel, Aman B.] Massachusetts Gen Hosp, Dept Neurosurg, 15 Parkman St,Wang 745, Boston, MA 02114 USA. [Stapleton, Christopher J.; Torok, Collin M.; Rabinov, James D.; Walcott, Brian P.; Leslie-Mazwi, Thabele M.; Hirsch, Joshua A.; Ogilvy, Christopher S.; Patel, Aman B.] Harvard Med Sch, Boston, MA USA. [Stapleton, Christopher J.; Torok, Collin M.; Rabinov, James D.; Leslie-Mazwi, Thabele M.; Hirsch, Joshua A.; Patel, Aman B.] Massachusetts Gen Hosp, Neuroendovasc Program, Boston, MA 02114 USA. [Mascitelli, Justin R.] Icahn Sch Med Mt Sinai, Dept Neurosurg, New York, NY 10029 USA. [Leslie-Mazwi, Thabele M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Yoo, Albert J.] Texas Stroke Inst, Plano, TX USA. [Ogilvy, Christopher S.] Beth Israel Deaconess Med Ctr, Brain Aneurysm Inst, Neurosurg Serv, Boston, MA 02215 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 0 TC 2 Z9 2 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 EI 1759-8486 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD SEP PY 2016 VL 8 IS 9 BP 927 EP 933 DI 10.1136/neurintsurg-2015-012035 PG 7 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA DU6VF UT WOS:000382352000011 PM 26438554 ER PT J AU Wong, JC Scott, T Wilde, P Li, YG Tucker, KL Gao, X AF Wong, Janice C. Scott, Tammy Wilde, Parke Li, Yin-Ge Tucker, Katherine L. Gao, Xiang TI Food Insecurity Is Associated with Subsequent Cognitive Decline in the Boston Puerto Rican Health Study SO JOURNAL OF NUTRITION LA English DT Article DE cognitive decline; dementia; epidemiology; public health; nutrition ID DEPRESSIVE SYMPTOMS; ALZHEIMERS-DISEASE; MEDITERRANEAN DIET; OLDER-PEOPLE; ADULTS; STRESS AB Background: Living with hunger and fear of not having enough food is a growing worldwide concern. In our previous cross-sectional study, we found that food insecurity was associated with poor cognitive function, but the direction of this relation remains unclear. Objective: We investigated whether food insecurity is associated with subsequent cognitive decline. Methods: This was a longitudinal study of 597 participants aged 40-75 y from the Boston Puerto Rican Health Study cohort, with a Mini-Mental State Examination score of >= 24 at baseline. Food security was assessed at baseline with the US Household Food Security Scale. Participants completed cognitive batteries, which included 7 cognitive tests, twice at baseline and again at a 2-y follow-up. The primary outcome was the change in global cognitive function over 2 y. Multiple linear regression was used to obtain adjusted mean differences and 95% Cls in cognitive decline across baseline food security status. Results: Food insecurity at baseline was associated with a 2-y decline in global cognitive function (P-trend = 0.03) after adjusting for relevant potential confounders, including age, sex, baseline cognitive score, body mass index, education, poverty, acculturation score, depression score, smoking status, use of alcohol, physical activity score, presence of diabetes and hypertension, apolipoprotein E status, plasma homocysteine, healthy eating index, and time between baseline and follow-up measures. Compared with the food-secure group, the decline in the very low food security group was greater [mean difference: -0.26 (95% CI: -0.41, -0.10)]. Baseline food insecurity was significantly associated with a faster decline in executive function (P-trend = 0.02) but not memory function (P-trend = 0.66). Conclusions: Food insecurity was associated with faster cognitive decline in this cohort of Puerto Rican adults. Our study emphasizes the importance of developing interventions for food insecurity that take into account the impact of food insecurity on cognition. C1 [Wong, Janice C.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Wong, Janice C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Scott, Tammy] Tufts Univ, Tufts Med Ctr, Boston, MA 02111 USA. [Wilde, Parke] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Li, Yin-Ge] Univ S Florida, Coll Publ Hlth, Dept Global Hlth, Tampa, FL USA. [Tucker, Katherine L.] Univ Massachusetts Lowell, Dept Clin Lab & Nutr Sci, Lowell, MA USA. [Gao, Xiang] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. RP Gao, X (reprint author), Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. EM xxg14@psu.edu FU NIH [P01 AG023394, P50 HL105185] FX Supported by NIH grants P01 AG023394 and P50 HL105185. NR 32 TC 0 Z9 0 U1 16 U2 16 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD SEP PY 2016 VL 146 IS 9 BP 1740 EP 1745 DI 10.3945/jn.115.228700 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU7VN UT WOS:000382422800016 PM 27466603 ER PT J AU Bostic, JQ AF Bostic, Jeff Q. TI Practice Makes Permanent (Not Necessarily Perfect) SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Editorial Material C1 [Bostic, Jeff Q.] MedStar Georgetown Univ Hosp, Washington, DC USA. [Bostic, Jeff Q.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bostic, Jeff Q.] Harvard Univ, Cambridge, MA 02138 USA. RP Bostic, JQ (reprint author), Child Psychiat, 2 Faith Rd, Windham, NH 03087 USA. EM jbostic@partners.org NR 3 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 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD SEP PY 2016 VL 55 IS 9 BP 749 EP 750 DI 10.1016/j.jaac.2016.06.007 PG 2 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DU9CU UT WOS:000382514600003 PM 27566114 ER PT J AU Sattler, M Salgia, R AF Sattler, Martin Salgia, Ravi TI MET in the Driver's Seat: Exon 14 Skipping Mutations as Actionable Targets in Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Editorial Material ID TIVANTINIB ARQ 197; C-MET; TYROSINE KINASE; DOUBLE-BLIND; GROWTH; AMPLIFICATION; ACTIVATION; INHIBITORS; PROGNOSIS; ERLOTINIB C1 [Sattler, Martin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Sattler, Martin] Harvard Med Sch, Dept Med, Boston, MA USA. [Salgia, Ravi] City Hope Natl Med Ctr, Dept Med Oncol & Therapeut Res, 1500 East Duarte Rd, Duarte, CA 91010 USA. RP Salgia, R (reprint author), City Hope Natl Med Ctr, 1500 East Duarte Rd, Duarte, CA 91010 USA. EM rsalgia@coh.org 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 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2016 VL 11 IS 9 BP 1381 EP 1383 DI 10.1016/j.jtho.2016.07.003 PG 3 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DU7UN UT WOS:000382420200003 PM 27565402 ER PT J AU Waciar, SN Bonomi, PD Govindan, R Hirsch, FR Riely, GJ Papadimitrakopoulou, V Kazandjian, D Khozin, S Larkins, E Dickson, DJ Malik, S Horn, L Ferris, A Shaw, AT Janne, PA Mok, TSK Herbst, R Keegan, P Pazdur, R Blumenthal, GM AF Waciar, Saiama N. Bonomi, Philip D. Govindan, Ramaswamy Hirsch, Fred R. Riely, Gregory J. Papadimitrakopoulou, Vassiliki Kazandjian, Dickran Khozin, Sean Larkins, Erin Dickson, Dane J. Malik, Shakun Horn, Leora Ferris, Andrea Shaw, Alice T. Janne, Pasi A. Mok, Tony S. K. Herbst, Roy Keegan, Patricia Pazdur, Richard Blumenthal, Gideon M. TI Clinician Perspectives on Current Issues in Lung Cancer Drug Development SO JOURNAL OF THORACIC ONCOLOGY LA English DT Review DE Lung cancer; Clinical trials; Targeted therapy; Immunotherapy ID TYROSINE KINASE INHIBITORS; RANDOMIZED PHASE-3 TRIAL; 1ST-LINE TREATMENT; ACQUIRED-RESISTANCE; PERFORMANCE STATUS; EGFR MUTATIONS; OPEN-LABEL; CHEMOTHERAPY; THERAPY; ERLOTINIB AB Recent advances in molecularly targeted therapy and immunotherapy offer a glimmer of hope for potentially realizing the dream of personalized therapy for lung cancer. This article highlights current questions in clinical trial design, enrollment strategies and patient focused drug development, with particular emphasis on unique issues in trials of targeted therapy and immunotherapy. Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer. C1 [Waciar, Saiama N.; Govindan, Ramaswamy] Washington Univ, Sch Med, Div Oncol, St Louis, MO USA. [Bonomi, Philip D.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Hirsch, Fred R.] Univ Colorado, Ctr Canc, Denver, CO 80262 USA. [Riely, Gregory J.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Papadimitrakopoulou, Vassiliki] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kazandjian, Dickran; Khozin, Sean; Larkins, Erin; Keegan, Patricia; Pazdur, Richard; Blumenthal, Gideon M.] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. [Dickson, Dane J.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Malik, Shakun] NCI, Bethesda, MD 20892 USA. [Horn, Leora] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Ferris, Andrea] LUNGev Fdn, Bethesda, MD USA. [Shaw, Alice T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Janne, Pasi A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Mok, Tony S. K.] Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Herbst, Roy] Yale Sch Med, New Haven, CT USA. RP Blumenthal, GM (reprint author), US FDA, Div Oncol Prod 2, OHOP, OND, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM Gideon.Blumenthal@fda.hhs.gov FU NCI/NIH [K12 CA167540] FX Dr. Waciar reports grant K12 CA167540 from the NCI/NIH during the conduct of the study, and grant PI on the 1 UM1 CA186704-01 from NIH/NCI outside the submitted work. Dr. Bonomi reports serving on advisory boards of Astra Zeneca, Clovis, Merck, Biodesics, Trovagene, and Eli Lilly and on data monitoring committees of Roche Genentech and Pfizer outside the submitted work. Dr. Govindan reports consulting fees from Boehringer Ingelheim, GlaxoSmithKline, Celgene, Roche, Bayer, Genentech, Clovis, Helsinn Healthcare, and honoraria from Baxalta, and Roche outside the submitted work. Dr. Hirsch reports participation in advisory boards of Bristol-Myers Squibb, Merck, Genentech/Roche, AstraZeneca, and Lilly outside the submitted work. Dr. Riely reports personal fees from Novartis and Roche and grants from Novartis, Millennium, GlaxoSmithKline, Pfizer, Infinity. Pharmaceuticals, and Ariad outside the submitted work. Dr. Papadimitrakopoulou is a scientific advisory committee member for Clovis Oncology and Genentech, reports consulting fees from Merck, AstraZeneca, Bristol-Myers Squibb, and ARIAD Pharmaceuticals and grants from the following: AstraZeneca; Bristol-Myers Squibb; the American Association for Cancer Research; the National Cancer Institute, National Institutes of Health; Cancer Prevention and Research Institute of Texas; and Hope Foundation outside the submitted work. Dr. Horn reports participation in paid advisory board for Lilly Genentech, and Merck, serving as an unpaid advisory board member and steering committee member at Bristol-Myers Squibb and an upaid advisory board member at Boehringer Ingelheim, performing unpaid consulting work for Xcovery, and serving as an uncompensated steering committee member at Bayer outside the submitted work. Dr. Shaw is a consulting and scientific advisory board member for Blueprint medicine and reports consulting fees from Novartis, Genentech/Roche, Ariad, Daiich-Sankyo, Ignyta, Taiho, EMD Serono, and Pfizer outside the submitted work. Dr. Janne reports grants and personal fees from AstraZeneca; consulting fees from Boehringer Ingelheim, Pfizer, Merrimack Pharmaceuticals, Chugai, and Roche; grants from Astellas; consulting fees from Ariad; and stock ownership in Gatekeeper Pharmaceuticals during the conduct of the study. In addition, Dr. Janne receives postmarketing royalties from Dana-Farber Cancer Institute-owned intellectual property on epidermal growth factor receptor mutations licensed to Lab Corp. Dr. Mok reports personal fees from AstraZeneca, Roche/Genentech, Pfizer, Lilly, Boeh, ringer Ingelheim, Merck Serono, Merck Sharp and Dohme, Janssen, Clovis Oncology, BioMarin, GlaxoSmithKline, Novartis, SFJ Pharmaceuticals, ACEA Biosciences, Vertex Pharmaceuticals, Bristol-Myers Squibb, AVEO and Biodesix, Prime Oncology, Amgen, Sanomics Ltd., and geneDecode outside the submitted work. Dr. Herbst reports personal fees from Diatech, Kolltan, AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Pfizer and grants and personal fees from Genentech/Roche and Merck outside the submitted work. The remaining authors declare no conflict of interest. NR 54 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 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2016 VL 11 IS 9 BP 1387 EP 1396 DI 10.1016/j.jtho.2016.05.009 PG 10 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DU7UN UT WOS:000382420200005 ER PT J AU Dagogo-Jack, I Gainor, JF Porter, RL Schultz, KR Solomon, BJ Stevens, S Azzoli, CG Sequist, LV Lennes, IT Shaw, AT AF Dagogo-Jack, Ibiayi Gainor, Justin F. Porter, Rebecca L. Schultz, Katherine R. Solomon, Benjamin J. Stevens, Sara Azzoli, Christopher G. Sequist, Lecia V. Lennes, Inga T. Shaw, Alice T. TI Clinicopathologic Features of NSCLC Diagnosed During Pregnancy or the Peripartum Period in the Era of Molecular Genotyping SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Pregnancy; ALK; EGFR; Lung cancer ID CELL LUNG-CANCER; ADENOCARCINOMA; CRIZOTINIB; ERLOTINIB; PATIENT AB Introduction: Cancer will be diagnosed in one in 1000 women during pregnancy. The outcomes of NSCLC diagnosed during pregnancy are dismal, with most patients dying within 1 year. Actionable mutations are more likely to be found among younger patients with NSCLC. However, most previous reports of NSCLC diagnosed during pregnancy did not include molecular genotyping. Methods: We performed a retrospective analysis of patients seen at our institution between 2009 and 2015 to identify women in whom NSCLC was diagnosed during pregnancy or the peripartum period and determined clinicopathologic features, including molecular genotype. Results: We identified 2422 women with NSCLC, including 160 women of reproductive age. Among the women of reproductive age, eight cases of NSCLC diagnosed during pregnancy or the peripartum period were identified; all were diagnosed in minimal or never-smokers with metastatic adenocarcinoma. Six of these patients were found to have anaplastic lymphoma kinase gene (ALK) rearrangements, whereas the remaining two were EGFR mutation positive. We observed a borderline significant association between a diagnosis of NSCLC: during pregnancy or the peripartum period and ALK positivity (p = 0.053). All eight women in whom NSCLC was diagnosed during pregnancy or the peripartum period received treatment with genotype directed therapies after delivery. The median overall survival has not been reached at a median follow-up of 30 months. Conclusions: Although a diagnosis of NSCLC during pregnancy or the peripartum period is rare, diagnostic evaluation should not be delayed in pregnant women presenting with symptoms worrisome for lung cancer. Evaluation should include testing for targetable molecular alterations. (C) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. C1 [Dagogo-Jack, Ibiayi; Gainor, Justin F.; Porter, Rebecca L.; Schultz, Katherine R.; Stevens, Sara; Azzoli, Christopher G.; Sequist, Lecia V.; Lennes, Inga T.; Shaw, Alice T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Solomon, Benjamin J.] Peter MacCallum Canc Ctr, Dept Med Oncol, East Melbourne, Vic, Australia. RP Shaw, AT (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St, Boston, MA 02114 USA. EM ashaw1@partners.org FU National Cancer Institute [5R01CA164273]; National Foundation for Cancer Research; Be a Piece of the Solution and LungStrong FX This work was supported by grants from the National Cancer Institute (5R01CA164273, to Dr. Shaw) and the National Foundation for Cancer Research (to Dr. Shaw) and by Be a Piece of the Solution and LungStrong. NR 22 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2016 VL 11 IS 9 BP 1522 EP 1528 DI 10.1016/j.jtho.2016.05.031 PG 7 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DU7UN UT WOS:000382420200018 PM 27296107 ER PT J AU Brose, MS Cabanillas, ME Cohen, EEW Wirth, LJ Riehl, T Yue, HB Sherman, SI Sherman, EJ AF Brose, Marcia S. Cabanillas, Maria E. Cohen, Ezra E. W. Wirth, Lori J. Riehl, Todd Yue, Huibin Sherman, Steven I. Sherman, Eric J. TI Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial SO LANCET ONCOLOGY LA English DT Article ID BRAF V600E MUTATION; DOUBLE-BLIND; CARCINOMA; LENVATINIB; SORAFENIB; MORTALITY; MELANOMA AB Background About half of patients with papillary thyroid cancer have tumours with activating BRAF(V600E) mutations. Vemurafenib, an oncogenic BRAF kinase inhibitor approved for BRAF-positive melanoma, showed clinical benefit in three patients with BRAF(V600E)-positive papillary thyroid cancer in a phase 1 trial. We aimed to establish the activity of vemurafenib in patients with BRAF(V600E)-positive papillary thyroid cancer. Methods We did an open-label, non-randomised, phase 2 trial at ten academic centres and hospitals worldwide in patients aged 18 years or older with histologically confirmed recurrent or metastatic papillary thyroid cancer refractory to radioactive iodine and positive for the BRAF(V600E) mutation. Participants either had never received a multikinase inhibitor targeting VEGFR (cohort 1) or had been treated previously with a VEGFR multikinase inhibitor (cohort 2). Patients received vemurafenib 960 mg orally twice daily.The primary endpoint was investigator-assessed best overall response in cohort 1 (confirmed on two assessments 4 weeks or longer apart). Analyses were planned to have a minimum median follow-up of 15 months (data cutoff April 18, 2014) and were done in safety, intention-to-treat, and per-protocol populations. This trial is closed and is registered at ClinicalTrials.gov, number NCT01286753. Findings Between June 23, 2011, and Jan 15, 2013, 51 patients were enrolled to the study, 26 in cohort 1 and 25 in cohort 2. Median duration of follow-up was 18.8 months (IQR 14.2-26.0) in cohort 1 and 12.0 months (6.7-20.3) in cohort 2. Partial responses were recorded in ten of 26 patients in cohort 1 (best overall response 38.5%, 95% CI 20.2-59.4). Grade 3 or 4 adverse events were recorded in 17 (65%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2; the most common grade 3 and 4 adverse events were squamous cell carcinoma of the skin (seven [27%] in cohort 1, five [20%] in cohort 2), lymphopenia (two [8%] in each cohort), and increased. -glutamyltransferase (one [4%] in cohort 1, three [12%] in cohort 2). Two individuals in cohort 2 died due to adverse events, one from dyspnoea and one from multiorgan failure, but neither was treatment related. Serious adverse events were reported for 16 (62%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2. Interpretation Vemurafenib showed antitumour activity in patients with progressive, BRAF(V600E)-positive papillary thyroid cancer refractory to radioactive iodine who had never been treated with a multikinase inhibitor. As such, this agent represents a potential new treatment option for these patients. C1 [Brose, Marcia S.] Univ Penn, Dept Otorhinolaryngol Head & Neck Surg, Philadelphia, PA 19104 USA. [Brose, Marcia S.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Cabanillas, Maria E.; Sherman, Steven I.] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Houston, TX 77030 USA. [Cohen, Ezra E. W.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Wirth, Lori J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Riehl, Todd] Genentech Inc, Prod Dev Clin Oncol, San Francisco, CA 94080 USA. [Yue, Huibin] Genentech Inc, Biostat, San Francisco, CA 94080 USA. [Sherman, Eric J.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. RP Brose, MS (reprint author), Univ Penn, Dept Otorhinolaryngol Head & Neck Surg, Philadelphia, PA 19104 USA.; Brose, MS (reprint author), Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. EM brosem@mail.med.upenn.edu FU F Hoffmann-La Roche FX F Hoffmann-La Roche. NR 25 TC 7 Z9 7 U1 5 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD SEP PY 2016 VL 17 IS 9 BP 1272 EP 1282 DI 10.1016/S1470-2045(16)30166-8 PG 11 WC Oncology SC Oncology GA DU7MP UT WOS:000382398700041 PM 27460442 ER PT J AU Younes, A Santoro, A Shipp, M Zinzani, PL Timmerman, JM Ansell, S Armand, P Fanale, M Ratanatharathorn, V Kuruvilla, J Cohen, JB Collins, G Savage, KJ Trneny, M Kato, K Farsaci, B Parker, SM Rodig, S Roemer, MGM Ligon, AH Engert, A AF Younes, Anas Santoro, Armando Shipp, Margaret Zinzani, Pier Luigi Timmerman, John M. Ansell, Stephen Armand, Philippe Fanale, Michelle Ratanatharathorn, Voravit Kuruvilla, John Cohen, Jonathon B. Collins, Graham Savage, Kerry J. Trneny, Marek Kato, Kazunobu Farsaci, Benedetto Parker, Susan M. Rodig, Scott Roemer, Margaretha G. M. Ligon, Azra H. Engert, Andreas TI Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial SO LANCET ONCOLOGY LA English DT Article ID CHEMOTHERAPY; EXPRESSION; DISEASE; CANCER AB Background Malignant cells of classical Hodgkin's lymphoma are characterised by genetic alterations at the 9p24.1 locus, leading to overexpression of PD-1 ligands and evasion of immune surveillance. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed and refractory classical Hodgkin's lymphoma, with an acceptable safety profile. We aimed to assess the clinical benefit and safety of nivolumab monotherapy in patients with classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin. Methods In this ongoing, single-arm phase 2 study, adult patients (aged = 18 years) with recurrent classical Hodgkin's lymphoma who had failed to respond to autologous stem-cell transplantation and had either relapsed after or failed to respond to brentuximab vedotin, and with an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled from 34 hospitals and academic centres across Europe and North America. Patients were given nivolumab intravenously over 60 min at 3 mg/kg every 2 weeks until progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was objective response following a prespecified minimum follow-up period of 6 months, assessed by an independent radiological review committee (IRRC). All patients who received at least one dose of nivolumab were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02181738. Findings Among 80 treated patients recruited between Aug 26, 2014, and Feb 20, 2015, the median number of previous therapies was four (IQR 4-7). At a median follow-up of 8 . 9 months (IQR 7 . 8-9 . 9), 53 (66 . 3%, 95% CI 54 . 8-76 . 4) of 80 patients achieved an IRRC-assessed objective response. The most common drug-related adverse events (those that occurred in >= 15% of patients) included fatigue (20 [25%] patients), infusion-related reaction (16 [20%]), and rash (13 [16%]). The most common drug-related grade 3 or 4 adverse events were neutropenia (four [5%] patients) and increased lipase concentrations (four [5%]). The most common serious adverse event (any grade) was pyrexia (three [4%] patients). Three patients died during the study; none of these deaths were judged to be treatment related. Interpretation Nivolumab resulted in frequent responses with an acceptable safety profile in patients with classical Hodgkin's lymphoma who progressed after autologous stem-cell transplantation and brentuximab vedotin. Therefore, nivolumab might be a new treatment option for a patient population with a high unmet need. Ongoing follow-up will help to assess the durability of response. C1 [Younes, Anas] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Santoro, Armando] Humanitas Univ, Humanitas Canc Ctr, Rozzano Milan, Italy. [Shipp, Margaret; Armand, Philippe; Roemer, Margaretha G. M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Zinzani, Pier Luigi] Univ Bologna, Inst Hematol Le A Seragnoli, Bologna, Italy. [Timmerman, John M.] Univ Calif Los Angeles, Los Angeles, CA USA. [Ansell, Stephen] Mayo Clin, Rochester, MN USA. [Fanale, Michelle] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Ratanatharathorn, Voravit] Barbara Ann Karmanos Canc Inst, Detroit, MI USA. [Kuruvilla, John] Univ Toronto, Toronto, ON, Canada. [Kuruvilla, John] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Cohen, Jonathon B.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Collins, Graham] Churchill Hosp, Oxford Canc & Haematol Ctr, Oxford, England. [Savage, Kerry J.] British Columbia Canc Agcy, Dept Med Oncol, Vancouver, BC, Canada. [Trneny, Marek] Charles Univ Prague, Prague, Czech Republic. [Trneny, Marek] Gen Univ Hosp Prague, Prague, Czech Republic. [Kato, Kazunobu; Farsaci, Benedetto; Parker, Susan M.] Bristol Myers Squibb, Princeton, NJ USA. [Rodig, Scott; Ligon, Azra H.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Engert, Andreas] Univ Hosp Cologne, Cologne, Germany. RP Younes, A (reprint author), Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. EM younesa@mskcc.org FU Bristol-Myers Squibb FX Bristol-Myers Squibb. NR 23 TC 14 Z9 14 U1 7 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD SEP PY 2016 VL 17 IS 9 BP 1283 EP 1294 DI 10.1016/S1470-2045(16)30167-X PG 12 WC Oncology SC Oncology GA DU7MP UT WOS:000382398700042 PM 27451390 ER PT J AU Asdourian, MS Skolny, MN Brunelle, C Seward, CE Salama, L Taghian, AG AF Asdourian, Maria S. Skolny, Melissa N. Brunelle, Cheryl Seward, Cara E. Salama, Laura Taghian, Alphonse G. TI Precautions for breast cancer-related lymphoedema: risk from air travel, ipsilateral arm blood pressure measurements, skin puncture, extreme temperatures, and cellulitis SO LANCET ONCOLOGY LA English DT Review ID ELECTIVE HAND SURGERY; AXILLARY DISSECTION; POSTMASTECTOMY LYMPHEDEMA; FOLLOW-UP; SEPARATING FACT; HUMAN LEG; SURVIVORS; WOMEN; PREVENTION; EDEMA AB Precautionary recommendations conveyed to survivors of cancer by health-care practitioners to reduce the risk of breast cancer-related lymphoedema are indispensable aspects of clinical care, yet remain unsubstantiated by high-level scientific evidence. By reviewing the literature, we identified 31 original research articles that examined whether lifestyle-associated risk factors (air travel, ipsilateral arm blood pressure measurements, skin puncture, extreme temperatures, and skin infections-eg, cellulitis) increase the risk of breast cancer-related lymphoedema. Among the few studies that lend support to precautionary guidelines, most provide low-level (levels 3-5) or inconclusive evidence of an association between lymphoedema and these risk factors, and only four level 2 studies show a significant association. Skin infections and previous infection or inflammation on the ipsilateral arm were among the most clearly defined and well established risk factors for lymphoedema. The paucity of high-level evidence and the conflicting nature of the existing literature make it difficult to establish definitive predictive factors for breast cancer-related lymphoedema, which could be a considerable source of patient distress and anxiety. Along with further research into these risk factors, continued discussion regarding modification of the guidelines and adoption of a risk-adjusted approach is needed. C1 [Asdourian, Maria S.; Skolny, Melissa N.; Seward, Cara E.; Salama, Laura; Taghian, Alphonse G.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St, Boston, MA 02114 USA. [Brunelle, Cheryl] Harvard Med Sch, Massachusetts Gen Hosp, Dept Phys & Occupat Therapy, Boston, MA USA. RP Taghian, AG (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St, Boston, MA 02114 USA. EM ataghian@partners.org FU National Cancer Institute [R01CA139118, P50CA089393]; Adele McKinnon Research Fund for Breast Cancer-Related Lymphedema FX The study was supported by award number R01CA139118 (to AGT), and award number P50CA089393 (to AGT) from the National Cancer Institute and the Adele McKinnon Research Fund for Breast Cancer-Related Lymphedema. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 86 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 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD SEP PY 2016 VL 17 IS 9 BP E392 EP E405 PG 14 WC Oncology SC Oncology GA DU7MP UT WOS:000382398700015 PM 27599144 ER PT J AU Bolton, CE Quint, JK Dransfield, MT AF Bolton, Charlotte E. Quint, Jennifer K. Dransfield, Mark T. TI Cardiovascular disease in COPD: time to quash a silent killer SO LANCET RESPIRATORY MEDICINE LA English DT Editorial Material ID OBSTRUCTIVE PULMONARY-DISEASE; MYOCARDIAL-INFARCTION; EXACERBATION; MORTALITY; SURVIVAL; TORCH; RISK C1 [Bolton, Charlotte E.] Univ Nottingham, Nottingham Resp Res Unit, Sch Med, Nottingham, England. [Quint, Jennifer K.] Imperial Coll London, Natl Heart & Lung Inst, Dept Resp Epidemiol Occupat Med & Publ Hlth, London, England. [Dransfield, Mark T.] Univ Alabama Birmingham, Div Pulm Allergy & Crit Care Med, Birmingham, AL 35294 USA. [Dransfield, Mark T.] Birmingham VA Med Ctr, Birmingham, AL 35294 USA. RP Dransfield, MT (reprint author), Univ Alabama Birmingham, Div Pulm Allergy & Crit Care Med, Birmingham, AL 35294 USA.; Dransfield, MT (reprint author), Birmingham VA Med Ctr, Birmingham, AL 35294 USA. EM mdransfield@uabmc.edu NR 11 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-2600 J9 LANCET RESP MED JI Lancet Resp. Med. PD SEP PY 2016 VL 4 IS 9 BP 687 EP 689 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DU7TO UT WOS:000382417700008 PM 27599243 ER PT J AU Pavord, ID Lettis, S Anzueto, A Barnes, N AF Pavord, Ian D. Lettis, Sally Anzueto, Antonio Barnes, Neil TI Blood eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: a patient-level meta-analysis SO LANCET RESPIRATORY MEDICINE LA English DT Article ID INHALED FLUTICASONE FUROATE; COMMUNITY-ACQUIRED PNEUMONIA; RANDOMIZED CONTROLLED-TRIALS; INCREASED MORTALITY; LUNG-FUNCTION; MU-G; COPD; EXACERBATIONS; CORTICOSTEROIDS; VILANTEROL AB Background Inhaled corticosteroids are important in the management of chronic obstructive pulmonary disease (COPD), but can slightly increase the risk of pneumonia in patients with moderate-to-severe COPD. Patients with circulating eosinophil counts of 2% or more of blood leucocytes respond better to inhaled corticosteroids than do those with counts of less than 2% and it was therefore postulated that blood eosinophil count might also have an effect on the risk of pneumonia in patients with COPD. In this post-hoc meta-analysis, we investigate whether a 2% threshold can identify patients who differ in their risk of pneumonia, irrespective of inhaled corticosteroid treatment. Methods From the GlaxoSmithRline trial registry, we selected randomised, double-blind, clinical trials of patients with COPD that had: inhaled corticosteroid arms (fluticasone propionate and salmeterol or fluticasone furoate and vilanterol); a control arm (not given inhaled fluticasone); and pre-randomisation measurements of blood eosinophil counts and were of at least 24 weeks in duration. With use of specified terms from the Medical Dictionary for Regulatory Activities we identified pneumonia adverse events in patient-level data. We calculated number of patients with pneumonia events, stratified by baseline blood eosinophil count (<2% vs >= 2% of blood leucocytes) and whether or not patients had received inhaled corticosteroids. Findings We identified ten trials (conducted between 1998 and 2011), with eosinophil count data available for 10 861 patients with COPD. 4043 patients had baseline blood eosinophil counts of less than 2% and 6818 patients had baseline blood eosinophil counts of 2% or more. 149 (3.7%) patients with counts less than 2% had one or more pneumonia adverse events compared with 215 (3.2%) with counts of 2% or more (hazard ratio [HR] 1.31; 95% CI 1.06-1.62). In patients not treated with inhaled corticosteroids, 40 (3.8%) patients with less than 2% blood eosinophil counts had a pneumonia event versus 48 (2.4%) with 2% or more blood eosinophils (HR 1.53; 95% CI 1.01-2.31). In patients treated with inhaled corticosteroids, events occurred in 107 (4.5%) versus 164 (3.9%; HR 1.25; 95% CI 0.98-1.60), respectively. Interpretation Using 2% baseline eosinophil count as a threshold, patients with COPD with lower blood eosinophil counts had more pneumonia events than did those with higher counts. The magnitude of this increased risk was small and should be further explored in large, prospective studies. These data should be considered when making treatment decisions, alongside existing evidence that patients with COPD and baseline blood eosinophil counts less than 2% have a poorer response to inhaled corticosteroids. C1 [Pavord, Ian D.] Univ Oxford, Nuffield Dept Med, Resp Med Unit, Oxford OX1 2JD, England. [Lettis, Sally] GSK, Stat & Programming, Stockley Pk, England. [Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Barnes, Neil] GSK, Resp Med Franchise, Brentford, England. [Barnes, Neil] Batts & London Sch Med & Dent, William Harvey Res Inst, London, England. RP Pavord, ID (reprint author), Univ Oxford, Nuffield Dept Med, Resp Med Unit, Oxford OX1 2JD, England.; Pavord, ID (reprint author), Univ Oxford, Oxford OX3 7FZ, England. EM ian.pavord@ndm.ox.ac.uk FU Glaxo SmithKline FX Glaxo SmithKline. NR 34 TC 2 Z9 2 U1 2 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-2600 J9 LANCET RESP MED JI Lancet Resp. Med. PD SEP PY 2016 VL 4 IS 9 BP 731 EP 741 DI 10.1016/S2213-2600(16)301485 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DU7TO UT WOS:000382417700020 PM 27460163 ER PT J AU Louis, DN O'Brien, MJ Young, RH AF Louis, David N. O'Brien, Michael J. Young, Robert H. TI The flowering of pathology as a medical discipline in Boston, 1892-c.1950: WT Councilman, FB Mallory, JH Wright, SB Wolbach and their descendants SO MODERN PATHOLOGY LA English DT Review ID CIRRHOSIS; FEVER; FILMS AB During most of the nineteenth century, the discipline of pathology in Boston made substantial strides as a result of physicians and surgeons who practiced pathology on a part-time basis. The present essay tells the subsequent story, beginning in 1892, when full-time pathologists begin to staff the medical schools and hospitals of Boston. Three individuals from this era deserve special mention: William T Councilman, Frank Burr Mallory and James Homer Wright, with Councilman remembered primarily as a visionary and teacher, Mallory as a trainer of many pathologists, and Wright as a scientist. Together with S Burt Wolbach in the early-to-mid-twentieth century, these pathologists went on to train the next generation of pathologists a generation that then populated the various hospitals that were developed in Boston in the early 1900s. This group of seminal pathologists in turn formed the diagnostically strong, academically productive, pathology departments that grew in Boston over the remainder of the twentieth century. C1 [Louis, David N.; Young, Robert H.] Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Pathol Serv, WRN225,55 Fruit St, Boston, MA 02114 USA. [Louis, David N.; Young, Robert H.] Harvard Med Sch, Dept Pathol, WRN225,55 Fruit St, Boston, MA 02114 USA. [O'Brien, Michael J.] Boston Univ, Med Ctr, Dept Pathol & Lab Med, Mallory Inst Pathol, Boston, MA USA. RP Louis, DN (reprint author), Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Pathol Serv, WRN225,55 Fruit St, Boston, MA 02114 USA.; Louis, DN (reprint author), Harvard Med Sch, Dept Pathol, WRN225,55 Fruit St, Boston, MA 02114 USA. EM DLOUIS@mgh.harvard.edu NR 68 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD SEP PY 2016 VL 29 IS 9 BP 944 EP 961 DI 10.1038/modpathol.2016.91 PG 18 WC Pathology SC Pathology GA DU7VA UT WOS:000382421500001 PM 27312063 ER PT J AU Rosenbaum, MW Bledsoe, JR Morales-Oyarvide, V Huynh, TG Mino-Kenudson, M AF Rosenbaum, Matthew W. Bledsoe, Jacob R. Morales-Oyarvide, Vicente Huynh, Tiffany G. Mino-Kenudson, Mari TI PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes SO MODERN PATHOLOGY LA English DT Article ID CELL LUNG-CANCER; DEATH-LIGAND 1; CLINICOPATHOLOGICAL ANALYSIS; SAFETY; CHECKPOINTS; ACTIVATION; NIVOLUMAB; BLOCKADE; MELANOMA; ANTIBODY AB Programmed cell death 1 (PD-1) and its ligand (PD-L1) are key suppressors of the cytotoxic immune response. PD-L1 expression on tumor cells may be induced by the immune microenvironment, resulting in immune escape (adaptive immune resistance), and an adverse prognosis in many malignancies. In colorectal carcinoma the response to PD-1/PD-L1 inhibition is correlated with microsatellite instability. However, little is known about the clinicopathologic, molecular, and prognostic characteristics of colorectal carcinoma with PD-L1 expression. We performed immunohistochemistry for PD-L1 on 181 cases of colorectal carcinoma with known microsatellite instability and mutational status, and correlated PD-L1 expression with clinicopathologic features including tumor-infiltrating lymphocyte burden/immunophenotype, tumor mutational profile, and disease-specific survival. PD-L1 was expressed in tumors from 16 patients (9%) who were more often older (P = 0.006) and female (P = 0.035), with tumors exhibiting a larger size (P = 0.013), but lower stage ( P < 0.001). PD-L1 expression was associated with increased CD8 and TBET-positive tumor-infiltrating lymphocytes, medullary phenotype, poor differentiation, microsatellite instability, BRAF mutation (P < 0.001 for each), and a lower frequency of KRAS mutation (P = 0.012). On multivariate analysis, PD-L1 expression was associated with medullary morphology and frequent CD8-positive tumor-infiltrating lymphocytes, suggesting adaptive immune resistance. PD-L1 positivity was not predictive of survival in the entire cohort, but it was associated with a lower disease-specific survival within the microsatellite-instability high cohort. PD-L1 expression in colorectal carcinoma is associated with clinicopathologic and molecular features of the serrated pathway of colorectal carcinogenesis, and is associated with a worse outcome within microsatellite-unstable tumors. These findings support the role of PD-L1 expression in providing normally immunogenic colorectal carcinoma a means of immune evasion and a more aggressive biology, provide a potential mechanistic explanation for the favorable response of microsatellite-unstable colorectal carcinoma to PD-1/PD-L1 pathway blockade, and suggest potential predictive and prognostic roles of PD-L1 immunohistochemistry in colorectal carcinoma. C1 [Rosenbaum, Matthew W.; Bledsoe, Jacob R.; Huynh, Tiffany G.; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 122, Boston, MA 02114 USA. [Morales-Oyarvide, Vicente] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. [Mino-Kenudson, Mari] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Mino-Kenudson, M (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 122, Boston, MA 02114 USA. EM mminokenudson@partners.org NR 28 TC 8 Z9 8 U1 3 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD SEP PY 2016 VL 29 IS 9 BP 1104 EP 1112 DI 10.1038/modpathol.2016.95 PG 9 WC Pathology SC Pathology GA DU7VA UT WOS:000382421500015 PM 27198569 ER PT J AU Jordan, NV Bardia, A Wittner, BS Benes, C Ligorio, M Zheng, Y Yu, M Sundaresan, TK Licausi, JA Desai, R O'Keefe, RM Ebright, RY Boukhali, M Sil, S Onozato, ML Iafrate, AJ Kapur, R Sgroi, D Ting, DT Toner, M Ramaswamy, S Haas, W Maheswaran, S Haber, DA AF Jordan, Nicole Vincent Bardia, Aditya Wittner, Ben S. Benes, Cyril Ligorio, Matteo Zheng, Yu Yu, Min Sundaresan, Tilak K. Licausi, Joseph A. Desai, Rushil O'Keefe, Ryan M. Ebright, Richard Y. Boukhali, Myriam Sil, Srinjoy Onozato, Maristela L. Iafrate, Anthony J. Kapur, Ravi Sgroi, Dennis Ting, David T. Toner, Mehmet Ramaswamy, Sridhar Haas, Wilhelm Maheswaran, Shyamala Haber, Daniel A. TI HER2 expression identifies dynamic functional states within circulating breast cancer cells SO NATURE LA English DT Article ID TUMOR-CELLS; STEM-CELLS; SIGNALING PATHWAYS; HEDGEHOG PATHWAY; NOTCH; INHIBITOR; TUMORIGENESIS; TRASTUZUMAB; RECURRENCE; AXIS AB Circulating tumour cells in women with advanced oestrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer acquire a HER2-positive subpopulation after multiple courses of therapy(1,2). In contrast to HER2-amplified primary breast cancer, which is highly sensitive to HER2-targeted therapy, the clinical significance of acquired HER2 heterogeneity during the evolution of metastatic breast cancer is unknown. Here we analyse circulating tumour cells from 19 women with ER+/HER2(-) primary tumours, 84% of whom had acquired circulating tumour cells expressing HER2. Cultured circulating tumour cells maintain discrete HER2(+) and HER2(-) subpopulations: HER2+ circulating tumour cells are more proliferative but not addicted to HER2(-), consistent with activation of multiple signalling pathways; HER2(-) circulating tumour cells show activation of Notch and DNA damage pathways, exhibiting resistance to cytotoxic chemotherapy, but sensitivity to Notch inhibition. HER2(+) and HER2(-) circulating tumour cells interconvert spontaneously, with cells of one phenotype producing daughters of the opposite within four cell doublings. Although HER2(+) and HER2(-) circulating tumour cells have comparable tumour initiating potential, differential proliferation favours the HER2(+) state, while oxidative stress or cytotoxic chemotherapy enhances transition to the HER2(-) phenotype. Simultaneous treatment with paclitaxel and Notch inhibitors achieves sustained suppression of tumorigenesis in orthotopic circulating tumour cell-derived tumour models. Together, these results point to distinct yet interconverting phenotypes within patient-derived circulating tumour cells, contributing to progression of breast cancer and acquisition of drug resistance. C1 [Jordan, Nicole Vincent; Bardia, Aditya; Wittner, Ben S.; Benes, Cyril; Ligorio, Matteo; Zheng, Yu; Yu, Min; Sundaresan, Tilak K.; Licausi, Joseph A.; Desai, Rushil; O'Keefe, Ryan M.; Ebright, Richard Y.; Boukhali, Myriam; Sil, Srinjoy; Onozato, Maristela L.; Iafrate, Anthony J.; Sgroi, Dennis; Ting, David T.; Ramaswamy, Sridhar; Haas, Wilhelm; Maheswaran, Shyamala; Haber, Daniel A.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Bardia, Aditya; Wittner, Ben S.; Benes, Cyril; Sundaresan, Tilak K.; Ting, David T.; Ramaswamy, Sridhar; Haas, Wilhelm; Haber, Daniel A.] Harvard Med Sch, Dept Med, Boston, MA 02114 USA. [Ligorio, Matteo; Toner, Mehmet; Maheswaran, Shyamala] Harvard Med Sch, Dept Surg, Boston, MA 02114 USA. [Onozato, Maristela L.; Iafrate, Anthony J.; Sgroi, Dennis] Harvard Med Sch, Dept Pathol, Boston, MA 02114 USA. [Kapur, Ravi; Toner, Mehmet] Harvard Med Sch, Ctr Bioengn Med, Boston, MA 02114 USA. [Kapur, Ravi; Toner, Mehmet] Harvard Med Sch, Shriners Hosp, Boston, MA 02114 USA. [Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Yu, Min] Univ Southern Calif, Dept Stem Cell Biol & Regenerat Med, Los Angeles, CA 90033 USA. RP Jordan, NV (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. OI Ting, David/0000-0002-3261-2322 FU National Institutes of Health (NIH) [2RO1CA129933]; Howard Hughes Medical Institute; Breast Cancer Research Foundation; National Foundation for Cancer Research; Wellcome Trust [102696]; NIH [2U01EB012493, T32 CA009361]; Susan G. Komen Foundation [PDF16376429, K12 5K12CA087723] FX We thank the patients who participated in this study. This work was supported by National Institutes of Health (NIH) 2RO1CA129933, the Howard Hughes Medical Institute, the Breast Cancer Research Foundation, the National Foundation for Cancer Research (DAH) and Wellcome Trust 102696 (C.B.), NIH Quantum 2U01EB012493 (M.T., D.A.H.), T32 CA009361, Susan G. Komen Foundation PDF16376429 (N.V.J.), K12 5K12CA087723 (A.B.) and T32GM007753 (RYE.). We thank D. Dombrowski (NIH 1S100D1016372-01) for expert flow cytometry. NR 25 TC 6 Z9 7 U1 43 U2 53 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD SEP 1 PY 2016 VL 537 IS 7618 BP 102 EP 106 DI 10.1038/nature19328 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU7XC UT WOS:000382426900047 PM 27556950 ER PT J AU Yam, FK Lew, T Eraly, SA Lin, HW Hirsch, JD Devor, M AF Yam, Felix K. Lew, Tiffany Eraly, Satish A. Lin, Hsiang-Wen Hirsch, Jan D. Devor, Michelle TI Changes in medication regimen complexity and the risk for 90-day hospital readmission and/or emergency department visits in US Veterans with heart failure SO RESEARCH IN SOCIAL & ADMINISTRATIVE PHARMACY LA English DT Article DE Medication regimen complexity index; MRCI; Heart failure; Patient readmission; Outcomes assessment; Polypharmacy ID OLDER-PEOPLE; ADHERENCE; INDEX; DISCHARGE; THERAPY; INTERVENTION; VALIDATION; MORTALITY AB Background: Heart failure (HF) hospitalization is associated with multiple medication modifications. These modifications often increase medication regimen complexity and may increase the risk of readmission and/or emergency department (ED) visit. Objectives: To determine the association between changes in medication regimen complexity (MRC) during hospitalization of patients with heart failure and the risk of readmission or ED visit at 90 days. Secondary objectives include examining the association between changes in MRC and time to readmission as well as the relationship between number of medications and MRC. Methods: This was a retrospective cohort study that included U.S. Veterans hospitalized with heart failure. MRC was quantified using the medication regimen complexity index (MRCI). The change in MRCI was the difference between admission MRCI and discharge MRCI recorded during the index hospitalization. Demographic and clinical data were collected to characterize the study population. Patient data for up to one year after discharge was recorded to identify hospital readmissions and ED visits. Results: A total of 174 patients were included in the analysis. Sixty-two patients (36%) were readmitted or had an ED visit at 90 days from the index hospitalization. The mean change (SD) in MRCI during the index hospitalization among the cohort was 4.7 (8.3). After multivariate logistic regression analysis, each unit increase in MRCI score was associated with a 4% lower odds of readmission or ED visit at 90 days but this finding was not statistically significant (OR 0.955; 95% CI 0.911-1.001). In the cox proportional hazard model, the median time to hospital readmission or ED visit was 214 days. Each unit increase in MRCI score was associated with a modest but non-significant increase in probability of survival from readmission or ED visit (HR 0.978; 95% CI 0.955, 1.001). Conclusion: Changes in medication regimen complexity that occur during hospitalization may also be associated with optimization of medical therapy and do not necessarily portend worse outcomes in patients with HF. Published by Elsevier Inc. C1 [Yam, Felix K.; Hirsch, Jan D.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, 9500 Gilman Dr,MC 0764, La Jolla, CA 92093 USA. [Yam, Felix K.; Eraly, Satish A.; Hirsch, Jan D.; Devor, Michelle] VA San Diego Healthcare Syst, 3350 La Jolla Village Dr, San Diego, CA USA. [Lew, Tiffany] San Francisco VA Med Ctr, 4150 Clement St 119, San Francisco, CA 94121 USA. [Eraly, Satish A.; Devor, Michelle] Univ Calif San Diego, Sch Med, 9500 Gilman Dr, La Jolla, CA 92093 USA. [Lin, Hsiang-Wen] China Med Univ, Coll Pharm, 91 Hsueh Shih Rd, Taichung 40402, Taiwan. RP Yam, FK (reprint author), Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, 9500 Gilman Dr,MC 0764, La Jolla, CA 92093 USA. EM fyam@ucsd.edu FU American Foundation for Pharmaceutical Education (AFPE) Pharmacy Faculty Fellow Award FX This work was supported by the American Foundation for Pharmaceutical Education (AFPE) Pharmacy Faculty Fellow Award. The funding source had no role in the design, conduct of the study; collection, management, analysis or interpretation of the data; or preparation, review or approval of the manuscript. NR 26 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7411 EI 1934-8150 J9 RES SOC ADMIN PHARM JI Res. Soc. Adm. Pharm. PD SEP-OCT PY 2016 VL 12 IS 5 BP 713 EP 721 DI 10.1016/j.sapharm.2015.10.004 PG 9 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA DU5SG UT WOS:000382271000004 PM 26621388 ER PT J AU Lee, SJ Kim, MJ Kwon, IC Roberts, TM AF Lee, So Jin Kim, Min Ju Kwon, Ick Chan Roberts, Thomas M. TI Delivery strategies and potential targets for siRNA in major cancer types SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE Small interfering RNA (siRNA); Delivery strategy of siRNAs; Cancer; siRNA therapeutics; Gene target ID SMALL INTERFERING RNA; IN-VIVO DELIVERY; HUMAN HEPATOCELLULAR-CARCINOMA; NANOPARTICLE-BASED DELIVERY; PEG-PLA NANOPARTICLES; TUMOR-BEARING MICE; PROTEIN-KINASE CK2; CELL LUNG-CANCER; BREAST-CANCER; OVARIAN-CANCER AB Small interfering RNA (siRNA) has gained attention as a potential therapeutic reagent due to its ability to inhibit specific genes in many genetic diseases. For many years, studies of siRNA have progressively advanced toward novel treatment strategies against cancer. Cancer is caused by various mutations in hundreds of genes including both proto-oncogenes and tumor suppressor genes. In order to develop siRNAs as therapeutic agents for cancer treatment, delivery strategies for siRNA must be carefully designed and potential gene targets carefully selected for optimal anti-cancer effects. In this review, various modifications and delivery strategies for siRNA delivery are discussed. In addition, we present current thinking on target gene selection in major tumor types. (C) 2016 Elsevier B.V. All rights reserved. C1 [Lee, So Jin; Kim, Min Ju; Roberts, Thomas M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Lee, So Jin; Kim, Min Ju; Kwon, Ick Chan] Korea Inst Sci & Technol, Biomed Res Inst, Ctr Theragnosis, Hwarangno 14 Gil 6, Seoul 136791, South Korea. [Kim, Min Ju; Kwon, Ick Chan] Korea Univ, KU KIST Grad Sch Converging Sci & Technol, 145 Anam Ro, Seoul 02841, South Korea. RP Roberts, TM (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM Thomas_Roberts@dfci.harvard.edu FU Global Innovative Research Center (GiRC) project of the National Research Foundation of Korea [2012K1A1A2A01055811]; Intramural Research Program (Global RNAi Carrier Initiative) of KIST; Women's Cancers Program of Dana-Farber Cancer Institute FX This study was supported by Global Innovative Research Center (GiRC) project (2012K1A1A2A01055811) of the National Research Foundation of Korea, the Intramural Research Program (Global RNAi Carrier Initiative) of KIST, and a grant from the Women's Cancers Program of Dana-Farber Cancer Institute. NR 217 TC 3 Z9 3 U1 42 U2 61 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 SEP 1 PY 2016 VL 104 BP 2 EP 15 DI 10.1016/j.addr.2016.05.010 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DT1JX UT WOS:000381239300002 PM 27259398 ER PT J AU Zand, S Buzney, E Duncan, LM Dadras, SS AF Zand, Sarvenaz Buzney, Elizabeth Duncan, Lyn M. Dadras, Soheil S. TI Heterogeneity of Metastatic Melanoma Correlation of MITF With Its Transcriptional Targets MLSN1, PEDF, HMB-45, and MART-1 SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Lymph node; Melanoma metastasis; MITF; Melastatin (MLSN1/TRPM1); PEDF; HMB-45; MART-1 ID EPITHELIUM-DERIVED-FACTOR; CUTANEOUS MALIGNANT-MELANOMA; MELANOCYTIC TUMORS; EXPRESSION; CELLS; ANGIOGENESIS AB Objectives: Histologic and molecular heterogeneity is well recognized in malignant melanoma; however, the diversity of expression of new and classic melanoma markers has not been correlated in serial sections of metastases. Methods: We examined and correlated the expression of microphthalmia transcription factor (MITF) with its transcriptional targets, including melastatin (MLSN1/TRPM1), pigment epithelium-derived factor (SERPINF1/PEDF), SILV/PMEL17/GP100 (human melanoma black 45 [HMB-45]), and melanoma antigen recognized by T cells 1 (MART-1)/MLANA, in 13 melanoma metastases in lymph nodes of 13 patients. The expression levels and patterns of marker expression were recorded by a semiquantitative, 4-point ordinal reactivity method. Results: Our results showed a consistently robust and diffuse expression of MITF protein in 12 (92%) of 13 metastatic tumors compared with variable expression of MLSN1 (46%) messenger RNA or PEDF (75%), HMB-45 (54%), and MART-1 (46%) proteins. Conclusions: Overall, in melanoma lymph node metastases, MITF protein expression was not tightly correlated with its gene targets. Moreover, the immunoreactivity for MITF, compared with MART-1 and HMB-45, was retained, supporting immunohistochemical detection of MITF as a more sensitive method of detecting metastatic melanoma. C1 [Zand, Sarvenaz] Cosmet & Laser Surg Inst, Kentfield, CA USA. [Buzney, Elizabeth] Brigham & Womens Hosp, Dept Dermatol, 75 Francis St, Boston, MA 02115 USA. [Duncan, Lyn M.] Harvard Med Sch, Massachusetts Gen Hosp, Dermatopathol Unit, Boston, MA USA. [Duncan, Lyn M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Dadras, Soheil S.] Univ Connecticut, Dept Dermatol, 263 Farmington Ave, Farmington, CT 06032 USA. [Dadras, Soheil S.] Univ Connecticut, Dept Pathol, 263 Farmington Ave, Farmington, CT 06032 USA. RP Dadras, SS (reprint author), Univ Connecticut, Dept Dermatol, 263 Farmington Ave, Farmington, CT 06032 USA.; Dadras, SS (reprint author), Univ Connecticut, Dept Pathol, 263 Farmington Ave, Farmington, CT 06032 USA. EM dadras@uchc.edu NR 27 TC 0 Z9 0 U1 4 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD SEP 1 PY 2016 VL 146 IS 3 BP 353 EP 360 DI 10.1093/AJCP/AQW115 PG 8 WC Pathology SC Pathology GA DU0DP UT WOS:000381871900011 PM 27515936 ER PT J AU Zantek, ND Hayward, CP Simcox, TG Smock, KJ Hsu, P Van Cott, EM AF Zantek, Nicole D. Hayward, Catherine P. Simcox, Trevor G. Smock, Kristi J. Hsu, Peihong Van Cott, Elizabeth M. TI An Assessment of the State of Current Practice in Coagulation Laboratories SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Staffing; Ebola; Rivaroxaban; Dabigatran; Apixaban; Direct oral anticoagulant (DOAC); Specialized coagulation laboratory ID ASSAYS; DABIGATRAN; APIXABAN AB Objectives: To assess the state of current practice in coagulation laboratories regarding three pressing issues: staffing, handling Ebola specimens, and testing/billing for tests that measure direct oral anticoagulants (DOAC). Methods: A survey and analysis of specialized coagulation laboratories in North America was conducted. Results: Approximately 4,000 special coagulation tests-per-technologist-per-year was rated as either a "good" staffing level or "adequate-but-ideally-need-more" employees. Requiring technologists to perform more than that was rated as an "inadequate" staffing level. For Ebola patients, coagulation testing is mostly performed by point-of-care. Only 26.1% would perform coagulation tests for Ebola specimens within their laboratory (rather than at the bed side or a separate designated space outside the laboratory). Coagulation tests offered for Ebola patients were limited: prothrombin time (63.0% of laboratories), activated partial thromboplastin time ( 37.0%), D-dimer (13.0%), and fibrinogen (8.7%); 26.1% of laboratories did not offer any coagulation tests for Ebola patients. Approximately 35% of special coagulation laboratories bill for at least one laboratory test for DOACs: 33% bill for an anti-Xa calibrated with rivaroxaban, 17% bill for an anti-Xa calibrated with apixaban, and 27% bill for at least one of several tests for dabigatran. Approximately 48% do not offer any tests for DOACs. Conclusions: These results may help laboratories negotiate for additional technologists if needed, prepare for Ebola specimens, and manage the demand for laboratory tests for new DOAC anticoagulants. C1 [Zantek, Nicole D.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Hayward, Catherine P.] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada. [Hayward, Catherine P.] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Simcox, Trevor G.; Van Cott, Elizabeth M.] Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. [Smock, Kristi J.] Univ Utah, Dept Pathol, ARUP Labs, Salt Lake City, UT USA. [Hsu, Peihong] Hofstra North Shore Long Isl Jewish Sch Med, Dept Pathol Lab Med, Lake Success, NY USA. RP Van Cott, EM (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. NR 14 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD SEP 1 PY 2016 VL 146 IS 3 BP 378 EP 383 DI 10.1093/AJCP/AQW121 PG 6 WC Pathology SC Pathology GA DU0DP UT WOS:000381871900015 PM 27510716 ER PT J AU Phillips, KA Keshaviah, A Dougherty, DD Stout, RL Menard, W Wilhelm, S AF Phillips, Katharine A. Keshaviah, Aparna Dougherty, Darin D. Stout, Robert L. Menard, William Wilhelm, Sabine TI Pharmacotherapy Relapse Prevention in Body Dysmorphic Disorder: A Double-Blind, Placebo-Controlled Trial SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID OBSESSIVE-COMPULSIVE SCALE; STRUCTURED CLINICAL INTERVIEW; POPULATION-BASED SURVEY; PSYCHOMETRIC EVALUATION; FUNCTIONAL IMPAIRMENT; BROWN ASSESSMENT; BELIEFS SCALE; RATING-SCALE; OPEN-LABEL; RELIABILITY AB Objective: Body dysmorphic disorder is common, distressing, and often severely impairing. Serotonin reuptake inhibitors appear efficacious, but the few existing pharmacotherapy studies were short term (4 months), and no relapse prevention studies or continuation phase studies have been conducted to the authors' knowledge. The authors report results from the first relapse prevention study in body dysmorphic disorder. Method: Adults (N=100) with DSM-IV body dysmorphic disorder received open-label escitalopram for 14 weeks (phase 1); 58 responders were then randomized to double-blind continuation treatment with escitalopram versus switch to placebo for 6 months (phase 2). Reliable and valid outcome measures were utilized. Results: In phase 1, 67.0% of treated subjects and 81.1% of subjects who completed phase 1 responded to escitalopram. Body dysmorphic disorder severity (in both the intent-to-treat and the completer groups) and insight, depressive symptoms, psychosocial functioning, and quality of life significantly improved from baseline to end of phase 1. In phase 2, time to relapse was significantly longer with escitalopram than with placebo treatment (hazard ratio=2.72, 95% CI =1.01-8.57). Phase 2 relapse proportions were 18% for escitalopram and 40% for placebo. Among escitalopram-treated subjects, body dysmorphic disorder severity significantly decreased over time during the continuation phase, with 35.7% of subjects showing further improvement. There were no significant group differences in body dysmorphic disorder severity or insight, depressive symptoms, psycho social functioning, or quality of life. Conclusions: Continuation-phase escitalopram delayed time to relapse, and fewer escitalopram-treated subjects relapsed than did placebo-treated subjects. Body dysmorphic disorder severity significantly improved during 6 additional months of escitalopram treatment following acute response; more than one-third of escitalopram-treated subjects experienced further improvement. C1 [Phillips, Katharine A.] Brown Univ, Rhode Isl Hosp, Butler Hosp, Providence, RI 02903 USA. Brown Univ, Dept Psychiat & Human Behav, Alpert Med Sch, Providence, RI 02912 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Med Sch, Dept Psychiat, Boston, MA USA. Decis Sci Inst, Pawtucket, RI USA. RP Phillips, KA (reprint author), Brown Univ, Rhode Isl Hosp, Butler Hosp, Providence, RI 02903 USA. EM katharine_phillips@brown.edu FU NIMH NIH HHS [R01 MH072854, R01 MH072917] NR 39 TC 1 Z9 1 U1 9 U2 11 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD SEP PY 2016 VL 173 IS 9 BP 887 EP 895 DI 10.1176/appi.ajp.2016.15091243 PG 9 WC Psychiatry SC Psychiatry GA DU1IK UT WOS:000381961200009 PM 27056606 ER PT J AU Marin, MF Song, HJ VanElzakker, MB Staples-Bradley, LK Linnman, C Pace-Schott, EF Lasko, NB Shin, LM Milad, MR AF Marin, Marie-France Song, Huijin VanElzakker, Michael B. Staples-Bradley, Lindsay K. Linnman, Clas Pace-Schott, Edward F. Lasko, Natasha B. Shin, Lisa M. Milad, Mohammed R. TI Association of Resting Metabolism in the Fear Neural Network With Extinction Recall Activations and Clinical Measures in Trauma-Exposed Individuals SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; VENTROMEDIAL PREFRONTAL CORTEX; ANTERIOR CINGULATE CORTEX; CONDITIONED FEAR; PTSD; AMYGDALA; HUMANS; FMRI; ACQUISITION; MODULATION AB Objective: Exposure-based therapy, an effective treatment for posttraumatic stress disorder (PTSD), relies on extinction learning principles. In PTSD patients, dysfunctional patterns in the neural circuitry underlying fear extinction have been observed using resting-state or functional activation measures. It remains undetermined whether resting activity predicts activations during extinction recall or PTSD symptom severity. Moreover, it remains unclear whether trauma exposure per se affects resting activity in this circuitry. The authors employed a multimodal approach to examine the relationships among resting metabolism, clinical symptoms, and activations during extinction recall. Method: Three cohorts were recruited: PTSD patients (N=24), trauma-exposed individuals with no PTSD (TENP) (N=20), and trauma-unexposed healthy comparison subjects (N=21). Participants underwent a resting positron emission tomography scan 4 days before a functional MRI fear conditioning and extinction paradigm. Results: Amygdala resting metabolism negatively correlated with clinical functioning (as measured by the Global Assessment of Functioning Scale) in the TENP group, and hippocampal resting metabolism negatively correlated with clinical functioning in the PTSD group. In the PTSD group, dorsal anterior cingulate cortex (dACC) resting metabolism positively correlated with PTSD symptom severity, and it predicted increased dACC activations but decreased hippocampal and ventromedial prefrontal cortex activations during extinction recall. The TENP group had lower amygdala resting metabolism compared with the PTSD and healthy comparison groups, and it exhibited lower hippocampus resting metabolism relative to the healthy comparison group. Conclusions: Resting metabolism in the fear circuitry correlated with functioning, PTSD symptoms, and extinction recall activations, further supporting the relevance of this network to the pathophysiology of PTSD. The study findings also highlight the fact that chronic dysfunction in the amygdala and hippocampus is demonstrable in PTSD and other trauma-exposed individuals, even without exposure to an evocative stimulus. C1 [Milad, Mohammed R.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Med Sch, Dept Psychiat, Boston, MA USA. Tufts Univ, Dept Psychol, Medford, MA 02155 USA. Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA USA. RP Milad, MR (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM milad@nmr.mgh.harvard.edu FU NIMH [R01 MH081975]; Fonds de Recherche Quebec-Sante; Banting Postdoctoral Fellowships FX Supported by NIMH grant R01 MH081975 to Dr. Milad and by postdoctoral fellowships from Fonds de Recherche Quebec-Sante (2012-2014) and Banting Postdoctoral Fellowships (2014 to present) to Dr. Milad. NR 31 TC 0 Z9 0 U1 4 U2 4 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD SEP PY 2016 VL 173 IS 9 BP 930 EP 938 DI 10.1176/appi.ajp.2015.14111460 PG 9 WC Psychiatry SC Psychiatry GA DU1IK UT WOS:000381961200014 PM 26917165 ER PT J AU Mirzakhani, H Guchelaar, HJ Welch, CA Cusin, C Doran, ME MacDonald, TO Bittner, EA Eikermann, M Nozari, A AF Mirzakhani, Hooman Guchelaar, Henk-Jan Welch, Charles A. Cusin, Cristina Doran, Mary E. MacDonald, Teresa O. Bittner, Edward A. Eikermann, Matthias Nozari, Ala TI Minimum Effective Doses of Succinylcholine and Rocuronium During Electroconvulsive Therapy: A Prospective, Randomized, Crossover Trial SO ANESTHESIA AND ANALGESIA LA English DT Article ID NEUROMUSCULAR BLOCKING-AGENTS; SEIZURE DURATION; RECOVERY; ONSET; SUXAMETHONIUM; ANESTHESIA; NEOSTIGMINE; VECURONIUM; ATRACURIUM; TRAIN-OF-4 AB BACKGROUND: Neuromuscular blockade is required to control excessive muscle contractions during electroconvulsive therapy (ECT). In a crossover, assessor-blinded, prospective randomized study, we studied the minimum effective dose (MED) of succinylcholine and rocuronium for ECT. The MED was the lowest dose to provide a predefined qualitative measure of acceptable control of muscle strength during induced convulsions. METHODS: Succinylcholine (0.8 mg kg(-1)) or rocuronium (0.4 mg kg(-1)) was randomly administered in 227 ECT sessions to 45 patients. The dose was incrementally increased or decreased by 10% based on 2 psychiatrists' (blinded to treatment) assessment of "acceptable" or "not acceptable" control of evoked muscle contractions (sufficient versus insufficient or excessive paralysis). The neuromuscular transmission was monitored quantitatively until full recovery. RESULTS: In our study, the MEDs of succinylcholine and rocuronium to produce acceptable ECT conditions in 50% of patients (MED50(ECT)) were 0.85 mg kg(-1)(95% confidence interval [CI], 0.77-0.94) and 0.41 mg kg(-1)(95% CI, 0.36-0.46) and in 90% of patients (MED90(ECT)) were 1.06 mg kg(-1) (95% CI, 1.0-1.27) and 0.57 mg kg(-1) (95% CI, 0.5-0.6), respectively. Nadir twitch height for acceptable muscle activity was 0% (0-4) and 4% (0-30; P < 0.001), respectively, and the time to recovery of the neuromuscular transmission was 9.7 3.5 and 19.5 5.7 minutes, respectively. CONCLUSIONS: A twitch suppression of >90% is needed for control of motor contractions during ECT. The initial ECT dose of succinylcholine should be selected based on each patient's procedural condition, ranging between 0.77 and 1.27 mg kg(-1) to produce acceptable muscle blockade in 50% to 90% of patients. Rocuronium neostigmine combination is a safe alternative if appropriately dosed C1 [Mirzakhani, Hooman; Bittner, Edward A.; Eikermann, Matthias; Nozari, Ala] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Mirzakhani, Hooman] Broad Inst MIT & Harvard, Cambridge, MA USA. [Mirzakhani, Hooman] Harvard Med Sch, Dept Biomed Informat, Boston, MA USA. [Mirzakhani, Hooman; Guchelaar, Henk-Jan] Leiden Univ, Med Ctr, Dept Clin Pharm & Toxicol, Leiden, Netherlands. [Welch, Charles A.; Cusin, Cristina] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Doran, Mary E.; MacDonald, Teresa O.] Massachusetts Gen Hosp, Patient Care Serv Special Care Nursery, Boston, MA 02114 USA. [Eikermann, Matthias] Essen Univ Hosp, Clin Anesthesiol & Intens Care, Essen, Germany. RP Mirzakhani, H (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM hoomi@post.harvard.edu OI Mirzakhani, Hooman/0000-0002-2290-4436 NR 49 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD SEP PY 2016 VL 123 IS 3 BP 587 EP 596 DI 10.1213/ANE.0000000000001218 PG 10 WC Anesthesiology SC Anesthesiology GA DT9RA UT WOS:000381838800009 PM 26967896 ER PT J AU Sigakis, MJG Leffert, LR Mirzakhani, H Sharawi, N Rajala, B Callaghan, WM Kuklina, EV Creanga, AA Mhyre, JM Bateman, BT AF Sigakis, Matthew J. G. Leffert, Lisa R. Mirzakhani, Hooman Sharawi, Nadir Rajala, Baskar Callaghan, William M. Kuklina, Elena V. Creanga, Andreea A. Mhyre, Jill M. Bateman, Brian T. TI The Validity of Discharge Billing Codes Reflecting Severe Maternal Morbidity SO ANESTHESIA AND ANALGESIA LA English DT Article ID UNITED-STATES; ADMINISTRATIVE DATA; ACCURACY; IDENTIFICATION; VALIDATION; DIAGNOSES; MORTALITY; DATABASE; MISS AB BACKGROUND: Discharge diagnoses are used to track national trends and patterns of maternal morbidity. There are few data regarding the validity of the International Classification of Diseases (ICD) codes used for this purpose. The goal of our study was to try to better understand the validity of administrative data being used to monitor and assess trends in morbidity. METHODS: Hospital stay billing records were queried to identify all delivery admissions at the Massachusetts General Hospital for the time period 2001 to 2011 and the University of Michigan Health System for the time period 2005 to 2011. From this, we identified patients with ICD-9-Clinical Modification (CM) diagnosis and procedure codes indicative of severe maternal morbidity. Each patient was classified with 1 of 18 different medical/obstetric categories (conditions or procedures) based on the ICD-9-CM code that was recorded. Within each category, 20 patients from each institution were selected at random, and the corresponding medical charts were reviewed to determine whether the ICD-9-CM code was assigned correctly. The percentage of correct codes for each of 18 preselected clinical categories was calculated yielding a positive predictive value (PPV) and 99% confidence interval (CI). RESULTS: The overall number of correctly assigned ICD-9-CM codes, or PPV, was 218 of 255 (86%; CI, 79%-90%) and 154 of 188 (82%; CI, 74%-88%) at Massachusetts General Hospital and University of Michigan Health System, respectively (combined PPV, 372/443 [84%; CI, 79-88%]). Codes within 4 categories (Hysterectomy, Pulmonary edema, Disorders of fluid, electrolyte and acid-base balance, and Sepsis) had a 99% lower confidence limit >= 75%. Codes within 8 additional categories demonstrated a 99% lower confidence limit between 74% and 50% (Acute respiratory distress, Ventilation, Other complications of obstetric surgery, Disorders of coagulation, Cardiomonitoring, Acute renal failure, Thromboembolism, and Shock). Codes within 6 clinical categories demonstrated a 99% lower confidence limit <50% (Puerperal cerebrovascular disorders, Conversion of cardiac rhythm, Acute heart failure [includes arrest and fibrillation], Eclampsia, Neurotrauma, and Severe anesthesia complications). CONCLUSIONS: ICD-9-CM codes capturing severe maternal morbidity during delivery hospitalization demonstrate a range of PPVs. The PPV was high when objective supportive evidence, such as laboratory values or procedure documentation supported the ICD-9-CM code. The PPV was low when greater judgment, interpretation, and synthesis of the clinical data (signs and symptoms) was required to support a code, such as with the category Severe anesthesia complications. As a result, these codes should be used for administrative research with more caution compared with codes primarily defined by objective data. C1 [Sigakis, Matthew J. G.; Sharawi, Nadir; Rajala, Baskar] Univ Michigan, Sch Med, Dept Anesthesiol, 1H247 UH,SPC 5048,1500 East Med Ctr Dr, Ann Arbor, MI 48109 USA. [Leffert, Lisa R.; Bateman, Brian T.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Div Obstet Anesthesia, Boston, MA 02114 USA. [Mirzakhani, Hooman] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Callaghan, William M.; Creanga, Andreea A.] Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA USA. [Kuklina, Elena V.] Ctr Dis Control & Prevent, Epidemiol & Surveillance Branch, Div Heart Dis & Stroke Prevent, Atlanta, GA USA. [Mhyre, Jill M.] Univ Arkansas Med Sci, Dept Anesthesiol, Little Rock, AR 72205 USA. RP Sigakis, MJG (reprint author), Univ Michigan, Sch Med, Dept Anesthesiol, 1H247 UH,SPC 5048,1500 East Med Ctr Dr, Ann Arbor, MI 48109 USA. EM msigakis@med.umich.edu OI Mirzakhani, Hooman/0000-0002-2290-4436 NR 28 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 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD SEP PY 2016 VL 123 IS 3 BP 731 EP 738 DI 10.1213/ANE.0000000000001436 PG 8 WC Anesthesiology SC Anesthesiology GA DT9RA UT WOS:000381838800025 PM 27387839 ER PT J AU Hood, RL Liguore, WA Moore, C Pflibsen, L Meshul, CK AF Hood, Rebecca L. Liguore, William A. Moore, Cynthia Pflibsen, Lacey Meshul, Charles K. TI Exercise intervention increases spontaneous locomotion but fails to attenuate dopaminergic system loss in a progressive MPTP model in aged mice SO BRAIN RESEARCH LA English DT Article DE Parkinson's disease; Aging; Exercise; MPTP; Dopamine; Striatum ID CHRONIC MOUSE MODEL; IDIOPATHIC PARKINSONS-DISEASE; RANDOMIZED CLINICAL-TRIAL; RESTORES MOTOR DEFICITS; TREADMILL EXERCISE; ENDURANCE EXERCISE; SUBSTANTIA-NIGRA; SEVERE NEURODEGENERATION; PHYSICAL-EXERCISE; LESIONED MOUSE AB While exercise is commonly recommended for PD patients to improve motor function, little is known about the disease-altering potential of exercise. Although others have demonstrated neuroprotective or neurorestorative effects of exercise in animal models of PD, the majority of these studies utilize young animals. In order to assess the effects of exercise intervention in a more clinically relevant model, we have subjected aged mice to progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioning and daily treadmill exercise, initiated early in the course of the disease. The MPTP model elicited a 55% reduction in striatal TH as measured by immunohistochemistry compared to sedentary controls, and exercise did not attenuate this loss in exercised MPTP animals. Furthermore, striatal TH and DAT loss, as assessed by western blotting, were not significantly impacted by treadmill exercise in MPTP-lesioned mice. We did find an increase in spontaneous locomotion in exercised mice that was not decreased by MPTP lesioning. This finding may be due, in part, to an increase in TH expression in the motor cortex in exercised MPTP mice. (C) 2016 Elsevier B.V. All rights reserved. C1 [Hood, Rebecca L.; Meshul, Charles K.] Oregon Hlth & Sci Univ, Dept Behav Neurosci, 3181 SW Sam Jackson Pk Rd,L470, Portland, OR 97239 USA. [Liguore, William A.; Moore, Cynthia; Pflibsen, Lacey; Meshul, Charles K.] Portland VA Med Ctr, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. RP Hood, RL (reprint author), Oregon Hlth & Sci Univ, Dept Behav Neurosci, 3181 SW Sam Jackson Pk Rd,L470, Portland, OR 97239 USA. EM hoodr@ohsu.edu; liguorew@gmail.com; moorecy@ohsu.edu; Pflibsel11@up.edu; meshulc@ohsu.edu FU United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development [1BX 001643] FX This work was supported by Merit Review #1BX 001643 to CKM from the United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. NR 62 TC 1 Z9 1 U1 6 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD SEP 1 PY 2016 VL 1646 BP 535 EP 542 DI 10.1016/j.brainres.2016.06.032 PG 8 WC Neurosciences SC Neurosciences & Neurology GA DT9TH UT WOS:000381844700060 PM 27350080 ER PT J AU Kumar, S Danik, SB Altman, RK Barrett, CD Lip, GYH Chatterjee, S Roubin, GS Natale, A Danik, JS AF Kumar, Shashi Danik, Stephan B. Altman, Robert K. Barrett, Conor D. Lip, Gregory Y. H. Chatterjee, Saurav Roubin, Gary S. Natale, Andrea Danik, Jacqueline S. TI Non-Vitamin K Antagonist Oral Anticoagulants and Antiplatelet Therapy for Stroke Prevention in Patients With Atrial Fibrillation A Meta-Analysis of Randomized Controlled Trials SO CARDIOLOGY IN REVIEW LA English DT Review DE atrial fibrillation; anticoagulation; aspirin; antiplatelet drug; stroke prevention ID WARFARIN; ASSOCIATION; DABIGATRAN; APIXABAN; DISEASE AB Non-vitamin K antagonist oral anticoagulants (NOACs) are frequently used to prevent stroke in patients with atrial fibrillation. These patients are often also on aspirin or other antiplatelet agents. It is possible that treatment with both NOACs and aspirin or other antiplatelet drug may be effective in decreasing stroke, but data are sparse regarding the efficacy and safety of using both agents for stroke prevention. To address these issues, data were pooled from the 4 recent randomized, controlled trials of NOACs: apixaban, rivaroxaban, dabigatran, and edoxaban, which included 42,411 patients; 14,148 (33.4%) were also on aspirin or other antiplatelet drug. The number of thromboembolic events among participants on NOAC and aspirin/antiplatelet was compared with the number of events in patients on NOAC alone. Bleeding rates were also compared between those on NOAC + aspirin/antiplatelet and on NOAC alone. These results were compared with thromboembolic and bleeding events in the warfarin + aspirin/antiplatelet versus warfarin alone. No greater risk for thromboembolism was seen in patients on NOACs compared with patients on both NOACs and aspirin/antiplatelet drug. In this nonrandomized comparison, there was initially a signal toward higher thromboembolic rates among NOAC users also on aspirin/antiplatelet drugs (relative risk, 1.16; 95% confidence intervals, 1.05, 1.29) when compared with NOAC alone. This likely reflected the higher CHADS(2) scores of those on aspirin/antiplatelet drugs. When the analysis was limited to studies that included aspirin rather than other antiplatelet drugs, no difference was seen for thromboembolic rates comparing dual therapy to NOAC alone (relative risk, 1.02; 95% confidence intervals, 0.90, 1.15). Higher rates of bleeding were seen with aspirin/antiplatelet drug in conjunction with NOAC. In this meta-analysis and nonrandomized comparison of aspirin/antiplatelet users and nonusers also on anticoagulation, there was no additional benefit seen of anticoagulation and antiplatelet therapy for stroke prevention when compared with anticoagulation alone. There was, however, an increased risk of bleeding. Careful assessment of the indications for antiplatelet drugs in patients with atrial fibrillation who are also receiving oral anticoagulants is warranted, and future randomized comparisons are needed. C1 [Kumar, Shashi] Mem Hosp, Dept Med, Rome, NY USA. [Danik, Stephan B.; Altman, Robert K.; Chatterjee, Saurav; Danik, Jacqueline S.] Mt Sinai St Lukes Hosp, Div Cardiol, New York, NY USA. [Danik, Stephan B.; Altman, Robert K.; Chatterjee, Saurav; Danik, Jacqueline S.] Mt Sinai West Hosp, New York, NY USA. [Barrett, Conor D.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Lip, Gregory Y. H.] Univ Birmingham, City Hosp, Div Cardiol, Ctr Cardiovasc Sci, Birmingham, W Midlands, England. [Roubin, Gary S.] Brookwood Med Ctr, Div Cardiol, Birmingham, AL USA. [Natale, Andrea] St Davids Med Ctr, Texas Cardiac Arrhythmia Inst, Div Cardiol, Austin, TX USA. [Danik, Jacqueline S.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. RP Danik, JS (reprint author), Mt Sinai St Lukes & Mt Sinai West Hosp, Div Cardiol, 1111 Amsterdam Ave, New York, NY 10025 USA. EM jacqueline.danik@mountsinai.org FU National Heart, Lung, and Blood Institute, the National Cancer Institute [NIH/NHLBI/NCI U01 CA138962, HL116690]; American Heart Association [11980009] FX Dr. Roubin reports serving as a consultant to Cook Inc. and Medicines Co Inc. Dr. Natale reports serving as a consultant to or receiving honoraria from JANSSEN, St Jude Medical, Biotronik, Biosense Webster, Medtronic and Boston Scientific. Dr. Lip has served as a consultant for Bayer, Merck, Sanofi, BMS/Pfizer, Daiichi-Sankyo, Biotronik, Medtronic, Portola and Boehringer Ingelheim and has been on the speakers bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Medtronic. Dr. Jacqueline Danik reports that she has currently or in the past 5 years received research funding support from not-for-profit entities including the National Heart, Lung, and Blood Institute, the National Cancer Institute (NIH/NHLBI/NCI U01 CA138962, HL116690) and the American Heart Association (11980009). The other authors have no conflicts of interest to report. Dr. J Danik had full access to all the data in the study and had final responsibility for the decision to submit for publication. NR 11 TC 1 Z9 1 U1 4 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1061-5377 EI 1538-4683 J9 CARDIOL REV JI Cardiol. Rev. PD SEP-OCT PY 2016 VL 24 IS 5 BP 218 EP 223 DI 10.1097/CRD.0000000000000088 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DT0GO UT WOS:000381161400002 PM 26274538 ER PT J AU Sajeev, G Weuve, J Jackson, JW VanderWeele, TJ Bennett, DA Grodstein, F Blacker, D AF Sajeev, Gautam Weuve, Jennifer Jackson, John W. VanderWeele, Tyler J. Bennett, David A. Grodstein, Francine Blacker, Deborah TI Late-life Cognitive Activity and Dementia A Systematic Review and Bias Analysis SO EPIDEMIOLOGY LA English DT Review ID INCIDENT ALZHEIMER-DISEASE; OLDER-ADULTS; LEISURE ACTIVITIES; SOCIOECONOMIC-STATUS; SENSITIVITY-ANALYSIS; CLINICAL-DIAGNOSIS; NATURAL-HISTORY; RISK; IMPAIRMENT; DECLINE AB Background: Engaging in late-life cognitive activity is often proposed as a strategy to delay or prevent Alzheimer's disease (AD) and other dementias. However, it is unclear to what extent the available evidence supports a causal effect of cognitive activity in dementia prevention. Methods: We systematically searched PubMed and EMBASE through June 2014 to identify peer-reviewed epidemiologic studies of cognitive activity and incidence of AD or all-cause dementia. Eligible articles analyzed data from cohort or nested case-control studies, explicitly defined cognitive activity, evaluated participants for AD or all-cause dementia using clearly defined criteria, and provided effect estimates adjusted for at least age and sex. We describe methodologic issues and biases relevant to interpretation of these studies, and quantify the degree of bias due to confounding and reverse causation required to nullify typically observed associations. Results: We reviewed 12 studies involving 13,939 participants and 1,663 dementia cases, of which 565 were specifically evaluated as AD. Most studies found associations between late-life cognitive activity and lower AD and/or all-cause dementia incidence. Differences in cognitive activity operationalization across studies precluded meta-analysis of effect estimates. Our bias analysis indicated that the observed inverse associations are probably robust to unmeasured confounding, and likely only partially explained by reverse causation. Conclusion: Our systematic review and bias analyses provide support for the hypothesis that late-life cognitive activity offers some reduction in AD and all-cause dementia risk. However, more data are needed to confirm this relationship and on the optimal type, duration, intensity, and timing of that activity. C1 [Sajeev, Gautam; Jackson, John W.; VanderWeele, Tyler J.; Grodstein, Francine; Blacker, Deborah] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Weuve, Jennifer] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [VanderWeele, Tyler J.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Grodstein, Francine] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Blacker, Deborah] Massachusetts Gen Hosp, Dept Psychiat, Gerontol Res Unit, Boston, MA 02114 USA. RP Blacker, D (reprint author), Massachusetts Gen Hosp, Gerontol Res Unit, 149 13th St, Charlestown, MA 02129 USA. EM blacker@psych.mgh.harvard.edu FU Canadian Institutes of Health Research [201110DFS-277667-DRB-217413]; Fidelity Biosciences; Alzheimer's Association [NIRG-12-242395]; National Institute of Environmental Health Sciences [R21ES020404, R01 ES017876]; National Institute on Aging [P50 AG005134, P30 AG10161, R01 AG15819, R01 AG17917] FX Gautam Sajeev was funded by a Doctoral Foreign Study Award from the Canadian Institutes of Health Research (201110DFS-277667-DRB-217413). Gautam Sajeev, Jennifer Weuve, John W. Jackson, and Deborah Blacker were supported by a grant from Fidelity Biosciences. Jennifer Weuve was also supported by the Alzheimer's Association (NIRG-12-242395) and by the National Institute of Environmental Health Sciences (R21ES020404). Deborah Blacker was also supported by the National Institute on Aging (P50 AG005134). Tyler J. VanderWeele was supported by the National Institute of Environmental Health Sciences (R01 ES017876). David A. Bennett was supported by the National Institute on Aging (P30 AG10161, R01 AG15819, R01 AG17917) and is on the Scientific Advisory Board for Vigorous Minds, Inc. NR 58 TC 1 Z9 1 U1 16 U2 18 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 SEP PY 2016 VL 27 IS 5 BP 732 EP 742 DI 10.1097/EDE.0000000000000513 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS8CR UT WOS:000381011000024 PM 27227783 ER PT J AU Afdhal, NH Serfaty, L AF Afdhal, Nezam H. Serfaty, Lawrence TI Effect of Registries and Cohort Studies on HCV Treatment SO GASTROENTEROLOGY LA English DT Editorial Material ID GENOTYPE 1 INFECTION; HEPATITIS-C VIRUS; COST-EFFECTIVENESS; SOFOSBUVIR; LEDIPASVIR; RIBAVIRIN; DASABUVIR; CIRRHOSIS; IMPACT C1 [Afdhal, Nezam H.] Harvard Med Sch, Ctr Liver, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Serfaty, Lawrence] Hop St Antoine, Serv Hepatol, Paris, France. [Serfaty, Lawrence] Univ Paris 06, Paris, France. RP Afdhal, NH (reprint author), BIDMC, Ctr Liver, 110 Francis St, Boston, MA 02125 USA. EM nafdhal@bidmc.harvard.edu NR 15 TC 0 Z9 0 U1 4 U2 4 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 SEP PY 2016 VL 151 IS 3 BP 387 EP 390 DI 10.1053/j.gastro.2016.07.024 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DU5CO UT WOS:000382230000010 PM 27456388 ER PT J AU Ioannou, GN Beste, LA Chang, MF Green, PK Lowy, E Tsui, JI Su, F Berry, K AF Ioannou, George N. Beste, Lauren A. Chang, Michael F. Green, Pamela K. Lowy, Elliott Tsui, Judith I. Su, Feng Berry, Kristin TI Effectiveness of Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir Regimens for Treatment of Patients With Hepatitis C in the Veterans Affairs National Health Care System SO GASTROENTEROLOGY LA English DT Article DE Harvoni; Viekira; DAA; VA ID GENOTYPE 1 INFECTION; SUSTAINED VIROLOGICAL RESPONSE; HEPATOCELLULAR-CARCINOMA; VIRUS-INFECTION; LIVER-DISEASE; US VETERANS; HCV; RIBAVIRIN; CIRRHOSIS; LEDIPASVIR AB BACKGROUND & AIMS: We investigated the real-world effectiveness of sofosbuvir, ledipasvir/sofosbuvir, and paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD) in treatment of different subgroups of patients infected with hepatitis C virus (HCV) genotypes 1, 2, 3, or 4. METHODS: We performed a retrospective analysis of data from 17,487 patients with HCV infection (13,974 with HCV genotype 1; 2131 with genotype 2; 1237 with genotype 3; and 135 with genotype 4) who began treatment with sofosbuvir (n = 2986), ledipasvir/sofosbuvir (n = 11,327), or PrOD (n = 3174), with or without ribavirin, from January 1, 2014 through June 20, 2015 in the Veterans Affairs health care system. Data through April 15, 2016 were analyzed to assess completion of treatments and sustained virologic response 12 weeks after treatment (SVR12). Mean age of patients was 61 = 7 years, 97% were male, 52% were non-Hispanic white, 29% were non-Hispanic black, 32% had a diagnosis of cirrhosis (9.9% with decompensated cirrhosis), 36% had a Fibrosis-4 index score >3.25 (indicator of cirrhosis), and 29% had received prior antiviral treatment. RESULTS: An SVR12 was achieved by 92.8% (95% confidence interval [CI], 92.3%-93.2%) of subjects with HCV genotype 1 infection (no significant difference between ledipasvir/sofosbuvir and PrOD regimens), 86.2% (95% CI, 84.6%-87.7%) of those with genotype 2 infection (treated with sofosbuvir and ribavirin), 74.8% (95% CI, 72.2%-77.3%) of those with genotype 3 infection (77.9% in patients given ledipasvir/sofosbuvir plus ribavirin, 87.0% in patients given sofosbuvir and pegylated-interferon plus ribavirin, and 70.6% of patients given sofosbuvir plus ribavirin), and 89.6% (95% CI 82.8%-93.9%) of those with genotype 4 infection. Among patients with cirrhosis, 90.6% of patients with HCV genotype 1, 77.3% with HCV genotype 2, 65.7% with HCV genotype 3, and 83.9% with HCV genotype 4 achieved an SVR12. Among previously treated patients, 92.6% with genotype 1; 80.2% with genotype 2; 69.2% with genotype 3; and 93.5% with genotype 4 achieved SVR12. Among treatment-naive patients, 92.8% with genotype 1; 88.0% with genotype 2; 77.5% with genotype 3; and 88.3% with genotype 4 achieved SVR12. Eight-week regimens of ledipasvir/sofosbuvir produced an SVR12 in 94.3% of eligible patients with HCV genotype 1 infection; this regimen was underused. CONCLUSIONS: High proportions of patients with HCV infections genotypes 1-4 (ranging from 75% to 93%) in the Veterans Affairs national health care system achieved SVR12, approaching the results reported in clinical trials, especially in patients with genotype 1 infection. An 8-week regimen of ledipasvir/sofosbuvir is effective for eligible patients with HCV genotype 1 infection and could reduce costs. There is substantial room for improvement in SVRs among persons with cirrhosis and genotype 2 or 3 infections. C1 [Ioannou, George N.] Vet Affairs Puget Sound Hlth Care Syst, Div Gastroenterol, S-111 Gastro,1660 S Columbian Way, Seattle, WA 98108 USA. [Ioannou, George N.; Beste, Lauren A.; Green, Pamela K.; Lowy, Elliott; Berry, Kristin] Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. [Ioannou, George N.] Univ Washington, Div Gastroenterol, Seattle, WA 98195 USA. [Beste, Lauren A.] Vet Affairs Puget Sound Hlth Care Syst, Div Gen Internal Med, Seattle, WA USA. [Beste, Lauren A.; Tsui, Judith I.; Su, Feng] Univ Washington, Div Gen Internal Med, Seattle, WA 98195 USA. [Chang, Michael F.] Vet Affairs Portland Hlth Care Syst, Div Gastroenterol, Portland, OR USA. [Chang, Michael F.] Oregon Hlth & Sci Univ, Portland, OR USA. RP Ioannou, GN (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Div Gastroenterol, S-111 Gastro,1660 S Columbian Way, Seattle, WA 98108 USA. EM georgei@medicine.washington.edu FU Merit Review grants [I01CX000320, I01CX001156]; Clinical Science Research and Development, Office of Research and Development, Veterans Affairs FX This study was funded by Merit Review grants (I01CX000320 and I01CX001156), Clinical Science Research and Development, Office of Research and Development, Veterans Affairs (to George N. Ioannou). The contents do not represent the views of the US Department of Veterans Affairs or the US Government. NR 36 TC 13 Z9 13 U1 4 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD SEP PY 2016 VL 151 IS 3 BP 457 EP + DI 10.1053/j.gastro.2016.05.049 PG 20 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DU5CO UT WOS:000382230000023 PM 27267053 ER PT J AU Yager, P Collins, C Blais, C O'Connor, K Donovan, P Martinez, M Cummings, B Hartnick, C Noviski, N AF Yager, Phoebe Collins, Corey Blais, Carlene O'Connor, Kathy Donovan, Patricia Martinez, Maureen Cummings, Brian Hartnick, Christopher Noviski, Natan TI Quality improvement utilizing in-situ simulation for a dual-hospital pediatric code response team SO INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY LA English DT Article DE Simulation; Quality improvement; Emergencies; Education ID DELIBERATE PRACTICE; EXPERT PERFORMANCE; CRITICAL-CARE; EMERGENCY; CARDIOPULMONARY; RESUSCITATION; ACQUISITION; MANAGEMENT; IMPACT AB Objective: Given the rarity of in-hospital pediatric emergency events, identification of gaps and inefficiencies in the code response can be difficult. In-situ, simulation-based medical education programs can identify unrecognized systems-based challenges. We hypothesized that developing an in-situ, simulation-based pediatric emergency response program would identify latent inefficiencies in a complex, dual-hospital pediatric code response system and allow rapid intervention testing to improve performance before implementation at an institutional level. Methods: Pediatric leadership from two hospitals with a shared pediatric code response team employed the Institute for Healthcare Improvement's (IHI) Breakthrough Model for Collaborative Improvement to design a program consisting of Plan-Do-Study-Act cycles occurring in a simulated environment. The objectives of the program were to 1) identify inefficiencies in our pediatric code response; 2) correlate to current workflow; 3) employ an iterative process to test quality improvement interventions in a safe environment; and 4) measure performance before actual implementation at the institutional level. Results: Twelve dual-hospital, in-situ, simulated, pediatric emergencies occurred over one year. The initial simulated event allowed identification of inefficiencies including delayed provider response, delayed initiation of cardiopulmonary resuscitation (CPR), and delayed vascular access. These gaps were linked to process issues including unreliable code pager activation, slow elevator response, and lack of responder familiarity with layout and contents of code cart. From first to last simulation with multiple simulated process improvements, code response time for secondary providers coming from the second hospital decreased from 29 to 7 min, time to CPR initiation decreased from 90 to 15 s, and vascular access obtainment decreased from 15 to 3 min. Some of these simulated process improvements were adopted into the institutional response while others continue to be trended over time for evidence that observed changes represent a true new state of control. Conclusions: Utilizing the IHI's Breakthrough Model, we developed a simulation-based program to 1) successfully identify gaps and inefficiencies in a complex, dual-hospital, pediatric code response system and 2) provide an environment in which to safely test quality improvement interventions before institutional dissemination. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Yager, Phoebe; Cummings, Brian; Noviski, Natan] MassGen Hosp Children, 175 Cambridge St,CPZS 5, Boston, MA 02114 USA. [Collins, Corey; Blais, Carlene; O'Connor, Kathy; Donovan, Patricia; Martinez, Maureen; Hartnick, Christopher] Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. RP Yager, P (reprint author), MassGen Hosp Children, Div Pediat Crit Care, Dept Pediat, 175 Cambridge St,CPZS 5, Boston, MA 02114 USA. EM pyager@partners.org FU Curing Kids Foundation at Massachusetts Eye Ear Infirmary FX This research was made possible with funding from the Curing Kids Foundation at Massachusetts Eye & Ear Infirmary. NR 24 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 0165-5876 EI 1872-8464 J9 INT J PEDIATR OTORHI JI Int. J. Pediatr. Otorhinolaryngol. PD SEP PY 2016 VL 88 BP 42 EP 46 DI 10.1016/j.ijporl.2016.06.026 PG 5 WC Otorhinolaryngology; Pediatrics SC Otorhinolaryngology; Pediatrics GA DT9SG UT WOS:000381842000010 PM 27497385 ER PT J AU Raol, N Hartnick, CJ Weissman, JS AF Raol, Nikhila Hartnick, Christopher J. Weissman, Joel S. TI Should obtaining a preoperative audiogram before tympanostomy tube placement be used as a quality metric? A survey of pediatric otolaryngologists SO INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY LA English DT Article DE Quality metrics; Audiograms; Tympanostomy tube ID CLINICAL-PRACTICE GUIDELINES; HEARING-LOSS; CHILDREN; TONSILLECTOMY; POLYSOMNOGRAPHY AB Introduction: Obtaining a preoperative audiogram prior to tympanostomy tube placement is recommended by the American Academy of Otolaryngology-Head and Neck Surgery clinical practice guideline (CPG): Tympanostomy tubes in Children, and this process measure is also used as a quality metric by payers. However, whether audiograms should be mandated in cases of tube placement for both chronic otitis media with effusion (COME) and recurrent acute otitis media (RAOM) is controversial. The objective of this study is to determine reports of practice patterns of pediatric otolaryngologists regarding obtaining audiograms before and after tympanostomy tube placement and opinions regarding utility of CPGs and use of this process measure as a quality metric. Methods: A 16-question cross-sectional survey of American Society of Pediatric Otolaryngology (ASPO) members was conducted. Per ASPO policy, no repeated requests or other enhanced response techniques were permitted. Independent t-tests for proportions were used to compare responses. Results: 127 pediatric otolaryngologists completed the survey (response rate 26.9%). Nearly 70% of respondents reported being in practice for >10 years. 74% of respondents reported obtaining preoperative audiograms "always" or "most of the time" for COME, vs. 56.7% for RAOM (p < 0.0001). 76% agreed that obtaining a preoperative audiogram was representative of high quality for COME, vs. 52% for RAOM (p < 0.0001). 12% of respondents "completely agreed" that compliance with all aspects of CPGs represented high quality, while 68.8% responded that they somewhat agreed. Conclusion: There is no consensus among pediatric otolaryngologists regarding the necessity of a preoperative audiogram in tympanostomy tube placement, especially for RAOM. Further evidence demonstrating the benefit of preoperative audiogram obtainment should be developed prior to inclusion as a guideline recommendation and as a quality metric. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Raol, Nikhila; Weissman, Joel S.] Harvard Med Sch, Harvard TH Chan Sch Publ Hlth, Brigham & Womens Hosp, Ctr Surg & Publ Hlth,Dept Surg, Boston, MA USA. [Raol, Nikhila; Hartnick, Christopher J.] Harvard Med Sch, Dept Otolaryngol, Massachusetts Eye & Ear Infirm, Boston, MA USA. RP Raol, N (reprint author), Brigham & Womens Hosp, Ctr Surg & Publ Hlth, One Brigham Circle,1620 Tremont St,4-020, Boston, MA 02120 USA. EM nraol@partners.org NR 15 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 0165-5876 EI 1872-8464 J9 INT J PEDIATR OTORHI JI Int. J. Pediatr. Otorhinolaryngol. PD SEP PY 2016 VL 88 BP 82 EP 88 DI 10.1016/j.ijporl.2016.06.004 PG 7 WC Otorhinolaryngology; Pediatrics SC Otorhinolaryngology; Pediatrics GA DT9SG UT WOS:000381842000016 PM 27497391 ER PT J AU Fuller, JC Sinha, S Caruso, PA Hersh, CJ Butler, WE Krishnamoorthy, KS Hartnick, CJ AF Fuller, Jennifer C. Sinha, Sumi Caruso, Paul A. Hersh, Cheryl J. Butler, William E. Krishnamoorthy, Kalpathy S. Hartnick, Christopher J. TI Chiari malformations: An important cause of pediatric aspiration SO INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY LA English DT Article DE Pediatric; Chronic aspiration; Chiari malformation ID CHRONIC PULMONARY ASPIRATION; AGE 6 YEARS; I MALFORMATIONS; CLINICAL ARTICLE; RISK-FACTORS; CHILDREN; DYSPHAGIA; EXPERIENCE; MANIFESTATION; DISORDERS AB Chronic aspiration poses a major health risk to the pediatric population. We describe four cases in which work up for chronic aspiration with a brain MRI revealed a Chiari I malformation, a poorly described etiology of pediatric aspiration. All patients had at least one non-specific neurologic symptom but had swallow studies more characteristic of an anatomic than a neurologic etiology. Patients were referred to neurosurgery and underwent posterior fossa decompression with symptom improvement. A high index of suspicion for Chiari malformation should be maintained when the standard work up for aspiration is non-diagnostic, particularly when non-specific neurologic symptoms are present. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Fuller, Jennifer C.; Sinha, Sumi; Hartnick, Christopher J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. [Caruso, Paul A.] Massachusetts Eye & Ear Infirm, Dept Radiol, 243 Charles St, Boston, MA 02114 USA. [Hersh, Cheryl J.] Massachusetts Gen Hosp Children, Massachusetts Eye & Ear Infirm, Pediat Airway Voice & Swallowing Ctr, 243 Charles St, Boston, MA 02114 USA. [Butler, William E.] Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St, Boston, MA 02114 USA. [Krishnamoorthy, Kalpathy S.] Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St, Boston, MA 02114 USA. RP Fuller, JC (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM Jennifer_Fuller@MEEI.HARVARD.EDU NR 36 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 0165-5876 EI 1872-8464 J9 INT J PEDIATR OTORHI JI Int. J. Pediatr. Otorhinolaryngol. PD SEP PY 2016 VL 88 BP 124 EP 128 DI 10.1016/j.ijporl.2016.06.019 PG 5 WC Otorhinolaryngology; Pediatrics SC Otorhinolaryngology; Pediatrics GA DT9SG UT WOS:000381842000024 PM 27497399 ER PT J AU Anand, V Hyun, C Khan, QM Hall, C Hessefort, N Sonnenberg, A Fimmel, CJ AF Anand, Vijay Hyun, Christian Khan, Qasim M. Hall, Curtis Hessefort, Norbert Sonnenberg, Amnon Fimmel, Claus J. TI Identification and Fibrosis Staging of Hepatitis C Patients Using the Electronic Medical Record System SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Article DE fibrosis scoring algorithm; hepatitis C virus infection; liver fibrosis; receiver operating characteristic curve ID VIRUS-INFECTION; CIRRHOSIS; INDEX AB Background and Aims: The aim of this study was to noninvasively assess the severity of chronic hepatitis C virus (HCV) in large patient populations. It would be helpful if fibrosis scores could be calculated solely on the basis of data contained in the patients' electronic medical records (EMR). We performed a pilot study to identify all HCV-infected patients in a large health care system, and predict their fibrosis stage on the basis of demographic and laboratory data using common data from their EMR. Materials and Methods: HCV-infected patients were identified using the EMR. The liver biopsies of 191 HCV patients were graded using the Ishak and Metavir scoring systems. Demographic and laboratory data were extracted from the EMR and used to calculate the aminotransferase to platelet ratio index, Fib-4, Fibrosis Index, Forns, Goteborg University Cirrhosis Index, Lok Index, and Vira-HepC. Results: In total, 869 HCV-infected patients were identified from a population of over 1 million. In the subgroup of patients with liver biopsies, all 7 algorithms were significantly correlated with the fibrosis stage. The degree of correlation was moderate, with correlation coefficients ranging from 0.22 to 0.60. For the detection of advanced fibrosis (Metavir 3 or 4), the areas under the receiver operating characteristic curve ranged from 0.71 to 0.84, with no significant differences between the individual scores. Sensitivities, specificities, and positive and negative predictive values were within the previously reported range. All scores tended to perform better for higher fibrosis stages. Conclusions: Our study demonstrates that HCV-infected patients can be identified and their fibrosis staged using commonly available EMR-based algorithms. C1 [Anand, Vijay; Hyun, Christian; Khan, Qasim M.; Hall, Curtis; Hessefort, Norbert; Fimmel, Claus J.] NorthShore Univ Hlth Syst, Dept Internal Med, Gastroenterol Sect, Evanston, IL 60201 USA. [Sonnenberg, Amnon] Portland VA Med Ctr, Portland, OR 97239 USA. [Sonnenberg, Amnon] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. RP Fimmel, CJ (reprint author), NorthShore Univ Hlth Syst, Div Gastroenterol, 2650 Ridge Ave, Evanston, IL 60201 USA. EM cfimmel@northshore.org FU Gilead Sciences Inc. FX Supported with funding from Gilead Sciences Inc. to C.J.F. NR 17 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 0192-0790 EI 1539-2031 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD SEP PY 2016 VL 50 IS 8 BP 664 EP 669 DI 10.1097/MCG.0000000000000519 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DT4TB UT WOS:000381472800013 PM 26974763 ER PT J AU Okeke, FC Shaw, S Hunt, KK Korsten, MA Rosman, AS AF Okeke, Francis C. Shaw, Spencer Hunt, Kristel K. Korsten, Mark A. Rosman, Alan S. TI Safety of Propofol Used as a Rescue Agent During Colonoscopy SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Article DE propofol; sedation; colonoscopy ID GASTROINTESTINAL ENDOSCOPY; ADMINISTERED PROPOFOL; SCREENING COLONOSCOPY; MODERATE SEDATION; ABDOMINAL-PAIN; METAANALYSIS AB Goal: The goal of this study was to evaluate the safety of propofol when used by gastroenterologists in patients who have an inadequate response to standard sedation (narcotics and benzodiazepines). Background: Many patients fail to achieve adequate sedation from narcotics and benzodiazepines during colonoscopy. The administration of propofol for colonoscopy is increasing, although its use by gastroenterologists is controversial. Study: We performed a retrospective review of our hospital's colonoscopy records from January 2006 to December 2009 to identify 403 subjects undergoing screening colonoscopies who required propofol (20 to 30mg every 3 min as needed) because of inadequate response to standard sedation. We also randomly selected 403 controls undergoing screening colonoscopies from the same time period that only required standard sedation. The incidence of adverse effects was then compared. Results: There were no major adverse events in either group. The rates of minor adverse events in the propofol and control group were 0.02 and 0.01, respectively (P=0.56). Adverse effects in the propofol group included: transient hypotension (n=1), nausea/vomiting (n=3), agitation (n=2), and rash (n=1). Adverse effects seen with standard sedation included: transient hypotension (n=2), nausea/vomiting (n=1), and oversedation (n=2). Patients who received propofol were more likely to be younger, had a history of illicit drug use, and a longer procedure time (P<0.05). Conclusions: Adjunctive propofol administered by gastroenterologist for conscious sedation was not associated with increased incidence of adverse events. It may be of value in patients who do not respond to conventional sedation. C1 [Okeke, Francis C.] Johns Hopkins Univ, Dept Med, Div Hosp Med CIMS, Bayview Med Ctr, Baltimore, MD 21218 USA. [Shaw, Spencer; Hunt, Kristel K.; Korsten, Mark A.; Rosman, Alan S.] James J Peters Vet Affairs Med Ctr, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. RP Rosman, AS (reprint author), James J Peters Vet Affairs Med Ctr, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM alan.rosman@va.gov NR 26 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 0192-0790 EI 1539-2031 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD SEP PY 2016 VL 50 IS 8 BP E77 EP E80 DI 10.1097/MCG.0000000000000445 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DT4TB UT WOS:000381472800003 PM 26565970 ER PT J AU Ibrahim, A Sharma, G Singh, K Ozaki, T AF Ibrahim, Akram Sharma, Gargi Singh, Kanwarpal Ozaki, Tsuneyuki TI Terahertz Detection Based on Spectral-Domain Interferometry Using Mach-Zehnder Interferometer SO JOURNAL OF INFRARED MILLIMETER AND TERAHERTZ WAVES LA English DT Article DE Spectral-domain interferometry; Mach-Zehnder interferometer; Intense terahertz electric field; Over-rotation ID OPTICAL RECTIFICATION; PULSES; GENERATION; TRANSITION AB We demonstrate the use of a Mach-Zehnder interferometer (MZI) to improve the performance of terahertz electric field measurements based on spectral-domain interferometry. The interferometer is introduced into the probe beam line to improve the temporal overlap between the two probe pulses. The probe pulse in the sample arm of the interferometer passes through the detection crystal and overlaps with the terahertz pulse, while the probe pulse in the reference arm does not. We measure the phase change between spectral components of these two pulses using spectral-domain interferometry. Using this new technique, we enable an unlimited temporal scanning window without the loss in the signal-to-noise ratio, thus overcoming the major limitation of conventional spectral-domain interferometry techniques for terahertz electric field detection. C1 [Ibrahim, Akram; Ozaki, Tsuneyuki] Univ Quebec, INRS EMT, Adv Laser Light Source, 1650 Boul Lionel Boulet, Varennes, PQ J3X 1S2, Canada. [Sharma, Gargi] Univ Massachusetts, 1 Univ Ave, Lowell, MA 01854 USA. [Singh, Kanwarpal] Harvard Med Sch, Massachusetts Gen Hosp, 40 Blossom St, Boston, MA 02114 USA. RP Ibrahim, A (reprint author), Univ Quebec, INRS EMT, Adv Laser Light Source, 1650 Boul Lionel Boulet, Varennes, PQ J3X 1S2, Canada. EM ibrahima@emt.inrs.ca FU Natural Sciences and Engineering Research Council of Canada (NSERC); Fonds de recherche du Quebec-Nature et technologies (FRQNT) FX The authors would like to acknowledge the assistance from technicians in Advanced Laser Light Source (ALLS) at INRS-EMT, Universite du Quebec, especially Mr. Philippe Lassonde for his technical advice. We also acknowledge the financial support from the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Fonds de recherche du Quebec-Nature et technologies (FRQNT). NR 23 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1866-6892 EI 1866-6906 J9 J INFRARED MILLIM TE JI J. Infrared Millim. Terahertz Waves PD SEP PY 2016 VL 37 IS 9 BP 837 EP 845 DI 10.1007/s10762-016-0275-8 PG 9 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA DT1AS UT WOS:000381214700002 ER PT J AU Roussin, CJ MacLean, TL Rudolph, JW AF Roussin, Christopher J. MacLean, Tammy L. Rudolph, Jenny W. TI The Safety in Unsafe Teams: A Multilevel Approach to Team Psychological Safety SO JOURNAL OF MANAGEMENT LA English DT Review DE psychological safety; team processes; subteams; multilevel theory; social networks ID LEADER-MEMBER EXCHANGE; PROCEDURAL JUSTICE CLIMATE; SOCIAL NETWORK RESEARCH; WORK TEAMS; BEHAVIORAL INTEGRITY; DIVERSITY FAULTLINES; STRUCTURAL-ANALYSIS; COMPOSITION MODELS; LEARNING-BEHAVIOR; PERFORMANCE AB Starting with the premise that subteam psychological safety (PS) microclimates are vitally important to team behavior yet invisible to team-level PS concepts and measures, we introduce a multilevel theory and model of PS within work teams. We first demonstrate the inevitability and influence of distinct PS microclimates in teams and highlight the limits of current team PS approaches, and then develop a multilevel PS theory using social network methods. We introduce multilevel PS measures and theorize their influence on specific aspects of team and subteam learning and performance outcomes. These include new applications of traditional network metrics (e.g., team PS density, member-only PS density, subteam PS density, and leader PS centrality) and a newly developed multilevel team PS index (mPSi). The mPSi measure synthesizes multilevel leader and member PS influences in a single number to better predict outcomes in teams that engage in multilevel (subteam and intact-team) activity to meet work demands. We employ the new metrics to examine four archetypal team PS structures, contrasting new and current approaches and illuminating the implications of incongruity between subteam and intact-team safety climates. We propose that this multilevel theory extends the team PS literature, effecting far greater understanding and prediction of team outcomes and development, while increasing the number of team PS studies that reach publication. C1 [Roussin, Christopher J.; MacLean, Tammy L.] Suffolk Univ, Boston, MA 02108 USA. [Rudolph, Jenny W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rudolph, Jenny W.] Harvard Med Sch, Boston, MA USA. RP Roussin, CJ (reprint author), Suffolk Univ, Management & Entrepreneurship Dept, 8 Ashburton Pl, Boston, MA 02108 USA. EM croussin@suffolk.edu NR 100 TC 2 Z9 2 U1 56 U2 63 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0149-2063 EI 1557-1211 J9 J MANAGE JI J. Manag. PD SEP PY 2016 VL 42 IS 6 BP 1409 EP 1433 DI 10.1177/0149206314525204 PG 25 WC Business; Psychology, Applied; Management SC Business & Economics; Psychology GA DS7XJ UT WOS:000380996100001 ER PT J AU Bi, WL Abedalthagafi, M Horowitz, P Agarwalla, PK Mei, Y Aizer, AA Brewster, R Dunn, GP Al-Mefty, O Alexander, BM Santagata, S Beroukhim, R Dunn, IF AF Bi, Wenya Linda Abedalthagafi, Malak Horowitz, Peleg Agarwalla, Pankaj K. Mei, Yu Aizer, Ayal A. Brewster, Ryan Dunn, Gavin P. Al-Mefty, Ossama Alexander, Brian M. Santagata, Sandro Beroukhim, Rameen Dunn, Ian F. TI Genomic landscape of intracranial meningiomas SO JOURNAL OF NEUROSURGERY LA English DT Review DE meningioma; genomics; tumor classification; tumor progression; molecular taxonomy; precision medicine; targeted therapy; oncology ID TUMOR-SUPPRESSOR GENE; ATYPICAL CRANIAL MENINGIOMAS; GERMLINE SMARCB1 MUTATION; CENTRAL-NERVOUS-SYSTEM; ANAPLASTIC MENINGIOMAS; MALIGNANT PROGRESSION; MULTIPLE MENINGIOMAS; TELOMERASE ACTIVITY; MOLECULAR-GENETICS; NF2 GENE AB Meningiomas are the most common primary intracranial neoplasms in adults. Current histopathological grading schemes do not consistently predict their natural history. Classic cytogenetic studies have disclosed a progressive course of chromosomal aberrations, especially in high-grade meningiomas. Furthermore, the recent application of unbiased next generation sequencing approaches has implicated several novel genes whose mutations underlie a substantial percentage of meningiomas. These insights may serve to craft a molecular taxonomy for meningiomas and highlight putative therapeutic targets in a new era of rational biology-informed precision medicine. C1 [Bi, Wenya Linda; Horowitz, Peleg; Mei, Yu; Al-Mefty, Ossama; Dunn, Ian F.] Harvard Med Sch, Brigham & Womens Hosp, Dept Neurosurg, Boston, MA USA. [Abedalthagafi, Malak; Brewster, Ryan; Santagata, Sandro] Harvard Med Sch, Brigham & Womens Hosp, Div Neuropathol, Dept Pathol, Boston, MA USA. [Agarwalla, Pankaj K.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA USA. [Bi, Wenya Linda; Agarwalla, Pankaj K.; Beroukhim, Rameen] Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA USA. [Aizer, Ayal A.; Alexander, Brian M.] Harvard Med Sch, Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA USA. [Dunn, Gavin P.] Washington Univ, Sch Med, Ctr Human Immunol & Immunotherapy Programs, Dept Neurosurg Pathol & Immunol, St Louis, MO USA. RP Dunn, IF (reprint author), Brigham & Womens Hosp, Dept Neurosurg, 15 Francis St, Boston, MA 02115 USA. EM idunn@partners.org OI Brewster, Ryan/0000-0003-0051-2623; Horowitz, Peleg/0000-0002-5177-1783 NR 103 TC 3 Z9 3 U1 4 U2 6 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD SEP PY 2016 VL 125 IS 3 BP 525 EP 535 DI 10.3171/2015.6.JNS15591 PG 11 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DT8YS UT WOS:000381782300001 PM 26771848 ER PT J AU Finn, AP Borboli-Gerogiannis, S Brauner, S Chang, HYP Chen, S Gardiner, M Greenstein, SH Kloek, C Miller, JW Chen, TC AF Finn, Avni P. Borboli-Gerogiannis, Sheila Brauner, Stacey Chang, Han-Ying Peggy Chen, Sherleen Gardiner, Matthew Greenstein, Scott H. Kloek, Carolyn Miller, Joan W. Chen, Teresa C. TI Assessing Resident Cataract Surgery Outcomes Using Medicare Physician Quality Reporting System Measures SO JOURNAL OF SURGICAL EDUCATION LA English DT Article DE surgical training; cataract; PQRS measures; benchmarks of surgical care; resident evaluation AB OBJECTIVES: To assess resident cataract surgery outcomes at an academic teaching institution using 2 Physician Quality Reporting System (PQRS) cataract measures, which are intended to serve as a proxy for quality of surgical care. DESIGN: A retrospective review comparing cataract surgery outcomes of resident and attending surgeries using 2 PQRS measures: (1) 20/40 or better best-corrected visual acuity following cataract surgery and (2) complications within 30 days following cataract surgery requiring additional surgical procedures. SETTING: An academic ophthalmology center. PARTICIPANTS: A total of 2487 surgeries performed at the Massachusetts Eye and Ear Infirmary from January 1, 2011 to December 31, 2012 were included in this study. RESULTS: Of all 2487 cataract surgeries, 98.95% achieved a vision of at least 20/40 at or before 90 days, and only 0.64% required a return to the operating room for postoperative complications. Of resident surgeries, 98.9% (1370 of 1385) achieved 20/40 vision at or before 90 days follow-up. Of attending surgeries, 99.0% (1091 of 1102) achieved 20/40 vision at or before 90 days (p = 1.00). There were no statistically significant differences between resident and attending cases regarding postoperative complications needing a return to the operating room (i.e., 0.65%, or 9 of 1385 resident cases vs 0.64%, or 7 of 1102 attending cases; p = 1.00). CONCLUSIONS: Using PQRS Medicare cataract surgery criteria, this study establishes new benchmarks for cataract surgery outcomes at a teaching institution and supplemental measure for assessing resident surgical performance. Excellent cataract outcomes were achieved at an academic teaching institution, with results exceeding Medicare thresholds of 50%. There appears to be no significant difference in supervised trainee and attending cataract surgeon outcomes using 2 PQRS measures currently used by Medicare to determine physician reimbursement and quality of care. (C) 2016 Published by Elsevier Inc. on behalf of the Association of Program Directors in Surgery C1 [Finn, Avni P.; Borboli-Gerogiannis, Sheila; Brauner, Stacey; Chang, Han-Ying Peggy; Chen, Sherleen; Gardiner, Matthew; Greenstein, Scott H.; Kloek, Carolyn; Miller, Joan W.; Chen, Teresa C.] Harvard Med Sch, Dept Ophthalmol, Boston, MA USA. [Borboli-Gerogiannis, Sheila; Brauner, Stacey; Chang, Han-Ying Peggy; Chen, Sherleen; Gardiner, Matthew; Greenstein, Scott H.; Kloek, Carolyn] Massachusetts Eye & Ear Infirm, Comprehens Ophthalmol & Cataract Consultat Serv, Boston, MA 02114 USA. [Miller, Joan W.] Massachusetts Eye & Ear Infirm, Retina Serv, Boston, MA 02114 USA. [Chen, Teresa C.] Massachusetts Eye & Ear Infirm, Glaucoma Serv, 243 Charles St, Boston, MA 02114 USA. RP Chen, TC (reprint author), Massachusetts Eye & Ear Infirm, Glaucoma Serv, 243 Charles St, Boston, MA 02114 USA. EM Teresa_Chen@meei.harvard.edu OI Gardiner, Matthew/0000-0002-8864-2379 FU Massachusetts Eye and Ear Infirmary; Department of Ophthalmology of the Harvard Medical School FX Funding for this project was provided by the Massachusetts Eye and Ear Infirmary and the Department of Ophthalmology of the Harvard Medical School under the direction of John Fernandez, President and CEO of the Massachusetts Eye and Ear Infirmary, and Joan W. Miller, MD, Chief of the Department of Ophthalmology for Harvard Medical School. NR 9 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 1931-7204 EI 1878-7452 J9 J SURG EDUC JI J. Surg. Educ. PD SEP-OCT PY 2016 VL 73 IS 5 BP 774 EP 779 DI 10.1016/j.jsurg.2016.04.007 PG 6 WC Education, Scientific Disciplines; Surgery SC Education & Educational Research; Surgery GA DU3GH UT WOS:000382098300003 PM 27211876 ER PT J AU Chen, BE Zheng, BH DeRan, M Jarugumilli, GK Fu, JJ Brooks, YS Wu, X AF Chen, Baoen Zheng, Baohui DeRan, Michael Jarugumilli, Gopala K. Fu, Jianjun Brooks, Yang S. Wu, Xu TI ZDHHC7-mediated S-palmitoylation of Scribble regulates cell polarity SO NATURE CHEMICAL BIOLOGY LA English DT Article ID PROMOTES MAMMARY TUMORIGENESIS; PROTEIN PALMITOYLATION; BREAST-CANCER; HIPPO PATHWAY; LOCALIZATION; RAS; DEREGULATION; EXPRESSION; STABILITY; ACYLATION AB Scribble (SCRIB) is a tumor-suppressor protein, playing critical roles in establishing and maintaining epithelial cell polarity. SCRIB is frequently amplified in human cancers but does not localize properly to cell-cell junctions, suggesting that mislocalization of SCRIB disrupts its tumor-suppressive activities. Using chemical reporters, here we showed that SCRIB localization was regulated by S-palmitoylation at conserved cysteine residues. Palmitoylation-deficient mutants of SCRIB were mislocalized, leading to disruption of cell polarity and loss of their tumor-suppressive activities to oncogenic YAP, MAPK and PI3K/AKT pathways. We further found that ZDHHC7 was the major palmitoyl acyltransferase regulating SCRIB. Knockout of ZDHHC7 led to SCRIB mislocalization and YAP activation, and disruption of SCRIB's suppressive activities in HRas(V12)-induced cell invasion. In summary, we demonstrated that ZDHHC7-mediated SCRIB palmitoylation is critical for SCRIB membrane targeting, cell polarity and tumor suppression, providing new mechanistic insights of how dynamic protein palmitoylation regulates cell polarity and tumorigenesis. C1 [Chen, Baoen; Zheng, Baohui; DeRan, Michael; Jarugumilli, Gopala K.; Fu, Jianjun; Brooks, Yang S.; Wu, Xu] Harvard Med Sch, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. RP Wu, X (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. EM xwu@cbrc2.mgh.harvard.edu FU Stewart Rahr-MRA (Melanoma Research Alliance) Young Investigator Award; American Cancer Society [124929-RSG-13-291-01-TBE]; National Institutes of Health [R01CA181537, R01DK107651-01]; [1S10RR027673-01] FX This work was supported by Stewart Rahr-MRA (Melanoma Research Alliance) Young Investigator Award, Research Scholar Award from American Cancer Society (124929-RSG-13-291-01-TBE), and grants from National Institutes of Health (R01CA181537 and R01DK107651-01) to X.W. We appreciate W.-L. Yan for his generous philanthropic donation to Massachusetts General Hospital to support Y.S.B.'s training and research. We thank M. Fukata (National Institute for Physiological Sciences, Japan) for the expression vectors of DHHC proteins, the Confocal Imaging Core at Cutaneous Biology Research Center of Massachusetts General Hospital, and the Shared Instrumentation Grant that covered the purchase of the microscope (1S10RR027673-01), and the Taplin Mass Spec Core at Harvard Medical School for proteomic studies. NR 46 TC 4 Z9 4 U1 8 U2 9 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 SEP PY 2016 VL 12 IS 9 BP 686 EP + DI 10.1038/nchembio.2119 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DU5MF UT WOS:000382255100009 PM 27380321 ER PT J AU Frederick, NN Kenney, L Vrooman, L Recklitis, CJ AF Frederick, Natasha N. Kenney, Lisa Vrooman, Lynda Recklitis, Christopher J. TI Fatigue in adolescent and adult survivors of non-CNS childhood cancer: a report from project REACH SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Fatigue; Childhood cancer; Survivorship; Late effects ID QUALITY-OF-LIFE; LONG-TERM SURVIVORS; ACUTE LYMPHOBLASTIC-LEUKEMIA; GENERIC CORE SCALES; HODGKINS-DISEASE; PEDIATRIC CANCER; RELIABILITY; POPULATION; VALIDITY; SLEEP AB Studies of fatigue in childhood cancer survivors (CCS) are inconclusive, with some reporting increased fatigue prevalence in this population while others do not. Given the potentially significant consequences of unmanaged fatigue, we sought to estimate the prevalence of fatigue and to identify factors associated with fatigue in a population of non-CNS CCS ranging from adolescence to middle adulthood using a single fatigue measurement tool. Two hundred sixty-eight CCS ages 12-49 years followed in a survivorship clinic at a single cancer center completed validated self-report measures of fatigue, depression, and quality of life. Demographic and current health data were collected by study questionnaire and chart review Based on age-adjusted population norms, the prevalence of fatigue was 13.8 %, which is not significantly different compared to results in healthy populations. Fatigue was independently associated with having a parts per thousand yen3 chronic health conditions (OR 4.27, 95 % CI 1.52-11.99). Fatigued participants reported lower overall quality of life scores (OR 0.86, 95 % CI 0.82-0.89) and were more likely to be depressed compared to non-fatigued patients (20.4 vs. 1.4 %, respectively, p < 0.0001). There were 41(78.8 %) survivors with fatigue in our population who did not report significant depression. CCS did not demonstrate increased fatigue compared to age-matched normative data. Fatigued survivors were more likely to have multiple chronic conditions, depression, and decreased quality of life. Longitudinal study will promote better understanding of the relationship between fatigue and specific chronic conditions, thereby facilitating early identification of those individuals most at risk. C1 [Frederick, Natasha N.; Vrooman, Lynda] Harvard Med Sch, Dana Farber Boston Childrens Blood Disorders Ctr, 450 Brookline Ave, Boston, MA 02215 USA. [Kenney, Lisa; Vrooman, Lynda; Recklitis, Christopher J.] Harvard Med Sch, Dana Farber Canc Inst, Perini Family Survivors Ctr, Boston, MA USA. RP Frederick, NN (reprint author), Harvard Med Sch, Dana Farber Boston Childrens Blood Disorders Ctr, 450 Brookline Ave, Boston, MA 02215 USA. EM natasha_frederick@dfci.harvard.edu NR 29 TC 0 Z9 0 U1 8 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD SEP PY 2016 VL 24 IS 9 BP 3951 EP 3959 DI 10.1007/s00520-016-3230-2 PG 9 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA DS3IV UT WOS:000380677200034 PM 27117558 ER PT J AU Wolf, EJ Sadeh, N Leritz, EC Logue, MW Stoop, TB McGlinchey, R Milberg, W Miller, MW AF Wolf, Erika J. Sadeh, Naomi Leritz, Elizabeth C. Logue, Mark W. Stoop, Tawni B. McGlinchey, Regina Milberg, William Miller, Mark W. TI Posttraumatic Stress Disorder as a Catalyst for the Association Between Metabolic Syndrome and Reduced Cortical Thickness SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Accelerated aging; Cortical thickness; Magnetic resonance imaging; Metabolic syndrome; Posttraumatic stress disorder; Structural equation modeling ID BODY-MASS INDEX; TYPE-2 DIABETES-MELLITUS; RANDOMIZED CONTROLLED-TRIAL; CORONARY-HEART-DISEASE; HEALTHY OLDER-ADULTS; CARDIOVASCULAR-DISEASE; OXIDATIVE STRESS; ALZHEIMERS-DISEASE; CARDIOMETABOLIC RISK; PREFRONTAL CORTEX AB BACKGROUND: Metabolic syndrome (MetS), defined by a constellation of cardiometabolic pathologies, is highly prevalent among veterans, especially veterans with posttraumatic stress disorder (PTSD), and poses a major risk for adverse health outcomes, including neurodegeneration and mortality. Given this, we evaluated 1) the association between MetS and neural integrity, indexed by cortical thickness; 2) the relationship between PTSD and MetS; and 3) whether PTSD was associated with cortical thickness indirectly through MetS. METHODS: The sample consisted of 346 U.S. military veterans (89.3% male; 71.4% white) who deployed to Iraq, Afghanistan, or both. Neuroimaging data were available for 274 participants. RESULTS: In whole-brain analyses, MetS was negatively associated with cortical thickness in two left and four right hemisphere regions, as follows: bilateral temporal lobe, including temporal pole, fusiform gyrus, and insula, and extending into occipital cortex (left hemisphere) and orbitofrontal cortex (right hemisphere); bilateral precuneus, posterior cingulate, calcarine, and occipital-parietal cortex; and right rostral anterior cingulate cortex and central sulcus/postcentral gyrus. Path models showed that PTSD predicted MetS (beta = .19, p < .001), which was associated with reduced cortical thickness (beta = -.29 to -.43, all p < .001). CONCLUSIONS: Results from this young veteran sample provide evidence that PTSD confers risk for cardiometabolic pathology and neurodegeneration and raise concern that this cohort may be aging prematurely and at risk for substantial medical and cognitive decline. This study highlights the need to identify the molecular mechanisms linking PTSD to MetS and effective interventions to reduce PTSD-related health comorbidities. C1 [Wolf, Erika J.; Sadeh, Naomi; Miller, Mark W.] VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, Boston, MA USA. [Leritz, Elizabeth C.] VA Boston Healthcare Syst, Neuroimaging Res Vet Ctr, Boston, MA USA. [Leritz, Elizabeth C.; McGlinchey, Regina; Milberg, William] VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, Boston, MA USA. [Leritz, Elizabeth C.; McGlinchey, Regina; Milberg, William] VA Boston Healthcare Syst, Translat Res Ctr TBI & Stress Disorders, Boston, MA USA. [Logue, Mark W.] VA Boston Healthcare Syst, Res Serv, Boston, MA USA. [Wolf, Erika J.; Sadeh, Naomi; Miller, Mark W.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Logue, Mark W.] Boston Univ, Sch Med, Biomed Genet, Boston, MA 02118 USA. [Leritz, Elizabeth C.; McGlinchey, Regina; Milberg, William] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Logue, Mark W.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Stoop, Tawni B.] Boston VA Res Inst Inc, Boston, MA USA. RP Wolf, EJ (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD 116B2, 150 South Huntington Ave, Boston, MA 02130 USA. EM erika.wolf@va.gov FU National Institute of Mental Health [R21MH102834]; Translational Research Center for TBI and Stress Disorders; Department of Veterans Affairs Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence [B9254-C]; Department of Veterans Affairs Cooperative Studies Program; National Institute of Neurological Disorders and Stroke [R01NS086882]; Department of Veterans Affairs Clinical Sciences Research and Development Program Career Development Award (EJW) FX This work was supported by the National Institute of Mental Health Grant No. R21MH102834 "Neuroimaging Genetics of PTSD," Translational Research Center for TBI and Stress Disorders, a Department of Veterans Affairs Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence (B9254-C), Department of Veterans Affairs Cooperative Studies Program, National Institute of Neurological Disorders and Stroke Grant No. R01NS086882, and Department of Veterans Affairs Clinical Sciences Research and Development Program Career Development Award (EJW). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the U.S. Department of Veterans Affairs or the U.S. Government. NR 103 TC 1 Z9 1 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 1 PY 2016 VL 80 IS 5 BP 363 EP 371 DI 10.1016/j.biopsych.2015.11.023 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DS5RR UT WOS:000380840500008 PM 26826875 ER PT J AU Yehuda, R Daskalakis, NP Bierer, LM Bader, HN Klengel, T Holsboer, F Binder, EB AF Yehuda, Rachel Daskalakis, Nikolaos P. Bierer, Linda M. Bader, Heather N. Klengel, Torsten Holsboer, Florian Binder, Elisabeth B. TI Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Cortisol; Epigenetics; FKBP5; Intergenerational; PTSD; Stress ID POSTTRAUMATIC-STRESS-DISORDER; TRADE-CENTER ATTACKS; CHILDHOOD TRAUMA; GLUCOCORTICOID-RECEPTOR; PARENTAL PTSD; CORTISOL-LEVELS; MATERNAL-CARE; SURVIVORS; RISK; EXPRESSION AB BACKGROUND: The involvement of epigenetic mechanisms in intergenerational transmission of stress effects has been demonstrated in animals but not in humans. METHODS: Cytosine methylation within the gene encoding for FK506 binding protein 5 (FKBP5) was measured in Holocaust survivors (n = 32), their adult offspring (n = 22), and demographically comparable parent (n = 8) and offspring (n 5 9) control subjects, respectively. Cytosine-phosphate-guanine sites for analysis were chosen based on their spatial proximity to the intron 7 glucocorticoid response elements. RESULTS: Holocaust exposure had an effect on FKBP5 methylation that was observed in exposed parents as well in their offspring. These effects were observed at bin 3/site 6. Interestingly, in Holocaust survivors, methylation at this site was higher in comparison with control subjects, whereas in Holocaust offspring, methylation was lower. Methylation levels for exposed parents and their offspring were significantly correlated. In contrast to the findings at bin 3/site 6, offspring methylation at bin 2/sites 3 to 5 was associated with childhood physical and sexual abuse in interaction with an FKBP5 risk allele previously associated with vulnerability to psychological consequences of childhood adversity. The findings suggest the possibility of site specificity to environmental influences, as sites in bins 3 and 2 were differentially associated with parental trauma and the offspring's own childhood trauma, respectively. FKBP5 methylation averaged across the three bins examined was associated with wake-up cortisol levels, indicating functional relevance of the methylation measures. CONCLUSIONS: This is the first demonstration of an association of preconception parental trauma with epigenetic alterations that is evident in both exposed parent and offspring, providing potential insight into how severe psychophysiological trauma can have intergenerational effects. C1 [Yehuda, Rachel; Daskalakis, Nikolaos P.; Bierer, Linda M.; Bader, Heather N.] Icahn Sch Med Mt Sinai, Traumat Stress Studies Div, Dept Psychiat, New York, NY 10029 USA. [Yehuda, Rachel; Daskalakis, Nikolaos P.; Bierer, Linda M.; Bader, Heather N.] James J Peters Vet Affairs Med Ctr, PTSD Clin Res Program, Mental Hlth Care Ctr, Bronx, NY USA. James J Peters Vet Affairs Med Ctr, Lab Clin Neuroendocrinol & Neurochem, Bronx, NY USA. [Klengel, Torsten; Binder, Elisabeth B.] Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany. [Holsboer, Florian] Max Planck Inst Psychiat, Munich, Germany. [Holsboer, Florian] HMNC Holding GmbH, Munich, Germany. [Klengel, Torsten; Binder, Elisabeth B.] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA. RP Yehuda, R (reprint author), Mt Sinai Sch Med, Mental Hlth Care Ctr, James J Peters Vet Affairs Med Ctr, Dept Psychiat, 526 OOMH PTSD 116-A,130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM rachel.yehuda@va.gov OI Klengel, Torsten/0000-0001-7045-9229; Daskalakis, Nikolaos/0000-0003-1660-9112 FU National Institute of Mental Health [R01 MH 64675-01, 1RC1MH088101-01]; National Institutes of Health [5 M01 RR00071]; European Research Council starting Grant, G x E molmech, FP7 framework program [281338] FX This work was supported by National Institute of Mental Health R01 MH 64675-01 "Biology of Risk and PTSD in Holocaust Survivor Offspring" and 1RC1MH088101-01 "Identification of an Epigenetic Risk Marker for PTSD" and, in part, by a Grant (5 M01 RR00071) for the Mount Sinai General Clinical Research Center from the National Institutes of Health. The National Institutes of Health had no further role in the study design; in the collection, analysis, and interpretation of the data; in the writing of the report; or in the decision to submit the article for publication. European Research Council starting Grant (Grant #281338) G x E molmech, FP7 framework program to EB. NR 56 TC 24 Z9 24 U1 39 U2 50 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 1 PY 2016 VL 80 IS 5 BP 372 EP 380 DI 10.1016/j.biopsych.2015.08.005 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DS5RR UT WOS:000380840500009 PM 26410355 ER PT J AU Barroso-Gonzalez, J Auclair, S Luan, S Thomas, L Atkins, KM Aslan, JE Thomas, LL Zhao, J Zhao, Y Thomas, G AF Barroso-Gonzalez, J. Auclair, S. Luan, S. Thomas, L. Atkins, K. M. Aslan, J. E. Thomas, L. L. Zhao, J. Zhao, Y. Thomas, G. TI PACS-2 mediates the ATM and NF-kappa B-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID I DOWN-REGULATION; ENDOPLASMIC-RETICULUM; MHC-I; GENOTOXIC STIMULI; IKK ACTIVATION; EXPRESSION; MITOCHONDRIA; MEMBRANE; BCL-X(L); COMPLEX AB Nuclear factor kappa B (NF-kappa B) promotes cell survival in response to genotoxic stress by inducing the expression of anti-apoptotic proteins including Bcl-xL, which protects mitochondria from stress-induced mitochondrial outer membrane permeabilization (MOMP). Here we show that the multifunctional sorting protein Pacs-2 (phosphofurin acidic cluster sorting protein-2) is required for Bcl-xL induction following DNA damage in primary mouse thymocytes. Consequently, in response to DNA damage, Pacs-2(-/-) thymocytes exhibit a blunted induction of Bcl-xL, increased MOMP and accelerated apoptosis. Biochemical studies show that cytoplasmic PACS-2 promotes this DNA damage-induced anti-apoptotic pathway by interacting with ataxia telangiectasia mutated (ATM) to drive NF-kappa B activation and induction of Bcl-xL. However, Pacs-2 was not required for tumor necrosis factor-alpha-induced NF-kappa B activation, suggesting a role for PACS-2 selectively in NF-kappa B activation in response to DNA damage. These findings identify PACS-2 as an in vivo mediator of the ATM and NF-kappa B-dependent induction of Bcl-xL that promotes cell survival in response to DNA damage. C1 [Barroso-Gonzalez, J.; Auclair, S.; Luan, S.; Thomas, L.; Thomas, L. L.; Thomas, G.] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA USA. [Atkins, K. M.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA USA. [Aslan, J. E.] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Portland, OR USA. [Zhao, J.; Zhao, Y.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. RP Thomas, G (reprint author), Univ Pittsburgh, Dept Microbiol & Mol Genet, 450 Technol Dr, Pittsburgh, PA 15219 USA. EM thomasg@pitt.edu FU NIH [R01 CA151564, HL112791, GM115389, AHA 12SDG9050005, ALA RG350146] FX We thank B Vogelstein, S Narayan, D Chen, G Xiao, C Bakkenist and L Lan for reagents; L Li for assistance with preliminary experiments; and G Xiao and M. Kveiborg for critically reading the manuscript. This work was supported by NIH R01 CA151564 (to GT), HL112791 (to YZ), GM115389 to (JZ), AHA 12SDG9050005 (to JZ) and ALA RG350146 (to JZ). NR 59 TC 2 Z9 2 U1 6 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD SEP PY 2016 VL 23 IS 9 BP 1448 EP 1457 DI 10.1038/cdd.2016.23 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DS8ZY UT WOS:000381072800003 PM 26943323 ER PT J AU Vergallo, R Xing, L Minami, Y Soeda, T Ong, DS Gao, L Lee, H Guagliumi, G Biasucci, LM Crea, F Yu, B Uemura, S O'Donnell, CJ Jang, IK AF Vergallo, Rocco Xing, Lei Minami, Yoshiyasu Soeda, Tsunenari Ong, Daniel S. Gao, Lei Lee, Hang Guagliumi, Giulio Biasucci, Luigi M. Crea, Filippo Yu, Bo Uemura, Shiro O'Donnell, Christopher J. Jang, Ik-Kyung TI Associations between the Framingham Risk Score and coronary plaque characteristics as assessed by three-vessel optical coherence tomography SO CORONARY ARTERY DISEASE LA English DT Article DE coronary artery disease; Framingham Risk Score; optical coherence tomography ID INTRAVASCULAR ULTRASOUND; ATHEROSCLEROTIC PLAQUE; HEART-DISEASE; ETHNIC-GROUPS; PROGRESSION; ARTERY; CALCIFICATION; BURDEN; VALIDATION; PREDICTION AB Objectives This study sought to explore the association between the Framingham Risk Score (FRS) and coronary plaque characteristics assessed by optical coherence tomography (OCT) imaging. Background Clinical prediction models are useful for identifying high-risk patients. However, coronary events often occur in individuals estimated to be at low risk. Methods A total of 254 patients with coronary artery disease who underwent three-vessel OCT were divided into tertiles according to FRS. Nonculprit plaque characteristics were compared among the three groups. Results A total of 663 plaques were analyzed. FRS was significantly associated with calcification [37% (low FRS) vs. 46% (intermediate FRS) vs. 70% (high FRS); P<0.001] and neovascularization [39% (low FRS) vs. 41% (intermediate FRS) vs. 56% (high FRS); P<0.001], but not with lipid-rich plaques or thin-cap fibroatheroma (TCFA). On multivariate analysis, FRS was an independent predictor of the presence of both calcification and neovascularization. There were no deaths, two acute myocardial infarctions, and 15 nontarget lesion revascularizations at the 1-year followup. The event rate increased progressively across FRS tertiles [2.4% (low FRS) vs. 7.1% (intermediate FRS) vs. 8.6% (high FRS); P=0.186]. The c-statistic for FRS to predict future clinical events was 0.628 (95% confidence interval, 0.500-0.757). The addition of both calcification and TCFA to FRS provided incremental prognostic value [c-statistics: 0.761 (95% confidence interval, 0.631-0.890)]. Conclusion The present study showed significant associations between FRS and the presence of coronary calcification and neovascularization in nonculprit plaques. The combination of FRS and OCT-detected calcifications and TCFA provides improved prognostic ability in identifying patients with known coronary artery disease who are at risk of recurrent events. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Vergallo, Rocco; Xing, Lei; Minami, Yoshiyasu; Soeda, Tsunenari; Ong, Daniel S.; Gao, Lei; O'Donnell, Christopher J.; Jang, Ik-Kyung] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, GRB 800,55 Fruit St, Boston, MA 02114 USA. [Lee, Hang] Harvard Med Sch, Massachusetts Gen Hosp, Biostat Ctr, Boston, MA USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Xing, Lei; Yu, Bo] Harbin Med Univ, Dept Cardiol, Affiliated Hosp 2, Harbin, Peoples R China. [Guagliumi, Giulio] Osped Papa Giovanni XXIII, Cardiovasc Dept, Bergamo, Italy. [Biasucci, Luigi M.; Crea, Filippo] Univ Cattolica Sacro Cuore, Dept Cardiovasc Med, Rome, Italy. [Uemura, Shiro] Nara Med Univ, Dept Cardiol, Nara, Japan. [Jang, Ik-Kyung] Kyung Hee Univ, Div Cardiol, 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 FU Michael and Kathryn Park; Gill and Allan Gray; St Jude Medical; Italian Society of Cardiology Award for Research Abroad and the 'Enrico ed Enrica Sovena' Foundation, Rome, Italy FX Dr Jang's research was supported by Michael and Kathryn Park, and by Gill and Allan Gray. Dr Jang has received grants and consulting fees from St Jude Medical. Dr Vergallo was supported by the 2013 Italian Society of Cardiology Award for Research Abroad and the 'Enrico ed Enrica Sovena' Foundation, Rome, Italy. For the remaining authors there are no conflicts of interest. NR 28 TC 0 Z9 0 U1 2 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 SEP PY 2016 VL 27 IS 6 BP 460 EP 466 DI 10.1097/MCA.0000000000000383 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DS5FI UT WOS:000380806300005 PM 27218146 ER PT J AU Nance, JW Hedgire, SS Digumarthy, SR Tolis, G Melnitchouk, S Ghoshhajra, BB AF Nance, John W. Hedgire, Sandeep S. Digumarthy, Subba R. Tolis, George, Jr. Melnitchouk, Serguei Ghoshhajra, Brian B. TI Retained wire with intra-aortic migration presenting with hemoptysis: case studies of the Massachusetts General Hospital SO CORONARY ARTERY DISEASE LA English DT Editorial Material C1 [Nance, John W.; Hedgire, Sandeep S.; Digumarthy, Subba R.; Ghoshhajra, Brian B.] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. [Tolis, George, Jr.; Melnitchouk, Serguei] Harvard Univ, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. RP Nance, JW (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM jwnance@mgh.harvard.edu NR 2 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 SEP PY 2016 VL 27 IS 6 BP 521 EP 522 DI 10.1097/MCA.0000000000000384 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DS5FI UT WOS:000380806300013 PM 27214276 ER PT J AU Alladina, JW Levy, SD Hibbert, KA Januzzi, JL Harris, RS Matthay, MA Thompson, BT Bajwa, EK AF Alladina, Jehan W. Levy, Sean D. Hibbert, Kathryn A. Januzzi, James L. Harris, R. Scott Matthay, Michael A. Thompson, B. Taylor Bajwa, Ednan K. CA Natl Heart Lung Blood Inst Acute R TI Plasma Concentrations of Soluble Suppression of Tumorigenicity-2 and Interleukin-6 Are Predictive of Successful Liberation From Mechanical Ventilation in Patients With the Acute Respiratory Distress Syndrome SO CRITICAL CARE MEDICINE LA English DT Article DE acute respiratory distress syndrome; biomarkers; critical care; interleukin-6 protein, human; mechanical ventilation; mechanical ventilator weaning; suppression of tumorigenicity-2 protein, human ID ACUTE LUNG INJURY; MYOCARDIAL-INFARCTION; NATRIURETIC PEPTIDE; CONTROLLED-TRIAL; HEART-FAILURE; FAMILY-MEMBER; ST2; DURATION; RISK; EXTUBATION AB Objectives: Soluble suppression of tumorigenicity-2 and interleukin-6 concentrations have been associated with the inflammatory cascade of acute respiratory distress syndrome. We determined whether soluble suppression of tumorigenicity-2 and interleukin-6 levels can be used as prognostic biomarkers to guide weaning from mechanical ventilation and predict the need for reintubation. Design, Setting, and Patients: We assayed plasma soluble suppression of tumorigenicity-2 (n = 826) concentrations and interleukin-6 (n = 755) concentrations in the Fluid and Catheter Treatment Trial, a multicenter randomized controlled trial of conservative fluid management in acute respiratory distress syndrome. We tested whether soluble suppression of tumorigenicity-2 and interleukin-6 levels were associated with duration of mechanical ventilation, the probability of passing a weaning assessment, and the need for reintubation. Measurements and Main Results: In models adjusted for Acute Physiology and Chronic Health Evaluation score and other relevant variables, patients with higher day 0 and day 3 median soluble suppression of tumorigenicity-2 and interleukin-6 concentrations had decreased probability of extubation over time (day 0 soluble suppression of tumorigenicity-2: hazard ratio, 0.85; 95% CI, 0.72-1.00; p = 0.05; day 0 interleukin-6: hazard ratio, 0.64; 95% CI, 0.54-0.75; p < 0.0001; day 3 soluble suppression of tumorigenicity-2: hazard ratio, 0.64; 95% CI, 0.54-0.75; p < 0.0001; and day 3 interleukin-6: hazard ratio, 0.73; 95% CI, 0.62-0.85; p = 0.0001). Higher biomarker concentrations were also predictive of decreased odds of passing day 3 weaning assessments (soluble suppression of tumorigenicity-2: odds ratio, 0.62: 95% CI, 0.44-0.87; p = 0.006 and interleukin-6: odds ratio, 0.61; 95% CI, 0.43-0.85; p = 0.004) and decreased odds of passing a spontaneous breathing trial (soluble suppression of tumorigenicity-2: odds ratio, 0.45; 95% CI, 0.28-0.71; p = 0.0007 and interleukin-6 univariate analysis only: odds ratio, 0.55; 95% CI, 0.36-0.83; p = 0.005). Finally, higher biomarker levels were significant predictors of the need for reintubation for soluble suppression of tumorigenicity-2 (odds ratio, 3.23; 95% CI, 1.04-10.07; p = 0.04) and for interleukin-6 (odds ratio, 2.58; 95% CI, 1.14-5.84; p = 0.02). Conclusions: Higher soluble suppression of tumorigenicity-2 and interleukin-6 concentrations are each associated with worse outcomes during weaning of mechanical ventilation and increased need for reintubation in patients with acute respiratory distress syndrome. Biomarker-directed ventilator management may lead to improved outcomes in weaning of mechanical ventilation in patients with acute respiratory distress syndrome. C1 [Alladina, Jehan W.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Levy, Sean D.; Hibbert, Kathryn A.; Harris, R. Scott; Thompson, B. Taylor; Bajwa, Ednan K.] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Januzzi, James L.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Matthay, Michael A.] Univ Calif San Francisco, Dept Anesthesia, San Francisco, CA USA. RP Bajwa, EK (reprint author), Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. EM ebajwa@partners.org FU National Heart, Lung, and Blood Institute (NHLBI) [HL60710, HL67197, HL084060, HL086667]; NHLBI [NO1-HR 46046-64, NO1-HR-16146-54]; National Institutes of Health (NIH); NIH; Critical Diagnostics; Merck; Glaxo Smith Kline; Cerus; Roche-Genentec; Amgen FX Supported, in part, by National Heart, Lung, and Blood Institute (NHLBI) grants HL60710, HL67197, HL084060, and HL086667. Soluble suppression of tumorigenicity-2 assays were donated by Critical Diagnostics. The Fluid and Catheter Treatment Trial study was supported, in part, by contracts (NO1-HR 46046-64 and NO1-HR-16146-54) with the NHLBI.; Dr. Alladina received support for this article research from the National Institutes of Health (NIH). Her institution received funding from the NIH. Dr. Januzzi received funding from Critical Diagnostics (consultancy) and disclosed off-label product use (soluble suppression of tumorigenicity-2 and interleukin-6 for weaning from ventilation). Dr. Harris received funding from Merck. Dr. Matthay disclosed other support (Quark Pharmaceuticals), received support for this article research from the NIH, and received funding from Glaxo Smith Kline, Cerus, and Roche-Genentec and Amgen. Dr. Thompson received support for this article research from the NIH. Dr. Bajwa received support for this article research from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 37 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 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD SEP PY 2016 VL 44 IS 9 BP 1735 EP 1743 DI 10.1097/CCM.0000000000001814 PG 9 WC Critical Care Medicine SC General & Internal Medicine GA DT8CZ UT WOS:000381718000013 PM 27525994 ER PT J AU Humbert, M Channick, RN AF Humbert, Marc Channick, Richard N. TI Pulmonary hypertension SO CURRENT OPINION IN PULMONARY MEDICINE LA English DT Editorial Material C1 [Humbert, Marc] Univ Paris 11, Hop Bicetre, AP HP, Serv Pneumol, Orsay, France. [Humbert, Marc] Univ Paris Saclay, INSERM, U999, Le Kremlin Bicetre, France. [Channick, Richard N.] Massachusetts Gen Hosp, Pulm & Crit Care, Boston, MA 02114 USA. RP Humbert, M (reprint author), Hop Bicetre, Serv Pneumol, 78 Rue Gen Leclerc, F-94270 Le Kremlin Bicetre, France. EM marc.humbert@aphp.fr NR 1 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 1070-5287 EI 1531-6971 J9 CURR OPIN PULM MED JI Curr. Opin. Pulm. Med. PD SEP PY 2016 VL 22 IS 5 BP 399 EP 399 DI 10.1097/MCP.0000000000000309 PG 1 WC Respiratory System SC Respiratory System GA DS5FP UT WOS:000380807100001 PM 27428648 ER PT J AU Tamura, Y Channick, RN AF Tamura, Yuichi Channick, Richard N. TI New paradigm for pulmonary arterial hypertension treatment SO CURRENT OPINION IN PULMONARY MEDICINE LA English DT Review DE event-driven trials; morbidity and mortality; new compounds; pulmonary arterial hypertension ID ENDOTHELIN RECEPTOR ANTAGONIST; RANDOMIZED CONTROLLED-TRIAL; 6-MINUTE WALK DISTANCE; 5 INHIBITOR THERAPY; LONG-TERM SURVIVAL; ORAL TREPROSTINIL; REGISTRY; REVEAL; PROSTACYCLIN; AMBRISENTAN AB Purpose of review Pulmonary arterial hypertension (PAH) was previously considered a uniformly fatal disease, with patients succumbing to right heart failure and death at an average of 3 years after diagnosis. The past 20 years, however, have seen the development of numerous targeted therapies that have changed the natural history of PAH. As more pharmacologic agents have been approved and utilized, further advances in the design of and endpoints for clinical trials. This study will review some of these notable developments. Recent findings The successful design and completion of long-term, event-driven trials is exemplified in three recent studies: SERAPHIN, GRIPHON, and AMBITION. SERAPHIN and GRIPHON evaluated the newer agents, macitentan, an endothelin receptor antagonist, and selexipag, a prostacyclin receptor agonist, respectively. Both trials were large-scale studies that, in addition to showing marked effect on the primary endpoint of morbidity/mortality, clearly demonstrated that assessment of long-term effects of PAH therapies is feasible for new compounds. The AMBITION study evaluated a treatment strategy, namely up-front combination therapy with tadalafil and ambrisentan compared with monotherapy and showed the combination approach to be superior at decreasing the likelihood of clinical failure. Summary The evolution of clinical trials in PAH has direct implications for care of these patients. The short and long-term benefits of combination regimens suggest that the multidrug approach to PAH should, in fact, be standard of care for this disease. C1 [Tamura, Yuichi] Int Univ Hlth & Welf, Mita Hosp, Ctr Pulm Hypertens, Tokyo, Japan. Massachusetts Gen Hosp, Pulm & Crit Care Div, Boston, MA 02114 USA. RP Tamura, Y (reprint author), Int Univ Hlth & Welf, Mita Hosp, Ctr Pulm Hypertens, Tokyo, Japan. EM u1@ta-mu.net FU Health Labour Sciences Research Grant, Japan FX Y.T. was supported by Health Labour Sciences Research Grant, Japan. NR 25 TC 0 Z9 0 U1 7 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1070-5287 EI 1531-6971 J9 CURR OPIN PULM MED JI Curr. Opin. Pulm. Med. PD SEP PY 2016 VL 22 IS 5 BP 429 EP 433 DI 10.1097/MCP.0000000000000308 PG 5 WC Respiratory System SC Respiratory System GA DS5FP UT WOS:000380807100006 PM 27434819 ER PT J AU Krajewski, KM Shinagare, AB AF Krajewski, Katherine M. Shinagare, Atul B. TI Novel imaging in renal cell carcinoma SO CURRENT OPINION IN UROLOGY LA English DT Review DE dual-energy computed tomography; magnetic resonance imaging; positron emission tomography; radiogenomics; texture analysis ID DUAL-ENERGY CT; APPARENT DIFFUSION-COEFFICIENT; LEVEL-DEPENDENT MRI; CONTRAST-ENHANCED CT; CLEAR-CELL; IODINE QUANTIFICATION; TEXTURE ANALYSIS; PATHOLOGICAL CORRELATION; PRELIMINARY EXPERIENCE; MASSES CORRELATION AB Purpose of review Renal cell carcinoma is a heterogeneous disease with a spectrum of subtypes and clinical behavior. Quantitative and qualitative imaging biomarkers are sought to correlate with genetic and histologic features and complement pathologic analysis. Recent findings Texture analysis, radiogenomics, and modality-specific advancements have yielded an array of renal cell carcinoma imaging biomarkers in the research domain. Although many techniques are promising, standardization and validation of these procedures are needed prior to implementation into clinical practice. Summary We introduce novel imaging techniques and analytic methods which have been shown to contribute to characterization of renal cell carcinoma and its subtypes, aggressiveness, and responsiveness to therapy, including associated advantages and limitations. C1 [Krajewski, Katherine M.] Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave,DL 147-C, Boston, MA 02215 USA. Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, Boston, MA USA. RP Krajewski, KM (reprint author), Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave,DL 147-C, Boston, MA 02215 USA. EM kmkrajewski@partners.org FU RSNA Research Scholar Grant [RSCH1422] FX A.B.S. is supported by RSNA Research Scholar Grant, #RSCH1422. NR 64 TC 0 Z9 0 U1 8 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0963-0643 EI 1473-6586 J9 CURR OPIN UROL JI Curr. Opin. Urol. PD SEP PY 2016 VL 26 IS 5 BP 388 EP 395 DI 10.1097/MOU.0000000000000314 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA DS4KX UT WOS:000380751100002 PM 27262139 ER PT J AU Lee, DC Long, JA Sevick, MA Yi, SS Athens, JK Elbel, B Wall, SP AF Lee, David C. Long, Judith A. Sevick, Mary Ann Yi, Stella S. Athens, Jessica K. Elbel, Brian Wall, Stephen P. TI The local geographic distribution of diabetic complications in New York City: Associated population characteristics and differences by type of complication SO DIABETES RESEARCH AND CLINICAL PRACTICE LA English DT Article DE Population health; Diabetic complications; Geographic variation ID FACTOR SURVEILLANCE SYSTEM; UNITED-STATES; DISEASE; RISK; PREVALENCE; VALIDATION; VALIDITY; DATABASE; CARE; IDENTIFICATION AB Aims: To identify population characteristics associated with local variation in the prevalence of diabetic complications and compare the geographic distribution of different types of complications in New York City. Methods: Using an all-payer database of emergency visits, we identified the proportion of unique adults with diabetes who also had cardiac, neurologic, renal and lower extremity complications. We performed multivariable regression to identify associations of demographic and socioeconomic factors, and diabetes-specific emergency department use with the prevalence of diabetic complications by Census tract. We also used geospatial analysis to compare local hotspots of diabetic complications. Results: We identified 4.6 million unique New York City adults, of which 10.5% had diabetes. Adjusting for demographic and socioeconomic factors, diabetes-specific emergency department use was associated with severe microvascular renal and lower extremity complications (p-values < 0.001), but not with severe macrovascular cardiac or neurologic complications (p-values of 0.39 and 0.29). Our hotspot analysis demonstrated significant geographic heterogeneity in the prevalence of diabetic complications depending on the type of complication. Notably, the geographic distribution of hotspots of myocardial infarction were inversely correlated with hotspots of end-stage renal disease and lower extremity amputations (coefficients: -0.28 and -0.28). Conclusions: We found differences in the local geographic distribution of diabetic complications, which highlight the contrasting risk factors for developing macrovascular versus microvascular diabetic complications. Based on our analysis, we also found that high diabetes-specific emergency department use was correlated with poor diabetic outcomes. Emergency department utilization data can help identify the location of specific populations with poor glycemic control. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Lee, David C.; Wall, Stephen P.] NYU, Sch Med, Ronald O Perelman Dept Emergency Med, 560 First Ave, New York, NY 10016 USA. [Lee, David C.; Sevick, Mary Ann; Yi, Stella S.; Athens, Jessica K.; Elbel, Brian] NYU, Sch Med, Dept Populat Hlth, 227 East 30th St, New York, NY 10016 USA. [Long, Judith A.] Univ Penn, Perelman Sch Med, Div Gen Internal Med, 423 Guardian Dr, Philadelphia, PA 19104 USA. [Long, Judith A.] Corporal Michael J Crescenz Vet Affairs Med Ctr, Ctr Hlth Equ Res, 3900 Woodland Ave, Philadelphia, PA 19104 USA. [Elbel, Brian] NYU, Wagner Grad Sch Publ Serv, 295 Lafayette St, New York, NY 10012 USA. RP Lee, DC (reprint author), 462 First Ave,Room A345, New York, NY 10016 USA. EM david.lee@nyumc.org OI Wall, Stephen/0000-0003-3965-5074; Elbel, Brian/0000-0003-1615-9430; Yi, Stella/0000-0002-9943-2609 NR 40 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 0168-8227 EI 1872-8227 J9 DIABETES RES CLIN PR JI Diabetes Res. Clin. Pract. PD SEP PY 2016 VL 119 BP 88 EP 96 DI 10.1016/j.diabres.2016.07.008 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT7DI UT WOS:000381646900012 PM 27497144 ER PT J AU Ho, AL Koch, MJ Tanaka, S Eichler, AF Batchelor, TT Tanboon, J Louis, DN Cahill, DP Chi, AS Curry, WT AF Ho, Allen L. Koch, Matthew J. Tanaka, Shota Eichler, April F. Batchelor, Tracy T. Tanboon, Jantima Louis, David N. Cahill, Daniel P. Chi, Andrew S. Curry, William T., Jr. TI Impact of histopathological transformation and overall survival in patients with progressive anaplastic glioma SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Anaplastic glioma; Glioblastoma; Malignant glioma; Recurrent glioma; Transformation ID PHASE-III TRIAL; MALIGNANT GLIOMA; CLINICAL-TRIALS; GRADE GLIOMAS; TUMORS; OLIGODENDROGLIOMAS; RADIOTHERAPY; CLASSIFICATION; CRITERIA; BRAIN AB Progression of anaplastic glioma (World Health Organization [WHO] grade III) is typically determined radiographically, and transformation to glioblastoma (GB) (WHO grade IV) is often presumed at that time. However, the frequency of actual histopathologic transformation of anaplastic glioma and the subsequent clinical impact is unclear. To determine these associations, we retrospectively reviewed all anaplastic glioma patients who underwent surgery at our center at first radiographic progression, and we examined the effects of histological diagnosis, clinical history, and molecular factors on transformation rate and survival. We identified 85 anaplastic glioma (39 astrocytoma, 24 oligodendroglioma, 22 oligoastrocytoma), of which 38.8% transformed to GB. Transformation was associated with shorter overall survival (OS) from the time of diagnosis (3.4 vs. 10.9 years, p = 0.0005) and second surgery (1.0 vs. 3.5 years, p < 0.0001). Original histologic subtype did not significantly impact the risk of transformation or OS. No other factors, including surgery, adjuvant therapy or molecular markers, significantly affected the risk of transformation. However, mutations in isocitrate dehydrogenase 1 (IDH1) was associated with longer time to progression (median 4.6 vs. 1.4 years, p = 0.008) and OS (median 10.0 vs. 4.2 years, p = 0.046). At radiographic progression, tissue diagnosis may be warranted as histologic grade may provide valuable prognostic information and affect therapeutic clinical trial selection criteria for this patient population. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Eichler, April F.; Batchelor, Tracy T.; Louis, David N.; Cahill, Daniel P.; Chi, Andrew S.; Curry, William T., Jr.] Massachusetts Gen Hosp, Ctr Canc, Stephen E & Catherine Pappas Ctr Neurooncol, 55 Fruit St Y9E, Boston, MA 02114 USA. [Eichler, April F.; Batchelor, Tracy T.; Louis, David N.; Cahill, Daniel P.; Chi, Andrew S.; Curry, William T., Jr.] Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, Dept Neurol, 55 Fruit St Y9E, Boston, MA 02114 USA. [Koch, Matthew J.; Cahill, Daniel P.; Curry, William T., Jr.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Koch, Matthew J.; Eichler, April F.; Batchelor, Tracy T.; Louis, David N.; Cahill, Daniel P.; Chi, Andrew S.; Curry, William T., Jr.] Harvard Med Sch, Boston, MA 02115 USA. [Ho, Allen L.] Stanford Univ, Dept Neurosurg, Palo Alto, CA 94304 USA. [Tanaka, Shota] Tokyo Univ Hosp, Tokyo, Japan. [Tanboon, Jantima; Louis, David N.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Curry, WT (reprint author), Massachusetts Gen Hosp, Ctr Canc, Stephen E & Catherine Pappas Ctr Neurooncol, 55 Fruit St Y9E, Boston, MA 02114 USA.; Curry, WT (reprint author), Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, Dept Neurol, 55 Fruit St Y9E, Boston, MA 02114 USA.; Curry, WT (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA.; Curry, WT (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM wcurry@mgh.harvard.edu OI Cahill, Daniel/0000-0003-2552-6546 NR 22 TC 2 Z9 2 U1 1 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD SEP PY 2016 VL 31 BP 99 EP 105 DI 10.1016/j.jocn.2016.02.019 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DT7EJ UT WOS:000381649600018 PM 27279154 ER PT J AU Walsh, K Zinzow, HM Badour, CL Ruggiero, KJ Kilpatrick, DG Resnick, HS AF Walsh, Kate Zinzow, Heidi M. Badour, Christal L. Ruggiero, Kenneth J. Kilpatrick, Dean G. Resnick, Heidi S. TI Understanding Disparities in Service Seeking Following Forcible Versus Drug- or Alcohol-Facilitated/Incapacitated Rape SO JOURNAL OF INTERPERSONAL VIOLENCE LA English DT Article DE sexual assault; alcohol and drugs; support seeking ID POSTTRAUMATIC-STRESS-DISORDER; CHILD SEXUAL-ABUSE; NATIONAL SAMPLE; COLLEGE-WOMEN; MEDICAL-CARE; ASSAULT; EXPERIENCES; CONSUMPTION; SURVIVORS; POLICE AB Victims of drug- or alcohol-facilitated/incapacitated rape (DAFR/IR) are substantially less likely to seek medical, rape crisis, or police services compared with victims of forcible rape (FR); however, reasons for these disparities are poorly understood. The current study examined explanatory mechanisms in the pathway from rape type (FR vs. DAFR/IR) to disparities in post-rape service seeking (medical, rape crisis, criminal justice). Participants were 445 adult women from a nationally representative household probability sample who had experienced FR, DAFR/IR, or both since age 14. Personal characteristics (age, race, income, prior rape history), rape characteristics (fear, injury, loss of consciousness), and post-rape acknowledgment, medical concerns, and service seeking were collected. An indirect effects model using bootstrapped standard errors was estimated to examine pathways from rape type to service seeking. DAFR/IR-only victims were less likely to seek services compared with FR victims despite similar post-rape medical concerns. FR victims were more likely to report fear during the rape and a prior rape history, and to acknowledge the incident as rape; each of these characteristics was positively associated with service seeking. However, only prior rape history and acknowledgment served as indirect paths to service seeking; acknowledgment was the strongest predictor of service seeking. Diminished acknowledgment of the incident as rape may be especially important to explaining why DAFR/IR victims are less likely than FR victims to seek services. Public service campaigns designed to increase awareness of rape definitions, particularly around DAFR/IR, are important to reducing disparities in rape-related service seeking. C1 [Walsh, Kate] Columbia Univ, New York, NY USA. [Zinzow, Heidi M.] Clemson Univ, Dept Psychol, Clemson, SC 29631 USA. [Badour, Christal L.; Kilpatrick, Dean G.; Resnick, Heidi S.] Med Univ South Carolina, Dept Psychiat & Behav Sci, Natl Crime Victims Res & Treatment Ctr, 67 President St MSC 861,2 South, Charleston, SC USA. [Ruggiero, Kenneth J.] Med Univ South Carolina, Coll Nursing, Technol Applicat Ctr Healthful Lifestyles, Charleston, SC USA. [Badour, Christal L.; Ruggiero, Kenneth J.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Resnick, HS (reprint author), Med Univ South Carolina, Dept Psychiat & Behav Sci, Natl Crime Victims Res & Treatment Ctr, 67 President St MSC 861,2 South, Charleston, SC USA. EM resnickh@musc.edu FU National Institute on Drug Abuse [R01DA023099, T32DA031099]; National Institute of Child Health and Human Development [5R01HD046830]; National Institute of Justice [2005-WG-BX-0006] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Manuscript preparation was supported by several grants from the National Institute on Drug Abuse (R01DA023099, T32DA031099). Study data collection was supported by grants from the National Institute of Child Health and Human Development (5R01HD046830) and the National Institute of Justice (2005-WG-BX-0006). NR 34 TC 0 Z9 0 U1 10 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0886-2605 EI 1552-6518 J9 J INTERPERS VIOLENCE JI J. Interpers. Violence PD SEP PY 2016 VL 31 IS 14 BP 2475 EP 2491 DI 10.1177/0886260515576968 PG 17 WC Criminology & Penology; Family Studies; Psychology, Applied SC Criminology & Penology; Family Studies; Psychology GA DS7TL UT WOS:000380985700005 PM 25846758 ER PT J AU Kieran, MW Goumnerova, LC Prados, M Gupta, N AF Kieran, Mark W. Goumnerova, Liliana C. Prados, Michael Gupta, Nalin TI Biopsy for diffuse intrinsic pontine glioma: a reappraisal SO JOURNAL OF NEUROSURGERY-PEDIATRICS LA English DT Editorial Material ID ACTIVATING ACVR1 MUTATIONS; CHILDREN; GRADE C1 [Kieran, Mark W.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Goumnerova, Liliana C.] Boston Childrens Hosp, Boston, MA USA. [Prados, Michael; Gupta, Nalin] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Kieran, MW (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 15 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1933-0707 EI 1933-0715 J9 J NEUROSURG-PEDIATR JI J. Neurosurg.-Pediatr. PD SEP PY 2016 VL 18 IS 3 BP 390 EP 391 DI 10.3171/2015.6.PEDS15374 PG 2 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA DT8YJ UT WOS:000381781300018 PM 27153377 ER PT J AU Wiener, L Viola, A Kearney, J Mullins, LL Sherman-Bien, S Zadeh, S Farkas-Patenaude, A Pao, M AF Wiener, Lori Viola, Adrienne Kearney, Julia Mullins, Larry L. Sherman-Bien, Sandra Zadeh, Sima Farkas-Patenaude, Andrea Pao, Maryland CA Lone Parent Study Grp TI Impact of Caregiving for a Child With Cancer on Parental Health Behaviors, Relationship Quality, and Spiritual Faith: Do Lone Parents Fare Worse? SO JOURNAL OF PEDIATRIC ONCOLOGY NURSING LA English DT Article DE health behavior; pediatric cancer; caregivers; psychosocial; spiritual faith; relationships ID PEDIATRIC CANCER; MOTHERS; STRESS; SINGLE; LIFE; FATHERS; CARE AB Caregiving stress has been associated with changes in the psychological and physical health of parents of children with cancer, including both partnered and single parents. While parents who indicate single on a demographic checklist are typically designated as single parents, a parent can be legally single and still have considerable support caring for an ill child. Correspondingly, an individual can be married/partnered and feel alone when caring for a child with serious illness. In the current study, we report the results from our exploratory analyses of parent self-reports of behavior changes during their child's treatment. Parents (N = 263) of children diagnosed with cancer were enrolled at 10 cancer centers. Parents reported significant worsening of all their own health behaviors surveyed, including poorer diet and nutrition, decreased physical activity, and less time spent engaged in enjoyable activities 6 to 18 months following their child's diagnosis. More partnered parents found support from friends increased or stayed the same since their child's diagnosis, whereas a higher proportion of lone parents reported relationships with friends getting worse. More lone parents reported that the quality of their relationship with the ill child's siblings had gotten worse since their child's diagnosis. Spiritual faith increased for all parents. C1 [Wiener, Lori; Viola, Adrienne; Zadeh, Sima] NCI, Pediat Oncol Branch, Bldg 10,Room 1-6466, Bethesda, MD 20892 USA. [Viola, Adrienne] Rutgers Robert Wood Johnson Med Sch, Newark, NJ USA. [Kearney, Julia] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Mullins, Larry L.] Oklahoma State Univ, Coll Arts & Sci, Dept Psychol, Psychol, Stillwater, OK 74078 USA. [Mullins, Larry L.] Oklahoma State Univ, Coll Arts & Sci, Res, Stillwater, OK 74078 USA. [Sherman-Bien, Sandra] Miller Childrens Hosp, Jonathan Jaques Childrens Canc Ctr, Long Beach, CA USA. [Farkas-Patenaude, Andrea] Dana Farber Canc Inst, Psychol Res Serv, Boston, MA 02115 USA. [Farkas-Patenaude, Andrea] Dana Farber Canc Inst, Clin Serv, Boston, MA 02115 USA. [Pao, Maryland] NIMH, Bethesda, MD 20892 USA. RP Wiener, L (reprint author), NCI, Pediat Oncol Branch, Bldg 10,Room 1-6466, Bethesda, MD 20892 USA. EM wienerl@nih.gov FU National Cancer Institute; National Institute of Mental Health intramural programs of the National Institutes of Health FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work is supported [in part] by the National Cancer Institute and the National Institute of Mental Health intramural programs of the National Institutes of Health. This funding supported the design and conduct of the study; the collection, management, analysis, and interpretation of the data; preparation, review, and approval of the article; and the decision to submit the article for publication. The Andre Sobel River of Life Foundation contributed the gift cards for the study participants.hD; and Sean Phipps, PhD. NR 24 TC 0 Z9 0 U1 5 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1043-4542 EI 1532-8457 J9 J PEDIATR ONCOL NURS JI J. Pediatr. Oncol. Nurs. PD SEP-OCT PY 2016 VL 33 IS 5 BP 378 EP 386 DI 10.1177/1043454215616610 PG 9 WC Oncology; Nursing SC Oncology; Nursing GA DS7JV UT WOS:000380960700007 PM 26668211 ER PT J AU Bacallado, S Pande, V Favaro, S Trippa, L AF Bacallado, Sergio Pande, Vijay Favaro, Stefano Trippa, Lorenzo TI Bayesian regularization of the length of memory in reversible sequences SO JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY LA English DT Article DE Bayesian analysis; Reinforced random walk; Reversibility; Variable order Markov model ID MARKOV-CHAINS; VARIABLE-ORDER AB Variable order Markov chains have been used to model discrete sequential data in a variety of fields. A host of methods exist to estimate the history-dependent lengths of memory which characterize these models and to predict new sequences. In several applications, the data-generating mechanism is known to be reversible, but combining this information with the procedures mentioned is far from trivial. We introduce a Bayesian analysis for reversible dynamics, which takes into account uncertainty in the lengths of memory. The model proposed is applied to the analysis of molecular dynamics simulations and compared with several popular algorithms. C1 [Bacallado, Sergio; Pande, Vijay] Stanford Univ, Stanford, CA 94305 USA. [Favaro, Stefano] Univ Turin, Turin, Italy. [Favaro, Stefano] Coll Carlo Alberto, Turin, Italy. [Trippa, Lorenzo] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Bacallado, S (reprint author), Stanford Univ, Stanford, CA 94305 USA.; Bacallado, S (reprint author), Stanford Univ, Dept Stat, 390 Serra Mall, Stanford, CA 94305 USA. EM sergiobacallado@gmail.com FU European Research Council [StG N-BNP 306406]; Claudia Adams Barr Program in Innovative Cancer Research; Stein Fellowship FX SF is supported by the European Research Council through grant StG N-BNP 306406, LT has been supported by the Claudia Adams Barr Program in Innovative Cancer Research and SB received funding from the Stein Fellowship. 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 1369-7412 EI 1467-9868 J9 J R STAT SOC B JI J. R. Stat. Soc. Ser. B-Stat. Methodol. PD SEP PY 2016 VL 78 IS 4 BP 933 EP 946 DI 10.1111/rssb.12140 PG 14 WC Statistics & Probability SC Mathematics GA DS3ZD UT WOS:000380720300011 ER PT J AU Schwehm, A Robinson, DG Gallego, JA Karlsgodt, KH Ikuta, T Peters, BD Malhotra, AK Szeszko, PR AF Schwehm, Andrew Robinson, Delbert G. Gallego, Juan A. Karlsgodt, Katherine H. Ikuta, Toshikazu Peters, Bart D. Malhotra, Anil K. Szeszko, Philip R. TI Age and Sex Effects on White Matter Tracts in Psychosis from Adolescence through Middle Adulthood SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID ONSET SCHIZOPHRENIA; 1ST-EPISODE SCHIZOPHRENIA; WORKING-MEMORY; ABNORMALITIES; INTEGRITY; DISORDER; ACTIVATION; ANISOTROPY; DEFICITS; RISK AB There is controversy regarding specificity of white matter abnormalities in psychosis, their deviation from healthy aging, and the influence of sex on these measures. We used diffusion tensor imaging to characterize putative white matter microstructure in 224 patients with psychosis and healthy volunteers across the age range of 15-64 years. Sixty-five younger (age <30 years; 47M/18F) patients with psychosis (all experiencing a first episode of illness) and 48 older (age >= 30 years; 30M/18F) patients were age-matched to younger and older healthy volunteer groups (N = 63 (40M/23F) and N = 48 (29M/19F), respectively). The trajectories of two inter-hemispheric (splenium and genu), two projection (cortico-pontine and anterior thalamic), and five bilateral association (inferior fronto-occipital, inferior longitudinal, superior longitudinal, cingulum, and uncinate) tracts were quantified using tractography to derive measures of fractional anisotropy and mean, axial, and radial diffusivity. Fractional anisotropy was significantly lower in the inferior longitudinal fasciculus and superior longitudinal fasciculus in all patients compared with all healthy volunteers, with comparable effect sizes observed in both the younger and older patients compared with their respective healthy volunteer groups. Moreover, age-associated differences in fractional anisotropy within these tracts were comparable between groups across the age span. In addition, female patients had significantly lower fractional anisotropy across all tracts compared with female controls regardless of age. Our findings demonstrate comparable putative white matter abnormalities in two independent samples of patients with psychosis and argue against their progression in patients. These data further highlight the novel and potentially underappreciated role of sex in understanding white matter dysfunction in the neurobiology of psychosis. C1 [Schwehm, Andrew] St Johns Univ, Dept Psychol, Jamaica, NY USA. [Robinson, Delbert G.; Gallego, Juan A.; Karlsgodt, Katherine H.; Peters, Bart D.; Malhotra, Anil K.] Feinstein Inst Med Res, Ctr Psychiat Neurosci, Manhasset, NY USA. [Robinson, Delbert G.; Gallego, Juan A.; Karlsgodt, Katherine H.; Peters, Bart D.; Malhotra, Anil K.] North Shore LIJ Hlth Syst, Zucker Hillside Hosp, Div Psychiat Res, Glen Oaks, NY USA. [Robinson, Delbert G.; Gallego, Juan A.; Karlsgodt, Katherine H.; Malhotra, Anil K.] Hofstra North Shore LIJ Sch Med, Dept Psychiat, Hempstead, NY USA. [Robinson, Delbert G.; Gallego, Juan A.; Karlsgodt, Katherine H.; Malhotra, Anil K.] Hofstra North Shore LIJ Sch Med, Dept Mol Med, Hempstead, NY USA. [Ikuta, Toshikazu] Univ Mississippi, Sch Appl Sci, Dept Commun Sci & Disorders, Oxford, MS USA. [Szeszko, Philip R.] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. [Szeszko, Philip R.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY USA. RP Szeszko, PR (reprint author), Mental Hlth Care Ctr, James J Peters Vet Affairs Med Ctr, 130W Kingsbridge Rd, Bronx, NY 10468 USA. EM Philip.Szeszko@va.gov OI Schwehm, Andrew/0000-0002-3840-9296; Ikuta, Toshikazu/0000-0003-0848-302X FU Brain and Behavior Research Foundation; National Institute of Mental Health [MH76995, MH079800]; NSLIJ Research Institute General Clinical Research Center [M01 RR18535]; Advanced Center for Intervention and Services Research [MH74543]; Center for Intervention Development and Applied Research [MH80173]; Bristol Meyers Squibb; Janssen; Otsuka FX This work was supported in part by grants from the Brain and Behavior Research Foundation (to Dr Szeszko) and the National Institute of Mental Health to Dr Szeszko (MH76995) and Dr Maihotra (MH079800), the NSLIJ Research Institute General Clinical Research Center (M01 RR18535), an Advanced Center for Intervention and Services Research (MH74543), and a Center for Intervention Development and Applied Research (MH80173). Dr Malhotra serves on the advisory boards of Genomind, LLC and FORUM Pharmaceuticals. Dr Robinson has been a consultant to Asubio and Otsuka, and he has received grants from Bristol Meyers Squibb, Janssen, and Otsuka. The other authors declare no conflict of interest. NR 41 TC 0 Z9 0 U1 3 U2 6 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 SEP PY 2016 VL 41 IS 10 BP 2473 EP 2480 DI 10.1038/npp.2016.47 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DT7FV UT WOS:000381653400006 PM 27067129 ER PT J AU Shorter, D Nielsen, DA Hamon, SC Nielsen, EM Kosten, TR Newton, TF De La Garza, R AF Shorter, Daryl Nielsen, David A. Hamon, Sara C. Nielsen, Ellen M. Kosten, Thomas R. Newton, Thomas F. De La Garza, Richard, II TI The alpha-1 adrenoceptor (ADRA1A) genotype moderates the magnitude of acute cocaine-induced subjective effects in cocaine-dependent individuals SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE ADRA1A; cocaine; genotype; polymorphism; subjective effects ID DOPAMINE-BETA-HYDROXYLASE; PHARMACOGENETIC RANDOMIZED-TRIAL; TRANSPORTER KNOCKOUT MICE; POPULATION-STRUCTURE; INCENTIVE SALIENCE; CONSTITUTIVE ACTIVITY; INDUCED REINSTATEMENT; INHIBITOR NEPICASTAT; PREFRONTAL CORTEX; STRIA TERMINALIS AB Objectives We examined whether a functional variant of the ADRA1A gene moderated cocaine-induced subjective effects in a group of cocaine-dependent individuals. Methods This study was a within-participant, double-blind, placebo-controlled inpatient human laboratory evaluation of 65 nontreatment-seeking, cocaine-dependent [ Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV)] individuals aged 18-55 years. Participants received both placebo (saline, IV) and cocaine (40 mg, IV), and subjective responses were assessed 15 min before receiving an infusion and at 5 min intervals for the subsequent 20 min. The rs1048101 variant of the alpha(1A)-adrenoceptor (ADRA1A) gene was genotyped and it was evaluated whether the Cys to Arg substitution at codon 347 in exon 2 (Cys347Arg) moderated the magnitude of the subjective effects produced by cocaine. Results Thirty (46%) participants were found to have the major allele CC genotype and 35 (44%) carried at least one minor T-allele of rs1048101 (TT or TC genotype). Individuals with the CC genotype showed greater responses for 'desire' (P < 0.0001),'high' (P < 0.0001),'any drug effect' (P < 0.0001), 'like cocaine' (P < 0.0001), and 'likely to use cocaine if given access' (P < 0.05) with experiment-wise significance. Conclusion This study indicates that the ADRA1A genotype could be used to identify individuals for whom acute cocaine exposure may be more rewarding and by inference may result in greater difficulty in establishing and/or maintaining abstinence from cocaine. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Shorter, Daryl; Nielsen, David A.; Kosten, Thomas R.; Newton, Thomas F.; De La Garza, Richard, II] Baylor Coll Med, Michael E DeBakey VA Med Ctr MEDVAMC, Houston, TX 77030 USA. [Shorter, Daryl; Nielsen, David A.; Nielsen, Ellen M.; Kosten, Thomas R.; Newton, Thomas F.; De La Garza, Richard, II] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Hamon, Sara C.] Rockefeller Univ, Lab Stat Genet, 1230 York Ave, New York, NY 10021 USA. RP Shorter, D (reprint author), Michael E DeBakey Vet Adm Med Ctr, 2002 Holcombe Blvd,Bldg 121,Off 121-137, Houston, TX 77030 USA. EM shorter@bcm.edu FU United States (US) Department of Veterans Affairs Clinical Sciences Research and Development Service [I01BX007080]; NIH/NIDA through MD Anderson's Cancer Center [P50 DA018197, NIH/NIDA DA026120]; Toomim Family Fund FX D.S. was supported in part by the Career Development Award I01BX007080 from the United States (US) Department of Veterans Affairs Clinical Sciences Research and Development Service. D.A.N., T.R.K., T.F.N., and R.D.L.G. were supported by NIH/NIDA P50 DA018197, through MD Anderson's Cancer Center Support Grant NIH/NIDA DA026120, and the Toomim Family Fund. This material is the result of work supported with resources and the use of facilities at the Michael E. DeBakey VA Medical Center. NR 57 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 1744-6872 EI 1744-6880 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD SEP PY 2016 VL 26 IS 9 BP 428 EP 435 DI 10.1097/FPC.0000000000000234 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA DS5ON UT WOS:000380831700004 PM 27379509 ER PT J AU Alvarez, K Wang, Y Alegria, M Ault-Brutus, A Ramanayake, N Yeh, YH Jeffries, JR Shrout, PE AF Alvarez, Kiara Wang, Ye Alegria, Margarita Ault-Brutus, Andrea Ramanayake, Natasha Yeh, Yi-Hui Jeffries, Julia R. Shrout, Patrick E. TI Psychometrics of Shared Decision Making and Communication as Patient Centered Measures for Two Language Groups SO PSYCHOLOGICAL ASSESSMENT LA English DT Article DE patient-provider communication; shared decision making; behavioral health; patient-centered; psychometrics ID MENTAL-HEALTH-CARE; PHYSICIAN COMMUNICATION; PROVIDER COMMUNICATION; CULTURAL-ADAPTATION; FIT INDEXES; SDM-Q; SATISFACTION; QUALITY; QUESTIONNAIRE; CONCORDANCE AB Shared decision making (SDM) and effective patient-provider communication are key and interrelated elements of patient-centered care that impact health and behavioral health outcomes. Measurement of SDM and communication from the patient's perspective is necessary in order to ensure that health care systems and individual providers are responsive to patient views. However, there is a void of research addressing the psychometric properties of these measures with diverse patients, including non-English speakers, and in the context of behavioral health encounters. This study evaluated the psychometric properties of 2 patient-centered outcome measures, the Shared Decision-Making Questionnaire-9 (SDM-Q) and the Kim Alliance Scale-Communication subscale (KAS-CM), in a sample of 239 English and Spanish-speaking behavioral health patients. One dominant factor was found for each scale and this structure was used to examine whether there was measurement invariance across the 2 language groups. One SDM-Q item was inconsistent with the configural invariance comparison and was removed. The remaining SDM-Q items exhibited strong invariance, meaning that item loadings and item means were similar across the 2 groups. The KAS-CM items had limited variability, with most respondents indicating high communication levels, and the invariance analysis was done on binary versions of the items. These had metric invariance (loadings the same over groups) but several items violated the strong invariance test. In both groups, the SDM-Q had high internal consistency, whereas the KAS-CM was only adequate. These findings help interpret results for individual patients, taking into account cultural and linguistic differences in how patients perceive SDM and patient-provider communication. C1 [Alvarez, Kiara; Wang, Ye; Alegria, Margarita; Ramanayake, Natasha; Yeh, Yi-Hui] Massachusetts Gen Hosp, Dept Med, Dispar Res Unit, 50 Staniford St,Suite 830, Boston, MA 02114 USA. [Alvarez, Kiara; Wang, Ye; Alegria, Margarita; Ault-Brutus, Andrea] Harvard Med Sch, Boston, MA USA. [Ault-Brutus, Andrea] Cambridge Hlth Alliance, Hlth Equ Res Lab, Cambridge, MA USA. [Jeffries, Julia R.] Mt Sinai Hosp, Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Shrout, Patrick E.] NYU, Dept Psychol, New York, NY 10003 USA. RP Alegria, M (reprint author), Massachusetts Gen Hosp, Dept Med, Dispar Res Unit, 50 Staniford St,Suite 830, Boston, MA 02114 USA. EM malegria@mgh.harvard.edu FU Patient-Centered Outcomes Research Institute (PCORI) [CD-12-11-4187]; National Institute of Mental Health [R01MH098374-03S1] FX The Effectiveness of DECIDE in Patient-Provider Communication, Therapeutic Alliance & Care Continuation study was supported by the Patient-Centered Outcomes Research Institute (PCORI) research Grant CD-12-11-4187. Dr. Alvarez was supported by Research Grant R01MH098374-03S1, funded by the National Institute of Mental Health. NR 54 TC 1 Z9 1 U1 4 U2 4 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 SEP PY 2016 VL 28 IS 9 SI SI BP 1074 EP 1086 DI 10.1037/pas0000344 PG 13 WC Psychology, Clinical SC Psychology GA DT7ZI UT WOS:000381706700006 PM 27537002 ER PT J AU Wander, PL Enquobahrie, DA Pritchard, CC McKnight, B Rice, K Christiansen, M Lemaitre, RN Rea, T Siscovick, D Sotoodehnia, N AF Wander, P. L. Enquobahrie, D. A. Pritchard, C. C. McKnight, B. Rice, K. Christiansen, M. Lemaitre, R. N. Rea, T. Siscovick, D. Sotoodehnia, N. TI Circulating microRNAs and sudden cardiac arrest outcomes SO RESUSCITATION LA English DT Article DE Cardiac arrest; Outcomes; Epigenetics; microRNAs; Epidemiology ID ACUTE MYOCARDIAL-INFARCTION; TRAUMATIC BRAIN-INJURY; PLASMA; BIOMARKER; DISEASE; MIR-124 AB Aim: MicroRNAs (miRNAs) have regulatory functions in organs critical in resuscitation from sudden cardiac arrest due to ventricular fibrillation (VF-SCA); therefore, circulating miRNAs may be markers of VF-SCA outcome. Methods: We measured candidate miRNAs (N=45) in plasma using qRT-PCR among participants of a population-based VF-SCA study. Participants were randomly selected cases who died in the field (DF, n=15), died in hospital (DH, n=15), or survived to discharge (DC, n=15), and, age-, sex-, and race-matched controls (n=15). MiRNA levels were compared using ANOVA, t-tests, and fold-changes. Results: Mean age of groups ranged from 66.9 to 69.7. Most participants were male (53-67%) and white (67%). Comparing cases to controls, plasma levels of 17 miRNAs expressed in heart, brain, liver, and other tissues (including miR-29c,-34a,-122,-145,-200a,-210,-499-5p, and-663b) were higher and three nonspecific miRNAs lower (miR-221,-330-3p, and-9-5p). Among DH or DC compared with DF cases, levels of two miRNAs (liver-specific miR-122 and non-specific miR-205) were higher and two heart-specific miRNAs (miR-208b and-499-5p) lower. Among DC vs. DF cases, levels of three miRNAs (miR-122, and non-specific miR-200a and-205) were higher and four heart-specific miRNAs (miR-133a,-133b,-208b, and-499-5p) lower. Among DC vs. DH cases, levels of two non-specific miRNAs (miR-135a and-9-3p) were lower. Conclusions: Circulating miRNAs expressed in heart, brain, and other tissues differ between VF-SCA cases and controls and are related to resuscitation outcomes. Measurement of miRNAs may clarify mechanisms underlying resuscitation, improve prognostication, and guide development of therapies. Results require replication. Published by Elsevier Ireland Ltd. C1 [Wander, P. L.; Christiansen, M.; Lemaitre, R. N.; Rea, T.; Sotoodehnia, N.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Enquobahrie, D. A.; Sotoodehnia, N.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Pritchard, C. C.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [McKnight, B.; Rice, K.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Wander, P. L.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Rea, T.] Publ Hlth Seattle & King Cty, Emergency Med Serv Div, Seattle, WA USA. [Siscovick, D.] New York Acad Med, New York, NY USA. [Sotoodehnia, N.] Univ Washington, Dept Med, Div Cardiol, Seattle, WA USA. RP Wander, PL (reprint author), Univ Washington, Dept Med, Div Gen Internal Med, 325 Ninth Ave,Box 359780, Seattle, WA 98104 USA. EM lwander@u.washington.edu OI Wander, Pandora/0000-0003-3671-1464 FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [K08DK103945]; National Heart, Lung, and Blood Institute [R01-HL091244, R01-HL092111, R01-HL088456, R01-HL111089]; University of Washington Nutrition and Obesity Research Center [P30 DK035816]; Locke Charitable Foundation; Medic One Foundation; Alpha Phi Foundation; Laughlin Family FX Our gratitude to Hye Son Yi, who performed the laboratory assays for this report. Research reported in this manuscript was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award number K08DK103945 and grants from the National Heart, Lung, and Blood Institute (R01-HL091244, R01-HL092111, R01-HL088456, R01-HL111089), the University of Washington Nutrition and Obesity Research Center (P30 DK035816), and the Locke Charitable Foundation, the Medic One Foundation, the Alpha Phi Foundation, and the Laughlin Family. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 28 TC 0 Z9 0 U1 2 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-9572 J9 RESUSCITATION JI Resuscitation PD SEP PY 2016 VL 106 BP 96 EP 101 PG 6 WC Critical Care Medicine; Emergency Medicine SC General & Internal Medicine; Emergency Medicine GA DT7DT UT WOS:000381648000031 PM 27423422 ER PT J AU Blumrosen, G Abazari, A Golberg, A Yarmush, ML Toner, M AF Blumrosen, Gadi Abazari, Alireza Golberg, Alexander Yarmush, Martin L. Toner, Mehmet TI Single-step electrical field strength screening to determine electroporation induced transmembrane transport parameters SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE Electroporation; High-throughput experiments; Concentric electrode system; Cell membrane permeability; Transport parameters ID MOLECULAR-DYNAMICS SIMULATIONS; LIPID-MEMBRANE ELECTROPORATION; IRREVERSIBLE ELECTROPORATION; CELL ELECTROPORATION; SPHEROIDAL CELLS; MAMMALIAN-CELLS; DENDRITIC CELLS; GENE-TRANSFER; ELECTROPERMEABILIZATION; SUSPENSION AB The design of effective electroporation protocols for molecular delivery applications requires the determination of transport parameters including diffusion coefficient, membrane resealing, and critical electric field strength for electroporation. The use of existing technologies to determine these parameters is time-consuming and labor-intensive, and often results in large inconsistencies in parameter estimation due to variations in the protocols and setups. In this work, we suggest using a set of concentric electrodes to screen a full range of electric field strengths in a single test to determine the electroporation-induced transmembrane transport parameters. Using Calcein as a fluorescent probe, we developed analytical methodology to determine the transport parameters based on the electroporation-induced pattern of fluorescence loss from cells. A monolayer of normal human dermal fibroblast (NHDF) cells were pre-loaded with Calcein and electroporated with an applied voltage of 750 V with 10 and 50 square pulses with 50 mu s duration. Using our analytical model, the critical electric field strength for electroporation was found for the 10 and 50 pulses experiments. An inverse correlation between the field strength and the molecular transport time decay constant, and a direct correlation between field strength and the membrane permeability were observed. The results of this work can simplify the development of electroporation-assisted technologies for research and therapies. (C) 2016 Elsevier B.V. All tights reserved. C1 [Blumrosen, Gadi] Tel Aviv Univ, Dept Comp Sci, IL-69978 Tel Aviv, Israel. [Abazari, Alireza; Golberg, Alexander; Yarmush, Martin L.; Toner, Mehmet] Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. [Abazari, Alireza; Golberg, Alexander; Yarmush, Martin L.; Toner, Mehmet] Harvard Med Sch, Boston, MA 02114 USA. [Golberg, Alexander] Tel Aviv Univ, Porter Sch Environm Studies, IL-69978 Tel Aviv, Israel. [Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. RP Yarmush, ML (reprint author), Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA.; Yarmush, ML (reprint author), Harvard Med Sch, Boston, MA 02114 USA.; Golberg, A (reprint author), Tel Aviv Univ, Porter Sch Environm Studies, IL-69978 Tel Aviv, Israel. EM agolberg@tauex.tau.ac.il; ireis@sbi.org FU Natural Sciences and Research Council (NSERC) of Canada; Eshkol Fund of Israeli Ministry of Science and Technology [3-11034/3804851] FX Alireza Abazari held a postdoctoral fellowship from the Natural Sciences and Research Council (NSERC) of Canada. The authors like to thank Dr. Kyle Smith from the Center for Engineering in Medicine and The BioMEMS Resource Center at Massachusetts General Hospital and Harvard Medical School for constructive comments. This research was partially supported by Eshkol Fund, 3-11034/3804851, of Israeli Ministry of Science and Technology. NR 56 TC 0 Z9 0 U1 2 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 EI 0006-3002 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD SEP PY 2016 VL 1858 IS 9 BP 2041 EP 2049 DI 10.1016/j.bbamem.2016.05.022 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DS2LR UT WOS:000380601500010 PM 27263825 ER PT J AU Patel, SS Schwab, JH AF Patel, Shalin S. Schwab, Joseph H. TI Immunotherapy as a Potential Treatment for Chordoma: a Review SO Current Oncology Reports LA English DT Review DE Antigen processing; Bone tumors; Carbon-ion; Chordoma; Chimeric antigen receptor; CSPG4; CTLA-4; HLA; Immune checkpoint; Immune escape; Immune system; Immunotherapy; MHC; PD-1; PD-L1; PD-L2; Proton; Radiation; Radiotherapy; Sarcoma; Tumor antigen; Vaccine ID TUMOR-INFILTRATING LYMPHOCYTES; CELL LUNG-CANCER; CLASS-I ANTIGEN; DOSE PHOTON/PROTON RADIOTHERAPY; HUMAN COLORECTAL-CANCER; GROWTH-FACTOR-BETA; CD8(+) T-CELLS; OVARIAN-CANCER; IMMUNE ESCAPE; PROGNOSTIC-FACTORS AB Chordoma is a locally aggressive primary malignancy of the axial skeleton. The gold standard for treatment is en bloc resection, with some centers now advocating for the use of radiation to help mitigate the risk of recurrence. Local recurrence is common, and salvaging local failures is quite difficult. Chemotherapy has been ineffective and small molecule targeted therapy has had only marginal benefits in small subsets of patients with rare tumor phenotypes or refractory disease. Recent successes utilizing immunotherapy in a variety of cancers has led to a resurgence of interest in modifying the host immune system to develop new ways to treat tumors. This review will discuss these studies and will highlight the early studies employing immune strategies for the treatment of chordoma. C1 [Patel, Shalin S.; Schwab, Joseph H.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St Yawkey Bldg Suite 3A, Boston, MA 02114 USA. RP Schwab, JH (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St Yawkey Bldg Suite 3A, Boston, MA 02114 USA. EM shalin@partners.org; jhschwab@partners.org NR 92 TC 1 Z9 1 U1 18 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3790 EI 1534-6269 J9 CURR ONCOL REP JI Curr. Oncol. Rep. PD SEP PY 2016 VL 18 IS 9 AR 55 DI 10.1007/s11912-016-0543-8 PG 8 WC Oncology SC Oncology GA DS3GJ UT WOS:000380670800003 PM 27475804 ER PT J AU Francini, E Sweeney, CJ AF Francini, Edoardo Sweeney, Christopher J. TI Docetaxel Activity in the Era of Life-prolonging Hormonal Therapies for Metastatic Castration-resistant Prostate Cancer SO EUROPEAN UROLOGY LA English DT Article DE mCRPC; Docetaxel; Abiraterone; Activity ID ABIRATERONE ACETATE; RETROSPECTIVE ANALYSIS; PREDNISONE; MITOXANTRONE; MULTICENTER; SURVIVAL; MEN AB For >6 yr, docetaxel with prednisone was the only treatment with survival benefits for metastatic castration-resistant prostate cancer (mCRPC). More recently, in clinical practice, abiraterone acetate has been commonly administered prior to docetaxel for the treatment of mCRPC. Our study aimed to review the activity of docetaxel after prior abiraterone. To this end, we analyzed all retrospective reports in the literature describing the overall survival (OS) of mCRPC patients treated with docetaxel after previous abiraterone. The mean OS observed was 12.7 mo, which suggested a significant decrement compared with the 19.2 mo seen in the updated analysis of the TAX 327 study; however, the data are quite similar to the OS of 13.6 mo (95% confidence interval, 12.1-15.1 mo) described in a retrospective single-institution study of 357 men with mCRPC treated with docetaxel with no prior abiraterone mostly in routine practice (86.3%). Because the characteristics of patients recruited in phase 3 trials tend to differ from the real-world setting, we deemed this data set a relevant comparison. Consequently, despite the limitations of retrospective cross-study comparisons, the data suggest that docetaxel retains activity when used as second-line therapy after abiraterone for mCRPC patients. Patient summary: We reviewed the activity of docetaxel after prior use of abiraterone and considered the results in the light of the outcomes of docetaxel used as firstline therapy for metastatic castration-resistant prostate cancer (mCRPC) patients in routine practice. We noted that docetaxel retains reasonable activity and is a useful agent for the treatment of mCRPC patients before or after abiraterone. (C) 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Francini, Edoardo] Univ Rome, Policlin Umberto Hosp 1, Med Oncol Unit, Via Policlin 155, I-00161 Rome, Italy. [Francini, Edoardo; Sweeney, Christopher J.] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, 450 Brookline Ave, Boston, MA 02215 USA. RP Francini, E (reprint author), Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM edoardo_francini@dfci.harvard.edu FU Sanofi; Janssen Pharmaceutical Companies; BIND Therapeutics Inc.; Astellas Pharma; Bayer FX Edoardo Francini certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Christopher J. Sweeney is a consultant with compensation from Sanofi, Janssen Pharmaceutical Companies, BIND Therapeutics Inc., Astellas Pharma, and Bayer. NR 11 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD SEP PY 2016 VL 70 IS 3 BP 410 EP 412 DI 10.1016/j.eururo.2016.05.002 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA DS4MA UT WOS:000380754000012 PM 27184379 ER PT J AU Pal, SK Choueiri, TK Wang, K Khaira, D Karam, JA Van Allen, E Palma, NA Stein, MN Johnson, A Squillace, R Elvin, JA Chmielecki, J Yelensky, R Yakirevich, E Lipson, D Lin, DI Miller, VA Stephens, PJ Ali, SM Ross, JS AF Pal, Sumanta K. Choueiri, Toni K. Wang, Kai Khaira, Depinder Karam, Jose A. Van Allen, Eliezer Palma, Norma A. Stein, Mark N. Johnson, Adrienne Squillace, Rachel Elvin, Julia A. Chmielecki, Juliann Yelensky, Roman Yakirevich, Evgeny Lipson, Doron Lin, Douglas I. Miller, Vincent A. Stephens, Philip J. Ali, Siraj M. Ross, Jeffrey S. TI Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling SO EUROPEAN UROLOGY LA English DT Article DE Collecting duct carcinoma; Genomic profiling; Medullary carcinoma; NF2 ID RENAL MEDULLARY CARCINOMA; SQUAMOUS-CELL CARCINOMA; UROTHELIAL CARCINOMA; TUMOR-SUPPRESSOR; HIGH-FREQUENCY; CANCER; SURVIVAL; MUTATION; NF2/MERLIN; EVEROLIMUS AB Background: Collecting duct carcinoma (CDC) is a rare type of renal cell carcinoma (RCC) originating from the renal medulla. Clinical outcomes are poor, and there are no consensus guidelines to guide therapy. Objective: To determine genomic alterations (GAs) in a series of patients with locally advanced or metastatic CDC for whom genomic profiling was performed during the course of clinical care. Design, setting, and participants: Formalin-fixed, paraffin-embedded blocks or slides were obtained for 17 patients with CDC. DNA was extracted and comprehensive genomic profiling was performed in a laboratory certified under the Clinical Laboratory Improvement Amendments. Outcome measurements and statistical analysis: Bayesian algorithms and local alignment algorithms were used to detect substitutions and insertions/deletions, respectively. A comparison to normal control samples was used to detect copy number alterations. Clinically relevant GAs (CRGAs) were defined as those linked to approved or investigational targeted therapies. Results and limitations: The median age in the cohort was 53 yr (range 26-73), and 14 primary tumors and three metastatic sites assessed. A total of 36 GAs were detected in this series of patients, with an average of 2.1 GAs per case. The most common GAs were in NF2 (5/17, 29%), SETD2 (4/17, 24%), SMARCB1 (3/17, 18%), and CDKN2A (2/17, 12%). Of nine cases assessed for FH GAs, two patients had FH homozygous loss. A limitation is that targeted interrogation of genes known to be implicated in other cancers was performed, so mutations outside of these cannot be excluded. Conclusions: Recurrent CRGAs were detected in this series of CDC cases and suggest a possible benefit from targeted therapy. In particular, mTOR inhibitors may be of interest in patients with NF2 alterations. Alterations in FH and SMARCB1 also occurred in a mutually exclusive manner to NF2 alterations. Patient summary: This report provides important genomic insights into collecting duct carcinoma, a rare type of renal cell carcinoma with a very aggressive course. These insights could further rationalize the use of targeted therapies for rare tumors according to the individual genomic alterations harbored. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Pal, Sumanta K.] City Hope Comprehens Canc Ctr, Dept Med Oncol & Expt Therapeut, Duarte, CA USA. [Choueiri, Toni K.; Van Allen, Eliezer] Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02115 USA. [Wang, Kai; Khaira, Depinder; Palma, Norma A.; Johnson, Adrienne; Squillace, Rachel; Elvin, Julia A.; Chmielecki, Juliann; Yelensky, Roman; Lipson, Doron; Miller, Vincent A.; Stephens, Philip J.; Ali, Siraj M.; Ross, Jeffrey S.] Fdn Med Inc, 150 Second St, Cambridge, MA 02141 USA. [Karam, Jose A.] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Stein, Mark N.] Rutgers Canc Inst New Jersey, Dept Med Oncol, New Brunswick, NJ USA. [Yakirevich, Evgeny] Brown Univ, Warren Alpert Sch Med, Dept Pathol & Lab Med, Providence, RI 02912 USA. [Lin, Douglas I.] Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. [Ross, Jeffrey S.] Albany Med Coll, Dept Pathol & Lab Med, Albany, NY 12208 USA. RP Ali, SM (reprint author), Fdn Med Inc, 150 Second St, Cambridge, MA 02141 USA. EM sali@foundationmedicine.com FU NCI NIH HHS [P30 CA016672] NR 34 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD SEP PY 2016 VL 70 IS 3 BP 516 EP 521 DI 10.1016/j.eururo.2015.06.019 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA DS4MA UT WOS:000380754000030 PM 26149668 ER PT J AU Mullane, SA Bellmunt, J AF Mullane, Stephanie A. Bellmunt, Joaquim TI Re: John P. Sfakianos, Eugene K. Cha, Gopa Iyer, et al. Genomic Characterization of Upper Tract Urothelial Carcinoma. Eur Urol 2015;68:970-7 SO EUROPEAN UROLOGY LA English DT Letter C1 [Mullane, Stephanie A.; Bellmunt, Joaquim] Dana Farber Canc Inst, Bladder Canc Ctr, Boston, MA 02115 USA. [Bellmunt, Joaquim] Harvard Med Sch, Boston, MA USA. RP Bellmunt, J (reprint author), Med Oncol Serv, 450 Brookline Ave, Boston, MA 02215 USA. EM joaquim_bellmunt@dfci.harvard.edu NR 4 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD SEP PY 2016 VL 70 IS 3 BP E71 EP E71 DI 10.1016/j.eururo.2016.01.036 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA DS4MA UT WOS:000380754000002 PM 26852077 ER PT J AU Ruben, MA Hall, JA AF Ruben, Mollie A. Hall, Judith A. TI Healthcare Providers' Nonverbal Behavior can Lead Patients to Show Their Pain More Accurately: An Analogue Study SO JOURNAL OF NONVERBAL BEHAVIOR LA English DT Article DE Nonverbal expression; Physical pain; Person perception; Interpersonal accuracy; Doctor-patient communication ID FACIAL EXPRESSIONS; COMMUNICATION; EMPATHY; MODEL; PERSONALITY; DECEPTION; PHYSICIAN; JUDGMENT AB Accurate pain assessment is a joint function of both the judge perceiving correct (valid) cues of pain and targets displaying valid indicators of pain. The present research examined whether the judgeability of pain expressions could be altered by manipulating the nonverbal supportiveness of a videotaped physician who guided targets through an experimentally induced pain experience in the laboratory. Ten-s video clips of these targets during their pain experience were viewed by 95 na < ve judges who assessed each target's pain on an 11-point numeric rating scale. In addition, the video clips were rated by independent coders on 9-point scales (focused, calm, tense, distressed, composed, fidgety, determined, bored, and nervous). Judges' pain assessment accuracy was calculated by correlating their inferred pain rating for each target with targets' self-reported pain. Pain targets assigned to interact with the nonverbally supportive physician displayed more valid impressions of their pain and judges had higher pain assessment accuracy when viewing these targets compared to targets assigned to interact with the nonverbally unsupportive physician. Interventions for caregivers and healthcare providers that emphasize the importance of nonverbal behavior when interacting with pain sufferers are discussed. C1 [Ruben, Mollie A.] US Dept Vet Affairs, CHOIR, 150 S Huntington Ave,Bdg 9, Boston, MA 02130 USA. [Hall, Judith A.] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. RP Ruben, MA (reprint author), US Dept Vet Affairs, CHOIR, 150 S Huntington Ave,Bdg 9, Boston, MA 02130 USA. EM Mollie.Ruben@va.gov NR 39 TC 0 Z9 0 U1 13 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0191-5886 EI 1573-3653 J9 J NONVERBAL BEHAV JI J. Nonverbal Behav. PD SEP PY 2016 VL 40 IS 3 BP 221 EP 234 DI 10.1007/s10919-016-0230-3 PG 14 WC Psychology, Social SC Psychology GA DS3JU UT WOS:000380679900004 ER PT J AU Tetrault, JM Tate, JP Edelman, EJ Gordon, AJ Lo Re, V Lim, JK Rimland, D Goulet, J Crystal, S Gaither, JR Gibert, CL Rodriguez-Barradas, MC Fiellin, LE Bryant, K Justice, AC Fiellin, DA AF Tetrault, Jeanette M. Tate, Janet P. Edelman, E. Jennifer Gordon, Adam J. Lo Re, Vincent, III Lim, Joseph K. Rimland, David Goulet, Joseph Crystal, Stephen Gaither, Julie R. Gibert, Cynthia L. Rodriguez-Barradas, Maria C. Fiellin, Lynn E. Bryant, Kendall Justice, Amy C. Fiellin, David A. TI Hepatic Safety of Buprenorphine in HIV-Infected and Uninfected Patients With Opioid Use Disorder: The Role of HCV-Infection SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Buprenorphine; HIV; Hepatitis C; Drug induced liver injury ID LIVER-ENZYME ELEVATION; DEPENDENT PATIENTS; NALOXONE TREATMENT; INDIVIDUALS; THERAPY; HEALTH; TRIAL; RISK AB Introduction: Individuals with HIV and hepatitis C (HCV) infection, alcohol use disorder, or who are prescribed potentially hepatotoxic medications may be at increased risk for buprenorphine (BUP) associated hepatotoxicity. Materials and methods: We examined a cohort of HIV-infected and uninfected patients receiving an initial BUP prescription between 2003 and 2012. We compared changes in alanine and aspartate aminotransferases (ALT and AST) and total bilirubin (TB) stratified by HIV status. We identified cases of liver enzyme elevation (LEE), TB elevation (TBE), and conducted chart review to assess for cases of drug induced liver injury (DILI) and death. We examined associations between age, sex, race, HIV-infection, HCV-infection, alcohol use disorder, and prescription of other potentially heptatotoxic medications with the composite endpoint of LEE, TBE, and DILI. Results: Of 666 patients prescribed BUP, 36% were HIV-infected, 98% were male, 60% had RNA-confirmed HCV infection, 50% had a recent diagnosis of alcohol use disorder, and 64% were prescribed other potentially hepatotoxic medications. No clinically significant changes were observed in median ALT, AST and TB and these changes did not differ between HIV-infected and uninfected patients. Compared with uninfected patients, HIV-infected (OR 73, 95% CI 2.1-26.1, p = 0.002), HCV-infected (OR 4.9 95% CI 1.6-15.2, p = 0.007) or HIV/HCV co-infected patients (OR 6.9, 95%CI 2.1-22.2, p = 0.001) were more likely to have the composite endpoint of LEE, TB elevation or DILI, in analyses that excluded 60 patients with evidence of pre-existing liver injury. 31 patients had LEE, 14/187 HIV-infected and 17/340 uninfected (p = 0.25); 11 had TBE, including 9/186 HIV-infected and 2/329 uninfected (p = 0.002); 8 experienced DILI, 4/202 HIV-infected and 4/204 uninfected (p = 0.45). There were no significant associations with alcohol use disorder or prescription of other potentially hepatotoxic medications after adjustment for HIV/HCV status. Conclusions: Liver enzymes and TB are rarely elevated in HIV-infected and uninfected patients receiving BUP. Risk of hepatotoxicity was greater in individuals infected with HIV, HCV, or HIV/HCV co-infection, who may benefit from increased monitoring. (C) 2016 Elsevier Inc. All rights reserved. C1 [Tetrault, Jeanette M.; Tate, Janet P.; Edelman, E. Jennifer; Lim, Joseph K.; Fiellin, Lynn E.; Justice, Amy C.; Fiellin, David A.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Tate, Janet P.; Lim, Joseph K.; Justice, Amy C.] VA Connecticut Hlth Care Syst, West Haven, CT USA. [Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Gordon, Adam J.] Univ Pittsburgh, Pittsburgh, PA USA. [Lo Re, Vincent, III] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Rimland, David] VA Med Ctr, Atlanta, GA USA. [Rimland, David] Emory Univ, Sch Med, Atlanta, GA USA. [Goulet, Joseph] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Crystal, Stephen] Rutgers State Univ, Inst Hlth, Ctr Hlth Serv Res, New Brunswick, NJ USA. [Gaither, Julie R.; Justice, Amy C.; Fiellin, David A.] Yale Univ, Sch Publ Hlth, Ctr Interdisciplinary Res AIDS, New Haven, CT USA. [Gibert, Cynthia L.] VA Med Ctr, Washington, DC USA. [Gibert, Cynthia L.] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. [Rodriguez-Barradas, Maria C.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Rodriguez-Barradas, Maria C.] Baylor Coll, Sch Med, Houston, TX USA. [Bryant, Kendall] NIAAA, Bethesda, MD USA. RP Tetrault, JM (reprint author), 367 Cedar St,Suite 305, New Haven, CT 06510 USA. EM jeanette.tetrault@yale.edu OI Fiellin, David/0000-0002-4006-010X; Goulet, Joseph/0000-0002-0842-804X FU Department of Veterans Affairs, Veterans Health Administration, and Office of Research and Development; [U10 AA013566]; [U24 AA020794]; [U01 AA020790]; [U19 HS021112]; [R01 HS018372] FX This material is based upon work supported by the Department of Veterans Affairs, Veterans Health Administration, and Office of Research and Development We must disclaim that 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.; Supported by. U10 AA013566, U24 AA020794, U01 AA020790, U19 HS021112, R01 HS018372 NR 25 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD SEP PY 2016 VL 68 BP 62 EP 67 DI 10.1016/j.jsat.2016.06.002 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA DS2GB UT WOS:000380579300008 PM 27431048 ER PT J AU Lafay-Cousin, L Smith, A Chi, SN Wells, E Madden, J Margol, A Ramaswamy, V Finlay, J Taylor, MD Dhall, G Strother, D Kieran, MW Foreman, NK Packer, RJ Bouffet, E AF Lafay-Cousin, Lucie Smith, Amy Chi, Susan N. Wells, Elizabeth Madden, Jennifer Margol, Ashley Ramaswamy, Vijay Finlay, Jonathan Taylor, Michael D. Dhall, Girish Strother, Douglas Kieran, Mark W. Foreman, Nicholas K. Packer, Roger J. Bouffet, Eric TI Clinical, Pathological, and Molecular Characterization of Infant Medulloblastomas Treated with Sequential High-Dose Chemotherapy SO PEDIATRIC BLOOD & CANCER LA English DT Article; Proceedings Paper CT 19th Annual Scientific Meeting of the Society-for-Neuro-Oncology (SNO) CY NOV 13-16, 2014 CL Miami, FL SP Soc Neuro Oncol DE high-dose chemotherapy; infant; medulloblastoma; molecular subgrouping; neurocognitive outcome ID PRIMITIVE NEUROECTODERMAL TUMORS; CHILDRENS ONCOLOGY GROUP; NERVOUS-SYSTEM TUMORS; STEM-CELL RESCUE; THAN 3 YEARS; YOUNG-CHILDREN; RADIATION-THERAPY; HIGH-RISK; INDUCTION CHEMOTHERAPY; INTENSIVE CHEMOTHERAPY AB BackgroundHigh-dose chemotherapy (HDC) strategies were developed to avoid unacceptable neurotoxicity associated with craniospinal irradiation in infants with embryonal brain tumors. However, the impact of molecular and pathological characterizations in such approaches and long-term outcome have not been widely described in young children. MethodsWe retrospectively collected information from seven North American institutions, on young children with medulloblastoma (MB) treated with sequential HDC, as per the CCG 99703 protocol. Data collection included clinical presentation, histology, molecular subgroup, irradiation, ototoxicity, and neurocognitive evaluations. ResultsThe cohort included 53 patients diagnosed at a median age of 24 months (2.9-63.2). Seventeen patients (32.1%) had nodular desmoplatic MB, all belonging to the sonic Hedgehog (SHH) subgroup, as did 30% of classic MB. The 5-year progression-free survival (PFS) and overall survival (OS) was 69.6% (+/- 69%) and 76.1% (+/- 6.5%), respectively. Seventeen (32.1%) patients received irradiation (nine adjuvant radiotherapy [RT]). Patients with SHH and group 3 MB had a 5-year PFS of 862% (+/- 7.4%) and 491% (+/- 14%), respectively (P = 0.03). The 5-year PFS radiation free for group 3 MB was 46.4%. Patients with macroscopic metastasis (M2 and M3) had a worst survival. Fifteen (45.5%) patients had significant ototoxicity. Mean Full Scale Intellectual Quotient (FSIQ) for 24 survivors was 91.6 (range 52-119). ConclusionsThis HDC strategy led to an encouraging OS while only 20% of the patients received adjuvant RT. SHH MB, irrespective of histological subgroup, had an excellent outcome. Such intensive therapy may not be needed for this subgroup. Patients with classic histology or group 3 had an encouraging PFS of 58% and 46.4%, respectively, in the absence of adjuvant RT. The neurocognitive profile of the survivors appears to be within the normal range. (C) 2016 Wiley Periodicals, Inc. C1 [Lafay-Cousin, Lucie; Strother, Douglas] Alberta Childrens Prov Gen Hosp, Dept Pediat & Oncol, 2888 Shaganappi Trail NW, Calgary, AB T3B 6A8, Canada. [Smith, Amy] Arnold Palmer Hosp, Orlando, FL USA. [Chi, Susan N.; Kieran, Mark W.] Dana Farber Canc Inst, Pediat Neurooncol, Boston, MA 02115 USA. [Wells, Elizabeth] Childrens Natl Hlth Syst, Dept Pediat, Neurol & Integrat Syst Biol Brain Tumor Inst, Washington, DC USA. [Madden, Jennifer; Foreman, Nicholas K.] Univ Colorado, Childrens Hosp Colorado, Aurora, CO USA. [Margol, Ashley; Dhall, Girish] Univ Southern Calif, Keck Sch Med, Childrens Hosp Los Angeles, Los Angeles, CA USA. [Ramaswamy, Vijay; Bouffet, Eric] Hosp Sick Children, Div Pediat Hematol Oncol, Toronto, ON, Canada. [Finlay, Jonathan] Nationwide Childrens Hosp, Columbus, OH USA. [Finlay, Jonathan] Ohio State Univ, Columbus, OH 43210 USA. [Taylor, Michael D.] Hosp Sick Children, Div Neurosurg, Toronto, ON, Canada. [Packer, Roger J.] Brain Tumor Inst Childrens Natl Hlth Syst, Ctr Neurosci & Behav Med, Washington, DC USA. RP Lafay-Cousin, L (reprint author), Alberta Childrens Prov Gen Hosp, Dept Pediat & Oncol, 2888 Shaganappi Trail NW, Calgary, AB T3B 6A8, Canada. EM lucie.lafay-cousin@ahs.ca OI Foreman, Nicholas/0000-0003-4848-4801 FU NCI NIH HHS [R01 CA148699, R01 CA159859] NR 24 TC 0 Z9 0 U1 2 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 SEP PY 2016 VL 63 IS 9 BP 1527 EP 1534 DI 10.1002/pbc.26042 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DR7WH UT WOS:000380109900005 PM 27145464 ER PT J AU Hord, JD Lawlor, J Werner, E Billett, AL Bundy, DG Winkle, C Gaur, AH AF Hord, Jeffrey D. Lawlor, John Werner, Eric Billett, Amy L. Bundy, David G. Winkle, Cindi Gaur, Aditya H. CA Children's Hosp Assoc TI Central Line Associated Blood Stream Infections in Pediatric Hematology/Oncology Patients With Different Types of Central Lines SO PEDIATRIC BLOOD & CANCER LA English DT Article DE central lines; CLABSI; infections; infections in immunocompromised hosts; pediatric hematology/oncology ID RISK-FACTORS; ONCOLOGY OUTPATIENTS; ACCESS DEVICES; CHILDREN; CLABSIS; CANCER; COMPLICATIONS; CATHETERS; LEUKEMIA; ADULTS AB BackgroundCentral line associated bloodstream infections (CLABSIs) are a significant cause of morbidity and mortality in pediatric hematology/oncology (PHO) patients. Understanding the differences in CLABSI rates by central line (CL) type is important to inform clinical decisions. ProcedureCLABSI, using similar definitions, noted with three commonly used CL types (totally implanted catheter [port], tunneled externalized catheter [TEC], peripherally inserted central catheter [PICC]) and CL-specific line days were prospectively tracked across 15 US PHO centers from May 2012 until April 2015 and CLABSI rates (CLABSI per 1,000 CL-specific line days) were calculated. Host and organism characterstics associated with the CLABSI events were analyzed. ResultsOver the course of 2.8 million line days, 1,113 CLABSI events (397 in inpatients and 716 in ambulatory patients) were noted. The inpatient CLABSI rate was higher than the ambulatory CLABSI rate for each of the CL types: 1.48 versus 0.16 for ports, 3.51 versus 1.38 for TECs, and 3.07 versus 1.16 for PICCs, respectively. TECs and PICCs were associated with higher CLABSI rates than ports, inpatient and ambulatory. ConclusionsWe found that CLABSI rates were significantly higher for inpatients compared to ambulatory PHO patients for all CL types. Among ambulatory patients, TECs had the highest CLABSI rate and ports the lowest. Among inpatients, TECs and PICCs had higher CLABSI rates than ports but were not statistically different from one another. Cognizant that host and underlying disease attributes may contribute to these differences, these results can still inform CL choice in clinical practice. (C) 2016 Wiley Periodicals, Inc. C1 [Hord, Jeffrey D.; Children's Hosp Assoc] Akron Childrens Hosp, Showers Family Ctr Childhood Canc & Blood Disorde, Akron, OH USA. [Lawlor, John] Childrens Hosp Assoc, Alexandria, VA USA. [Werner, Eric] Childrens Hosp, Kings Daughters & Childrens Specialty Grp, Norfolk, VA USA. [Billett, Amy L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Billett, Amy L.] Boston Childrens Hosp, Boston, MA USA. [Bundy, David G.] Med Univ South Carolina, Charleston, SC USA. [Winkle, Cindi] Childrens Med Ctr, Dallas, TX 75235 USA. [Gaur, Aditya H.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. RP Hord, JD (reprint author), Akron Childrens Hosp, Showers Family Ctr Childhood Canc & Blood Disorde, Pediat Subspecialty Practices, Akron, OH 44308 USA. EM jhord@chmca.org NR 18 TC 1 Z9 1 U1 2 U2 9 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 SEP PY 2016 VL 63 IS 9 BP 1603 EP 1607 DI 10.1002/pbc.26053 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DR7WH UT WOS:000380109900016 PM 27198806 ER PT J AU Frederick, NN Recklitis, CJ Blackmon, JE Bober, S AF Frederick, Natasha N. Recklitis, Christopher J. Blackmon, Jaime E. Bober, Sharon TI Sexual Dysfunction in Young Adult Survivors of Childhood Cancer SO PEDIATRIC BLOOD & CANCER LA English DT Article DE cancer survivorship sexual dysfunction; childhood cancer survivor; sexual health ID QUALITY-OF-LIFE; ROMANTIC RELATIONSHIPS; BREAST-CANCER; UNITED-STATES; HEALTH; OUTCOMES; WOMEN; COMMUNICATION; INTERVIEWS; MALIGNANCY AB BackgroundDisruption of psychosexual development and sexual dysfunction are well recognized as profoundly distressing long-term side effects of pediatric cancer treatment. However, little is known about the specific sexual problems facing young adult survivors of childhood cancer (YASCC) and their unmet clinical needs. In this study, we aimed to utilize qualitative methods to characterize sexual dysfunction in YASCC and identify survivor-reported unmet clinical need regarding sexual health information and care. ProcedureSemistructured interviews were conducted with 22 YASCC (ages 18-31; 10 men, 12 women) reporting sexual dysfunction. Interviews were conducted in English by phone or in person. All interviews were audiorecorded, transcribed verbatim, and analyzed using a thematic analysis approach. Inductive open-coding procedures identified participants' experiences with sexual dysfunction and clinical care needs. Themes were identified by grouping pattern-forming codes in the data. ResultsInterviews with YASCC reporting sexual dysfunction revealed five overarching themes including interruption of adolescent psychosocial development, physical and psychological problems with sexual function, altered perceptions of body image, concern about fertility, and inadequate clinical support. ConclusionsThe experiences described by YASCC provide valuable insight into the nature of sexual dysfunction in this population and their clinical care needs. These data provide the framework for future research on sexual dysfunction screening measures, patient-physician communication, and effective interventions to address sexual dysfunction in YASCC. (C) 2016 Wiley Periodicals, Inc. C1 [Frederick, Natasha N.] Harvard Med Sch, Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. [Frederick, Natasha N.; Recklitis, Christopher J.; Blackmon, Jaime E.; Bober, Sharon] Harvard Med Sch, Perini Family Survivors Ctr, Dana Farber Canc Inst, Boston, MA USA. RP Frederick, NN (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM natasha_frederick@dfci.harvard.edu FU Pedals for Pediatrics of Dana-Farber/Boston Children's Cancer and Blood Disorders Center FX Grant sponsor: Pedals for Pediatrics of Dana-Farber/Boston Children's Cancer and Blood Disorders Center. NR 38 TC 0 Z9 0 U1 7 U2 7 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 SEP PY 2016 VL 63 IS 9 BP 1622 EP 1628 DI 10.1002/pbc.26041 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DR7WH UT WOS:000380109900019 PM 27163396 ER PT J AU Rozanova, J Noulas, P Smart, K Roy, A Southwick, SM Davidson, L Harpaz-Rotem, I AF Rozanova, Julia Noulas, Paraskevi Smart, Kathleen Roy, Alicia Southwick, Steven M. Davidson, Larry Harpaz-Rotem, Ilan TI "I'm Coming Home, Tell the World I'm Coming Home". The Long Homecoming and Mental Health Treatment of Iraq and Afghanistan War Veterans SO PSYCHIATRIC QUARTERLY LA English DT Article DE Young US veterans; Mental healthcare resistance; Qualitative interviews; Sense of identity; Pragmatic career-building goals ID MILITARY PERSONNEL; PERCEIVED BARRIERS; CARE; STIGMA; RISK; HOMELESSNESS; ACCOUNTS AB This study explored the journey of American armed forces personnel from their decision to join the service, through their service in an active military conflict and how these factors may be associated with potential resistance for mental healthcare. The data came from qualitative interviews with 46 OIF/OEF/OND active-duty military, reservists, and discharged veterans of the average age of 25 years, who presented for a new episode of mental health treatment to a large Veterans Affairs Hospital (VAH) in Northeastern United States in 2011-2012. Qualitative analysis of veterans' perceptions revealed several major themes describing how a mental health diagnosis would negatively impact both their sense of identity and pragmatic career-building goals: enlisting as a career-building avenue, 'noble superhero' identity, escaping from hardship, and mental illness as a career-killer. Findings suggest that factors making young veterans resist mental healthcare may be reduced by partnering VAH psychiatrists with career counselors, and by enhancing military leadership's awareness and understanding about how to support soldiers with emotional and mental health needs, with a goal to eliminating stigma. C1 [Rozanova, Julia] Yale Sch Med, Dept Internal Med, 135 Coll St Suite 351, New Haven, CT 06510 USA. [Noulas, Paraskevi; Smart, Kathleen; Roy, Alicia] VA Connecticut Healthcare Syst, 950 Campbell Ave, West Haven, CT 06516 USA. [Roy, Alicia; Southwick, Steven M.; Davidson, Larry; Harpaz-Rotem, Ilan] US Dept Vet Affairs, Natl Ctr Posttraumat Stress Disorder, 950 Campbell Ave, West Haven, CT 06516 USA. [Southwick, Steven M.; Harpaz-Rotem, Ilan] Yale Sch Med, Dept Psychiat, 300 George St,Suite 901, New Haven, CT 06511 USA. [Davidson, Larry] Yale Program Recovery & Community Hlth, 319 Peck St,Bldg 1, New Haven, CT 06513 USA. RP Rozanova, J (reprint author), Yale Sch Med, Dept Internal Med, 135 Coll St Suite 351, New Haven, CT 06510 USA. EM julia.rozanova@yale.edu; Paraskevi.Noulas2@va.gov; steven.southwick@yale.edu; larry.davidson@yale.edu; ilan.harpaz-rotem@yale.edu FU Department of Veterans Affairs (VA) Health Services Research & Development (HSRD) [PPO-09-265-1] FX Funding for this research was available through a Department of Veterans Affairs (VA) Health Services Research & Development (HSR&D) Merit Review award PPO-09-265-1 awarded to the senior author. The views presented here are those of the authors and do not represent the position of any federal agency or of the United States Government. NR 37 TC 0 Z9 0 U1 14 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-2720 EI 1573-6709 J9 PSYCHIAT QUART JI Psychiatr. Q. PD SEP PY 2016 VL 87 IS 3 BP 427 EP 443 DI 10.1007/s11126-015-9398-7 PG 17 WC Psychiatry SC Psychiatry GA DR6IL UT WOS:000380005500005 PM 26566926 ER PT J AU Sebro, R O'Brien, L Torriani, M Bredella, MA AF Sebro, Ronnie O'Brien, Liam Torriani, Martin Bredella, Miriam A. TI Assessment of trunk muscle density using CT and its association with degenerative disc and facet joint disease of the lumbar spine SO SKELETAL RADIOLOGY LA English DT Article DE Rectus abdominis; Transverse abdominis; Internal oblique; External oblique; Psoas; Multifidus; Longissimus; Gluteus maximus; CT; Trunk muscle; Atrophy; Degenerative disc disease; Facet joint disease ID LOW-BACK-PAIN; SKELETAL-MUSCLE; PSOAS MUSCLE; ATTENUATION AB The purpose of this study was (1) to evaluate the association of trunk muscle density assessed by computed tomography (CT) with age, gender, and BMI and (2) to evaluate the association between trunk muscle CT density and degenerative disc and facet joint disease of the lumbar spine. The study was IRB approved and HIPAA compliant. The study group comprised 100 subjects (mean age 44.4 +/- 22.2 years, 51 % male) who underwent CT of the abdomen and pelvis without intravenous contrast. Exclusion criteria included prior abdominal or spine surgery, active malignancy and scoliosis. CTs were reviewed and the attenuation of the rectus abdominis, transverse abdominis, internal and external obliques, psoas, multifidus, longissimus and gluteus maximus were measured bilaterally at consistent levels. Degenerative disc and bilateral facet joint disease were scored using established methods. Univariate analyses were performed using linear regression. Multivariate linear regression was performed to adjust for age, gender and BMI. CT density of each trunk muscle correlated inversely with age (p < 0.001) and BMI (p < 0.001). CT density of each trunk muscle correlated inversely with degenerative disc and facet joint disease in the univariate analyses (p < 0.001); however, only the gluteus maximus and the transverse abdominis remained significant predictors of degenerative disc and facet joint disease respectively in the multivariate analysis. Fatty infiltration of trunk musculature increases with age and BMI. Fatty infiltration of the gluteus maximus and transverse abdominis are associated with degenerative disc and facet joint disease, independent of age, gender and BMI. C1 [Sebro, Ronnie] Univ Penn, Musculoskeletal Sect, Dept Radiol, 3737 Market St,6175, Philadelphia, PA 19104 USA. [O'Brien, Liam] Colby Coll, Dept Math & Stat, Waterville, ME 04901 USA. [O'Brien, Liam] Univ New England, Sch Community & Populat Hlth, Portland, ME 04103 USA. [Torriani, Martin; Bredella, Miriam A.] Massachusetts Gen Hosp, Dept Radiol, Musculoskeletal Imaging & Intervent, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. [Bredella, Miriam A.] Harvard Med Sch, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. RP Bredella, MA (reprint author), Massachusetts Gen Hosp, Dept Radiol, Musculoskeletal Imaging & Intervent, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA.; Bredella, MA (reprint author), Harvard Med Sch, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. EM mbredella@mgh.harvard.edu FU Ralph Schlaeger Research Award FX This study was supported by the Ralph Schlaeger Research Award. NR 19 TC 1 Z9 1 U1 9 U2 10 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 SEP PY 2016 VL 45 IS 9 BP 1221 EP 1226 DI 10.1007/s00256-016-2405-8 PG 6 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA DR7ID UT WOS:000380072300005 PM 27179651 ER PT J AU Veld, J O'Donnell, EK Reagan, MR Yee, AJ Torriani, M Rosen, CJ Bredella, MA AF Veld, Joyce O'Donnell, Elizabeth K. Reagan, Michaela R. Yee, Andrew J. Torriani, Martin Rosen, Clifford J. Bredella, Miriam A. TI Abdominal adipose tissue in MGUS and multiple myeloma SO SKELETAL RADIOLOGY LA English DT Article DE Multiple myeloma; MGUS; FDG-PET/CT; Abdominal adiposity ID CANCER-RISK; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; COMPUTED-TOMOGRAPHY; UNITED-STATES; OBESITY; ADIPONECTIN; PET/CT; DIET; FAT AB To determine abdominal adipose tissue parameters on PET/CT in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) that may serve as predictors of progression of MGUS to MM. We hypothesized that patients with MM had higher abdominal adiposity and higher fat metabolic activity compared to patients with MGUS. Our retrospective study was IRB approved and HIPAA compliant. The study group comprised 40 patients (mean age 64 +/- 13 years) with MGUS and 32 patients (mean age 62 +/- 10 years) with recently diagnosed MM (mean time since diagnosis of MM 3.0 +/- 3.9 months) who had not undergone MM treatment. All patients underwent whole body FDG-PET/CT. Total abdominal adipose tissue (TAT), abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) cross sectional areas (CSA) (cm(2)) and metabolic activity (SUV) were assessed. Groups were compared using ANOVA. ROC curve analysis was performed to determine cutoff values for abdominal adipose tissue parameters to detect MM. Patients with recently diagnosed MM had higher TAT and SAT CSA (p a parts per thousand currency signaEuro parts per thousand 0.03) and higher fat metabolic activity (p < 0.01). VAT metabolic activity showed the highest sensitivity and specificity for identifying patients with MM (area under the curve 0.95 with cutoff value of > 0.34, sensitivity 90.6 %, specificity 92.5 %, p < 0.0001). Patients who were recently diagnosed with MM had higher abdominal fat CSA and higher fat metabolic activity compared to patients with MGUS. These parameters may serve as novel biomarkers of progression of MGUS to MM. C1 [Veld, Joyce; Torriani, Martin; Bredella, Miriam A.] Massachusetts Gen Hosp, Dept Radiol, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. [Veld, Joyce; O'Donnell, Elizabeth K.; Yee, Andrew J.; Torriani, Martin; Bredella, Miriam A.] Harvard Med Sch, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. [O'Donnell, Elizabeth K.; Yee, Andrew J.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Reagan, Michaela R.; Rosen, Clifford J.] Maine Med Ctr Res Inst, Scarborough, ME 04074 USA. RP Bredella, MA (reprint author), Massachusetts Gen Hosp, Dept Radiol, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA.; Bredella, MA (reprint author), Harvard Med Sch, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. EM mbredella@mgh.harvard.edu RI Reagan, Michaela/E-3549-2017; OI Reagan, Michaela/0000-0003-2884-6481 NR 37 TC 1 Z9 1 U1 2 U2 3 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 SEP PY 2016 VL 45 IS 9 BP 1277 EP 1283 DI 10.1007/s00256-016-2425-4 PG 7 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA DR7ID UT WOS:000380072300013 PM 27344672 ER PT J AU den Hertog, TN de Jong, M van der Ham, AJ Hinton, D Reis, R AF den Hertog, T. N. de Jong, M. van der Ham, A. J. Hinton, D. Reis, R. TI "Thinking a Lot" Among the Khwe of South Africa: A Key Idiom of Personal and Interpersonal Distress SO CULTURE MEDICINE AND PSYCHIATRY LA English DT Article DE Mental health; Thinking too much; Idioms of distress; South Africa; San ID HAITI CENTRAL PLATEAU; MENTAL-HEALTH; TRAUMA; CARE; TOO AB "Thinking too much", and variations such as "thinking a lot", are common idioms of distress across the world. The contextual meaning of this idiom of distress in particular localities remains largely unknown. This paper reports on a systematic study of the content and cause, consequences, and social response and coping related to the local terms |x'an n|a te and |eu-ca n|a te, both translated as "thinking a lot", and was part of a larger ethnographic study among the Khwe of South Africa. Semi-structured exploratory interviews with community members revealed that "thinking a lot" refers to a common experience of reflecting on personal and interpersonal problems. Consequences were described in emotional, psychological, social, behavioral, and physical effects. Coping strategies included social support, distraction, and religious practices. Our contextualized approach revealed meanings and experiences of "thinking a lot" that go beyond a psychological state or psychopathology. The common experience of "thinking a lot" is situated in socio-political, economic, and social context that reflect the marginalized and displaced position of the Khwe. We argue that "thinking a lot" and associated local meanings may vary across settings, may not necessarily indicate psychopathology, and should be understood in individual, interpersonal, community, and socio-political dimensions. C1 [den Hertog, T. N.; Reis, R.] Univ Amsterdam, Amsterdam Inst Social Sci Res, Postbus 15718, NL-1001 NE Amsterdam, Netherlands. [den Hertog, T. N.] African Studies Ctr, Leiden, Netherlands. [de Jong, M.] Reha Prime, Rehabil & Physiotherapy, Zurich, Switzerland. [van der Ham, A. J.] Vrije Univ Amsterdam, Athena Inst Res Innovat & Commun Hlth & Life Sci, Amsterdam, Netherlands. [Hinton, D.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Reis, R.] Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, Leiden, Netherlands. [Reis, R.] Univ Cape Town, Childrens Inst, Sch Child & Adolescent Hlth, Cape Town, South Africa. RP den Hertog, TN (reprint author), Univ Amsterdam, Amsterdam Inst Social Sci Res, Postbus 15718, NL-1001 NE Amsterdam, Netherlands.; den Hertog, TN (reprint author), African Studies Ctr, Leiden, Netherlands. EM t.n.denhertog@uva.nl; dejong_marije@hotmail.com; a.j.vander.ham@vu.nl; devon_hinton@hms.harvard.edu; r.reis@lumc.nl NR 46 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0165-005X EI 1573-076X J9 CULT MED PSYCHIAT JI Cult. Med. Psychiatr. PD SEP PY 2016 VL 40 IS 3 BP 383 EP 403 DI 10.1007/s11013-015-9475-2 PG 21 WC Anthropology; Psychiatry; Social Sciences, Biomedical SC Anthropology; Psychiatry; Biomedical Social Sciences GA DR6BI UT WOS:000379985700004 PM 26487660 ER PT J AU Townsend, EL Bibeau, C Holmes, TM AF Townsend, Elise L. Bibeau, Christine Holmes, Tara M. TI Supported Standing in Boys With Duchenne Muscular Dystrophy SO PEDIATRIC PHYSICAL THERAPY LA English DT Article DE adolescence; bone mineral density; Duchenne muscular dystrophy; exercise therapy; exercise tolerance; patient safety; physical therapy methods; range of motion; standing position; weight-bearing ID BONE-MINERAL DENSITY; X-RAY ABSORPTIOMETRY; DISTAL FEMUR; CHILDREN; MANAGEMENT; RELIABILITY; CONTRACTURE; ADOLESCENTS; AMBULATION; FRACTURES AB Purpose: To evaluate the safety, tolerability, and efficacy of supported standing in a small sample of boys with Duchenne muscular dystrophy (DMD). Methods: Four 12- to 15-year-old boys with DMD engaged in a home-based supported standing program for 6 to 12 months. A single-subject design was employed to examine muscle length. Bone mineral density was assessed at 4-month intervals using dual-energy x-ray absorptiometry. Results: Upright, sustained supported standing was tolerated in 3 of the 4 boys. Mean weekly stand times ranged from 1.3 to 3.3 hours. Improved hip or knee flexor muscle length was seen in 3 of the 4 boys. No boys showed improved plantar flexor muscle length or increased lumbar bone mineral density. Conclusions: Findings offer preliminary empirical evidence addressing the safety, tolerability, and efficacy of standing in boys with DMD. Additional research with an emphasis on better program adherence is indicated. C1 [Townsend, Elise L.] MGH Inst Hlth Profess, Sch Hlth & Rehabil Sci, Dept Phys Therapy, Boston, MA USA. [Townsend, Elise L.] Massachusetts Gen Hosp, Dept Phys & Occupat Therapy, Boston, MA 02114 USA. [Holmes, Tara M.] Massachusetts Gen Hosp, Clin Res Ctr, Boston, MA 02114 USA. [Bibeau, Christine] Winchester Hosp, Dept Rehabil, Winchester, MA USA. RP Townsend, EL (reprint author), MGH Inst Hlth Profess, 36 1st Ave, Boston, MA 02129 USA. EM etownsend@mghihp.edu FU Harvard Clinical and Translational Science Center [1 UL1 RR025758-04]; National Center for Research Resources; MGH Institute of Health Professions; Hike for Hope Fund through Massachusetts General Hospital, Department of Neurology, Division of Pediatric Neurology FX This work was supported by Grant Number 1 UL1 RR025758-04, Harvard Clinical and Translational Science Center, from the National Center for Research Resources, a Research Fellow Award from the MGH Institute of Health Professions, and the Hike for Hope Fund through Massachusetts General Hospital, Department of Neurology, Division of Pediatric Neurology. NR 41 TC 0 Z9 0 U1 5 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0898-5669 EI 1538-005X J9 PEDIATR PHYS THER JI Pediatr. Phys. Ther. PD FAL PY 2016 VL 28 IS 3 BP 320 EP 329 DI 10.1097/PEP.0000000000000251 PG 10 WC Pediatrics; Rehabilitation SC Pediatrics; Rehabilitation GA DQ7DR UT WOS:000379367600013 PM 27008581 ER PT J AU Smucny, J Olincy, A Tregellas, JR AF Smucny, Jason Olincy, Ann Tregellas, Jason R. TI Nicotine restores functional connectivity of the ventral attention network in schizophrenia SO NEUROPHARMACOLOGY LA English DT Article DE Attention; Connectivity; fMRI; Nicotine; Schizophrenia; Ventral attention network ID AUDITORY SELECTIVE ATTENTION; PURSUIT EYE-MOVEMENT; BRAIN NETWORKS; PSYCHOPHYSIOLOGICAL INTERACTIONS; HEMODYNAMIC-RESPONSE; TRANSDERMAL NICOTINE; LEVEL METAANALYSIS; STIMULUS; FMRI; NONSMOKERS AB While previous work has suggested that nicotine may transiently improve attention deficits in schizophrenia, the neuronal mechanisms are poorly understood. This study is the first to examine the effects of nicotine on connectivity within the ventral attention network (VAN) during a selective attention task in schizophrenia. Using a crossover design, 17 nonsmoking patients with schizophrenia and 20 age/gender-matched nonsmoking healthy controls performed a go/no-go task with environmental noise distractors during application of a 7 mg nicotine or placebo patch. Psychophysiological interaction analysis was performed to analyze task-associated changes in connectivity between a ventral parietal cortex (VPC) seed and the inferior frontal gyrus (IFG), key components of the human VAN. Effects of nicotine on resting state VAN connectivity were also examined. A significant diagnosis x drug interaction was observed on task-associated connectivity between the VPC seed and the left IFG (F(1,35) = 8.03, p < 0.01). This effect was driven by decreased connectivity after placebo in patients and greater connectivity after nicotine. Resting state connectivity analysis showed a significant main effect of diagnosis between the seed and right IFG (F = 4.25, p = 0.023) due to increased connectivity in patients during placebo, but no drug x diagnosis interactions or main effects of drug. This study is the first to demonstrate that 1) the VAN is disconnected in schizophrenia during selective attention, and 2) nicotine may normalize this pathological state. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Smucny, Jason; Tregellas, Jason R.] Univ Colorado Anschutz Med Campus, Neurosci Program, Aurora, CO 80045 USA. [Olincy, Ann; Tregellas, Jason R.] Denver VA Med Ctr, Res Serv, Denver, CO 80220 USA. [Smucny, Jason; Olincy, Ann; Tregellas, Jason R.] Univ Colorado Anschutz Med Campus, Dept Psychiat, Aurora, CO 80045 USA. RP Smucny, J (reprint author), Univ Colorado Anschutz Med Campus, Dept Psychiat, Aurora, CO 80045 USA. EM Jason.smucny@ucdenver.edu OI Smucny, Jason/0000-0001-5656-7987 FU VA Biomedical Laboratory and Clinical Science Research and Development Service [CX000459]; Brain and Behavior Research Foundation; NIH [MH-089095, DK-103691, MH-102224]; NIH fellowship [MH-102879] FX This work was supported by the VA Biomedical Laboratory and Clinical Science Research and Development Service grant CX000459 (grant to Dr. Tregellas), the Brain and Behavior Research Foundation (grant to Dr. Tregellas), NIH grants MH-089095, DK-103691, MH-102224 (grants to Dr. Tregellas), and NIH fellowship MH-102879 (grant to Mr. Smucny). NR 62 TC 2 Z9 2 U1 5 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD SEP PY 2016 VL 108 BP 144 EP 151 DI 10.1016/j.neuropharm.2016.04.015 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DQ1IA UT WOS:000378953500015 PM 27085606 ER PT J AU Jenkins, BG Zhu, AJ Poutiainen, P Choi, JK Kil, KE Zhang, ZD Kuruppu, D Aytan, N Dedeoglu, A Brownell, AL AF Jenkins, Bruce G. Zhu, Aijun Poutiainen, Pekka Choi, Ji-Kyung Kil, Kun-Eek Zhang, Zhaoda Kuruppu, Darshini Aytan, Nurgul Dedeoglu, Alpaslan Brownell, Anna-Liisa TI Functional modulation of G-protein coupled receptors during Parkinson disease-like neurodegeneration SO NEUROPHARMACOLOGY LA English DT Article DE Metabotropic glutamate receptor; mGlu(4); mGlu(5); Parkinson's disease; Positron emission tomography; Pharmacological magnetic resonance imaging ID METABOTROPIC GLUTAMATE RECEPTORS; ALLOSTERIC MODULATORS; BASAL GANGLIA; RAT-BRAIN; PHARMACOLOGICAL MRI; DOPAMINE TERMINALS; PET RADIOTRACER; CEREBRAL-CORTEX; MGLUR5; LOCALIZATION AB G-protein coupled dopamine and metabotropic glutamate receptors (mGlu) can modulate neurotransmission during Parkinson's disease (PD)-like neurodegeneration. PET imaging studies in a unilateral dopamine denervation model (6-OHDA) showed a significant inverse correlation of presynaptic mGlu(4) and postsynaptic mGlu(5) expression in the striatum and rapidly declining mGlu(4) and enhanced mGlu(5) expression in the hippocampus during progressive degeneration over time. Immunohistochemical studies verified the decreased mGlu(4) expression in the hippocampus on the lesion side but did not show difference in mGlu(5) expression between lesion and control side. Pharmacological MRI studies showed enhanced hemodynamic response in several brain areas on the lesion side compared to the control side after challenge with mGlu(4) positive allosteric modulator or mGlu(5) negative allosteric modulator. However, mGlu(4) response was biphasic having short enhancement followed by negative response on both sides of brain. Studies in mGlu(4) expressing cells demonstrated that glutamate induces cooperative increase in binding of mGlu(4) ligands especially at high glutamate levels consistent with in vivo concentration. This suggests that mGlu allosteric modulators as drug candidates will be highly sensitive to changes in glutamate concentration and hence metabolic state. These experiments demonstrate the importance of the longitudinal imaging studies to investigate temporal changes in receptor functions to obtain individual response for experimental drugs. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Jenkins, Bruce G.; Zhu, Aijun; Poutiainen, Pekka; Choi, Ji-Kyung; Kil, Kun-Eek; Zhang, Zhaoda; Brownell, Anna-Liisa] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, 13th St, Charlestown, MA 02129 USA. [Kuruppu, Darshini] Massachusetts Gen Hosp, Dept Med, Surg Oncol, 55 Fruit St, Boston, MA 02114 USA. [Aytan, Nurgul; Dedeoglu, Alpaslan] VA Boston Healthcare Syst, Dept Vet Affairs, Boston, MA 02130 USA. [Dedeoglu, Alpaslan] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. RP Brownell, AL (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, 13th St, Charlestown, MA 02129 USA. EM abrownell@partners.org FU NIH [NIBIB-R01EB012864, NIMH-R01MH91684]; Orion Farmos Research Foundation; Kuopio University Foundation FX Funding by NIH grants NIBIB-R01EB012864 and NIMH-R01MH91684 to ALB is acknowledged. PP was supported by the Orion Farmos Research Foundation and Kuopio University Foundation. NR 59 TC 0 Z9 0 U1 2 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD SEP PY 2016 VL 108 BP 462 EP 473 DI 10.1016/j.neuropharm.2015.11.010 PG 12 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DQ1IA UT WOS:000378953500045 PM 26581500 ER PT J AU Yoon, YS Jung, S Zhang, XH Ogino, S Giovannucci, EL Cho, E AF Yoon, Yeong Sook Jung, Seungyoun Zhang, Xuehong Ogino, Shuji Giovannucci, Edward L. Cho, Eunyoung TI Vitamin B2 intake and colorectal cancer risk; results from the Nurses' Health Study and the Health Professionals Follow-Up Study cohort SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE vitamin B2; colorectal neoplasms; cohort studies; alcohol; folate; diet; supplements; latency ID FOOD FREQUENCY QUESTIONNAIRE; ONE-CARBON METABOLISM; TOTAL-ENERGY-INTAKE; DIETARY-INTAKE; B-VITAMINS; GENETIC POLYMORPHISMS; WOMENS HEALTH; FOLATE; REPRODUCIBILITY; MICRONUTRIENTS AB Vitamin B2 serves as a cofactor to enhance one-carbon metabolism, maintain mucous membranes, and has been implicated in lowering colorectal cancer (CRC) risk. However, few prospective studies have examined the association between vitamin B2 intake and CRC. In this study, we estimated the associations between vitamin B2 intake and CRC risk using the Nurses' Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) cohorts. Vitamin B2 intake was measured by a validated food frequency questionnaire every 4 years. Among 100,033 women in the NHS and 44,007 men in the HPFS we documented a total of 3,037 incident CRC cases (2,093 women and 944 men) during 24-26 years of follow-up until 2010. Intakes of total (from food and supplements), dietary (from food only), and supplemental vitamin B2 were inversely related to CRC risk in age-adjusted analysis in NHS. However, the association was attenuated and no longer statistically significant in multivariate analysis (p-trend >= 0.08). The pooled multivariate relative risks (95% confidence interval) comparing individuals in the extreme quintiles of intakes were 0.93 (0.81-1.06) for total vitamin B2, 0.89 (0.61-1.28) for dietary vitamin B2 and 0.94 (0.81-1.08) for supplemental vitamin B2. These associations of total vitamin B2 intake were similar for risk of CRC with varying lag-time periods (0-4, 4-8, 8-12 or 12-16 years), for risk of CRC subtypes by tumor location, and across strata of intake of folate or alcohol. Our prospective data do not support a beneficial role of vitamin B2 intake in lowering incidence of CRC. C1 [Yoon, Yeong Sook; Giovannucci, Edward L.] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ogino, Shuji; Giovannucci, Edward L.] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Yoon, Yeong Sook] Inje Univ, Ilsan Paik Hosp, Dept Family Med, Goyang Si, Gyeonggi Do, South Korea. [Jung, Seungyoun] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Zhang, Xuehong; Giovannucci, Edward L.; Cho, Eunyoung] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Ogino, Shuji] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Cho, Eunyoung] Brown Univ, Dept Dermatol, Warren Alpert Med Sch, 222 Richmond St, Providence, RI 02903 USA. [Cho, Eunyoung] Brown Univ, Dept Epidemiol, Sch Publ Hlth, Providence, RI 02912 USA. RP Cho, E (reprint author), Brown Univ, Dept Dermatol, Warren Alpert Med Sch, 222 Richmond St, Providence, RI 02903 USA. EM eunyoung_cho@brown.edu FU National Institutes of Health [P01 CA87969, P01 CA55075, UM1 CA186107, UM1 CA167552, R01 CA151993, RO1 CA136950, R35 CA197735]; Inje University [20140191] FX Grant sponsor: National Institutes of Health; Grant number: P01 CA87969, P01 CA55075, UM1 CA186107, UM1 CA167552, R01 CA151993, RO1 CA136950 and R35 CA197735; Grant sponsor: Inje University (2014-2015); Grant number: 20140191 NR 43 TC 0 Z9 0 U1 14 U2 19 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 SEP 1 PY 2016 VL 139 IS 5 BP 996 EP 1008 DI 10.1002/ijc.30141 PG 13 WC Oncology SC Oncology GA DP3TR UT WOS:000378418800004 PM 27081929 ER PT J AU Kocarnik, JM Chan, AT Slattery, ML Potter, JD Meyerhardt, J Phipps, A Nan, HM Harrison, T Rohan, TE Qi, LH Hou, LF Caan, B Kroenke, CH Strickler, H Hayes, RB Schoen, RE Chong, DQ White, E Berndt, SI Peters, U Newcomb, PA AF Kocarnik, Jonathan M. Chan, Andrew T. Slattery, Martha L. Potter, John D. Meyerhardt, Jeffrey Phipps, Amanda Nan, Hongmei Harrison, Tabitha Rohan, Thomas E. Qi, Lihong Hou, Lifang Caan, Bette Kroenke, Candyce H. Strickler, Howard Hayes, Richard B. Schoen, Robert E. Chong, Dawn Q. White, Emily Berndt, Sonja I. Peters, Ulrike Newcomb, Polly A. TI Relationship of prediagnostic body mass index with survival after colorectal cancer: Stage-specific associations SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE body mass index (BMI); cancer stage; colorectal cancer (CRC); mortality; survival ID OBESITY PARADOX; WOMENS HEALTH; COLON-CANCER; SUSCEPTIBILITY LOCI; PROSPECTIVE COHORT; PHYSICAL-ACTIVITY; MORTALITY; DIAGNOSIS; OVERWEIGHT; DEATH AB Higher body mass index (BMI) is a well-established risk factor for colorectal cancer (CRC), but is inconsistently associated with CRC survival. In 6 prospective studies participating in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), 2,249 non-Hispanic white CRC cases were followed for a median 4.5 years after diagnosis, during which 777 died, 554 from CRC-related causes. Associations between prediagnosis BMI and survival (overall and CRC-specific) were evaluated using Cox regression models adjusted for age at diagnosis, sex, study and smoking status (current/former/never). The association between BMI category and CRC survival varied by cancer stage at diagnosis (I-IV) for both all-cause (p-interaction=0.03) and CRC-specific mortality (p-interaction=0.04). Compared to normal BMI (18.5-24.9 kg/m(2)), overweight (BMI 25.0-29.9) was associated with increased mortality among those with Stage I disease, and decreased mortality among those with Stages II-IV disease. Similarly, obesity (BMI >= 30) was associated with increased mortality among those with Stages I-II disease, and decreased mortality among those with Stages III-IV disease. These results suggest the relationship between BMI and survival after CRC diagnosis differs by stage at diagnosis, and may emphasize the importance of adequate metabolic reserves for colorectal cancer survival in patients with late-stage disease. C1 [Kocarnik, Jonathan M.; Phipps, Amanda; White, Emily; Peters, Ulrike; Newcomb, Polly A.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Kocarnik, Jonathan M.; Potter, John D.; Phipps, Amanda; Harrison, Tabitha; White, Emily; Peters, Ulrike; Newcomb, Polly A.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Chan, Andrew T.; Chong, Dawn Q.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Slattery, Martha L.] Univ Utah, Dept Internal Med, Hlth Sci Ctr, Salt Lake City, UT 84112 USA. [Meyerhardt, Jeffrey] Dana Farber Canc Inst, Boston, MA 02115 USA. [Meyerhardt, Jeffrey] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Nan, Hongmei] Indiana Univ, Richard M Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46204 USA. [Nan, Hongmei] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. [Rohan, Thomas E.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Qi, Lihong] Univ Calif Davis, Sch Med, Dept Publ Hlth Sci, Davis, CA 95616 USA. [Hou, Lifang] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Hou, Lifang] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Caan, Bette; Kroenke, Candyce H.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Hayes, Richard B.] NYU, Div Epidemiol, Sch Med, New York, NY USA. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA. [Chong, Dawn Q.] Natl Canc Ctr Singapore, Div Med Oncol, Singapore, Singapore. [Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Kocarnik, JM (reprint author), Kocarnik 1100 Fairview Ave N Mailstop M4-B402, Seattle, WA 98199 USA. EM jkocarni@fredhutch.org OI Hayes, Richard/0000-0002-0918-661X; Kocarnik, Jonathan/0000-0001-8084-1608 FU National Center for Advancing Translational Sciences (National Institutes of Health) [KL2 TR000421]; National Cancer Institute [K05 CA152715, T32 CA 09168, U01 CA137088, R01 CA059045, P01 CA055075, UM1 CA167552, R01 CA137178, R01 CA151993, P50 CA127003, UM1 CA186107, P01 CA87969, R01 CA042182, K05 CA154337]; Division of Cancer Epidemiology; Division of Cancer Prevention (PLCO); National Heart, Lung, and Blood Institute, National Institutes of Health [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C] FX Grant sponsor: National Center for Advancing Translational Sciences (National Institutes of Health); Grant number: KL2 TR000421; Grant sponsor: National Cancer Institute; Grant numbers: K05 CA152715, T32 CA 09168; U01 CA137088 and R01 CA059045 (GECCO); P01 CA055075, UM1 CA167552, R01 CA137178, R01 CA151993 and P50 CA127003 (HPFS); UM1 CA186107, R01 CA137178, P01 CA87969, R01 CA151993 and P50 CA127003 (NHS); R01 CA042182 (PHS); K05 CA154337 (VITAL); Intramural Research Program of the Division of Cancer Epidemiology and contracts from the Division of Cancer Prevention (PLCO); Grant sponsor: National Heart, Lung, and Blood Institute, National Institutes of Health; Grant numbers: HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C (WHI) NR 47 TC 2 Z9 2 U1 2 U2 13 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 SEP 1 PY 2016 VL 139 IS 5 BP 1065 EP 1072 DI 10.1002/ijc.30163 PG 8 WC Oncology SC Oncology GA DP3TR UT WOS:000378418800011 PM 27121247 ER PT J AU Keles, HO Barbour, RL Omurtag, A AF Keles, Hasan Onur Barbour, Randall L. Omurtag, Ahmet TI Hemodynamic correlates of spontaneous neural activity measured by human whole-head resting state EEG plus fNIRS SO NEUROIMAGE LA English DT Article DE Simultaneous EEG plus fNIRS; Resting state; Neurovascular coupling ID NEAR-INFRARED SPECTROSCOPY; ALPHA-RHYTHM; BOLD FMRI; FUNCTIONAL CONNECTIVITY; BRAIN ACTIVATION; SIGNAL; SYNCHRONIZATION; OSCILLATIONS; NETWORKS; DYNAMICS AB The brains of awake, resting human subjects display spontaneously occurring neural activity patterns whose magnitude is typically many times greater than those triggered by cognitive or perceptual performance. Evoked and resting state activations affect local cerebral hemodynamic properties through processes collectively referred to as neurovascular coupling. Its investigation calls for an ability to track both the neural and vascular aspects of brain function. We used scalp electroencephalography (EEG), which provided a measure of the electrical potentials generated by cortical postsynaptic currents. Simultaneously we utilized functional near-infrared spectroscopy (NIRS) to continuously monitor hemoglobin concentration changes in superficial cortical layers. The multi-modal signal from 18 healthy adult subjects allowed us to investigate the association of neural activity in a range of frequencies over the whole-head to local changes in hemoglobin concentrations. Our results verified the delayed alpha (8-16 Hz) modulation of hemodynamics in posterior areas known from the literature. They also indicated strong beta (16-32 Hz) modulation of hemodynamics. Analysis revealed, however, that beta modulation was likely generated by the alpha-beta coupling in EEG. Signals from the inferior electrode sites were dominated by scalp muscle related activity. Our study aimed to characterize the phenomena related to neurovascular coupling observable by practical, cost-effective, and non-invasive multi-modal techniques. (C) 2016 Elsevier Inc. All rights reserved. C1 [Keles, Hasan Onur] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Barbour, Randall L.] SUNY, Opt Tomog Grp, Dept Pathol, Brooklyn, NY 11203 USA. [Omurtag, Ahmet] Univ Houston, Dept Biomed Engn, Houston, TX 77204 USA. RP Omurtag, A (reprint author), Univ Houston, Dept Biomed Engn, Houston, TX 77204 USA. EM aomurtag@uh.edu FU National Science Foundation I/UCRC for Cyber-Physical Systems for the Hospital Operating Room [IIP-1266334]; Department of Biomedical Engineering at University of Houston [R413022]; Cullen College of Engineering at University of Houston [R413022] FX The authors are grateful to Robert Grossman, Marc Garbey, Harry Graber, and Dino Dvorak for their helpful criticism during the preparation of the manuscript. The manuscript also benefitted from the incisive comments of anonymous reviewers. Special thanks to Haleh Aghajani for her support in synchronizing the measurement systems. A. Omurtag holds a financial interest in Bio-Signal Group which makes microEEG and R.L. Barbour is Founder & CEO, Chief Scientist, of NIRx which makes NIRScout, devices that were used in this research. This work is based partly on support by the National Science Foundation I/UCRC for Cyber-Physical Systems for the Hospital Operating Room under Grant no. IIP-1266334 and by industry partners. We would also like to thank the Department of Biomedical Engineering and the Cullen College of Engineering at University of Houston for its financial support (Award no. R413022). NR 87 TC 0 Z9 0 U1 18 U2 32 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 SEP PY 2016 VL 138 BP 76 EP 87 DI 10.1016/j.neuroimage.2016.05.058 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DP5ET UT WOS:000378519500006 PM 27236081 ER PT J AU Baggett, TP Campbell, EG Chang, YC Rigotti, NA AF Baggett, Travis P. Campbell, Eric G. Chang, Yuchiao Rigotti, Nancy A. TI Other tobacco product and electronic cigarette use among homeless cigarette smokers SO ADDICTIVE BEHAVIORS LA English DT Article DE Homeless persons; Tobacco use; Tobacco products; Electronic cigarettes ID ADDICTION SEVERITY INDEX; SMOKELESS TOBACCO; SMOKING-CESSATION; HEALTH-CARE; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; LOGISTIC-REGRESSION; PUBLIC-HEALTH; UNITED-STATES; LOS-ANGELES AB Objective: We determined the prevalence and correlates of other tobacco product and electronic cigarette (e-cigarette) use in a clinic-based sample of homeless cigarette smokers. Methods: In April July 2014, we used time-location sampling to conduct a cross-sectional, in-person survey of 306 currently homeless adult cigarette smokers recruited from 5 clinical sites at Boston Health Care for the Homeless Program. We assessed past-month use of large cigars, little cigars, smokeless tobacco, and e-cigarettes. Among those who had used e-cigarettes, we assessed the reasons for doing so. We used logistic regression analysis to identify the participant characteristics associated with the use of each product. Results: Eighty-six percent of eligible individuals participated in the survey. In the past month, 37% of respondents used large cigars, 44% used little cigars, 8% used smokeless tobacco, 24% used an e-cigarette, and 68% used any of these products. Reasons for e-cigarette use included curiosity (85%) and to help quit conventional cigarettes (69%). In multivariable regression analyses, homeless smokers with greater subsistence difficulties were more likely to use little cigars (p = 0.01) and less likely to use e-cigarettes (p = 0.001). Non-Hispanic black (p = 0.01), Hispanic (p < 0.001), and rough-sleeping (p = 0.04) participants were more likely to use large cigars. Readiness to quit was not associated with other tobacco product use but was significantly associated with e-cigarette use to help quit smoking (p = 0.02). Conclusions: Health care providers who serve homeless people should consider routine screening for the use of other tobacco products and e-cigarettes to help guide smoking cessation discussions and tobacco treatment planning. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Baggett, Travis P.; Chang, Yuchiao; Rigotti, Nancy A.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Baggett, Travis P.; Campbell, Eric G.; Chang, Yuchiao; Rigotti, Nancy A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Baggett, Travis P.] Boston Hlth Care Homeless Program, Boston, MA USA. [Campbell, Eric G.; Rigotti, Nancy A.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. RP Baggett, TP (reprint author), 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM tbaggett@mgh.harvard.edu FU National Institute on Drug Abuse at the National Institutes of Health [K23DA034008] FX This study was funded by the National Institute on Drug Abuse at the National Institutes of Health under award number K23DA034008 to Dr. Baggett The funding agency had no role in any aspect of this study. The study content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 60 TC 1 Z9 1 U1 2 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD SEP PY 2016 VL 60 BP 124 EP 130 DI 10.1016/j.addbeh.2016.04.006 PG 7 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA DO4DH UT WOS:000377731500021 PM 27128808 ER PT J AU Salcedo, S Gold, AK Sheikh, S Marcus, PH Nierenberg, AA Deckersbach, T Sylvia, LG AF Salcedo, Stephanie Gold, Alexandra K. Sheikh, Sana Marcus, Peter H. Nierenberg, Andrew A. Deckersbach, Thilo Sylvia, Louisa G. TI Empirically supported psychosocial interventions for bipolar disorder: Current state of the research SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Review DE Bipolar disorder; Cognitive behavior therapy; Family therapy; Interpersonal and social rhythm therapy; Dialectical behavior therapy; Psychosocial interventions ID DIALECTICAL BEHAVIOR-THERAPY; RANDOMIZED CONTROLLED-TRIAL; SOCIAL RHYTHM THERAPY; BORDERLINE PERSONALITY-DISORDER; FAMILY-FOCUSED TREATMENT; QUALITY-OF-LIFE; COGNITIVE THERAPY; RELAPSE PREVENTION; FOLLOW-UP; GROUP PSYCHOEDUCATION AB Objectives: Bipolar disorder requires psychiatric medications, but even guideline-concordant treatment fails to bring many patients to remission or keep them euthymic. To address this gap, researchers have developed adjunctive psychotherapies. The purpose of this paper is to critically review the evidence for the efficacy of manualized psychosocial interventions for bipolar disorder. Methods: We conducted a search of the literature to examine recent (2007-present), randomized controlled studies of the following psychotherapy interventions for bipolar disorder: psychoeducation (PE), cognitive behavioral therapy (CBT), interpersonal and social rhythm therapy (IPSRT), dialectical behavior therapy (DBT), mindfulness-based cognitive therapy (MBCT), and family therapies such as family focused therapy (FFT). Results: All of the psychotherapy interventions appear to be effective in reducing depressive symptoms. Psychoeducation and CBT are associated with increased time to mood episode relapse or recurrence. MBCT has demonstrated a particular effectiveness in improving depressive and anxiety symptoms. Online psychotherapy interventions, programs combining one or more psychotherapy interventions, and targeted interventions centering on particular symptoms have been the focus of recent, randomized controlled studies in bipolar disorder. Conclusions: Psychotherapy interventions for the treatment of bipolar disorder have substantial evidence for efficacy. The next challenge will to disseminate these psychotherapies into the community. (C) 2016 Elsevier B.V. All rights reserved. C1 [Salcedo, Stephanie] Univ N Carolina, Dept Psychol & Neurosci, Chapel Hill, NC USA. [Gold, Alexandra K.; Sheikh, Sana; Marcus, Peter H.; Nierenberg, Andrew A.; Deckersbach, Thilo; Sylvia, Louisa G.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Marcus, Peter H.; Nierenberg, Andrew A.; Deckersbach, Thilo; Sylvia, Louisa G.] Harvard Univ, Sch Med, Boston, MA USA. [Sheikh, Sana] Suffolk Univ, Dept Psychol, Boston, MA 02114 USA. RP Salcedo, S (reprint author), Univ N Carolina, Dept Psychol & Neurosci, Chapel Hill, NC USA. EM ssalcedo@email.unc.edu NR 97 TC 4 Z9 4 U1 25 U2 40 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 SEP 1 PY 2016 VL 201 BP 203 EP 214 DI 10.1016/j.jad.2016.05.018 PG 12 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DN9IM UT WOS:000377392900028 PM 27243619 ER PT J AU Jung, J Lee, JS Dickson, MA Schwartz, GK Le Cesne, A Varga, A Bahleda, R Wagner, AJ Choy, E de Jonge, MJ Light, M Rowley, S Mace, S Watters, J AF Jung, Joonil Lee, Joon Sang Dickson, Mark A. Schwartz, Gary K. Le Cesne, Axel Varga, Andrea Bahleda, Rastilav Wagner, Andrew J. Choy, Edwin de Jonge, Maja J. Light, Madelyn Rowley, Steve Mace, Sandrine Watters, James TI TP53 mutations emerge with HDM2 inhibitor SAR405838 treatment in de-differentiated liposarcoma SO NATURE COMMUNICATIONS LA English DT Article ID ACUTE MYELOID-LEUKEMIA; POINT MUTATIONS; P53 MUTATIONS; CANCER; DNA; EVOLUTION; NUTLIN-3 AB In tumours that harbour wild-type p53, p53 protein function is frequently disabled by the mouse double minute 2 protein (MDM2, or HDM2 in humans). Multiple HDM2 antagonists are currently in clinical development. Preclinical data indicate that TP53 mutations are a possible mechanism of acquired resistance to HDM2 inhibition; however, this resistance mechanism has not been reported in patients. Utilizing liquid biopsies, here we demonstrate that TP53 mutations appear in circulating cell-free DNA obtained from patients with de-differentiated liposarcoma being treated with an inhibitor of the HDM2-p53 interaction (SAR405838). TP53 mutation burden increases over time and correlates with change in tumour size, likely representing selection of TP53 mutant clones resistant to HDM2 inhibition. These results provide the first clinical demonstration of the emergence of TP53 mutations in response to an HDM2 antagonist and have significant implications for the clinical development of this class of molecules. C1 [Jung, Joonil; Lee, Joon Sang; Light, Madelyn; Rowley, Steve; Watters, James] Sanofi Oncol, Cambridge, MA 02139 USA. [Dickson, Mark A.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Schwartz, Gary K.] Columbia Univ, Med Ctr, New York, NY 10032 USA. [Le Cesne, Axel; Varga, Andrea; Bahleda, Rastilav] Gustave Roussy, Dept Canc Med, F-94800 Villejuif, France. [Wagner, Andrew J.] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Dept Med Oncol, Boston, MA 02215 USA. [Choy, Edwin] Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. [de Jonge, Maja J.] Erasmus MC, Inst Canc, Dept Med Oncol, NL-3015 CE Rotterdam, Netherlands. [Mace, Sandrine] Sanofi Oncol, F-94400 Vitry Sur Seine, France. RP Jung, J; Watters, J (reprint author), Sanofi Oncol, Cambridge, MA 02139 USA. EM joonil.jung@sanofi.com; james.watters@gmail.com FU Sanofi FX We acknowledge Barbara Kalinowska for tumour specimen processing and sectioning, and Rafaelle Baffa for pathological review of tumour specimens. We acknowledge Colette Dib, Wilson Dos-Santos-Bele, Sandrine Valence, Edouard Turlotte and Stephane Soubigou for TP53 and MDM2 status determination in baseline tumour biopsies. We acknowledge Karl Hsu, Wei Zheng and Koruth Thomas from the clinical study team for providing clinical data for the preparation of this manuscript. This study was funded by Sanofi. We received editorial support from Simone Blagg of MediTech Media, funded by Sanofi. NR 26 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 AUG 31 PY 2016 VL 7 AR 12609 DI 10.1038/ncomms12609 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH6GS UT WOS:000391871600001 PM 27576846 ER PT J AU Gagnon, L Smith, AF Boas, DA Devor, A Secomb, TW Sakadzic, S AF Gagnon, Louis Smith, Amy F. Boas, David A. Devor, Anna Secomb, Timothy W. Sakadzic, Sava TI Modeling of Cerebral Oxygen Transport Based on In vivo Microscopic Imaging of Microvascular Network Structure, Blood Flow, and Oxygenation SO FRONTIERS IN COMPUTATIONAL NEUROSCIENCE LA English DT Review DE cerebral blood flow (CBF); cerebral blood flow measurement; cerebrovascular circulation; brain imaging methods; modeling and simulations ID OPTICAL COHERENCE TOMOGRAPHY; ENDOTHELIAL SURFACE-LAYER; TRANSIT-TIME HETEROGENEITY; 2-PHOTON MICROSCOPY; VASCULAR NETWORKS; PHOTOACOUSTIC MICROSCOPY; TISSUE OXYGENATION; CAPILLARY NETWORK; MOUSE-BRAIN; ACOUSTIC SUPERRESOLUTION AB Oxygen is delivered to brain tissue by a dense network of microvessels, which actively control cerebral blood flow (CBF) through vasodilation and contraction in response to changing levels of neural activity. Understanding these network-level processes is immediately relevant for (1) interpretation of functional Magnetic Resonance Imaging (fMRI) signals, and (2) investigation of neurological diseases in which a deterioration of neurovascular and neuro-metabolic physiology contributes to motor and cognitive decline. Experimental data on the structure, flow and oxygen levels of microvascular networks are needed, together with theoretical methods to integrate this information and predict physiologically relevant properties that are not directly measurable. Recent progress in optical imaging technologies for high-resolution in vivo measurement of the cerebral microvascular architecture, blood flow, and oxygenation enables construction of detailed computational models of cerebral hemodynamics and oxygen transport based on realistic three-dimensional microvascular networks. In this article, we review state-of-the-art optical microscopy technologies for quantitative in vivo imaging of cerebral microvascular structure, blood flow and oxygenation, and theoretical methods that utilize such data to generate spatially resolved models for blood flow and oxygen transport. These "bottom-up" models are essential for the understanding of the processes governing brain oxygenation in normal and disease states and for eventual translation of the lessons learned from animal studies to humans. C1 [Gagnon, Louis; Boas, David A.; Devor, Anna; Sakadzic, Sava] Massachusetts Gen Hosp, Dept Radiol, Opt Div, MHG MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA 02129 USA. [Gagnon, Louis; Boas, David A.; Devor, Anna; Sakadzic, Sava] Harvard Med Sch, Charlestown, MA 02129 USA. [Smith, Amy F.] Inst Mecan Fluides Toulouse, Toulouse, France. [Smith, Amy F.; Secomb, Timothy W.] Univ Arizona, Dept Physiol, Tucson, AZ USA. [Devor, Anna] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Devor, Anna] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. RP Gagnon, L (reprint author), Massachusetts Gen Hosp, Dept Radiol, Opt Div, MHG MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA 02129 USA.; Gagnon, L (reprint author), Harvard Med Sch, Charlestown, MA 02129 USA. EM lgagnon@nmr.mgh.harvard.edu FU NIH [NS091230, EB018464, NS092986, NS055104, EB021018, HL070657] FX Supported by NIH grants NS091230, EB018464, NS092986, NS055104, EB021018, and HL070657. NR 181 TC 2 Z9 2 U1 16 U2 16 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5188 J9 FRONT COMPUT NEUROSC JI Front. Comput. Neurosci. PD AUG 31 PY 2016 VL 10 DI 10.3389/fncom.2016.00082 PG 20 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA DU5UI UT WOS:000382278200001 ER PT J AU Chambers, AR Salazar, JJ Polley, DB AF Chambers, Anna R. Salazar, Juan J. Polley, Daniel B. TI Persistent Thalamic Sound Processing Despite Profound Cochlear Denervation SO FRONTIERS IN NEURAL CIRCUITS LA English DT Article DE medial geniculate body; hearing loss; homeostatic plasticity; compensatory plasticity; cochlear neuropathy ID MEDIAL GENICULATE-BODY; EXTRASYNAPTIC GABA(A) RECEPTORS; UNILATERAL HEARING-LOSS; AUDITORY BRAIN-STEM; HAIR CELL LOSS; INFERIOR COLLICULUS; BEHAVIORAL EVIDENCE; SPEECH RECOGNITION; NERVE DEGENERATION; GABAERGIC NEURONS AB Neurons at higher stages of sensory processing can partially compensate for a sudden drop in peripheral input through a homeostatic plasticity process that increases the gain on weak afferent inputs. Even after a profound unilateral auditory neuropathy where >95% of afferent synapses between auditory nerve fibers and inner hair cells have been eliminated with ouabain, central gain can restore cortical processing and perceptual detection of basic sounds delivered to the denervated ear. In this model of profound auditory neuropathy, auditory cortex (ACtx) processing and perception recover despite the absence of an auditory brainstem response (ABR) or brainstem acoustic reflexes, and only a partial recovery of sound processing at the level of the inferior colliculus (IC), an auditory midbrain nucleus. In this study, we induced a profound cochlear neuropathy with ouabain and asked whether central gain enabled a compensatory plasticity in the auditory thalamus comparable to the full recovery of function previously observed in the ACtx, the partial recovery observed in the IC, or something different entirely. Unilateral ouabain treatment in adult mice effectively eliminated the ABR, yet robust sound-evoked activity persisted in a minority of units recorded from the contralateral medial geniculate body (MGB) of awake mice. Sound driven MGB units could decode moderate and high-intensity sounds with accuracies comparable to sham-treated control mice, but low-intensity classification was near chance. Pure tone receptive fields and synchronization to broadband pulse trains also persisted, albeit with significantly reduced quality and precision, respectively. MGB decoding of temporally modulated pulse trains and speech tokens were both greatly impaired in ouabain-treated mice. Taken together, the absence of an ABR belied a persistent auditory processing at the level of the MGB that was likely enabled through increased central gain. Compensatory plasticity at the level of the auditory thalamus was less robust overall than previous observations in cortex or midbrain. Hierarchical differences in compensatory plasticity following sensorineural hearing loss may reflect differences in GABA circuit organization within the MGB, as compared to the ACtx or IC. C1 [Chambers, Anna R.; Salazar, Juan J.; Polley, Daniel B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. [Salazar, Juan J.] PSL Res Univ, Ecole Normale Super, Dept Biol, Paris, France. [Polley, Daniel B.] Harvard Med Sch, Dept Otolaryngol, Boston, MA USA. [Chambers, Anna R.] Univ Oslo, Inst Basic Med Sci, Oslo, Norway. [Salazar, Juan J.] Ecole Normale Super Paris, Paris, France. RP Polley, DB (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA.; Polley, DB (reprint author), Harvard Med Sch, Dept Otolaryngol, Boston, MA USA. EM daniel_polley@epl.meei.harvard.edu FU National Institutes of Health [R01DC009836]; Lauer Tinnitus Research Center; Research Award from Autifony Therapeutics FX This work was supported by National Institutes of Health-R01DC009836, The Lauer Tinnitus Research Center and a Research Award from Autifony Therapeutics. NR 83 TC 0 Z9 0 U1 1 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5110 J9 FRONT NEURAL CIRCUIT JI Front. Neural Circuits PD AUG 31 PY 2016 VL 10 AR 72 DI 10.3389/fncir.2016.00072 PG 13 WC Neurosciences SC Neurosciences & Neurology GA DU6CR UT WOS:000382301600001 PM 27630546 ER PT J AU Bighamian, R Reisner, AT Hahn, JO AF Bighamian, Ramin Reisner, Andrew T. Hahn, Jin-Oh TI A Lumped-Parameter Subject-Specific Model of Blood Volume Response to Fluid Infusion SO FRONTIERS IN PHYSIOLOGY LA English DT Article DE fluid shifts; blood volume; fluid resuscitation; mathematical model; lumped-parameter model; subject-specific model ID MATHEMATICAL-MODEL; TRANSCAPILLARY REFILL; COMPUTER-SIMULATION; PLASMA-VOLUME; HEMORRHAGE; RESUSCITATION; KINETICS; HEMODIALYSIS; THERAPY; RESTITUTION AB This paper presents a lumped-parameter model that can reproduce blood volume response to fluid infusion. The model represents the fluid shift between the intravascular and interstitial compartments as the output of a hypothetical feedback controller that regulates the ratio between the volume changes in the intravascular and interstitial fluid at a target value (called "target volume ratio"). The model is characterized by only three parameters: the target volume ratio, feedback gain (specifying the speed of fluid shift), and initial blood volume. This model can obviate the need to incorporate complex mechanisms involved in the fluid shift in reproducing blood volume response to fluid infusion. The ability of the model to reproduce real-world blood volume response to fluid infusion was evaluated by fitting it to a series of data reported in the literature. The model reproduced the data accurately with average error and root-mean-squared error (RMSE) of 0.6 and 9.5% across crystalloid and colloid fluids when normalized by the underlying responses. Further, the parameters derived for the model showed physiologically plausible behaviors. It was concluded that this simple model may accurately reproduce a variety of blood volume responses to fluid infusion throughout different physiological states by fitting three parameters to a given dataset. This offers a tool that can quantify the fluid shift in a dataset given the measured fractional blood volumes. C1 [Bighamian, Ramin; Hahn, Jin-Oh] Univ Maryland, Dept Mech Engn, College Pk, MD 20742 USA. [Reisner, Andrew T.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Hahn, JO (reprint author), Univ Maryland, Dept Mech Engn, College Pk, MD 20742 USA. EM jhahn12@umd.edu FU Office of Naval Research (ONR) [N000141410591, N000141512018] FX This material is based on work supported by the Office of Naval Research (ONR) under Grant No. N000141410591 and N000141512018. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the ONR. NR 35 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD AUG 31 PY 2016 VL 7 AR 390 DI 10.3389/fphys.2016.00390 PG 11 WC Physiology SC Physiology GA DU6DX UT WOS:000382305200002 PM 27642283 ER PT J AU Kuffer, AL O'Donovan, A Burri, A Maercker, A AF Kuffer, Andreas Lorenz O'Donovan, Aoife Burri, Andrea Maercker, Andreas TI Posttraumatic Stress Disorder, Adverse Childhood Events, and Buccal Cell Telomere Length in Elderly Swiss Former Indentured Child Laborers SO FRONTIERS IN PSYCHIATRY LA English DT Article DE PTSD; adverse childhood events; old adults; buccal cell telomere length; qPCR; Swiss indentured child laborers ID TRAUMA QUESTIONNAIRE; GERIATRIC DEPRESSION; GERMAN VERSION; RELIABILITY; VALIDITY; MORTALITY; SYNCHRONY; VETERANS; DISEASE; HEALTH AB Posttraumatic stress disorder (PTSD) is associated with increased risk for age-related diseases and early mortality. Accelerated biological aging could contribute to this elevated risk. The aim of the present study was to assess buccal cell telomere length (BTL) - a proposed marker of biological age - in men and women with and without PTSD. The role of childhood trauma was assessed as a potential additional risk factor for shorter telomere length. The sample included 62 former indentured Swiss child laborers (age: M = 76.19, SD = 6.18) and 58 healthy controls (age: M = 71.85, SD = 5.97). Structured clinical interviews were conducted to screen for PTSD and other psychiatric disorders. The Childhood Trauma Questionnaire (CTQ) was used to assess childhood trauma exposure. Quantitative polymerase chain reaction was used to measure BTL. Covariates include age, sex, years of education, self-evaluated financial situation, depression, and mental and physical functioning. Forty-eight (77.42%) of the former indentured child laborers screened positive for childhood trauma, and 21 (33.87%) had partial or full-blown PTSD. Results did not support our hypotheses that PTSD and childhood trauma would be associated with shorter BTL. In fact, results revealed a trend toward longer BTL in participants with partial or full PTSD [F(2,109) = 3.27, p = 0.04, eta(2) = 0.06], and longer BTL was marginally associated with higher CTQ scores (age adjusted: beta = 0.17 [95% CI: - 0.01 to 0.35], t = 1.90, p = 0.06). Furthermore, within- group analyses indicated no significant association between BTL and CTQ scores. To the best of our knowledge, this is the first study exploring the association between childhood trauma and BTL in older individuals with and without PTSD. Contrary to predictions, there were no significant differences in BTL between participants with and without PTSD in our adjusted analyses, and childhood adversity was not associated with BTL. Possible explanations and future research possibilities are discussed. C1 [Kuffer, Andreas Lorenz; Maercker, Andreas] Univ Zurich, Dept Psychol, Div Psychopathol & Clin Intervent, Zurich, Switzerland. [Kuffer, Andreas Lorenz; Maercker, Andreas] Univ Zurich, Univ Res Prior Program Dynam Hlth Aging, Zurich, Switzerland. [Kuffer, Andreas Lorenz; O'Donovan, Aoife] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Kuffer, Andreas Lorenz; O'Donovan, Aoife] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Burri, Andrea] Auckland Univ Technol, Hlth & Rehabil Res Inst, Auckland, New Zealand. [Burri, Andrea] North Shore Hosp, Dept Anaesthesia & Perioperat Med, Waitemata Pain Serv, Auckland, New Zealand. RP Kuffer, AL (reprint author), Univ Zurich, Dept Psychol, Div Psychopathol & Clin Intervent, Zurich, Switzerland.; Kuffer, AL (reprint author), Univ Zurich, Univ Res Prior Program Dynam Hlth Aging, Zurich, Switzerland.; Kuffer, AL (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA.; Kuffer, AL (reprint author), San Francisco VA Med Ctr, San Francisco, CA 94121 USA. EM andreas.kueffer@ucsf.edu FU NCATS NIH HHS [KL2 TR000143]; NIMH NIH HHS [K01 MH109871] NR 52 TC 0 Z9 0 U1 7 U2 7 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 AUG 31 PY 2016 VL 7 AR 147 DI 10.3389/fpsyt.2016.00147 PG 9 WC Psychiatry SC Psychiatry GA DU5YW UT WOS:000382290600001 PM 27630582 ER PT J AU Du, PC Sohaskey, CD Shi, LB AF Du, Peicheng Sohaskey, Charles D. Shi, Lanbo TI Transcriptional and Physiological Changes during Mycobacterium tuberculosis Reactivation from Non-replicating Persistence SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE tuberculosis; gene expression profiling; RNA-Seq; reactivation; lag phase; metabolism and physiology; transcription regulon/subnetwork ID SIGNAL-TRANSDUCTION SYSTEM; ALTERNATIVE SIGMA-FACTOR; GLOBAL GENE-EXPRESSION; IRON ACQUISITION; IN-VITRO; LATENT TUBERCULOSIS; CRYSTAL-STRUCTURE; HYPOXIC RESPONSE; NITRIC-OXIDE; DNA-REPAIR AB Mycobacterium tuberculosis can persist for years in the hostile environment of the host in a non-replicating or slowly replicating state. While active disease predominantly results from reactivation of a latent infection, the molecular mechanisms of M. tuberculosis reactivation are still poorly understood. We characterized the physiology and global transcriptomic profiles of M. tuberculosis during reactivation from hypoxia-induced non-replicating persistence. We found that M. tuberculosis reactivation upon reaeration was associated with a lag phase, in which the recovery of cellular physiological and metabolic functions preceded the resumption of cell replication. Enrichment analysis of the transcriptomic dynamics revealed changes to many metabolic pathways and transcription regulons/subnetworks that orchestrated the metabolic and physiological transformation in preparation for cell division. In particular, we found that M. tuberculosis reaeration lag phase is associated with down-regulation of persistence-associated regulons/subnetworks, including DosR, MprA, SigH, SigE, and CIgR, as well as metabolic pathways including those involved in the uptake of lipids and their catabolism. More importantly, we identified a number of up-regulated transcription regulons and metabolic pathways, including those involved in metal transport and remobilization, second messenger-mediated responses, DNA repair and recombination, and synthesis of major cell wall components. We also found that inactivation of the major alternative sigma factors SigE or SigH disrupted exit from persistence, underscoring the importance of the global transcriptional reprogramming during M. tuberculosis reactivation. Our observations suggest that M. tuberculosis lag phase is associated with a global gene expression reprogramming that defines the initiation of a reactivation process. C1 [Du, Peicheng] Rutgers State Univ, Off Adv Res Comp, New Brunswick, NJ USA. [Sohaskey, Charles D.] US Dept Vet Affairs, VA Long Beach Healthcare Syst, Long Beach, CA USA. [Shi, Lanbo] Rutgers State Univ, New Jersey Med Sch, Publ Hlth Res Inst, Newark, NJ 08901 USA. RP Shi, LB (reprint author), Rutgers State Univ, New Jersey Med Sch, Publ Hlth Res Inst, Newark, NJ 08901 USA. EM shila@njms.rutgers.edu FU National Institutes of Health [AI090328A, AI083855Z] FX We thank Erika Shor for commenting and editing the manuscript and Pratik Datta for critical reading of the manuscript. The work was supported by National Institutes of Health Grants AI090328A and AI083855Z to LS. NR 85 TC 0 Z9 0 U1 7 U2 7 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 AUG 31 PY 2016 VL 7 AR 1346 DI 10.3389/fmicb.2016.01346 PG 15 WC Microbiology SC Microbiology GA DU5QO UT WOS:000382266600001 PM 27630619 ER PT J AU Epel, ES Puterman, E Lin, J Blackburn, EH Lum, PY Beckmann, ND Zhu, J Lee, E Gilbert, A Rissman, RA Tanzi, RE Schadt, EE AF Epel, E. S. Puterman, E. Lin, J. Blackburn, E. H. Lum, P. Y. Beckmann, N. D. Zhu, J. Lee, E. Gilbert, A. Rissman, R. A. Tanzi, R. E. Schadt, E. E. TI Meditation and vacation effects have an impact on disease-associated molecular phenotypes SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID INFLAMMATORY GENE-EXPRESSION; PLASMA AMYLOID-BETA; LIFE-STYLE CHANGES; ALZHEIMERS-DISEASE; TELOMERASE ACTIVITY; STRESS REDUCTION; OLDER-ADULTS; METAANALYSIS; CANCER; LENGTH AB Meditation is becoming increasingly practiced, especially for stress-related medical conditions. Meditation may improve cellular health; however, studies have not separated out effects of meditation from vacation-like effects in a residential randomized controlled trial. We recruited healthy women non-meditators to live at a resort for 6 days and randomized to either meditation retreat or relaxing on-site, with both groups compared with 'regular meditators' already enrolled in the retreat. Blood drawn at baseline and post intervention was assessed for transcriptome-wide expression patterns and aging-related biomarkers. Highly significant gene expression changes were detected across all groups (the 'vacation effect') that could accurately predict (96% accuracy) between baseline and post-intervention states and were characterized by improved regulation of stress response, immune function and amyloid beta (A beta) metabolism. Although a smaller set of genes was affected, regular meditators showed post-intervention differences in a gene network characterized by lower regulation of protein synthesis and viral genome activity. Changes in well-being were assessed post intervention relative to baseline, as well as 1 and 10 months later. All groups showed equivalently large immediate post-intervention improvements in well-being, but novice meditators showed greater maintenance of lower distress over time compared with those in the vacation arm. Regular meditators showed a trend toward increased telomerase activity compared with randomized women, who showed increased plasma A beta 42/A beta 40 ratios and tumor necrosis factor alpha (TNF-alpha) levels. This highly controlled residential study showed large salutary changes in gene expression networks due to the vacation effect, common to all groups. For those already trained in the practice of meditation, a retreat appears to provide additional benefits to cellular health beyond the vacation effect. C1 [Epel, E. S.; Puterman, E.; Gilbert, A.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Lin, J.; Blackburn, E. H.] Univ Calif San Francisco, Dept Biochem, San Francisco, CA 94143 USA. [Lin, J.; Blackburn, E. H.] Univ Calif San Francisco, Dept Biophys, San Francisco, CA 94143 USA. [Lum, P. Y.] Capella Biosci Inc, Palo Alto, CA USA. [Beckmann, N. D.; Zhu, J.; Lee, E.; Schadt, E. E.] Mt Sinai Sch Med, Inst Genom & Multiscale Biol, New York, NY USA. [Rissman, R. A.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Tanzi, R. E.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Genet & Aging Res Unit, Charlestown, MA USA. RP Schadt, EE (reprint author), Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA. EM Eric.Schadt@mssm.edu FU NHGRI NIH HHS [U01 HG008451] NR 49 TC 2 Z9 2 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD AUG 30 PY 2016 VL 6 AR e880 DI 10.1038/tp.2016.164 PG 8 WC Psychiatry SC Psychiatry GA DW1SR UT WOS:000383423400006 PM 27576169 ER PT J AU Kantarci, K Tosakulwong, N Lesnick, TG Zuk, SM Gunter, JL Gleason, CE Wharton, W Dowling, NM Vemuri, P Senjem, ML Shuster, LT Bailey, KR Rocca, WA Jack, CR Asthana, S Miller, VM AF Kantarci, Kejal Tosakulwong, Nirubol Lesnick, Timothy G. Zuk, Samantha M. Gunter, Jeffrey L. Gleason, Carey E. Wharton, Whitney Dowling, N. Maritza Vemuri, Prashanthi Senjem, Matthew L. Shuster, Lynne T. Bailey, Kent R. Rocca, Walter A. Jack, Clifford R., Jr. Asthana, Sanjay Miller, Virginia M. TI Effects of hormone therapy on brain structure A randomized controlled trial SO NEUROLOGY LA English DT Article ID WHITE-MATTER HYPERINTENSITIES; ESTROGEN REPLACEMENT THERAPY; CONJUGATED EQUINE ESTROGENS; POSTMENOPAUSAL WOMEN; ALZHEIMER-DISEASE; MENOPAUSAL WOMEN; MENSTRUAL-CYCLE; OLDER WOMEN; WHIMS-MRI; VOLUMES AB Objective: To investigate the effects of hormone therapy on brain structure in a randomized, double-blinded, placebo-controlled trial in recently postmenopausal women. Methods: Participants (aged 42-56 years, within 5-36 months past menopause) in the Kronos Early Estrogen Prevention Study were randomized to (1) 0.45 mg/d oral conjugated equine estrogens (CEE), (2) 50 mu g/d transdermal 17 beta-estradiol, or (3) placebo pills and patch for 48 months. Oral progesterone (200 mg/d) was given to active treatment groups for 12 days each month. MRI and cognitive testing were performed in a subset of participants at baseline, and at 18, 36, and 48 months of randomization (n = 95). Changes in whole brain, ventricular, and white matter hyperintensity volumes, and in global cognitive function, were measured. Results: Higher rates of ventricular expansion were observed in both the CEE and the 17b-estradiol groups compared to placebo; however, the difference was significant only in the CEE group (p = 0.01). Rates of ventricular expansion correlated with rates of decrease in brain volume (r = -0.58; p <= 0.001) and with rates of increase in white matter hyperintensity volume (r = 0.27; p = 0.01) after adjusting for age. The changes were not different between the CEE and 17 beta-estradiol groups for any of the MRI measures. The change in global cognitive function was not different across the groups. Conclusions: Ventricular volumes increased to a greater extent in recently menopausal women who received CEE compared to placebo but without changes in cognitive performance. Because the sample size was small and the follow-up limited to 4 years, the findings should be interpreted with caution and need confirmation. Classification of evidence: This study provides Class I evidence that brain ventricular volume increased to a greater extent in recently menopausal women who received oral CEE compared to placebo. C1 [Kantarci, Kejal; Zuk, Samantha M.; Gunter, Jeffrey L.; Vemuri, Prashanthi; Senjem, Matthew L.; Jack, Clifford R., Jr.] Mayo Clin, Dept Radiol, Rochester, MN USA. [Tosakulwong, Nirubol; Lesnick, Timothy G.; Bailey, Kent R.; Rocca, Walter A.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Shuster, Lynne T.] Mayo Clin, Dept Internal Med, Rochester, MN USA. [Rocca, Walter A.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Miller, Virginia M.] Mayo Clin, Dept Surg & Physiol & Biomed Engn, Rochester, MN USA. [Gleason, Carey E.; Asthana, Sanjay] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI USA. [Wharton, Whitney] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Dowling, N. Maritza] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI USA. RP Kantarci, K (reprint author), Mayo Clin, Dept Radiol, Rochester, MN USA. EM kantarci.kejal@mayo.edu FU Aurora Foundation [NS66147, AG029624, AG44170] FX This study is funded by the Aurora Foundation to the Kronos Longevity Research Institute and the NIH (NS66147, AG029624, and AG44170). The funding sources had no role in study design, collection, analysis, interpretation, or decision to submit this paper. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. NR 38 TC 4 Z9 4 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 AUG 30 PY 2016 VL 87 IS 9 BP 887 EP 896 DI 10.1212/WNL.0000000000002970 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA DW9LJ UT WOS:000383980600013 PM 27473135 ER PT J AU Chhatwal, JP Schultz, AP Marshall, GA Boot, B Gomez-Isla, T Dumurgier, J LaPoint, M Scherzer, C Roe, AD Hyman, BT Sperling, RA Johnson, KA AF Chhatwal, Jasmeer P. Schultz, Aaron P. Marshall, Gad A. Boot, Brendon Gomez-Isla, Teresa Dumurgier, Julien LaPoint, Molly Scherzer, Clemens Roe, Allyson D. Hyman, Bradley T. Sperling, Reisa A. Johnson, Keith A. TI Temporal T807 binding correlates with CSF tau and phospho-tau in normal elderly SO NEUROLOGY LA English DT Article ID ALZHEIMERS-DISEASE; PATHOLOGY; MARKERS; DECLINE AB Objective: To better understand cross-sectional relationships between CSF and PET measures of tau pathology, we compared regional and global measures of F-18-T807 (AV-1451) PET to CSF protein levels of total tau (t-tau), phosphorylated tau (p-tau), and beta-amyloid 1-42 (A beta 42). Methods: T-tau, p-tau, and A beta 42 levels were assessed using INNOTEST xMAP immunoassays. Linear regression was used to compare regional and global measures of F-18-T807 standardized uptake value ratios (SUVR) to CSF protein levels using data from 31 cognitively unimpaired elderly participants in the Harvard Aging Brain study. Results: After controlling for sex and age, total cortical F-18-T807 binding was significantly correlated with p-tau (partial r = 0.48; p < 0.01) and at trend level with t-tau (partial r = 0.30; p = 0.12). Regional F-18-T807 measures were more strongly correlated with CSF protein levels than the global measure, with both t-tau and p-tau significantly correlated with F-18-T807 SUVR in entorhinal, parahippocampal, and inferior temporal cortical regions (partial r = 0.53-0.73). Peak correlations between CSF and PET measures of tau were similar to those between CSF and PET measures of amyloid burden. Finally, we observed significantly higher temporal T807 SUVR in individuals with high amyloid burden. Conclusions: These data support the link between F-18-T807 PET and CSF measures of tau pathology. In these cognitively normal individuals with F-18-T807 binding largely restricted to the temporal lobe, F-18-T807 SUVR in temporal regions appeared more reflective of CSF t-tau and p-tau than a total cortical measure. C1 [Chhatwal, Jasmeer P.; Schultz, Aaron P.; Marshall, Gad A.; Boot, Brendon; Gomez-Isla, Teresa; Scherzer, Clemens; Hyman, Bradley T.; Sperling, Reisa A.; Johnson, Keith A.] Harvard Med Sch, Boston, MA 02115 USA. [Chhatwal, Jasmeer P.; Schultz, Aaron P.; Marshall, Gad A.; Boot, Brendon; Gomez-Isla, Teresa; Dumurgier, Julien; LaPoint, Molly; Roe, Allyson D.; Hyman, Bradley T.; Sperling, Reisa A.; Johnson, Keith A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chhatwal, Jasmeer P.; Schultz, Aaron P.; LaPoint, Molly; Sperling, Reisa A.; Johnson, Keith A.] Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Marshall, Gad A.; Boot, Brendon; Scherzer, Clemens; Sperling, Reisa A.; Johnson, Keith A.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Boot, Brendon] Biogen, Cambridge, MA USA. [Dumurgier, Julien] Univ Paris 07, Lariboisiere Hosp, APHP, Memory Ctr, Paris, France. [Scherzer, Clemens] Harvard NeuroDiscovery Ctr, Boston, MA USA. RP Johnson, KA (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM kajohnson@pet.mgh.harvard.edu FU National Institute on Aging [P01 AG36694, R01 AG046396]; Massachusetts Alzheimer's Disease Research Center [P50 AG005134]; Harvard NeuroDiscovery Center Biomarker Study; Parkinson's Disease Biomarkers Program [NINDS U01 NS082157]; Harvard Clinical and Translational Science Center [8UL1 TR000170-05, 1UL1 TR001102-02]; National Center for Advancing Translational Science; BrightFocus Foundation; American Brain Foundation/American Academy of Neurology; NIA [K23 AG049087]; NIH [U01 NS082157]; US Department of Defense; M.E.M.O. Hoffman Foundation FX Data collection for this project was supported by the National Institute on Aging via P01 AG36694 (HAB; Sperling/Johnson PIs), R01 AG046396 (Johnson PI), and the Massachusetts Alzheimer's Disease Research Center (P50 AG005134). Additional support for this project was provided by the Harvard NeuroDiscovery Center Biomarker Study, supported in part by the Parkinson's Disease Biomarkers Program (NINDS U01 NS082157) and Rick and Nancy Moskovitz. The Partners Clinical Research Center provided additional support to this project through grant numbers 8UL1 TR000170-05 and 1UL1 TR001102-02, Harvard Clinical and Translational Science Center, from the National Center for Advancing Translational Science. Fellowship support for J.P.C. was provided by the BrightFocus Foundation, the American Brain Foundation/American Academy of Neurology, and the NIA (K23 AG049087). C.R.S.' work was supported in part by NIH grant U01 NS082157, the US Department of Defense, and the M.E.M.O. Hoffman Foundation. NR 24 TC 6 Z9 6 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 AUG 30 PY 2016 VL 87 IS 9 BP 920 EP 926 DI 10.1212/WNL.0000000000003050 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DW9LJ UT WOS:000383980600018 PM 27473132 ER PT J AU Haider, HA Esteller, R Hahn, CD Westover, MB Halford, JJ Lee, JW Shafi, MM Gaspard, N Herman, ST Gerard, EE Hirsch, LJ Ehrenberg, JA LaRoche, SM AF Haider, Hiba A. Esteller, Rosana Hahn, Cecil D. Westover, M. Brandon Halford, Jonathan J. Lee, Jong W. Shafi, Mouhsin M. Gaspard, Nicolas Herman, Susan T. Gerard, Elizabeth E. Hirsch, Lawrence J. Ehrenberg, Joshua A. LaRoche, Suzette M. CA Critical Care EEG Monitoring Res TI Sensitivity of quantitative EEG for seizure identification in the intensive care unit SO NEUROLOGY LA English DT Article ID AMPLITUDE-INTEGRATED ELECTROENCEPHALOGRAPHY; NONCONVULSIVE STATUS EPILEPTICUS; CEREBRAL FUNCTION MONITOR; CRITICALLY-ILL CHILDREN; DENSITY SPECTRAL ARRAY; TRAUMATIC BRAIN-INJURY; ELECTROGRAPHIC SEIZURES; TERMINOLOGY; CRITERIA; ADULTS AB Objective: To evaluate the sensitivity of quantitative EEG (QEEG) for electrographic seizure identification in the intensive care unit (ICU). Methods: Six-hour EEG epochs chosen from 15 patients underwent transformation into QEEG displays. Each epoch was reviewed in 3 formats: raw EEG, QEEG + raw, and QEEG-only. Epochs were also analyzed by a proprietary seizure detection algorithm. Nine neurophysiologists reviewed raw EEGs to identify seizures to serve as the gold standard. Nine other neurophysiologists with experience in QEEG evaluated the epochs in QEEG formats, with and without concomitant raw EEG. Sensitivity and false-positive rates (FPRs) for seizure identification were calculated and median review time assessed. Results: Mean sensitivity for seizure identification ranged from 51% to 67% for QEEG-only and 63%-68% for QEEG + raw. FPRs averaged 1/h for QEEG-only and 0.5/h for QEEG + raw. Mean sensitivity of seizure probability software was 26.2%-26.7%, with FPR of 0.07/h. Epochs with the highest sensitivities contained frequent, intermittent seizures. Lower sensitivities were seen with slow-frequency, low-amplitude seizures and epochs with rhythmic or periodic patterns. Median review times were shorter for QEEG (6 minutes) and QEEG + raw analysis (14.5 minutes) vs raw EEG (19 minutes; p = 0.00003). Conclusions: A panel of QEEG trends can be used by experts to shorten EEG review time for seizure identification with reasonable sensitivity and low FPRs. The prevalence of false detections confirms that raw EEG review must be used in conjunction with QEEG. Studies are needed to identify optimal QEEG trend configurations and the utility of QEEG as a screening tool for non-EEG personnel. Classification of evidence review: This study provides Class II evidence that QEEG + raw interpreted by experts identifies seizures in patients in the ICU with a sensitivity of 63%-68% and FPR of 0.5 seizures per hour. C1 [Haider, Hiba A.; Ehrenberg, Joshua A.; LaRoche, Suzette M.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Esteller, Rosana] Neuropace Inc, Mountain View, CA USA. [Hahn, Cecil D.] Hosp Sick Children, Div Neurol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. Univ Toronto, Dept Paediat, Toronto, ON M5S 1A1, Canada. [Westover, M. Brandon] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Halford, Jonathan J.] Med Univ South Carolina, Dept Neurol, Charleston, SC USA. [Lee, Jong W.; Shafi, Mouhsin M.; Herman, Susan T.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Gaspard, Nicolas] Univ Libre Bruxelles, Brussels, Belgium. [Gerard, Elizabeth E.] Northwestern Univ, Dept Neurol, Feinberg Sch Med, Chicago, IL 60611 USA. [Hirsch, Lawrence J.] Yale Univ Hosp, New Haven, CT USA. RP Haider, HA (reprint author), Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. EM hiba.arif@emory.edu RI Hahn, Cecil/J-3372-2016 OI Hahn, Cecil/0000-0002-0887-8761 FU NINDS R25 Research Education Training Grant FX H. Haider: Supported by an NINDS R25 Research Education Training Grant. R. Esteller, C. Hahn, M. Westover, J. Halford, J. Lee, M. Shafi, N. Gaspard, S. Herman, E. Gerard, L. Hirsch, J. Ehrenberg, and S. LaRoche report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures. NR 33 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 30 PY 2016 VL 87 IS 9 BP 935 EP 944 DI 10.1212/WNL.0000000000003034 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA DW9LJ UT WOS:000383980600020 PM 27466474 ER PT J AU Bar-Or, A Hintzen, RQ Dale, RC Rostasy, K Bruck, W Chitnis, T AF Bar-Or, Amit Hintzen, Rogier Q. Dale, Russell C. Rostasy, Kevin Bruck, Wolfgang Chitnis, Tanuja TI Immunopathophysiology of pediatric CNS inflammatory demyelinating diseases SO NEUROLOGY LA English DT Article ID MYELIN OLIGODENDROCYTE GLYCOPROTEIN; ACUTE DISSEMINATED ENCEPHALOMYELITIS; MULTIPLE-SCLEROSIS LESIONS; ACUTE AXONAL DAMAGE; NEUROMYELITIS-OPTICA; POTASSIUM CHANNEL; OLIGOCLONAL BANDS; ANTIBODIES; CHILDREN; MS AB Elucidating pathophysiologic mechanisms underlying the spectrum of pediatric-onset CNS demyelinating diseases, particularly those that may distinguish multiple sclerosis (MS) from other entities, promises to both improve diagnostics and guide more-informed therapeutic decisions. Observations that pediatric-and adult-onset MS share the same genetic and environmental risk factors support the view that these conditions represent essentially the same illness manifesting at different ages. Nonetheless, special consideration must be given when CNS inflammation manifests in early life, at a time when multiple organs (including immune and nervous systems) are actively maturing. CSF analysis in pediatric-onset MS points to chronic CNS inflammation, supported by observations from limited pathologic material available for study. Emerging results implicate abnormalities in both effector and regulatory T cell subsets, and potentially immune senescence, in children with MS. Although CNS-directed antibodies (including antibodies recognizing myelin antigens; Kir4.1) can be documented in pediatric-onset MS, their pathophysiologic significance (as in adults) remains unclear. This is in contrast to the presence of serum and/or CSF antibodies recognizing aquaporin-4, which, when measured using validated cell-based assays, supports the diagnosis of a neuromyelitis optica spectrumdisorder, distinct from MS. Presence of anti-myelin oligodendrocyte glycoprotein antibodies documented with similar cell-based assays may also be associated with pathophysiologically distinct disease phenotypes in children. The substantial impact of pediatriconset MS on normal brain development and function underscores the importance of elucidating both the immunobiology and neurobiology of disease. Ongoing efforts are aimed at developing and validating biological measures that define pathophysiologically distinct monophasic and chronic forms of pediatric CNS demyelination. C1 [Bar-Or, Amit] McGill Univ, Montreal Neurol Inst, Neuroimmunol Unit, Montreal, PQ, Canada. [Bar-Or, Amit] McGill Univ, Montreal Neurol Inst, Expt Therapeut Program, Montreal, PQ, Canada. [Hintzen, Rogier Q.] Erasmus MC, MS Ctr ErasMS, Dept Neurol, Neurol, Rotterdam, Netherlands. [Dale, Russell C.] Univ Sydney, Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Neuroimmunol Grp, Sydney, NSW 2006, Australia. [Rostasy, Kevin] Univ Witten Herdecke, Childrens Hosp Datteln, Dept Pediat Neurol, Datteln, Germany. [Bruck, Wolfgang] Univ Gottingen, Univ Med Ctr Gottingen, Dept Neuropathol, Gottingen, Germany. [Chitnis, Tanuja] Harvard Med Sch, Massachusetts Gen Hosp, Partners Pediat MS Ctr, Boston, MA USA. RP Bar-Or, A (reprint author), McGill Univ, Montreal Neurol Inst, Neuroimmunol Unit, Montreal, PQ, Canada.; Bar-Or, A (reprint author), McGill Univ, Montreal Neurol Inst, Expt Therapeut Program, Montreal, PQ, Canada. EM amit.bar-or@mcgill.ca FU MS Cure Fund; Danish MS Society; German MS Society; Italian MS Association; MS International Federation; MS Research Foundation (Netherlands); National MS Society (USA); Swiss MS Society FX This supplement is made possible by funding from the MS Cure Fund, Danish MS Society, German MS Society, Italian MS Association, MS International Federation, MS Research Foundation (Netherlands), National MS Society (USA) and Swiss MS Society. NR 55 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 30 PY 2016 VL 87 IS 9 SU 1 BP S12 EP S19 DI 10.1212/WNL.0000000000002821 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DW9LQ UT WOS:000383981500004 PM 27572856 ER PT J AU Chitnis, T Pohl, D AF Chitnis, Tanuja Pohl, Daniela CA Int Pediat MS Study Grp IPMSSG TI Pediatric demyelinating disorders Global updates, controversies, and future directions INTRODUCTION SO NEUROLOGY LA English DT Editorial Material C1 [Chitnis, Tanuja] Harvard Med Sch, Massachusetts Gen Hosp, Partners Pediat MS Ctr, Boston, MA 02115 USA. [Pohl, Daniela] Univ Ottawa, Childrens Hosp Eastern Ontario, Div Neurol, Ottawa, ON K1N 6N5, Canada. RP Chitnis, T (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Partners Pediat MS Ctr, Boston, MA 02115 USA. EM tchitnis@partners.org 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 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 30 PY 2016 VL 87 IS 9 SU 1 BP S1 EP S3 DI 10.1212/WNL.0000000000002882 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA DW9LQ UT WOS:000383981500001 ER PT J AU Chitnis, T Ghezzi, A Bajer-Kornek, B Boyko, A Giovannoni, G Pohl, D AF Chitnis, Tanuja Ghezzi, Angelo Bajer-Kornek, Barbara Boyko, Alexey Giovannoni, Gavin Pohl, Daniela TI Pediatric multiple sclerosis Escalation and emerging treatments SO NEUROLOGY LA English DT Article ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; DISEASE-ACTIVITY; NATALIZUMAB THERAPY; NO EVIDENCE; MITOXANTRONE; ONSET; MS; PATIENT; SAFETY; RISK AB Over the last 20 years, there have been significant advances in multiple sclerosis (MS) therapeutics, with regulatory approval for 13 therapies in adults by the European Medicines Agency (EMA) and Food and Drug Administration. However, there is only limited approval for interferon-beta and glatiramer acetate use in children 12 years and older by the EMA. Availability of disease-modifying therapies to children and adolescents with MS is variable by region, and is extremely limited in some regions of the world. Up to 30% of children experience breakthrough disease requiring therapies beyond traditional first-line agents. Recent legislation in both the United States and Europe has mandated clinical studies for all new therapeutics applicable to children. Several clinical trials in children are underway that will provide important information regarding the efficacy and safety of newer drugs. This review summarizes the current knowledge of breakthrough disease, escalation, and induction treatment approaches in children with MS, especially pertaining to disease course and disability outcomes in this group of patients. In addition, ongoing clinical trials and approaches and challenges in conducting clinical trials in the pediatric population are discussed. C1 [Chitnis, Tanuja] Harvard Med Sch, Massachusetts Gen Hosp, Partners Pediat MS Ctr, Boston, MA 02115 USA. [Ghezzi, Angelo] Osped Gallarate, Ctr Studi Sclerosi Multipla, Div Neurol 2, Gallarate, Italy. [Bajer-Kornek, Barbara] Med Univ Vienna, Dept Neurol, Vienna, Austria. [Boyko, Alexey] Pirogovs Russian Natl Res Med Univ, Dept Neurol Neurosurg & Med Genet, Moscow, Russia. [Giovannoni, Gavin] Barts & London Queen Marys Sch Med & Dent, London, England. [Pohl, Daniela] Univ Ottawa, Childrens Hosp Eastern Ontario, Dept Neurol, Ottawa, ON K1N 6N5, Canada. RP Chitnis, T (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Partners Pediat MS Ctr, Boston, MA 02115 USA. EM tchitnis@partners.org FU MS Cure Fund; Danish MS Society; German MS Society; Italian MS Association; MS International Federation; MS Research Foundation (Netherlands); National MS Society (USA); Swiss MS Society FX This supplement is made possible by funding from the MS Cure Fund, Danish MS Society, German MS Society, Italian MS Association, MS International Federation, MS Research Foundation (Netherlands), National MS Society (USA) and Swiss MS Society. 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 AUG 30 PY 2016 VL 87 IS 9 SU 1 BP S103 EP S109 DI 10.1212/WNL.0000000000002884 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DW9LQ UT WOS:000383981500016 PM 27572854 ER PT J AU Krupp, LB Rintell, D Charvet, LE Milazzo, M Wassmer, E AF Krupp, Lauren B. Rintell, David Charvet, Leigh E. Milazzo, Maria Wassmer, Evangeline TI Pediatric multiple sclerosis Perspectives from adolescents and their families SO NEUROLOGY LA English DT Article ID HEALTH-CARE; CHRONIC ILLNESS; ABILITY; PARENTS AB Supporting young people with pediatric multiple sclerosis can be challenging for families and health care providers. Adolescents may be more resilient than adults in reaction to the diagnosis but can have more difficulty planning for their futures. Appropriate, sensitive, and focused health provision should include consideration of the perspective of both the patient and parents. Multidisciplinary management strategies are often effective, as are referrals to programs that enhance individual and family coping and strengthen a sense of community. C1 [Krupp, Lauren B.; Charvet, Leigh E.] NYU Langone, Pediat MS Ctr, New York, NY 10016 USA. [Rintell, David] Massachusetts Gen Hosp, Partners Pediat MS Ctr, Boston, MA 02114 USA. [Milazzo, Maria] Stony Brook Childrens Hosp, Dept Nursing, Stony Brook, NY USA. [Wassmer, Evangeline] Birmingham Childrens Hosp, Birmingham, W Midlands, England. RP Krupp, LB (reprint author), NYU Langone, Pediat MS Ctr, New York, NY 10016 USA. EM lauren.krupp@nyumc.org OI Charvet, Leigh/0000-0003-4429-9713 FU MS Cure Fund; Danish MS Society; German MS Society; Italian MS Association; MS International Federation; MS Research Foundation (Netherlands); National MS Society (USA); Swiss MS Society FX This supplement is made possible by funding from the MS Cure Fund, Danish MS Society, German MS Society, Italian MS Association, MS International Federation, MS Research Foundation (Netherlands), National MS Society (USA) and Swiss MS Society. 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 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 30 PY 2016 VL 87 IS 9 SU 1 BP S4 EP S7 DI 10.1212/WNL.0000000000002879 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA DW9LQ UT WOS:000383981500002 PM 27572860 ER PT J AU Tenembaum, S Chitnis, T Nakashima, I Collongues, N McKeon, A Levy, M Rostasy, K AF Tenembaum, Silvia Chitnis, Tanuja Nakashima, Ichiro Collongues, Nicolas McKeon, Andrew Levy, Michael Rostasy, Kevin TI Neuromyelitis optica spectrum disorders in children and adolescents SO NEUROLOGY LA English DT Article ID OLIGODENDROCYTE GLYCOPROTEIN ANTIBODIES; MULTIPLE-SCLEROSIS; AQUAPORIN-4 AUTOIMMUNITY; DIAGNOSTIC-CRITERIA; PEDIATRIC-PATIENTS; CLINICAL-FEATURES; CHILDHOOD; BRAIN; NMO; AUTOANTIBODIES AB Neuromyelitis optica (NMO) is a severe autoimmune disease of the CNS characterized by recurrent inflammatory events primarily involving the optic nerves and spinal cord. NMO is infrequent in children, but early recognition is important to start adequate treatment. In this article, we review the evolving diagnostic criteria of NMO and provide an update on the clinical and neuroimaging spectrum of the disorder in pediatric patients, including current knowledge on immunopathogenesis and treatment recommendations for children with NMO. C1 [Tenembaum, Silvia] Natl Pediat Hosp Dr Juan P Garrahan, Dept Pediat Neurol, Buenos Aires, DF, Argentina. [Chitnis, Tanuja] Harvard Med Sch, Massachusetts Gen Hosp, Partners Pediat MS Ctr, Boston, MA USA. [Nakashima, Ichiro] Tohoku Univ, Sch Med, Dept Neurol, Sendai, Miyagi, Japan. [Collongues, Nicolas] Univ Hosp Strasbourg, Ctr Clin Invest, INSERM, Dept Neurol, Strasbourg, France. [McKeon, Andrew] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [McKeon, Andrew] Mayo Clin, Dept Neurol, Rochester, MN USA. [Levy, Michael] Johns Hopkins Univ, Dept Neurol, Neuromyelitis Opt Clin, Baltimore, MD 21218 USA. [Rostasy, Kevin] Univ Witten Herdecke, Childrens Hosp Datteln, Dept Pediat Neurol, Witten, Germany. RP Tenembaum, S (reprint author), Natl Pediat Hosp Dr Juan P Garrahan, Dept Pediat Neurol, Buenos Aires, DF, Argentina. EM silviatenembaum@gmail.com RI collongues, nicolas/J-9830-2016 OI collongues, nicolas/0000-0002-3683-5582 FU MS Cure Fund; Danish MS Society; German MS Society; Italian MS Association; MS International Federation; MS Research Foundation (Netherlands); National MS Society (USA); Swiss MS Society FX This supplement is made possible by funding from the MS Cure Fund, Danish MS Society, German MS Society, Italian MS Association, MS International Federation, MS Research Foundation (Netherlands), National MS Society (USA) and Swiss MS Society. NR 40 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 AUG 30 PY 2016 VL 87 IS 9 SU 1 BP S59 EP S66 DI 10.1212/WNL.0000000000002824 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DW9LQ UT WOS:000383981500010 PM 27572863 ER PT J AU Wassmer, E Chitnis, T Pohl, D Amato, MP Banwell, B Ghezzi, A Hintzen, RQ Krupp, LB Makhani, N Rostasy, K Tardieu, M Tenembaum, S Waldman, A Waubant, E Kornberg, AJ AF Wassmer, Evangeline Chitnis, Tanuja Pohl, Daniela Amato, Maria Pia Banwell, Brenda Ghezzi, Angelo Hintzen, Rogier Q. Krupp, Lauren B. Makhani, Naila Rostasy, Kevin Tardieu, Marc Tenembaum, Silvia Waldman, Amy Waubant, Emmanuelle Kornberg, Andrew J. TI International Pediatric MS Study Group Global Members Symposium report SO NEUROLOGY LA English DT Article ID ONSET MULTIPLE-SCLEROSIS; CENTRAL-NERVOUS-SYSTEM; VITAMIN-D LEVELS; COGNITIVE IMPAIRMENT; PSYCHOSOCIAL FEATURES; 25-HYDROXYVITAMIN D; RELAPSE RISK; JUVENILE MS; CHILDREN; CHILDHOOD AB The International Pediatric Multiple Sclerosis Study Group held its inaugural educational program, "The World of Pediatric MS: A Global Update," in September 2014 to discuss advances and challenges in the diagnosis and management of pediatric multiple sclerosis (MS) and other neuroinflammatory CNS disorders. Highlights included a discussion on the revised diagnostic criteria, which enable the differentiation of MS, acute disseminated encephalomyelitis, neuromyelitis optica, and other neuroinflammatory disorders. While these criteria currently identify clinical and MRI features for a particular diagnosis, advances in biomarkers may prove to be useful in the future. An update was also provided on environmental factors associated with pediatric MS risk and possibly outcomes, notably vitamin D deficiency. However, optimal vitamin D intake and its role in altering MS course in children have yet to be established. Regarding MS outcomes, our understanding of the cognitive consequences of early-onset MS has grown. However, further work is needed to define the course of cognitive function and its long-term outcome in diverse patient samples and to develop strategies for effective cognitive rehabilitation specifically tailored to children and adolescents. Finally, treatment strategies were discussed, including a need to consider additional drug treatment options and paradigms (escalation vs induction), although treatment should be tailored to the individual child. Of critical importance, clinical trials of newer MS agents in children are required. Although our understanding of childhood MS has improved, further research is needed to have a positive impact for children and their families. C1 [Wassmer, Evangeline] Birmingham Childrens Hosp, Dept Neurol, Birmingham, W Midlands, England. [Chitnis, Tanuja] Harvard Med Sch, Massachusetts Gen Hosp, Partners Pediat MS Ctr, Boston, MA USA. [Pohl, Daniela] Univ Ottawa, Childrens Hosp Eastern Ontario, Dept Neurol, Ottawa, ON K1N 6N5, Canada. [Amato, Maria Pia] Univ Florence, Sect Neurosci, Dept NEUROFARBA, I-50121 Florence, Italy. [Waldman, Amy] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Div Neurol, Philadelphia, PA 19104 USA. [Ghezzi, Angelo] Osped Gallarate, Ctr Studi Sclerosi Multipla, Div Neurol 2, Gallarate, Italy. [Hintzen, Rogier Q.] Erasmus MC, MS Ctr ErasMS, Dept Neurol, Rotterdam, Netherlands. [Krupp, Lauren B.] SUNY Stony Brook, Stony Brook Childrens, Lourie Ctr Pediat MS, Stony Brook, NY 11794 USA. [Makhani, Naila] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Makhani, Naila] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. [Rostasy, Kevin] Univ Witten Herdecke, Childrens Hosp Datteln, Dept Pediat Neurol, Witten, Germany. [Tardieu, Marc] Univ Paris 11, Hop Univ Paris Sud, Natl Reference Ctr Inflammatory Dis Brain, Orsay, France. [Tenembaum, Silvia] Natl Pediat Hosp Dr Juan P Garrahan, Dept Neurol, Buenos Aires, DF, Argentina. [Waubant, Emmanuelle] UCSF Benioff Childrens Hosp, Pediat MS Ctr, San Francisco, CA USA. UCSF, Dept Neurol, San Francisco, CA USA. [Kornberg, Andrew J.] Royal Childrens Hosp, Dept Neurol, Parkville, Vic, Australia. RP Wassmer, E (reprint author), Birmingham Childrens Hosp, Dept Neurol, Birmingham, W Midlands, England. EM Evangeline.wassmer@bch.nhs.uk FU MS Cure Fund; Danish MS Society; German MS Society; Italian MS Association; MS International Federation; MS Research Foundation (Netherlands); National MS Society (USA); Swiss MS Society FX This supplement is made possible by funding from the MS Cure Fund, Danish MS Society, German MS Society, Italian MS Association, MS International Federation, MS Research Foundation (Netherlands), National MS Society (USA) and Swiss MS Society. NR 44 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 30 PY 2016 VL 87 IS 9 SU 1 BP S110 EP S116 DI 10.1212/WNL.0000000000002880 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DW9LQ UT WOS:000383981500017 PM 27572855 ER PT J AU Wang, YB Begley, M Li, Q Huang, HT Lako, A Eck, MJ Gray, NS Mitchison, TJ Cantley, LC Zhao, JJ AF Wang, Yubao Begley, Michael Li, Qing Huang, Hai-Tsang Lako, Ana Eck, Michael J. Gray, Nathanael S. Mitchison, Timothy J. Cantley, Lewis C. Zhao, Jean J. TI Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE MELK; eIF4B; MCL1; protein synthesis; mitosis ID INITIATION-FACTOR 4B; SELECTIVE SMALL-MOLECULE; TRANSLATION INITIATION; KINASE; PHOSPHORYLATION; CANCER; INHIBITOR; MITOSIS; PROLIFERATION; SPECIFICITY AB The protein kinase maternal and embryonic leucine zipper kinase (MELK) is critical for mitotic progression of cancer cells; however, its mechanisms of action remain largely unknown. By combined approaches of immunoprecipitation/mass spectrometry and peptide library profiling, we identified the eukaryotic translation initiation factor 4B (eIF4B) as a MELK-interacting protein during mitosis and a bona fide substrate of MELK. MELK phosphorylates eIF4B at Ser406, a modification found to be most robust in the mitotic phase of the cell cycle. We further show that the MEL-KeIF4B signaling axis regulates protein synthesis during mitosis. Specifically, synthesis of myeloid cell leukemia 1 (MCL1), an antiapoptotic protein known to play a role in cancer cell survival during cell division, depends on the function of MELK-elF4B. Inactivation of MELK or eIF4B results in reduced protein synthesis of MCL1, which, in turn, induces apoptotic cell death of cancer cells. Our study thus defines a MELK-eIF4B signaling axis that regulates protein synthesis during mitosis, and consequently influences cancer cell survival. C1 [Wang, Yubao; Li, Qing; Huang, Hai-Tsang; Lako, Ana; Eck, Michael J.; Gray, Nathanael S.; Zhao, Jean J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Wang, Yubao; Li, Qing; Huang, Hai-Tsang; Lako, Ana; Eck, Michael J.; Gray, Nathanael S.; Zhao, Jean J.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Begley, Michael; Cantley, Lewis C.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Begley, Michael; Mitchison, Timothy J.; Cantley, Lewis C.] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA. [Cantley, Lewis C.] Weill Cornell Med Coll, Dept Med, Meyer Canc Ctr, New York, NY 10065 USA. RP Zhao, JJ (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA.; Zhao, JJ (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Cantley, LC (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA.; Cantley, LC (reprint author), Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA.; Cantley, LC (reprint author), Weill Cornell Med Coll, Dept Med, Meyer Canc Ctr, New York, NY 10065 USA. EM cantley@med.cornell.edu; jean_zhao@dfci.harvard.edu FU Breast Cancer Research Foundation; NIH [R01GM039565, R01GM041890, R01CA172461, 1P50CA168504, R35CA210057] FX We thank Dr. Thomas Roberts for scientific discussions. We thank the Harvard Medical School (HMS) LINCS Center for providing kinase inhibitors and the HMS Taplin Biological Mass Spectrometry Facility for mass spectrometry analysis. This work was supported by the Breast Cancer Research Foundation (J.J.Z.) and by NIH Grants R01GM039565 (to T.J.M.), R01GM041890 (to L.C.C.), R01CA172461 (to J.J.Z.), 1P50CA168504 (to J.J.Z.), and R35CA210057 (to J.J.Z.). NR 34 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 AUG 30 PY 2016 VL 113 IS 35 BP 9810 EP 9815 DI 10.1073/pnas.1606862113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV7BL UT WOS:000383090700052 PM 27528663 ER PT J AU McCoy, LE van Gils, MJ Ozorowski, G Messmer, T Briney, B Voss, JE Kulp, DW Macauley, MS Sok, D Pauthner, M Menis, S Cottrell, CA Torres, JL Hsueh, J Schief, WR Wilson, IA Ward, AB Sanders, RW Burton, DR AF McCoy, Laura E. van Gils, Marit J. Ozorowski, Gabriel Messmer, Terrence Briney, Bryan Voss, James E. Kulp, Daniel W. Macauley, Matthew S. Sok, Devin Pauthner, Matthias Menis, Sergey Cottrell, Christopher A. Torres, Jonathan L. Hsueh, Jessica Schief, William R. Wilson, Ian A. Ward, Andrew B. Sanders, Rogier W. Burton, Dennis R. TI Holes in the Glycan Shield of the Native HIV Envelope Are a Target of Trimer-Elicited Neutralizing Antibodies SO CELL REPORTS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; BINDING-SITE; DEPENDENT EPITOPE; HUMORAL IMMUNITY; IMMUNOGEN DESIGN; ENV TRIMERS; RESPONSES; ESCAPE; IMMUNIZATION; VACCINE AB A major advance in the search for an HIV vaccine has been the development of a near-native Envelope trimer (BG505 SOSIP. 664) that can induce robust autologous Tier 2 neutralization. Here, potently neutralizing monoclonal antibodies (nAbs) from rabbits immunized with BG505 SOSIP. 664 are shown to recognize an immunodominant region of gp120 centered on residue 241. Residue 241 occupies a hole in the glycan defenses of the BG505 isolate, with fewer than 3% of global isolates lacking a glycan site at this position. However, at least one conserved glycan site is missing in 89% of viruses, suggesting the presence of glycan holes in most HIV isolates. Serum evidence is consistent with targeting of holes in natural infection. The immunogenic nature of breaches in the glycan shield has been under-appreciated in previous attempts to understand autologous neutralizing antibody responses and has important potential consequences for HIV vaccine design. C1 [McCoy, Laura E.; Messmer, Terrence; Briney, Bryan; Voss, James E.; Kulp, Daniel W.; Sok, Devin; Pauthner, Matthias; Menis, Sergey; Hsueh, Jessica; Schief, William R.; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [McCoy, Laura E.; Ozorowski, Gabriel; Messmer, Terrence; Briney, Bryan; Voss, James E.; Kulp, Daniel W.; Sok, Devin; Pauthner, Matthias; Menis, Sergey; Cottrell, Christopher A.; Torres, Jonathan L.; Hsueh, Jessica; Schief, William R.; Wilson, Ian A.; Ward, Andrew B.; Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [McCoy, Laura E.] UCL, Div Infect & Immun, London WC1E 6BT, England. [van Gils, Marit J.; Sanders, Rogier W.] Univ Amsterdam, Acad Med Ctr, Dept Med Microbiol, NL-1105 AZ Amsterdam, Netherlands. [Ozorowski, Gabriel; Cottrell, Christopher A.; Torres, Jonathan L.; Wilson, Ian A.; Ward, Andrew B.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Macauley, Matthew S.] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA. [Sanders, Rogier W.] Cornell Univ, Weill Med Coll, New York, NY 10065 USA. [Burton, Dennis R.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02139 USA. RP Burton, DR (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA.; Ward, AB; Burton, DR (reprint author), Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA.; Sanders, RW (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Med Microbiol, NL-1105 AZ Amsterdam, Netherlands.; Ward, AB (reprint author), Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA.; Sanders, RW (reprint author), Cornell Univ, Weill Med Coll, New York, NY 10065 USA.; Burton, DR (reprint author), Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02139 USA. EM abward@scripps.edu; r.w.sanders@amc.uva.nl; burton@scripps.edu RI Ward, Andrew/F-9203-2014 OI Ward, Andrew/0000-0001-7153-3769 FU Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery Grant [UM1AI100663]; NIH HIVRAD Grant [P01 AI110657]; International AIDS Vaccine Initiative Neutralizing Antibody Consortium through Collaboration for AIDS Vaccine Discovery [OPP1084519, OPP1115782]; Marie-Curie Fellowship (FP7-PEOPLE-IOF); Aids fonds Netherlands [2012041]; EMBO [ASTF260-2013]; Netherlands Organization for Scientific Research [917.11.314]; European Research Council [ERC-StG-2011-280829-SHEV]; IAVI; USAID; Bill & Melinda Gates Foundation FX This work was supported by Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery Grant UM1AI100663 (to D.R.B., I.A.W., A.B.W., and W.R.S.), NIH HIVRAD Grant P01 AI110657 (to R.W.S., I.A.W., and A.B.W.), and the International AIDS Vaccine Initiative Neutralizing Antibody Consortium through Collaboration for AIDS Vaccine Discovery grants OPP1084519 and OPP1115782. In addition, this study was financially supported by a Marie-Curie Fellowship (FP7-PEOPLE-2013-IOF to L.E.M.). M.J.v.G. received funding from the Aids fonds Netherlands (grant 2012041) and EMBO (grant ASTF260-2013). R.W.S. is a recipient of a Vidi grant from the Netherlands Organization for Scientific Research (917.11.314) and a Starting Investigator Grant from the European Research Council (ERC-StG-2011-280829-SHEV). This work was partially funded by IAVI with the generous support of USAID and the Bill & Melinda Gates Foundation; a full list of IAVI donors is available at http://www.iavi.org/. The contents of this manuscript are the responsibility of the authors and do not necessarily reflect the views of USAID, the U.S. Government, or the other funding bodies. The authors thank James C. Paulson for his support and Christina Corbaci for assistance with figure preparation. NR 54 TC 10 Z9 10 U1 1 U2 5 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 AUG 30 PY 2016 VL 16 IS 9 BP 2327 EP 2338 DI 10.1016/j.celrep.2016.07.074 PG 12 WC Cell Biology SC Cell Biology GA DU6GC UT WOS:000382311300007 PM 27545891 ER PT J AU Hirsch, J Vacas, S Terrando, N Yuan, M Sands, LP Kramer, J Bozic, K Maze, MM Leung, JM AF Hirsch, Jan Vacas, Susana Terrando, Niccolo Yuan, Miao Sands, Laura P. Kramer, Joel Bozic, Kevin Maze, Mervyn M. Leung, Jacqueline M. TI Perioperative cerebrospinal fluid and plasma inflammatory markers after orthopedic surgery SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Blood-brain barrier; Surgery; Delirium; Immune response ID POSTOPERATIVE COGNITIVE DYSFUNCTION; NON-NEUROLOGICAL SURGERY; MARROW-DERIVED MACROPHAGES; TOTAL KNEE ARTHROPLASTY; CENTRAL-NERVOUS-SYSTEM; HIP-FRACTURE; CYTOKINE PRODUCTION; FEMUR FRACTURE; RATING-SCALE; DELIRIUM AB Background: Postoperative delirium is prevalent in older patients and associated with worse outcomes. Recent data in animal studies demonstrate increases in inflammatory markers in plasma and cerebrospinal fluid (CSF) even after aseptic surgery, suggesting that inflammation of the central nervous system may be part of the pathogenesis of postoperative cognitive changes. We investigated the hypothesis that neuroinflammation was an important cause for postoperative delirium and cognitive dysfunction after major non-cardiac surgery. Methods: After Institutional Review Board approval and informed consent, we recruited patients undergoing major knee surgery who received spinal anesthesia and femoral nerve block with intravenous sedation. All patients had an indwelling spinal catheter placed at the time of spinal anesthesia that was left in place for up to 24 h. Plasma and CSF samples were collected preoperatively and at 3, 6, and 18 h postoperatively. Cytokine levels were measured using ELISA and Luminex. Postoperative delirium was determined using the confusion assessment method, and cognitive dysfunction was measured using validated cognitive tests (word list, verbal fluency test, digit symbol test). Results: Ten patients with complete datasets were included. One patient developed postoperative delirium, and six patients developed postoperative cognitive dysfunction. Postoperatively, at different time points, statistically significant changes compared to baseline were present in IL-5, IL-6, I-8, IL-10, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1 alpha, IL-6/IL-10, and receptor for advanced glycation end products in plasma and in IFN-gamma, IL-6, IL-8, IL-10, MCP-1, MIP-1 alpha, MIP-1 beta, IL-8/IL-10, and TNF-alpha in CSF. Conclusions: Substantial pro-and anti-inflammatory activity in the central neural system after surgery was found. If confirmed by larger studies, persistent changes in cytokine levels may serve as biomarkers for novel clinical trials. C1 [Hirsch, Jan; Vacas, Susana; Terrando, Niccolo; Maze, Mervyn M.; Leung, Jacqueline M.] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, 521 Parnassus Ave, San Francisco, CA 94143 USA. [Hirsch, Jan] San Francisco VA Med Ctr, Anesthesia Serv, Mail 129,4150 Clement St, San Francisco, CA 94121 USA. [Yuan, Miao; Sands, Laura P.] Virginia Tech Univ, Ctr Gerontol, 230 Grove Lane,0555, Blacksburg, VA 24061 USA. [Kramer, Joel] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, 1500 Owens St 320, San Francisco, CA 94158 USA. [Bozic, Kevin] Univ Calif San Francisco, Dept Orthoped Surg, 500 Parnassus Ave,MU 320W, San Francisco, CA 94143 USA. RP Hirsch, J (reprint author), Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, 521 Parnassus Ave, San Francisco, CA 94143 USA.; Hirsch, J (reprint author), San Francisco VA Med Ctr, Anesthesia Serv, Mail 129,4150 Clement St, San Francisco, CA 94121 USA. EM jan.hirsch@ucsf.edu RI Sands, Laura/E-8919-2015 OI Sands, Laura/0000-0003-2446-4486 FU National Institutes of Health of the United States [NIH 1RO1AG031795-05, NIH 1R01 GM104194] FX This manuscript received funding from the National Institutes of Health of the United States (NIH 1RO1AG031795-05 to JL and NIH 1R01 GM104194 to MM). NR 63 TC 0 Z9 0 U1 8 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD AUG 30 PY 2016 VL 13 AR 211 DI 10.1186/s12974-016-0681-9 PG 12 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DV4ET UT WOS:000382878900003 PM 27577265 ER PT J AU Dong, YZ Wang, WH Veiseh, O Appel, EA Xue, K Webber, MJ Tang, BC Yang, XW Weir, GC Langer, R Anderson, DG AF Dong, Yizhou Wang, Weiheng Veiseh, Omid Appel, Eric A. Xue, Kun Webber, Matthew J. Tang, Benjamin C. Yang, Xi-Wen Weir, Gordon C. Langer, Robert Anderson, Daniel G. TI Injectable and Glucose-Responsive Hydrogels Based on Boronic Acid-Glucose Complexation SO LANGMUIR LA English DT Article ID INSULIN-DELIVERY-SYSTEM; PHENYLBORONIC ACID; NANO-NETWORK; PROTEINS; RELEASE; GEL; PH AB Injectable hydrogels have been widely used for a number of biomedical applications. Here, we report a new strategy to form an injectable and glucose-responsive hydrogel using the boronic acid glucose complexation. The ratio of boronic acid and glucose functional groups is critical for hydrogel formation. In our system, polymers with 10-60% boronic acid, with the balance being glucose-modified, are favorable to form hydrogels. These hydrogels are shear thinning and self-healing, recovering from shear-induced flow to a gel state within seconds. More importantly, these polymers displayed glucose-responsive release of an encapsulated model drug. The hydrogel reported here is an injectable and glucose responsive hydrogel constructed from the complexation of boronic acid and glucose within a single component polymeric material. C1 [Dong, Yizhou] Ohio State Univ, Coll Pharm, Div Pharmaceut & Pharmaceut Chem, 500 W 12Th Ave, Columbus, OH 43210 USA. [Wang, Weiheng; Veiseh, Omid; Appel, Eric A.; Xue, Kun; Webber, Matthew J.; Tang, Benjamin C.; Yang, Xi-Wen; Langer, Robert; Anderson, Daniel G.] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Veiseh, Omid; Langer, Robert; Anderson, Daniel G.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Xue, Kun] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Wang, Weiheng; Veiseh, Omid; Webber, Matthew J.; Tang, Benjamin C.; Langer, Robert; Anderson, Daniel G.] Harvard Med Sch, Childrens Hosp Boston, Dept Anesthesiol, Boston, MA 02115 USA. [Weir, Gordon C.] Joslin Diabet Ctr, Div Res, Sect Islet Cell & Regenerat Biol, One Joslin Pl, Boston, MA 02215 USA. [Langer, Robert; Anderson, Daniel G.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Anderson, DG (reprint author), MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Anderson, DG (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA.; Anderson, DG (reprint author), Harvard Med Sch, Childrens Hosp Boston, Dept Anesthesiol, Boston, MA 02115 USA.; Anderson, DG (reprint author), MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM dgander@mit.edu RI Dong, Yizhou/O-9057-2015 OI Dong, Yizhou/0000-0001-5786-0659 FU Leona M. and Harry B. Helmsley Charitable trust [2014PG-T1D002]; Juvenile Diabetes Research Foundation [3-2011-310, 3-2013-144]; National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases) through Ruth L. Kirschstein National Research Service Award [F32DK101335]; A*STAR Predoctoral National Science Scholarship FX This work was supported by a grant from the Leona M. and Harry B. Helmsley Charitable trust (Award 2014PG-T1D002) along with a generous gift from the Tayebati Family Foundation. Y.D. and B.C.T. acknowledge support from Juvenile Diabetes Research Foundation Postdoctoral Fellowships 3-2011-310 and 3-2013-144, respectively. M.J.W. acknowledges support from the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases) through Ruth L. Kirschstein National Research Service Award F32DK101335. K.X. acknowledges support from the A*STAR Predoctoral National Science Scholarship. NR 29 TC 0 Z9 0 U1 71 U2 72 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD AUG 30 PY 2016 VL 32 IS 34 BP 8743 EP 8747 DI 10.1021/acs.langmuir.5b04755 PG 5 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA DU9CN UT WOS:000382513900022 PM 27455412 ER PT J AU Buchy, L Mathalon, DH Cannon, TD Cadenhead, KS Cornblatt, BA McGlashan, TH Perkins, DO Seidman, LJ Tsuang, MT Walker, EF Woods, SW Bearden, CE Addington, J AF Buchy, Lisa Mathalon, Daniel H. Cannon, Tyrone D. Cadenhead, Kristin S. Cornblatt, Barbara A. McGlashan, Thomas H. Perkins, Diana O. Seidman, Larry J. Tsuang, Ming T. Walker, Elaine F. Woods, Scott W. Bearden, Carrie E. Addington, Jean TI Relation between cannabis use and subcortical volumes in people at clinical high risk of psychosis SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Amygdala; Hippocampus; Marijuana; Magnetic resonance imaging; Neuroanatomy; Schizophrenia; Thalamus ID ULTRA-HIGH-RISK; SUBSTANCE USE; ADULT PSYCHOSIS; BRAIN STRUCTURE; SCHIZOPHRENIA; INDIVIDUALS; METAANALYSIS; TRANSITION; DEFICITS; OUTCOMES AB Among people at genetic risk of schizophrenia, those who use cannabis show smaller thalamic and hippocampal volumes. We evaluated this relationship in people at clinical high risk (CHR) of psychosis. The Alcohol and Drug Use Scale was used to identify 132 CHR cannabis users, the majority of whom were non-dependent cannabis users, 387 CHR non-users, and 204 healthy control non-users, and all participants completed magnetic resonance imaging scans. Volumes of the thalamus, hippocampus and amygdala were extracted with FreeSurfer, and compared across groups. Comparing all CHR participants with healthy control participants revealed no significant differences in volumes of any ROI. However, when comparing CHR users to CHR non-users, a significant ROICannabis group effect emerged: CHR users showed significantly smaller amygdala compared to CHR non-users. However, when limiting analysis to CHR subjects who reported using alcohol at a 'use without impairment' severity level, the amygdala effect was non-significant; rather, smaller hippocampal volumes were seen in CHR cannabis users compared to non-users. Controlling statistically for effects of alcohol and tobacco use rendered all results non-significant. These results highlight the importance of controlling for residual confounding effects of other substance use when examining the relationship between cannabis use and neural structure. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Buchy, Lisa; Addington, Jean] Univ Calgary, Dept Psychiat, Calgary, AB, Canada. [Mathalon, Daniel H.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Cannon, Tyrone D.] Yale Univ, Dept Psychol, New Haven, CT USA. [Cadenhead, Kristin S.; Tsuang, Ming T.] UCSD, Dept Psychiat, La Jolla, CA USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Dept Psychiat, Long Isl City, NY USA. [McGlashan, Thomas H.; Woods, Scott W.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Perkins, Diana O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Seidman, Larry J.] Beth Israel Deaconess Med Ctr, Dept Psychiat, Harvard Med Sch, Boston, MA 02215 USA. [Seidman, Larry J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Walker, Elaine F.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Walker, Elaine F.] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Los Angeles, CA USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA. RP Addington, J (reprint author), Univ Calgary, Mathison Ctr Mental Hlth Res & Educ, 3280 Hosp Dr NW, Calgary, AB T2N 4Z6, Canada. EM jmadding@ucalgary.ca FU National Institute of Mental Health [U01MH081984, U01 MH081928, P50 MH080272, R01 MH60720, U01 MH082022, K24 MH76191, U01MH081902, P50 MH066286, U01MH082004, U01MH081988, U01MH082022, U01 MH081857-05]; National Institute of Mental Health (Commonwealth of Massachusetts) [SCDMH82101008006] FX This study was supported by the National Institute of Mental Health (grant U01MH081984 to Dr Addington; grants U01 MH081928; P50 MH080272; Commonwealth of Massachusetts SCDMH82101008006 to Dr Seidman; grants R01 MH60720, U01 MH082022 and K24 MH76191 to Dr Cadenhead; grant U01MH081902 to Dr Cannon; P50 MH066286 (Prodromal Core) to Dr Bearden; grant U01MH082004 to Dr Perkins; grant U01MH081988 to Dr Walker; grant U01MH082022 to Dr Woods; and U01 MH081857-05 grant to Dr Cornblatt). The NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 32 TC 0 Z9 0 U1 7 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 EI 1872-7506 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD AUG 30 PY 2016 VL 254 BP 3 EP 9 DI 10.1016/j.pscychresns.2016.06.001 PG 7 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DU6HU UT WOS:000382316000002 PM 27289213 ER PT J AU Kanzaki, H Shinohara, F Suzuki, M Wada, S Miyamoto, Y Yamaguchi, Y Katsumata, Y Makihira, S Kawai, T Taubman, MA Nakamura, Y AF Kanzaki, Hiroyuki Shinohara, Fumiaki Suzuki, Maiko Wada, Satoshi Miyamoto, Yutaka Yamaguchi, Yuuki Katsumata, Yuta Makihira, Seicho Kawai, Toshi Taubman, Martin A. Nakamura, Yoshiki TI A-Disintegrin and Metalloproteinase (ADAM) 17 Enzymatically Degrades Interferon-gamma SO SCIENTIFIC REPORTS LA English DT Article ID NECROSIS-FACTOR-ALPHA; CELL LUNG CARCINOMAS; IFN-GAMMA; SKELETAL METASTASIS; BONE METASTASIS; IMMUNE ESCAPE; BREAST-CANCER; IN-VIVO; TUMOR; PROLIFERATION AB Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that exerts anti-tumor and anti-osteoclastogenic effects. Although transcriptional and post-transcriptional regulation of IFN-gamma is well understood, subsequent modifications of secreted IFN-gamma are not fully elucidated. Previous research indicates that some cancer cells escape immune surveillance and metastasize into bone tissue by inducing osteoclastic bone resorption. Peptidases of the a-disintegrin and metalloproteinase (ADAM) family are implicated in cancer cell proliferation and tumor progression. We hypothesized that the ADAM enzymes expressed by cancer cells degrades IFN-gamma and attenuates IFN-gamma-mediated anti-tumorigenic and anti-osteoclastogenic effects. Recombinant ADAM17 degraded IFN-gamma into small fragments. The addition of ADAM17 to the culture supernatant of stimulated mouse splenocytes decreased IFN-gamma concentration. However, ADAM17 inhibition in the stimulated mouse T-cells prevented IFN-gamma degradation. ADAM17-expressing human breast cancer cell lines MCF-7 and MDA-MB-453 also degraded recombinant IFN-gamma, but this was attenuated by ADAM17 inhibition. Degraded IFN-gamma lost the functionality including the inhibititory effect on osteoclastogenesis. This is the first study to demonstrate the extracellular proteolytic degradation of IFN-gamma by ADAM17. These results suggest that ADAM17-mediated degradation of IFN-gamma may block the anti-tumorigenic and anti-osteoclastogenic effects of IFN-gamma. ADAM17 inhibition may be useful for the treatment of attenuated cancer immune surveillance and/or bone metastases. C1 [Kanzaki, Hiroyuki; Wada, Satoshi; Miyamoto, Yutaka; Yamaguchi, Yuuki; Katsumata, Yuta; Nakamura, Yoshiki] Tsurumi Univ, Sch Dent Med, Dept Orthodont, Tsurumi Ku, 2-1-3 Tsurumi, Yokohama, Kanagawa 2308501, Japan. [Kanzaki, Hiroyuki] Tohoku Univ Hosp, Maxillooral Disorders, Aoba Ku, 4-1 Seiryo Machi, Sendai, Miyagi 9808575, Japan. [Shinohara, Fumiaki] Tohoku Univ, Grad Sch Dent, Oral Microbiol, Aoba Ku, 4-1 Seiryo Machi, Sendai, Miyagi 9808575, Japan. [Suzuki, Maiko; Kawai, Toshi; Taubman, Martin A.] Forsyth Inst, Dept Immunol & Infect Dis, 245 First St, Cambridge, MA 02142 USA. [Suzuki, Maiko] Dept Mineralized Tissue Biol, 245 First St, Cambridge, MA 02142 USA. [Makihira, Seicho] Kyushu Univ, Fac Dent Sci, Div Oral Rehabil, Sect Fixed Prosthodont, 3-1-1 Maidashi Higashi Ku, Fukuoka 8128582, Japan. [Kawai, Toshi] Harvard Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Taubman, Martin A.] Harvard Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. RP Kanzaki, H (reprint author), Tsurumi Univ, Sch Dent Med, Dept Orthodont, Tsurumi Ku, 2-1-3 Tsurumi, Yokohama, Kanagawa 2308501, Japan.; Kanzaki, H (reprint author), Tohoku Univ Hosp, Maxillooral Disorders, Aoba Ku, 4-1 Seiryo Machi, Sendai, Miyagi 9808575, Japan. EM kanzaki-h@tsurumi-u.ac.jp OI Kanzaki, Hiroyuki/0000-0003-3473-1218 FU Japan Society for the Promotion of Science [23689081, 25670841, 15K11376]; Nestle Nutrition Council, Japan; Translational Research Network Program from the Japanese Ministry of Education, Culture, Sports, Science and Technology [A-03]; Adaptable and Seamless Technology Transfer Program through Target-driven R&D from the Japan Science and Technology Agency [AS231Z01205G]; Astellas Foundation for Research on Metabolic Disorders, NIH from NIDCR [DE-018499, DE-019917, DE03420] FX This research was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (23689081, 25670841, and 15K11376); the Nestle Nutrition Council, Japan; the Translational Research Network Program from the Japanese Ministry of Education, Culture, Sports, Science and Technology (A-03); the Adaptable and Seamless Technology Transfer Program through Target-driven R&D from the Japan Science and Technology Agency (AS231Z01205G); and the Astellas Foundation for Research on Metabolic Disorders, NIH grants DE-018499, DE-019917 & DE03420 from NIDCR. The authors acknowledge the Center of Research Instruments, Institute of Development, Aging and Cancer, Tohoku University, for their generous permission to use the experimental instruments. The authors also acknowledge Tecan Japan Co., Ltd. for giving us the opportunity to use the fluorescent microplate reader (Spark 10M). Finally, the authors (HK and FS) give their heartfelt appreciation to the experimental reagent and instrument companies for their support during the rehabilitation process following the damage caused by the Tohoku Earthquake on March 11, 2011. NR 50 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 AUG 30 PY 2016 VL 6 AR 32259 DI 10.1038/srep32259 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU4AI UT WOS:000382153700001 PM 27573075 ER PT J AU Wagner, EK Raychaudhuri, S Villalonga, MB Java, A Triebwasser, MP Daly, MJ Atkinson, JP Seddon, JM AF Wagner, Erin K. Raychaudhuri, Soumya Villalonga, Mercedes B. Java, Anuja Triebwasser, Michael P. Daly, Mark J. Atkinson, John P. Seddon, Johanna M. TI Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD SO SCIENTIFIC REPORTS LA English DT Article ID COMPLEMENT FACTOR-H; HEMOLYTIC-UREMIC SYNDROME; GENOME-WIDE ASSOCIATION; AGE-RELATED MACULOPATHY; MACULAR DEGENERATION; HIGH-RISK; SUSCEPTIBILITY LOCI; GENETIC-VARIANTS; C3; POLYMORPHISM AB The genetic architecture of age-related macular degeneration (AMD) involves numerous genetic variants, both common and rare, in the coding region of complement factor H (CFH). While these variants explain high disease burden in some families, they fail to explain the pathology in all. We selected families whose AMD was unexplained by known variants and performed whole exome sequencing to probe for other rare, highly penetrant variants. We identified four rare loss-of-function variants in CFH associated with AMD. Missense variant CFH 1: 196646753 (C192F) segregated perfectly within a family characterized by advanced AMD and drusen temporal to the macula. Two families, each comprising a pair of affected siblings with extensive extramacular drusen, carried essential splice site variant CFH 1:196648924 (IVS6+1G>A) or missense variant rs139360826 (R175P). In a fourth family, missense variant rs121913058 (R127H) was associated with AMD. Most carriers had early onset bilateral advanced AMD and extramacular drusen. Carriers tended to have low serum Factor H levels, especially carriers of the splice variant. One missense variant (R127H) has been previously shown not to be secreted. The two other missense variants were produced recombinantly: compared to wild type, one (R175P) had no functional activity and the other (C192F) had decreased secretion. C1 [Wagner, Erin K.; Villalonga, Mercedes B.; Seddon, Johanna M.] Tufts Med Ctr, New England Eye Ctr, Ophthalm Epidemiol & Genet Serv, Boston, MA 02111 USA. [Wagner, Erin K.; Seddon, Johanna M.] Tufts Univ, Sch Med, Dept Ophthalmol, Boston, MA 02111 USA. [Raychaudhuri, Soumya; Daly, Mark J.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Raychaudhuri, Soumya; Daly, Mark J.] Partners HealthCare Ctr Personalized Genet Med, Boston, MA 02115 USA. [Raychaudhuri, Soumya] Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Raychaudhuri, Soumya] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, 75 Francis St, Boston, MA 02115 USA. [Raychaudhuri, Soumya] Univ Manchester, Fac Med & Human Sci, Manchester M13 9PL, Lancs, England. [Java, Anuja] Washington Univ, Sch Med, Dept Med, Div Nephrol, St Louis, MO 63110 USA. [Triebwasser, Michael P.; Atkinson, John P.] Washington Univ, Sch Med, Dept Med, Div Rheumatol, St Louis, MO 63110 USA. [Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Seddon, Johanna M.] Tufts Univ, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA. RP Seddon, JM (reprint author), Tufts Med Ctr, New England Eye Ctr, Ophthalm Epidemiol & Genet Serv, Boston, MA 02111 USA.; Seddon, JM (reprint author), Tufts Univ, Sch Med, Dept Ophthalmol, Boston, MA 02111 USA.; Seddon, JM (reprint author), Tufts Univ, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA. EM jseddon@tuftsmedicalcenter.org FU NIH [R01-EY11309, 1R01AR063759-01A1, 5U01GM092691-04, 1U01HG007690-01, F30HL103072, R01-AI041592, U54 HL112303]; Doris Duke Clinical Scientist Development Award; NIH-Arthritis and Musculoskeletal and Skin Diseases [P30 AR48335]; Massachusetts Lions Eye Research Fund, Inc.; Research to Prevent Blindness Challenge Grant to the New England Eye Center, Department of Ophthalmology, Tufts University School of Medicine; Macular Degeneration Research Fund of the Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine; F30 Ruth L. Kirschstein National Research Service Award (National Heart, Lung and Blood Institute) FX This research was supported in part by NIH grants R01-EY11309 (J.M.S.), 1R01AR063759-01A1 (S.R.), 5U01GM092691-04 (S.R.), 1U01HG007690-01 (S.R.), F30HL103072 (M.T.), R01-AI041592 (J.P.A.), U54 HL112303 (J.P.A.); the Doris Duke Clinical Scientist Development Award (S.R.); the Rheumatic Disease Core Center supported by NIH-Arthritis and Musculoskeletal and Skin Diseases P30 AR48335 (J.P.A.), Massachusetts Lions Eye Research Fund, Inc. (J.M.S.); Research to Prevent Blindness Challenge Grant to the New England Eye Center, Department of Ophthalmology, Tufts University School of Medicine; and the Macular Degeneration Research Fund of the Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine. M.T. is a F30 Ruth L. Kirschstein National Research Service Award recipient (National Heart, Lung and Blood Institute). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 49 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 AUG 30 PY 2016 VL 6 AR 31531 DI 10.1038/srep31531 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU4BR UT WOS:000382157300001 PM 27572114 ER PT J AU Nakhnikian, A Ito, S Dwiel, LL Grasse, LM Rebec, GV Lauridsen, LN Beggs, JM AF Nakhnikian, A. Ito, S. Dwiel, L. L. Grasse, L. M. Rebec, G. V. Lauridsen, L. N. Beggs, J. M. TI A novel cross-frequency coupling detection method using the generalized Morse wavelets SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Cross-frequency coupling; Generalized Morse wavelets; In vivo electrophysiology; Anesthesia; Signal processing ID FALSE DISCOVERY RATE; OSCILLATIONS; NEOCORTEX AB Background: Cross-frequency coupling (CFC) occurs when non-identical frequency components entrain one another. A ubiquitous example from neuroscience is low frequency phase to high frequency amplitude coupling in electrophysiological signals. Seminal work by Canolty revealed CFC in human ECoG data. Established methods band-pass the data into component frequencies then convert the band-passed signals into the analytic representation, from which we infer the instantaneous amplitude and phase of each component. Though powerful, such methods resolve signals with respect to time and frequency without addressing the multiresolution problem. New method: We build upon the ground-breaking work of Canolty and others and derive a wavelet based CFC detection algorithm that efficiently searches a range of frequencies using a sequence of filters with optimal trade-off between time and frequency resolution. We validate our method using simulated data and analyze CFC within and between the primary motor cortex and dorsal striatum of rats under ketamine-xylazine anesthesia. Results: Our method detects the correct CFC in simulated data and reveals CFC between frequency bands that were previously shown to participate in corticostriatal effective connectivity. Comparison with existing methods: Other CFC detection methods address the need to increase bandwidth when analyzing high frequency components but none to date permit rigorous bandwidth selection with no a priori knowledge of underlying CFC. Our method is thus particularly useful for exploratory studies. Conclusions: The method developed here permits rigorous and efficient exploration of a hypothesis space and is particularly useful when the frequencies participating in CFC are unknown. Published by Elsevier B.V. C1 [Nakhnikian, A.; Rebec, G. V.; Beggs, J. M.] Program Neurosci, 1101 E 10th St, Bloomington, IN 47405 USA. [Nakhnikian, A.] Cognit Sci Program, 1900 E 10th St, Bloomington, IN 47405 USA. [Ito, S.] Santa Cruz Inst Particle Phys, 1156 High St, Santa Cruz, CA 95064 USA. [Dwiel, L. L.; Grasse, L. M.; Rebec, G. V.; Lauridsen, L. N.] Dept Psychol & Brain Sci, 1101 E 10th St, Bloomington, IN 47405 USA. [Beggs, J. M.] Dept Phys, 727 E 3rd St, Bloomington, IN 47405 USA. [Nakhnikian, A.; Dwiel, L. L.; Grasse, L. M.; Rebec, G. V.; Lauridsen, L. N.; Beggs, J. M.] Indiana Univ, Bloomington, IN USA. [Ito, S.] Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA. [Nakhnikian, A.] Harvard Med Sch, Boston, MA USA. [Grasse, L. M.] MD Anderson Canc Ctr, 7777 Knight Rd,Smith Res Bldg, Houston, TX 77054 USA. [Grasse, L. M.] Childrens Canc Hosp, 7777 Knight Rd,Smith Res Bldg, Houston, TX 77054 USA. [Lauridsen, L. N.] Indiana Univ, Sch Med, Bloomington, IN USA. RP Nakhnikian, A (reprint author), VA Boston Healthcare Syst, 940 Belmont St, Brockton, MA 02301 USA. EM alexander_nakhnikian@hms.harvard.edu FU NSF [1058291, 0904912]; National Science Foundation Graduate Research Fellowship Program; [R01 DA 12964]; [P50 DA 05312]; [R21 AG 039818]; [4NIH MH016259] FX Supported by: R01 DA 12964, P50 DA 05312, and R21 AG 039818 (GVR); NSF 1058291, and NSF 0904912 (JMB); 4NIH MH016259 and the National Science Foundation Graduate Research Fellowship Program (AN). We thank Drs. Francisco Parada and Aina Puce for input on CFC analysis and Dr. Parada for assistance with software design. Faye Caylor, Bill Freeman, and Paul Langley provided technical and administrative support. Jeff Sturgeon and Dr. Tony Walker provided useful input on data acquisition, signal processing, and filter design. Tommy Wilson provided assistance with experimental design and data acquisition. Dr. Benjamin Pittman-Polletta provided code to implement EMD-based CFC analysis and provided helpful discussions of the underlying theory. We thank Dr. Jonathan Lilly for discussions of the Generalized Morse Wavelets. NR 24 TC 1 Z9 1 U1 2 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD AUG 30 PY 2016 VL 269 BP 61 EP 73 DI 10.1016/j.jneumeth.2016.04.019 PG 13 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DR7JQ UT WOS:000380076300007 PM 27129446 ER PT J AU Baenninger, A Hernandez, LD Rieger, K Ford, JM Kottlow, M Koenig, T AF Baenninger, Anja Hernandez, Laura Diaz Rieger, Kathryn Ford, Judith M. Kottlow, Mara Koenig, Thomas TI inefficient Preparatory fMri-BoLD network Activations Predict Working Memory Dysfunctions in Patients with Schizophrenia (vol 7, 29, 2016) SO FRONTIERS IN PSYCHIATRY LA English DT Correction DE schizophrenia; working memory; temporally coherent networks; state-dependent information processing; simultaneous EEG-fMRI; covariance mapping C1 [Baenninger, Anja; Hernandez, Laura Diaz; Kottlow, Mara; Koenig, Thomas] Univ Bern, Univ Hosp Psychiat & Psychotherapy, Translat Res Ctr, Bern, Switzerland. [Baenninger, Anja; Ford, Judith M.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Hernandez, Laura Diaz; Rieger, Kathryn; Kottlow, Mara; Koenig, Thomas] Univ Bern, Ctr Cognit Learning & Memory, Bern, Switzerland. [Ford, Judith M.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. RP Baenninger, A (reprint author), Univ Bern, Univ Hosp Psychiat & Psychotherapy, Translat Res Ctr, Bern, Switzerland.; Baenninger, A (reprint author), San Francisco VA Med Ctr, San Francisco, CA 94121 USA. EM anja.baenninger@puk.unibe.ch NR 1 TC 0 Z9 0 U1 3 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-0640 J9 FRONT PSYCHIATRY JI Front. Psychiatry PD AUG 29 PY 2016 VL 7 AR 141 DI 10.3389/fpsyt.2016.00141 PG 3 WC Psychiatry SC Psychiatry GA DU1UH UT WOS:000381994800001 PM 27582711 ER PT J AU Choby, JE Skaar, EP AF Choby, Jacob E. Skaar, Eric P. TI Heme Synthesis and Acquisition in Bacterial Pathogens SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE iron uptake; hemoglobin; Isd system; heme toxicity; NEAT domain ID NONTYPABLE HAEMOPHILUS-INFLUENZAE; TRANSFER-RNA REDUCTASE; STAPHYLOCOCCUS-AUREUS HEME; DELTA-AMINOLEVULINIC-ACID; OUTER-MEMBRANE PROTEIN; GROUP-A STREPTOCOCCUS; SMALL-COLONY VARIANTS; HAPTOGLOBIN BINDING-PROTEINS; SHIGELLA-DYSENTERIAE SHUS; DETERMINANT ISD PROTEINS AB Bacterial pathogens require the iron-containing cofactor heme to cause disease. Heme is essential to the function of hemoproteins, which are involved in energy generation by the electron transport chain, detoxification of host immune effectors, and other processes. During infection, bacterial pathogens must synthesize heme or acquire heme from the host; however, host heme is sequestered in high-affinity hemoproteins. Pathogens have evolved elaborate strategies to acquire heme from host sources, particularly hemoglobin, and both heme acquisition and synthesis are important for pathogenesis. Paradoxically, excess heme is toxic to bacteria and pathogens must rely on heme detoxification strategies. Heme is a key nutrient in the struggle for survival between host and pathogen, and its study has offered significant insight into the molecular mechanisms of bacterial pathogenesis. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Choby, Jacob E.; Skaar, Eric P.] Vanderbilt Univ, Sch Med, Dept Pathol Microbiol & Immunol, 1161 21st Ave S, Nashville, TN 37212 USA. [Skaar, Eric P.] US Dept Vet Affairs, Tennessee Valley Healthcare Syst, Nashville, TN 37203 USA. RP Skaar, EP (reprint author), Vanderbilt Univ, Sch Med, Dept Pathol Microbiol & Immunol, 1161 21st Ave S, Nashville, TN 37212 USA.; Skaar, EP (reprint author), US Dept Vet Affairs, Tennessee Valley Healthcare Syst, Nashville, TN 37203 USA. EM eric.skaar@vanderbilt.edu FU NIH [T32 GM065086, AI069233, AI073843] FX We thank members of the Skaar laboratory for critical review of this manuscript. J.E.C. is supported by NIH T32 GM065086. Heme acquisition, synthesis, and toxicity research in the Skaar laboratory is supported by NIH grants AI069233 and AI073843. NR 246 TC 6 Z9 6 U1 7 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD AUG 28 PY 2016 VL 428 IS 17 SI SI BP 3408 EP 3428 DI 10.1016/j.jmb.2016.03.018 PG 21 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DW0FD UT WOS:000383315400006 PM 27019298 ER PT J AU Roberts, DJ Frosch, MP AF Roberts, Drucilla J. Frosch, Matthew P. TI Zika and histopathology in first trimester infections SO LANCET LA English DT Editorial Material ID CRANIOSYNOSTOSIS; INTERVILLOSITIS; PREGNANCY; PLACENTA; VIRUS C1 [Roberts, Drucilla J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Boston, MA 02114 USA. [Frosch, Matthew P.] Harvard Med Sch, Boston, MA 02115 USA. RP Roberts, DJ (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM djroberts@mgh.harvard.edu NR 15 TC 0 Z9 0 U1 10 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD AUG 27 PY 2016 VL 388 IS 10047 BP 847 EP 849 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DU0RI UT WOS:000381911800007 PM 27372399 ER PT J AU Fitchett, JRA Sharara, N Head, MG Huang, F Atun, R AF Fitchett, Joseph R. A. Sharara, Nour Head, Michael G. Huang, Franklin Atun, Rifat TI Transparency and availability of data for cancer research SO LANCET LA English DT Letter C1 [Fitchett, Joseph R. A.; Atun, Rifat] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Sharara, Nour; Huang, Franklin] Dana Farber Canc Inst, Boston, MA 02115 USA. [Head, Michael G.] Univ Southampton, Global Hlth Res Inst, Southampton, Hants, England. RP Fitchett, JRA (reprint author), Harvard Univ, Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA. EM joseph@mail.harvard.edu0 OI Head, Michael/0000-0003-1189-0531 NR 5 TC 0 Z9 0 U1 3 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD AUG 27 PY 2016 VL 388 IS 10047 BP 866 EP 867 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DU0RI UT WOS:000381911800019 PM 27597460 ER PT J AU Wang, HJ Becuwe, M Housden, BE Chitraju, C Porras, AJ Graham, MM Liu, XRN Thiam, AR Savage, DB Agarwal, AK Garg, A Olarte, MJ Lin, QQ Frohlich, F Hannibal-Bach, HK Upadhyayula, S Perrimon, N Kirchhausen, T Ejsing, CS Walther, TC Farese, RV AF Wang, Huajin Becuwe, Michel Housden, Benjamin E. Chitraju, Chandramohan Porras, Ashley J. Graham, Morven M. Liu, Xinran N. Thiam, Abdou Rachid Savage, David B. Agarwal, Anil K. Garg, Abhimanyu Olarte, Maria-Jesus Lin, Qingqing Froehlich, Florian Hannibal-Bach, Hans Kristian Upadhyayula, Srigokul Perrimon, Norbert Kirchhausen, Tomas Ejsing, Christer S. Walther, Tobias C. Farese, Robert V., Jr. TI Seipin is required for converting nascent to mature lipid droplets SO ELIFE LA English DT Article ID LIPODYSTROPHY PROTEIN SEIPIN; TRIACYLGLYCEROL SYNTHESIS; CONGENITAL LIPODYSTROPHY; ENDOPLASMIC-RETICULUM; FAT STORAGE; YEAST; BIOGENESIS; METABOLISM; ER; IDENTIFICATION AB How proteins control the biogenesis of cellular lipid droplets (LDs) is poorly understood. Using Drosophila and human cells, we show here that seipin, an ER protein implicated in LD biology, mediates a discrete step in LD formation-the conversion of small, nascent LDs to larger, mature LDs. Seipin forms discrete and dynamic foci in the ER that interact with nascent LDs to enable their growth. In the absence of seipin, numerous small, nascent LDs accumulate near the ER and most often fail to grow. Those that do grow prematurely acquire lipid synthesis enzymes and undergo expansion, eventually leading to the giant LDs characteristic of seipin deficiency. Our studies identify a discrete step of LD formation, namely the conversion of nascent LDs to mature LDs, and define a molecular role for seipin in this process, most likely by acting at ER-LD contact sites to enable lipid transfer to nascent LDs. C1 [Wang, Huajin] Carnegie Mellon Univ, Dept Biol Sci, 4400 5th Ave, Pittsburgh, PA 15213 USA. [Wang, Huajin; Becuwe, Michel; Chitraju, Chandramohan; Porras, Ashley J.; Olarte, Maria-Jesus; Lin, Qingqing; Froehlich, Florian; Walther, Tobias C.; Farese, Robert V., Jr.] Harvard TH Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Wang, Huajin; Becuwe, Michel; Chitraju, Chandramohan; Porras, Ashley J.; Olarte, Maria-Jesus; Lin, Qingqing; Froehlich, Florian; Walther, Tobias C.; Farese, Robert V., Jr.] Harvard Med Sch, Dept Cell Biol, Boston, MA USA. [Housden, Benjamin E.; Perrimon, Norbert] Harvard Med Sch, Dept Genet, Boston, MA USA. [Graham, Morven M.; Liu, Xinran N.] Yale Sch Med, Dept Cell Biol, Ctr Cellular & Mol Imaging, New Haven, CT USA. [Thiam, Abdou Rachid] Univ Paris 04, Univ Paris 06, PSL Res Univ,Univ Paris Diderot,Ecole Normale Sup, Lab Phys Stat,CNRS UMR 8550,Sorbonne Paris Cite, Paris, France. [Savage, David B.] Univ Cambridge, Metab Res Labs, Wellcome Trust MRC Inst Metab Sci, Cambridge, England. [Agarwal, Anil K.] UT Southwestern Med Ctr, Div Nutr & Metab Dis, Dept Internal Med, Dallas, TX USA. [Garg, Abhimanyu; Froehlich, Florian] Univ Osnabruck, Mol Membrane Biol Sect, Dept Biol Chem, Osnabruck, Germany. [Hannibal-Bach, Hans Kristian; Ejsing, Christer S.] Univ Southern Denmark, Dept Biochem & Mol Biol, VILLUM Ctr Bioanalyt Sci, Odense, Denmark. [Upadhyayula, Srigokul; Kirchhausen, Tomas] Harvard Med Sch, Dept Cell Biol, Boston, MA USA. [Upadhyayula, Srigokul; Kirchhausen, Tomas] Harvard Med Sch, Dept Pediat, Boston, MA USA. [Upadhyayula, Srigokul; Kirchhausen, Tomas] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Perrimon, Norbert; Walther, Tobias C.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Walther, Tobias C.; Farese, Robert V., Jr.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. RP Walther, TC; Farese, RV (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA.; Walther, TC (reprint author), Howard Hughes Med Inst, Boston, MA 02115 USA.; Walther, TC; Farese, RV (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. EM twalther@hsph.harvard.edu; robert@hsph.harvard.edu RI Ejsing, Christer/R-5922-2016; OI Housden, Benjamin/0000-0001-9134-4279 FU Canadian Institutes of Health Research; European Molecular Biology Organization Longterm Fellowship [EMBOLFT355]; Wellcome Trust [WT107064]; NIHR Cambridge Biomedical Research Centre; Howard Hughes Medical Institute; Biogen; National Institutes of Health [GM-075252, GM097194, GM099844]; Villum Fonden [VKR023439]; Strategiske Forskningsrad [11-116196]; G Harold and Leila Y. Mathers Foundation FX Canadian Institutes of Health Research Fellowship Award Huajin Wang; European Molecular Biology Organization Longterm Fellowship EMBOLFT355 Michel Becuwe; Wellcome Trust WT107064 David B Savage; NIHR Cambridge Biomedical Research Centre David B Savage; Howard Hughes Medical Institute Norbert Perrimon Tobias C Walther; Biogen Tomas Kirchhausen; National Institutes of Health GM-075252 Tomas Kirchhausen; Villum Fonden VKR023439 Christer S Ejsing; Strategiske Forskningsrad 11-116196 Christer S Ejsing; National Institutes of Health GM097194 Tobias C Walther; G Harold and Leila Y. Mathers Foundation Tobias C Walther; National Institutes of Health GM099844 Robert V Farese Jr; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 45 TC 2 Z9 2 U1 4 U2 4 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD AUG 26 PY 2016 VL 5 AR e16582 DI 10.7554/eLife.16582 PG 28 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DX7GN UT WOS:000384554900001 ER PT J AU Shi, H Braun, A Wang, L Liang, SH Vasdev, N Ritter, T AF Shi, Hang Braun, Augustin Wang, Lu Liang, Steven H. Vasdev, Neil Ritter, Tobias TI Synthesis of F-18-Difluoromethylarenes from Aryl (Pseudo) Halides SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE aryl (pseudo) halides; difluoromethylarenes; fluorine-18; positron emission tomography; radiopharmaceuticals ID POSITRON-EMISSION-TOMOGRAPHY; LATE-STAGE; OXIDATIVE FLUORINATION; ALPHA-ARYLATION; BORONIC ACIDS; PET; FLUORIDE; ARENES; F-18; IODIDES AB A general method for the synthesis of [F-18]difluoromethylarenes from [F-18]fluoride for radiopharmaceutical discovery is reported. The method is practical, operationally simple, tolerates a wide scope of functional groups, and enables the labeling of a variety of arenes and heteroarenes with radiochemical yields (RCYs, not decay-corrected) from 10 to 60%. The F-18-fluorination precursors are readily prepared from aryl chlorides, bromides, iodides, and triflates. Seven F-18-difluoromethylarene drug analogues and radiopharmaceuticals including Claritin, fluoxetine (Prozac), and [F-18]DAA1106 were synthesized to show the potential of the method for applications in PET radiopharmaceutical design. C1 [Shi, Hang; Braun, Augustin; Ritter, Tobias] Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA. [Shi, Hang; Wang, Lu; Liang, Steven H.; Vasdev, Neil; Ritter, Tobias] Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, 55 Fruit St, Boston, MA 02114 USA. [Shi, Hang; Wang, Lu; Liang, Steven H.; Vasdev, Neil; Ritter, Tobias] Massachusetts Gen Hosp, Gordon Ctr Med Imaging, 55 Fruit St, Boston, MA 02114 USA. [Liang, Steven H.; Vasdev, Neil] Harvard Med Sch, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. [Ritter, Tobias] Max Planck Inst Kohlenforsch, Kaiser Wilhelm Pl 1, D-45470 Mulheim, Germany. RP Ritter, T (reprint author), Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA.; Liang, SH; Vasdev, N; Ritter, T (reprint author), Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, 55 Fruit St, Boston, MA 02114 USA.; Liang, SH; Vasdev, N; Ritter, T (reprint author), Massachusetts Gen Hosp, Gordon Ctr Med Imaging, 55 Fruit St, Boston, MA 02114 USA.; Liang, SH; Vasdev, N (reprint author), Harvard Med Sch, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA.; Ritter, T (reprint author), Max Planck Inst Kohlenforsch, Kaiser Wilhelm Pl 1, D-45470 Mulheim, Germany. EM liang.steven@mgh.harvard.edu; vasdev.neil@mgh.harvard.edu; ritter@chemistry.harvard.edu FU NIH [GM088237]; NIH (NIH/NIDA) [K01DA038000] FX We thank the NIH for funding (GM088237 and Erica M. D'Amato, Constanze N. Neumann, Anthony R. Mazzotti, and Ziyang Zhang for helpful discussions. S.H.L is a recipient of an NIH career development award (NIH/NIDA K01DA038000). NR 47 TC 4 Z9 4 U1 23 U2 25 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD AUG 26 PY 2016 VL 55 IS 36 BP 10786 EP 10790 DI 10.1002/anie.201604106 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA DW2LJ UT WOS:000383473600047 PM 27491349 ER PT J AU Guo, JP Chakraborty, AA Liu, PD Gan, WJ Zheng, XN Inuzuka, H Wang, B Zhang, JF Zhang, LL Yuan, M Novak, J Cheng, JQ Toker, A Signoretti, S Zhang, Q Asara, JM Kaelin, WG Wei, WY AF Guo, Jianping Chakraborty, Abhishek A. Liu, Pengda Gan, Wenjian Zheng, Xingnan Inuzuka, Hiroyuki Wang, Bin Zhang, Jinfang Zhang, Linli Yuan, Min Novak, Jesse Cheng, Jin Q. Toker, Alex Signoretti, Sabina Zhang, Qing Asara, John M. Kaelin, William G. Wei, Wenyi TI pVHL suppresses kinase activity of Akt in a proline-hydroxylation-dependent manner SO SCIENCE LA English DT Article ID RENAL-CELL CARCINOMA; PROLYL HYDROXYLATION; KIDNEY CANCER; HIF-ALPHA; VHL; PROTEIN; BINDING; MTOR; HYDROXYPROLINE; RECOGNITION AB Activation of the serine-threonine kinase Akt promotes the survival and proliferation of various cancers. Hypoxia promotes the resistance of tumor cells to specific therapies. We therefore explored a possible link between hypoxia and Akt activity. We found that Akt was prolyl-hydroxylated by the oxygen-dependent hydroxylase EglN1. The von Hippel-Lindau protein (pVHL) bound directly to hydroxylated Akt and inhibited Akt activity. In cells lacking oxygen or functional pVHL, Akt was activated to promote cell survival and tumorigenesis. We also identified cancer-associated Akt mutations that impair Akt hydroxylation and subsequent recognition by pVHL, thus leading to Akt hyperactivation. Our results show that microenvironmental changes, such as hypoxia, can affect tumor behaviors by altering Akt activation, which has a critical role in tumor growth and therapeutic resistance. C1 [Guo, Jianping; Liu, Pengda; Gan, Wenjian; Inuzuka, Hiroyuki; Wang, Bin; Zhang, Jinfang; Zhang, Linli; Toker, Alex; Wei, Wenyi] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Chakraborty, Abhishek A.; Kaelin, William G.] Harvard Med Sch, Dept Med, Dana Farber Canc Inst, Boston, MA 02215 USA. [Chakraborty, Abhishek A.; Novak, Jesse; Signoretti, Sabina; Kaelin, William G.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02215 USA. [Zheng, Xingnan; Zhang, Qing] Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Yuan, Min; Asara, John M.] Harvard Med Sch, Div Signal Transduct, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Yuan, Min; Asara, John M.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Novak, Jesse; Signoretti, Sabina] Harvard Med Sch, Dept Pathol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Cheng, Jin Q.] H Lee Moffitt Canc Ctr & Res Inst, Dept Mol Oncol, Tampa, FL 33612 USA. [Kaelin, William G.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Wei, WY (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. EM wwei2@bidmc.harvard.edu FU NIH [GM094777, CA177910, 1S10OD010612, 5P01CA120964, 5P30CA006516]; [5T32HL007893-17] FX We thank B. North, L. Wan, and other Wei laboratory members for critical reading of the manuscript; W. Yu for his critical help in providing the triple mutant form of VHL to analyze the critical amino acids in proline-hydroxylation binding pocket of VHL that mediates its interaction with hydroxylated Akt1; as well as members of Kaelin, Zhang, Toker, and Cheng laboratories for helpful discussions. J.G. is an NRSA T32 trainee and supported by 5T32HL007893-17. W.W. is an ACS research scholar. This work was supported in part by NIH grants (W.W., GM094777; W.W. and A.T., CA177910; and J.A., 1S10OD010612, 5P01CA120964, and 5P30CA006516). NR 30 TC 4 Z9 4 U1 11 U2 14 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 AUG 26 PY 2016 VL 353 IS 6302 BP 929 EP 932 DI 10.1126/science.aad5755 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU0CA UT WOS:000381867700039 PM 27563096 ER PT J AU Song, Y Pimentel, C Walters, K Boller, L Ghiasvand, S Liu, J Staley, KJ Berdichevsky, Y AF Song, Yu Pimentel, Corrin Walters, Katherine Boller, Lauren Ghiasvand, Shabnam Liu, Jing Staley, Kevin J. Berdichevsky, Yevgeny TI Neuroprotective levels of IGF-1 exacerbate epileptogenesis after brain injury SO SCIENTIFIC REPORTS LA English DT Article ID GROWTH-FACTOR-I; TEMPORAL-LOBE EPILEPSY; TUBEROUS SCLEROSIS COMPLEX; HIPPOCAMPAL SLICE CULTURES; MAMMALIAN TARGET; RAT-BRAIN; SIGNALING PATHWAY; CELL-DEATH; POSTTRAUMATIC EPILEPSY; SYNAPTIC CONNECTIONS AB Exogenous Insulin-Like Growth Factor-1 (IGF-1) is neuroprotective in animal models of brain injury, and has been considered as a potential therapeutic. Akt-mTOR and MAPK are downstream targets of IGF-1 signaling that are activated after brain injury. However, both brain injury and mTOR are linked to epilepsy, raising the possibility that IGF-1 may be epileptogenic. Here, we considered the role of IGF-1 in development of epilepsy after brain injury, using the organotypic hippocampal culture model of post-traumatic epileptogenesis. We found that IGF-1 was neuroprotective within a few days of injury but that long-term IGF-1 treatment was pro-epileptic. Pro-epileptic effects of IGF-1 were mediated by Akt-mTOR signaling. We also found that IGF-1-mediated increase in epileptic activity led to neurotoxicity. The dualistic nature of effects of IGF-1 treatment demonstrates that anabolic enhancement through IGF-1 activation of mTOR cascade can be beneficial or harmful depending on the stage of the disease. Our findings suggest that epilepsy risk may need to be considered in the design of neuroprotective treatments for brain injury. C1 [Song, Yu; Pimentel, Corrin; Boller, Lauren; Ghiasvand, Shabnam; Berdichevsky, Yevgeny] Lehigh Univ, Bioengn Program, Bethlehem, PA 18015 USA. [Walters, Katherine] Lehigh Univ, IDEAS Program, Bethlehem, PA 18015 USA. [Liu, Jing; Berdichevsky, Yevgeny] Lehigh Univ, Dept Elect & Comp Engn, Bethlehem, PA 18015 USA. [Staley, Kevin J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02129 USA. [Staley, Kevin J.] Harvard Med Sch, Boston, MA 02129 USA. RP Berdichevsky, Y (reprint author), Lehigh Univ, Bioengn Program, Bethlehem, PA 18015 USA.; Berdichevsky, Y (reprint author), Lehigh Univ, Dept Elect & Comp Engn, Bethlehem, PA 18015 USA. EM berdichevsky@lehigh.edu FU Taking Flight Award from Citizens United for Research in Epilepsy (CURE) FX This work was supported by Taking Flight Award from Citizens United for Research in Epilepsy (CURE). NR 68 TC 2 Z9 2 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 AUG 26 PY 2016 VL 6 AR 32095 DI 10.1038/srep32095 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU1KN UT WOS:000381966700003 PM 27561791 ER PT J AU Matulonis, UA Sood, AK Fallowfield, L Howitt, BE Sehouli, J Karlan, BY AF Matulonis, Ursula A. Sood, Anil K. Fallowfield, Lesley Howitt, Brooke E. Sehouli, Jalid Karlan, Beth Y. TI Ovarian cancer SO NATURE REVIEWS DISEASE PRIMERS LA English DT Article ID GYNECOLOGIC-ONCOLOGY-GROUP; GRADE SEROUS CARCINOMA; PHASE-III TRIAL; PEGYLATED LIPOSOMAL DOXORUBICIN; RANDOMIZED CONTROLLED-TRIAL; SMALL-CELL CARCINOMA; TUBAL-INTRAEPITHELIAL-CARCINOMA; OLAPARIB MAINTENANCE THERAPY; RECURRENT EPITHELIAL OVARIAN; CARBOPLATIN PLUS PACLITAXEL AB Ovarian cancer is not a single disease and can be subdivided into at least five different histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically diagnosed at a late stage and has no effective screening strategy. Standard treatments for newly diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent cancer, chemotherapy, anti-angiogenic agents and poly( ADP-ribose) polymerase inhibitors are used, and immunological therapies are currently being tested. High-grade serous carcinoma( HGSC) is the most commonly diagnosed form of ovarian cancer and at diagnosis is typically very responsive to platinum-based chemotherapy. However, in addition to the other histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy. Consequently, understanding the mechanisms underlying platinum resistance and finding ways to overcome them are active areas of study in ovarian cancer. Substantial progress has been made in identifying genes that are associated with a high risk of ovarian cancer( such as BRCA1 and BRCA2), as well as a precursor lesion of HGSC called serous tubal intraepithelial carcinoma, which holds promise for identifying individuals at high risk of developing the disease and for developing prevention strategies. C1 [Matulonis, Ursula A.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX 77030 USA. [Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNA, Houston, TX 77030 USA. [Fallowfield, Lesley] Univ Sussex, Brighton & Sussex Med Sch, Sussex Hlth Outcomes Res & Educ Canc, Falmer, E Sussex, England. [Howitt, Brooke E.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Sehouli, Jalid] Charite, Charite Campus Virchow Klinikum, Berlin, Germany. [Karlan, Beth Y.] Cedars Sinai Med Ctr, Womens Canc Program, Los Angeles, CA 90048 USA. RP Matulonis, UA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM ursula_matulonis@dfci.harvard.edu FU Ovarian Cancer Research Foundation; Breast Cancer Research Foundation; US Department of Defense; US National Institute of Health [CA109298, P50 CA083639, P50 CA098258] FX U.A.M. has received research support from the Ovarian Cancer Research Foundation, the Breast Cancer Research Foundation and the US Department of Defense. A.S. has received research support from the US National Institute of Health (CA109298, P50 CA083639 and P50 CA098258). NR 227 TC 2 Z9 2 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2056-676X J9 NAT REV DIS PRIMERS JI Nat. Rev. Dis. Primers PD AUG 25 PY 2016 VL 2 AR 16061 DI 10.1038/nrdp.2016.61 PG 22 WC Medicine, General & Internal SC General & Internal Medicine GA DY1TH UT WOS:000384876800001 PM 27558151 ER PT J AU Wang, X Wang, MP Viswanath, K Wan, A Lam, TH Chan, SS AF Wang, Xin Wang, Man Ping Viswanath, Kasisomayajula Wan, Alice Lam, Tai Hing Chan, Sophia S. TI Smoking and Secondhand Smoke Exposure at Home Were Associated with Poor Perceived Family Well-Being: Findings of FAMILY Project SO PLOS ONE LA English DT Article ID HONG-KONG; TOBACCO CONTROL; HARMONY; HEALTH; PERSPECTIVES; HAPPINESS; CONFLICT; CHINA; MODEL AB Introduction To investigate the associations of cigarette smoking and secondhand (SHS) exposure at home with family well-being among Chinese adults in Hong Kong. Methods Telephone surveys were conducted among 3043 randomly selected adults (response rate 70%) in 2010 and 2012 to monitor family health information and tobacco use in Hong Kong. Family well-being was measured using three questions of perceived family harmony, happiness and health (3Hs) with responses ranging from 0-10 and a higher score indicating better family well-being. Smoking status, nicotine dependence, quitting behaviours and SHS exposure at home were recorded. Multiple linear regressions were used to calculate beta-coefficients for individual family 3Hs component and an overall composite score representing family well-being. Results Compared with never smokers, current smokers reported lower levels of family harmony (adjusted beta = -0.15, 95% CI: -0.35 to -0.10), happiness (adjusted beta = -0.12, 95% CI: -0.28 to -0.02), health (adjusted beta = -0.15, 95% CI: -0.30 to -0.03) and overall family well-being (adjusted beta = -0.17, 95% CI: -0.32 to -0.06). Quit attempt and intention to quit were not associated with family well-being. SHS exposure at home was associated with lower levels of family harmony (adjusted beta = -0.17, 95% CI: -0.30 to -0.07), happiness (adjusted beta = -0.19, 95% CI: -0.32 to -0.08), health (adjusted beta = -0.13, 95% CI: -0.26 to -0.03) and family wellbeing (adjusted beta = -0.19, 95% CI: -0.32 to -0.09). Conclusions Smoking and SHS exposure at home were associated with the lower levels of perceived family well-being. Prospective studies are needed to confirm the results. C1 [Wang, Xin; Wan, Alice; Lam, Tai Hing] Univ Hong Kong, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China. [Wang, Man Ping; Chan, Sophia S.] Univ Hong Kong, Sch Nursing, Hong Kong, Hong Kong, Peoples R China. [Viswanath, Kasisomayajula] Harvard Sch Publ Hlth, Dept Social & Behav Sci, Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA USA. RP Lam, TH (reprint author), Univ Hong Kong, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China. EM hrmrlth@hku.hk FU Hong Kong Jockey Club Charities Trust FX This study was a part of the project "FAMILY: A Jockey Club Initiative for a Harmonious Society," which was funded by The Hong Kong Jockey Club Charities Trust. NR 28 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 AUG 25 PY 2016 VL 11 IS 8 AR e0161761 DI 10.1371/journal.pone.0161761 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU5NN UT WOS:000382258600092 PM 27560663 ER PT J AU Louissaint, A Schafernak, KT Geyer, JT Kovach, AE Ghandi, M Gratzinger, D Roth, CG Paxton, CN Kim, S Namgyal, C Morin, R Morgan, EA Neuberg, DS South, ST Harris, MH Hasserjian, RP Hochberg, EP Garraway, LA Harris, NL Weinstock, DM AF Louissaint, Abner, Jr. Schafernak, Kristian T. Geyer, Julia T. Kovach, Alexandra E. Ghandi, Mahmoud Gratzinger, Dita Roth, Christine G. Paxton, Christian N. Kim, Sunhee Namgyal, Chungdak Morin, Ryan Morgan, Elizabeth A. Neuberg, Donna S. South, Sarah T. Harris, Marian H. Hasserjian, Robert P. Hochberg, Ephraim P. Garraway, Levi A. Harris, Nancy Lee Weinstock, David M. TI Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations SO BLOOD LA English DT Article ID LANGERHANS CELL HISTIOCYTOSIS; SOMATIC MUTATIONS; MAP2K1 MUTATIONS; CHILDREN; BRAF; LANDSCAPE; PROGNOSIS; UTERUS; ADULTS AB Pediatric-type nodal follicular lymphoma (PTNFL) is a variant of follicular lymphoma (FL) characterized by limited-stage presentation and invariably benign behavior despite often high-grade histological appearance. It is important to distinguish PTNFL from typical FL in order to avoid unnecessary treatment; however, this distinction relies solely on clinical and pathological criteria, which may be variably applied. To define the genetic landscape of PTNFL, we performed copy number analysis and exome and/or targeted sequencing of 26 PTNFLs (16 pediatric and 10 adult). The most commonly mutated gene in PTNFL was MAP2K1, encoding MEK1, with a mutation frequency of 43%. All MAP2K1 mutations were activating missense mutations localized to exons 2 and 3, which encode negative regulatory and catalytic domains, respectively. Missense mutations in MAPK1 (2/22) and RRAS (1/22) were identified in cases that lacked MAP2K1 mutations. The second most commonly mutated gene in PTNFL was TNFRSF14, with a mutation frequency of 29%, similar to that seen in limited-stage typical FL (P =.35). PTNFL was otherwise genomically bland and specifically lacked recurrent mutations in epigenetic modifiers (eg, CREBBP, KMT2D). Copy number aberrations affected a mean of only 0.5% of PTNFL genomes, compared with 10% of limited-stage typical FL genomes (P<. 02). Importantly, the mutational profiles of PTNFLs in children and adults were highly similar. Together, these findings define PTNFL as a biologically and clinically distinct indolent lymphoma of children and adults characterized by a high prevalence of MAPK pathway mutations and a near absence of mutations in epigenetic modifiers. C1 [Louissaint, Abner, Jr.; Hasserjian, Robert P.; Harris, Nancy Lee] Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 2, Boston, MA 02114 USA. [Louissaint, Abner, Jr.; Kim, Sunhee; Garraway, Levi A.; Weinstock, David M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Schafernak, Kristian T.] Ann & Robert H Lurie Childrens Hosp Chicago, Dept Pathol & Lab Med, Chicago, IL 60611 USA. [Geyer, Julia T.] New York Presbyterian Hosp, Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY USA. [Kovach, Alexandra E.; Harris, Marian H.] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Ghandi, Mahmoud; Garraway, Levi A.; Weinstock, David M.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Gratzinger, Dita] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Roth, Christine G.] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. [Paxton, Christian N.] Univ Utah, Dept Pathol, ARUP Inst Clin & Expt Pathol, Salt Lake City, UT USA. [Namgyal, Chungdak; Morgan, Elizabeth A.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Morin, Ryan] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC, Canada. [Neuberg, Donna S.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [South, Sarah T.] Univ Utah, Dept Pathol, ARUP Labs, Salt Lake City, UT USA. [Hochberg, Ephraim P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Louissaint, A (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 2, Boston, MA 02114 USA. EM alouissaint@partners.org OI Morgan, Elizabeth/0000-0001-5880-9337; Ghandi, Mahmoud/0000-0003-1897-2265; Gratzinger, Dita/0000-0002-9182-8123; Schafernak, Kristian/0000-0003-3052-8925 FU National Institutes of Health, National Cancer Institute [K23CA184279]; American Cancer Society; American Society of Hematology/Amos Medical Faculty Development Program; Harvard Catalyst Program for Faculty Development and Diversity Inclusion FX This work was supported by a grant from the National Institutes of Health, National Cancer Institute (K23CA184279). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A.L. receives research support from American Cancer Society, the American Society of Hematology/Amos Medical Faculty Development Program, and Harvard Catalyst Program for Faculty Development and Diversity Inclusion. A.L. and E.P.H. gratefully acknowledge funding support from an anonymous foundation. D.M.W. is a Leukemia and Lymphoma Society Scholar. NR 31 TC 3 Z9 3 U1 2 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD AUG 25 PY 2016 VL 128 IS 8 BP 1093 EP 1100 DI 10.1182/blood-2015-12-682591 PG 8 WC Hematology SC Hematology GA DW7LT UT WOS:000383832900017 PM 27325104 ER PT J AU Jurinovic, V Kridel, R Staiger, AM Szczepanowski, M Horn, H Dreyling, MH Rosenwald, A Ott, G Klapper, W Zelenetz, AD Barr, PM Friedberg, JW Ansell, S Sehn, LH Connors, JM Gascoyne, RD Hiddemann, W Unterhalt, M Weinstock, DM Weigert, O AF Jurinovic, Vindi Kridel, Robert Staiger, Annette M. Szczepanowski, Monika Horn, Heike Dreyling, Martin H. Rosenwald, Andreas Ott, German Klapper, Wolfram Zelenetz, Andrew D. Barr, Paul M. Friedberg, Jonathan W. Ansell, Stephen Sehn, Laurie H. Connors, Joseph M. Gascoyne, Randy D. Hiddemann, Wolfgang Unterhalt, Michael Weinstock, David M. Weigert, Oliver TI Clinicogenetic risk models predict early progression of follicular lymphoma after first-line immunochemotherapy SO BLOOD LA English DT Article ID B-CELL LYMPHOMA; MINIMAL RESIDUAL DISEASE; FREE SURVIVAL; RITUXIMAB; TRIAL; MUTATIONS; CHOP; CYCLOPHOSPHAMIDE; VINCRISTINE; DOXORUBICIN AB Follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease. Posttreatment surrogate end points, such as progression of disease within 24 months (POD24) are promising predictors for overall survival (OS) but are of limited clinical value, primarily because they cannot guide up-front treatment decisions. We used the clinical and molecular data from 2 independent cohorts of symptomatic patients in need of first-line immunochemotherapy (151 patients from a German Low-Grade Lymphoma Study Group [GLSG] trial and 107 patients from a population-based registry of the British Columbia Cancer Agency [BCCA]) to validate the predictive utility of POD24, and to evaluate the ability of pretreatment risk models to predict early treatment failure. POD24 occurred in 17% and 23% of evaluable GLSG and BCCA patients, with 5-year OS rates of 41% (vs 91% for those without POD24, P <.0001) and 26% (vs 86%, P <.0001), respectively. The m7-FL International Prognostic Index (m7-FLIPI), a prospective clinicogenetic risk model for failure-free survival, had the highest accuracy to predict POD24 (76% and 77%, respectively) with an odds ratio of 5.82 in GLSG (P =.00031) and 4.76 in BCCA patients (P=.0052). A clinicogenetic risk model specifically designed to predict POD24, the POD24-PI, had the highest sensitivity to predict POD24, but at the expense of a lower specificity. In conclusion, the m7-FLIPI prospectively identifies the smallest subgroup of patients (28% and 22%, respectively) at highest risk of early failure of first-line immunochemotherapy and death, including patients not fulfilling the POD24 criteria, and should be evaluated in prospective trials of precision medicine approaches in FL. C1 [Jurinovic, Vindi; Dreyling, Martin H.; Hiddemann, Wolfgang; Unterhalt, Michael; Weigert, Oliver] Univ Munich, Univ Hosp, Dept Med 3, Munich, Germany. [Jurinovic, Vindi] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Kridel, Robert; Sehn, Laurie H.; Connors, Joseph M.; Gascoyne, Randy D.] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC, Canada. [Staiger, Annette M.; Horn, Heike; Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Staiger, Annette M.; Horn, Heike] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Staiger, Annette M.; Horn, Heike] Univ Tubingen, Tubingen, Germany. [Szczepanowski, Monika; Klapper, Wolfram] Univ Hosp Schleswig Holstein, Hematopathol Sect, Campus Kiel, Kiel, Germany. [Rosenwald, Andreas] Univ Wurzburg, Inst Pathol, Wurzburg, Germany. [Rosenwald, Andreas] Comprehens Canc Ctr Mainfranken, Wurzburg, Germany. [Zelenetz, Andrew D.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Zelenetz, Andrew D.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Barr, Paul M.; Friedberg, Jonathan W.] Univ Rochester, Wilmot Canc Inst, Rochester, NY USA. [Ansell, Stephen] Mayo Clin, Div Hematol, Rochester, MN USA. [Hiddemann, Wolfgang; Weigert, Oliver] German Canc Consortium, Heidelberg, Germany. [Hiddemann, Wolfgang; Weigert, Oliver] German Canc Res Ctr, Heidelberg, Germany. [Weinstock, David M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Weigert, O (reprint author), Univ Munich, Univ Hosp, Dept Med 3, Lab Expt Leukemia & Lymphoma Res ELLF, Max Lebsche Pl 30, D-81377 Munich, Germany. EM oliver.weigert@med.uni-muenchen.de RI Klapper, Wolfram/S-6314-2016 FU Max-Eder Program of the Deutsche Krebshilfe e.V. [110659]; Deutsche Forschungsgemeinschaft [DFG-SFB/CRC-1243, TP-A11]; Program Project Grant from the Terry Fox Research Institute [1023]; Robert-Bosch-Foundation FX This study was supported by the Max-Eder Program of the Deutsche Krebshilfe e.V. (110659) (O.W.), the Deutsche Forschungsgemeinschaft (DFG-SFB/CRC-1243, TP-A11) (O.W.), and in part by a Program Project Grant from the Terry Fox Research Institute (1023) (J.M.C. and R.D.G.).; G.O. receives funding from the Robert-Bosch-Foundation. D.M.W. is a Leukemia and Lymphoma Scholar. NR 26 TC 4 Z9 4 U1 4 U2 4 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 AUG 25 PY 2016 VL 128 IS 8 BP 1112 EP 1120 DI 10.1182/blood-2016-05-717355 PG 9 WC Hematology SC Hematology GA DW7LT UT WOS:000383832900019 PM 27418643 ER PT J AU Katz, IT Bogart, LM Fu, CM Liu, YN Cox, JE Samuels, RC Chase, T Schubert, P Schuster, MA AF Katz, Ingrid T. Bogart, Laura M. Fu, Chong Min Liu, Yingna Cox, Joanne E. Samuels, Ronald C. Chase, Tami Schubert, Pamela Schuster, Mark A. TI Barriers to HPV immunization among blacks and latinos: a qualitative analysis of caregivers, adolescents, and providers SO BMC PUBLIC HEALTH LA English DT Article DE HPV immunization; Adolescents; Parental preferences; Provider preferences; Qualitative methods ID HUMAN-PAPILLOMAVIRUS VACCINATION; AFRICAN-AMERICAN; LOW-INCOME; CONSPIRACY BELIEFS; UNITED-STATES; COVERAGE; HEALTH; WOMEN; GIRLS; COMMUNICATION AB Background: Despite recommendations that 11-12-year-olds receive the full three-shot Human papillomavirus (HPV) vaccine series, national HPV immunization coverage rates remain low. Disparities exist, with Blacks and Latinos being less likely than Whites to complete the series. We aimed to identify and compare barriers to HPV immunization perceived by healthcare providers, Black and Latino adolescents, and their caregivers to inform a clinic-based intervention to improve immunization rates. Methods: We conducted semi-structured interviews between March and July 2014 with Black and Latino adolescents (n = 24), their caregivers (n = 24), and nurses (n = 18), and 2 focus groups with 18 physicians recruited from two pediatric primary care clinics. Qualitative protocol topics included: general perceptions and attitudes towards vaccines; HPV knowledge; and perceived individual and systems-level barriers affecting vaccine initiation and completion. Results: Themes were identified and organized by individual and systems-level barriers to HPV immunization. Adolescents and their caregivers, particularly Blacks, expressed concerns about HPV being an untested, "newer" vaccine. All families felt they needed more information on HPV and found it difficult to return for multiple visits to complete the vaccine series. Providers focused on challenges related to administering multiple vaccines simultaneously, and perceptions of parental reluctance to discuss sexually transmitted infections. Conclusions: Optimizing HPV immunization rates may benefit from a multi-pronged approach to holistically address provider, structural, and individual barriers to care. Further research should examine strategies for providing multiple modalities of support for providers, including a routinized system of vaccine promotion and delivery, and for addressing families' concerns about vaccine safety and efficacy. C1 [Katz, Ingrid T.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Katz, Ingrid T.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Katz, Ingrid T.; Bogart, Laura M.; Cox, Joanne E.; Samuels, Ronald C.; Schuster, Mark A.] Harvard Med Sch, Boston, MA USA. [Bogart, Laura M.; Fu, Chong Min; Liu, Yingna; Cox, Joanne E.; Samuels, Ronald C.; Chase, Tami; Schubert, Pamela; Schuster, Mark A.] Boston Childrens Hosp, Div Gen Pediat, Boston, MA USA. [Bogart, Laura M.] RAND Corp, Santa Monica, CA USA. [Katz, Ingrid T.] Div Womens Hlth, 1620 Tremont St,3rd Floor BWH, Boston, MA 02120 USA. RP Katz, IT (reprint author), Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA.; Katz, IT (reprint author), Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. EM ikatz2@partners.org FU The National Institutes of Health [R24MD001648] FX The National Institutes of Health (R24MD001648) supported this work. NR 40 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD AUG 25 PY 2016 VL 16 AR 874 DI 10.1186/s12889-016-3529-4 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DU1QE UT WOS:000381982500001 PM 27558506 ER PT J AU Dong, TT Zhi, L Bhayana, B Wu, MX AF Dong, Tingting Zhi, Liang Bhayana, Brijesh Wu, Mei X. TI Cortisol-induced immune suppression by a blockade of lymphocyte egress in traumatic brain injury SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE TBI; T lymphocytes; Cortisol; Inflammation; cAMP ID SPINAL-CORD-INJURY; CENTRAL-NERVOUS-SYSTEM; SPHINGOSINE 1-PHOSPHATE; T-CELLS; TREATMENT STRATEGIES; CONTROLLED-TRIAL; PROGESTERONE; METHYLPREDNISOLONE; NEUROGENESIS; RECEPTORS AB Background: Acute traumatic brain injury (TBI) represents one of major causes of mortality and disability in the USA. Neuroinflammation has been regarded both beneficial and detrimental, probably in a time-dependent fashion. Methods: To address a role for neuroinflammation in brain injury, C57BL/6 mice were subjected to a closed head mild TBI (mTBI) by a standard controlled cortical impact, along with or without treatment of sphingosine 1-phosphate (S1P) or rolipram, after which the brain tissue of the impact site was evaluated for cell morphology via histology, inflammation by qRT-PCR and T cell staining, and cell death with Caspase-3 and TUNEL staining. Circulating lymphocytes were quantified by flow cytometry, and plasma hydrocortisone was analyzed by LC-MS/MS. To investigate the mechanism whereby cortisol lowered the number of peripheral T cells, T cell egress was tracked in lymph nodes by intravital confocal microscopy after hydrocortisone administration. Results: We detected a decreased number of circulating lymphocytes, in particular, T cells soon after mTBI, which was inversely correlated with a transient and robust increase of plasma cortisol. The transient lymphocytopenia might be caused by cortisol in part via a blockade of lymphocyte egress as demonstrated by the ability of cortisol to inhibit T cell egress from the secondary lymphoid tissues. Moreover, exogenous hydrocortisone severely suppressed periphery lymphocytes in uninjured mice, whereas administering an egress-promoting agent SIP normalized circulating T cells in mTBI mice and increased T cells in the injured brain. Likewise, rolipram, a cAMP phosphodiesterase inhibitor, was also able to elevate cAMP levels in T cells in the presence of hydrocortisone in vitro and abrogate the action of cortisol in mTBI mice. The investigation demonstrated that the number of circulating T cells in the early phase of TBI was positively correlated with T cell infiltration and inflammatory responses as well as cell death at the cerebral cortex and hippocampus beneath the impact site. Conclusions: Decreases in intracellular cAMP might be part of the mechanism behind cortisol-mediated blockade of T cell egress. The study argues strongly for a protective role of cortisol-induced immune suppression in the early stage of TBI. C1 [Dong, Tingting; Zhi, Liang; Bhayana, Brijesh; Wu, Mei X.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, 50 Blossom St, Boston, MA 02114 USA. RP Wu, MX (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, 50 Blossom St, Boston, MA 02114 USA. EM mwu5@mgh.harvard.edu FU Department of Defense/Air Force Office of Scientific Research Militory Photomedicine Program; Department of Defense; CDMRP/BAA; Wellman Center for Photomedicine; [FA9550-11-1-0415]; [FA9550-13-1-0068]; [W81XWH-13-2-0067] FX This work is supported by FA9550-11-1-0415 and FA9550-13-1-0068, Department of Defense/Air Force Office of Scientific Research Militory Photomedicine Program, W81XWH-13-2-0067, Department of Defense, CDMRP/BAA, and the fund of Wellman Center for Photomedicine to MXW. NR 50 TC 1 Z9 1 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD AUG 25 PY 2016 VL 13 AR 197 DI 10.1186/s12974-016-0663-y PG 13 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DV3QI UT WOS:000382837500002 PM 27561600 ER PT J AU Sousa, CM Biancur, DE Wang, XX Halbrook, CJ Sherman, MH Zhang, L Kremer, D Hwang, RF Witkiewicz, AK Ying, HQ Asara, JM Evans, RM Cantley, LC Lyssiotis, CA Kimmelman, AC AF Sousa, Cristovao M. Biancur, Douglas E. Wang, Xiaoxu Halbrook, Christopher J. Sherman, Mara H. Zhang, Li Kremer, Daniel Hwang, Rosa F. Witkiewicz, Agnes K. Ying, Haoqiang Asara, John M. Evans, Ronald M. Cantley, Lewis C. Lyssiotis, Costas A. Kimmelman, Alec C. TI Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion SO NATURE LA English DT Article ID CANCER; FIBROBLASTS; GROWTH; PROGRESSION; PROTEIN AB Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by an intense fibrotic stromal response and deregulated metabolism(1-4). The role of the stroma in PDAC biology is complex and it has been shown to play critical roles that differ depending on the biological context(5-10). The stromal reaction also impairs the vasculature, leading to a highly hypoxic, nutrient-poor environment(4,11,12). As such, these tumours must alter how they capture and use nutrients to support their metabolic needs(11,13). Here we show that stroma-associated pancreatic stellate cells (PSCs) are critical for PDAC metabolism through the secretion of non-essential amino acids (NEAA). Specifically, we uncover a previously undescribed role for alanine, which outcompetes glucose and glutamine-derived carbon in PDAC to fuel the tricarboxylic acid (TCA) cycle, and thus NEAA and lipid biosynthesis. This shift in fuel source decreases the tumour's dependence on glucose and serum-derived nutrients, which are limited in the pancreatic tumour microenvironment(4,11). Moreover, we demonstrate that alanine secretion by PSCs is dependent on PSC autophagy, a process that is stimulated by cancer cells. Thus, our results demonstrate a novel metabolic interaction between PSCs and cancer cells, in which PSC-derived alanine acts as an alternative carbon source. This finding highlights a previously unappreciated metabolic network within pancreatic tumours in which diverse fuel sources are used to promote growth in an austere tumour microenvironment. C1 [Sousa, Cristovao M.; Biancur, Douglas E.; Wang, Xiaoxu; Kimmelman, Alec C.] Harvard Med Sch, Dana Farber Canc Inst, Dept Radiat Oncol, Div Genom Stabil & DNA Repair, Boston, MA 02215 USA. [Halbrook, Christopher J.; Zhang, Li; Kremer, Daniel; Lyssiotis, Costas A.] Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Sherman, Mara H.; Evans, Ronald M.] Salk Inst Biol Studies, Howard Hughes Med Inst, Gene Express Lab, La Jolla, CA 92037 USA. [Hwang, Rosa F.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77230 USA. [Witkiewicz, Agnes K.] UT Southwestern, Dept Pathol, Dallas, TX 75390 USA. [Witkiewicz, Agnes K.] UT Southwestern, Simmons Canc Ctr, Dallas, TX 75390 USA. [Ying, Haoqiang] UT MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. [Asara, John M.] Beth Israel Deaconess Med Ctr, Dept Med, Div Signal Transduct, Boston, MA 02115 USA. [Asara, John M.] Harvard Med Sch, Boston, MA 02115 USA. [Cantley, Lewis C.] Weill Cornell Med Coll, Dept Med, Meyer Canc Ctr, New York, NY 10065 USA. [Lyssiotis, Costas A.] Univ Michigan, Sch Med, Div Gastroenterol, Dept Internal Med, Ann Arbor, MI 48109 USA. [Kimmelman, Alec C.] NYU, Langone Med Ctr, Perlmutter Canc Ctr, Dept Radiat Oncol, New York, NY 10016 USA. RP Kimmelman, AC (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Radiat Oncol, Div Genom Stabil & DNA Repair, Boston, MA 02215 USA.; Lyssiotis, CA (reprint author), Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA.; Lyssiotis, CA (reprint author), Univ Michigan, Sch Med, Div Gastroenterol, Dept Internal Med, Ann Arbor, MI 48109 USA.; Kimmelman, AC (reprint author), NYU, Langone Med Ctr, Perlmutter Canc Ctr, Dept Radiat Oncol, New York, NY 10016 USA. EM clyssiot@med.umich.edu; alec.kimmelman@nyumc.org FU NIH [5P30CA06516, GM095567, DK097153]; NCI [R01CA157490, R01CA188048]; ACS [RSG-13-298-01-TBG]; Lustgarten Foundation; PanCAN-AACRPathway to Leadership award; Dale F. Frey award from Damon Runyon Cancer Research Foundation [DFS-09-14]; PanCAN-AACR; Stand Up to Cancer Dream Team Translational Cancer Research Grant, a Program of the Entertainment Industry Foundation [SU2C-AACR-DT0509]; [P01CA117969]; [P30CA006516]; [P01CA120964] FX We thank Kimmelman laboratory members for reading the manuscript, A. Yang for help with orthotopic injections, M. Yuan and S. Breitkopf for technical support with mass spectrometry, E. Sicinska for resected PDAC specimens, and the Dana-Farber/Harvard Cancer Center Rodent Histopathology Core for assistance with tissue processing. DFHCC is supported in part by NIH 5P30CA06516. A.C.K. is supported by NIH grant GM095567, NCI grants R01CA157490, R01CA188048, ACS Research Scholar Grant (RSG-13-298-01-TBG), and the Lustgarten Foundation. C.A.L. is supported by a PanCAN-AACRPathway to Leadership award and a Dale F. Frey award from the Damon Runyon Cancer Research Foundation (DFS-09-14). Metabolomics studies performed at the University of Michigan were supported by NIH grant DK097153. L.C.C. was supported by P01CA117969, PanCAN-AACR and the Lustgarten Foundation. J.M.A. was supported by P30CA006516 and P01CA120964. R.M.E. is an investigator of the Howard Hughes Medical Institute and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute, and is supported in part by grants from The Lustgarten Foundation and a Stand Up to Cancer Dream Team Translational Cancer Research Grant, a Program of the Entertainment Industry Foundation (SU2C-AACR-DT0509). NR 29 TC 26 Z9 26 U1 29 U2 29 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 AUG 25 PY 2016 VL 536 IS 7617 BP 479 EP + DI 10.1038/nature19084 PG 25 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV0YL UT WOS:000382646600046 PM 27509858 ER PT J AU Kantarjian, HM DeAngelo, DJ Stelljes, M Martinelli, G Liedtke, M Stock, W Gokbuget, N O'Brien, S Wang, KM Wang, T Paccagnella, ML Sleight, B Vandendries, E Advani, AS AF Kantarjian, Hagop M. DeAngelo, Daniel J. Stelljes, Matthias Martinelli, Giovanni Liedtke, Michaela Stock, Wendy Gokbuget, Nicola O'Brien, Susan Wang, Kongming Wang, Tao Paccagnella, M. Luisa Sleight, Barbara Vandendries, Erik Advani, Anjali S. TI Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE LYMPHOCYTIC-LEUKEMIA; TERM-FOLLOW-UP; HEMATOLOGICAL MALIGNANCIES; INTENSIVE CONSOLIDATION; MONOCLONAL-ANTIBODY; INDUCTION THERAPY; SALVAGE THERAPY; LALA-94 TRIAL; ADULTS; CHEMOTHERAPY AB BACKGROUND The prognosis for adults with relapsed acute lymphoblastic leukemia is poor. We sought to determine whether inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, results in better outcomes in patients with relapsed or refractory acute lymphoblastic leukemia than does standard therapy. METHODS In this phase 3 trial, we randomly assigned adults with relapsed or refractory acute lymphoblastic leukemia to receive either inotuzumab ozogamicin (inotuzumab ozogamicin group) or standard intensive chemotherapy (standard-therapy group). The primary end points were complete remission (including complete remission with incomplete hematologic recovery) and overall survival. RESULTS Of the 326 patients who underwent randomization, the first 218 (109 in each group) were included in the primary intention-to-treat analysis of complete remission. The rate of complete remission was significantly higher in the inotuzumab ozogamicin group than in the standard-therapy group (80.7% [95% confidence interval {CI}, 72.1 to 87.7] vs. 29.4% [95% CI, 21.0 to 38.8], P < 0.001). Among the patients who had complete remission, a higher percentage in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease (0.01% marrow blasts) (78.4% vs. 28.1%, P < 0.001); the duration of remission was longer in the inotuzumab ozogamicin group (median, 4.6 months [95% CI, 3.9 to 5.4] vs. 3.1 months [95% CI, 1.4 to 4.9]; hazard ratio, 0.55 [95% CI, 0.31 to 0.96]; P = 0.03). In the survival analysis, which included all 326 patients, progression-free survival was significantly longer in the inotuzumab ozogamicin group (median, 5.0 months [95% CI, 3.7 to 5.6] vs. 1.8 months [95% CI, 1.5 to 2.2]; hazard ratio, 0.45 [97.5% CI, 0.34 to 0.61]; P < 0.001); the median overall survival was 7.7 months (95% CI, 6.0 to 9.2) versus 6.7 months (95% CI, 4.9 to 8.3), and the hazard ratio was 0.77 (97.5% CI, 0.58 to 1.03) (P = 0.04). In the safety population, the most frequent grade 3 or higher nonhematologic adverse events with inotuzumab ozogamicin were liver-related. Veno-occlusive liver disease of any grade occurred in 15 patients (11%) who received inotuzumab ozogamicin and in 1 patient (1%) who received standard therapy. CONCLUSIONS The rate of complete remission was higher with inotuzumab ozogamicin than with standard therapy, and a higher percentage of patients in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease. Both progression-free and overall survival were longer with inotuzumab ozogamicin. Veno-occlusive liver disease was a major adverse event associated with inotuzumab ozogamicin. (Funded by Pfizer; INO-VATE ALL ClinicalTrials.gov number, NCT01564784.) C1 [Kantarjian, Hagop M.] Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd, Houston, TX 77030 USA. [DeAngelo, Daniel J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Vandendries, Erik] Pfizer, Cambridge, MA USA. [Stelljes, Matthias] Univ Klinikum Munster, Munster, Germany. [Gokbuget, Nicola] Goethe Univ Frankfurt, Frankfurt, Germany. [Martinelli, Giovanni] Univ Bologna, DIMES Dept Expt Diagnost & Specialty Med, Inst Seragnoli, Bologna, Italy. [Liedtke, Michaela] Stanford Canc Inst, Stanford, CA USA. [O'Brien, Susan] Univ Calif Irvine, Med Ctr, Orange, CA 92668 USA. [Stock, Wendy] Univ Chicago, Chicago, IL 60637 USA. [Wang, Kongming] Pfizer, Pearl River, NY USA. [Wang, Tao; Paccagnella, M. Luisa; Sleight, Barbara] Pfizer, Groton, CT USA. [Advani, Anjali S.] Cleveland Clin, Cleveland, OH 44106 USA. RP Kantarjian, HM (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Leukemia, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM hkantarjian@mdanderson.org FU Pfizer FX Supported by Pfizer. NR 38 TC 22 Z9 22 U1 9 U2 9 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 AUG 25 PY 2016 VL 375 IS 8 BP 740 EP 753 DI 10.1056/NEJMoa1509277 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA DT9ET UT WOS:000381799300012 PM 27292104 ER PT J AU Choy, E Hornicek, FJ Chen, YL Rosenthal, DI Kerr, DA AF Choy, Edwin Hornicek, Francis J. Chen, Yen-Lin Rosenthal, Daniel I. Kerr, Darcy A. TI Case 26-2016: A 28-Year-Old Woman with Back Pain and a Lesion in the Lumbar Spine SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GIANT-CELL TUMOR; ANTIANGIOGENIC THERAPY; RECEIVING DENOSUMAB; BONE; BISPHOSPHONATE; RISK; RADIOTHERAPY; RECURRENT; EFFICACY; SAFETY C1 [Choy, Edwin] Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. [Hornicek, Francis J.] Massachusetts Gen Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Chen, Yen-Lin] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Rosenthal, Daniel I.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02115 USA. [Kerr, Darcy A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA. [Choy, Edwin] Harvard Med Sch, Dept Med, Boston, MA USA. [Hornicek, Francis J.] Harvard Med Sch, Dept Orthoped Surg, Boston, MA USA. [Chen, Yen-Lin] Harvard Med Sch, Dept Radiat Oncol, Boston, MA USA. [Rosenthal, Daniel I.] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Kerr, Darcy A.] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Choy, E (reprint author), Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. FU Bayer; Amgen; EMD Serono; Pfizer; NPS Pharmaceuticals; Stryker FX Dr. Choy reports receiving fees for serving on advisory boards from Bayer, Amgen, and EMD Serono, consulting fees from Pfizer and NPS Pharmaceuticals, and grant support from Amgen; and Dr. Hornicek, receiving fees for educational courses from Stryker. No other potential conflict of interest relevant to this article was reported. NR 33 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 AUG 25 PY 2016 VL 375 IS 8 BP 779 EP 788 DI 10.1056/NEJMcpc1505482 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DT9ET UT WOS:000381799300016 PM 27557305 ER PT J AU Anderson, EC Barrett, LF AF Anderson, Eric C. Barrett, Lisa Feldman TI Affective Beliefs Influence the Experience of Eating Meat SO PLOS ONE LA English DT Article ID VEGETABLE CONSUMPTION; RISK; METAANALYSIS; PREFERENCES; VEGETARIAN; COGNITION; COHORT; FRUIT; TASTE; DIET AB People believe they experience the world objectively, but research continually demonstrates that beliefs influence perception. Emerging research indicates that beliefs influence the experience of eating. In three studies, we test whether beliefs about how animals are raised can influence the experience of eating meat. Samples of meat were paired with descriptions of animals raised on factory farms or raised on humane farms. Importantly, the meat samples in both conditions were identical. However, participants experienced the samples differently: meat paired with factory farm descriptions looked, smelled, and tasted less pleasant. Even basic properties of flavor were influenced: factory farmed samples tasted more salty and greasy. Finally, actual behavior was influenced: participants consumed less when samples were paired with factory farm descriptions. These findings demonstrate that the experience of eating is not determined solely by physical properties of stimuli-beliefs also shape experience. C1 [Anderson, Eric C.] Tufts Univ, Ctr Appl Brain & Cognit Sci, Medford, MA 02155 USA. [Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Barrett, Lisa Feldman] Harvard Med Sch, Boston, MA USA. RP Anderson, EC (reprint author), Tufts Univ, Ctr Appl Brain & Cognit Sci, Medford, MA 02155 USA. EM ericmranderson@gmail.com NR 41 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 24 PY 2016 VL 11 IS 8 AR e0160424 DI 10.1371/journal.pone.0160424 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU5NI UT WOS:000382258100014 PM 27556643 ER PT J AU Frelinger, AL Gerrits, AJ Garner, AL Torres, AS Caiafa, A Morton, CA Berny-Lang, MA Carmichael, SL Neculaes, VB Michelson, AD AF Frelinger, Andrew L., III Gerrits, Anja J. Garner, Allen L. Torres, Andrew S. Caiafa, Antonio Morton, Christine A. Berny-Lang, Michelle A. Carmichael, Sabrina L. Neculaes, V. Bogdan Michelson, Alan D. TI Modification of Pulsed Electric Field Conditions Results in Distinct Activation Profiles of Platelet-Rich Plasma SO PLOS ONE LA English DT Article ID IRREVERSIBLE ELECTROPORATION; MEMBRANE PERMEABILIZATION; NANOSECOND PULSES; EPITHELIAL-CELLS; BOVINE THROMBIN; ELECTROPERMEABILIZATION; DURATION; IMPACT; GROWTH; GEL AB Background Activated autologous platelet-rich plasma (PRP) used in therapeutic wound healing applications is poorly characterized and standardized. Using pulsed electric fields (PEF) to activate platelets may reduce variability and eliminate complications associated with the use of bovine thrombin. We previously reported that exposing PRP to sub-microsecond duration, high electric field (SMHEF) pulses generates a greater number of platelet-derived microparticles, increased expression of prothrombotic platelet surfaces, and differential release of growth factors compared to thrombin. Moreover, the platelet releasate produced by SMHEF pulses induced greater cell proliferation than plasma. Aims To determine whether sub-microsecond duration, low electric field (SMLEF) bipolar pulses results in differential activation of PRP compared to SMHEF, with respect to profiles of activation markers, growth factor release, and cell proliferation capacity. Methods PRP activation by SMLEF bipolar pulses was compared to SMHEF pulses and bovine thrombin. PRP was prepared using the Harvest SmartPreP2 System from acid citrate dextrose anticoagulated healthy donor blood. PEF activation by either SMHEF or SMLEF pulses was performed using a standard electroporation cuvette preloaded with CaCl2 and a prototype instrument designed to take into account the electrical properties of PRP. Flow cytometry was used to assess platelet surface P-selectin expression, and annexin V binding. Platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), endothelial growth factor (EGF) and platelet factor 4 (PF4), and were measured by ELISA. The ability of supernatants to stimulate proliferation of human epithelial cells in culture was also evaluated. Controls included vehicle-treated, unactivated PRP and PRP with 10 mM CaCl2 activated with 1 U/mL bovine thrombin. Results PRP activated with SMLEF bipolar pulses or thrombin had similar light scatter profiles, consistent with the presence of platelet-derived microparticles, platelets, and platelet aggregates whereas SMHEF pulses primarily resulted in platelet-derived microparticles. Microparticles and platelets in PRP activated with SMLEF bipolar pulses had significantly lower annexin V-positivity than those following SMHEF activation. In contrast, the% P-selectin positivity and surface P-selectin expression (MFI) for platelets and microparticles in SMLEF bipolar pulse activated PRP was significantly higher than that in SMHEF-activated PRP, but not significantly different from that produced by thrombin activation. Higher levels of EGF were observed following either SMLEF bipolar pulses or SMHEF pulses of PRP than after bovine thrombin activation while VEGF, PDGF, and PF4 levels were similar with all three activating conditions. Cell proliferation was significantly increased by releasates of both SMLEF bipolar pulse and SMHEF pulse activated PRP compared to plasma alone. Conclusions PEF activation of PRP at bipolar low vs. monopolar high field strength results in differential platelet-derived microparticle production and activation of platelet surface procoagulant markers while inducing similar release of growth factors and similar capacity to induce cell proliferation. Stimulation of PRP with SMLEF bipolar pulses is gentler than SMHEF pulses, resulting in less platelet microparticle generation but with overall activation levels similar to that obtained with thrombin. These results suggest that PEF provides the means to alter, in a controlled fashion, PRP properties thereby enabling evaluation of their effects on wound healing and clinical outcomes. C1 [Frelinger, Andrew L., III; Gerrits, Anja J.; Berny-Lang, Michelle A.; Carmichael, Sabrina L.; Michelson, Alan D.] Harvard Med Sch, Boston Childrens Hosp, Dana Farber Canc Inst, Ctr Platelet Res Studies,Div Hematol Oncol, Boston, MA 02115 USA. [Garner, Allen L.] Purdue Univ, Sch Nucl Engn, W Lafayette, IN 47907 USA. [Torres, Andrew S.; Caiafa, Antonio; Morton, Christine A.; Neculaes, V. Bogdan] GE Global Res Ctr, Niskayuna, NY 12309 USA. [Torres, Andrew S.] Regeneron Pharmaceut Inc, Rensselaer, NY USA. RP Frelinger, AL (reprint author), Harvard Med Sch, Boston Childrens Hosp, Dana Farber Canc Inst, Ctr Platelet Res Studies,Div Hematol Oncol, Boston, MA 02115 USA.; Neculaes, VB (reprint author), GE Global Res Ctr, Niskayuna, NY 12309 USA. EM Andrew.Frelinger@childrens.harvard.edu; Neculaes@research.ge.com FU GE Healthcare FX This work was funded by a research grant from GE Healthcare to Boston Children's Hospital, Principal Investigator, ALF. The funders participated in study design, data collection, and preparation of the manuscript, but had no role in data analysis or the decision to publish. NR 63 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 AUG 24 PY 2016 VL 11 IS 8 AR e0160933 DI 10.1371/journal.pone.0160933 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU5NI UT WOS:000382258100023 PM 27556645 ER PT J AU Jodar, M Sendler, E Moskovtsev, SI Librach, CL Goodrich, R Swanson, S Hauser, R Diamond, MP Krawetz, SA AF Jodar, Meritxell Sendler, Edward Moskovtsev, Sergey I. Librach, Clifford L. Goodrich, Robert Swanson, Sonja Hauser, Russ Diamond, Michael P. Krawetz, Stephen A. TI Response to Comment on "Absence of sperm RNA elements correlates with idiopathic male infertility" SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material ID HUMAN SEMEN AB RNAs from other cell types have minimal impact on male fecundity-associated sperm RNA elements. C1 [Jodar, Meritxell; Sendler, Edward; Goodrich, Robert; Diamond, Michael P.; Krawetz, Stephen A.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Jodar, Meritxell; Sendler, Edward; Goodrich, Robert; Krawetz, Stephen A.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Moskovtsev, Sergey I.; Librach, Clifford L.; Swanson, Sonja] CReATe Fertil Ctr, Toronto, ON M5G 1N8, Canada. [Moskovtsev, Sergey I.; Librach, Clifford L.] Univ Toronto, Dept Obstet & Gynaecol, Toronto, ON M5G 1E2, Canada. [Librach, Clifford L.] Womens Coll Hosp, Dept Gynaecol, Toronto, ON M5S 1B2, Canada. [Hauser, Russ] Harvard Med Sch, Massachusetts Gen Hosp, Vincent Mem Obstet & Gynecol Serv, Boston, MA 02114 USA. [Hauser, Russ] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Hauser, Russ] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Diamond, Michael P.] Augusta Univ, Dept Obstet & Gynecol, Augusta, GA 30912 USA. [Jodar, Meritxell] Univ Barcelona, Inst Invest Biomed August Pi & Sunyer IDIBAPS, E-08036 Barcelona, Spain. RP Krawetz, SA (reprint author), Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA.; Krawetz, SA (reprint author), Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. EM steve@compbio.med.wayne.edu NR 14 TC 0 Z9 0 U1 4 U2 4 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 AUG 24 PY 2016 VL 8 IS 353 AR 353tr1 DI 10.1126/scitranslmed.aaf4550 PG 5 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DW9WU UT WOS:000384014200005 ER PT J AU Karimi, M Zangabad, PS Ghasemi, A Amiri, M Bahrami, M Malekzad, H Asl, HG Mandieh, Z Bozorgomid, M Ghasemi, A Boyuk, MRRT Hamblin, MR AF Karimi, Mandi Zangabad, Parham Sahandi Ghasemi, Alireza Amiri, Mohammad Bahrami, Mohsen Malekzad, Hedieh Asl, Hadi Ghahramanzadeh Mandieh, Zahra Bozorgomid, Mahnaz Ghasemi, Amir Boyuk, Mohammad Reza Rahmani Taji Hamblin, Michael R. TI Temperature-Responsive Smart Nanocarriers for Delivery Of Therapeutic Agents: Applications and Recent Advances SO ACS APPLIED MATERIALS & INTERFACES LA English DT Review DE smart drug delivery systems; temperature-responsive nanocarriers; LCST/UCST behavior; gene delivery; dual/multi responsive; synthesis; characterization; anticancer delivery ID BLOCK-COPOLYMER MICELLES; CONTROLLED DRUG-RELEASE; POLY(N-ISOPROPYLACRYLAMIDE-CO-ACRYLIC ACID) NANOGELS; THERMORESPONSIVE POLYMERIC MICELLES; INTENSITY FOCUSED ULTRASOUND; GUIDED-PHOTOTHERMAL THERAPY; IRON-OXIDE NANOPARTICLES; GENE DELIVERY; IN-VITRO; ANTICANCER DRUG AB Smart drug delivery systems (DDSs) have attracted the attention of many scientists, as carriers that can be stimulated by changes in environmental parameters such as temperature, pH, light, electromagnetic fields, mechanical forces, etc. These smart nanocarriers can release their cargo on demand when their target is reached and the stimulus is applied. Using the techniques of nanotechnology, these nanocarriers can be tailored to be target-specific, and exhibit delayed or controlled release of drugs. Temperature-responsive nanocarriers are one of most important groups of smart nanoparticles (NPs) that have been investigated during the past decades. Temperature can either act as an external stimulus when heat is applied from the outside, or can be internal when pathological lesions have a naturally elevated termperature. A low critical solution temperature (LCST) is a special feature of some polymeric materials, and most of the temperature-responsive nanocarriers have been designed based on this feature. In this review, we attempt to summarize recent efforts to prepare innovative temperature-responsive nanocarriers and discuss their novel applications. C1 [Zangabad, Parham Sahandi] TUOMS, RCPN, Tabriz, Iran. [Zangabad, Parham Sahandi; Ghasemi, Alireza; Amiri, Mohammad; Bahrami, Mohsen; Asl, Hadi Ghahramanzadeh; Ghasemi, Amir; Boyuk, Mohammad Reza Rahmani Taji] Sharif Univ Technol, Dept Mat Sci & Engn, Azadi Ave, Tehran 14588, Iran. [Karimi, Mandi] Iran Univ Med Sci, Fac Adv Technol Med, Dept Med Nanotechnol, Tehran, Iran. [Karimi, Mandi; Zangabad, Parham Sahandi; Malekzad, Hedieh; Ghasemi, Amir] Iran Univ Med Sci, ANNRG, Tehran, Iran. [Karimi, Mandi; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Malekzad, Hedieh] Kharazmi Univ Tehran, Dept Chem, Tehran, Iran. [Mandieh, Zahra] Univ Montana, Dept Biomed & Pharmaceut Sci, Mat Sci & Engn, Missoula, MT 59812 USA. [Bozorgomid, Mahnaz] Islamic Azad Univ Tehran, Cent Branch, Dept Appl Chem, Tehran, Iran. [Hamblin, Michael R.] Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA.; Hamblin, MR (reprint author), Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. EM hamblin@helix.mgh.harvard.edu FU NIAID NIH HHS [R01 AI050875, R21 AI121700] NR 292 TC 8 Z9 8 U1 95 U2 95 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 AUG 24 PY 2016 VL 8 IS 33 BP 21107 EP 21133 DI 10.1021/acsami.6b00371 PG 27 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA DU4JR UT WOS:000382179400001 PM 27349465 ER PT J AU Hightower, CD Hightower, LS Tatman, PJ Morgan, PM Gioe, T Singh, JA AF Hightower, Charles D. Hightower, Lisa S. Tatman, Penny J. Morgan, Patrick M. Gioe, Terence Singh, Jasvinder A. TI How often is the office visit needed? Predicting total knee arthroplasty revision risk using pain/function scores SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Total knee arthroplasty; TKA; Revision risk; Pain; Function; American Knee Society Scores; AKS scores ID TOTAL JOINT REPLACEMENT; CLINICAL RATING SYSTEM; OUTPATIENT FOLLOW-UP; TOTAL HIP; UNITED-STATES; OXFORD HIP; ASSOCIATION; POPULATION; DEMAND; LONG AB Background: Most patients have favorable outcomes after primary total knee arthroplasty (TKA). Well-validated methods to predict the risk of poor outcomes have not been developed or implemented. Several patients have annual clinic visits despite well-funcitoning TKA, as a routine practice, to detect early failure requiring revision surgery. It is not known whether assessment of pain and function can be used as a predictive tool for early failure and revision to guide practice. Our objective was to determine whether pain and function can predict revision after TKA. Methods: We retrospectively studied data from a large prospectively gathered TKA registry to examine changes in outcome scores for primary TKAs undergoing revision compared to those not requiring revision to determine the factors that are predictive for revision. Results: Of the 1,012 patients, 721 had had a single-sided primary TKA and had American Knee Society (AKS) Scores for three or more visits. 46 patients underwent revision, 23 acutely (fracture, traumatic component failure or acute infection) and 23 for latent causes (late implant loosening, progressive osteolysis, or pain and indolent infection). Mean age was 70 years for the non-revision patients, and 64 years for those revised. Both AKS Clinical and AKS Function Scores for non-revised patients were higher than in revision patients, higher in acute revision compared to latent revision patients. Significant predictors of revision surgery were preoperative, 3- and 15-month postoperative AKS Clinical Scores and 3-month AKS Function Scores. At 15-month post-TKA, a patient with a low calculated probability of revision, 32 % or less, was unlikely to require revision surgery with a negative predictive value of 99 %. Conclusion: Time dependent interval evaluation post-TKA with the AKS outcome scores may provide the ability to assign risk of revision to patients at the 15-month follow-up visit. If these findings can be replicated using a patient-reported measure, a virtual follow-up with patient-reported outcomes and X-ray review may be an alternative to clinic visit for patients doing well. C1 [Hightower, Charles D.] Alaska Native Med Ctr, Anchorage, AK USA. [Hightower, Lisa S.] Virginia Tech, Dept Agr & Extens Educ, Blacksburg, VA USA. [Tatman, Penny J.] Hlth East Educ & Res Dept, St Paul, MN USA. [Morgan, Patrick M.] Univ MN, Dept Orthopaed Surg, Sch Med, Minneapolis, MN USA. [Gioe, Terence] Minneapolis VAMC, Dept Orthopaed Surg, Minneapolis, MN USA. [Singh, Jasvinder A.] Birmingham VAMC, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA. RP Singh, JA (reprint author), Birmingham VAMC, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA.; Singh, JA (reprint author), Univ Alabama Birmingham, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA. EM Jasvinder.md@gmail.com FU Birmingham Veterans affairs medical centers FX This material is the result of work supported by the facilities and resources at the Minneapolis and the Birmingham Veterans affairs medical centers. No additional funding was obtained to conduct this study. NR 25 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 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD AUG 24 PY 2016 VL 16 AR 429 DI 10.1186/s12913-016-1669-y PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DU8DV UT WOS:000382444400001 PM 27553056 ER PT J AU Xue, CY Yu, DMT Gherardi, S Koach, J Milazzo, G Gamble, L Liu, B Valli, E Russell, AJ London, WB Liu, T Cheung, BB Marshall, GM Perini, G Haber, M Norris, MD AF Xue, Chengyuan Yu, Denise M. T. Gherardi, Samuele Koach, Jessica Milazzo, Giorgio Gamble, Laura Liu, Bing Valli, Emanuele Russell, Amanda J. London, Wendy B. Liu, Tao Cheung, Belamy B. Marshall, Glenn M. Perini, Giovanni Haber, Michelle Norris, Murray D. TI MYCN promotes neuroblastoma malignancy by establishing a regulatory circuit with transcription factor AP4 SO ONCOTARGET LA English DT Article DE neuroblastoma; cancer; MYCN oncogene; TFAP4; cell migration ID EPITHELIAL-MESENCHYMAL TRANSITION; NF-KAPPA-B; C-MYC; CHILDHOOD NEUROBLASTOMA; SPONTANEOUS REGRESSION; CANCER PROGRESSION; COLORECTAL-CANCER; GENE-EXPRESSION; IN-VIVO; CELLS AB Amplification of the MYCN oncogene, a member of the MYC family of transcriptional regulators, is one of the most powerful prognostic markers identified for poor outcome in neuroblastoma, the most common extracranial solid cancer in childhood. While MYCN has been established as a key driver of malignancy in neuroblastoma, the underlying molecular mechanisms are poorly understood. Transcription factor activating enhancer binding protein-4 ( TFAP4) has been reported to be a direct transcriptional target of MYC. We show for the first time that high expression of TFAP4 in primary neuroblastoma patients is associated with poor clinical outcome. siRNA-mediated suppression of TFAP4 in MYCN-expressing neuroblastoma cells led to inhibition of cell proliferation and migration. Chromatin immunoprecipitation assay demonstrated that TFAP4 expression is positively regulated by MYCN. Microarray analysis identified genes regulated by both MYCN and TFAP4 in neuroblastoma cells, including Phosphoribosyl-pyrophosphate synthetase-2 ( PRPS2) and Syndecan-1 ( SDC1), which are involved in cancer cell proliferation and metastasis. Overall this study suggests a regulatory circuit in which MYCN by elevating TFAP4 expression, cooperates with it to control a specific set of genes involved in tumor progression. These findings highlight the existence of a MYCN-TFAP4 axis in MYCN-driven neuroblastoma as well as identifying potential therapeutic targets for aggressive forms of this disease. C1 [Xue, Chengyuan; Yu, Denise M. T.; Koach, Jessica; Gamble, Laura; Liu, Bing; Valli, Emanuele; Russell, Amanda J.; Liu, Tao; Cheung, Belamy B.; Marshall, Glenn M.; Haber, Michelle; Norris, Murray D.] Univ New South Wales, Childrens Canc Inst, Lowy Canc Res Ctr, Sydney, NSW, Australia. [Gherardi, Samuele; Milazzo, Giorgio; Perini, Giovanni] Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy. [London, Wendy B.] Boston Childrens Hosp, Boston, MA USA. [London, Wendy B.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Marshall, Glenn M.] Sydney Childrens Hosp, Kids Canc Ctr, Sydney, NSW, Australia. [Perini, Giovanni] Univ Bologna, CIRI Hlth Sci & Technol, Bologna, Italy. [Norris, Murray D.] Univ New South Wales, Ctr Childhood Canc Res, Sydney, NSW, Australia. RP Haber, M; Norris, MD (reprint author), Univ New South Wales, Childrens Canc Inst, Lowy Canc Res Ctr, Sydney, NSW, Australia.; Norris, MD (reprint author), Univ New South Wales, Ctr Childhood Canc Res, Sydney, NSW, Australia. EM MHaber@ccia.unsw.edu.au; MNorris@ccia.unsw.edu.au RI Liu, Tao/A-3922-2015 NR 52 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 AUG 23 PY 2016 VL 7 IS 34 BP 54937 EP 54951 DI 10.18632/oncotarget.10709 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY9DY UT WOS:000385435000068 PM 27448979 ER PT J AU Mima, K Nowak, JA Qian, ZR Cao, Y Song, MY Masugi, Y Shi, Y da Silva, A Gu, MC Li, WW Hamada, T Zhang, XH Wu, KN Meyerhardt, JA Baba, H Giovannucci, EL Chan, AT Fuchs, CS Ogino, S Nishihara, R AF Mima, Kosuke Nowak, Jonathan A. Qian, Zhi Rong Cao, Yin Song, Mingyang Masugi, Yohei Shi, Yan da Silva, Annacarolina Gu, Mancang Li, Wanwan Hamada, Tsuyoshi Zhang, Xuehong Wu, Kana Meyerhardt, Jeffrey A. Baba, Hideo Giovannucci, Edward L. Chan, Andrew T. Fuchs, Charles S. Ogino, Shuji Nishihara, Reiko TI Tumor LINE-1 methylation level and colorectal cancer location in relation to patient survival SO ONCOTARGET LA English DT Article DE epigenetics; left-sided; molecular pathological epidemiology; prognosis; right-sided ID MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; COLON-CANCER; MICROSATELLITE INSTABILITY; DNA METHYLATION; PIK3CA MUTATION; PHENOTYPE; HYPOMETHYLATION; MICROBIOTA; COHORT; ASSOCIATION AB Colorectal tumors arise with genomic and epigenomic alterations through interactions between neoplastic cells, immune cells, and microbiota that vary along the proximal to distal axis of colorectum. Long interspersed nucleotide element-1 ( LINE-1) hypomethylation in colorectal cancer has been associated with worse clinical outcome. Utilizing 1,317 colon and rectal carcinoma cases in two U. S.-nationwide prospective cohort studies, we examined patient survival according to LINE-1 methylation level stratified by tumor location. Cox proportional hazards model was used to assess a statistical interaction between LINE-1 methylation level and tumor location in colorectal cancer-specific mortality analysis, controlling for potential confounders including microsatellite instability, CpG island methylator phenotype, and KRAS, BRAF, and PIK3CA mutations. A statistically significant interaction was found between LINE-1 methylation level and tumor location in colorectal cancer-specific mortality analysis ( P-interaction = 0.011). The association of LINE-1 hypomethylation with higher colorectal cancer-specific mortality was stronger in proximal colon cancers ( multivariable hazard ratio [ HR], 1.66; 95% confidence interval [ CI], 1.21 to 2.28) than in distal colon cancers ( multivariable HR, 1.18; 95% CI, 0.81 to 1.72) or rectal cancers ( multivariable HR, 0.87; 95% CI, 0.57 to 1.34). Our data suggest the interactive effect of LINE-1 methylation level and colorectal cancer location on clinical outcome. C1 [Mima, Kosuke; Qian, Zhi Rong; Masugi, Yohei; Shi, Yan; da Silva, Annacarolina; Gu, Mancang; Li, Wanwan; Hamada, Tsuyoshi; Meyerhardt, Jeffrey A.; Fuchs, Charles S.; Ogino, Shuji; Nishihara, Reiko] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Mima, Kosuke; Nowak, Jonathan A.; Qian, Zhi Rong; Cao, Yin; Song, Mingyang; Masugi, Yohei; Shi, Yan; da Silva, Annacarolina; Gu, Mancang; Li, Wanwan; Hamada, Tsuyoshi; Zhang, Xuehong; Wu, Kana; Meyerhardt, Jeffrey A.; Giovannucci, Edward L.; Chan, Andrew T.; Fuchs, Charles S.; Ogino, Shuji; Nishihara, Reiko] Harvard Med Sch, Boston, MA 02115 USA. [Nowak, Jonathan A.; Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Div MPE Mol Pathol Epidemiol, 75 Francis St, Boston, MA 02115 USA. [Cao, Yin; Song, Mingyang; Chan, Andrew T.] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA. [Cao, Yin; Song, Mingyang; Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Cao, Yin; Song, Mingyang; Wu, Kana; Giovannucci, Edward L.; Nishihara, Reiko] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Zhang, Xuehong; Wu, Kana; 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. [Baba, Hideo] Kumamoto Univ, Grad Sch Med Sci, Dept Surg Gastroenterol, Kumamoto, Japan. [Giovannucci, Edward L.; Ogino, Shuji] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Ogino, S; Nishihara, R (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Ogino, S; Nishihara, R (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Ogino, S (reprint author), Brigham & Womens Hosp, Dept Pathol, Div MPE Mol Pathol Epidemiol, 75 Francis St, Boston, MA 02115 USA.; Nishihara, R (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.; Ogino, S (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu; rnishiha@hsph.harvard.edu OI Masugi, Yohei/0000-0002-6952-4043 FU NCI NIH HHS [K07 CA190673, P01 CA055075, P01 CA087969, P50 CA127003, R01 CA118553, R01 CA137178, R01 CA151993, R01 CA169141, R03 CA176717, R35 CA197735, UM1 CA167552, K07 CA188126, UM1 CA186107] NR 66 TC 1 Z9 1 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 AUG 23 PY 2016 VL 7 IS 34 BP 55098 EP 55109 DI 10.18632/oncotarget.10398 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY9DY UT WOS:000385435000080 PM 27391152 ER PT J AU Vranceanu, AM Riklin, E Merker, VL Macklin, EA Park, ER Plotkin, SR AF Vranceanu, Ana-Maria Riklin, Eric Merker, Vanessa L. Macklin, Eric A. Park, Elyse R. Plotkin, Scott R. TI Mind-body therapy via videoconferencing in patients with neurofibromatosis: An RCT SO NEUROLOGY LA English DT Article ID QUALITY-OF-LIFE; RESILIENCY PROGRAM 3RP; RELAXATION RESPONSE; THE-LITERATURE; SAMPLE-SIZE; PILOT; PAIN; SCHWANNOMATOSIS; OUTCOMES; CANCER AB Objective:To test, within a single-blind randomized controlled trial, the feasibility, acceptability, efficacy, and durability of a mind-body program (the Relaxation Response Resiliency Program for neurofibromatosis [3RP-NF]) vs an attention placebo control (Health Enhancement Program for NF [HEP-NF]), both delivered via group videoconferencing.Methods:Sixty-three patients completed baseline assessments and were randomized. Primary outcomes were physical health and psychological quality of life (QoL), measured by the WHOQOL-BREF (World Health Organization QoL abbreviated instrument). Secondary outcomes were social relations and environment QoL, depression, anxiety, pain intensity, and pain interference.Results:Sixty-three participants completed the intervention (100%) and 52 the 6-month follow-up (82.5%). Acceptability was 4.1 (5-point scale). Patients in the 3RP-NF showed greater improvement in physical health QoL (7.69; 95% confidence interval [CI]: 0.29-15.10; p = 0.040), psychological QoL (5.57; 95% CI: 0.17-11.34; p = 0.056), social relations QoL (10.95; 95% CI: 1.57-20.31; p = 0.021), environment QoL (8.02; 95% CI: 2.57-13.48; p = 0.005), and anxiety (-2.32; 95% CI: -3.96 to 0.69; p = 0.006) compared to those in HEP-NF, and gains were maintained at follow-up. Patients in the 3RP-NF did not improve more than those in HEP-NF on depression, with both groups showing improvement. Patients in the 3RP-NF with baseline pain 5 of 10 showed improvement in pain intensity from baseline to posttest (1.30; 95% CI: -2.26 to -0.34; p = 0.009) with effects maintained at follow-up; this improvement was not greater than that in HEP-NF. There were more treatment responders in the 3RP-NF group (p < 0.05).Conclusions:The 3RP-NF delivered via videoconferencing was highly feasible and accepted by patients, and resulted in sustained improvement in QoL.Classification of evidence:This study provides Class II evidence that for patients with NF, a mind-body program is superior to an attention placebo control in improving QoL. C1 [Vranceanu, Ana-Maria] Massachusetts Gen Hosp, Behav Med Serv, Boston, MA 02114 USA. [Riklin, Eric; Park, Elyse R.] Massachusetts Gen Hosp, Benson Henry Inst Mind Body Med, Boston, MA 02114 USA. [Merker, Vanessa L.; Plotkin, Scott R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Merker, Vanessa L.; Plotkin, Scott R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Macklin, Eric A.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Vranceanu, AM (reprint author), Massachusetts Gen Hosp, Behav Med Serv, Boston, MA 02114 USA. EM avranceanu@partners.org FU Children's Tumor Foundation FX This study was fully funded by the Children's Tumor Foundation through a clinical research grant awarded to Ana-Maria Vranceanu. NR 31 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 23 PY 2016 VL 87 IS 8 BP 806 EP 814 DI 10.1212/WNL.0000000000003005 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DW4IG UT WOS:000383605800017 PM 27449066 ER PT J AU DeTomaso, D Yosef, N AF DeTomaso, David Yosef, Nir TI FastProject: a tool for low-dimensional analysis of single-cell RNA-Seq data SO BMC BIOINFORMATICS LA English DT Article DE Single-Cell; RNA-Seq; Dimensionality reduction ID GENE-EXPRESSION; HETEROGENEITY; GLIOBLASTOMA; RECONSTRUCTION; REGULATORS; REDUCTION; DYNAMICS; GROWTH AB Background: A key challenge in the emerging field of single-cell RNA-Seq is to characterize phenotypic diversity between cells and visualize this information in an informative manner. A common technique when dealing with high-dimensional data is to project the data to 2 or 3 dimensions for visualization. However, there are a variety of methods to achieve this result and once projected, it can be difficult to ascribe biological significance to the observed features. Additionally, when analyzing single-cell data, the relationship between cells can be obscured by technical confounders such as variable gene capture rates. Results: To aid in the analysis and interpretation of single-cell RNA-Seq data, we have developed FastProject, a software tool which analyzes a gene expression matrix and produces a dynamic output report in which two-dimensional projections of the data can be explored. Annotated gene sets (referred to as gene ` signatures') are incorporated so that features in the projections can be understood in relation to the biological processes they might represent. FastProject provides a novel method of scoring each cell against a gene signature so as to minimize the effect of missed transcripts as well as a method to rank signature-projection pairings so that meaningful associations can be quickly identified. Additionally, FastProject is written with a modular architecture and designed to serve as a platform for incorporating and comparing new projection methods and gene selection algorithms. Conclusions: Here we present FastProject, a software package for two-dimensional visualization of single cell data, which utilizes a plethora of projection methods and provides a way to systematically investigate the biological relevance of these low dimensional representations by incorporating domain knowledge. C1 [DeTomaso, David; Yosef, Nir] Univ Calif Berkeley, Dept Elect & Comp Sci, Berkeley, CA 97420 USA. [DeTomaso, David; Yosef, Nir] Univ Calif Berkeley, Ctr Computat Biol, Berkeley, CA 97420 USA. [Yosef, Nir] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02139 USA. [Yosef, Nir] Harvard Univ, Boston, MA 02139 USA. RP Yosef, N (reprint author), Univ Calif Berkeley, Dept Elect & Comp Sci, Berkeley, CA 97420 USA.; Yosef, N (reprint author), Univ Calif Berkeley, Ctr Computat Biol, Berkeley, CA 97420 USA.; Yosef, N (reprint author), MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02139 USA.; Yosef, N (reprint author), Harvard Univ, Boston, MA 02139 USA. EM niryosef@berkeley.edu FU National Institutes of Health NRSA Trainee appointment [T32]; California Research Alliance by BASF (CARA); NIH [U01MH105979, U01HG007910] FX DD was funded by a National Institutes of Health NRSA Trainee appointment on grant number T32 and by the California Research Alliance by BASF (CARA). NY was supported by NIH grants U01MH105979 and U01HG007910. NR 36 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 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD AUG 23 PY 2016 VL 17 AR 315 DI 10.1186/s12859-016-1176-5 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DV3OD UT WOS:000382831200001 PM 27553427 ER PT J AU Heo, SJ Han, WM Szczesny, SE Cosgrove, BD Elliott, DM Lee, DA Duncan, RL Mauck, RL AF Heo, Su-Jin Han, Woojin M. Szczesny, Spencer E. Cosgrove, Brian D. Elliott, Dawn M. Lee, David A. Duncan, Randall L. Mauck, Robert L. TI Mechanically Induced Chromatin Condensation Requires Cellular Contractility in Mesenchymal Stem Cells SO BIOPHYSICAL JOURNAL LA English DT Article ID TGF-BETA; GENE-EXPRESSION; BIOPHYSICAL REGULATION; HISTONE MODIFICATIONS; DIFFERENTIATION; PROTEIN; STRAIN; PROLIFERATION; ORGANIZATION; ARCHITECTURE AB Mechanical cues play important roles in directing the lineage commitment of mesenchymal stem cells (MSCs). In this study, we explored the molecular mechanisms by which dynamic tensile loading (DL) regulates chromatin organization in this cell type. Our previous findings indicated that the application of DL elicited a rapid increase in chromatin condensation through purinergic signaling mediated by ATP. Here, we show that the rate and degree of condensation depends on the frequency and duration of mechanical loading, and that ATP release requires actomyosin-based cellular contractility. Increases in baseline cellular contractility via the addition of an activator of G-protein coupled receptors (lysophosphatidic acid) induced rapid ATP release, resulting in chromatin condensation independent of loading. Conversely, inhibition of contractility through pretreatment with either a RhoA/Rock inhibitor (Y27632) or MLCK inhibitor (ML7) abrogated ATP release in response to DL, blocking load-induced chromatin condensation. With loading, ATP release occurred very rapidly (within the first 10-20 s), whereas changes in chromatin occurred at a later time point (similar to 10 min), suggesting a downstream biochemical pathway mediating this process. When cells were pretreated with blockers of the transforming growth factor (TGF) superfamily, purinergic signaling in response to DL was also eliminated. Further analysis showed that this pretreatment decreased contractility, implicating activity in the TGF pathway in the establishment of the baseline contractile state of MSCs (in the absence of exogenous ligands). These data indicate that chromatin condensation in response to DL is regulated through the interplay between purinergic and RhoA/Rock signaling, and that ligandless activity in the TGF/bone morphogenetic proteins signaling pathway contributes to the establishment of baseline contractility in MSCs. C1 [Heo, Su-Jin; Szczesny, Spencer E.; Cosgrove, Brian D.; Mauck, Robert L.] Univ Penn, Perelman Sch Med, Dept Orthopaed Surg, McKay Orthopaed Res Lab, Philadelphia, PA 19104 USA. [Heo, Su-Jin; Han, Woojin M.; Cosgrove, Brian D.; Mauck, Robert L.] Univ Penn, Sch Engn & Appl Sci, Dept Bioengn, Philadelphia, PA 19104 USA. [Szczesny, Spencer E.; Cosgrove, Brian D.; Mauck, Robert L.] Philadelphia VA Med Ctr, Translat Musculoskeletal Res Ctr, Philadelphia, PA USA. [Elliott, Dawn M.; Duncan, Randall L.] Univ Delaware, Dept Biomed Engn, Newark, DE USA. [Duncan, Randall L.] Univ Delaware, Dept Biol Sci, Newark, DE USA. [Lee, David A.] Queen Mary Univ London, Sch Engn & Mat Sci, Inst Bioengn, London, England. RP Mauck, RL (reprint author), Univ Penn, Perelman Sch Med, Dept Orthopaed Surg, McKay Orthopaed Res Lab, Philadelphia, PA 19104 USA.; Mauck, RL (reprint author), Univ Penn, Sch Engn & Appl Sci, Dept Bioengn, Philadelphia, PA 19104 USA.; Mauck, RL (reprint author), Philadelphia VA Med Ctr, Translat Musculoskeletal Res Ctr, Philadelphia, PA USA. EM lemauck@mail.med.upenn.edu FU National Institutes of Health [R01AR056624, R01 EB02425, T32 AR007132, P30 AR050950]; Perelman School of Medicine; University of Pennsylvania University Research Foundation Award FX This work was supported by the National Institutes of Health (R01AR056624, R01 EB02425, T32 AR007132, and P30 AR050950). Additional support was provided by a Montague Research Award from the Perelman School of Medicine and a University of Pennsylvania University Research Foundation Award. The authors would like to acknowledge technical contributions to this work from Dr. Stephen D. Thorpe, and J. Caplan for assistance with confocal microscopy. NR 48 TC 1 Z9 1 U1 4 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD AUG 23 PY 2016 VL 111 IS 4 BP 864 EP 874 DI 10.1016/j.bpj.2016.07.006 PG 11 WC Biophysics SC Biophysics GA DU3GR UT WOS:000382099300019 PM 27558729 ER PT J AU Khankari, NK Murff, HJ Zeng, C Wen, W Eeles, RA Easton, DF Kote-Jarai, Z Al Olama, AA Benlloch, S Muir, K Giles, GG Wiklund, F Gronberg, H Haiman, CA Schleutker, J Nordestgaard, BG Travis, RC Donovan, JL Pashayan, N Khaw, KT Stanford, JL Blot, WJ Thibodeau, SN Maier, C Kibel, AS Cybulski, C Cannon-Albright, L Brenner, H Park, J Kaneva, R Batra, J Teixeira, MR Pandha, H Zheng, W AF Khankari, Nikhil K. Murff, Harvey J. Zeng, Chenjie Wen, Wanqing Eeles, Rosalind A. Easton, Douglas F. Kote-Jarai, Zsofia Al Olama, Ali Amin Benlloch, Sara Muir, Kenneth Giles, Graham G. Wiklund, Fredrik Gronberg, Henrik Haiman, Christopher A. Schleutker, Johanna Nordestgaard, Borge G. Travis, Ruth C. Donovan, Jenny L. Pashayan, Nora Khaw, Kay-Tee Stanford, Janet L. Blot, William J. Thibodeau, Stephen N. Maier, Christiane Kibel, Adam S. Cybulski, Cezary Cannon-Albright, Lisa Brenner, Hermann Park, Jong Kaneva, Radka Batra, Jyotsna Teixeira, Manuel R. Pandha, Hardev Zheng, Wei CA PRACTICAL Consortium TI Polyunsaturated fatty acids and prostate cancer risk: a Mendelian randomisation analysis from the PRACTICAL consortium SO BRITISH JOURNAL OF CANCER LA English DT Article DE polyunsaturated fatty acids; prostate cancer; Mendelian randomisation; polygenic risk score; omega-3 fatty acids; omega-6 fatty acids ID PLEIOTROPIC GENETIC-VARIANTS; SUSCEPTIBILITY LOCI; METAANALYSIS; IDENTIFICATION; INSTRUMENTS; DISEASE; HEART AB Background: Prostate cancer is a common cancer worldwide with no established modifiable lifestyle factors to guide prevention. The associations between polyunsaturated fatty acids (PUFAs) and prostate cancer risk have been inconsistent. Using Mendelian randomisation, we evaluated associations between PUFAs and prostate cancer risk. Methods: We used individual-level data from a consortium of 22 721 cases and 23 034 controls of European ancestry. Externally-weighted PUFA-specific polygenic risk scores (wPRSs), with explanatory variation ranging from 0.65 to 33.07%, were constructed and used to evaluate associations with prostate cancer risk per one standard deviation (s.d.) increase in genetically-predicted plasma PUFA levels using multivariable-adjusted unconditional logistic regression. Results: No overall association was observed between the genetically-predicted PUFAs evaluated in this study and prostate cancer risk. However, risk reductions were observed for short-chain PUFAs, linoleic (ORLA = 0.95, 95% CI = 0.92, 0.98) and a-linolenic acids (ORALA = 0.96, 95% CI = 0.93, 0.98), among men <62 years; whereas increased risk was found among men >= 62 years for LA (ORLA = 1.04, 95% CI = 1.01, 1.07). For long-chain PUFAs (i.e., arachidonic, eicosapentaenoic, and docosapentaenoic acids), increased risks were observed among men <62 years (ORAA = 1.05, 95% CI = 1.02, 1.08; OREPA = 1.04, 95% CI = 1.01, 1.06; ORDPA = 1.05, 95% CI = 1.02, 1.08). Conclusion: Results from this study suggest that circulating omega-3 and omega-6 PUFAs may have a different role in the aetiology of earlyand late-onset prostate cancer. C1 [Khankari, Nikhil K.; Murff, Harvey J.; Zeng, Chenjie; Wen, Wanqing; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. [Eeles, Rosalind A.; Kote-Jarai, Zsofia] Inst Canc Res, 15 Cotswold Rd, Sutton SM2 5NG, Surrey, England. [Eeles, Rosalind A.] Royal Marsden NHS Fdn Trust, Fulham Rd, London SW3 6JJ, England. [Easton, Douglas F.; Al Olama, Ali Amin; Benlloch, Sara; Pashayan, Nora] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Strangeways Res Lab, 2 Worts Causeway, Cambridge CB1 8RN, England. [Muir, Kenneth] Univ Warwick, Inst Populat Hlth, Coventry CV4 7AL, W Midlands, England. [Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, 615 St Kilda Rd, Melbourne, Vic 3004, Australia. [Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Wiklund, Fredrik; Gronberg, Henrik] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Haiman, Christopher A.] Univ Southern Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. [Schleutker, Johanna] Univ Turku, Dept Med Biochem & Genet, Turku 20014, Finland. [Schleutker, Johanna] Univ Tampere, BioMediTech, Inst Biomed Technol, Kalevantie 4, Tampere 33014, Finland. [Schleutker, Johanna] FimLab Labs, Kalevantie 4, Tampere 33014, Finland. [Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev Ringvej 75, DK-2730 Herlev, Denmark. [Travis, Ruth C.] Nuffield Dept Populat Hlth, Canc Epidemiol, Oxford OX3 7LF, England. [Donovan, Jenny L.] Univ Bristol, Sch Social & Community Med, Canynge Hall,39 Whatley Rd, Bristol BS8 2PS, Avon, England. [Pashayan, Nora] UCL, Dept Appl Hlth Res, 1-19 Torrington Pl, London WC1E 7HB, England. [Khaw, Kay-Tee] Univ Cambridge, Cambridge Inst Publ Hlth, Forvie Site,Robinson Way, Cambridge CB2 0SR, England. [Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Blot, William J.] Int Epidemiol Inst, 1455 Res Blvd,Suite 550, Rockville, MD 20850 USA. [Thibodeau, Stephen N.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Maier, Christiane] Univ Hosp Ulm, Inst Human Genet, Albert Einstein Allee 11, D-89081 Ulm, Germany. [Maier, Christiane] Univ Hosp Ulm, Dept Urol, Albert Einstein Allee 11, D-89081 Ulm, Germany. [Kibel, Adam S.] Dana Farber Canc Inst, Brigham & Womens Hosp, Div Urol, 45 Francis St ASB 2-3, Boston, MA 02115 USA. [Kibel, Adam S.] Washington Univ, 660 S Euclid Ave, St Louis, MO 63110 USA. [Cybulski, Cezary] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Rybacka 1, Szczecin, Poland. [Cannon-Albright, Lisa] Univ Utah, Sch Med, Dept Med, Div Genet Epidemiol, Salt Lake City, UT 84108 USA. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, D-69120 Heidelberg, Germany. [Park, Jong] H Lee Moffitt Canc Ctr & Res Inst, Div Canc Prevent & Control, 12902 Magnolia Dr, Tampa, FL 33612 USA. [Kaneva, Radka] Med Univ Sofia, Mol Med Ctr, Dept Med Chem & Biochem, 2 Zdrave St, Sofia 1431, Bulgaria. [Batra, Jyotsna] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Australian Prostate Canc Res Ctr Queensland, Brisbane, Qld 4102, Australia. [Batra, Jyotsna] Queensland Univ Technol, Sch Life Sci, Brisbane, Qld 4102, Australia. [Batra, Jyotsna] Queensland Univ Technol, Sch Publ Hlth, Brisbane, Qld 4102, Australia. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, P-4200072 Oporto, Portugal. [Pandha, Hardev] Univ Surrey, Targeted Canc Therapy, Dept Clin & Expt Med, Guildford GU2 7XH, Surrey, England. RP Zheng, W (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. EM wei.zheng@vanderbilt.edu RI Zheng, Wei/O-3351-2013; Brenner, Hermann/B-4627-2017; OI Zheng, Wei/0000-0003-1226-070X; Brenner, Hermann/0000-0002-6129-1572; albright, lisa/0000-0003-2602-3668 FU NIH grant [R25CA160056] FX Dr Nikhil K Khankari was supported by NIH grant R25CA160056. NR 25 TC 0 Z9 0 U1 4 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 AUG 23 PY 2016 VL 115 IS 5 BP 624 EP 631 DI 10.1038/bjc.2016.228 PG 8 WC Oncology SC Oncology GA DU6OX UT WOS:000382335600022 PM 27490808 ER PT J AU Kim, TH Saadatpour, A Guo, GJ Saxena, M Cavazza, A Desai, N Jadhav, U Jiang, L Rivera, MN Orkin, SH Yuan, GC Shivdasani, RA AF Kim, Tae-Hee Saadatpour, Assieh Guo, Guoji Saxena, Madhurima Cavazza, Alessia Desai, Niyati Jadhav, Unmesh Jiang, Lan Rivera, Miguel N. Orkin, Stuart H. Yuan, Guo-Cheng Shivdasani, Ramesh A. TI Single-Cell Transcript Profiles Reveal Multilineage Priming in Early Progenitors Derived from Lgr5(+) Intestinal Stem Cells SO CELL REPORTS LA English DT Article ID LINEAGE COMMITMENT; EXPRESSION; HETEROGENEITY; PLASTICITY; MATH1 AB Lgr5(+) intestinal stem cells (ISCs) drive epithelial self-renewal, and their immediate progeny-intestinal bipotential progenitors-produce absorptive and secretory lineages via lateral inhibition. To define features of early transit from the ISC compartment, we used a microfluidics approach to measure selected stem- and lineage-specific transcripts in single Lgr5(+) cells. We identified two distinct cell populations, one that expresses known ISC markers and a second, abundant population that simultaneously expresses markers of stemand mature absorptive and secretory cells. Single-molecule mRNA in situ hybridization and immunofluorescence verified expression of lineage-restricted genes in a subset of Lgr5(+) cells in vivo. Transcriptional network analysis revealed that one group of Lgr5(+) cells arises from the other and displays characteristics expected of bipotential progenitors, including activation of Notch ligand and cell-cycle-inhibitor genes. These findings define the earliest steps in ISC differentiation and reveal multilineage gene priming as a fundamental property of the process. C1 [Kim, Tae-Hee; Saxena, Madhurima; Cavazza, Alessia; Jadhav, Unmesh; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Kim, Tae-Hee; Saxena, Madhurima; Cavazza, Alessia; Jadhav, Unmesh; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. [Kim, Tae-Hee; Saxena, Madhurima; Cavazza, Alessia; Jadhav, Unmesh; Shivdasani, Ramesh A.] Harvard Med Sch, Dept Med, Boston, MA 02215 USA. [Saadatpour, Assieh; Jiang, Lan; Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Saadatpour, Assieh; Jiang, Lan; Yuan, Guo-Cheng] Harvard TH Chan Sch Publ Hlth, Boston, MA 02215 USA. [Guo, Guoji; Orkin, Stuart H.] Boston Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Guo, Guoji; Orkin, Stuart H.] Harvard Med Sch, Boston, MA 02215 USA. [Desai, Niyati; Rivera, Miguel N.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Desai, Niyati; Rivera, Miguel N.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Desai, Niyati; Rivera, Miguel N.] Harvard Med Sch, Boston, MA 02114 USA. [Orkin, Stuart H.; Yuan, Guo-Cheng; Shivdasani, Ramesh A.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Kim, Tae-Hee] Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON M5G 0A4, Canada. [Kim, Tae-Hee] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [Guo, Guoji] Zhejiang Univ, Ctr Stem Cell & Regenerat Med, Hangzhou 310058, Zhejiang, Peoples R China. RP Shivdasani, RA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Shivdasani, RA (reprint author), Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA.; Shivdasani, RA (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02215 USA.; Yuan, GC (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA.; Yuan, GC (reprint author), Harvard TH Chan Sch Publ Hlth, Boston, MA 02215 USA.; Yuan, GC; Shivdasani, RA (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM gcyuan@jimmy.harvard.edu; ramesh_shivdasani@dfci.harvard.edu FU American-Italian Cancer Foundation fellowship; Harvard Stem Cell Institute; Affymetrix; Lind family; [R01DK081113]; [U01DK103152]; [K99DK095983]; [F32DK103453]; [P50CA127003] FX This work was supported by grants R01DK081113 (including a supplement from the Office of the Director [NIH Common Fund]), U01DK103152 (the Intestinal Stem Cell Consortium of the NIDDK and NIAID), K99DK095983 (to T-H.K.), F32DK103453 (to U.J.), and P50CA127003; an American-Italian Cancer Foundation fellowship (to A.C.); and funds from the Harvard Stem Cell Institute (to G-C.Y. and S.H.O.), Affymetrix (to N.D. and M.N.R.), and the Lind family (to R.A.S.). We thank L. Deary and D. Breault for help with microscopy. NR 27 TC 3 Z9 3 U1 1 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 AUG 23 PY 2016 VL 16 IS 8 BP 2053 EP 2060 DI 10.1016/j.celrep.2016.07.056 PG 8 WC Cell Biology SC Cell Biology GA DU6FQ UT WOS:000382310100003 PM 27524622 ER PT J AU Kolar, MJ Kamat, SS Parsons, WH Homan, EA Maher, T Peroni, OD Syed, I Fjeld, K Molven, A Kahn, BB Cravatt, BF Saghateliann, A AF Kolar, Matthew J. Kamat, Siddhesh S. Parsons, William H. Homan, Edwin A. Maher, Tim Peroni, Odile D. Syed, Ismail Fjeld, Karianne Molven, Anders Kahn, Barbara B. Cravatt, Benjamin F. Saghateliann, Alan TI Branched Fatty Acid Esters of Hydroxy Fatty Acids Are Preferred Substrates of the MODY8 Protein Carboxyl Ester Lipase SO BIOCHEMISTRY LA English DT Article ID PANCREATIC EXOCRINE DYSFUNCTION; SALT-STIMULATED LIPASE; CHOLESTERYL ESTER; ADIPOSE-TISSUE; KNOCKOUT MICE; HUMAN-MILK; HYDROLYSIS; ABSORPTION; CEL; HYDROLASES AB A recently discovered class of endogenous mammalian lipids, branched fatty acid esters of hydroxy fatty acids (FAHFAs), possesses anti-diabetic and anti-inflammatory activities. Here, we identified and validated carboxyl ester lipase (CEL), a pancreatic enzyme hydrolyzing cholesteryl esters and other dietary lipids, as a FAHFA hydrolase. Variants of CEL have been linked to maturity-onset diabetes of the young, type 8 (MODY8), and to chronic pancreatitis. We tested the FAHFA hydrolysis activity of the CEL MODY8 variant and found a modest increase in activity as compared with that of the normal enzyme. Together, the data suggest that CEL might break down dietary FAHFAs. C1 [Kolar, Matthew J.; Saghateliann, Alan] Salk Inst Biol Studies, Helmsley Ctr Genom Med, Peptide Biol Labs, La Jolla, CA 92037 USA. [Kamat, Siddhesh S.; Parsons, William H.; Cravatt, Benjamin F.] Scripps Res Inst, Skaggs Inst Chem Biol, Dept Physiol Chem, La Jolla, CA 92037 USA. [Homan, Edwin A.; Maher, Tim] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Peroni, Odile D.; Syed, Ismail; Kahn, Barbara B.] Harvard Med Sch, Div Endocrinol Diabet & Metab, Dept Med, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Fjeld, Karianne] Univ Bergen, KG Jebsen Ctr Diabet Res, Dept Clin Sci, N-5021 Bergen, Norway. [Fjeld, Karianne] Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. [Molven, Anders] Univ Bergen, Dept Clin Med, Gade Lab Pathol, N-5021 Bergen, Norway. [Molven, Anders] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway. [Homan, Edwin A.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA. [Maher, Tim] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Saghateliann, A (reprint author), Salk Inst Biol Studies, Helmsley Ctr Genom Med, Peptide Biol Labs, La Jolla, CA 92037 USA.; Cravatt, BF (reprint author), Scripps Res Inst, Skaggs Inst Chem Biol, Dept Physiol Chem, La Jolla, CA 92037 USA. EM cravatt@scripps.edu; asaghatelian@salk.edu OI Parsons, William/0000-0001-6065-2340; Kolar, Matthew/0000-0001-8054-9121 FU National Institutes of Health [DA033760, DK909810]; Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]; National Cancer Institute Cancer Center Support Grant [P30 (CA014195)]; Dr. Frederick Paulsen Chair/Ferring Pharmaceuticals [DK098002]; JPB foundation; Hewitt Foundation; Chapman Charitable Trust Fellowship; UCSD Medical Scientist Training Program funding [T32 GM007198]; Irving S. Sigal postdoctoral fellowship from the American Chemical Society; Western Norway Regional Health Authority; Novo Nordisk Foundation; KG Jebsen Foundation; [DK106210] FX This work was supported by the National Institutes of Health (DA033760 and DK909810), The Leona M. and Harry B. Helmsley Charitable Trust (Grant 2012-PG-MED002 to A.S.), National Cancer Institute Cancer Center Support Grant P30 (CA014195 MASS core, A.S.), Dr. Frederick Paulsen Chair/Ferring Pharmaceuticals (A.S.), DK098002 (B.B.K.), a grant from the JPB foundation (B.B.K.), DK106210 (A.S. and B.B.K.), a Hewitt Foundation for Medical Research Fellowship (to W.H.P.), a Chapman Charitable Trust Fellowship (to M.J.K.), UCSD Medical Scientist Training Program funding (T32 GM007198 to MJ.K.), an Irving S. Sigal postdoctoral fellowship from the American Chemical Society (to S.S.K.), and grants from the Western Norway Regional Health Authority (A.M.), Novo Nordisk Foundation (A.M.), and KG Jebsen Foundation (K.F.). NR 34 TC 0 Z9 0 U1 9 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 23 PY 2016 VL 55 IS 33 BP 4636 EP 4641 DI 10.1021/acs.biochem.6b00565 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DU1HZ UT WOS:000381960100005 PM 27509211 ER PT J AU Forde, NJ Kanaan, AS Widomska, J Padmanabhuni, SS Nespoli, E Alexander, J Arranz, JIR Fan, SY Houssari, R Nawaz, MS Rizzo, F Pagliaroli, L Zilhao, NR Aranyi, T Barta, C Boeckers, TM Boomsma, DI Buisman, WR Buitelaar, JK Cath, D Dietrich, A Driessen, N Drineas, P Dunlap, M Gerasch, S Glennon, J Hengerer, B van den Heuvel, OA Jespersgaard, C Moller, HE Muller-Vahl, KR Openneer, TJC Poelmans, G Pouwels, PJW Scharf, JM Stefansson, H Tumer, Z Veltman, DJ van der Werf, YD Hoekstra, PJ Ludolph, A Paschou, P AF Forde, Natalie J. Kanaan, Ahmad S. Widomska, Joanna Padmanabhuni, Shanmukha S. Nespoli, Ester Alexander, John Arranz, Juan I. Rodriguez Fan, Siyan Houssari, Rayan Nawaz, Muhammad S. Rizzo, Francesca Pagliaroli, Luca Zilhao, Nuno R. Aranyi, Tamas Barta, Csaba Boeckers, Tobias M. Boomsma, Dorret I. Buisman, Wim R. Buitelaar, Jan K. Cath, Danielle Dietrich, Andrea Driessen, Nicole Drineas, Petros Dunlap, Michelle Gerasch, Sarah Glennon, Jeffrey Hengerer, Bastian van den Heuvel, Odile A. Jespersgaard, Cathrine Moeller, Harald E. Mueller-Vahl, Kirsten R. Openneer, Thaira J. C. Poelmans, Geert Pouwels, Petra J. W. Scharf, Jeremiah M. Stefansson, Hreinn Tumer, Zeynep Veltman, Dick J. van der werf, Ysbrand D. Hoekstra, Pieter J. Ludolph, Andrea Paschou, Peristera TI TS-EUROTRAIN: A European-Wide Investigation and Training Network on the Etiology and Pathophysiology of de la Tourtte Syndrome SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE Initial Training Network; Gilles de la Tourette Syndrome; tourette disorder; etiology; genetics; neuroimaging; animal models ID OBSESSIVE-COMPULSIVE DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DANISH CLINICAL COHORT; COPY NUMBER VARIANTS; 35 YEAR PERSPECTIVE; TOURETTE-SYNDROME; GENE-EXPRESSION; TIC SEVERITY; ASSOCIATION; BLOOD AB Gilles de la Tourette Syndrome (GTS) is characterized by the presence of multiple motor and phonic tics with a fluctuating course of intensity, frequency, and severity. Up to 90% of patients with GTS present with comorbid conditions, most commonly attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD), thus providing an excellent model for the exploration of shared etiology across disorders. TS-EUROTRAIN (FP7-PEOPLE-2012-ITN, Grant Agr.No. 316978) is a Marie Curie Initial Training Network (http://ts-eurotrain.eu) that aims to elucidate the complex etiology of the onset and clinical course of GTS, investigate the neurobiological underpinnings of GTS and related disorders, translate research findings into clinical applications, and establish a pan-European infrastructure for the study of GTS. This includes the challenges of (i) assembling a large genetic database for the evaluation of the genetic architecture with high statistical power; (ii) exploring the role of gene-environment interactions including the effects of epigenetic phenomena; (iii) employing endophenotype-based approaches to understand the shared etiology between GTS, OCD, and ADHD; (iv) establishing a developmental animal model for GTS; (v) gaining new insights into the neurobiological mechanisms of GTS via cross-sectional and longitudinal neuroimaging studies; and (vi) partaking in outreach activities including the dissemination of scientific knowledge about GTS to the public. Fifteen partners from academia and industry and 12 PhD candidates pursue the project. Here, we aim to share the design of an interdisciplinary project, showcasing the potential of large-scale collaborative efforts in the field of GTS. Our ultimate aims are to elucidate the complex etiology and neurobiological underpinnings of GTS, translate research findings into clinical applications, and establish Pan-European infrastructure for the study of GTS and associated disorders. C1 [Forde, Natalie J.; Dietrich, Andrea; Openneer, Thaira J. C.; Hoekstra, Pieter J.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Forde, Natalie J.; Widomska, Joanna; Buitelaar, Jan K.; Driessen, Nicole; Glennon, Jeffrey; Poelmans, Geert] Radboud Univ Nijmegen, Dept Cognit Neurosci, Donders Inst Brain Cognit & Behav, Med Ctr, Nijmegen, Netherlands. [Kanaan, Ahmad S.; Gerasch, Sarah; Mueller-Vahl, Kirsten R.] Hannover Med Sch, Clin Psychiat Social Psychiat & Psychotherapy, Hannover, Germany. [Kanaan, Ahmad S.; Moeller, Harald E.] Max Planck Inst Human Cognit & Brain Sci, Leipzig, Germany. [Padmanabhuni, Shanmukha S.; Alexander, John; Paschou, Peristera] Democritus Univ Thrace, Dept Mol Biol & Genet, Alexandropoulos, Greece. [Nespoli, Ester; Hengerer, Bastian] Boehringer Ingelheim Pharma GmbH & Co KG, CNS Res, Biberach, Germany. [Nespoli, Ester; Rizzo, Francesca; Ludolph, Andrea] Univ Ulm, Dept Child & Adolescent Psychiat, Ulm, Germany. [Arranz, Juan I. Rodriguez; Houssari, Rayan; Jespersgaard, Cathrine; Tumer, Zeynep] Rigshosp, Copenhagen Univ Hosp, Kennedy Ctr, Dept Clin Genet,Appl Human Mol Genet, Copenhagen, Denmark. [Fan, Siyan; Zilhao, Nuno R.; Cath, Danielle] Univ Utrecht, Dept Clin & Hlth Psychol, Utrecht, Netherlands. [Fan, Siyan; van den Heuvel, Odile A.; Veltman, Dick J.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Fan, Siyan; van den Heuvel, Odile A.; van der werf, Ysbrand D.] Vrije Univ Amsterdam, Med Ctr, Dept Anat & Neurosci, Amsterdam, Netherlands. [Nawaz, Muhammad S.; Stefansson, Hreinn] deCODE Genet Amgen, Reykjavik, Iceland. [Nawaz, Muhammad S.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Rizzo, Francesca; Boomsma, Dorret I.] Univ Ulm, Inst Anat & Cell Biol, Ulm, Germany. [Pagliaroli, Luca; Barta, Csaba] Semmelweis Univ, Inst Med Chem Mol Biol & Pathobiochem, Budapest, Hungary. [Pagliaroli, Luca; Aranyi, Tamas] Hungarian Acad Sci, Inst Enzymol, Res Ctr Nat Sci, Budapest, Hungary. [Zilhao, Nuno R.; Boeckers, Tobias M.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Aranyi, Tamas] Univ Angers, BNMI, INSERM 1083, CNRS, Angers, France. [Boomsma, Dorret I.] Vrije Univ Amsterdam, Med Ctr, Inst Hlth & Care Res, EMGO, Amsterdam, Netherlands. [Buisman, Wim R.] Stichting Gilles Tourette, Rhoon, Netherlands. [Buitelaar, Jan K.] Univ Ctr, Karakter Child & Adolescent Psychiat, Nijmegen, Netherlands. [Drineas, Petros] Rensselaer Polytech Inst, Troy, NY USA. [Dunlap, Michelle] Tourette Gesell Deutschland eV, Hannover, Germany. [Poelmans, Geert] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands. [Poelmans, Geert] Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Donders Inst Brain Cognit & Behav, Dept Mol Anim Physiol, Nijmegen, Netherlands. [Pouwels, Petra J. W.] Vrije Univ Amsterdam, Med Ctr, Dept Phys & Med Technol, Amsterdam, Netherlands. [Scharf, Jeremiah M.] Harvard Med Sch, Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Dept Psychiat, Boston, MA USA. [Scharf, Jeremiah M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Boston, MA USA. [van der werf, Ysbrand D.] Netherlands Inst Neurosci, Amsterdam, Netherlands. RP Paschou, P (reprint author), Democritus Univ Thrace, Dept Mol Biol & Genet, Alexandropoulos, Greece. EM ppaschou@mbg.duth.gr RI Glennon, Jeffrey/D-2379-2013 FU European Union [316978, 278948, 278367]; Semmelweis University; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences [BO/00987/16/5] FX This network has been funded by the European Union under the Seventh Framework People Programme (TS-EUROTRAIN (FP7-PEOPLE-2012-ITN), Grant Agr. No. 316978); we further acknowledge support by the European Union Seventh Framework Programmes [TACTICS (FP7/2007-2013), Grant Agr. No. 278948 and EMTICS (FP7/2007-2013), Grant Agr. No. 278367]. CB was supported by the Merit-prize scholarship of Semmelweis University and the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences BO/00987/16/5. NR 48 TC 0 Z9 0 U1 7 U2 8 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD AUG 23 PY 2016 VL 10 AR 384 DI 10.3389/fnins.2016.00384 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DT9FY UT WOS:000381802600001 PM 27601976 ER PT J AU Taylor, SP Smith, CM Keeley, KL McGuone, D Dodge, CP Duhaime, AC Costine, BA AF Taylor, Sabrina P. Smith, Colin M. Keeley, Kristen L. McGuone, Declan Dodge, Carter P. Duhaime, Ann-Christine Costine, Beth A. TI Neuroblast Distribution after Cortical Impact Is Influenced by White Matter Injury in the Immature Gyrencephalic Brain SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE neurogenesis; neuroplasticity; gyrencephalic; pediatric brain injury; traumatic brain injury; calretinin; interstitial neurons ID MATURATION-DEPENDENT RESPONSE; SUBVENTRICULAR ZONE; POSTNATAL-DEVELOPMENT; CELL-MIGRATION; ENHANCED NEUROGENESIS; ADULT NEUROGENESIS; PIGLET BRAIN; NEURONS; MICE; INTERNEURONS AB Cortical contusions are a common type of traumatic brain injury (TBI) in children. Current knowledge of neuroblast response to cortical injury arises primarily from studies utilizing aspiration or cryoinjury in rodents. In infants and children, cortical impact affects both gray and white matter and any neurogenic response may be complicated by the large expanse of white matter between the subventricular zone (SVZ) and the cortex, and the large number of neuroblasts in transit along the major white matter tracts to populate brain regions. Previously, we described an age-dependent increase of neuroblasts in the SVZ in response to cortical impact in the immature gyrencephalic brain. Here, we investigate if neuroblasts target the injury, if white matter injury influences repair efforts, and if postnatal population of brain regions are disrupted. Piglets received a cortical impact to the rostral gyrus cortex or sham surgery at postnatal day (PND) 7, BrdU 2 days prior to (PND 5 and 6) or after injury (PND 7 and 8), and brains were collected at PND 14. Injury did not alter the number of neuroblasts in the white matter between the SVZ and the rostral gyrus. In the gray matter of the injury site, neuroblast density was increased in cavitated lesions, and the number of BrdU+ neuroblasts was increased, but comprised less than 1% of all neuroblasts. In the white matter of the injury site, neuroblasts with differentiating morphology were densely arranged along the cavity edge. In a ventral migratory stream, neuroblast density was greater in subjects with a cavitated lesion, indicating that TBI may alter postnatal development of regions supplied by that stream. Cortical impact in the immature gyrencephalic brain produced complicated and variable lesions, increased neuroblast density in cavitated gray matter, resulted in potentially differentiating neuroblasts in the white matter, and may alter the postnatal population of brain regions utilizing a population of neuroblasts that were born prior to PND 5. This platform may be useful to continue to study potential complications of white matter injury and alterations of postnatal population of brain regions, which may contribute to the chronic effects of TBI in children. C1 [Taylor, Sabrina P.] Spaulding Rehabil Hospita, Dept Phys Med & Rehabil, Charlestown, MA USA. [Smith, Colin M.; Keeley, Kristen L.; Duhaime, Ann-Christine; Costine, Beth A.] Massachusetts Gen Hosp, Dept Neurosurg, Brain Trauma Lab, Boston, MA 02114 USA. [Dodge, Carter P.] Childrens Hosp Dartmouth, Dartmouth Med Sch, Dept Anesthesiol, Lebanon, PA USA. [Costine, Beth A.] Harvard Med Sch, Dept Neurosurg, Boston, MA USA. RP Costine, BA (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Brain Trauma Lab, Boston, MA 02114 USA.; Costine, BA (reprint author), Harvard Med Sch, Dept Neurosurg, Boston, MA USA. EM bcostine@mgh.harvard.edu FU Nicholas T. Zervas Chair of Harvard Medical School; Joel Alan Viktor Research Fund; John G. Price Memorial Fund at Massachusetts General Hospital; NICHD [K01HD083759]; NINDS [5P30NS045776]; Harvard Catalyst; Harvard Clinical and Translational Science Center (National Center for Research Resources, National Institutes of Health) [UL1 TR001102]; Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [UL1 TR001102]; Harvard University and its affiliated academic healthcare centers FX This work was supported by the Nicholas T. Zervas Chair of Harvard Medical School, the Joel Alan Viktor Research Fund and John G. Price Memorial Fund at Massachusetts General Hospital to AD, NICHD grant K01HD083759 to BC, and the MGH Neuroscience Center Imaging Core supported by NINDS grant 5P30NS045776. 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 Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. The authors express their gratitude to Rebecca Zhu, Christopher Seufert, Marissa Fiorello, and Monica Shifman for their assistance with animal handling, immunohistochemistry, and quantification. We thank George Price for his assistance with immunohistochemistry and assistance with the preparation of the results section of the manuscript. NR 43 TC 0 Z9 0 U1 1 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD AUG 23 PY 2016 VL 10 AR 387 DI 10.3389/fnins.2016.00387 PG 15 WC Neurosciences SC Neurosciences & Neurology GA DT9GA UT WOS:000381803000002 PM 27601978 ER PT J AU Miyoshi, N Stel, JM Shioda, K Qu, N Odahima, J Mitsunaga, S Zhang, XF Nagano, M Hochedlinger, K Isselbacher, KJ Shioda, T AF Miyoshi, Norikatsu Stel, Jente M. Shioda, Keiko Qu, Na Odahima, Junko Mitsunaga, Shino Zhang, Xiangfan Nagano, Makoto Hochedlinger, Konrad Isselbacher, Kurt J. Shioda, Toshi TI Erasure of DNA methylation, genomic imprints, and epimutations in a primordial germ-cell model derived from mouse pluripotent stem cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE PGCLC; epigenetic reprogramming; genetic imprinting; epimutation ID IN-VITRO; NONGENETIC INHERITANCE; GENES; MICE; 5-HYDROXYMETHYLCYTOSINE; DIFFERENTIATION; DEMETHYLATION; EPIGENOME; DYNAMICS; EPIGENETICS AB The genome-wide depletion of 5-methylcytosines (5meCs) caused by passive dilution through DNA synthesis without daughter strand methylation and active enzymatic processes resulting in replacement of 5meCs with unmethylated cytosines is a hallmark of primordial germ cells (PGCs). Although recent studies have shown that in vitro differentiation of pluripotent stem cells (PSCs) to PGC-like cells (PGCLCs) mimics the in vivo differentiation of epiblast cells to PGCs, how DNA methylation status of PGCLCs resembles the dynamics of 5meC erasure in embryonic PGCs remains controversial. Here, by differential detection of genome-wide 5meC and 5-hydroxymethyl-cytosine (5hmeC) distributions by deep sequencing, we show that PGCLCs derived from mouse PSCs recapitulated the process of genome-wide DNA demethylation in embryonic PGCs, including significant demethylation of imprint control regions (ICRs) associated with increased mRNA expression of the corresponding imprinted genes. Although 5hmeCs were also significantly diminished in PGCLCs, they retained greater amounts of 5hmeCs than intragonadal PGCs. The genomes of both PGCLCs and PGCs selectively retained both 5meCs and 5hmeCs at a small number of repeat sequences such as GSAT_MM, of which the significant retention of bisulfite-resistant cytosines was corroborated by reanalysis of previously published whole-genome bisulfite sequencing data for intragonadal PGCs. PSCs harboring abnormal hypermethylation at ICRs of the Dlk1-Gtl2-Dio3 imprinting cluster diminished these 5meCs upon differentiation to PGCLCs, resulting in transcriptional reactivation of the Gtl2 gene. These observations support the usefulness of PGCLCs in studying the germline epigenetic erasure including imprinted genes, epimutations, and erasure-resistant loci, which may be involved in transgenerational epigenetic inheritance. C1 [Miyoshi, Norikatsu; Stel, Jente M.; Shioda, Keiko; Qu, Na; Odahima, Junko; Mitsunaga, Shino; Hochedlinger, Konrad; Isselbacher, Kurt J.; Shioda, Toshi] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Stel, Jente M.] Vrije Univ Amsterdam, Inst Environm Studies, NL-1081 HV Amsterdam, Netherlands. [Zhang, Xiangfan; Nagano, Makoto] McGill Univ, Dept Obstet & Gynecol, Montreal, PQ H4A 3J1, Canada. [Zhang, Xiangfan; Nagano, Makoto] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ H4A 3J1, Canada. [Hochedlinger, Konrad] Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Isselbacher, KJ; Shioda, T (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. EM kisselbacher@mgh.harvard.edu; tshioda@mgh.harvard.edu FU Canadian Institutes of Health Research Grant [MOP-130467]; National Institutes of Health Grants [HD058013, ES023316, ES024861] FX We thank Haley Ellis and Shiomi (Misa) Yawata for technical assistance. This work was supported by Canadian Institutes of Health Research Grant MOP-130467 (to M.N.) and National Institutes of Health Grants HD058013 (to K.H.) and ES023316 and ES024861 (to T.S.). NR 38 TC 1 Z9 1 U1 15 U2 15 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 AUG 23 PY 2016 VL 113 IS 34 BP 9545 EP 9550 DI 10.1073/pnas.1610259113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT9ZK UT WOS:000381860800053 PM 27486249 ER PT J AU Humar, M Araoka, F Takezoe, H Musevic, I AF Humar, Matjaz Araoka, Fumito Takezoe, Hideo Musevic, Igor TI Lasing properties of polymerized chiral nematic Bragg onion microlasers SO OPTICS EXPRESS LA English DT Article ID CHOLESTERIC LIQUID-CRYSTALS; LASERS; EDGE; BAND; MICRORESONATORS; MICRODROPLETS; RESONATORS; DROPLETS; EMISSION AB Dye doped photocurable cholesteric liquid crystal was used to produce solid Bragg onion omnidirectional lasers. The lasers were produced by dispersing and polymerizing chiral nematic LC with parallel surface anchoring of LC molecules at the interface, extracted and transferred into another medium. Lasing characteristics were studied in carrier medium with different refractive index. The lasing in spherical cholesteric liquid crystal was attributed to two mechanisms, photonic bandedge lasing and lasing of whispering-gallery modes. The latter can be suppressed by using a higher index carrier fluid to prevent total internal reflection on the interface of the spheres. Pulse-to-pulse stability and threshold characteristics were also studied and compared to non-polymerized lasers. The polymerization process greatly increases the lasing stability. (C) 2016 Optical Society of America. C1 [Humar, Matjaz; Musevic, Igor] J Stefan Inst, Jamova 39, SI-1000 Ljubljana, Slovenia. [Humar, Matjaz; Musevic, Igor] Univ Ljubljana, Fac Math & Phys, Jadranska 19, SI-1000 Ljubljana, Slovenia. [Humar, Matjaz] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, 65 Landsdowne St UP-5, Cambridge, MA 02139 USA. [Araoka, Fumito] RIKEN Ctr Emergent Matter Sci, 2-1 Hirosawa, Wako, Saitama 3510198, Japan. [Takezoe, Hideo] Toyota Phys & Chem Res Inst, 41-1 Yokomichi, Nagakute, Aichi 4801192, Japan. RP Humar, M (reprint author), J Stefan Inst, Jamova 39, SI-1000 Ljubljana, Slovenia.; Humar, M (reprint author), Univ Ljubljana, Fac Math & Phys, Jadranska 19, SI-1000 Ljubljana, Slovenia.; Humar, M (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, 65 Landsdowne St UP-5, Cambridge, MA 02139 USA. EM matjaz.humar@ijs.si RI Araoka, Fumito/A-8919-2014 OI Araoka, Fumito/0000-0002-9387-6081 FU Slovenian Research Agency (ARRS) [J16732]; Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme [627274] FX The authors would like to thank the Slovenian Research Agency (ARRS) for grant No. J16732 (I.M.) and Marie Curie International Outgoing Fellowship 627274 within the 7th European Community Framework Programme (M.H.). NR 27 TC 1 Z9 1 U1 16 U2 16 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD AUG 22 PY 2016 VL 24 IS 17 BP 19237 EP 19244 DI 10.1364/OE.24.019237 PG 8 WC Optics SC Optics GA DY6KV UT WOS:000385227100038 PM 27557203 ER PT J AU Debbane, M Salaminios, G Luyten, P Badoud, D Armando, M Tozzi, AS Fonagy, P Brent, BK AF Debbane, Martin Salaminios, George Luyten, Patrick Badoud, Deborah Armando, Marco Tozzi, Alessandra Solida Fonagy, Peter Brent, Benjamin K. TI Attachment, Neurobiology, and Mentalizing along the Psychosis Continuum SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Review DE schizophrenia; mentalizing; HPA; schizotypy; UHR; theory of mind; self ID ULTRA-HIGH-RISK; 1ST-DEGREE BIOLOGICAL RELATIVES; BORDERLINE PERSONALITY-DISORDER; AGE-RELATED-CHANGES; THEORY-OF-MIND; CHILDHOOD TRAUMA; SOCIAL COGNITION; 1ST-EPISODE PSYCHOSIS; ADULT ATTACHMENT; OXIDATIVE STRESS AB In this review article, we outline the evidence linking attachment adversity to psychosis, from the premorbid stages of the disorder to its clinical forms. To better understand the neurobiological mechanisms through which insecure attachment may contribute to psychosis, we identify at least five neurobiological pathways linking attachment to risk for developing psychosis. Besides its well documented influence on the hypothalamic-pituary-adrenal (HPA) axis, insecure attachment may also contribute to neurodevelopmental risk through the dopaminergic and oxytonergic systems, as well as bear influence on neuroinflammation and oxidative stress responses. We further consider the neuroscientific and behavioral studies that underpin mentalization as a suite of processes potentially moderating the risk to transition to psychotic disorders. In particular, mentalization may help the individual compensate for endophenotypical impairments in the integration of sensory and metacognitive information. We propose a model where embodied mentalization would lie at the core of a protective, resilience response mitigating the adverse and potentially pathological influence of the neurodevelopmental cascade of risk for psychosis. C1 [Debbane, Martin; Badoud, Deborah] Univ Geneva, Fac Psychol & Educ Sci, Geneva, Switzerland. [Debbane, Martin; Salaminios, George; Luyten, Patrick; Fonagy, Peter] UCL, Res Dept Clin Educ & Hlth Psychol, London, England. [Debbane, Martin; Armando, Marco] Off Med Pedagog, Geneva, Switzerland. [Luyten, Patrick] Univ Leuven, Fac Psychol & Educ Sci, Leuven, Belgium. [Tozzi, Alessandra Solida] Lausanne Univ Hosp CHUV, Dept Psychiat, Lausanne, Switzerland. [Brent, Benjamin K.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. RP Debbane, M (reprint author), Univ Geneva, Fac Psychol & Educ Sci, Geneva, Switzerland.; Debbane, M (reprint author), UCL, Res Dept Clin Educ & Hlth Psychol, London, England.; Debbane, M (reprint author), Off Med Pedagog, Geneva, Switzerland. EM martin.debbane@unige.ch FU Swiss National Science Foundation [100019_159440]; Gertrude Von Meissner Foundation [ML 7871] FX For this work, MD was supported by the Swiss National Science Foundation (100019_159440) and Gertrude Von Meissner Foundation (ML 7871). NR 193 TC 0 Z9 0 U1 20 U2 26 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 AUG 22 PY 2016 VL 10 AR 406 DI 10.3389/finhum.2016.00406 PG 22 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA DT7PJ UT WOS:000381678400001 PM 27597820 ER PT J AU Hamouda, MA Jacquel, A Robert, G Puissant, A Richez, V Cassel, R Fenouille, N Roulland, S Gilleron, J Griessinger, E Dubois, A Bailly-Maitre, B Goncalves, D Mallavialle, A Colosetti, P Marchetti, S Amiot, M Gomez-Bougie, P Rochet, N Deckert, M Avet-Loiseau, H Hofman, P Karsenti, JM Jeandel, PY Blin-Wakkach, C Nadel, B Cluzeau, T Anderson, KC Fuzibet, JG Auberger, P Luciano, F AF Hamouda, Mohamed-Amine Jacquel, Arnaud Robert, Guillaume Puissant, Alexandre Richez, Valentine Cassel, Romeo Fenouille, Nina Roulland, Sandrine Gilleron, Jerome Griessinger, Emmanuel Dubois, Alix Bailly-Maitre, Beatrice Goncalves, Diogo Mallavialle, Aude Colosetti, Pascal Marchetti, Sandrine Amiot, Martine Gomez-Bougie, Patricia Rochet, Nathalie Deckert, Marcel Avet-Loiseau, Herve Hofman, Paul Karsenti, Jean-Michel Jeandel, Pierre-Yves Blin-Wakkach, Claudine Nadel, Bertrand Cluzeau, Thomas Anderson, Kenneth C. Fuzibet, Jean-Gabriel Auberger, Patrick Luciano, Frederic TI BCL-B (BCL2L10) is overexpressed in patients suffering from multiple myeloma (MM) and drives an MM-like disease in transgenic mice SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID PLASMA-CELL NEOPLASMS; FAMILY-MEMBER; MOUSE MODEL; CHROMOSOMAL TRANSLOCATION; BONE-DISEASE; C-MYC; X-L; BIM; EXPRESSION; SURVIVAL AB Multiple myeloma (MM) evolves from a premalignant condition known as monoclonal gammopathy of undetermined significance (MGUS). However, the factors underlying the malignant transformation of plasmocytes in MM are not fully characterized. We report here that E mu-directed expression of the antiapoptotic Bcl-B protein in mice drives an MM phenotype that reproduces accurately the human disease. Indeed, with age, E mu-bcl-b transgenic mice develop the characteristic features of human MM, including bone malignant plasma cell infiltration, a monoclonal immunoglobulin peak, immunoglobulin deposit in renal tubules, and highly characteristic bone lytic lesions. In addition, the tumors are serially transplantable in irradiated wildtype mice, underlying the tumoral origin of the disease. E mu-bcl-b plasmocytes show increased expression of a panel of genes known to be dysregulated in human MM pathogenesis. Treatment of E mu-bcl-b mice with drugs currently used to treat patients such as melphalan and VEL CADE efficiently kills malignant plasmocytes in vivo. Finally, we find that Bcl-B is overexpressed in plasmocytes from MM patients but neither in MGUS patients nor in healthy individuals, suggesting that Bcl-B may drive MM. These findings suggest that Bcl-B could be an important factor in MM disease and pinpoint E mu-bcl-b mice as a pertinent model to validate new therapies in MM. C1 [Hamouda, Mohamed-Amine; Jacquel, Arnaud; Robert, Guillaume; Richez, Valentine; Cassel, Romeo; Dubois, Alix; Cluzeau, Thomas; Auberger, Patrick; Luciano, Frederic] INSERM, U1065, C3M, Team 2, F-06204 Nice, France. [Gilleron, Jerome] INSERM, U1065, C3M, Team 7, F-06204 Nice, France. [Griessinger, Emmanuel] INSERM, U1065, C3M, Team 4, F-06204 Nice, France. [Bailly-Maitre, Beatrice] INSERM, U1065, C3M, Team 8, F-06204 Nice, France. [Mallavialle, Aude] INSERM, U1065, C3M, Team 11, F-06204 Nice, France. [Hamouda, Mohamed-Amine; Jacquel, Arnaud; Robert, Guillaume; Puissant, Alexandre; Cassel, Romeo; Gilleron, Jerome; Griessinger, Emmanuel; Dubois, Alix; Bailly-Maitre, Beatrice; Goncalves, Diogo; Mallavialle, Aude; Colosetti, Pascal; Marchetti, Sandrine; Rochet, Nathalie; Deckert, Marcel; Blin-Wakkach, Claudine; Cluzeau, Thomas; Auberger, Patrick; Luciano, Frederic] Univ Nice Sophia Antipolis, F-06000 Nice, France. [Hamouda, Mohamed-Amine; Jacquel, Arnaud; Robert, Guillaume; Cassel, Romeo; Dubois, Alix; Goncalves, Diogo; Colosetti, Pascal; Marchetti, Sandrine; Cluzeau, Thomas; Auberger, Patrick; Luciano, Frederic] Equipe Labellisee Ligue Natl Canc, F-75013 Paris, France. [Puissant, Alexandre; Anderson, Kenneth C.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA. [Puissant, Alexandre; Anderson, Kenneth C.] Harvard Med Sch, Boston Childrens Hosp, Boston, MA 02115 USA. [Fenouille, Nina] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA. [Roulland, Sandrine; Nadel, Bertrand] Aix Marseille Univ, CNRS, INSERM, U1104,Ctr Immunol Marseille Luminy,UMR 7280, F-13288 Marseille, France. [Amiot, Martine; Gomez-Bougie, Patricia] INSERM, U892, Team 10, F-44007 Nantes, France. [Rochet, Nathalie] UMR 7277, F-06108 Nice, France. [Avet-Loiseau, Herve] Univ Toulouse 3, CNRS, INSERM, Canc Res Ctr Toulouse,UMR 1037,UPS, F-31037 Toulouse, France. [Hofman, Paul] CHU Nice, Serv Anatomopathol, F-06003 Nice, France. [Karsenti, Jean-Michel; Cluzeau, Thomas] CHU Nice, Serv Hematol Clin, F-06003 Nice, France. [Jeandel, Pierre-Yves; Fuzibet, Jean-Gabriel] CHU Nice, Serv Med Interne, F-06003 Nice, France. [Blin-Wakkach, Claudine] CNRS, UMR 7370, F-06108 Nice, France. RP Luciano, F (reprint author), INSERM, U1065, C3M, Team 2, F-06204 Nice, France.; Luciano, F (reprint author), Univ Nice Sophia Antipolis, F-06000 Nice, France.; Luciano, F (reprint author), Equipe Labellisee Ligue Natl Canc, F-75013 Paris, France. EM fluciano@unice.fr RI PUISSANT, ALEXANDRE/O-9575-2016; Nadel, Bertrand/J-2197-2014; Marchetti, Sandrine/P-6479-2016; AUBERGER, Patrick/G-1491-2013; OI PUISSANT, ALEXANDRE/0000-0002-3997-9282; Marchetti, Sandrine/0000-0001-8326-5730; AUBERGER, Patrick/0000-0002-2481-8275; Jacquel, Arnaud/0000-0001-5062-8048; GRIESSINGER, Emmanuel/0000-0001-7529-4187; ROCHET, Nathalie/0000-0002-9995-6699; Gilleron, Jerome/0000-0002-6389-8685 FU Ligue Nationale Contre le Cancer [R08001AA]; Fondation de France [R08080AA]; ARC Foundation program [PGA120140200777]; ARC project; French government (French National Research Agency, ANR) [ANR-11-LABX-0028-01] FX This work was supported by the Ligue Nationale Contre le Cancer (Equipe Labellisee grant R08001AA), the Fondation de France (grant R08080AA), and an ARC Foundation program (grant PGA120140200777) and an ARC project (2015-2016). This work was also funded by the French government (French National Research Agency, ANR) through the "Investments for the future" LABEX SIGNALIFE: program reference #ANR-11-LABX-0028-01. NR 50 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 AUG 22 PY 2016 VL 213 IS 9 BP 1705 EP 1722 DI 10.1084/jem.20150983 PG 18 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DU9FE UT WOS:000382520900007 PM 27455953 ER PT J AU Zhao, LJ Frock, RL Du, Z Hu, JZ Chen, L Krangel, MS Alt, FW AF Zhao, Lijuan Frock, Richard L. Du, Zhou Hu, Jiazhi Chen, Liang Krangel, Michael S. Alt, Frederick W. TI Orientation-specific RAG activity in chromosomal loop domains contributes to Tcrd V(D)J recombination during T cell development SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID DOUBLE-STRANDED BREAKS; RECEPTOR DELTA-GENE; GENOMIC INSTABILITY; B-CELLS; REARRANGEMENTS; GAMMA; MECHANISMS; THYMOCYTES; ELEMENTS; ENHANCER AB T cell antigen receptor delta (Tcrd) variable region exons are assembled by RAG-initiated V(D)J recombination events in developing gamma delta thymocytes. Here, we use linear amplification-mediated high-throughput genome-wide translocation sequencing (LAM-HTGTS) to map hundreds of thousands of RAG-initiated Tcrd D segment (Trdd1 and Trdd2) rearrangements in CD4(-)CD8(-)double- negative thymocyte progenitors differentiated in vitro from bone marrow-derived hematopoietic stem cells. We find that Trdd2 joins directly to Trdv, Trdd1, and Trdj segments, whereas Trdd1 joining is ordered with joining to Trdd2, a prerequisite for further rearrangement. We also find frequent, previously unappreciated, Trdd1 and Trdd2 rearrangements that inactivate Tcrd, including sequential rearrangements from V(D) J recombination signal sequence fusions. Moreover, we find dozens of RAG off-target sequences that are generated via RAG tracking both upstream and downstream from the Trdd2 recombination center across the Tcrd loop domain that is bounded by the upstream INT1-2 and downstream TEA elements. Disruption of the upstream INT1-2 boundary of this loop domain allows spreading of RAG on-and off-target activity to the proximal Trdv domain and, correspondingly, shifts the Tcrd V(D) J recombination landscape by leading to predominant V(D) J joining to a proximal Trdv3 pseudogene that lies just upstream of the normal boundary. C1 [Zhao, Lijuan; Frock, Richard L.; Du, Zhou; Hu, Jiazhi; Alt, Frederick W.] Harvard Med Sch, Childrens Hosp Boston, Dept Genet, Howard Hughes Med Inst,Program Cellular & Mol Med, Boston, MA 02115 USA. [Chen, Liang; Krangel, Michael S.] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. RP Alt, FW (reprint author), Harvard Med Sch, Childrens Hosp Boston, Dept Genet, Howard Hughes Med Inst,Program Cellular & Mol Med, Boston, MA 02115 USA.; Krangel, MS (reprint author), Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. EM michael.krangel@duke.edu; alt@enders.tch.harvard.edu OI Frock, Richard/0000-0001-6963-4931 FU National Institutes of Health (NIH) [AI020047, R37 GM41052]; NIH National Research Service Award [T32AI007512] FX This work was supported by National Institutes of Health (NIH) grants AI020047 (F.W. Alt) and R37 GM41052 (M.S. Krangel). F.W. Alt is a Howard Hughes Medical Institute Investigator. R.L. Frock was supported by the NIH National Research Service Award T32AI007512. NR 43 TC 2 Z9 2 U1 2 U2 2 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 AUG 22 PY 2016 VL 213 IS 9 BP 1921 EP 1936 DI 10.1084/jem.20160670 PG 16 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DU9FE UT WOS:000382520900019 PM 27526713 ER PT J AU Pak, E Segal, RA AF Pak, Ekaterina Segal, Rosalind A. TI Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy SO DEVELOPMENTAL CELL LA English DT Review ID BASAL-CELL CARCINOMA; BET BROMODOMAIN INHIBITION; COUPLED RECEPTOR GPR161; BRAIN-TUMOR CONSORTIUM; PROTEIN-KINASE-A; SONIC HEDGEHOG; PATHWAY INHIBITOR; PRIMARY CILIUM; PHASE-I; SUBGROUP MEDULLOBLASTOMA AB The Hedgehog (Hh) signaling pathway governs complex developmental processes, including proliferation and patterning within diverse tissues. These activities rely on a tightly regulated transduction system that converts graded Hh input signals into specific levels of pathway activity. Uncontrolled activation of Hh signaling drives tumor initiation and maintenance. However, recent entry of pathway-specific inhibitors into the clinic reveals mixed patient responses and thus prompts further exploration of pathway activation and inhibition. In this review, we share emerging insights into regulated and oncogenic Hh signaling, supplemented with updates on the development and use of Hh pathway-targeted therapies. C1 [Pak, Ekaterina; Segal, Rosalind A.] Harvard Med Sch, Dept Neurobiol, Boston, MA 02115 USA. [Pak, Ekaterina; Segal, Rosalind A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. RP Segal, RA (reprint author), Harvard Med Sch, Dept Neurobiol, Boston, MA 02115 USA.; Segal, RA (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM rosalind_segal@dfci.harvard.edu FU US NIH [P01CA142536, F31CA183145]; Alex's Lemonade Stand Foundation FX We thank members of the Segal laboratory for comments. This work was supported by US NIH grants (P01CA142536 to R.A.S. and F31CA183145 to E.P.) and Alex's Lemonade Stand Foundation. NR 114 TC 5 Z9 5 U1 36 U2 38 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 AUG 22 PY 2016 VL 38 IS 4 BP 333 EP 344 DI 10.1016/j.devcel.2016.07.026 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA DU3FP UT WOS:000382096500001 PM 27554855 ER PT J AU Nappi, AG Boden, WE AF Nappi, Anthony G. Boden, William E. TI Should Beta-Blockers Continue to Be Used in Post-Percutaneous Coronary Intervention Patients Without Myocardial Infarction? SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material DE beta-blockers; coronary artery disease; percutaneous coronary intervention ID FRACTIONAL FLOW RESERVE; CLINICAL-OUTCOMES; RANDOMIZED TRIAL; MEDICAL THERAPY; HEART-FAILURE; DISEASE; METAANALYSIS; MORTALITY; PCI C1 [Nappi, Anthony G.] Albany Med Coll, Albany, NY 12208 USA. [Boden, William E.] VA New England Healthcare Syst, Clin Trials Network, Boston, MA USA. RP Boden, WE (reprint author), VA Boston Healthcare Syst, 150 South Huntington Ave, Boston, MA 02130 USA. EM william.boden@va.gov NR 19 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD AUG 22 PY 2016 VL 9 IS 16 BP 1649 EP 1651 DI 10.1016/j.jcin.2016.07.001 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DT8NI UT WOS:000381747300005 PM 27539684 ER PT J AU Sherwood, MW Cyr, DD Jones, WS Becker, RC Berkowitz, SD Washam, JB Breithardt, G Fox, KAA Halperin, JL Hankey, GJ Singer, DE Piccini, JP Nessel, CC Mahaffey, KW Patel, MR AF Sherwood, Matthew W. Cyr, Derek D. Jones, W. Schuyler Becker, Richard C. Berkowitz, Scott D. Washam, Jeffrey B. Breithardt, Guenter Fox, Keith A. A. Halperin, Jonathan L. Hankey, Graeme J. Singer, Daniel E. Piccini, Jonathan P. Nessel, Christopher C. Mahaffey, Kenneth W. Patel, Manesh R. TI Use of Dual Antiplatelet Therapy and Patient Outcomes in Those Undergoing Percutaneous Coronary Intervention The ROCKET AF Trial SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE anticoagulants; coronary disease; direct-acting oral anticoagulants; fibrillation; percutaneous coronary intervention ID ATRIAL-FIBRILLATION PATIENTS; TRIPLE ANTITHROMBOTIC THERAPY; CARDIOLOGY WORKING GROUP; RHYTHM ASSOCIATION EHRA; VITAMIN-K ANTAGONISM; MYOCARDIAL-INFARCTION; ORAL ANTICOAGULATION; EUROPEAN ASSOCIATION; CONCOMITANT ASPIRIN; CONSENSUS DOCUMENT AB OBJECTIVES The authors assessed the use of dual antiplatelet therapy (DAPT) and outcomes in patients undergoing percutaneous coronary intervention (PCI) during the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). BACKGROUND The frequency, patterns, and outcomes when adding DAPT to non-vitamin K antagonist oral anticoagulants in the setting of PCI in patients with AF are largely unknown. METHODS The study population included all patients in the treatment group of the ROCKET AF trial divided by the receipt of PCI during follow-up. Clinical characteristics, PCI frequency, and rates of DAPT were reported. Clinical outcomes were adjudicated independently as part of the trial. RESULTS Among 14,171 patients, 153 (1.1%) underwent PCI during a median 806 days of follow-up. Patients treated with rivaroxaban were significantly less likely to undergo PCI compared with warfarin-treated patients (61 vs. 92; p = 0.01). Study drug was continued during PCI in 81% of patients. Long-term DAPT (>= 30 days) was used in 37% and single antiplatelet therapy in 34%. A small number switched from DAPT to monotherapy within 30 days of PCI (n = 19 [ 12.3%]) and 15% of patients received no antiplatelet therapy after PCI. Rates of stroke/systemic embolism and major bleeding events were high in post-PCI patients (4.5/100 patient-years and 10.2/100 patient-years) in both treatment groups. CONCLUSIONS In patients with AF at moderate to high risk for stroke, PCI occurred in <1% per year. DAPT was used in a variable manner, with the majority of patients remaining on study drug after PCI. Rates of both thrombotic and bleeding events were high after PCI, highlighting the need for studies to determine the optimal antithrombotic therapy. (C) 2016 by the American College of Cardiology Foundation. Published by Elsevier. C1 [Sherwood, Matthew W.; Cyr, Derek D.; Jones, W. Schuyler; Piccini, Jonathan P.; Patel, Manesh R.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Jones, W. Schuyler; Washam, Jeffrey B.; Piccini, Jonathan P.; Patel, Manesh R.] Duke Univ, Sch Med, Duke Heart Ctr, Durham, NC USA. [Becker, Richard C.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Berkowitz, Scott D.] Bayer HealthCare Pharmaceut, Parsippany, NJ USA. [Breithardt, Guenter] Hosp Univ Munster, Munster, Germany. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. [Halperin, Jonathan L.] Mt Sinai Med Ctr, Zena & Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Crawley, WA, Australia. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Med Sch, Boston, MA USA. [Nessel, Christopher C.] Janssen Pharmaceut Res & Dev, Raritan, NJ USA. [Mahaffey, Kenneth W.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. RP Sherwood, MW (reprint author), Duke Clin Res Inst, 2400 Pratt St,POB 17969, Durham, NC 27715 USA. EM matthew.sherwood@dm.duke.edu RI Hankey, Graeme /H-4968-2014 OI Hankey, Graeme /0000-0002-6044-7328 FU Johnson & Johnson Pharmaceutical Research & Development (Raritan, New Jersey); Bayer HealthCare AG (Leverkusen, Germany); NIH T-32 training grant [5 T32 HL 7101-37]; American Heart Association; AstraZeneca; Boston Scientific Corporation; Daiichi-Sankyo; Bayer HealthCare; Johnson Johnson; Boehringer Ingelheim; Sanofi; Merck Sharp Dohme; 3M; Bayer; Janssen; Lilly; Bayer AG HealthCare; Ortho-McNeil-Janssen Pharmaceuticals; Pfizer; Sanofi-Aventis; Bristol-Myers Squibb; Medtronic; CVS Health; Merck; St. Jude Medical; ARCA biopharma; Boston Scientific; Gilead; Janssen Pharmaceuticals; ResMed; GlaxoSmithKline; Laguna Pharmaceuticals; Spectranetics; Genzyme FX From the aDuke Clinical Research Institute, bDuke Heart Center, Duke University School of Medicine, Durham, North Carolina; cUniversity of Cincinnati College of Medicine, Cincinnati, Ohio; dBayer HealthCare Pharmaceuticals, Parsippany, New Jersey; eHospital of the University of Munster, Munster, Germany; fUniversity of Edinburgh and Royal Infirmary of Edinburgh, Edinburgh, UK; gZena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, New York, New York; hSchool of Medicine and Pharmacology, University of Western Australia, Crawley, WA, Australia; iMassachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts; jJanssen Pharmaceutical Research and Development, Raritan, New Jersey; and the kDepartment of Medicine, Stanford University, Stanford, California. The ROCKET AF trial was supported by Johnson & Johnson Pharmaceutical Research & Development (Raritan, New Jersey) and Bayer HealthCare AG (Leverkusen, Germany). Dr. Sherwood was funded by NIH T-32 training grant #5 T32 HL 7101-37. Dr. Jones received research grants from the American Heart Association, AstraZeneca, Boston Scientific Corporation, and Daiichi-Sankyo. Dr. Becker is a consultant/advisory board member for Janssen Research & Development, Portola, Cook, and Boehringer Ingelheim. Dr. Berkowitz is an employee of Bayer HealthCare Pharmaceuticals. Dr. Breithardt has received consulting fees from Bayer HealthCare, Johnson & Johnson, Boehringer Ingelheim, Sanofi, Merck Sharp & Dohme, and 3M. Dr. Fox has received research funding from Bayer, Janssen, and AstraZeneca; honoraria from Bayer, AstraZeneca, GlaxoSmithKline, Janssen, and Sanofi; consulting fees from Bayer, Lilly, AstraZeneca, and Sanofi. Dr. Halperin has received consulting fees from Bayer AG HealthCare, Boehringer Ingelheim, Daiichi-Sankyo, Johnson & Johnson, Ortho-McNeil-Janssen Pharmaceuticals, Pfizer, and Sanofi-Aventis. Dr. Hankey has received consulting fees from Bayer and Sanofi. Dr. Inger has received research funding from Johnson & Johnson, Bristol-Myers Squibb, Boehringer Ingelheim, and Medtronic; consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb, CVS Health, Johnson & Johnson, Merck, Pfizer, and St. Jude Medical. Dr. Piccini has received research grants from ARCA biopharma, Boston Scientific, Gilead, Janssen Pharmaceuticals, ResMed, and St Jude Medical; and consulting fees from GlaxoSmithKline, Johnson & Johnson, Laguna Pharmaceuticals, Medtronic, and Spectranetics. Dr. Nessel is an employee of Janssen Research and Development. Dr. Mahaffey has provided full disclosures prior to August 1, 2013, available at www.dcri.org. Disclosures after August 1, 2013 available at https://med.stanford.edu/profiles/47970?tab=research-and-scholarship. Dr. Patel has received research funding from Johnson & Johnson, AstraZeneca; advisory board fees from Bayer, Janssen, AstraZeneca, and Genzyme. NR 33 TC 3 Z9 3 U1 4 U2 5 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 AUG 22 PY 2016 VL 9 IS 16 BP 1694 EP 1702 DI 10.1016/j.jcin.2016.05.03 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DT8NI UT WOS:000381747300012 PM 27539689 ER PT J AU Guthier, CV Aschenbrenner, KP Muller, R Polster, L Cormack, RA Hesser, JW AF Guthier, C. V. Aschenbrenner, K. P. Mueller, R. Polster, L. Cormack, R. A. Hesser, J. W. TI Real-time inverse high-dose-rate brachytherapy planning with catheter optimization by compressed sensing-inspired optimization strategies SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE brachytherapy; HDR; inverse treatment planning; compressed sensing; real-time ID PROSTATE HDR BRACHYTHERAPY; CANCER; RECOMMENDATIONS; APPROXIMATIONS; TOXICITY; QUALITY; UPDATE AB This paper demonstrates that optimization strategies derived from the field of compressed sensing (CS) improve computational performance in inverse treatment planning (ITP) for high-dose-rate (HDR) brachytherapy. Following an approach applied to low-dose-rate brachytherapy, we developed a reformulation of the ITP problem with the same mathematical structure as standard CS problems. Two greedy methods, derived from hard thresholding and subspace pursuit are presented and their performance is compared to state-of-the-art ITP solvers. Applied to clinical prostate brachytherapy plans speed-up by a factor of 56-350 compared to state-of-the-art methods. Based on a Wilcoxon signed rank-test the novel method statistically significantly decreases the final objective function value (p < 0.01). The optimization times were below one second and thus planing can be considered as real-time capable. The novel CS inspired strategy enables real-time ITP for HDR brachytherapy including catheter optimization. The generated plans are either clinically equivalent or show a better performance with respect to dosimetric measures. C1 [Guthier, C. V.; Aschenbrenner, K. P.; Mueller, R.; Polster, L.; Hesser, J. W.] Heidelberg Univ, Med Fac Mannheim, Dept Expt Radiat Oncol, Mannheim, Germany. [Aschenbrenner, K. P.; Polster, L.; Hesser, J. W.] Heidelberg Univ, IWR, Heidelberg, Germany. [Guthier, C. V.; Mueller, R.; Cormack, R. A.] Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. [Cormack, R. A.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Guthier, C. V.; Cormack, R. A.] Harvard Med Sch, Boston, MA 02115 USA. RP Guthier, CV (reprint author), Heidelberg Univ, Med Fac Mannheim, Dept Expt Radiat Oncol, Mannheim, Germany.; Guthier, CV (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA.; Guthier, CV (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM Christian.Guthier@medma.uni-heidelberg.de; Katharina.Aschenbrenner@medma.uni-heidelberg.de; RMueller@lroc.harvard.edu; Lisa.Polster@medma.uni-heidelberg.de; RCormack@lroc.harvard.edu; Juergen.Hesser@medma.uni-heidelberg.de FU DFG grant [HE 3011/36-1]; OCP FX The project was funded by DFG grant HE 3011/36-1. We gratefully thank D Stsepankou for his support in this project as well as Dr Martin Polednik for his support with OCP. NR 29 TC 0 Z9 0 U1 0 U2 0 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD AUG 21 PY 2016 VL 61 IS 16 BP 5956 EP 5972 DI 10.1088/0031-9155/61/16/5956 PG 17 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DX2NZ UT WOS:000384208600010 PM 27435044 ER PT J AU McNamara, AL Kam, WWY Scales, N McMahon, SJ Bennett, JW Byrne, HL Schuemann, J Paganetti, H Banati, R Kuncic, Z AF McNamara, A. L. Kam, W. W. Y. Scales, N. McMahon, S. J. Bennett, J. W. Byrne, H. L. Schuemann, J. Paganetti, H. Banati, R. Kuncic, Z. TI Dose enhancement effects to the nucleus and mitochondria from gold nanoparticles in the cytosol SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE Monte Carlo; gold nanoparticles; mitochondria ID MEGAVOLTAGE RADIATION-THERAPY; MONTE-CARLO-SIMULATION; IONIZING-RADIATION; CELL-DEATH; ENERGY; DNA; RADIOTHERAPY; IRRADIATION; DELETION; BIOLOGY AB Gold nanoparticles (GNPs) have shown potential as dose enhancers for radiation therapy. Since damage to the genome affects the viability of a cell, it is generally assumed that GNPs have to localise within the cell nucleus. In practice, however, GNPs tend to localise in the cytoplasm yet still appear to have a dose enhancing effect on the cell. Whether this effect can be attributed to stress-induced biological mechanisms or to physical damage to extranuclear cellular targets is still unclear. There is however growing evidence to suggest that the cellular response to radiation can also be influenced by indirect processes induced when the nucleus is not directly targeted by radiation. The mitochondrion in particular may be an effective extra-nuclear radiation target given its many important functional roles in the cell. To more accurately predict the physical effect of radiation within different cell organelles, we measured the full chemical composition of a whole human lymphocytic JURKAT cell as well as two separate organelles; the cell nucleus and the mitochondrion. The experimental measurements found that all three biological materials had similar ionisation energies similar to 70 eV, substantially lower than that of liquid water similar to 78 eV. Monte Carlo simulations for 10-50 keV incident photons showed higher energy deposition and ionisation numbers in the cell and organelle materials compared to liquid water. Adding a 1% mass fraction of gold to each material increased the energy deposition by a factor of similar to 1.8 when averaged over all incident photon energies. Simulations of a realistic compartmentalised cell show that the presence of gold in the cytosol increases the energy deposition in the mitochondrial volume more than within the nuclear volume. We find this is due to sub-micron delocalisation of energy by photoelectrons, making the mitochondria a potentially viable indirect radiation target for GNPs that localise to the cytosol. C1 [McNamara, A. L.; McMahon, S. J.; Schuemann, J.; Paganetti, H.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA. [McNamara, A. L.; Byrne, H. L.; Kuncic, Z.] Univ Sydney, Sch Phys, Sydney, NSW 2006, Australia. [Kam, W. W. Y.; Scales, N.; Bennett, J. W.; Banati, R.] Australian Nucl Sci & Technol Org, Lucas Heights, NSW 2234, Australia. [Banati, R.] Univ Sydney, Med Radiat Sci, Fac Hlth Sci, Sydney, NSW 2141, Australia. [Kam, W. W. Y.] Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Hong Kong, Hong Kong, Peoples R China. [McMahon, S. J.] Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast, Antrim, North Ireland. [Banati, R.] Univ Sydney, Natl Imaging Facil, BMC, Sydney, NSW 2050, Australia. RP McNamara, AL (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA.; McNamara, AL (reprint author), Univ Sydney, Sch Phys, Sydney, NSW 2006, Australia. EM amcnamara2@mgh.harvard.edu RI McNamara, Aimee/C-9432-2009; OI McNamara, Aimee/0000-0001-8792-0464; McMahon, Stephen/0000-0001-5980-6728 FU Cancer Institute of NSW; National Institutes of Health (NIH)/National Cancer Institute (NCI) grant [R01 CA187003] FX The authors acknowledge the Cancer Institute of NSW for funding the Advanced Computing Facility for Cancer Research which was used in this study. This work was in part supported by the National Institutes of Health (NIH)/National Cancer Institute (NCI) grant R01 CA187003. NR 59 TC 3 Z9 3 U1 9 U2 9 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 AUG 21 PY 2016 VL 61 IS 16 BP 5993 EP 6010 DI 10.1088/0031-9155/61/16/5993 PG 18 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DX2NZ UT WOS:000384208600012 PM 27435339 ER PT J AU Saleh, Z Thor, M Apte, AP Sharp, G Tang, XL Veeraraghavan, H Muren, L Deasy, J AF Saleh, Ziad Thor, Maria Apte, Aditya P. Sharp, Gregory Tang, Xiaoli Veeraraghavan, Harini Muren, Ludvig Deasy, Joseph TI A multiple-image-based method to evaluate the performance of deformable image registration in the pelvis SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE deformable image registration; distance discordance metric ( DDM); uncertainties; adaptive radiotherapy ID MORBIDITY FOLLOWING RADIOTHERAPY; ADAPTIVE RADIOTHERAPY; PROSTATE-CANCER; COMPUTED-TOMOGRAPHY; HEAD; UNCERTAINTIES; SEGMENTATION; ACCUMULATION; CONSISTENCY; DELINEATION AB Deformable image registration (DIR) is essential for adaptive radiotherapy (RT) for tumor sites subject to motion, changes in tumor volume, as well as changes in patient normal anatomy due to weight loss. Several methods have been published to evaluate DIR-related uncertainties but they are not widely adopted. The aim of this study was, therefore, to evaluate intra-patient DIR for two highly deformable organs-the bladder and the rectum-in prostate cancer RT using a quantitative metric based on multiple image registration, the distance discordance metric (DDM). Voxel-by-voxel DIR uncertainties of the bladder and rectum were evaluated using DDM on weekly CT scans of 38 subjects previously treated with RT for prostate cancer (six scans/subject). The DDM was obtained from group-wise B-spline registration of each patient's collection of repeat CT scans. For each structure, registration uncertainties were derived from DDM-related metrics. In addition, five other quantitative measures, including inverse consistency error (ICE), transitivity error (TE), Dice similarity (DSC) and volume ratios between corresponding structuresfrom pre-and post-registered images were computed and compared with the DDM. The DDM varied across subjects and structures; DDMmean of the bladder ranged from 2 to 13 mm and from 1 to 11 mm for the rectum. There was a high correlation between DDMmean of the bladder and the rectum (Pearson's correlation coefficient, R-p = 0.62). The correlation between DDMmean and the volume ratios post-DIR was stronger (R-p = 0.51; 0.68) than the correlation with the TE (bladder: R-p = 0.46; rectum: R-p = 0.47), or the ICE (bladder: R-p = 0.34; rectum: R-p = 0.37). There was a negative correlation between DSC and DDMmean of both the bladder (R-p = -0.23) and the rectum (R-p = -0.63). The DDM uncertainty metric indicated considerable DIR variability across subjects and structures. Our results show a stronger correlation with volume ratios and with the DSC using DDM compared to using ICE and TE. The DDM has the potential to quantitatively identify regions of large DIR uncertainties and consequently identify anatomical/scan outliers. The DDM can, thus, be applied to improve the adaptive RT process for tumor sites subject to motion. C1 [Saleh, Ziad; Thor, Maria; Apte, Aditya P.; Tang, Xiaoli; Veeraraghavan, Harini; Deasy, Joseph] Mem Sloan Kettering Canc Ctr, Dept Med Phys, 1275 York Ave, New York, NY 10065 USA. [Sharp, Gregory] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Muren, Ludvig] Aarhus Univ, Aarhus Univ Hosp, Dept Med Phys, Aarhus C, Denmark. [Muren, Ludvig] Univ Bergen, Dept Phys & Technol, Bergen, Norway. RP Saleh, Z (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med Phys, 1275 York Ave, New York, NY 10065 USA. EM salehz@mskcc.org FU MSK Cancer Center [P30 CA008748]; NIH [R01 CA85181] FX The CT data were collected at Haukeland University Hospital, Bergen, Norway and provided by the responsible oncologist Svein Inge Helle and physicist Liv Bolstad Hysing. Lise Bentzen, Aarhus University Hospital, is acknowledged for approving the manually contoured bladder and rectal structures. This research was partially supported by the MSK Cancer Center Support Grant/Core Grant (P30 CA008748). This project was also supported in part through the NIH Grant R01 CA85181. NR 33 TC 0 Z9 0 U1 5 U2 5 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 AUG 21 PY 2016 VL 61 IS 16 BP 6172 EP 6180 DI 10.1088/0031-9155/61/16/6172 PG 9 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DX2NZ UT WOS:000384208600022 PM 27469495 ER PT J AU Bentefour, E Schnuerer, R Lu, HM AF Bentefour, El H. Schnuerer, Roland Lu, Hsiao-Ming TI Concept of proton radiography using energy resolved dose measurement SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE proton radiography; energy resolved dose; single detector; PBS; IMPT; WEPL ID VIVO RANGE VERIFICATION; STOPPING POWER; THERAPY; CT; SCANNER; SYSTEM; BEAMS AB Energy resolved dosimetry offers a potential path to single detector based proton imaging using scanned proton beams. This is because energy resolved dose functions encrypt the radiological depth at which the measurements are made. When a set of predetermined proton beams 'proton imaging field' are used to deliver a well determined dose distribution in a specific volume, then, at any given depth x of this volume, the behavior of the dose against the energies of the proton imaging field is unique and characterizes the depth x. This concept applies directly to proton therapy scanning delivery methods (pencil beam scanning and uniform scanning) and it can be extended to the proton therapy passive delivery methods (single and double scattering) if the delivery of the irradiation is time-controlled with a known time-energy relationship. To derive the water equivalent path length (WEPL) from the energy resolved dose measurement, one may proceed in two different ways. A first method is by matching the measured energy resolved dose function to a preestablished calibration database of the behavior of the energy resolved dose in water, measured over the entire range of radiological depths with at least 1 mm spatial resolution. This calibration database can also be made specific to the patient if computed using the patient x-CT data. A second method to determine the WEPL is by using the empirical relationships between the WEPL and the integral dose or the depth at 80% of the proximal fall off of the energy resolved dose functions in water. In this note, we establish the evidence of the fundamental relationship between the energy resolved dose and the WEPL at the depth of the measurement. Then, we illustrate this relationship with experimental data and discuss its imaging dynamic range for 230 MeV protons. C1 [Bentefour, El H.] Ion Beam Applicat SA, Adv Technol Grp, Louvain La Neuve, Belgium. [Schnuerer, Roland; Lu, Hsiao-Ming] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Bentefour, E (reprint author), Ion Beam Applicat SA, Adv Technol Grp, Louvain La Neuve, Belgium. EM Hassan.Bentefour@iba-group.com NR 20 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 AUG 21 PY 2016 VL 61 IS 16 BP N386 EP N393 DI 10.1088/0031-9155/61/16/N386 PG 8 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DX2NZ UT WOS:000384208600001 ER PT J AU Han, ZH Brivio, D Sajo, E Zygmanski, P AF Han, Zhaohui Brivio, Davide Sajo, Erno Zygmanski, Piotr TI Topological detector: measuring continuous dosimetric quantities with few-element detector array SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE dosimetry; thin film detector; detector array; quality assurance ID HIGH-ENERGY CURRENT; QUALITY-ASSURANCE; STRIP DETECTOR; RADIATION; RADIOTHERAPY; QA AB A prototype topological detector was fabricated and investigated for quality assurance of radiation producing medical devices. Unlike a typical array or flat panel detector, a topological detector, while capable of achieving a very high spatial resolution, consists of only a few elements and therefore is much simpler in construction and more cost effective. The key feature allowing this advancement is a geometry-driven design that is customized for a specific dosimetric application. In the current work, a topological detector of two elements was examined for the positioning verification of the radiation collimating devices (jaws, MLCs, and blades etc). The detector was diagonally segmented from a rectangular thin film strip (2.5 cm x 15 cm), giving two contiguous but independent detector elements. The segmented area was the central portion of the strip measuring 5 cm in length. Under irradiation, signals from each detector element were separately digitized using a commercial multichannel data acquisition system. The center and size of an x-ray field, which were uniquely determined by the collimator positions, were shown mathematically to relate to the difference and sum of the two signals. As a proof of concept, experiments were carried out using slit x-ray fields ranging from 2 mm to 20 mm in size. It was demonstrated that, the collimator positions can be accurately measured with sub-millimeter precisions. C1 [Han, Zhaohui; Brivio, Davide; Zygmanski, Piotr] Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. [Han, Zhaohui; Brivio, Davide; Zygmanski, Piotr] Dana Farber Canc Inst, Boston, MA 02115 USA. [Han, Zhaohui; Brivio, Davide; Zygmanski, Piotr] Harvard Med Sch, Boston, MA USA. [Sajo, Erno] Univ Massachusetts Lowell, Med Phys Program, Dept Phys & Appl Phys, Lowell, MA USA. RP Han, ZH (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA.; Han, ZH (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA.; Han, ZH (reprint author), Harvard Med Sch, Boston, MA USA. EM zhan@lroc.harvard.edu RI Brivio, Davide/R-1330-2016 OI Brivio, Davide/0000-0002-4127-9955 NR 15 TC 1 Z9 1 U1 2 U2 2 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 AUG 21 PY 2016 VL 61 IS 16 BP N403 EP N414 DI 10.1088/0031-9155/61/16/N403 PG 12 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DX2NZ UT WOS:000384208600003 ER PT J AU Baggish, AL AF Baggish, Aaron L. TI Pre-participation athlete screening: there is no 'one size fits all' SO EUROPEAN HEART JOURNAL LA English DT News Item C1 [Baggish, Aaron L.] Massachusetts Gen Hosp, Cardiovasc Performance Program, Boston, MA 02114 USA. RP Baggish, AL (reprint author), Massachusetts Gen Hosp, Cardiovasc Performance Program, Boston, MA 02114 USA. EM abaggish@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG 21 PY 2016 VL 37 IS 32 BP 2509 EP 2510 DI 10.1093/eurheartj/ehw309 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DW5OV UT WOS:000383696500004 ER PT J AU Baggish, AL AF Baggish, Aaron L. TI Athlete safety is a shared responsibility: insights from the RACE Paris Registry SO EUROPEAN HEART JOURNAL LA English DT Editorial Material ID CARDIAC-ARREST; DEATH; LIFE C1 [Baggish, Aaron L.] Massachusetts Gen Hosp, Cardiovasc Performance Program, Yawkey Suite 5B,55 Fruit St, Boston, MA 02114 USA. RP Baggish, AL (reprint author), Massachusetts Gen Hosp, Cardiovasc Performance Program, Yawkey Suite 5B,55 Fruit St, Boston, MA 02114 USA. EM abaggish@partners.org NR 8 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG 21 PY 2016 VL 37 IS 32 BP 2542 EP 2543 DI 10.1093/eurheartj/ehv740 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DW5OV UT WOS:000383696500013 PM 26787440 ER PT J AU Crino, L Ahn, MJ De Marinis, F Groen, HJM Wakelee, H Hida, T Mok, T Spigel, D Felip, E Nishio, M Scagliotti, G Branle, F Emeremni, C Quadrigli, M Zhang, J Shaw, AT AF Crino, Lucio Ahn, Myung-Ju De Marinis, Filippo Groen, Harry J. M. Wakelee, Heather Hida, Toyoaki Mok, Tony Spigel, David Felip, Enriqueta Nishio, Makoto Scagliotti, Giorgio Branle, Fabrice Emeremni, Chetachi Quadrigli, Massimiliano Zhang, Jie Shaw, Alice T. TI Multicenter Phase II Study of Whole-Body and Intracranial Activity With Ceritinib in Patients With ALK-Rearranged Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy and Crizotinib: Results From ASCEND-2 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID KINASE INHIBITORS; BRAIN METASTASES; RESISTANCE; DISEASE AB Purpose Phase I data (ASCEND-1) showed ceritinib efficacy in patients with ALK-rearranged non-small-cell lung cancer (NSCLC), regardless of brain metastases status and with or without prior therapy with an inhibitor of the ALK protein. Data are presented from a phase II trial (ASCEND-2) in which ceritinib efficacy and safety were evaluated in patients who had ALK-rearranged NSCLC previously treated with at least one platinum-based chemotherapy and who had experienced progression during crizotinib treatment as their last prior therapy. Patients and Methods Patients with advanced ALK-rearranged NSCLC, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/d. Whole-body and intracranial responses were investigator assessed (according to RECIST version 1.1). Patient-reported outcomes were evaluated with the Lung Cancer Symptom Scale and European Organisation for Research and Treatment of Cancer surveys (the core-30 and the 13-item lung cancer-specific quality-of-life questionnaires). Results All 140 patients enrolled had received two or more previous treatment regimens, and all patients had received crizotinib. The median duration of exposure and the follow-up time with ceritinibwere 8.8 months (range, 0.1 to 19.4 months) and 11.3 months (range, 0.1 to 18.9 months), respectively. Investigator-assessed overall response rate was 38.6% (95% CI, 30.5% to 47.2%). Secondary end points, all investigator assessed, included disease control rate (77.1%; 95% CI, 69.3% to 83.8%), time to response (median, 1.8 months; range, 1.6 to 5.6 months), duration of response (median, 9.7 months; 95% CI, 7.1 to 11.1 months), and progression-free survival (median, 5.7 months; 95% CI, 5.4 to 7.6 months). Of 100 patients with baseline brain metastases, 20 had active target lesions at baseline; investigator-assessed intracranial overall response rate was 45.0% (95% CI, 23.1% to 68.5%). The most common adverse events (majority, grade 1 or 2) for all treated patients were nausea (81.4%), diarrhea (80.0%), and vomiting (62.9%). Patient-reported outcomes showed a trend toward improved symptom burden. The global quality-of-life score was maintained during treatment. Conclusion Consistent with its activity in ASCEND-1, ceritinib treatment provided clinically meaningful and durable responses with manageable tolerability in chemotherapy-and crizotinib-pretreated patients, including those with brain metastases. (C) 2016 by American Society of Clinical Oncology C1 [Crino, Lucio] Univ Med Sch Perugia, Azienda Osped Perugia, Perugia, Italy. [De Marinis, Filippo] European Inst Oncol, Milan, Italy. [Scagliotti, Giorgio] Univ Turin, Turin, Italy. [Ahn, Myung-Ju] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea. [Groen, Harry J. M.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Wakelee, Heather] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Hida, Toyoaki] Aichi Canc Ctr, Nagoya, Aichi, Japan. [Nishio, Makoto] Japanese Fdn Canc Res, Tokyo, Japan. [Mok, Tony] Chinese Univ Hong Kong, Shatin, Hong Kong, Peoples R China. [Spigel, David] Sarah Cannon Res Inst, Nashville, TN USA. [Felip, Enriqueta] Vall dHebron Univ, Barcelona, Spain. [Branle, Fabrice; Quadrigli, Massimiliano] Novartis Pharma AG, Basel, Switzerland. [Emeremni, Chetachi; Zhang, Jie] Novartis Pharmaceut, E Hanover, NJ USA. [Shaw, Alice T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Crino, L (reprint author), Univ Med Sch Perugia, Azienda Osped Perugia, Perugia, Italy. EM lucio.crino@ospedale.perugia.it NR 29 TC 17 Z9 17 U1 3 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 AUG 20 PY 2016 VL 34 IS 24 BP 2866 EP + DI 10.1200/JCO.2015.65.5936 PG 13 WC Oncology SC Oncology GA DU8MZ UT WOS:000382469100011 PM 27432917 ER PT J AU Yuan, C Qian, ZR Babic, A Morales-Oyarvide, V Rubinson, DA Kraft, P Ng, K Bao, Y Giovannucci, EL Ogino, S Stampfer, MJ Gaziano, JM Sesso, HD Buring, JE Cochrane, BB Chlebowski, RT Snetselaar, LG Manson, JE Fuchs, CS Wolpin, BM AF Yuan, Chen Qian, Zhi Rong Babic, Ana Morales-Oyarvide, Vicente Rubinson, Douglas A. Kraft, Peter Ng, Kimmie Bao, Ying Giovannucci, Edward L. Ogino, Shuji Stampfer, Meir J. Gaziano, John Michael Sesso, Howard D. Buring, Julie E. Cochrane, Barbara B. Chlebowski, Rowan T. Snetselaar, Linda G. Manson, JoAnn E. Fuchs, Charles S. Wolpin, Brian M. TI Prediagnostic Plasma 25-Hydroxyvitamin D and Pancreatic Cancer Survival SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID VITAMIN-D DEFICIENCY; PROSTATE-CANCER; PRIMARY PREVENTION; WOMENS HEALTH; D ANALOGS; IN-VITRO; RISK; CELLS; ADENOCARCINOMA; PROLIFERATION AB Purpose Although vitamin D inhibits pancreatic cancer proliferation in laboratory models, the association of plasma 25-hydroxyvitamin D [25(OH) D] with patient survival is largely unexplored. Patients and Methods We analyzed survival among 493 patients from five prospective US cohorts who were diagnosed with pancreatic cancer from 1984 to 2008. We estimated hazard ratios (HRs) for death by plasma level of 25(OH) D (insufficient, < 20 ng/mL; relative insufficiency, 20 to, 30 ng/mL; sufficient >= 30 ng/mL) by using Cox proportional hazards regression models adjusted for age, cohort, race and ethnicity, smoking, diagnosis year, stage, and blood collection month. We also evaluated 30 tagging single-nucleotide polymorphisms in the vitamin D receptor gene, requiring P < .002 (0.05 divided by 30 genotyped variants) for statistical significance. Results Mean prediagnostic plasma level of 25(OH) D was 24.6 ng/mL, and 165 patients (33%) were vitamin D insufficient. Compared with patients with insufficient levels, multivariable-adjusted HRs for death were 0.79 (95% CI, 0.48 to 1.29) for patients with relative insufficiency and 0.66 (95% CI, 0.49 to 0.90) for patients with sufficient levels (P trend = .01). These results were unchanged after further adjustment for body mass index and history of diabetes (P trend = .02). The association was strongest among patients with blood collected within 5 years of diagnosis, with an HR of 0.58 (95% CI, 0.35 to 0.98) comparing patients with sufficient to patients with insufficient 25(OH) D levels. No single-nucleotide polymorphism at the vitamin D receptor gene met our corrected significance threshold of P < .002; rs7299460 was most strongly associated with survival (HR per minor allele, 0.80; 95% CI, 0.68 to 0.95; P = .01). Conclusion We observed longer overall survival in patients with pancreatic cancer who had sufficient prediagnostic plasma levels of 25(OH) D. (C) 2016 by American Society of Clinical Oncology C1 [Yuan, Chen; Qian, Zhi Rong; Babic, Ana; Morales-Oyarvide, Vicente; Rubinson, Douglas A.; Ng, Kimmie; Ogino, Shuji; Fuchs, Charles S.; Wolpin, Brian M.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Yuan, Chen; Qian, Zhi Rong; Babic, Ana; Morales-Oyarvide, Vicente; Rubinson, Douglas A.; Ng, Kimmie; Giovannucci, Edward L.; Ogino, Shuji; Stampfer, Meir J.; Gaziano, John Michael; Sesso, Howard D.; Manson, JoAnn E.; Fuchs, Charles S.; Wolpin, Brian M.] Harvard Med Sch, Boston, MA USA. [Kraft, Peter; Giovannucci, Edward L.; Ogino, Shuji; Stampfer, Meir J.; Sesso, Howard D.; Buring, Julie E.; Manson, JoAnn E.] Harvard Sch Publ Hlth, Boston, MA USA. [Giovannucci, Edward L.; Ogino, Shuji; Stampfer, Meir J.; Gaziano, John Michael; Sesso, Howard D.; Manson, JoAnn E.; Fuchs, Charles S.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Gaziano, John Michael] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Cochrane, Barbara B.] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [Chlebowski, Rowan T.] Harbor Univ Calif Los Angeles Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA USA. [Snetselaar, Linda G.] Univ Iowa, Coll Publ Hlth, Iowa City, IA USA. RP Wolpin, BM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM bwolpin@partners.org FU National Institutes of Health (NIH), National Cancer Institute (NCI) [K07-CA148894]; NIH NCI Grant [R35-CA197735, R01-CA124908, P50-CA127003]; Robert T. and Judith B. Hale Fund for Pancreatic Cancer; Perry S. Levy Fund for Gastrointestinal Cancer Research; Pappas Family Research Fund for Pancreatic Cancer; Department of Defense [CA130288]; Lustgarten Foundation; Noble Effort Fund; Peter R. Leavitt Family Fund; Promises for Purple; NIH [UM1 CA167552, UM1 CA186107, P01 CA87969, R01 CA49449, CA 34944, CA 40360, HL 26490, HL 34595, N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221] FX Supported by National Institutes of Health (NIH), National Cancer Institute (NCI) Grant No. K07-CA148894 (to K.N.); NIH NCI Grant No. R35-CA197735 (to S.O.); the Robert T. and Judith B. Hale Fund for Pancreatic Cancer, Perry S. Levy Fund for Gastrointestinal Cancer Research, Pappas Family Research Fund for Pancreatic Cancer, and NIH NCI Grants No. R01-CA124908 and P50-CA127003 (to C.S.F.); and by Department of Defense Grant No. CA130288, Lustgarten Foundation, the Noble Effort Fund, the Peter R. Leavitt Family Fund, and Promises for Purple (to B.M.W.). The Health Professionals Follow-Up Study is supported by NIH Grant No. UM1 CA167552. The Nurses' Health Study is supported by NIH Grants No. UM1 CA186107, P01 CA87969, and R01 CA49449. The Physicians' Health Study is supported by NIH Grants No. CA 34944, CA 40360, HL 26490, and HL 34595. The Women's Health Initiative program is funded by the NIH through Contracts No. N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. NR 43 TC 2 Z9 2 U1 3 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2016 VL 34 IS 24 BP 2899 EP + DI 10.1200/JCO.2015.66.3005 PG 11 WC Oncology SC Oncology GA DU8MZ UT WOS:000382469100015 PM 27325858 ER PT J AU Schnipper, LE Davidson, NE Wollins, DS Blayney, DW Dicker, AP Ganz, PA Hoverman, JR Langdon, R Lyman, GH Meropol, NJ Mulvey, T Newcomer, L Peppercorn, J Polite, B Raghavan, D Rossi, G Saltz, L Schrag, D Smith, TJ Yu, PP Hudis, CA Vose, JM Schilsky, RL AF Schnipper, Lowell E. Davidson, Nancy E. Wollins, Dana S. Blayney, Douglas W. Dicker, Adam P. Ganz, Patricia A. Hoverman, J. Russell Langdon, Robert Lyman, Gary H. Meropol, Neal J. Mulvey, Therese Newcomer, Lee Peppercorn, Jeffrey Polite, Blase Raghavan, Derek Rossi, Gregory Saltz, Leonard Schrag, Deborah Smith, Thomas J. Yu, Peter P. Hudis, Clifford A. Vose, Julie M. Schilsky, Richard L. TI Updating the American Society of Clinical Oncology Value Framework: Revisions and Reflections in Response to Comments Received SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PLUS ADJUVANT CHEMOTHERAPY; PROSTATE-CANCER; BREAST-CANCER; ENZALUTAMIDE; TRIAL C1 [Schnipper, Lowell E.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Mulvey, Therese; Peppercorn, Jeffrey] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02115 USA. [Davidson, Nancy E.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Davidson, Nancy E.] Univ Pittsburgh, Med Ctr, Ctr Canc, Pittsburgh, PA USA. [Dicker, Adam P.] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Philadelphia, PA 19107 USA. [Wollins, Dana S.; Schilsky, Richard L.] Amer Soc Clin Oncol, Alexandria, VA USA. [Blayney, Douglas W.] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Yu, Peter P.] Palo Alto Med Fdn, Palo Alto, CA USA. [Hoverman, J. Russell] Texas Oncol, Dallas, TX USA. [Langdon, Robert] Nebraska Canc Specialists, Omaha, NE USA. [Vose, Julie M.] Univ Nebraska Med Ctr, Omaha, NE USA. [Lyman, Gary H.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Lyman, Gary H.] Univ Washington, Seattle, WA 98195 USA. [Meropol, Neal J.] Univ Hosp Cleveland, Case Med Ctr, Seidman Canc Ctr, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Meropol, Neal J.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Newcomer, Lee] UnitedHealthcare, Minneapolis, MN USA. [Polite, Blase] Univ Chicago, Med, Chicago, IL 60637 USA. [Raghavan, Derek] Levine Canc Inst, Charlotte, NC USA. [Rossi, Gregory] AstraZeneca, Macclesfield, Cheshire, England. [Saltz, Leonard; Hudis, Clifford A.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Smith, Thomas J.] Johns Hopkins Univ, Sidney Kimmel Canc Ctr, Baltimore, MD USA. RP Schnipper, LE (reprint author), Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA. EM lschnipp@bidmc.harvard.edu FU Amgen; Genomic Health; Pfizer; Merck; Taiho Pharmaceutical; Berg Pharma; Spectrum Pharmaceuticals; Bristol-Myers Squibb; Celgene; Genentech; GlaxoSmithKline; Incyte; Janssen Biotech; Pharmacyclics; Acerta Pharma; Kite Pharma; Seattle Genetics; Novartis FX Keryx (I); Amgen (Inst); Genomic Health; Pfizer; Merck; Taiho Pharmaceutical; Berg Pharma (Inst); Spectrum Pharmaceuticals (Inst), Bristol-Myers Squibb (Inst), Celgene (Inst), Genentech (Inst), GlaxoSmithKline (Inst), Incyte (Inst), Janssen Biotech (Inst), Pharmacyclics (Inst), Acerta Pharma (Inst), Kite Pharma (Inst), Seattle Genetics (Inst), Novartis (Inst), Amgen (Inst) NR 13 TC 38 Z9 38 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 AUG 20 PY 2016 VL 34 IS 24 BP 2925 EP + DI 10.1200/JCO.2016.68.2518 PG 14 WC Oncology SC Oncology GA DU8MZ UT WOS:000382469100018 PM 27247218 ER PT J AU Dacks, PA Armstrong, JJ Brannan, SK Carman, AJ Green, AM Kirkman, MS Krakoff, LR Kuller, LH Launer, LJ Lovestone, S Merikle, E Neumann, PJ Rockwood, K Shineman, DW Stefanacci, RG Velentgas, P Viswanathan, A Whitmer, RA Williamson, JD Fillit, HM AF Dacks, Penny A. Armstrong, Joshua J. Brannan, Stephen K. Carman, Aaron J. Green, Allan M. Kirkman, M. Sue Krakoff, Lawrence R. Kuller, Lewis H. Launer, Lenore J. Lovestone, Simon Merikle, Elizabeth Neumann, Peter J. Rockwood, Kenneth Shineman, Diana W. Stefanacci, Richard G. Velentgas, Priscilla Viswanathan, Anand Whitmer, Rachel A. Williamson, Jeff D. Fillit, Howard M. TI A call for comparative effectiveness research to learn whether routine clinical care decisions can protect from dementia and cognitive decline SO ALZHEIMERS RESEARCH & THERAPY LA English DT Review DE Comparative effectiveness; Dementia; Alzheimer's; Prevention; Cognitive decline; Cognitive aging; Comorbidity; Repurposing; Hypertension; Diabetes ID CALCIUM-CHANNEL BLOCKERS; ALZHEIMERS-DISEASE; ANTIHYPERTENSIVE DRUGS; HYPERTENSIVE PATIENTS; PROSPECTIVE COHORT; BLOOD-PRESSURE; HEART-FAILURE; OLDER-ADULTS; IMPAIRMENT; PREVENTION AB Common diseases like diabetes, hypertension, and atrial fibrillation are probable risk factors for dementia, suggesting that their treatments may influence the risk and rate of cognitive and functional decline. Moreover, specific therapies and medications may affect long-term brain health through mechanisms that are independent of their primary indication. While surgery, benzodiazepines, and anti-cholinergic drugs may accelerate decline or even raise the risk of dementia, other medications act directly on the brain to potentially slow the pathology that underlies Alzheimer's and other dementia. In other words, the functional and cognitive decline in vulnerable patients may be influenced by the choice of treatments for other medical conditions. Despite the importance of these questions, very little research is available. The Alzheimer's Drug Discovery Foundation convened an advisory panel to discuss the existing evidence and to recommend strategies to accelerate the development of comparative effectiveness research on how choices in the clinical care of common chronic diseases may protect from cognitive decline and dementia. C1 [Dacks, Penny A.; Carman, Aaron J.; Shineman, Diana W.; Fillit, Howard M.] Alzheimers Drug Discovery Fdn, 57 West 57th St Suite 901, New York, NY 10019 USA. [Armstrong, Joshua J.; Rockwood, Kenneth] Dalhousie Univ, Dept Med, Geriatr Med Res Unit, Halifax, NS, Canada. [Brannan, Stephen K.; Merikle, Elizabeth] Takeda Pharmaceut, Deerfield, IL USA. [Green, Allan M.] Attorney Law, Cambridge, MA USA. [Kirkman, M. Sue] Univ N Carolina, Div Endocrinol & Metab, Dept Med, Sch Med, Chapel Hill, NC USA. [Krakoff, Lawrence R.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Kuller, Lewis H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Launer, Lenore J.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Lovestone, Simon] Univ Oxford, Dept Psychiat, Oxford, England. [Neumann, Peter J.] Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Ctr Evaluat Value & Risk Hlth, Boston, MA USA. [Rockwood, Kenneth] DGI Clin, Halifax, NS, Canada. [Rockwood, Kenneth] Nova Scotia Hlth Author, Halifax, NS, Canada. [Stefanacci, Richard G.] Thomas Jefferson Coll Populat Hlth, Access Grp, Philadelphia, PA USA. [Velentgas, Priscilla] Quintiles Real World Late Phase Res, Sci Affairs, Cambridge, MA USA. [Viswanathan, Anand] Amer Heart Assoc, Boston, MA USA. [Viswanathan, Anand] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Stroke Res, Dept Neurol,Hemorrhag Stroke Res Program, Boston, MA USA. [Whitmer, Rachel A.] Kaiser Permanente Div Res Populat Sci & Brain Agi, Oakland, CA USA. [Williamson, Jeff D.] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. RP Dacks, PA (reprint author), Alzheimers Drug Discovery Fdn, 57 West 57th St Suite 901, New York, NY 10019 USA. EM pdacks@alzdiscovery.org FU Alzheimer's Drug Discovery Foundation; Canadian Consortium on Neurodegeneration in Aging; Intramural Research Program, National Institute on Aging, NIH; NIH-NIA grants [K23 AG028726, R01AG047975] FX This position paper and the corresponding advisory panel were funded by the Alzheimer's Drug Discovery Foundation. Support for authors' time was provided by the Canadian Consortium on Neurodegeneration in Aging (JJA); the Intramural Research Program, National Institute on Aging, NIH (LJL); NIH-NIA grants K23 AG028726 and R01AG047975 (AV). Takeda Pharmaceuticals provided some support for the advisory panel; the American Heart Association supported the cost of travel for their representative (AV). NR 68 TC 0 Z9 0 U1 8 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-9193 J9 ALZHEIMERS RES THER JI Alzheimers Res. Ther. PD AUG 20 PY 2016 VL 8 AR 33 DI 10.1186/s13195-016-0200-3 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DU9FR UT WOS:000382522300001 PM 27543171 ER PT J AU Steensma, DP Abedi, M Bejar, R Cogle, CR Foucar, K Garcia-Manero, G George, TI Grinblatt, D Komrokji, R Ma, XM Maciejewski, J Pollyea, DA Savona, MR Scott, B Sekeres, MA Thompson, MA Swern, AS Nifenecker, M Sugrue, MM Erba, H AF Steensma, David P. Abedi, Medrdad Bejar, Rafael Cogle, Christopher R. Foucar, Kathryn Garcia-Manero, Guillermo George, Tracy I. Grinblatt, David Komrokji, Rami Ma, Xiaomei Maciejewski, Jaroslaw Pollyea, Daniel A. Savona, Michael R. Scott, Bart Sekeres, Mikkael A. Thompson, Michael A. Swern, Arlene S. Nifenecker, Melissa Sugrue, Mary M. Erba, Harry TI Connect MDS/AML: design of the myelodysplastic syndromes and acute myeloid leukemia disease registry, a prospective observational cohort study SO BMC CANCER LA English DT Article DE Myelodysplastic syndromes; Acute myeloid leukemia; Idiopathic cytopenia of undetermined significance; Registry; Treatment patterns; Clinical outcomes; Patient-reported outcomes; Biomarkers; Clonal hematopoiesis of indeterminate potential (CHIP) ID WORLD-HEALTH-ORGANIZATION; ADULTS RECOMMENDATIONS; EUROPEAN LEUKEMIANET; SYNDROMES DIAGNOSIS; SCORING SYSTEM; CLASSIFICATION; HEMATOPOIESIS; DISTINCTION; NEOPLASMS AB Background: Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are myeloid neoplasms in which outgrowth of neoplastic clones disrupts normal hematopoiesis. Some patients with unexplained persistent cytopenias may not meet minimal diagnostic criteria for MDS but an alternate diagnosis is not apparent; the term idiopathic cytopenia of undetermined significance (ICUS) has been used to describe this state. MDS and AML occur primarily in older patients who are often treated outside the clinical trial setting. Consequently, our understanding of the patterns of diagnostic evaluation, management, and outcomes of these patients is limited. Furthermore, there are few natural history studies of ICUS. To better understand how patients who have MDS, ICUS, or AML are managed in the routine clinical setting, the Connect MDS/AML Disease Registry, a multicenter, prospective, observational cohort study of patients newly diagnosed with these conditions has been initiated. Methods/Design: The Connect MDS/AML Disease Registry will capture diagnosis, risk assessment, treatment, and outcomes data for approximately 1500 newly diagnosed patients from approximately 150 community and academic sites in the United States in 4 cohorts: (1) lower-risk MDS (International Prognostic Scoring System [IPSS] low and intermediate-1 risk), with and without del(5q); (2) higher-risk MDS (IPSS intermediate-2 and high risk); (3) ICUS; and (4) AML in patients aged >= 55 years (excluding acute promyelocytic leukemia). Diagnosis will be confirmed by central review. Baseline patient characteristics, diagnostic patterns, treatment patterns, clinical outcomes, health economics outcomes, and patient-reported health-related quality of life will be entered into an electronic data capture system at enrollment and quarterly for 8 years. A tissue substudy to explore the relationship between karyotypes, molecular markers, and clinical outcomes will be conducted, and is optional for patients. Discussion: The Connect MDS/AML Disease Registry will be the first prospective, observational, non-interventional study in the United States to collect clinical information, patient-reported outcomes, and tissue samples from patients with MDS, ICUS, or AML receiving multiple therapies. Results from this registry may provide new insights into the relationship between diagnostic practices, treatment regimens, and outcomes in patients with these diseases and identify areas for future investigation. C1 [Steensma, David P.] Dana Farber Canc Inst, Adult Leukemia Program, Boston, MA 02115 USA. [Abedi, Medrdad] Univ Calif Davis, Ctr Comprehens Canc, Div Hematol & Oncol, Sacramento, CA 95817 USA. [Bejar, Rafael] Univ Calif San Diego, Moores Canc Ctr, Div Hematol & Oncol, La Jolla, CA 92093 USA. [Cogle, Christopher R.] Univ Florida, Div Hematol & Oncol, Dept Med, Gainesville, FL USA. [Foucar, Kathryn; George, Tracy I.] Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA. [Garcia-Manero, Guillermo] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Div Canc Med, Houston, TX 77030 USA. [Grinblatt, David] North Shore Univ Hlth Syst, Hematol, Evanston, IL USA. [Komrokji, Rami] H Lee Moffitt Canc Ctr & Res Inst, Med Oncol, Tampa, FL USA. [Ma, Xiaomei] Yale Sch Publ Hlth, New Haven, CT USA. [Maciejewski, Jaroslaw] Cleveland Clin Fdn, Dept Translat Hematol & Oncol Res, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Pollyea, Daniel A.] Univ Colorado, Ctr Canc, Div Hematol, Aurora, CO USA. [Savona, Michael R.] Vanderbilt Univ, Med Ctr, Div Hematol Oncol, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Scott, Bart] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Sekeres, Mikkael A.] Cleveland Clin Fdn, Div Hematol & Oncol, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Thompson, Michael A.] Aurora Hlth Care, Aurora Res Inst, Milwaukee, WI USA. [Swern, Arlene S.; Nifenecker, Melissa; Sugrue, Mary M.] Celgene Corp, Summit, NJ USA. [Erba, Harry] Univ Alabama Birmingham, Div Hematol & Oncol, Birmingham, AL USA. RP Steensma, DP (reprint author), Dana Farber Canc Inst, Adult Leukemia Program, Boston, MA 02115 USA. EM david_steensma@dfci.harvard.edu FU Celgene Corporation FX This registry is funded by Celgene Corporation. The trial was designed by the investigators in collaboration with Celgene Corporation. The study design was decided by the sponsor in collaboration with the study steering committee. All authors and the study sponsor will gather, analyze, and interpret the data. The corresponding author of any manuscript will have the final decision to submit for publication. Publications will adhere to the International Committee of Medical Journal Editors guidelines and Good Publication Practice (GPP3) guidelines [32, 33]. NR 32 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 1471-2407 J9 BMC CANCER JI BMC Cancer PD AUG 19 PY 2016 VL 16 AR 652 DI 10.1186/s12885-016-2710-6 PG 10 WC Oncology SC Oncology GA DX2HP UT WOS:000384189200001 PM 27538433 ER PT J AU Wang, J Sinnett-Smith, J Stevens, JV Young, SH Rozengurt, E AF Wang, Jia Sinnett-Smith, James Stevens, Jan V. Young, Steven H. Rozengurt, Enrique TI Biphasic Regulation of Yes-associated Protein (YAP) Cellular Localization, Phosphorylation, and Activity by G Protein-coupled Receptor Agonists in Intestinal Epithelial Cells: A NOVEL ROLE FOR PROTEIN KINASE D (PKD) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE angiotensin II; G protein-coupled receptor (GPCR); protein kinase C (PKC); protein kinase D (PKD); yes-associated protein (YAP) ID ACTIVATION LOOP SER(744); NUCLEAR EXPORT SIGNALS; HIPPO PATHWAY; IN-VIVO; DNA-SYNTHESIS; ANG-II; G(Q)-COUPLED RECEPTORS; LYSOPHOSPHATIDIC ACID; ANTITUMOR-ACTIVITY; PHORBOL ESTERS AB We examined the regulation of Yes-associated protein (YAP) localization, phosphorylation, and transcriptional activity in intestinal epithelial cells. Our results show that stimulation of intestinal epithelial IEC-18 cells with the G protein-coupled receptor (GPCR) agonist angiotensin II, a potent mitogen for these cells, induced rapid translocation of YAP from the nucleus to the cytoplasm (within 15 min) and a concomitant increase in YAP phosphorylation at Ser(127) and Ser(397). Angiotensin II elicited YAP phosphorylation and cytoplasmic accumulation in a dose-dependent manner (ED50 = 0.3 nm). Similar YAP responses were provoked by stimulation with vasopressin or serum. Treatment of the cells with the protein kinase D (PKD) family inhibitors CRT0066101 and kb NB 142-70 prevented the increase in YAP phosphorylation on Ser(127) and Ser(397) via Lats2, YAP cytoplasmic accumulation, and increase in the mRNA levels of YAP/TEAD-regulated genes (Ctgf and Areg). Furthermore, siRNA-mediated knockdown of PKD1, PKD2, and PKD3 markedly attenuated YAP nuclear-cytoplasmic shuttling, phosphorylation at Ser(127), and induction of Ctgf and Areg expression in response to GPCR activation. These results identify a novel role for the PKD family in the control of biphasic localization, phosphorylation, and transcriptional activity of YAP in intestinal epithelial cells. In turn, YAP and TAZ are necessary for the stimulation of the proliferative response of intestinal epithelial cells to GPCR agonists that act via PKD. The discovery of interaction between YAP and PKD pathways identifies a novel cross-talk in signal transduction and demonstrates, for the first time, that the PKDs feed into the YAP pathway. C1 [Wang, Jia; Sinnett-Smith, James; Stevens, Jan V.; Young, Steven H.; Rozengurt, Enrique] Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Dept Med, Los Angeles, CA 90095 USA. [Sinnett-Smith, James; Rozengurt, Enrique] Univ Calif Los Angeles, CURE Digest Dis Res Ctr, Los Angeles, CA 90095 USA. [Rozengurt, Enrique] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. [Sinnett-Smith, James; Young, Steven H.; Rozengurt, Enrique] Vet Affairs Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90073 USA. RP Rozengurt, E (reprint author), Univ Calif Los Angeles, Dept Med, Sch Med, 900 Vet Ave,Warren Hall Rm 11-124, Los Angeles, CA 90095 USA. EM erozengurt@mednet.ucla.edu FU National Institutes of Health [R01DK100405, P30DK41301, P01CA163200]; Department of Veterans Affair Grant [1I01BX001473]; Ronald S. Hirshberg Endowed Chair of Pancreatic Cancer Research FX This work was supported by National Institutes of Health Grants R01DK100405, P30DK41301, and P01CA163200, by Department of Veterans Affair Grant 1I01BX001473 (to E.R.), and by the Ronald S. Hirshberg Endowed Chair of Pancreatic Cancer Research (to E.R.). 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 75 TC 1 Z9 1 U1 3 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 19 PY 2016 VL 291 IS 34 BP 17988 EP 18005 DI 10.1074/jbc.M115.711275 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV9DX UT WOS:000383241300041 PM 27369082 ER PT J AU Giecold, G Marco, E Garcia, SP Trippa, L Yuan, GC AF Giecold, Gregory Marco, Eugenio Garcia, Sara P. Trippa, Lorenzo Yuan, Guo-Cheng TI Robust lineage reconstruction from high-dimensional single-cell data SO NUCLEIC ACIDS RESEARCH LA English DT Article ID FATE DECISIONS; RNA-SEQ; CYTOMETRY AB Single-cell gene expression data provide invaluable resources for systematic characterization of cellular hierarchy in multi-cellular organisms. However, cell lineage reconstruction is still often associated with significant uncertainty due to technological constraints. Such uncertainties have not been taken into account in current methods. We present ECLAIR (Ensemble Cell Lineage Analysis with Improved Robustness), a novel computational method for the statistical inference of cell lineage relationships fromsinglecell gene expression data. ECLAIR uses an ensemble approach to improve the robustness of lineage predictions, and provides a quantitative estimate of the uncertainty of lineage branchings. We show that the application of ECLAIR to published datasets successfully reconstructs known lineage relationships and significantly improves the robustness of predictions. ECLAIR is a powerful bioinformatics tool for single-cell data analysis. It can be used for robust lineage reconstruction with quantitative estimate of prediction accuracy. C1 [Giecold, Gregory; Marco, Eugenio; Garcia, Sara P.; Trippa, Lorenzo; Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Giecold, Gregory; Marco, Eugenio; Garcia, Sara P.; Trippa, Lorenzo; Yuan, Guo-Cheng] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Yuan, Guo-Cheng] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Marco, Eugenio] Editas Med, Cambridge, MA 02142 USA. RP Yuan, GC (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA.; Yuan, GC (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA.; Yuan, GC (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM gcyuan@jimmy.harvard.edu OI Garcia, Sara/0000-0003-3312-6454 FU Claudia Barr Award; NIH [R01HL119099] FX Claudia Barr Award (to G.C.Y.); NIH [R01HL119099 to G.C.Y.]. Funding for open access charge: NIH. NR 24 TC 0 Z9 0 U1 3 U2 3 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 AUG 19 PY 2016 VL 44 IS 14 AR e122 DI 10.1093/nar/gkw452 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV5VX UT WOS:000382999900002 PM 27207878 ER PT J AU Lai, DM Shu, Q Fan, J AF Lai, Deng-Ming Shu, Qiang Fan, Jie TI The origin and role of innate lymphoid cells in the lung SO MILITARY MEDICAL RESEARCH LA English DT Review DE Innate lymphoid cells; Innate immunity; Lung diseases; Airway; Cell interaction; Cytokines ID OBSTRUCTIVE PULMONARY-DISEASE; TRANSCRIPTION FACTOR GATA3; ANTI-INTERLEUKIN-17 MONOCLONAL-ANTIBODY; ALTERNATIVELY ACTIVATED MACROPHAGES; INDUCED AIRWAY HYPERREACTIVITY; NATURAL HELPER-CELLS; TYPE-2 IMMUNITY; T-CELL; ALLERGIC INFLAMMATION; INTESTINAL INFLAMMATION AB Innate lymphoid cells (ILCs), a newly identified member of the lymphoid population, play a critical role in the transition from innate to adaptive immunity in host defense. ILCs are important in mucosal barrier immunity, tissue homeostasis, and immune regulation throughout the body. Significant alterations in ILC responses in lung diseases have been observed and reported. Emerging evidence has shown that ILCs are importantly involved in the pathogenesis and development of a variety of lung diseases, i.e., helminth infections, allergic airway inflammation, and airway hyper-responsiveness. However, as a tissue-resident cell population, the role of ILCs in the lung remains poorly characterized. In this review, we discuss the role of ILCs in lung diseases, the mechanisms underlying the ILC-mediated regulation of immunity, and the therapeutic potential of modulating ILC responses. C1 [Lai, Deng-Ming; Shu, Qiang] Zhejiang Univ, Dept Cardiovasc Surg, Sch Med, Childrens Hosp, Hangzhou 310052, Zhejiang, Peoples R China. [Lai, Deng-Ming; Fan, Jie] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA. [Fan, Jie] Vet Affairs Pittsburgh Healthcare Syst, Res & Dev, Pittsburgh, PA 15240 USA. RP Fan, J (reprint author), Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA.; Fan, J (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Res & Dev, Pittsburgh, PA 15240 USA. EM jif7@pitt.edu FU BLRD VA [I01 BX002729]; NHLBI NIH HHS [R01 HL076179, R56 HL123882, R01 HL079669] NR 124 TC 2 Z9 2 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2054-9369 J9 MILITARY MED RES JI MILITARY MED. RES. PD AUG 19 PY 2016 VL 3 AR UNSP 25 DI 10.1186/s40779-016-0093-2 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DU3CT UT WOS:000382089100002 PM 27547445 ER PT J AU Elias, KM Emori, MM Westerling, T Long, H Budina-Kolomets, A Li, F MacDuffie, E Davis, MR Holman, A Lawney, B Freedman, ML Quackenbush, J Brown, M Drapkin, R AF Elias, Kevin M. Emori, Megan M. Westerling, Thomas Long, Henry Budina-Kolomets, Anna Li, Fugen MacDuffie, Emily Davis, Michelle R. Holman, Alexander Lawney, Brian Freedman, Matthew L. Quackenbush, John Brown, Myles Drapkin, Ronny TI Epigenetic remodeling regulates transcriptional changes between ovarian cancer and benign precursors SO JCI INSIGHT LA English DT Article ID SECRETORY EPITHELIAL-CELLS; FALLOPIAN-TUBE; EXPRESSION ANALYSIS; LINEAGE SURVIVAL; GENE; CARCINOMA; TUMORS; PAX8; CARCINOGENESIS; IDENTIFICATION AB Regulation of lineage-restricted transcription factors has been shown to influence malignant transformation in several types of cancer. Whether similar mechanisms are involved in ovarian cancer pathogenesis is unknown. PAX8 is a nuclear transcription factor that controls the embryologic development of the Mullerian system, including the fallopian tubes. Recent studies have shown that fallopian tube secretory epithelial cells (FTSECs) give rise to the most common form of ovarian cancer, high-grade serous ovarian carcinomas (HGSOCs). We designed the present study in order to understand whether changes in gene expression between FTSECs and HGSOCs relate to alterations in PAX8 binding to chromatin. Using whole transcriptome shotgun sequencing (RNA-Seq) after PAX8 knockdown and ChIP-Seq, we show that FTSECs and HGSOCs are distinguished by marked reprogramming of the PAX8 cistrome. Genes that are significantly altered between FTSECs and HGSOCs are enriched near PAX8 binding sites. These sites are also near TEAD binding sites, and these transcriptional changes may be related to PAX8 interactions with the TEAD/YAP1 signaling pathway. These data suggest that transcriptional changes after transformation in ovarian cancer are closely related to epigenetic remodeling in lineage-specific transcription factors. C1 [Elias, Kevin M.; Emori, Megan M.; MacDuffie, Emily; Davis, Michelle R.; Freedman, Matthew L.; Drapkin, Ronny] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Elias, Kevin M.; Davis, Michelle R.] Brigham & Womens Hosp, Dept Obstet & Gynecol & Reprod Biol, Div Gynecol Oncol, 75 Francis St, Boston, MA 02115 USA. [Elias, Kevin M.; Davis, Michelle R.; Drapkin, Ronny] Harvard Med Sch, Boston, MA USA. [Emori, Megan M.] Harvard Univ, Grad Sch Arts & Sci, Cambridge, MA 02138 USA. [Westerling, Thomas; Long, Henry; Li, Fugen; Freedman, Matthew L.; Brown, Myles] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA. [Budina-Kolomets, Anna; Drapkin, Ronny] Univ Penn, Dept Obstet & Gynecol, Perelman Sch Med, Penn Ovarian Canc Res Ctr, Biomed Res Bldg 2-3,Room 1215,421 Curie Blvd, Philadelphia, PA 19104 USA. [Holman, Alexander; Lawney, Brian; Quackenbush, John] Harvard Sch Publ Hlth, Dana Farber Canc Inst, Computat Biol & Funct Genom Lab, Boston, MA USA. [Freedman, Matthew L.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. RP Drapkin, R (reprint author), Univ Penn, Dept Obstet & Gynecol, Perelman Sch Med, Penn Ovarian Canc Res Ctr, Biomed Res Bldg 2-3,Room 1215,421 Curie Blvd, Philadelphia, PA 19104 USA. EM rdrapkin@mail.med.upenn.edu NR 51 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 AUG 18 PY 2016 VL 1 IS 13 AR e87988 DI 10.1172/jci.insight.87988 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1NO UT WOS:000387119700007 ER PT J AU Ojha, S Fainberg, HP Wilson, V Pelella, G Castellanos, M May, ST Lotto, AA Sacks, H Symonds, ME Budge, H AF Ojha, Shalini Fainberg, Hernan P. Wilson, Victoria Pelella, Giuseppe Castellanos, Marcos May, Sean T. Lotto, Attilio A. Sacks, Harold Symonds, Michael E. Budge, Helen TI Gene pathway development in human epicardial adipose tissue during early life SO JCI INSIGHT LA English DT Article ID BROWN FAT; PROTEIN; OBESITY; TRANSCRIPTOME; ADIPOCYTES; NETWORKS AB Studies in rodents and newborn humans demonstrate the influence of brown adipose tissue (BAT) in temperature control and energy balance and a critical role in the regulation of body weight. Here, we obtained samples of epicardial adipose tissue (EAT) from neonates, infants, and children in order to evaluate changes in their transcriptional landscape by applying a systems biology approach. Surprisingly, these analyses revealed that the transition to infancy is a critical stage for changes in the morphology of EAT and is reflected in unique gene expression patterns of a substantial proportion of thermogenic gene transcripts (similar to 10%). Our results also indicated that the pattern of gene expression represents a distinct developmental stage, even after the rebound in abundance of thermogenic genes in later childhood. Using weighted gene coexpression network analyses, we found precise anthropometric-specific correlations with changes in gene expression and the decline of thermogenic capacity within EAT. In addition, these results indicate a sequential order of transcriptional events affecting cellular pathways, which could potentially explain the variation in the amount, or activity, of BAT in adulthood. Together, these results provide a resource to elucidate gene regulatory mechanisms underlying the progressive development of BAT during early life. C1 [Ojha, Shalini; Fainberg, Hernan P.; Wilson, Victoria; Symonds, Michael E.; Budge, Helen] Univ Nottingham, Univ Hosp, Queens Med Ctr, Div Child Hlth Obstet & Gynaecol,Sch Med, Nottingham, England. [Pelella, Giuseppe; Lotto, Attilio A.] Univ Hosp Leicester NHS Trust, Leicester, Leics, England. [Castellanos, Marcos; May, Sean T.] Univ Nottingham, Sch Biosci, Nottingham Arabidopsis Stock Ctr, Nottingham, England. [Sacks, Harold] Univ Calif Los Angeles, David Geffen Sch Med, VA Endocrinol & Diabet Div, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. [Sacks, Harold] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Pelella, Giuseppe; Lotto, Attilio A.] Alder Hey Childrens NHS Fdn Trust, Liverpool, Merseyside, England. RP Symonds, ME (reprint author), Univ Nottingham, Div Child Hlth Obstet & Gynaecol, Queens Med Ctr, Univ Hosp, Nottingham NG7 2UH, England. EM Michael.symonds@nottingham.ac.uk RI may, sean/B-6838-2012 OI may, sean/0000-0001-5282-3250 FU Biotechnology and Biological Sciences Research Council [G17764, G18881, BB/E01772X/1, BB/I001271/1, BB/E022758/1, BBS/B/1356X] NR 38 TC 0 Z9 0 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 AUG 18 PY 2016 VL 1 IS 13 AR e87460 DI 10.1172/jci.insight.87460 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1NO UT WOS:000387119700005 PM 27699231 ER PT J AU Peloquin, JM Goel, G Kong, L Huang, H Haritunians, T Sartor, RB Daly, MJ Newberry, RD McGovern, DP Yajnik, V Lira, SA Xavier, RJ AF Peloquin, Joanna M. Goel, Gautam Kong, Lingjia Huang, Hailiang Haritunians, Talin Sartor, R. Balfour Daly, Mark J. Newberry, Rodney D. McGovern, Dermot P. Yajnik, Vijay Lira, Sergio A. Xavier, Ramnik J. TI Characterization of candidate genes in inflammatory bowel disease-associated risk loci SO JCI INSIGHT LA English DT Article ID QUANTITATIVE TRAIT LOCI; CROHNS-DISEASE; ULCERATIVE-COLITIS; MULTIPLE TISSUES; IMMUNE CELLS; HUMAN COLON; L-CARNITINE; EXPRESSION; GENOME; COEXPRESSION AB GWAS have linked SNPs to risk of inflammatory bowel disease (IBD), but a systematic characterization of disease-associated genes has been lacking. Prior studies utilized microarrays that did not capture many genes encoded within risk loci or defined expression quantitative trait loci (eQTLs) using peripheral blood, which is not the target tissue in IBD. To address these gaps, we sought to characterize the expression of IBD-associated risk genes in disease-relevant tissues and in the setting of active IBD. Terminal ileal (TI) and colonic mucosal tissues were obtained from patients with Crohn's disease or ulcerative colitis and from healthy controls. We developed a NanoString code set to profile 678 genes within IBD risk loci. A subset of patients and controls were genotyped for IBD-associated risk SNPs. Analyses included differential expression and variance analysis, weighted gene coexpression network analysis, and eQTL analysis. We identified 116 genes that discriminate between healthy TI and colon samples and uncovered patterns in variance of gene expression that highlight heterogeneity of disease. We identified 107 coexpressed gene pairs for which transcriptional regulation is either conserved or reversed in an inflammation-independent or -dependent manner. We demonstrate that on average approximately 60% of disease-associated genes are differentially expressed in inflamed tissue. Last, we identified eQTLs with either genotype-only effects on expression or an interaction effect between genotype and inflammation. Our data reinforce tissue specificity of expression in disease-associated candidate genes, highlight genes and gene pairs that are regulated in disease-relevant tissue and inflammation, and provide a foundation to advance the understanding of IBD pathogenesis. C1 [Peloquin, Joanna M.; Goel, Gautam; Kong, Lingjia; Yajnik, Vijay; Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Peloquin, Joanna M.; Goel, Gautam; Kong, Lingjia; Yajnik, Vijay; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Peloquin, Joanna M.; Goel, Gautam; Kong, Lingjia; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, 185 Cambridge St Simches 7222, Boston, MA 02114 USA. [Huang, Hailiang; Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. [Huang, Hailiang; Daly, Mark J.; Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Haritunians, Talin; McGovern, Dermot P.] Cedars Sinai Med Ctr, F Widjaja Fdn Inflammatory Bowel & Immunobiol Res, Los Angeles, CA 90048 USA. [Sartor, R. Balfour] Univ North Carolina Chapel Hill, Ctr Gastrointestinal Biol & Dis, Dept Med, Chapel Hill, NC USA. [Newberry, Rodney D.] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA. [Lira, Sergio A.] Icahn Sch Med Mt Sinai, Immunol Inst, New York, NY 10029 USA. [Peloquin, Joanna M.] Johns Hopkins Univ Hosp, Div Gastroenterol & Hepatol, Baltimore, MD 21287 USA. RP Xavier, RJ (reprint author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, 185 Cambridge St Simches 7222, Boston, MA 02114 USA. EM xavier@molbio.mgh.harvard.edu FU NIDDK NIH HHS [P30 DK043351] NR 69 TC 0 Z9 0 U1 4 U2 4 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 AUG 18 PY 2016 VL 1 IS 13 AR e87899 DI 10.1172/jci.insight.87899 PG 18 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1NO UT WOS:000387119700006 PM 27668286 ER PT J AU Keibler, MA Wasylenko, TM Kelleher, JK Iliopoulos, O Vander Heiden, MG Stephanopoulos, G AF Keibler, Mark A. Wasylenko, Thomas M. Kelleher, Joanne K. Iliopoulos, Othon Vander Heiden, Matthew G. Stephanopoulos, Gregory TI Metabolic requirements for cancer cell proliferation SO CANCER & METABOLISM LA English DT Article DE Cancer metabolism; Proliferation; Biosynthesis; Anabolism; Stoichiometric analysis; Metabolic modeling ID REDUCTIVE GLUTAMINE-METABOLISM; ACTIVATED PROTEIN-KINASE; RAS-TRANSFORMED CELLS; ONE-CARBON METABOLISM; AEROBIC GLYCOLYSIS; BREAST-CANCER; LUNG-CANCER; TUMOR-CELLS; PYRUVATE-CARBOXYLASE; LINEAR OPTIMIZATION AB Background: The study of cancer metabolism has been largely dedicated to exploring the hypothesis that oncogenic transformation rewires cellular metabolism to sustain elevated rates of growth and division. Intense examination of tumors and cancer cell lines has confirmed that many cancer-associated metabolic phenotypes allow robust growth and survival; however, little attention has been given to explicitly identifying the biochemical requirements for cell proliferation in a rigorous manner in the context of cancer metabolism. Results: Using a well-studied hybridoma line as a model, we comprehensively and quantitatively enumerate the metabolic requirements for generating new biomass in mammalian cells; this indicated a large biosynthetic requirement for ATP, NADPH, NAD(+), acetyl-CoA, and amino acids. Extension of this approach to serine/glycine and glutamine metabolic pathways suggested lower limits on serine and glycine catabolism to supply one-carbon unit synthesis and significant availability of glutamine-derived carbon for biosynthesis resulting from nitrogen demands alone, respectively. We integrated our biomass composition results into a flux balance analysis model, placing upper bounds on mitochondrial NADH oxidation to simulate metformin treatment; these simulations reproduced several empirically observed metabolic phenotypes, including increased reductive isocitrate dehydrogenase flux. Conclusions: Our analysis clarifies the differential needs for central carbon metabolism precursors, glutamine-derived nitrogen, and cofactors such as ATP, NADPH, and NAD(+), while also providing justification for various extracellular nutrient uptake behaviors observed in tumors. Collectively, these results demonstrate how stoichiometric considerations alone can successfully predict empirically observed phenotypes and provide insight into biochemical dynamics that underlie responses to metabolic perturbations. C1 [Keibler, Mark A.; Wasylenko, Thomas M.; Kelleher, Joanne K.; Stephanopoulos, Gregory] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Vander Heiden, Matthew G.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Wasylenko, Thomas M.] Sanofi Genzyme, Late Stage Proc Dev, 31 New York Ave, Framingham, MA 01701 USA. [Iliopoulos, Othon] Massachusetts Gen Hosp, Ctr Canc, Ctr Canc Res, Charlestown, MA 02129 USA. [Iliopoulos, Othon] Massachusetts Gen Hosp, Div Hematol Oncol, Dept Med, Boston, MA 02114 USA. RP Stephanopoulos, G (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA. EM gregstep@mit.edu FU NCI NIH HHS [R01 CA160458, R01 CA168653]; NIDDK NIH HHS [R01 DK075850] NR 90 TC 4 Z9 4 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2049-3002 J9 CANCER METAB JI Cancer Metab. PD AUG 18 PY 2016 VL 4 AR 16 DI 10.1186/s40170-016-0156-6 PG 16 WC Oncology SC Oncology GA EA7WT UT WOS:000386844000001 PM 27540483 ER PT J AU McDonald-Hyman, C Flynn, R Panoskaltsis-Mortari, A Peterson, N MacDonald, KPA Hill, GR Luznik, L Serody, JS Murphy, WJ Maillard, I Munn, DH Turka, LA Koreth, J Cutler, CS Soiffer, RJ Antin, JH Ritz, J Blazar, BR AF McDonald-Hyman, Cameron Flynn, Ryan Panoskaltsis-Mortari, Angela Peterson, Nicholas MacDonald, Kelli P. A. Hill, Geoffrey R. Luznik, Leo Serody, Jonathan S. Murphy, William J. Maillard, Ivan Munn, David H. Turka, Laurence A. Koreth, John Cutler, Corey S. Soiffer, Robert J. Antin, Joseph H. Ritz, Jerome Blazar, Bruce R. TI Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; FOLLICULAR HELPER-CELLS; BRONCHIOLITIS OBLITERANS; B-CELLS; TRANSPLANTATION; RESPONSES; ANTIGENS; VIVO AB Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. In cGVHD, alloreactive T cells and germinal center (GC) B cells often participate in GC reactions to produce pathogenic antibodies. Although regulatory T cells (Tregs) can inhibitGCreactions, Treg numbers are reduced in cGVHD, contributing to cGVHD pathogenesis. Here, we explored 2 means to increase Tregs in cGVHD: interleukin-2/monoclonal antibody (IL-2/mAb) complexes and donor Treg infusions. IL-2/mAb complexes given over 1 month were efficacious in expanding Tregs and treating established cGVHD in a multi-organ-system disease mouse model characterized by GC reactions, antibody deposition, and lung dysfunction. In an acute GVHD (aGVHD) model, IL-2/mAb complexes given for only 4 days resulted in rapid mortality, indicating IL-2/mAb complexes can drive conventional T-cell (Tcon)-mediated injury. In contrast, Treg infusions, which uniformly suppress aGVHD, increased Treg frequency and were effective in preventing the onset of, and treating, established cGVHD. Efficacy was dependent upon CXCR5-sufficient Tregs homing to, and inhibiting, GC reactions. These studies indicate that the infusion of Tregs, especially ones enriched for GC homing, may be desirable for cGVHD therapy. Although IL-2/mAb complexes can be efficacious in cGVHD, a cautious approach needs to be taken in settings in which aGVHD elements, and associated Tcon, are present. C1 [McDonald-Hyman, Cameron; Flynn, Ryan; Panoskaltsis-Mortari, Angela; Peterson, Nicholas; Blazar, Bruce R.] Univ Minnesota, Dept Pediat, Masonic Canc Ctr, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. [MacDonald, Kelli P. A.; Hill, Geoffrey R.] Queensland Inst Med Res, Dept Immunol, Brisbane, Qld, Australia. [Luznik, Leo] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Luznik, Leo] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [Serody, Jonathan S.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Div Hematol Oncol, Chapel Hill, NC USA. [Murphy, William J.] Univ Calif Davis, Dept Dermatol, Sacramento, CA 95817 USA. [Maillard, Ivan] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. [Maillard, Ivan] Univ Michigan, Dept Internal Med, Div Hematol Oncol, Ann Arbor, MI 48109 USA. [Munn, David H.] Georgia Hlth Sci Univ, Dept Pediat, Augusta, GA USA. [Turka, Laurence A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Ctr Transplantat Sci, Boston, MA USA. [Koreth, John; Cutler, Corey S.; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Blazar, BR (reprint author), Univ Minnesota, MMC 109,420 Delaware St SE, Minneapolis, MN 55455 USA. EM blaza001@umn.edu RI MacDonald, Kelli/O-2722-2016 OI MacDonald, Kelli/0000-0003-3451-4221 FU National Institutes of Health, National Cancer Institute [P01 CA142106-08A1, R01 CA183560]; National Institute of Allergy and Infectious Diseases [P01 AI056299-13, T32 AI007313]; National Heart, Lung, and Blood Institute [F30 HL121873]; Leukemia and Lymphoma Society [6458-15, 6462-15] FX This study was funded by the National Institutes of Health, National Cancer Institute grants P01 CA142106-08A1 (B.R.B.) and R01 CA183560 (J.R.); National Institute of Allergy and Infectious Diseases grants P01 AI056299-13 (B.R.B.) and T32 AI007313 (C.M.-H. and R.F.); National Heart, Lung, and Blood Institute F30 HL121873 (C.M.-H.); and Leukemia and Lymphoma Society Translational Research grants 6458-15 (B.R.B.) and 6462-15 (I.M. and B.R.B.). NR 25 TC 4 Z9 4 U1 2 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD AUG 18 PY 2016 VL 128 IS 7 BP 1013 EP 1017 DI 10.1182/blood-2016-05-715896 PG 5 WC Hematology SC Hematology GA DW7ML UT WOS:000383834800018 PM 27385791 ER PT J AU Lek, M Karczewski, KJ Minikel, EV Samocha, KE Banks, E Fennell, T O'Donnell-Luria, AH Ware, JS Hill, AJ Cummings, BB Tukiainen, T Birnbaum, DP Kosmicki, JA Duncan, LE Estrada, K Zhao, FM Zou, J Pierce-Hollman, E Berghout, J Cooper, DN Deflaux, N DePristo, M Do, R Flannick, J Fromer, M Gauthier, L Goldstein, J Gupta, N Howrigan, D Kiezun, A Kurki, MI Moonshine, AL Natarajan, P Orozeo, L Peloso, GM Poplin, R Rivas, MA Ruano-Rubio, V Rose, SA Ruderfer, DM Shakir, K Stenson, PD Stevens, C Thomas, BP Tiao, G Tusie-Luna, MT Weisburd, B Won, HH Yu, DM Altshuler, DM Ardissino, D Boehnke, M Danesh, J Donnelly, S Elosua, R Florez, JC Gabriel, SB Getz, G Glatt, SJ Hultman, CM Kathiresan, S Laakso, M NcCarroll, S McCarthy, MI McGovern, D McPherson, R Neale, BM Palotie, A Purcell, SM Saleheen, D Scharf, JM Sklar, P Sullivan, PF Tuomilehto, J Tsuang, MT Watkins, HC Wilson, JG Daly, MJ MacArthur, DG AF Lek, Monkol Karczewski, Konrad J. Minikel, Eric V. Samocha, Kaitlin E. Banks, Eric Fennell, Timothy O'Donnell-Luria, Anne H. Ware, James S. Hill, Andrew J. Cummings, Beryl B. Tukiainen, Taru Birnbaum, Daniel P. Kosmicki, Jack A. Duncan, Laramie E. Estrada, Karol Zhao, Fengmei Zou, James Pierce-Hollman, Emma Berghout, Joanne Cooper, David N. Deflaux, Nicole DePristo, Mark Do, Ron Flannick, Jason Fromer, Menachem Gauthier, Laura Goldstein, Jackie Gupta, Namrata Howrigan, Daniel Kiezun, Adam Kurki, Mitja I. Moonshine, Ami Levy Natarajan, Pradeep Orozeo, Lorena Peloso, Gina M. Poplin, Ryan Rivas, Manuel A. Ruano-Rubio, Valentin Rose, Samuel A. Ruderfer, Douglas M. Shakir, Khalid Stenson, Peter D. Stevens, Christine Thomas, Brett P. Tiao, Grace Tusie-Luna, Maria T. Weisburd, Ben Won, Hong-Hee Yu, Dongmei Altshuler, David M. Ardissino, Diego Boehnke, Michael Danesh, John Donnelly, Stacey Elosua, Roberto Florez, Jose C. Gabriel, Stacey B. Getz, Gad Glatt, Stephen J. Hultman, Christina M. Kathiresan, Sekar Laakso, Markku NcCarroll, Steven McCarthy, Mark I. McGovern, Dermot McPherson, Ruth Neale, Benjamin M. Palotie, Aarno Purcell, Shaun M. Saleheen, Danish Scharf, Jeremiah M. Sklar, Pamela Sullivan, Patrick F. Tuomilehto, Jaakko Tsuang, Ming T. Watkins, Hugh C. Wilson, James G. Daly, Mark J. MacArthur, Daniel G. CA Exome Aggregation Consortium TI Analysis of protein-coding genetic variation in 60,706 humans SO NATURE LA English DT Article ID HUMAN-POPULATION HISTORY; HUMAN-DISEASE; SEQUENCE VARIANTS; MUTATION; GUIDELINES; EVOLUTION; DISCOVERY; FRAMEWORK; NETWORKS AB Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes. C1 [Lek, Monkol; Karczewski, Konrad J.; Minikel, Eric V.; Samocha, Kaitlin E.; O'Donnell-Luria, Anne H.; Hill, Andrew J.; Cummings, Beryl B.; Tukiainen, Taru; Kosmicki, Jack A.; Duncan, Laramie E.; Estrada, Karol; Pierce-Hollman, Emma; Fromer, Menachem; Goldstein, Jackie; Howrigan, Daniel; Thomas, Brett P.; Neale, Benjamin M.; Palotie, Aarno; Daly, Mark J.; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Lek, Monkol; Karczewski, Konrad J.; Minikel, Eric V.; Samocha, Kaitlin E.; Banks, Eric; O'Donnell-Luria, Anne H.; Ware, James S.; Hill, Andrew J.; Cummings, Beryl B.; Tukiainen, Taru; Birnbaum, Daniel P.; Kosmicki, Jack A.; Duncan, Laramie E.; Estrada, Karol; Zou, James; Pierce-Hollman, Emma; Flannick, Jason; Goldstein, Jackie; Gupta, Namrata; Howrigan, Daniel; Kurki, Mitja I.; Natarajan, Pradeep; Peloso, Gina M.; Rivas, Manuel A.; Stevens, Christine; Thomas, Brett P.; Weisburd, Ben; Altshuler, David M.; Donnelly, Stacey; Florez, Jose C.; Gabriel, Stacey B.; Kathiresan, Sekar; Neale, Benjamin M.; Palotie, Aarno; Scharf, Jeremiah M.; Daly, Mark J.; MacArthur, Daniel G.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Lek, Monkol] Univ Sydney, Sch Paediat & Child Hlth, Sydney, NSW 2145, Australia. [Lek, Monkol] Childrens Hosp VVestmead, Inst Neurosci & Muscle Res, Sydney, NSW 2145, Australia. [Minikel, Eric V.; Samocha, Kaitlin E.; Cummings, Beryl B.; Palotie, Aarno] Harvard Med Sch, Program Biol & Biomed Sci, Boston, MA 02115 USA. [Samocha, Kaitlin E.; Kosmicki, Jack A.; Duncan, Laramie E.; Fromer, Menachem; Goldstein, Jackie; Howrigan, Daniel; Rose, Samuel A.; Yu, Dongmei; NcCarroll, Steven; Neale, Benjamin M.; Scharf, Jeremiah M.; Daly, Mark J.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [O'Donnell-Luria, Anne H.] Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA. [Ware, James S.; NcCarroll, Steven] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Ware, James S.] Imperial Coll London, Natl Heart & Lung Inst, London SW7 2AZ, England. [Ware, James S.] Royal Brompton Hosp, NIHR Royal Brompton Cardiovasc Biomed Res Unit, London SW3 6NP, England. [Ware, James S.] Imperial Coll London, MRC Clin Sci Ctr, London SW7 2AZ, England. [Hill, Andrew J.; Zhao, Fengmei] Univ Washington, Genome Sci, Seattle, WA 98195 USA. [Kosmicki, Jack A.] Harvard Med Sch, Program Bioinformat & Integrat Genom, Boston, MA 02115 USA. [Berghout, Joanne] Jackson Lab, Mouse Genome Informat, 600 Main St, Bar Harbor, ME 04609 USA. [Berghout, Joanne] Univ Arizona, Ctr Biomed Informat & Biostat, Tucson, AZ 85721 USA. [Cooper, David N.; Stenson, Peter D.] Cardiff Univ, Inst Med Genet, Cardiff CF10 3XQ, S Glam, Wales. [Deflaux, Nicole] Google, Mountain View, CA 94043 USA. [DePristo, Mark; Gauthier, Laura; Kiezun, Adam; Moonshine, Ami Levy; Poplin, Ryan; Ruano-Rubio, Valentin; Shakir, Khalid; Tiao, Grace; Getz, Gad] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Do, Ron; Fromer, Menachem; Ruderfer, Douglas M.; Purcell, Shaun M.; Sklar, Pamela] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Fennell, Timothy; Do, Ron; Fromer, Menachem; Ruderfer, Douglas M.; Purcell, Shaun M.; Sklar, Pamela] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Do, Ron] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Do, Ron] Icahn Sch Med Mt Sinai, Ctr Stat Genet, New York, NY 10029 USA. [Flannick, Jason] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Fromer, Menachem; Ruderfer, Douglas M.; Purcell, Shaun M.; Sklar, Pamela] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Kurki, Mitja I.; Yu, Dongmei; Scharf, Jeremiah M.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Natarajan, Pradeep; Florez, Jose C.; Getz, Gad; Kathiresan, Sekar] Harvard Med Sch, Boston, MA 02115 USA. [Natarajan, Pradeep; Peloso, Gina M.; Yu, Dongmei; Florez, Jose C.; Kathiresan, Sekar; Scharf, Jeremiah M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Natarajan, Pradeep; Peloso, Gina M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Orozeo, Lorena] Inst Nacl Med Genom, Immunogen & Metab Dis Lab, Mexico City 14610, DF, Mexico. [Tusie-Luna, Maria T.] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mol Biol & Genom Med Unit, Mexico City 14080, DF, Mexico. [Won, Hong-Hee] Sungkyunkwan Univ, Samsung Med Ctr, Samsung Adv Inst Hlth Sci & Technol SAIHST, Seoul, South Korea. [Yu, Dongmei; Scharf, Jeremiah M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Altshuler, David M.] Vertex Pharmaceut, Boston, MA 02210 USA. [Ardissino, Diego] Univ Hosp, Dept Cardiol, I-43100 Parma, Italy. [Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Danesh, John] Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Elosua, Roberto] Hosp Mar Med Res Inst, Cardiovasc Epidemiol & Genet, Barcelona 08003, Spain. [Getz, Gad] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Getz, Gad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Glatt, Stephen J.] SUNY Upstate Med Univ, Psychiat Genet Epidemiol & Neurobiol Lab, Syracuse, NY 13210 USA. [Glatt, Stephen J.] SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, Syracuse, NY 13210 USA. [Glatt, Stephen J.] SUNY Upstate Med Univ, Dept Neurobiol & Physiol, Syracuse, NY 13210 USA. [Hultman, Christina M.] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Laakso, Markku] Univ Eastern Finland, Dept Med, Kuopio 70211, Finland. [Laakso, Markku] Kuopio Univ Hosp, Kuopio 70211, Finland. [McCarthy, Mark I.; Watkins, Hugh C.] Univ Oxford, Wellcome Trust Ctr Human Genet, S Parks Rd, Oxford OX1 2JD, England. [McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, S Parks Rd, Oxford OX1 2JD, England. [McCarthy, Mark I.] Oxford Univ Hosp Fdn Trust, Oxford NIHR Biomed Res Ctr, Oxford OX1 2JD, England. [McGovern, Dermot] Cedars Sinai Med Ctr, Inflammatory Bowel Dis & Immunobiol Res Inst, Los Angeles, CA 90048 USA. [McPherson, Ruth] Univ Ottawa, Atherogen Lab, Inst Heart, Ottawa, ON K1Y 4W7, Canada. [Palotie, Aarno] Univ Helsinki, Inst Mol Med Finland FIMM, SF-00100 Helsinki, Finland. [Saleheen, Danish] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Saleheen, Danish] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Saleheen, Danish] Ctr Noncommunicable Dis, Karachi, Pakistan. [Sklar, Pamela] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Sklar, Pamela] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Sullivan, Patrick F.] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Tuomilehto, Jaakko] Univ Helsinki, Dept Publ Hlth, SF-00100 Helsinki, Finland. [Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Watkins, Hugh C.] Univ Oxford, Racicliffe Dept Med, S Parks Rd, Oxford OX1 2JD, England. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. RP MacArthur, DG (reprint author), Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. EM danmac@broadinstitute.org OI Ruderfer, Douglas/0000-0002-2365-386X; Natarajan, Pradeep/0000-0001-8402-7435; Berghout, Joanne/0000-0002-9250-9159; Ware, James/0000-0002-6110-5880 FU British Heart Foundation [FS/14/55/30806]; Canadian Institutes of Health Research [MOP136936, MOP77682, MOP82810]; Medical Research Council [G0601261, G0800509, G0801418]; NHGRI NIH HHS [5 U54 HG003067-13, 5U54HG003067-11, U41 HG000330, U54HG003067]; NHLBI NIH HHS [K01HL125751, R01HL107816, R01HL24799, T32 HL007208]; NIDDK NIH HHS [1RC2DK088389, DK085545, DK088389, DK098032, P30 DK043351, R01DK062370, R01DK098032, RC2-DK088389, RC2DK088389, RC2F DK088389, U01 DK062370, U01 DK085501, U01 DK085524, U01 DK085526, U01 DK085545, U01 DK085584, U01-DK085545, U01DK085526, U54 DK105566]; NIGMS NIH HHS [F32GM115208, R01 GM104371]; NIMH NIH HHS [2P50MH066392-05A1, MH077139, MH089905, MH094421, MH095034, R01 MH077139, R01MH085521, R01MH085560]; NINDS NIH HHS [K02 NS085048, NS085048, NS40024-09S1, U01 NS040024, U01 NS40024-09S1]; PHS HHS [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C, NIMHRC2MH089905]; Wellcome Trust [090367, 090532, 098381] NR 40 TC 236 Z9 236 U1 39 U2 41 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 AUG 18 PY 2016 VL 536 IS 7616 BP 285 EP + DI 10.1038/nature19057 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT9GN UT WOS:000381804900026 PM 27535533 ER PT J AU Manrai, AK Funke, BH Rehm, HL Olesen, MS Maron, BA Szolovits, P Margulies, DM Loscalzo, J Kohane, IS AF Manrai, Arjun K. Funke, Birgit H. Rehm, Heidi L. Olesen, Morten S. Maron, Bradley A. Szolovits, Peter Margulies, David M. Loscalzo, Joseph Kohane, Isaac S. TI Genetic Misdiagnoses and the Potential for Health Disparities SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HYPERTROPHIC CARDIOMYOPATHY; DILATED CARDIOMYOPATHY; VARIANTS; MUTATIONS; PATHOGENICITY; POPULATION; STANDARDS; GENOMICS; DATABASE; ADULTS AB BACKGROUND For more than a decade, risk stratification for hypertrophic cardiomyopathy has been enhanced by targeted genetic testing. Using sequencing results, clinicians routinely assess the risk of hypertrophic cardiomyopathy in a patient's relatives and diagnose the condition in patients who have ambiguous clinical presentations. However, the benefits of genetic testing come with the risk that variants may be misclassified. METHODS Using publicly accessible exome data, we identified variants that have previously been considered causal in hypertrophic cardiomyopathy and that are overrepresented in the general population. We studied these variants in diverse populations and reevaluated their initial ascertainments in the medical literature. We reviewed patient records at a leading genetic-testing laboratory for occurrences of these variants during the near-decade-long history of the laboratory. RESULTS Multiple patients, all of whom were of African or unspecified ancestry, received positive reports, with variants misclassified as pathogenic on the basis of the understanding at the time of testing. Subsequently, all reported variants were recategorized as benign. The mutations that were most common in the general population were significantly more common among black Americans than among white Americans ( P<0.001). Simulations showed that the inclusion of even small numbers of black Americans in control cohorts probably would have prevented these misclassifications. We identified methodologic shortcomings that contributed to these errors in the medical literature. CONCLUSIONS The misclassification of benign variants as pathogenic that we found in our study shows the need for sequencing the genomes of diverse populations, both in asymptomatic controls and the tested patient population. These results expand on current guidelines, which recommend the use of ancestry-matched controls to interpret variants. As additional populations of different ancestry backgrounds are sequenced, we expect variant reclassifications to increase, particularly for ancestry groups that have historically been less well studied. ( Funded by the National Institutes of Health.) C1 [Manrai, Arjun K.; Margulies, David M.; Kohane, Isaac S.] Harvard Med Sch, Dept Biomed Informat, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Funke, Birgit H.] Harvard Med Sch, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Maron, Bradley A.; Loscalzo, Joseph] Harvard Med Sch, Dept Pathol, Massachusetts Gen Hosp, Dept Med, Boston, MA 02115 USA. [Rehm, Heidi L.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Maron, Bradley A.] Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Maron, Bradley A.; Loscalzo, Joseph] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Manrai, Arjun K.; Kohane, Isaac S.] Harvard Massachusetts Inst Technol MIT, Div Hlth Sci & Technol, Cambridge, MA USA. [Funke, Birgit H.; Rehm, Heidi L.] Partners HealthCare Personalized Med, Mol Med Lab, Cambridge, MA USA. [Szolovits, Peter] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Olesen, Morten S.] Univ Copenhagen Hosp, Rigshosp, Lab Mol Cardiol, Dept Cardiol,Heart Ctr, Copenhagen, Denmark. [Olesen, Morten S.] Univ Copenhagen, Dept Biomed Sci, Fac Hlth & Med Sci, Copenhagen, Denmark. RP Kohane, IS (reprint author), 10 Shattuck St, Boston, MA 02115 USA. EM isaac_kohane@harvard.edu FU National Institutes of Health FX Funded by the National Institutes of Health. NR 40 TC 15 Z9 15 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 AUG 18 PY 2016 VL 375 IS 7 BP 655 EP 665 DI 10.1056/NEJMsa1507092 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DT4VF UT WOS:000381478600007 PM 27532831 ER PT J AU Zeidman, JA Shellito, PC Davis, BT Zukerberg, LR AF Zeidman, Jessica A. Shellito, Paul C. Davis, Benjamin T. Zukerberg, Lawrence R. TI Case 25-2016: A 33-Year-Old Man with Rectal Pain and Bleeding SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SEXUALLY-TRANSMITTED INFECTIONS; SECONDARY SYPHILIS; LYMPHOGRANULOMA-VENEREUM; PROCTITIS; DISEASE; MEN; SEX; PROCTOSIGMOIDITIS C1 [Zeidman, Jessica A.; Davis, Benjamin T.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Shellito, Paul C.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Zukerberg, Lawrence R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Zeidman, Jessica A.; Davis, Benjamin T.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Shellito, Paul C.] Harvard Med Sch, Dept Surg, Boston, MA 02115 USA. [Zukerberg, Lawrence R.] Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA. RP Zeidman, JA (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 24 TC 0 Z9 0 U1 4 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 18 PY 2016 VL 375 IS 7 BP 676 EP 682 DI 10.1056/NEJMcpc1602815 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA DT4VF UT WOS:000381478600011 PM 27532834 ER PT J AU Pratt, DS AF Pratt, Daniel S. TI Primary Biliary Cholangitis - A New Name and a New Treatment SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID URSODEOXYCHOLIC ACID; BIOCHEMICAL RESPONSE; END-POINTS; CIRRHOSIS C1 [Pratt, Daniel S.] Massachusetts Gen Hosp, Autoimmune & Cholestat Liver Ctr, Boston, MA 02114 USA. [Pratt, Daniel S.] Harvard Med Sch, Boston, MA 02115 USA. RP Pratt, DS (reprint author), Massachusetts Gen Hosp, Autoimmune & Cholestat Liver Ctr, Boston, MA 02114 USA.; Pratt, DS (reprint author), Harvard Med Sch, Boston, MA 02115 USA. NR 9 TC 2 Z9 2 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 AUG 18 PY 2016 VL 375 IS 7 BP 685 EP 687 DI 10.1056/NEJMe1607744 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DT4VF UT WOS:000381478600013 PM 27532836 ER PT J AU Hu, KJ Xu, WD Williams, Z AF Hu, Kejia Xu, Wendong Williams, Ziv TI Pioglitazone after Ischemic Stroke or Transient Ischemic Attack SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Hu, Kejia; Xu, Wendong] Huashan Hosp, Shanghai, Peoples R China. [Williams, Ziv] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hu, KJ (reprint author), Huashan Hosp, Shanghai, Peoples R China. EM khu3@mgh.harvard.edu NR 4 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 AUG 18 PY 2016 VL 375 IS 7 BP 703 EP 704 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DT4VF UT WOS:000381478600024 PM 27532848 ER PT J AU Coca, SG Nadkarni, GN Garg, AX Koyner, J Thiessen-Philbrook, H McArthur, E Shlipak, MG Parikh, CR AF Coca, Steven G. Nadkarni, Girish N. Garg, Amit X. Koyner, Jay Thiessen-Philbrook, Heather McArthur, Eric Shlipak, Michael G. Parikh, Chirag R. CA TRIBE-AKI Consortium TI First Post-Operative Urinary Kidney Injury Biomarkers and Association with the Duration of AKI in the TRIBE-AKI Cohort SO PLOS ONE LA English DT Article ID LONG-TERM SURVIVAL; CARDIAC-SURGERY; PREVENTION TRIALS; POOR OUTCOMES; IMPACT AB Background We previously demonstrated that assessment of the duration of AKI, in addition to magnitude of rise in creatinine alone, adds prognostic information for long-term survival. We evaluated whether post-operative kidney injury biomarkers in urine collected immediately after cardiac surgery associate with duration of serum creatinine elevation. Methods We studied 1199 adults undergoing cardiac surgery in a prospective cohort study (TRIBE-AKI) and examined the association between the levels of five urinary biomarkers individually at 0-6 hours after surgery: interleukin-18 (IL-18), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver fatty acid binding protein (L-FABP) and albumin with duration of serum creatinine-based AKIN criteria for AKI (0 (no AKI), 1-2, 3-6, >= 7 days). Results Overall, 407 (34%) patients had at least stage 1 AKI, of whom 251 (61.7%) had duration of 1-2 days, 118 (28.9%) had duration 3-6 days, and 38 (9.3%) had duration of >= 7 days. Higher concentrations of all biomarkers (per log increase) were independently associated with a greater odds of a longer duration of AKI; odds ratios and 95% confidence intervals using ordinal logistic regression were the following: IL-18: 1.22, 1.13-1.32; KIM-1: 1.36, 1.21-1.52; albumin 1.20, 1.09-1.32; L-FABP 1.11, 1.04-1.19; NGAL 1.06, 1.00-1.14). AKI duration of 7 days or longer was associated with a 5-fold adjusted risk of mortality at 3 years. Conclusions There was an independent dose-response association between urinary levels of injury biomarkers immediately after cardiac surgery and longer duration of AKI. Duration of AKI was also associated with long term mortality. Future studies should explore the potential utility of these urinary kidney injury biomarkers to enrich enrollment of patients at risk for longer duration of AKI into trials of interventions to prevent or treat post-operative AKI. C1 [Coca, Steven G.; Nadkarni, Girish N.] Icahn Sch Med Mt Sinai, Dept Med, Div Nephrol, New York, NY 10029 USA. [Garg, Amit X.; Thiessen-Philbrook, Heather; McArthur, Eric] Western Univ, Dept Med, Div Nephrol, London, ON, Canada. [Koyner, Jay] Univ Chicago, Pritzker Sch Med, Dept Med, Nephrol Sect, Chicago, IL 60637 USA. [Shlipak, Michael G.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. [Parikh, Chirag R.] Yale Univ, Sch Med, Dept Internal Med, Program Appl Translat Res, New Haven, CT 06510 USA. RP Parikh, CR (reprint author), Yale Univ, Sch Med, Dept Internal Med, Program Appl Translat Res, New Haven, CT 06510 USA. EM chirag.parikh@yale.edu FU Institute for Clinical Evaluative Sciences (ICES) - Ontario Ministry of Health and Long-Term Care (MOHLTC); National Institutes of Health (NIH) [R01HL085757]; NIH [K23DK080132, T32-DK007757, K24DK090203, P30 DK079310-07, U01DK082185]; Dr. Adam Linton Chair in Kidney Health Analytics; [K23 DK081616] FX This study was supported by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the MOHLTC is intended or should be inferred. This study was supported by the National Institutes of Health (NIH) (R01HL085757 to CRP) to fund the TRIBE-AKI Consortium to study novel biomarkers of AKI in cardiac surgery. SGC has been supported by an NIH Career Development Award (K23DK080132). GNN is supported in part by the NIH (T32-DK007757). JLK has been supported by K23 DK081616. C.R.P. is supported by the NIH (K24DK090203) and P30 DK079310-07 O'Brien Center Grant. SGC, AXG, and CRP are also members of the NIH-sponsored Assess, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury Consortium (U01DK082185). AXG is supported by the Dr. Adam Linton Chair in Kidney Health Analytics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Lead Author of the TRIBE AKI consortium: Chirag R. Parikh. Email: chirag.parikh@yale.edu. Section of Nephrology, Department of Medicine, Yale University School of Medicine, VA CT Healthcare System, and the Program of Applied Translational Research, New Haven, CT, USA. Members of TRIBE-AKI consortium: U of Chicago: Dr. Jai Raman, Dr. Valluvan Jeevanandam, Dr. Shahab Akhter. U of Colorado: Dr. Charles Edelstein. Danbury Hospital: Dr. Cary Passik, Ms. Judy Nagy. Duke University: Dr. Madhav Swaminathan. London, Ontario: Dr. Michael Chu, Dr. Martin Goldbach, Dr. Lin Ruo Guo, Dr. Neil McKenzie, Dr. Mary Lee Myers, Dr. Richard Novick, Dr. Mac Quantz. Montreal Children's: Dr. Michael Zappitelli, Dr. Ana Palijan. Yale-New Haven: Dr. Michael Dewar, Dr. Umer Darr, Dr. Sabet Hashim, Dr. John Elefteriades, Dr. Arnar Geirsson, Dr. Susan Garwood, Dr. Isabel Butrymowicz, Dr. Harlan Krumholz. Additional Contributions: We thank Dr. Stephanie Dixon for her analytic support. This study was supported by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the MOHLTC is intended or should be inferred. This study was supported by the National Institutes of Health (NIH) (R01HL085757 to C.R.P.) to fund the TRIBE-AKI Consortium to study novel biomarkers of AKI in cardiac surgery. S.G.C. has been supported by an NIH Career Development Award (K23DK080132). G.N.N is supported in part by the NIH (T32-DK007757). JLK has been supported by K23 DK081616. C.R.P. is supported by the NIH (K24DK090203) and P30 DK079310-07 O'Brien Center Grant. S.G.C., A.X.G., and C.R.P. are also members of the NIH-sponsored Assess, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury Consortium (U01DK082185). AXG is supported by the Dr. Adam Linton Chair in Kidney Health Analytics. NR 15 TC 1 Z9 1 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 AUG 18 PY 2016 VL 11 IS 8 AR e0161098 DI 10.1371/journal.pone.0161098 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT6ES UT WOS:000381577000053 PM 27537050 ER PT J AU Jiang, F He, JY Navarro-Alvarez, N Xu, J Li, X Li, P Wu, WX AF Jiang, Fei He, Jinyan Navarro-Alvarez, Nalu Xu, Jian Li, Xia Li, Peng Wu, Wenxue TI Elongation Factor Tu and Heat Shock Protein 70 Are Membrane-Associated Proteins from Mycoplasma ovipneumoniae Capable of Inducing Strong Immune Response in Mice SO PLOS ONE LA English DT Article ID BIGHORN SHEEP; RECOMBINANT PROTEIN; HYOPNEUMONIAE; PNEUMONIA; FIBRONECTIN; ANTIGENS; ADHESIN; SUBUNIT; DISEASE; INNATE AB Chronic non-progressive pneumonia, a disease that has become a worldwide epidemic has caused considerable loss to sheep industry. Mycoplasma ovipneumoniae (M. ovipneumoniae) is the causative agent of interstitial pneumonia in sheep, goat and bighorn. We here have identified by immunogold and immunoblotting that elongation factor Tu (EF-Tu) and heat shock protein 70 (HSP 70) are membrane-associated proteins on M. ovipneumonaiea. We have evaluated the humoral and cellular immune responses in vivo by immunizing BALB/c mice with both purified recombinant proteins rEF-Tu and rHSP70. The sera of both rEF-Tu and rHSP70 treated BALB/c mice demonstrated increased levels of IgG, IFN-gamma, TNF-alpha, IL-12(p70), IL-4, IL-5 and IL-6. In addition, ELISPOT assay showed significant increase in IFN-gamma(+) secreting lymphocytes in the rHSP70 group when compared to other groups. Collectively our study reveals that rHSP70 induces a significantly better cellular immune response in mice, and may act as a Th1 cytokine-like adjuvant in immune response induction. Finally, growth inhibition test (GIT) of M. ovipneumoniae strain Y98 showed that sera from rHSP70 or rEF-Tu-immunized mice inhibited in vitro growth of M. ovipneumoniae. Our data strongly suggest that EF-Tu and HSP70 of M. ovipneumoniae are membrane-associated proteins capable of inducing antibody production, and cytokine secretion. Therefore, these two proteins may be potential candidates for vaccine development against M. ovipneumoniae infection in sheep. C1 [Jiang, Fei; He, Jinyan; Xu, Jian; Li, Xia; Li, Peng; Wu, Wenxue] China Agr Univ, Coll Vet Med, Lab Rapid Diagnost Technol Anim Dis, Beijing 100193, Peoples R China. [Jiang, Fei; He, Jinyan; Xu, Jian; Li, Xia; Li, Peng; Wu, Wenxue] China Agr Univ, Coll Vet Med, Minist Agr, Key Lab Anim Epidemiol & Zoonosis, Beijing 100193, Peoples R China. [Navarro-Alvarez, Nalu] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Transplantat Sci, Charlestown, MA 02129 USA. RP Wu, WX (reprint author), China Agr Univ, Coll Vet Med, Lab Rapid Diagnost Technol Anim Dis, Beijing 100193, Peoples R China.; Wu, WX (reprint author), China Agr Univ, Coll Vet Med, Minist Agr, Key Lab Anim Epidemiol & Zoonosis, Beijing 100193, Peoples R China. EM wuwenxue@cau.edu.cn FU Special Fund for Agro-scientific Research in the Public Interest of China [201203056] FX This research was supported by Special Fund for Agro-scientific Research in the Public Interest of China, No. 201203056. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 1 Z9 1 U1 9 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 18 PY 2016 VL 11 IS 8 AR e0161170 DI 10.1371/journal.pone.0161170 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT6ES UT WOS:000381577000064 ER PT J AU Meimetis, LG Giedt, RJ Mikula, H Carlson, JC Kohler, RH Pirovich, DB Weissleder, R AF Meimetis, Labros G. Giedt, Randy J. Mikula, Hannes Carlson, Jonathan C. Kohler, Rainer H. Pirovich, David B. Weissleder, Ralph TI Fluorescent vinblastine probes for live cell imaging SO CHEMICAL COMMUNICATIONS LA English DT Article ID DIMERIC CATHARANTHUS ALKALOIDS; TUBULIN; MICROTUBULES; VINCRISTINE; AGENTS AB Herein we describe the synthesis of several fluorescent analogues of the clinically approved microtubule destabilizing agent vinblastine. The evaluated probes are the most potent described and provides the first example of uptake, distribution and live cell imaging using this well known antimitotic agent. C1 [Meimetis, Labros G.; Giedt, Randy J.; Mikula, Hannes; Carlson, Jonathan C.; Kohler, Rainer H.; Pirovich, David B.; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St,CPZN 5206, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Med Sch, Dept Syst Biol, 200 Longwood Ave, Boston, MA 02115 USA. RP Meimetis, LG; Giedt, RJ (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St,CPZN 5206, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu FU National Institutes of Health (NIH) [5RO1EB010011-06]; Department of Defense Breast Cancer Research Program [BC134081] FX This work was supported in part by the National Institutes of Health (NIH) grant 5RO1EB010011-06 and the Department of Defense Breast Cancer Research Program BC134081. NR 25 TC 2 Z9 2 U1 11 U2 14 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1359-7345 EI 1364-548X J9 CHEM COMMUN JI Chem. Commun. PD AUG 18 PY 2016 VL 52 IS 64 BP 9953 EP 9956 DI 10.1039/c6cc04129a PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA DU3FC UT WOS:000382095200022 PM 27439765 ER PT J AU Rotstein, BH Placzek, MS Krishnan, HS Pekosak, A Collier, TL Wang, CN Liang, SH Burstein, ES Hooker, JM Vasdev, N AF Rotstein, Benjamin H. Placzek, Michael S. Krishnan, Hema S. Pekosak, Aleksandra Collier, Thomas Lee Wang, Changning Liang, Steven H. Burstein, Ethan S. Hooker, Jacob M. Vasdev, Neil TI Preclinical PET Neuroimaging of [C-11]Bexarotene SO MOLECULAR IMAGING LA English DT Article DE bexarotene; carbon-11; positron emission tomography; retinoid X receptor; neuroimaging ID RETINOID-X-RECEPTOR; T-CELL LYMPHOMA; ORAL BEXAROTENE; DOUBLE-BLIND; TRIAL; ACID; SCHIZOPHRENIA; FIXATION; DISEASE; MODELS AB Activation of retinoid X receptors (RXRs) has been proposed as a therapeutic mechanism for the treatment of neurodegeneration, including Alzheimer's and Parkinson's diseases. We previously reported radiolabeling of a Food and Drug Administration-approved RXR agonist, bexarotene, by copper-mediated [C-11]CO2 fixation and preliminary positron emission tomography (PET) neuroimaging that demonstrated brain permeability in nonhuman primate with regional binding distribution consistent with RXRs. In this study, the brain uptake and saturability of [C-11]bexarotene were studied in rats and nonhuman primates by PET imaging under baseline and greater target occupancy conditions. [C-11]Bexarotene displays a high proportion of nonsaturable uptake in the brain and is unsuitable for RXR occupancy measurements in the central nervous system. C1 [Rotstein, Benjamin H.; Krishnan, Hema S.; Pekosak, Aleksandra; Collier, Thomas Lee; Liang, Steven H.; Vasdev, Neil] Massachusetts Gen Hosp, Gordon Ctr Mol Imaging, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Rotstein, Benjamin H.; Placzek, Michael S.; Krishnan, Hema S.; Pekosak, Aleksandra; Collier, Thomas Lee; Wang, Changning; Liang, Steven H.; Hooker, Jacob M.; Vasdev, Neil] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Placzek, Michael S.; Wang, Changning; Hooker, Jacob M.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Placzek, Michael S.] McLean Hosp, McLean Imaging Ctr, Dept Psychiat, 115 Mill St, Belmont, MA 02178 USA. [Collier, Thomas Lee] Advion Inc, Ithaca, NY USA. [Burstein, Ethan S.] ACADIA Pharmaceut Inc, San Diego, CA USA. RP Rotstein, BH; Vasdev, N (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM benjamin.rotstein@uottawa.ca; vasdev.neil@mgh.harvard.edu FU Michael J. Fox Foundation [11786]; NIH [DA038000] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Research was supported by the Michael J. Fox Foundation (grant #11786). S.H.L is a recipient of NIH career development award (DA038000). NR 25 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 1536-0121 J9 MOL IMAGING JI Mol. Imaging PD AUG 17 PY 2016 VL 15 AR UNSP 1536012116663054 DI 10.1177/1536012116663054 PG 5 WC Biochemical Research Methods; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Radiology, Nuclear Medicine & Medical Imaging GA EL7GF UT WOS:000394788400001 ER PT J AU Fan, FQ He, ZX Kong, LL Chen, QH Yuan, Q Zhang, SH Ye, JJ Liu, H Sun, XF Geng, J Yuan, LZ Hong, LX Xiao, C Zhang, WJ Sun, XH Li, YZ Wang, P Huang, LH Wu, XR Ji, ZL Wu, Q Xia, NS Gray, NS Chen, LF Yun, CH Deng, XM Zhou, DW AF Fan, Fuqin He, Zhixiang Kong, Lu-Lu Chen, Qinghua Yuan, Quan Zhang, Shihao Ye, Jinjin Liu, Hao Sun, Xiufeng Geng, Jing Yuan, Lunzhi Hong, Lixin Xiao, Chen Zhang, Weiji Sun, Xihuan Li, Yunzhan Wang, Ping Huang, Lihong Wu, Xinrui Ji, Zhiliang Wu, Qiao Xia, Ning-Shao Gray, Nathanael S. Chen, Lanfen Yun, Cai-Hong Deng, Xianming Zhou, Dawang TI Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID CELL CONTACT INHIBITION; HIPPO SIGNALING PATHWAY; YES-ASSOCIATED PROTEIN; ORGAN SIZE CONTROL; HUMAN HEPATOCYTES; STRUCTURAL BASIS; LIVER-INJURY; CANCER; YAP; ACTIVATION AB Tissue repair and regenerative medicine address the important medical needs to replace damaged tissue with functional tissue. Most regenerative medicine strategies have focused on delivering biomaterials and cells, yet there is the untapped potential for drug-induced regeneration with good specificity and safety profiles. The Hippo pathway is a key regulator of organ size and regeneration by inhibiting cell proliferation and promoting apoptosis. Kinases MST1 and MST2 (MST1/2), the mammalian Hippo orthologs, are central components of this pathway and are, therefore, strong target candidates for pharmacologically induced tissue regeneration. We report the discovery of a reversible and selective MST1/2 inhibitor, 4-((5,10-dimethyl-6-oxo-6,10-dihydro-5H-pyrimido[5,4-b] thieno[3,2-e][1,4] diazepin-2-yl) amino) benzenesulfonamide (XMU-MP-1), using an enzyme-linked immunosorbent assay-based high-throughput biochemical assay. The cocrystal structure and the structure-activity relationship confirmed that XMU-MP-1 is on-target to MST1/2. XMU-MP-1 blocked MST1/2 kinase activities, thereby activating the downstream effector Yes-associated protein and promoting cell growth. XMU-MP-1 displayed excellent in vivo pharmacokinetics and was able to augment mouse intestinal repair, as well as liver repair and regeneration, in both acute and chronic liver injury mouse models at a dose of 1 to 3 mg/kg via intraperitoneal injection. XMU-MP-1 treatment exhibited substantially greater repopulation rate of human hepatocytes in the Fah-deficient mouse model than in the vehicle-treated control, indicating that XMU-MP-1 treatment might facilitate human liver regeneration. Thus, the pharmacological modulation of MST1/2 kinase activities provides a novel approach to potentiate tissue repair and regeneration, with XMU-MP-1 as the first lead for the development of targeted regenerative therapeutics. C1 [Fan, Fuqin; He, Zhixiang; Chen, Qinghua; Zhang, Shihao; Ye, Jinjin; Liu, Hao; Sun, Xiufeng; Geng, Jing; Hong, Lixin; Xiao, Chen; Zhang, Weiji; Sun, Xihuan; Li, Yunzhan; Wang, Ping; Huang, Lihong; Wu, Xinrui; Ji, Zhiliang; Wu, Qiao; Chen, Lanfen; Deng, Xianming; Zhou, Dawang] Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Signaling Network, State Key Lab Cellular Stress Biol, Xiamen 361102, Fujian, Peoples R China. [Fan, Fuqin; He, Zhixiang; Chen, Qinghua; Zhang, Shihao; Ye, Jinjin; Liu, Hao; Sun, Xiufeng; Geng, Jing; Hong, Lixin; Xiao, Chen; Zhang, Weiji; Sun, Xihuan; Li, Yunzhan; Wang, Ping; Huang, Lihong; Wu, Xinrui; Ji, Zhiliang; Wu, Qiao; Chen, Lanfen; Deng, Xianming; Zhou, Dawang] Xiamen Univ, State Prov Joint Engn Lab Targeted Drugs Nat Prod, Xiamen 361102, Fujian, Peoples R China. [Kong, Lu-Lu; Yun, Cai-Hong] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Biophys,Inst Syst Biomed, Beijing 100191, Peoples R China. [Kong, Lu-Lu; Yun, Cai-Hong] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Beijing Key Lab Tumor Syst Biol, Beijing 100191, Peoples R China. [Yuan, Quan; Yuan, Lunzhi; Xia, Ning-Shao] Xiamen Univ, Sch Life Sci, Natl Inst Diagnost & Vaccine Dev Infect Dis, State Key Lab Mol Vaccinol & Mol Diagnost, Xiamen 361102, Fujian, Peoples R China. [Yuan, Quan; Yuan, Lunzhi; Xia, Ning-Shao] Xiamen Univ, Sch Publ Hlth, Xiamen 361102, Fujian, Peoples R China. [Gray, Nathanael S.] Harvard Med Sch, Dana Farber Canc Inst, Longwood Ctr 2207, Dept Biol Chem & Mol Pharmacol, 360 Longwood Ave, Boston, MA 02215 USA. [Gray, Nathanael S.] Harvard Med Sch, Dana Farber Canc Inst, Longwood Ctr 2207, Dept Canc Biol, 360 Longwood Ave, Boston, MA 02215 USA. RP Deng, XM; Zhou, DW (reprint author), Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Signaling Network, State Key Lab Cellular Stress Biol, Xiamen 361102, Fujian, Peoples R China.; Deng, XM; Zhou, DW (reprint author), Xiamen Univ, State Prov Joint Engn Lab Targeted Drugs Nat Prod, Xiamen 361102, Fujian, Peoples R China.; Yun, CH (reprint author), Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Biophys,Inst Syst Biomed, Beijing 100191, Peoples R China.; Yun, CH (reprint author), Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Beijing Key Lab Tumor Syst Biol, Beijing 100191, Peoples R China. EM yunch@hsc.pku.edu.cn; xmdeng@xmu.edu.cn; dwzhou@xmu.edu.cn FU National Basic Research Program (973) of China [2015CB910502, 2012CB917202]; National Natural Science Foundation of China [31270918, U1505224, J1310027, 81422045, U1405223, 21272195, 81372617, 81422018, U1405225, 31270769, 81472229]; 111 Projects [B12001, B06016]; Fundamental Research Funds for the Central Universities of China-Xiamen University [CXB2014004, 20720140551, 20720160064, 2013121032, 2013121034, 20720140537] FX This work was supported by the National Basic Research Program (973) of China [2015CB910502 (to L.C.) and 2012CB917202 (to C.-H.Y.)], the National Natural Science Foundation of China [31270918, U1505224, and J1310027 (to D.Z.); 81422045, U1405223, and 21272195 (to X.D.); 81372617, 81422018, and U1405225 (to L.C.); 31270769 (to C.-H.Y.); and 81472229 (to L.H.)], the 111 Projects (B12001 and B06016), the Fundamental Research Funds for the Central Universities of China-Xiamen University [CXB2014004 (to Z.J.), 20720140551 (to L.C.), 20720160064 and 2013121032 (to X.D.), and 2013121034 and 20720140537 (to D.Z.)]. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 0 Z9 0 U1 16 U2 16 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 AUG 17 PY 2016 VL 8 IS 352 AR 352ra108 DI 10.1126/scitranslmed.aaf2304 PG 14 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DW9WP UT WOS:000384013700002 ER PT J AU Ramsey, MM Freire, MO Gabrilska, RA Rumbaugh, KP Lemon, KP AF Ramsey, Matthew M. Freire, Marcelo O. Gabrilska, Rebecca A. Rumbaugh, Kendra P. Lemon, Katherine P. TI Staphylococcus aureus Shifts toward Commensalism in Response to Corynebacterium Species SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE quorum sensing(QS); Corynebacterium; Staphylococcus aureus; agr system; microbiome; commensal bacteria ID NASAL COLONIZATION; PROTEIN-A; IN-VITRO; UNITED-STATES; AGR; INFECTIONS; EXPRESSION; IDENTIFICATION; USA300; SARA AB Staphylococcus aureus-human interactions result in a continuum of outcomes from commensalism to pathogenesis. S. aureus is a clinically important pathogen that asymptomatically colonizes similar to 25% of humans as a member of the nostril and skin microbiota, where it resides with other bacteria including commensal Corynebacterium species. Commensal Corynebacterium spp. are also positively correlated with S. aureus in chronic polymicrobial diabetic foot infections, distinct from acute monomicrobial S. aureus infections. Recent work by our lab and others indicates that microbe-microbe interactions between S. aureus and human skin/nasal commensals, including Corynebacterium species, affect S. aureus behavior and fitness. Thus, we hypothesized that S. aureus interactions with Corynebacterium spp. diminish S. aureus virulence. We tested this by assaying for changes in S. aureus gene expression during in vitro mono- versus coculture with Corynebacterium striatum, a common skin and nasal commensal. We observed a broad shift in S. aureus gene transcription during in vitro growth with C. striatum, including increased transcription of genes known to exhibit increased expression during human nasal colonization and decreased transcription of virulence genes. S. aureus uses several regulatory pathways to transition between commensal and pathogenic states. One of these, the quorum signal accessory gene regulator (agr) system, was strongly inhibited in response to Corynebacterium spp. Phenotypically, S. aureus exposed to C. striatum exhibited increased adhesion to epithelial cells, reflecting a commensal state, and decreased hemolysin activity, reflecting an attenuation of virulence. Consistent with this, S. aureus displayed diminished fitness in experimental in vivo coinfection with C. striatum when compared to monoinfection. These data support a model in which S. aureus shifts from virulence toward a commensal state when exposed to commensal Corynebacterium species. C1 [Ramsey, Matthew M.; Lemon, Katherine P.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Ramsey, Matthew M.; Freire, Marcelo O.] Harvard Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA USA. [Freire, Marcelo O.] Forsyth Inst, Dept Appl Oral Sci, Cambridge, MA USA. [Gabrilska, Rebecca A.; Rumbaugh, Kendra P.] Texas Tech Univ, Hlth Sci Ctr, Dept Surg, Lubbock, TX 79430 USA. [Lemon, Katherine P.] Harvard Med Sch, Boston Childrens Hosp, Div Infect Dis, Boston, MA USA. RP Lemon, KP (reprint author), Forsyth Inst, Dept Microbiol, Cambridge, MA USA.; Lemon, KP (reprint author), Harvard Med Sch, Boston Childrens Hosp, Div Infect Dis, Boston, MA USA. EM klemon@forsyth.org FU National Institutes of Health NIAID [F32 AI102498, R00 DE023584, R15 AI105763, R01 AI101018] FX This work was supported by the National Institutes of Health NIAID grants F32 AI102498 (MR), R00 DE023584 (MF), R15 AI105763 (KR) and R01 AI101018 (KL). The funders had no role in study design, data collection and interpretation or the decision to submit the work for publication. NR 67 TC 3 Z9 3 U1 9 U2 9 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 AUG 17 PY 2016 VL 7 AR 1230 DI 10.3389/fmicb.2016.01230 PG 15 WC Microbiology SC Microbiology GA DT5US UT WOS:000381549100001 PM 27582729 ER PT J AU Guan, YC Guo, LK Zukerberg, L Rueda, BR Styer, AK AF Guan, Yichun Guo, Lankai Zukerberg, Lawrence Rueda, Bo R. Styer, Aaron K. TI MicroRNA-15b regulates reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression in human uterine leiomyoma SO REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY LA English DT Article DE Uterine leiomyoma; Fibroids; miR-15b; RECK; Myometrium ID MATRIX-METALLOPROTEINASE REGULATOR; COLORECTAL-CANCER; DIFFERENTIAL EXPRESSION; PROGNOSTIC INDICATOR; INHIBITOR RECK; GASTRIC-CANCER; CELL INVASION; LUNG-CANCER; ANGIOGENESIS; PATHOGENESIS AB Background: Human uterine leiomyoma (fibroids; LYO) are the most common benign neoplasms in reproductive-aged women. Dysregulated extracellular matrix and irregular LYO reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression are thought to be mediated by aberrant microRNA (miR) expression. The relationship of miR-15b and RECK expression in LYO has not been studied. Methods: The expression levels of miR-15b and RECK were determined by quantitative RT-PCR, Western blot, and immunohistochemistry in cultures derived from commercial primary leiomyoma (cpLYO) and myometrial (cpMYO) cell lines and leiomyoma (pLYO) and myometrium (pMYO) tissue from surgical samples respectively. The relationship between miR-15b and RECK expression in cpLYO and pLYO (compared to their respective myometrial controls) was evaluated following transfection of cell cultures with either miR-15b mimic or inhibitor. Results: Elevated levels of miR-15b were observed in cpLYO (2.82-fold; p = 0.04) and pLYO cell (1.30-fold; p = 0.0001) cultures respectively compared to corresponding MYO cell controls. Following transfection with miR-15b mimic, cpLYO cells (0.62-fold; p < 0.0001) and pLYO cells (0.68-fold; p < 0.0001) demonstrated reduced RECK protein expression. Following transfection with miR-15b inhibitor, cpLYO cells (1.20-fold; p < 0.0001) and pLYO cells (1.31-fold; p = 0.0007) demonstrated elevated RECK protein expression. RECK protein expression was reduced in pLYO tissues (0.73-fold; p < 0.0001) and pLYO (0.47-fold; p = 0.047) cells when compared to the corresponding MYO tissue controls. Conclusion: Our findings suggest that miR-15b negatively regulates RECK expression in LYO, and increased miR-15b and decreased RECK expression may contribute to the pathobiology of LYO. The functional significance of miR-15b and RECK expression warrants further investigation as potential therapeutic targets for the treatment of human LYO. C1 [Guan, Yichun] Zhengzhou Univ, Affiliated Hosp 3, Ctr Reprod Med, Zhengzhou 450052, Henan Province, Peoples R China. [Guan, Yichun; Guo, Lankai; Rueda, Bo R.; Styer, Aaron K.] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Vincent Dept Obstet & Gynecol, Their 9,55 Fruit St, Boston, MA 02114 USA. [Zukerberg, Lawrence] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Rueda, Bo R.; Styer, Aaron K.] Harvard Med Sch, Dept Obstet, Boston, MA 02115 USA. [Rueda, Bo R.; Styer, Aaron K.] Harvard Med Sch, Dept Gynecol, Boston, MA 02115 USA. [Rueda, Bo R.; Styer, Aaron K.] Harvard Med Sch, Dept Reprod Biol, Boston, MA 02115 USA. RP Rueda, BR; Styer, AK (reprint author), Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Vincent Dept Obstet & Gynecol, Their 9,55 Fruit St, Boston, MA 02114 USA. EM brueda@mgh.harvard.edu; astyer@mgh.harvard.edu FU Vincent Memorial Research Funds; Scientific and Technological Project of Henan Province [201203049]; Merck Serono China Research Fund for Fertility FX This work was supported, in part, by the Vincent Memorial Research Funds. Dr. Guan was supported by grants from the Scientific and Technological Project of Henan Province (NO. 201203049). Support was provided in part by the Merck Serono China Research Fund for Fertility. All funding supported, in part, the efforts of authors in conducting experiments and data collection. NR 49 TC 1 Z9 1 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7827 J9 REPROD BIOL ENDOCRIN JI Reprod. Biol. Endocrinol. PD AUG 17 PY 2016 VL 14 AR 45 DI 10.1186/s12958-016-0180-y PG 10 WC Endocrinology & Metabolism; Reproductive Biology SC Endocrinology & Metabolism; Reproductive Biology GA DT4WJ UT WOS:000381481700001 PM 27530410 ER PT J AU Jackson, CL Agenor, M Johnson, DA Austin, SB Kawachi, I AF Jackson, Chandra L. Agenor, Madina Johnson, Dayna A. Austin, S. Bryn Kawachi, Ichiro TI Sexual orientation identity disparities in health behaviors, outcomes, and services use among men and women in the United States: a cross-sectional study SO BMC PUBLIC HEALTH LA English DT Article DE Sexual orientation; Health behaviors; Health outcomes; United States ID SAME-SEX; BISEXUAL POPULATIONS; MINORITY STRESS; GAY; ADULTS; ACCESS; INSURANCE; ALCOHOL; STIGMA; DISCRIMINATION AB Background: Research shows that sexual minorities (e.g., lesbian, gay, and bisexual individuals) experience higher levels of discrimination, stigma, and stress and are at higher risk of some poor health outcomes and health behaviors compared to their heterosexual counterparts. However, the majority of studies have examined sexual orientation disparities in a narrow range of health outcomes and behaviors using convenience samples comprised of either men or women living in restricted geographic areas. Methods: To investigate the relationship between sexual orientation identity and health among U.S. women and men, we used Poisson regression with robust variance to estimate prevalence ratios for health behaviors, outcomes, and services use comparing sexual minorities to heterosexual individuals using 2013 and 2014 National Health Interview Survey data (N = 69,270). Results: Three percent of the sample identified as sexual minorities. Compared to heterosexual women, lesbian (prevalence ratio (PR) = 1.65 [95 % confidence interval (CI): 1.14, 2.37]) and bisexual (PR = 2.16 [1.46, 3.18]) women were more likely to report heavy drinking. Lesbians had a higher prevalence of obesity (PR = 1.20 [1.02, 1.42]), stroke (PR = 1.96 [1.14, 3.39]), and functional limitation (PR = 1.17 [1.02, 1.34] than heterosexual women. Gay men were more likely to have hypertension (PR = 1.21 [1.03, 1.43]) and heart disease (PR = 1.39 [1.02, 1.88]). Despite no difference in health insurance status, sexual minorities were more likely than heterosexual individuals to delay seeking healthcare because of cost; however, members of this group were also more likely to have received an HIV test and initiated HPV vaccination. Conclusion: Sexual minorities had a higher prevalence of some poor health behaviors and outcomes. C1 [Jackson, Chandra L.] Harvard Med Sch, Clin & Translat Sci Ctr, Harvard Catalyst, 10 Shattuck St, Boston, MA 02215 USA. [Agenor, Madina; Austin, S. Bryn; Kawachi, Ichiro] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Agenor, Madina] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Johnson, Dayna A.] Harvard Med Sch, Brigham & Womens Hosp, Div Sleep & Circadian Disorders, Boston, MA USA. [Austin, S. Bryn] Boston Childrens Hosp, Div Adolescent & Young Adult Med, Boston, MA USA. RP Jackson, CL (reprint author), Harvard Med Sch, Clin & Translat Sci Ctr, Harvard Catalyst, 10 Shattuck St, Boston, MA 02215 USA. EM Chandra_Jackson@hms.harvard.edu RI Jackson, Chandra/A-6291-2017 OI Jackson, Chandra/0000-0002-0915-8272 FU Harvard Catalyst Clinical and Translational Science Center [1UL1 TR001102-07]; National Institutes of Health [R25CA057711-20]; National Heart, Lung, And Blood Institute of the National Institutes of Health [R01HL110068]; U.S. Maternal and Child Health Bureau [T71-MC00009, T76-MC00001] FX Dr. Jackson was supported by the Harvard Catalyst Clinical and Translational Science Center (grant 1UL1 TR001102-07). Dr. Agenor was supported by National Institutes of Health grant R25CA057711-20. Dr. Johnson was supported by The National Heart, Lung, And Blood Institute of the National Institutes of Health (R01HL110068). Dr. Austin is supported by U.S. Maternal and Child Health Bureau training grants T71-MC00009 and T76-MC00001. The funding sources were not involved in the data collection, data analysis, manuscript writing and publication. NR 38 TC 0 Z9 0 U1 12 U2 20 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD AUG 17 PY 2016 VL 16 AR 807 DI 10.1186/s12889-016-3467-1 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DT5UY UT WOS:000381549700002 PM 27534616 ER PT J AU Osier, ND Dixon, CE AF Osier, Nicole D. Dixon, C. Edward TI The Controlled Cortical Impact Model: Applications, Considerations for Researchers, and Future Directions SO FRONTIERS IN NEUROLOGY LA English DT Review DE controlled cortical impact; experimental brain injury; brain trauma; pre-clinical; review ID TRAUMATIC BRAIN-INJURY; CHRONIC METHYLPHENIDATE TREATMENT; WATER MAZE PERFORMANCE; SPINAL-CORD CONTUSION; RATS POSSIBLE ROLE; COGNITIVE DEFICITS; MEMORY DEFICITS; AXONAL INJURY; HEAD-INJURY; ENVIRONMENTAL ENRICHMENT AB Controlled cortical impact (CCI) is a mechanical model of traumatic brain injury (TBI) that was developed nearly 30 years ago with the goal of creating a testing platform to determine the biomechanical properties of brain tissue exposed to direct mechanical deformation. Initially used to model TB's produced by automotive crashes, the CCI model rapidly transformed into a standardized technique to study TBI mechanisms and evaluate therapies. CCI is most commonly produced using a device that rapidly accelerates a rod to impact the surgically exposed cortical dural surface. The tip of the rod can be varied in size and geometry to accommodate scalability to difference species. Typically, the rod is actuated by a pneumatic piston or electromagnetic actuator. With some limits, CCI devices can control the velocity, depth, duration, and site of impact. The CCI model produces morphologic and cerebrovascular injury responses that resemble certain aspects of human TBI. Commonly observed are graded histologic and axonal derangements, disruption of the blood brain barrier, subdural and intra-parenchymal hematoma, edema, inflammation, and alterations in cerebral blood flow. The CCI model also produces neurobehavioral and cognitive impairments similar to those observed clinically. In contrast to other TBI models, the CCI device induces a significantly pronounced cortical contusion, but is limited in the extent to which it models the diffuse effects of TBI; a related limitation is that not all clinical TBI cases are characterized by a contusion. Another perceived limitation is that a non -clinically relevant craniotomy is performed. Biomechanically, this is irrelevant at the tissue level. However, craniotomies are not atraumatic and the effects of surgery should be controlled by including surgical sham control groups. CCI devices have also been successfully used to impact closed skulls to study mild and repetitive TBI. Future directions for CCI research surround continued refinements to the model through technical improvements in the devices (e.g., minimizing mechanical sources of variation). Like all TBI models, publications should report key injury parameters as outlined in the NIH common data elements (CDEs) for pre-clinical TBI. C1 [Osier, Nicole D.] Univ Pittsburgh, Sch Nursing, Dept Acute & Tertiary Care, Pittsburgh, PA 15261 USA. [Osier, Nicole D.; Dixon, C. Edward] Safar Ctr Resuscitat Res, Pittsburgh, PA USA. [Dixon, C. Edward] Univ Pittsburgh, Sch Med, Dept Neurosurg, Pittsburgh, PA 15261 USA. [Dixon, C. Edward] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Dixon, CE (reprint author), Safar Ctr Resuscitat Res, Pittsburgh, PA USA.; Dixon, CE (reprint author), Univ Pittsburgh, Sch Med, Dept Neurosurg, Pittsburgh, PA 15261 USA.; Dixon, CE (reprint author), VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. EM dixoec@upmc.edu FU National Institute of Health (NIH) [R01NS40125, R01NS091062, F31NR014957, T32NR009759]; Department of Veterans Affairs grant [I01RX001127]; American Association of Neuroscience Nursing/Neuroscience Nursing Foundation; International Society for Nurses in Genetics, Sigma Theta Tau International Eta Chapter; Pittsburgh foundation FX This work was supported by several grants from the National Institute of Health (NIH) Grants: R01NS40125, R01NS091062, F31NR014957, and T32NR009759. Additional support came from the Department of Veterans Affairs grant I01RX001127. Further support for this work comes from the following professional societies: the American Association of Neuroscience Nursing/Neuroscience Nursing Foundation, the International Society for Nurses in Genetics, Sigma Theta Tau International Eta Chapter, and The Pittsburgh foundation. NR 165 TC 0 Z9 0 U1 2 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2295 J9 FRONT NEUROL JI Front. Neurol. PD AUG 17 PY 2016 VL 7 AR UNSP 134 DI 10.3389/fneur.2016.00134 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DT7MA UT WOS:000381669700001 PM 27582726 ER PT J AU He, XY Qian, YB Li, ZG Fan, EK Li, YH Wu, L Billiar, TR Wilson, MA Shi, XY Fan, J AF He, Xingying Qian, Yongbing Li, Zhigang Fan, Erica K. Li, Yuehua Wu, Liang Billiar, Timothy R. Wilson, Mark A. Shi, Xueyin Fan, Jie TI TLR4-Upregulated IL-1 beta and IL-1RI Promote Alveolar Macrophage Pyroptosis and Lung Inflammation through an Autocrine Mechanism SO SCIENTIFIC REPORTS LA English DT Article ID INTERLEUKIN-1 RECEPTOR COMPLEX; ACTIVATION; DISEASE; INFLAMMASOMES; RECRUITMENT; EXPRESSION; APOPTOSIS; PROTEIN; DOMAIN; DEATH AB Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome (MODS) following pulmonary infection. Alveolar macrophages (AM) are at the center of the pathogenesis of the development of ALI. Interleukin-1 beta (IL-1 beta) is one of the key pro-inflammatory mediators, and its maturation is tightly controlled by the formation and activation of the inflammasome. The biological effects of IL-1 beta are mediated through IL-1 receptor (IL-1R). In this study, we investigated the influence of LPS-induced IL-1 beta release and IL-1RI upregulation on the development of lung inflammation. We demonstrated that in AM, LPS-TLR4 signaling not only activates Nlrp3 inflammasome activation and subsequent release of IL-1 beta, but also up-regulates IL-1RI expression on AM surface through MyD88 and NF-kappa B dependent signaling. The upregulated IL-1RI, therefore, sensitizes AM to IL-1 beta and results in pyroptosome formation, which in turn leads to AM pyroptosis, a type of caspase-1-dependent inflammatory cell death. We further showed that AM pyroptosis exaggerates lung inflammation. The present study demonstrates a novel mechanism underlying LPS-induced innate immunity; that is, a secondary upregulation of IL-1 beta-IL-1RI signaling is responsible for AM pyroptosis and augmented lung injury in response to LPS. C1 [He, Xingying; Wu, Liang; Shi, Xueyin] Second Mil Med Univ, Changzheng Hosp, Dept Anesthesiol, Shanghai 200003, Peoples R China. [He, Xingying; Li, Zhigang; Li, Yuehua; Wu, Liang; Billiar, Timothy R.; Wilson, Mark A.; Fan, Jie] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA. [Qian, Yongbing] Jiaotong Univ, Shanghai Hosp 1, Dept Crit Care Med, Sch Med, Shanghai 201600, Peoples R China. [Fan, Erica K.] Univ Pittsburgh, Dept Biol Sci, Sch Arts & Sci, Pittsburgh, PA 15213 USA. [Li, Yuehua; Wilson, Mark A.; Fan, Jie] Vet Affairs Pittsburgh Healthcare Syst, Res & Dev, Pittsburgh, PA 15240 USA. [Billiar, Timothy R.; Fan, Jie] Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA 15219 USA. [Shi, Xueyin] Jiaotong Univ, Sch Med, Shanghai Xinghua Hosp, Dept Anesthesiol, Shanghai 200092, Peoples R China. RP Shi, XY (reprint author), Second Mil Med Univ, Changzheng Hosp, Dept Anesthesiol, Shanghai 200003, Peoples R China.; Fan, J (reprint author), Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA.; Fan, J (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Res & Dev, Pittsburgh, PA 15240 USA.; Fan, J (reprint author), Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA 15219 USA.; Shi, XY (reprint author), Jiaotong Univ, Sch Med, Shanghai Xinghua Hosp, Dept Anesthesiol, Shanghai 200092, Peoples R China. EM shixueyin1128@163.com; jif7@pitt.edu FU National Institutes of Health Grant [R01-HL-079669, R56-HL-123882]; National Institutes of Health Center Grant [P50-GM-53789]; VA Merit Award [1I01BX002729]; Key Program of Medical Science Development of PLA [BWS12J027]; National Natural Science Foundation of China [81372103]; Shanghai Pujiang Program [15PJD003] FX This work was supported by the National Institutes of Health Grant R01-HL-079669 (J.F. and M.A.W.), National Institutes of Health Center Grant P50-GM-53789 (T.R.B. and J.F.), National Institutes of Health Grant R56-HL-123882 (J.F.), VA Merit Award 1I01BX002729 (J.F.), Key Program of Medical Science Development of PLA BWS12J027 (X.S.), National Natural Science Foundation of China 81372103 (X.S.), and Shanghai Pujiang Program 15PJD003 (X.H.). NR 23 TC 3 Z9 3 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 AUG 16 PY 2016 VL 6 AR 31663 DI 10.1038/srep31663 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH9XJ UT WOS:000392124800001 PM 27526865 ER PT J AU Liu, XC Wang, AL Liang, XF Liu, JJ Zou, FM Chen, C Zhao, Z Deng, YX Wu, H Qi, ZP Wang, BL Wang, L Liu, FY Xu, YH Wang, WC Fernandes, SM Stone, RM Galinsky, IA Brown, JR Loh, T Griffin, JD Zhang, SC Weisberg, EL Zhang, X Liu, J Liu, QS AF Liu, Xiaochuan Wang, Aoli Liang, Xiaofei Liu, Juanjuan Zou, Fengming Chen, Cheng Zhao, Zheng Deng, Yuanxin Wu, Hong Qi, Ziping Wang, Beilei Wang, Li Liu, Feiyang Xu, Yunhe Wang, Wenchao Fernandes, Stacey M. Stone, Richard M. Galinsky, Ilene A. Brown, Jennifer R. Loh, Teckpeng Griffin, James. D. Zhang, Shanchun Weisberg, Ellen L. Zhang, Xin Liu, Jing Liu, Qingsong TI Simultaneous inhibition of Vps34 kinase would enhance PI3K delta inhibitor cytotoxicity in the B-cell malignancies SO ONCOTARGET LA English DT Article DE PI3K delta; Vps34; combination; chronic lymphatic leukemia; acute myeloid leukemia ID SELECTIVE INHIBITOR; AUTOPHAGY; 3-KINASE; P110-DELTA; SURVIVAL; DYNAMIN; PI3K AB PI3K delta has been found to be over-expressed in B-Cell-related malignancies. Despite the clinical success of the first selective PI3Kd inhibitor, CAL-101, inhibition of PI3K delta itself did not show too much cytotoxic efficacy against cancer cells. One possible reason is that PI3K delta inhibition induced autophagy that protects the cells from death. Since class III PI3K isoform PIK3C3/Vps34 participates in autophagy initiation and progression, we predicted that a PI3K delta and Vps34 dual inhibitor might improve the anti-proliferative activity observed for PI3K delta-targeted inhibitors. We discovered a highly potent ATP-competitive PI3K delta/Vps34 dual inhibitor, PI3KD/V-IN-01, which displayed 10-1500 fold selectivity over other PI3K isoforms and did not inhibit any other kinases in the kinome. In cells, PI3KD/V-IN-01 showed 30-300 fold selectivity between PI3K delta and other class I PI3K isoforms. PI3KD/V-IN-01 exhibited better anti-proliferative activity against AML, CLL and Burkitt lymphoma cell lines than known selective PI3K delta and Vps34 inhibitors. Interestingly, we observed FLT3-ITD AML cells are more sensitive to PI3KD/V-IN-01 than the FLT3 wt expressing cells. In AML cell inoculated xenograft mouse model, PI3KD/V-IN-01 exhibited dose-dependent anti-tumor growth efficacies. These results suggest that dual inhibition of PI3K delta and Vps34 might be a useful approach to improve the PI3K delta inhibitor's anti-tumor efficacy. C1 [Liu, Xiaochuan; Xu, Yunhe; Loh, Teckpeng] Univ Sci & Technol China, Dept Chem, Hefei 230036, Anhui, Peoples R China. [Liu, Xiaochuan; Wang, Aoli; Liang, Xiaofei; Liu, Juanjuan; Zou, Fengming; Chen, Cheng; Zhao, Zheng; Deng, Yuanxin; Wu, Hong; Qi, Ziping; Wang, Beilei; Wang, Li; Liu, Feiyang; Wang, Wenchao; Zhang, Xin; Liu, Jing; Liu, Qingsong] Chinese Acad Sci, High Magnet Field Lab, Hefei 230031, Anhui, Peoples R China. [Wang, Aoli; Liu, Juanjuan; Deng, Yuanxin; Wu, Hong; Liu, Feiyang; Liu, Qingsong] Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China. [Liang, Xiaofei; Zou, Fengming; Chen, Cheng; Zhao, Zheng; Qi, Ziping; Wang, Beilei; Wang, Li; Wang, Wenchao; Zhang, Shanchun; Liu, Jing] CHMFL HCMTC Target Therapy Joint Lab, Hefei 230031, Anhui, Peoples R China. [Fernandes, Stacey M.; Stone, Richard M.; Galinsky, Ilene A.; Brown, Jennifer R.; Griffin, James. D.; Weisberg, Ellen L.] Harvard Med Sch, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Zhang, Shanchun] Hefei Cosource Med Technol Co LTD, Hefei 230031, Anhui, Peoples R China. [Liu, Qingsong] Chinese Acad Sci, Hefei Sci Ctr, Hefei 230031, Anhui, Peoples R China. RP Zhang, X; Liu, J; Liu, QS (reprint author), Chinese Acad Sci, High Magnet Field Lab, Hefei 230031, Anhui, Peoples R China.; Liu, QS (reprint author), Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China.; Liu, J (reprint author), CHMFL HCMTC Target Therapy Joint Lab, Hefei 230031, Anhui, Peoples R China.; Weisberg, EL (reprint author), Harvard Med Sch, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA.; Liu, QS (reprint author), Chinese Acad Sci, Hefei Sci Ctr, Hefei 230031, Anhui, Peoples R China. EM Ellen_weisberg@dfci.harvard.edu; xinzhang@hmfl.ac.cn; jingliu@hmfl.ac.cn; qsliu97@hmfl.ac.cn FU grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences; Anhui Province Natural Science Foundation Annual Key Program [1301023011]; Chinese Academy of Sciences; National Program for Support of Top-notch Young Professionals; CAS/SAFEA international partnership program; China "Thousand Talents Program" FX W. Wang, J. Liu and Q. Liu are supported by the grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation (2014-2016)" from Chinese Academy of Sciences. Z. Zhao is supported by Anhui Province Natural Science Foundation Annual Key Program (grant number: 1301023011). We want to thank China "Thousand Talents Program" support for Prof. Q. Liu and "Hundred Talents Program" of The Chinese Academy of Sciences support for Prof. J. Liu, and W. Wang. J.L. is also supported by the National Program for Support of Top-notch Young Professionals. Q. L. is also supported by the CAS/SAFEA international partnership program for creative research teams. NR 17 TC 0 Z9 0 U1 6 U2 6 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD AUG 16 PY 2016 VL 7 IS 33 BP 53515 EP 53525 DI 10.18632/oncotarget.10650 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY9DG UT WOS:000385433000068 PM 27447747 ER PT J AU Sahai, V Redig, AJ Collier, KA Eckerdt, FD Munshi, HG AF Sahai, Vaibhav Redig, Amanda J. Collier, Katharine A. Eckerdt, Frank D. Munshi, Hidayatullah G. TI Targeting bet bromodomain proteins in solid tumors SO ONCOTARGET LA English DT Review DE NUT midline carcinoma; breast and prostate cancers; lung cancers; gastrointestinal cancers; brain tumors ID RESISTANT PROSTATE-CANCER; CELL LUNG-CANCER; CLINICAL-PRACTICE GUIDELINE; NUT MIDLINE CARCINOMA; PANCREATIC DUCTAL ADENOCARCINOMA; HEDGEHOG PATHWAY INHIBITOR; NEGATIVE BREAST-CANCER; AMERICAN SOCIETY; GENOMIC LANDSCAPE; COLORECTAL-CANCER AB There is increasing interest in inhibitors targeting BET (bromodomain and extra-terminal) proteins because of the association between this family of proteins and cancer progression. BET inhibitors were initially shown to have efficacy in hematologic malignancies; however, a number of studies have now shown that BET inhibitors can also block progression of non-hematologic malignancies. In this Review, we summarize the efficacy of BET inhibitors in select solid tumors; evaluate the role of BET proteins in mediating resistance to current targeted therapies; and consider potential toxicities of BET inhibitors. We also evaluate recently characterized mechanisms of resistance to BET inhibitors; summarize ongoing clinical trials with these inhibitors; and discuss potential future roles of BET inhibitors in patients with solid tumors. C1 [Sahai, Vaibhav] Univ Michigan, Med Ctr, Dept Med, Ann Arbor, MI 48109 USA. [Redig, Amanda J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Redig, Amanda J.] Harvard Med Sch, Boston, MA USA. [Collier, Katharine A.; Munshi, Hidayatullah G.] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Eckerdt, Frank D.; Munshi, Hidayatullah G.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Munshi, Hidayatullah G.] Jesse Brown VA Med Ctr, Chicago, IL USA. RP Munshi, HG (reprint author), Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA.; Munshi, HG (reprint author), Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. EM h-munshi@northwestern.edu FU NCI [R01CA186885, T32CA009172]; Department of Veterans Affairs [I01BX001363] FX This work was supported by grant R01CA186885 (to H.G. Munshi) and T32CA009172 (to A.J. Redig) from the NCI, and a Merit award I01BX001363 (to H.G. Munshi) from the Department of Veterans Affairs. NR 99 TC 4 Z9 4 U1 4 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD AUG 16 PY 2016 VL 7 IS 33 BP 53997 EP 54009 DI 10.18632/oncotarget.9804 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY9DG UT WOS:000385433000104 PM 27283767 ER PT J AU Aparici, CM Win, AZ AF Aparici, Carina Mari Win, Aung Zaw TI Acute Calculous Cholecystitis Missed on Computed Tomography and Ultrasound but Diagnosed with Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography SO JOURNAL OF CLINICAL IMAGING SCIENCE LA English DT Article DE Acute calculous cholecystitis; computed tomography; fluorodeoxyglucose-positron emission tomography/computed tomography; ultrasound ID GALLBLADDER AB We present a case of a 69-year-old patient who underwent ascending aortic aneurysm repair with aortic valve replacement. On postsurgical day 12, he developed leukocytosis and low-grade fevers. The chest computed tomography (CT) showed a periaortic hematoma which represents a postsurgical change from aortic aneurysm repair, and a small pericardial effusion. The abdominal ultrasound showed cholelithiasis without any sign of cholecystitis. Finally, a fluorodeoxyglucose (FDG) - positron emission tomography (PET)/CT examination was ordered to find the cause of fever of unknown origin, and it showed increased FDG uptake in the gallbladder wall, with no uptake in the lumen. FDG-PET/CT can diagnose acute cholecystitis in patients with nonspecific clinical symptoms and laboratory results. C1 [Aparici, Carina Mari] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. [Win, Aung Zaw] San Francisco VA Med Ctr, Dept Radiol, 4150 Clement St, San Francisco, CA 94121 USA. RP Win, AZ (reprint author), San Francisco VA Med Ctr, Dept Radiol, 4150 Clement St, San Francisco, CA 94121 USA. EM aungzwin@gmail.com NR 11 TC 0 Z9 0 U1 0 U2 0 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 2156-7514 EI 2156-5597 J9 J CLIN IMAG SCI JI J. Clin. Imag. Sci. PD AUG 16 PY 2016 VL 6 BP 1 EP 3 AR UNSP 31 DI 10.4103/2156-7514.188474 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DX6WC UT WOS:000384524800001 PM 27625897 ER PT J AU Lehrbach, NJ Ruvkun, G AF Lehrbach, Nicolas J. Ruvkun, Gary TI Proteasome dysfunction triggers activation of SKN-1A/Nrf1 by the aspartic protease DDI-1 SO ELIFE LA English DT Article ID TRANSCRIPTION FACTOR NRF1; CAENORHABDITIS-ELEGANS GENOME; ENDOPLASMIC-RETICULUM; QUALITY-CONTROL; C-ELEGANS; EUKARYOTIC PROTEASOME; DEGRADATION; PROTEINS; INHIBITION; UBIQUITIN AB Proteasomes are essential for protein homeostasis in eukaryotes. To preserve cellular function, transcription of proteasome subunit genes is induced in response to proteasome dysfunction caused by pathogen attacks or proteasome inhibitor drugs. In Caenorhabditis elegans, this response requires SKN-1, a transcription factor related to mammalian Nrf1/2. Here, we use comprehensive genetic analyses to identify the pathway required for C. elegans to detect proteasome dysfunction and activate SKN-1. Genes required for SKN-1 activation encode regulators of ER traffic, a peptide N-glycanase, and DDI-1, a conserved aspartic protease. DDI-1 expression is induced by proteasome dysfunction, and we show that DDI-1 is required to cleave and activate an ER-associated isoform of SKN-1. Mammalian Nrf1 is also ER-associated and subject to proteolytic cleavage, suggesting a conserved mechanism of proteasome surveillance. Targeting mammalian DDI1 protease could mitigate effects of proteasome dysfunction in aging and protein aggregation disorders, or increase effectiveness of proteasome inhibitor cancer chemotherapies. C1 [Lehrbach, Nicolas J.; Ruvkun, Gary] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Lehrbach, Nicolas J.; Ruvkun, Gary] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. RP Ruvkun, G (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Ruvkun, G (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. EM ruvkun@molbio.mgh.harvard.edu FU National Institutes of Health [R01 AG016636]; Human Frontier Science Program FX National Institutes of Health R01 AG016636 Gary Ruvkun; Human Frontier Science Program Long Term Fellowship Nicolas J Lehrbach; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 66 TC 6 Z9 6 U1 2 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD AUG 16 PY 2016 VL 5 AR e17721 DI 10.7554/eLife.17721 PG 19 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DW6QB UT WOS:000383774900001 ER PT J AU Williams, CAC Fernandez-Alonso, R Wang, JH Toth, R Gray, NS Findlay, GM AF Williams, Charles A. C. Fernandez-Alonso, Rosalia Wang, Jinhua Toth, Rachel Gray, Nathanael S. Findlay, Greg M. TI Erk5 Is a KeyRegulator of Naive-Primed Transition and Embryonic Stem Cell Identity SO CELL REPORTS LA English DT Article ID SELF-RENEWAL; TRANSCRIPTIONAL ACTIVATION; GENE; PLURIPOTENCY; EXPRESSION; BROMODOMAIN; INHIBITORS; DOMAINS; BRD4 AB Embryonic stem cells (ESCs) can self-renew or differentiate into any cell type, a phenomenon known as pluripotency. Distinct pluripotent states, termed naive and primed pluripotency, have been described. However, the mechanisms that control naive-primed pluripotent transition are poorly understood. Here, we perform a targeted screen for kinase inhibitors, which modulate the naive-primed pluripotent transition. We find that XMD compounds, which selectively inhibit Erk5 kinase and BET bromodomain family proteins, drive ESCs toward primed pluripotency. Using compound selectivity engineering and CRISPR/Cas9 genome editing, we reveal distinct functions for Erk5 and Brd4 in pluripotency regulation. We show that Erk5 signaling maintains ESCs in the naive state and suppresses progression toward primed pluripotency and neuroectoderm differentiation. Additionally, we identify a specialized role for Erk5 in defining ESC lineage selection, whereby Erk5 inhibits a cardiomyocyte-specific differentiation program. Our data therefore reveal multiple critical functions for Erk5 in controlling ESC identity. C1 [Williams, Charles A. C.; Fernandez-Alonso, Rosalia; Findlay, Greg M.] Univ Dundee, Sch Life Sci, MRC Prot Phosphorylat & Ubiquitylat Unit, Dundee DD1 5EH, Scotland. [Wang, Jinhua; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Wang, Jinhua; Gray, Nathanael S.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Toth, Rachel] Univ Dundee, Sch Life Sci, Div Signal Transduct Therapy, Dundee DD1 5EH, Scotland. RP Findlay, GM (reprint author), Univ Dundee, Sch Life Sci, MRC Prot Phosphorylat & Ubiquitylat Unit, Dundee DD1 5EH, Scotland. EM g.m.findlay@dundee.ac.uk FU Medical Research Council New Investigator Award [MR/N000609/1]; Tenovus Scotland research grant FX The authors thank Dr. Rosie Clarke for technical expertise and FACS analysis, Dr. Tom Macartney for cloning, and Prof. Karim Labib and Drs. Vicky Cowling and Marios Stavridis (School of Life Sciences, University of Dundee) for advice and critical insights. G.M.F. is supported in part by a Medical Research Council New Investigator Award (MR/N000609/1) and a Tenovus Scotland research grant. NR 31 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 AUG 16 PY 2016 VL 16 IS 7 BP 1820 EP 1828 DI 10.1016/j.celrep.2016.07.033 PG 9 WC Cell Biology SC Cell Biology GA DT3JH UT WOS:000381376500005 PM 27498864 ER PT J AU Sarkar, A Huebner, AJ Sulahian, R Anselmo, A Xu, XS Flattery, K Desai, N Sebastian, C Yram, MA Arnold, K Rivera, M Mostoslavsky, R Bronson, R Bass, AJ Sadreyev, R Shivdasani, RA Hochedlinger, K AF Sarkar, Abby Huebner, Aaron J. Sulahian, Rita Anselmo, Anthony Xu, Xinsen Flattery, Kyle Desai, Niyati Sebastian, Carlos Yram, Mary Anna Arnold, Katrin Rivera, Miguel Mostoslavsky, Raul Bronson, Roderick Bass, Adam J. Sadreyev, Ruslan Shivdasani, Ramesh A. Hochedlinger, Konrad TI Sox2 Suppresses Gastric Tumorigenesis in Mice SO CELL REPORTS LA English DT Article ID EMBRYONIC STEM-CELLS; TRANSCRIPTIONAL REGULATORY CIRCUITRY; SIGNALING PATHWAY; CANCER CELLS; EXPRESSION; DIFFERENTIATION; SURVIVAL; GENES; CDX2; PROLIFERATION AB Sox2 expression marks gastric stem and progenitor cells, raising important questions regarding the genes regulated by Sox2 and the role of Sox2 itself during stomach homeostasis and disease. By using ChIP-seq analysis, we have found that the majority of Sox2 targets in gastric epithelial cells are tissue specific and related to functions such as endoderm development, Wnt signaling, and gastric cancer. Unexpectedly, we found that Sox2 itself is dispensable for gastric stem cell and epithelial self-renewal, yet Sox(2+) cells are highly susceptible to tumorigenesis in an Apc/Wnt-driven mouse model. Moreover, Sox2 loss enhances, rather than impairs, tumor formation in Apc-deficient gastric cells in vivo and in vitro by inducing Tcf/Lef-dependent transcription and upregulating intestinal metaplasia-associated genes, providing a mechanistic basis for the observed phenotype. Together, these data identify Sox2 as a context-dependent tumor suppressor protein that is dispensable for normal tissue regeneration but restrains stomach adenoma formation through modulation of Wnt-responsive and intestinal genes. C1 [Sarkar, Abby; Huebner, Aaron J.; Flattery, Kyle; Sebastian, Carlos; Yram, Mary Anna; Arnold, Katrin; Mostoslavsky, Raul; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Sarkar, Abby; Huebner, Aaron J.; Flattery, Kyle; Sebastian, Carlos; Yram, Mary Anna; Arnold, Katrin; Mostoslavsky, Raul; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Sarkar, Abby; Huebner, Aaron J.; Anselmo, Anthony; Flattery, Kyle; Yram, Mary Anna; Arnold, Katrin; Sadreyev, Ruslan; Hochedlinger, Konrad] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Sarkar, Abby; Huebner, Aaron J.; Sulahian, Rita; Flattery, Kyle; Yram, Mary Anna; Arnold, Katrin; Shivdasani, Ramesh A.; Hochedlinger, Konrad] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Sarkar, Abby; Huebner, Aaron J.; Flattery, Kyle; Yram, Mary Anna; Arnold, Katrin; Hochedlinger, Konrad] Harvard Univ, Howard Hughes Med Inst, 7 Divin Ave, Cambridge, MA 02138 USA. [Sarkar, Abby; Huebner, Aaron J.; Flattery, Kyle; Yram, Mary Anna; Arnold, Katrin; Hochedlinger, Konrad] Harvard Univ, Dept Stem Cell & Regenerat Biol, 7 Divin Ave, Cambridge, MA 02138 USA. [Sulahian, Rita; Xu, Xinsen; Bass, Adam J.; Shivdasani, Ramesh A.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Sulahian, Rita; Xu, Xinsen; Bass, Adam J.; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Desai, Niyati; Rivera, Miguel] Massachusetts Gen Hosp, Div Pathol, Boston, MA 02114 USA. [Bronson, Roderick] Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA. RP Hochedlinger, K (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA.; Hochedlinger, K (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA.; Hochedlinger, K (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Hochedlinger, K (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA.; Hochedlinger, K (reprint author), Harvard Univ, Howard Hughes Med Inst, 7 Divin Ave, Cambridge, MA 02138 USA.; Hochedlinger, K (reprint author), Harvard Univ, Dept Stem Cell & Regenerat Biol, 7 Divin Ave, Cambridge, MA 02138 USA. EM khochedlinger@mgh.harvard.edu FU NIH [R01CA187119, R01DK081113, R01DK096034]; Harvard Stem Cell Institute; Affymetrix FX We thank Yasuhiro Yamada, Rushika Perera, and members of the K.H. lab for helpful suggestions and their critical reading of the manuscript. We also thank Kevin Haigis for Apcfl/fl mice and Calvin Kuo for WNT3A- and RSPONDIN-expressing lines. This study was supported by NIH grants (R01CA187119 to A.J.B., R01DK081113 to R.A.S., and R01DK096034 to K.H.) and the Harvard Stem Cell Institute (to K.H. and A.S.). N.D. and M.N.R. received research support from Affymetrix. NR 43 TC 0 Z9 0 U1 7 U2 7 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 AUG 16 PY 2016 VL 16 IS 7 BP 1929 EP 1941 DI 10.1016/j.celrep.2016.07.034 PG 13 WC Cell Biology SC Cell Biology GA DT3JH UT WOS:000381376500014 PM 27498859 ER PT J AU Zhao, Y Liu, Q Acharya, P Stengel, KR Sheng, QH Zhou, XF Kwak, H Fischer, MA Bradner, JE Strickland, SA Mohan, SR Savona, MR Venters, BJ Zhou, MM Lis, JT Hiebert, SW AF Zhao, Yue Liu, Qi Acharya, Pankaj Stengel, Kristy R. Sheng, Quanhu Zhou, Xiaofan Kwak, Hojoong Fischer, Melissa A. Bradner, James E. Strickland, Stephen A. Mohan, Sanjay R. Savona, Michael R. Venters, Bryan J. Zhou, Ming-Ming Lis, John T. Hiebert, Scott W. TI High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML SO CELL REPORTS LA English DT Article ID ACUTE MYELOID-LEUKEMIA; TRANSCRIPTION ELONGATION-FACTOR; II-DEPENDENT TRANSCRIPTION; BROMODOMAIN PROTEIN BRD4; P-TEFB; C-KIT; CELL-LINES; MUTATIONS; CANCER; INITIATION AB Bromodomain and extra-terminal domain (BET) family inhibitors offer an approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML), as these polymerases are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1,400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8; 21) AML. PRO-seq also identified an enhancer 30 to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PROseq also identified microRNAs, including MIR29C and MIR29B2, that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was upregulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET-inhibitor-induced cell death. C1 [Zhao, Yue; Acharya, Pankaj; Stengel, Kristy R.; Hiebert, Scott W.] Vanderbilt Univ, Dept Biochem, Sch Med, Nashville, TN 37232 USA. [Liu, Qi; Sheng, Quanhu] Vanderbilt Univ, Ctr Quantitat Sci, Sch Med, Nashville, TN 37232 USA. [Liu, Qi] Vanderbilt Univ, Dept Biomed Informat, Sch Med, Nashville, TN 37232 USA. [Zhou, Xiaofan] Vanderbilt Univ, Dept Biol Sci, Nashville, TN 37212 USA. [Kwak, Hojoong; Lis, John T.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. [Fischer, Melissa A.; Strickland, Stephen A.; Mohan, Sanjay R.; Savona, Michael R.] Vanderbilt Univ, Dept Med, Sch Med, Nashville, TN 37232 USA. [Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Strickland, Stephen A.; Mohan, Sanjay R.; Savona, Michael R.; Hiebert, Scott W.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Venters, Bryan J.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Zhou, Ming-Ming] Icahn Sch Med Mt Sinai, Dept Struct & Chem Biol, New York, NY 10029 USA. RP Hiebert, SW (reprint author), Vanderbilt Univ, Dept Biochem, Sch Med, Nashville, TN 37232 USA.; Hiebert, SW (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. EM scott.hiebert@vanderbilt.edu FU T. J. Martell Foundation; Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation; NIH [RO1-CA109355, RO1-CA164605, RO1-GM25232, R01-CA64140]; Vanderbilt Digestive Disease Research grant [NIDDK P30DK58404]; Vanderbilt-Ingram Cancer Center support grant [NCI P30CA68485]; American Cancer Society [5 T32 CA009582-26, PF-13-303-01-DMC]; National Center for Research Resources [UL1 RR024975-01]; National Center for Advancing Translational Sciences [2 UL1 TR000445-06] FX We thank all the members of S.W.H. lab for helpful discussions, reagents, and advice. We thank the Translational Pathology, the Hematological Sample Repository, Flow Cytometry, and VANTAGE Shared Resources for services and support. This work was supported by the T. J. Martell Foundation, the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, NIH grants (RO1-CA109355, RO1-CA164605, RO1-GM25232 and R01-CA64140), and core services performed through a Vanderbilt Digestive Disease Research grant (NIDDK P30DK58404) and a Vanderbilt-Ingram Cancer Center support grant (NCI P30CA68485). K.S. was supported by 5 T32 CA009582-26 and a postdoctoral fellowship (PF-13-303-01-DMC) from the American Cancer Society. The project described was also supported by the National Center for Research Resources (grant UL1 RR024975-01) and is now at the National Center for Advancing Translational Sciences (grant 2 UL1 TR000445-06). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 63 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 AUG 16 PY 2016 VL 16 IS 7 BP 2003 EP 2016 DI 10.1016/j.celrep.2016.07.032 PG 14 WC Cell Biology SC Cell Biology GA DT3JH UT WOS:000381376500020 PM 27498870 ER PT J AU Shlien, A Raine, K Fuligni, F Arnold, R Nik-Zainal, S Dronov, S Mamanova, L Rosic, A Ju, YS Cooke, SL Ramakrishna, M Papaemmanuil, E Davies, HR Tarpey, PS Van Loo, P Wedge, DC Jones, DR Martin, S Marshall, J Anderson, E Hardy, C Barbashina, V Aparicio, SAJR Sauer, T Garred, O Vincent-Salomon, A Mariani, O Boyault, S Fatima, A Langerod, A Borg, A Thomas, G Richardson, AL Borresen-Dale, AL Polyak, K Stratton, MR Campbell, PJ AF Shlien, Adam Raine, Keiran Fuligni, Fabio Arnold, Roland Nik-Zainal, Serena Dronov, Serge Mamanova, Lira Rosic, Andrej Ju, Young Seok Cooke, Susanna L. Ramakrishna, Manasa Papaemmanuil, Elli Davies, Helen R. Tarpey, Patrick S. Van Loo, Peter Wedge, David C. Jones, David R. Martin, Sancha Marshall, John Anderson, Elizabeth Hardy, Claire Barbashina, Violetta Aparicio, Samuel A. J. R. Sauer, Torill Garred, Oystein Vincent-Salomon, Anne Mariani, Odette Boyault, Sandrine Fatima, Aquila Langerod, Anita Borg, Ake Thomas, Gilles Richardson, Andrea L. Borresen-Dale, Anne-Lise Polyak, Kornelia Stratton, Michael R. Campbell, Peter J. CA ICGC Breast Canc Working Grp Oslo Breast Canc Res Consortium TI Direct Transcriptional Consequences of Somatic Mutation in Breast Cancer SO CELL REPORTS LA English DT Article ID ACUTE MYELOID-LEUKEMIA; GENOMIC CHARACTERIZATION; GENE-EXPRESSION; FUSION TRANSCRIPTS; SEQUENCING DATA; CELL; REARRANGEMENT; IDENTIFICATION; LANDSCAPE; DISCOVERY AB Disordered transcriptomes of cancer encompass direct effects of somatic mutation on transcription, coordinated secondary pathway alterations, and increased transcriptional noise. To catalog the rules governing how somatic mutation exerts direct transcriptional effects, we developed an exhaustive pipeline for analyzing RNA sequencing data, which we integrated with whole genomes from 23 breast cancers. Using X-inactivation analyses, we found that cancer cells are more transcriptionally active than intermixed stromal cells. This is especially true in estrogen receptor (ER)-negative tumors. Overall, 59% of substitutions were expressed. Nonsense mutations showed lower expression levels than expected, with patterns characteristic of nonsense-mediated decay. 14% of 4,234 rearrangements caused transcriptional abnormalities, including exon skips, exon reusage, fusions, and premature polyadenylation. We found productive, stable transcription from sense-to-antisense gene fusions and gene-to-intergenic rearrangements, suggesting that these mutation classes drive more transcriptional disruption than previously suspected. Systematic integration of transcriptome with genome data reveals the rules by which transcriptional machinery interprets somatic mutation. C1 [Shlien, Adam; Raine, Keiran; Nik-Zainal, Serena; Dronov, Serge; Mamanova, Lira; Ju, Young Seok; Cooke, Susanna L.; Ramakrishna, Manasa; Papaemmanuil, Elli; Davies, Helen R.; Tarpey, Patrick S.; Van Loo, Peter; Wedge, David C.; Jones, David R.; Martin, Sancha; Marshall, John; Anderson, Elizabeth; Hardy, Claire; Stratton, Michael R.; Campbell, Peter J.] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, Cambs, England. [Van Loo, Peter] Univ Leuven, Dept Human Genet, B-3000 Leuven, Belgium. [Barbashina, Violetta] Inst Canc Res, Breakthrough Breast Canc, Sutton SM2 5NG, Surrey, England. [Aparicio, Samuel A. J. R.] British Columbia Canc Agcy, Vancouver, BC V5Z 1L3, Canada. [Sauer, Torill; Garred, Oystein] Oslo Univ Hosp, Dept Pathol, N-0450 Oslo, Norway. [Vincent-Salomon, Anne; Mariani, Odette] Inst Curie, F-75005 Paris, France. [Boyault, Sandrine; Thomas, Gilles] Ctr Leon Berard, Synergie Lyon Canc, F-69008 Lyon, France. [Fatima, Aquila; Richardson, Andrea L.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Langerod, Anita; Borresen-Dale, Anne-Lise] Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Genet, N-0379 Oslo, Norway. [Langerod, Anita; Borresen-Dale, Anne-Lise] Univ Oslo, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, Fac Med, N-0316 Oslo, Norway. [Borg, Ake] Lund Univ, Dept Oncol, SE-22100 Lund, Sweden. [Polyak, Kornelia] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Campbell, Peter J.] Addenbrookes Hosp, Dept Haematol, Cambridge CB2 0QQ, England. [Campbell, Peter J.] Univ Cambridge, Dept Haematol, Cambridge CB2 1TN, England. [Shlien, Adam; Fuligni, Fabio; Arnold, Roland; Rosic, Andrej] Hosp Sick Children, Dept Genet & Genome Biol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. RP Shlien, A; Campbell, PJ (reprint author), Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, Cambs, England.; Campbell, PJ (reprint author), Addenbrookes Hosp, Dept Haematol, Cambridge CB2 0QQ, England.; Campbell, PJ (reprint author), Univ Cambridge, Dept Haematol, Cambridge CB2 1TN, England.; Shlien, A (reprint author), Hosp Sick Children, Dept Genet & Genome Biol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM adam.shlien@sickkids.ca; pc8@sanger.ac.uk OI Ju, Young Seok/0000-0002-5514-4189; Wedge, David/0000-0002-7572-3196; Martin, Sancha/0000-0001-6213-5259 FU Wellcome Trust [077012/Z/05/Z, WT088340MA]; HL Holmes Award from the National Research Council Canada; European Molecular Biology Organization (EMBO) Fellowship; BASIS project - European Community [242006]; Southern and Eastern Norway Regional Health Authority [2011079]; Norwegian Cancer Society [0332]; Norwegian Radium Hospital Research Foundation FX This work was supported by the Wellcome Trust (grant reference 077012/Z/05/Z). P.J.C. is personally funded through a Wellcome Trust Senior Clinical Research Fellowship (grant reference WT088340MA). A.S. is supported by an HL Holmes Award from the National Research Council Canada and an European Molecular Biology Organization (EMBO) Fellowship. S.D., S.M., and A.L. are funded through the BASIS project, which is a European research project funded by the European Community's Seventh Framework Programme (FP7/2010-2014) under the grant agreement 242006. A.L. and A.-L.B.-D. are supported by Southern and Eastern Norway Regional Health Authority (2011079), Norwegian Cancer Society (0332), and the Norwegian Radium Hospital Research Foundation. We also would like to acknowledge the Core Sequencing Facility and Information Technology groups of the Wellcome Trust Sanger Institute; support for samples, sample banking, and processing from the Breakthrough Breast Cancer Unit; and members of the ICGC Breast Cancer Working Group as well as the Pathology Review subgroup of the Breast Cancer Working Group. NR 31 TC 2 Z9 2 U1 5 U2 5 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 AUG 16 PY 2016 VL 16 IS 7 BP 2032 EP 2046 DI 10.1016/j.celrep.2016.07.028 PG 15 WC Cell Biology SC Cell Biology GA DT3JH UT WOS:000381376500022 PM 27498871 ER PT J AU Amin, A Lawson, DH Salama, AKS Koon, HB Guthrie, T Thomas, SS O'Day, SJ Shaheen, MF Zhang, B Francis, S Hodi, FS AF Amin, Asim Lawson, David H. Salama, April K. S. Koon, Henry B. Guthrie, Troy, Jr. Thomas, Sajeve S. O'Day, Steven J. Shaheen, Montaser F. Zhang, Bin Francis, Stephen Hodi, F. Stephen TI Phase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article DE Vemurafenib; Ipilimumab; Melanoma; CTLA-4; Immune checkpoint inhibitor; BRAF inhibitor; Immunotherapy; Targeted agent ID RECEIVED IPILIMUMAB; PLUS DACARBAZINE; MUTANT MELANOMA; SURVIVAL; INHIBITION; NIVOLUMAB; TRIAL; MULTICENTER; MONOTHERAPY; CANCER AB Background: Ipilimumab (IPI), an anti-CTLA-4 antibody, and vemurafenib (VEM), a BRAF inhibitor, have distinct mechanisms of action and shared toxicities (e.g., skin, gastrointestinal [GI] and hepatobiliary disorders) that may preclude concomitant administration. Concurrent administration of IPI and VEM previously showed significant dose-limiting hepatotoxicity in advanced melanoma. This single-arm, open-label, phase II study evaluated a sequencing strategy with these two agents in previously untreated patients with BRAF-mutated advanced melanoma. Methods: This study was divided into two parts. During Part 1 (VEM1-IPI), patients received VEM 960 mg twice daily for 6 weeks followed by IPI 10 mg/kg every 3 weeks for 4 doses (induction), then every 12 weeks (maintenance) beginning at week 24 until disease progression or unacceptable toxicity. During Part 2 (VEM2), patients who progressed after IPI received VEM at their previously tolerated dose. The primary objective was to estimate the incidence of grade 3/4 drug-related skin adverse events (AEs) during VEM1-IPI. Results: All patients who were initially treated with VEM (n = 46) received IPI induction therapy; 8 received IPI maintenance and 19 were treated during VEM2. During VEM1-IPI, the incidence of grade 3/4 drug-related AEs associated with the skin, GI tract, and hepatobiliary system was 32.6 %, 21.7 %, and 4.3 %, respectively. There were no drug-related deaths. At a median follow-up of 15.3 months, median overall survival was 18.5 months. Median progression-free survival was 4.5 months. Conclusions: VEM (960 mg twice daily for 6 weeks) followed by IPI 10 mg/kg has a manageable safety profile. The benefits/risks of BRAF inhibitors followed by immunotherapy should be evaluated further in light of continuing developments in treatment options for metastatic melanoma. C1 [Amin, Asim] Levine Canc Inst, Carolinas Healthcare Syst, Med Oncol, 1021 Morehead Med Dr, Charlotte, NC 28204 USA. [Lawson, David H.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Salama, April K. S.] Duke Canc Inst, Durham, NC USA. [Koon, Henry B.] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Guthrie, Troy, Jr.] Baptist Canc Inst, Jacksonville, FL USA. [Thomas, Sajeve S.] MD Anderson Canc Ctr Orlando, Orlando, FL USA. [O'Day, Steven J.] Providence St Johns Hlth Ctr, John Wayne Canc Inst, Santa Monica, CA USA. [Shaheen, Montaser F.] Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA. [Zhang, Bin; Francis, Stephen] Bristol Myers Squibb, Princeton, NJ USA. [Hodi, F. Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Zhang, Bin] KBP BioSci, Princeton, NJ USA. RP Amin, A (reprint author), Levine Canc Inst, Carolinas Healthcare Syst, Med Oncol, 1021 Morehead Med Dr, Charlotte, NC 28204 USA. EM Asim.Amin@carolinashealthcare.org NR 27 TC 2 Z9 2 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD AUG 16 PY 2016 VL 4 AR 44 DI 10.1186/s40425-016-0148-7 PG 10 WC Oncology SC Oncology GA DT3IG UT WOS:000381373700002 PM 27532019 ER PT J AU Heinzerling, L Ott, PA Hodi, FS Husain, AN Tajmir-Riahi, A Tawbi, H Pauschinger, M Gajewski, TF Lipson, EJ Luke, JJ AF Heinzerling, Lucie Ott, Patrick A. Hodi, F. Stephen Husain, Aliya N. Tajmir-Riahi, Azadeh Tawbi, Hussein Pauschinger, Matthias Gajewski, Thomas F. Lipson, Evan J. Luke, Jason J. TI Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article DE Checkpoint inhibitor; Immune-related adverse events; Melanoma; Immunotherapy; Myocarditis; Cardiomyopathy; Ipilimumab; Nivolumab; Pembrolizumab ID METASTATIC MELANOMA; DILATED CARDIOMYOPATHY; AUTOIMMUNE MYOCARDITIS; IPILIMUMAB; PEMBROLIZUMAB; ANTIBODY; PATIENT; MICE; REGRESSION; REMISSION AB Immune-checkpoint blocking antibodies have demonstrated objective antitumor responses in multiple tumor types including melanoma, non-small cell lung cancer (NSCLC), and renal cell cancer (RCC). In melanoma, an increase in overall survival has been demonstrated with anti-CTLA-4 and PD-1 inhibition. However, a plethora of immune-mediated adverse events has been reported with these agents. Immune-mediated cardiotoxicity induced by checkpoint inhibitors has been reported in single cases with variable presentation, including myocarditis and pericarditis. Among six clinical cancer centers with substantial experience in the administration of immune-checkpoint blocking antibodies, eight cases of immune-related cardiotoxicity after ipilimumab and/or nivolumab/pembrolizumab were identified. Diagnostic findings, treatment and follow-up are reported. A large variety of cardiotoxic events with manifestations such as heart failure, cardiomyopathy, heart block, myocardial fibrosis and myocarditis was documented. This is the largest case series to date describing cardiotoxicity of immune-checkpoint blocking antibodies. Awareness, monitoring of patients with pre-existing cardiac disorders and prompt evaluation by the treatment team is essential. Treatment including application of steroids is critical for patient safety. C1 [Heinzerling, Lucie; Tajmir-Riahi, Azadeh] Univ Hosp Erlangen, Erlangen, Germany. [Ott, Patrick A.; Hodi, F. Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Husain, Aliya N.; Gajewski, Thomas F.; Luke, Jason J.] Univ Chicago, Comprehens Canc Ctr & Pathol, Chicago, IL 60637 USA. [Tawbi, Hussein] Univ Texas MD Anderson Ctr, Houston, TX USA. [Pauschinger, Matthias] Paracelsus Univ Hosp Nuremberg, Nurnberg, Germany. [Lipson, Evan J.] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Heinzerling, Lucie] Univ Hosp Erlangen, Dept Dermatol, Ulmenweg 18, D-91054 Erlangen, Germany. RP Heinzerling, L (reprint author), Univ Hosp Erlangen, Erlangen, Germany.; Heinzerling, L (reprint author), Univ Hosp Erlangen, Dept Dermatol, Ulmenweg 18, D-91054 Erlangen, Germany. EM lucie.heinzerling@uk-erlangen.de FU NCI NIH HHS [K12 CA139160] NR 36 TC 4 Z9 4 U1 9 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD AUG 16 PY 2016 VL 4 AR 50 DI 10.1186/s40425-016-0152-y PG 11 WC Oncology SC Oncology GA DT3IG UT WOS:000381373700008 PM 27532025 ER PT J AU Hirschtritt, ME Dy, ME Yang, KG Scharf, JM AF Hirschtritt, Matthew E. Dy, Marisela E. Yang, Kelly G. Scharf, Jeremiah M. TI Child Neurology: Diagnosis and treatment of Tourette syndrome SO NEUROLOGY LA English DT Editorial Material ID PREVALENCE; METAANALYSIS; DISORDER; RISK; TICS C1 [Hirschtritt, Matthew E.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Dy, Marisela E.] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. [Dy, Marisela E.; Scharf, Jeremiah M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Yang, Kelly G.; Scharf, Jeremiah M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Scharf, Jeremiah M.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Scharf, Jeremiah M.] Brigham & Womens Hosp, Dept Neurol, Div Cognit & Behav Neurol, 75 Francis St, Boston, MA 02115 USA. RP Hirschtritt, ME (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. EM matthew.hirschtritt@ucsf.edu NR 10 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 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 16 PY 2016 VL 87 IS 7 BP E65 EP E67 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA DU6LV UT WOS:000382327300002 PM 27527544 ER PT J AU Ahlawat, S Fayad, LM Khan, MS Bredella, MA Harris, GJ Evans, DG Farschtschi, S Jacobs, MA Chhabra, A Salamon, JM Wenzel, R Mautner, VF Dombi, E Cai, WL Plotkin, SR Blakeley, JO AF Ahlawat, Shivani Fayad, Laura M. Khan, Muhammad Shayan Bredella, Miriam A. Harris, Gordon J. Evans, D. Gareth Farschtschi, Said Jacobs, Michael A. Chhabra, Avneesh Salamon, Johannes M. Wenzel, Ralph Mautner, Victor F. Dombi, Eva Cai, Wenli Plotkin, Scott R. Blakeley, Jaishri O. CA Whole Body MRI Comm REiNS TI Current whole-body MRI applications in the neurofibromatoses NF1, NF2, and schwannomatosis SO NEUROLOGY LA English DT Article ID NERVE SHEATH TUMORS; PLEXIFORM NEUROFIBROMAS; INTRAOBSERVER VARIABILITY; DIAGNOSTIC-CRITERIA; METASTATIC-DISEASE; BURDEN; TYPE-1; GROWTH; INTEROBSERVER; FEASIBILITY AB Objectives: The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration Whole-Body MRI (WB-MRI) Working Group reviewed the existing literature on WB-MRI, an emerging technology for assessing disease in patients with neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN), to recommend optimal image acquisition and analysis methods to enable WB-MRI as an endpoint in NF clinical trials. Methods: A systematic process was used to review all published data about WB-MRI in NF syndromes to assess diagnostic accuracy, feasibility and reproducibility, and data about specific techniques for assessment of tumor burden, characterization of neoplasms, and response to therapy. Results: WB-MRI at 1.5T or 3.0T is feasible for image acquisition. Short tau inversion recovery (STIR) sequence is used in all investigations to date, suggesting consensus about the utility of this sequence for detection of WB tumor burden in people with NF. There are insufficient data to support a consensus statement about the optimal imaging planes (axial vs coronal) or 2D vs 3D approaches. Functional imaging, although used in some NF studies, has not been systematically applied or evaluated. There are no comparative studies between regional vs WB-MRI or evaluations of WB-MRI reproducibility. Conclusions: WB-MRI is feasible for identifying tumors using both 1.5T and 3.0T systems. The STIR sequence is a core sequence. Additional investigation is needed to define the optimal approach for volumetric analysis, the reproducibility of WB-MRI in NF, and the diagnostic performance of WB-MRI vs regional MRI. C1 [Ahlawat, Shivani; Fayad, Laura M.; Jacobs, Michael A.] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. [Jacobs, Michael A.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Blakeley, Jaishri O.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Khan, Muhammad Shayan] Khyber Med Coll, Peshawar, Pakistan. [Bredella, Miriam A.; Harris, Gordon J.; Cai, Wenli] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. Harvard Med Sch, Boston, MA USA. [Evans, D. Gareth] Univ Manchester, Manchester Acad Hlth Sci Ctr, Genom Med, Manchester M13 9PL, Lancs, England. [Farschtschi, Said; Mautner, Victor F.] Univ Med Ctr Hamburg Eppendorf, Dept Neurol, Hamburg, Germany. [Chhabra, Avneesh] Univ Texas Southwestern Med Ctr Dallas, Radiol & Orthoped Surg, Dallas, TX 75390 USA. [Salamon, Johannes M.] Univ Hosp Hamburg Eppendorf, Dept Diagnost & Intervent Radiol, Hamburg, Germany. [Wenzel, Ralph] Radiol Practice Altona, Hamburg, Germany. [Dombi, Eva] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Plotkin, Scott R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Plotkin, Scott R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Ahlawat, S (reprint author), Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. EM sahlawa1@jhmi.edu RI North, Kathryn/K-6476-2012; OI North, Kathryn/0000-0003-0841-8009; Evans, Gareth/0000-0002-8482-5784 FU NICHD NIH HHS [U54 HD090255] NR 37 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 16 PY 2016 VL 87 SU 1 BP S31 EP S39 DI 10.1212/WNL.0000000000002929 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DU6MD UT WOS:000382328100006 PM 27527647 ER PT J AU Hanemann, CO Blakeley, JO Nunes, FP Robertson, K Stemmer-Rachamimov, A Mautner, V Kurtz, A Ferguson, M Widemann, BC Evans, DG Ferner, R Carroll, SL Korf, B Wolkenstein, P Knight, P Plotkin, SR AF Hanemann, C. Oliver Blakeley, Jaishri O. Nunes, Fabio P. Robertson, Kent Stemmer-Rachamimov, Anat Mautner, Victor Kurtz, Andreas Ferguson, Michael Widemann, Brigitte C. Evans, D. Gareth Ferner, Rosalie Carroll, Steven L. Korf, Bruce Wolkenstein, Pierre Knight, Pamela Plotkin, Scott R. CA REiNS Int Collaboration TI Current status and recommendations for biomarkers and biobanking in neurofibromatosis SO NEUROLOGY LA English DT Article ID NERVE-SHEATH TUMORS; CLINICAL-TRIALS; TYPE-1; SERUM; MANAGEMENT; EXPRESSION; DIAGNOSIS; CONSENSUS AB Objective: Clinically validated biomarkers for neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis (SWN) have not been identified to date. The biomarker working group's goals are to (1) define biomarker needs in NF1, NF2, and SWN; (2) summarize existing data on biomarkers in NF1, NF2, and SWN; (3) outline recommendations for sample collection and biomarker development; and (4) standardize sample collection and methodology protocols where possible to promote comparison between studies by publishing standard operating procedures (SOPs). Methods: The biomarker group reviewed published data on biomarkers in NF1, NF2, and SWN and on biobanking efforts outside these diseases via literature search, defined the need for biomarkers in NF, and developed recommendations in a series of consensus meetings. Results: We describe existing biomarkers in NF and report consensus recommendations for SOP and a minimal clinical dataset to accompany samples derived from patients with NF1, NF2, and SWN in decentralized biobanks. Conclusions: These recommendations are intended to provide clinicians and researchers with a common set of guidelines to collect and store biospecimens and for establishment of biobanks for NF1, NF2, and SWN. C1 [Hanemann, C. Oliver] Univ Plymouth, Peninsula Sch Med & Dent, Inst Translat & Stratified Med, Plymouth, Devon, England. [Blakeley, Jaishri O.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Nunes, Fabio P.] Indiana Univ, Dept Pediat, Bloomington, IN 47405 USA. [Robertson, Kent; Ferguson, Michael] Indiana Univ, Dept Pediat, Sch Med, Bloomington, IN 47405 USA. [Nunes, Fabio P.] Eli Lilly & Co, Tailored Therapeut, Indianapolis, IN 46285 USA. [Stemmer-Rachamimov, Anat] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Plotkin, Scott R.] Massachusetts Gen Hosp, Neurooncol, Boston, MA 02114 USA. [Mautner, Victor] Uniklin Eppendorf, Neurol Klin, Hamburg, Germany. [Kurtz, Andreas] Charite, Berlin Brandenburg Ctr Regenerat Therapies, Berlin, Germany. [Kurtz, Andreas] Seoul Natl Univ, Coll Vet Med, Seoul, South Korea. [Kurtz, Andreas] Seoul Natl Univ, Res Inst Vet Sci, Seoul, South Korea. [Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Evans, D. Gareth] Univ Manchester, Genom Med, Manchester M13 9PL, Lancs, England. [Ferner, Rosalie] Guys & St Thomas NHS Fdn Trust, Dept Neurol, Natl Neurofibromatosis Serv, London, England. [Carroll, Steven L.] Med Univ S Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. [Korf, Bruce] Univ Alabama Birmingham, Heflin Ctr Genom Sci, Birmingham, AL USA. GHU Henri Mondor, Paris, France. [Knight, Pamela] Childrens Tumor Fdn, New York, NY USA. RP Hanemann, CO (reprint author), Univ Plymouth, Peninsula Sch Med & Dent, Inst Translat & Stratified Med, Plymouth, Devon, England. EM Oliver.Hanemann@plymouth.ac.uk RI North, Kathryn/K-6476-2012; OI North, Kathryn/0000-0003-0841-8009; Hanemann, Clemens Oliver/0000-0002-1951-1025; Evans, Gareth/0000-0002-8482-5784 FU NICHD NIH HHS [U54 HD090255] NR 22 TC 1 Z9 1 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 16 PY 2016 VL 87 SU 1 BP S40 EP S48 DI 10.1212/WNL.0000000000002932 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DU6MD UT WOS:000382328100007 PM 27527649 ER PT J AU Plotkin, SR Davis, SD Robertson, KA Akshintala, S Allen, J Fisher, MJ Blakeley, JO Widemann, BC Ferner, RE Marcus, CL AF Plotkin, Scott R. Davis, Stephanie D. Robertson, Kent A. Akshintala, Srivandana Allen, Julian Fisher, Michael J. Blakeley, Jaishri O. Widemann, Brigitte C. Ferner, Rosalie E. Marcus, Carole L. CA REiNS Int Collaboration TI Sleep and pulmonary outcomes for clinical trials of airway plexiform neurofibromas in NF1 SO NEUROLOGY LA English DT Article ID PHASE-I TRIAL; APNEA SYNDROME; REFERENCE VALUES; RESPIRATORY INDICATIONS; PRACTICE PARAMETERS; CYSTIC-FIBROSIS; CPAP TREATMENT; CHILDREN; POLYSOMNOGRAPHY; SPIROMETRY AB Objective: Plexiform neurofibromas (PNs) are complex, benign nerve sheath tumors that occur in approximately 25%-50% of individuals with neurofibromatosis type 1 (NF1). PNs that cause airway compromise or pulmonary dysfunction are uncommon but clinically important. Because improvement in sleep quality or airway function represents direct clinical benefit, measures of sleep and pulmonary function may be more meaningful than tumor size as endpoints in therapeutic clinical trials targeting airway PN. Methods: The Response Evaluation in Neurofibromatosis and Schwannomatosis functional outcomes group reviewed currently available endpoints for sleep and pulmonary outcomes and developed consensus recommendations for response evaluation in NF clinical trials. Results: For patients with airway PNs, polysomnography, impulse oscillometry, and spirometry should be performed to identify abnormal function that will be targeted by the agent under clinical investigation. The functional group endorsed the use of the apnea hypopnea index (AHI) as the primary sleep endpoint, and pulmonary resistance at 10 Hz (R-10) or forced expiratory volume in 1 or 0.75 seconds (FEV1 or FEV0.75) as primary pulmonary endpoints. The group defined minimum changes in AHI, R-10, and FEV1 or FEV0.75 for response criteria. Secondary sleep outcomes include desaturation and hypercapnia during sleep and arousal index. Secondary pulmonary outcomes include pulmonary resistance and reactance measurements at 5, 10, and 20 Hz; forced vital capacity; peak expiratory flow; and forced expiratory flows. Conclusions: These recommended sleep and pulmonary evaluations are intended to provide researchers with a standardized set of clinically meaningful endpoints for response evaluation in trials of NF1-related airway PNs. C1 [Plotkin, Scott R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Plotkin, Scott R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Davis, Stephanie D.] Indiana Univ Sch Med, Riley Childrens Hosp, Sect Pediat Pulmonol Allergy & Sleep Med, Indianapolis, IN 46202 USA. [Robertson, Kent A.] Indiana Univ Sch Med, Riley Childrens Hosp, Stem Cell Transplantat Program, Indianapolis, IN 46202 USA. [Akshintala, Srivandana; Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Allen, Julian] Childrens Hosp Philadelphia, Div Pulm Med, Philadelphia, PA 19104 USA. [Fisher, Michael J.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Marcus, Carole L.] Childrens Hosp Philadelphia, Sleep Ctr, Philadelphia, PA 19104 USA. [Fisher, Michael J.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Marcus, Carole L.] Univ Penn, Sleep Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA. [Allen, Julian] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Blakeley, Jaishri O.] Johns Hopkins Med Inst, Dept Neurol, Baltimore, MD 21205 USA. [Ferner, Rosalie E.] Guys & St Thomas NHS Fdn Trust, Dept Neurol, London, England. Kings Coll London, Inst Psychiat, London WC2R 2LS, England. RP Plotkin, SR (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.; Plotkin, SR (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. EM splotkin@partners.org RI North, Kathryn/K-6476-2012; OI North, Kathryn/0000-0003-0841-8009; Evans, Gareth/0000-0002-8482-5784 FU NICHD NIH HHS [U54 HD090255] NR 42 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 16 PY 2016 VL 87 SU 1 BP S13 EP S20 DI 10.1212/WNL.0000000000002933 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DU6MD UT WOS:000382328100004 PM 27527645 ER PT J AU Widemann, BC Plotkin, SR AF Widemann, Brigitte C. Plotkin, Scott R. TI Consensus for NF clinical trials Recommendations of the REiNS collaboration (Supplement II) INTRODUCTION SO NEUROLOGY LA English DT Editorial Material ID PROGRESSIVE VESTIBULAR SCHWANNOMAS; INTERNATIONAL COLLABORATION; NEUROFIBROMATOSIS TYPE-2; PHASE-II; OUTCOMES AB The neurofibromatoses (NFs) can result in substantial morbidity in affected patients. In order to accelerate the development of effective therapies for NF-related tumor and nontumor manifestations, the development of standardized meaningful outcome measures for clinical trials is critical. The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration was established with the goal to develop consensus recommendations for outcome measures and endpoints in future NF trials and provided the first set of recommendations in a Neurology (R) supplement in 2013. This second supplement updates on clinical trials that have incorporated the recommended measures and provides new recommendations for (1) standardized and specific cognitive assessment tools for use in NF clinical trials, (2) patient-reported outcome measures including pain and physical functioning, (3) functional outcome measures for airway plexiform neurofibromas, (4) the use of whole-body MRI in NF, and (5) the development of biomarkers in NF and guidelines for collection of biospecimens and establishment of biobanks for neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis. Through engagement of the NF research community, regulatory agencies, NF advocacy groups, industry, and patients with NF, REiNS will provide a framework for comprehensive review of these recommendations, continue development of outcome measures relevant to patients, and compare results of trials, which use identical outcome measures. C1 [Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Plotkin, Scott R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Widemann, BC (reprint author), NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. EM widemanb@mail.nih.gov NR 14 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 AUG 16 PY 2016 VL 87 SU 1 BP S1 EP S3 DI 10.1212/WNL.0000000000002930 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA DU6MD UT WOS:000382328100001 ER PT J AU Wolters, PL Martin, S Merker, VL Tonsgard, JH Solomon, SE Baldwin, A Bergner, AL Walsh, K Thompson, HL Gardner, KL Hingtgen, CM Schorry, E Dudley, WN Franklin, B AF Wolters, Pamela L. Martin, Staci Merker, Vanessa L. Tonsgard, James H. Solomon, Sondra E. Baldwin, Andrea Bergner, Amanda L. Walsh, Karin Thompson, Heather L. Gardner, Kathy L. Hingtgen, Cynthia M. Schorry, Elizabeth Dudley, William N. Franklin, Barbara CA REiNS Int Collaboration TI Patient-reported outcomes of pain and physical functioning in neurofibromatosis clinical trials SO NEUROLOGY LA English DT Article ID QUALITY-OF-LIFE; PROMISA(R) PEDIATRIC SCALES; INFORMATION-SYSTEM PROMIS; ITEM RESPONSE THEORY; PLEXIFORM NEUROFIBROMAS; INTERFERENCE INDEX; CHILDREN; TYPE-1; HEALTH; VALIDATION AB Objective: Tumors and other disease complications of neurofibromatosis (NF) can cause pain and negatively affect physical functioning. To document the clinical benefit of treatment in NF trials targeting these manifestations, patient-reported outcomes (PROs) assessing pain and physical functioning should be included as study endpoints. Currently, there is no consensus on the selection and use of such measures in the NF population. This article presents the recommendations of the PRO group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration for assessing the domains of pain and physical functioning for NF clinical trials. Methods: The REiNS PRO group reviewed and rated existing PRO measures assessing pain intensity, pain interference, and physical functioning using their systematic method. Final recommendations are based primarily on 4 main criteria: patient characteristics, item content, psychometric properties, and feasibility for clinical trials. Results: The REiNS PRO group chose the Numeric Rating Scale-11 (>= 8 years) to assess pain intensity, the Pain Interference Index (6-24 years) and the Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference Scale (>= 18 years) to evaluate pain interference, and the PROMIS Physical Functioning Scale to measure upper extremity function and mobility (>= 5 years) for NF clinical trials. Conclusions: The REiNS Collaboration currently recommends these PRO measures to assess the domains of pain and physical functioning for NF clinical trials; however, further research is needed to evaluate their use in individuals with NF. A final consensus recommendation for the pain interference measure will be disseminated in a future publication based on findings from additional published research. C1 [Wolters, Pamela L.; Martin, Staci; Baldwin, Andrea] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Merker, Vanessa L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Merker, Vanessa L.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Tonsgard, James H.] Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. [Solomon, Sondra E.] Univ Vermont, Dept Psychol Sci, Burlington, VT 05405 USA. [Bergner, Amanda L.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Bergner, Amanda L.] Johns Hopkins Univ, Dept Genet, Baltimore, MD USA. [Walsh, Karin] Childrens Natl Hlth Syst, Washington, DC USA. [Walsh, Karin] George Washington Sch Med, Washington, DC USA. [Thompson, Heather L.] Calif State Univ Sacramento, Dept Speech Pathol & Audiol, Sacramento, CA 95819 USA. [Gardner, Kathy L.] Vet Adm Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Gardner, Kathy L.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Hingtgen, Cynthia M.] Michigan State Univ, Dept Clin Neurosci, Spectrum Hlth Med Grp, E Lansing, MI 48824 USA. [Hingtgen, Cynthia M.] Michigan State Univ, Coll Human Med, E Lansing, MI 48824 USA. [Schorry, Elizabeth] Cincinnati Childrens Hosp, Div Human Genet, Cincinnati, OH USA. [Dudley, William N.] Univ N Carolina, Sch Hlth & Human Sci, Dept Publ Hlth Educ, Greensboro, NC USA. [Franklin, Barbara] Advocure NF2 Inc, Los Angeles, CA USA. RP Wolters, PL (reprint author), NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. EM woltersp@mail.nih.gov RI North, Kathryn/K-6476-2012; OI North, Kathryn/0000-0003-0841-8009; Merker, Vanessa/0000-0002-4542-5227; Evans, Gareth/0000-0002-8482-5784 FU NICHD NIH HHS [U54 HD090255] NR 44 TC 2 Z9 2 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 AUG 16 PY 2016 VL 87 SU 1 BP S4 EP S12 DI 10.1212/WNL.0000000000002927 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DU6MD UT WOS:000382328100002 PM 27527648 ER PT J AU Hess, PL Hernandez, AF Bhatt, DL Hellkamp, AS Yancy, CW Schwamm, LH Peterson, ED Schulte, PJ Fonarow, GC Al-Khatib, SM AF Hess, Paul L. Hernandez, Adrian F. Bhatt, Deepak L. Hellkamp, Anne S. Yancy, Clyde W. Schwamm, Lee H. Peterson, Eric D. Schulte, Phillip J. Fonarow, Gregg C. Al-Khatib, Sana M. TI Sex and Race/Ethnicity Differences in Implantable Cardioverter-Defibrillator Counseling and Use Among Patients Hospitalized With Heart Failure Findings from the Get With The Guidelines-Heart Failure Program SO CIRCULATION LA English DT Article DE defibrillators, implantable; ethnic groups; healthcare disparities; heart failure; sex ID RACIAL DISPARITIES; EJECTION FRACTION; THERAPY; PREVENTION; TRIAL; DEATH AB BACKGROUND: Previous studies have found that women and black patients eligible for a primary prevention implantable cardioverter-defibrillator (ICD) are less likely than men or white patients to receive one. METHODS: We performed an observational analysis of the Get With The Guidelines-Heart Failure Program from January 1, 2011, to March 21, 2014. Patients admitted with heart failure and an ejection fraction <= 35% without an ICD were included. Rates of ICD counseling among eligible patients and ICD receipt among counseled patients were examined by sex and race/ethnicity. RESULTS: Among 21 059 patients from 236 sites, 4755 (22.6%) received predischarge ICD counseling. Women were counseled less frequently than men (19.3% versus 24.6%, P<0.001, adjusted odds ratio [OR], 0.84; 95% confidence interval [CI], 0.78-0.91). Racial and ethnic minorities were less likely to receive counseling than white patients (black 22.6%, Hispanic 18.6%, other race/ethnic group 14.4% versus white 24.3%, P< 0.001 for each): adjusted OR versus white, 0.69; 95% CI, 0.63 to 0.76 for black patients; adjusted OR, 0.62; 95% CI, 0.55 to 0.70 for Hispanic patients; adjusted OR, 0.53; 95% CI, 0.43 to 0.65 for other patients. Among the 4755 counseled patients, 2977 (62.6%) received an ICD or had one planned for placement after hospital stay. Among those counseled, women and men were similarly likely to receive an ICD (adjusted OR, 1.13; 95% CI, 0.99-1.29). However, black (adjusted OR, 0.70; 95% CI, 0.56-0.88) and Hispanic patients (adjusted OR, 0.68; 95% CI, 0.46-1.01) were less likely to receive an ICD. CONCLUSIONS: Up to 4 of 5 hospitalized patients with heart failure eligible for ICD counseling did not receive it, particularly women and minority patients. Among counseled patients, ICD use differences by race and ethnicity persisted. C1 [Hess, Paul L.] VA Eastern Colorado Hlth Care Syst, Denver, CO USA. [Hess, Paul L.] Univ Colorado, Sch Med, Dept Med, Denver, CO USA. [Hernandez, Adrian F.; Hellkamp, Anne S.; Peterson, Eric D.; Schulte, Phillip J.; Al-Khatib, Sana M.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Heart & Vasc Ctr, 75 Francis St, Boston, MA 02115 USA. [Bhatt, Deepak L.; Schwamm, Lee H.] Harvard Med Sch, Boston, MA USA. [Yancy, Clyde W.] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Fonarow, Gregg C.] Ronald Reagan UCLA Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. RP Hess, PL (reprint author), Dept Vet Affairs, Cardiol Sect 111B, 1055 Clermont St, Denver, CO 80220 USA. EM paul.hess@ucdenver.edu NR 17 TC 2 Z9 2 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD AUG 16 PY 2016 VL 134 IS 7 BP 517 EP 526 DI 10.1161/CIRCULATIONAHA.115.021048 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DU5XC UT WOS:000382286000007 PM 27492903 ER PT J AU Shekelle, P AF Shekelle, Paul TI In adults = 75 years of age with hypertension, intensive vs standard BP-lowering treatment reduced CV events SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 Greater Los Angeles VA Healthcare Syst, Los Angeles, CA USA. RP Shekelle, P (reprint author), Greater Los Angeles VA Healthcare Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 2 U2 2 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 AUG 16 PY 2016 VL 165 IS 4 BP JC14 EP JC14 DI 10.7326/ACPJC-2016-165-4-014 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DT1UI UT WOS:000381267200032 PM 27538175 ER PT J AU Zhang, XC Brown, JC Schmitz, KH AF Zhang, Xiaochen Brown, Justin C. Schmitz, Kathryn H. TI Association between Body Mass Index and Physical Function among Endometrial Cancer Survivors SO PLOS ONE LA English DT Article ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; LOWER-EXTREMITY LYMPHEDEMA; LOWER-LIMB LYMPHEDEMA; OLDER-ADULTS; IQOLA PROJECT; EXERCISE; MORTALITY; DISABILITY; CARE AB Objectives We sought to quantify the relationship between body mass index (BMI) and physical function among endometrial cancer survivors. Understanding this relationship would help healthcare providers target efforts to refer obese endometrial cancer survivors to weight loss and exercise interventions. Methods We conducted a survey of 213 endometrial cancer survivors who received cancer care at an academic l health system between 2006 and 2010. Physical function subscale was quantified using physical functional component score from the SF-12 questionnaire. We compared physical function of endometrial cancer survivors to population-based age-standardized normative values. Results Among the 213 patients, 16% were normal weight (BMI <= 25 kg/m(2)), and 52% were obese (>= 30 kg/m(2)). Higher BMI categories were associated with lower physical function (P-trend = 0.003), as a continuous variable each 5kg/m(2) higher BMI, physical function score was lower by 0.15 points (beta = -0.15; P = 0.045). Compared to population-based age-standardized normative values, patients < 75yrs reported lower physical function, whereas patients >= 75yrs reported better physical function. BMI was the only covariate associated with differences in physical function between survivors and age-standardized normative values (P = 0.039). Conclusions Among endometrial cancer survivors, higher BMI is associated with lower physical function. Younger endometrial cancer survivors report lower physical function compared to age-standardized normative values. Healthcare providers should be aware that younger, obese endometrial cancer survivors may particularly benefit from interventions such as exercise and weight loss to increase or preserve physical function. C1 [Zhang, Xiaochen; Schmitz, Kathryn H.] Penn State Coll Med, Publ Hlth Sci, Hershey, PA USA. [Brown, Justin C.] Dana Farber Canc Inst, Dept Med Oncol, Div Populat Sci, Boston, MA 02115 USA. RP Schmitz, KH (reprint author), Penn State Coll Med, Publ Hlth Sci, Hershey, PA USA. EM kschmitz@phs.psu.edu OI Zhang, Xiaochen/0000-0003-3086-1285 FU NIH NCI [1U54CA155850-01] FX This work was supported by NIH NCI 1U54CA155850-01. NR 44 TC 0 Z9 1 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 16 PY 2016 VL 11 IS 8 AR e0160954 DI 10.1371/journal.pone.0160954 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT4UN UT WOS:000381476700033 PM 27529546 ER PT J AU Quyen, MLV Muller, LE Telenczuk, B Halgren, E Cash, S Hatsopoulos, NG Dehghani, N Destexhe, A AF Michel Le Van Quyen Muller, Lyle E., II Telenczuk, Bartosz Halgren, Eric Cash, Sydney Hatsopoulos, Nicholas G. Dehghani, Nima Destexhe, Alain TI High-frequency oscillations in human and monkey neocortex during the wake-sleep cycle SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE excitation; inhibition; state-dependent firing; wave propagation; synchrony ID FIELD POTENTIAL OSCILLATIONS; PRIMATE MOTOR CORTEX; GAMMA-OSCILLATIONS; VISUAL-CORTEX; MACAQUE MONKEY; THALAMOCORTICAL NETWORKS; NEURONAL RESPONSES; SLOW OSCILLATIONS; DYNAMIC BALANCE; CEREBRAL-CORTEX AB Beta (beta)-and gamma (gamma)-oscillations are present in different cortical areas and are thought to be inhibition-driven, but it is not known if these properties also apply to gamma-oscillations in humans. Here, we analyze such oscillations in high-density microelectrode array recordings in human and monkey during the wake-sleep cycle. In these recordings, units were classified as excitatory and inhibitory cells. We find that gamma-oscillations in human and beta-oscillations in monkey are characterized by a strong implication of inhibitory neurons, both in terms of their firing rate and their phasic firing with the oscillation cycle. The beta- and gamma-waves systematically propagate across the array, with similar velocities, during both wake and sleep. However, only in slow-wave sleep (SWS) beta- and gamma-oscillations are associated with highly coherent and functional interactions across several millimeters of the neocortex. This interaction is specifically pronounced between inhibitory cells. These results suggest that inhibitory cells are dominantly involved in the genesis of beta- and gamma-oscillations, as well as in the organization of their large-scale coherence in the awake and sleeping brain. The highest oscillation coherence found during SWS suggests that fast oscillations implement a highly coherent reactivation of wake patterns that may support memory consolidation during SWS. C1 [Michel Le Van Quyen] Hop La Pitie Salpetriere, CNRS UMR 7225, Inst Cerveau & Moelle Epiniere, UMRS 1127, F-75013 Paris, France. [Muller, Lyle E., II] Salk Inst Biol Studies, Computat Neurobiol Lab, La Jolla, CA 92037 USA. [Telenczuk, Bartosz; Destexhe, Alain] CNRS, Lab Computat Neurosci, Unite Neurosci Informat & Complexite, F-91190 Gif Sur Yvette, France. [Halgren, Eric] Univ Calif San Diego, Dept Neurosci, Multimodal Imaging Lab, La Jolla, CA 92093 USA. [Halgren, Eric] Univ Calif San Diego, Dept Radiol, Multimodal Imaging Lab, La Jolla, CA 92093 USA. [Cash, Sydney] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Cash, Sydney] Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. [Hatsopoulos, Nicholas G.] Univ Chicago, Dept Organismal Biol & Anat, Comm Computat Neurosci, Chicago, IL 60637 USA. [Dehghani, Nima] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Dehghani, Nima] New England Complex Syst Inst, Cambridge, MA 02142 USA. RP Destexhe, A (reprint author), CNRS, Lab Computat Neurosci, Unite Neurosci Informat & Complexite, F-91190 Gif Sur Yvette, France.; Dehghani, N (reprint author), Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA.; Dehghani, N (reprint author), New England Complex Syst Inst, Cambridge, MA 02142 USA. EM nima.dehghani@wyss.harvard.edu; destexhe@unic.cnrs-gif.fr OI Dehghani, Nima/0000-0003-2032-8903; Muller, Lyle/0000-0001-5165-9890 FU Harvard's Wyss Institute for Biologically Inspired Engineering; Agence Nationale de le Recherche [ANR-10-IAIHU-06]; CNSR European Community Future and Emerging Technologies program (BrainScales) [FP7-269921]; CNSR European Community Future and Emerging Technologies program (Human Brain Project) [FP7-604102]; ONR (Multidisciplinary University Research Initiatives Award) [N00014-13-1-0672]; NIH Grants [5R01NS062092, R01EB009282, R01NS045853, R01MH099645]; NIH Training Grant [5T32EY20503-5] FX We thank Zach Haga for monkey data collection. Research was funded by Harvard's Wyss Institute for Biologically Inspired Engineering; Agence Nationale de le Recherche ANR-10-IAIHU-06; the CNSR European Community Future and Emerging Technologies program (BrainScales FP7-269921 and The Human Brain Project FP7-604102); the ONR (Multidisciplinary University Research Initiatives Award N00014-13-1-0672); and NIH Grants 5R01NS062092, R01EB009282, R01NS045853, and R01MH099645. L.E.M. was supported by NIH Training Grant 5T32EY20503-5. NR 71 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 AUG 16 PY 2016 VL 113 IS 33 BP 9363 EP 9368 DI 10.1073/pnas.1523583113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT3RS UT WOS:000381399200069 ER PT J AU Sherman, MA Lee, S Law, R Haegens, S Thorn, CA Hamalainen, MS Moore, CI Jones, SR AF Sherman, Maxwell A. Lee, Shane Law, Robert Haegens, Saskia Thorn, Catherine A. Hamalainen, Matti S. Moore, Christopher I. Jones, Stephanie R. TI Neural mechanisms of transient neocortical beta rhythms: Converging evidence from humans, computational modeling, monkeys, and mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE beta rhythm; magnetoencephalography; computational modeling; sensorimotor processing; Parkinson's disease ID PRIMARY SOMATOSENSORY CORTEX; GLOBUS-PALLIDUS NETWORK; MOTOR CORTEX; BAND OSCILLATIONS; SPATIAL ATTENTION; SENSORIMOTOR-CORTEX; PARKINSONS-DISEASE; GAMMA OSCILLATIONS; EVOKED-RESPONSES; MU RHYTHM AB Human neocortical 15-29-Hz beta oscillations are strong predictors of perceptual and motor performance. However, the mechanistic origin of beta in vivo is unknown, hindering understanding of its functional role. Combining human magnetoencephalography (MEG), computational modeling, and laminar recordings in animals, we present a new theory that accounts for the origin of spontaneous neocortical beta. In our MEG data, spontaneous beta activity from somatosensory and frontal cortex emerged as noncontinuous beta events typically lasting < 150 ms with a stereotypical waveform. Computational modeling uniquely designed to infer the electrical currents underlying these signals showed that beta events could emerge from the integration of nearly synchronous bursts of excitatory synaptic drive targeting proximal and distal dendrites of pyramidal neurons, where the defining feature of a beta event was a strong distal drive that lasted one beta period (similar to 50 ms). This beta mechanism rigorously accounted for the beta event profiles; several other mechanisms did not. The spatial location of synaptic drive in the model to supragranular and infragranular layers was critical to the emergence of beta events and led to the prediction that beta events should be associated with a specific laminar current profile. Laminar recordings in somatosensory neocortex from anesthetized mice and awake monkeys supported these predictions, suggesting this beta mechanism is conserved across species and recording modalities. These findings make several predictions about optimal states for perceptual and motor performance and guide causal interventions to modulate beta for optimal function. C1 [Sherman, Maxwell A.; Lee, Shane; Law, Robert; Thorn, Catherine A.; Moore, Christopher I.; Jones, Stephanie R.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Sherman, Maxwell A.] Brown Univ, Dept Appl Math, Providence, RI 02912 USA. [Haegens, Saskia] Nathan S Kline Inst Psychiat Res, Cognit Neurosci & Schizophrenia Program, Orangeburg, NY 10962 USA. [Haegens, Saskia] Columbia Univ, Coll Phys & Surg, Dept Neurol Surg, New York, NY 10032 USA. [Hamalainen, Matti S.] Massachusetts Gen Hosp, Athinola A Martinos Ctr, Boston, MA 02129 USA. [Hamalainen, Matti S.] Aalto Univ, Sch Sci, Dept Neurosci & Biomed Engn, Espoo 02150, Finland. [Hamalainen, Matti S.] Harvard Med Sch, Boston, MA 02115 USA. RP Jones, SR (reprint author), Brown Univ, Dept Neurosci, Providence, RI 02912 USA. EM stephanie_jones@brown.edu FU National Science Foundation Grant [CRCNS-1131850]; NIH Grants [R01 MH106174, 5T32MH019118-23, R01 MH060358, P41EB015896, R01 EB009048] FX We thank the editor and anonymous reviewers for thoughtful input; Charles Schroeder for generously providing the monkey data; and Hyeyoung Shin for help in analysis of mouse data and input on the manuscript. This work was supported by National Science Foundation Grant CRCNS-1131850 and NIH Grants R01 MH106174, 5T32MH019118-23, R01 MH060358, P41EB015896, and R01 EB009048. NR 66 TC 3 Z9 3 U1 3 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 AUG 16 PY 2016 VL 113 IS 33 BP E4885 EP E4894 DI 10.1073/pnas.1604135113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT3RS UT WOS:000381399200018 PM 27469163 ER PT J AU Halpern, JA Sedrakyan, A Hsu, WC Mao, JL Daskivich, TJ Nguyen, PL Golden, EB Kang, J Hu, JC AF Halpern, Joshua A. Sedrakyan, Art Hsu, Wei-Chun Mao, Jialin Daskivich, Timothy J. Nguyen, Paul L. Golden, Encouse B. Kang, Josephine Hu, Jim C. TI Use, Complications, and Costs of Stereotactic Body Radiotherapy for Localized Prostate Cancer SO CANCER LA English DT Article DE health care costs; prostate cancer; proton beam therapy; radiosurgery; radiotherapy; stereotactic body radiotherapy; toxicity ID MODULATED RADIATION-THERAPY; RADICAL PROSTATECTOMY; SBRT; EXPERIENCE; OUTCOMES; TRENDS AB BACKGROUND: Stereotactic body radiotherapy (SBRT) for localized prostate cancer has potential advantages over traditional radiotherapies. Herein, the authors compared national trends in use, complications, and costs of SBRT with those of traditional radiotherapies. METHODS: The authors identified men who underwent SBRT, intensity-modulated radiotherapy (IMRT), brachytherapy, and proton beam therapy as primary treatment of prostate cancer between 2004 and 2011 from Surveillance, Epidemiology, and End Results Program (SEER)-Medicare linked data. Temporal trend of therapy use was assessed using the Cochran-Armitage test. Two-year outcomes were compared using the chi-square test. Median treatment costs were compared using the Kruskal-Wallis test. RESULTS: A total of 542 men received SBRT, 9647 received brachytherapy, 23,408 received IMRT, and 800 men were treated with proton beam therapy. There was a significant increase in the use of SBRT and proton beam therapy (P<.001), whereas brachytherapy use decreased (P<.001). A higher percentage of patients treated with SBRT and brachytherapy had low-grade cancer (Gleason score- <6 vs >7) compared with individuals treated with IMRT and proton beam therapy (54.0% and 64.2% vs 35.2% and 49.6%, respectively; P<.001). SBRT compared with brachytherapy and IMRT was associated with equivalent gastrointestinal toxicity but more erectile dysfunction at 2-year follow-up (P<.001). SBRT was associated with more urinary incontinence compared with IMRT and proton beam therapy but less compared with brachytherapy (P<.001, respectively). The median cost of SBRT was $27,145 compared with $17,183 for brachytherapy, $37,090 for IMRT, and $54,706 for proton beam therapy (P<.001). CONCLUSIONS: The use of SBRT and proton beam therapy for localized prostate cancer has increased over time. Despite men of lower disease stage undergoing SBRT, SBRT was found to be associated with greater toxicity but lower health care costs compared with IMRT and proton beam therapy. (C) 2016 American Cancer Society. C1 [Halpern, Joshua A.; Hu, Jim C.] Weill Cornell Med Coll, Dept Urol, 525 East 68th St,Starr 900, New York, NY 10065 USA. [Sedrakyan, Art; Hsu, Wei-Chun; Mao, Jialin] Weill Cornell Med Coll, Dept Healthcare Policy & Res, New York, NY 10065 USA. [Daskivich, Timothy J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. [Nguyen, Paul L.] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA USA. [Golden, Encouse B.; Kang, Josephine] Weill Cornell Med Coll, Dept Radiat Oncol, New York, NY 10065 USA. RP Halpern, JA (reprint author), Weill Cornell Med Coll, Dept Urol, 525 East 68th St,Starr 900, New York, NY 10065 USA. EM jah2031@med.cornell.edu OI Mao, Jialin/0000-0001-6671-3474 FU National Institutes of Health [NIH-1U01FD004494-01]; US Food and Drug Administration FX Funded in part through a UO1 grant (NIH-1U01FD004494-01) from the National Institutes of Health and the US Food and Drug Administration. NR 34 TC 2 Z9 2 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2016 VL 122 IS 16 BP 2496 EP 2504 DI 10.1002/cncr.30101 PG 9 WC Oncology SC Oncology GA DW4MG UT WOS:000383616600009 PM 27224858 ER PT J AU Greenzang, KA Cronin, AM Mack, JW AF Greenzang, Katie A. Cronin, Angel M. Mack, Jennifer W. TI Parental Preparedness for Late Effects and Long-Term Quality of Life in Survivors of Childhood Cancer SO CANCER LA English DT Article DE child; health communication; neoplasms; parents; prognosis; survivors ID INFORMATION NEEDS; PROSPECTIVE COHORT; PEDIATRIC CANCER; ADULT SURVIVORS; ILL PATIENTS; CHILDREN; DIAGNOSIS; PROGNOSIS; ILLNESS; CARE AB BACKGROUND: Parents of children with cancer desire information regarding the late effects of treatment. In the current study, the authors assessed parents' preparedness for late effects at least 5 years after their child's diagnosis. METHODS: A cross-sectional survey was conducted of all eligible parents of children with cancer between April 2004 and September 2005 at Dana-Farber/Boston Children's Cancer and Blood Disorders Center within 1 year of diagnosis, and a follow-up questionnaire was administered at least 5 years later. RESULTS: Approximately 66% of parents of children who were still living, and who were able to be contacted, completed the follow-up questionnaire (91 of 138 parents). Approximately 77% of respondents (70 of 91 respondents) were parents of disease-free survivors and 23% (21 of 91 respondents) were parents of children with recurrent disease. The majority of parents believed they were well prepared for their child's oncology treatment (87%), but fewer felt prepared for future limitations experienced by their children (70%; P=.003 using the McNemar test) or for life after cancer (62%; P<.001). On bivariable analysis among parents of disease-free survivors, parents were more likely to believe themselves to be prepared for future limitations when they also reported that communication with the oncologist helped to address worries regarding the future (odds ratio, 4.50; P=.01). At the time of diagnosis, both parents and physicians underestimated a child's risk of future limitations; 45% of parents and 39% of clinicians predicted future limitations in physical abilities, intelligence, or quality of life, but at the time of the follow-up questionnaire >5 years later, 72% of children experienced limitations in at least 1 domain. CONCLUSIONS: Parents believe themselves to be less prepared for survivorship than for treatment. High-quality communication may help parents to feel more prepared for life after cancer therapy. (C) 2016 American Cancer Society. C1 [Greenzang, Katie A.; Mack, Jennifer W.] Dana Farber Boston Childrens Canc & Blood Disorde, 450 Brookline Ave, Boston, MA 02215 USA. [Greenzang, Katie A.; Cronin, Angel M.; Mack, Jennifer W.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Greenzang, KA (reprint author), Dana Farber Boston Childrens Canc & Blood Disorde, 450 Brookline Ave, Boston, MA 02215 USA. EM katie_greenzang@dfci.harvard.edu FU National Institutes of Health [T32 CA136432]; St. Baldrick's Foundation FX Supported by National Institutes of Health training grant T32 CA136432 (to Katie A. Greenzang) and a St. Baldrick's Foundation Supportive Care Research Grant (to Jennifer W. Mack). NR 24 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2016 VL 122 IS 16 BP 2587 EP 2594 DI 10.1002/cncr.30092 PG 8 WC Oncology SC Oncology GA DW4MG UT WOS:000383616600019 PM 27219336 ER PT J AU Boneschansker, L Nakayama, H Eisenga, M Wedel, J Klagsbrun, M Irimia, D Briscoe, DM AF Boneschansker, Leo Nakayama, Hironao Eisenga, Michele Wedel, Johannes Klagsbrun, Michael Irimia, Daniel Briscoe, David M. TI Netrin-1 Augments Chemokinesis in CD4(+) T Cells In Vitro and Elicits a Proinflammatory Response In Vivo SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; ENDOTHELIAL GROWTH-FACTOR; INHIBITS LEUKOCYTE MIGRATION; REPULSIVE GUIDANCE MOLECULE; AXON GUIDANCE; AUTOIMMUNE ENCEPHALOMYELITIS; PULMONARY INFLAMMATION; LYMPHOCYTE MIGRATION; CYTOKINE PRODUCTION; LUNG INJURY AB Netrin-1 is a neuronal guidance cue that regulates cellular activation, migration, and cytoskeleton rearrangement in multiple cell types. It is a chemotropic protein that is expressed within tissues and elicits both attractive and repulsive migratory responses. Netrin-1 has recently been found to modulate the immune response via the inhibition of neutrophil and macrophage migration. However, the ability of Netrin-1 to interact with lymphocytes and its in-depth effects on leukocyte migration are poorly understood. In this study, we profiled the mRNA and protein expression of known Netrin-1 receptors on human CD4(+) T cells. Neogenin, uncoordinated-5 (UNC5) A, and UNC5B were expressed at low levels in unstimulated cells, but they increased following mitogen-dependent activation. By immunofluorescence, we observed a cytoplasmic staining pattern of neogenin and UNC5A/B that also increased following activation. Using a novel microfluidic assay, we found that Netrin-1 stimulated bidirectional migration and enhanced the size of migratory subpopulations of mitogen-activated CD4(+) T cells, but it had no demonstrable effects on the migration of purified CD4(+)CD25(+)CD127(dim) T regulatory cells. Furthermore, using a short hairpin RNA knockdown approach, we observed that the promigratory effects of Netrin-1 on T effectors is dependent on its interactions with neogenin. In the humanized SCID mouse, local injection of Netrin-1 into skin enhanced inflammation and the number of neogenin-expressing CD3(+) T cell infiltrates. Neogenin was also observed on CD3(+) T cell infiltrates within human cardiac allograft biopsies with evidence of rejection. Collectively, our findings demonstrate that Netrin-1/neogenin interactions augment CD4(+) T cell chemokinesis and promote cellular infiltration in association with acute inflammation in vivo. C1 [Boneschansker, Leo; Eisenga, Michele; Wedel, Johannes; Briscoe, David M.] Boston Childrens Hosp, Div Nephrol, Dept Med, Transplant Res Program, Boston, MA 02115 USA. [Boneschansker, Leo; Wedel, Johannes; Briscoe, David M.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Boneschansker, Leo; Irimia, Daniel] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Ctr Engn Med,Shriners Hosp Children, Boston, MA 02114 USA. [Nakayama, Hironao; Klagsbrun, Michael] Harvard Med Sch, Boston Childrens Hosp, Dept Surg, Vasc Biol Program, Boston, MA 02115 USA. RP Briscoe, DM (reprint author), Boston Childrens Hosp, Transplant Res Program, Div Nephrol, 300 Longwood Ave, Boston, MA 02115 USA. EM david.briscoe@childrens.harvard.edu FU NIAID NIH HHS [R01 AI092305, R01 AI046756, T32 AI007529]; NIBIB NIH HHS [P41 EB002503]; NIDDK NIH HHS [T32 DK007726]; NIGMS NIH HHS [R01 GM092804] NR 49 TC 1 Z9 1 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 AUG 15 PY 2016 VL 197 IS 4 BP 1389 EP 1398 DI 10.4049/jimmunol.1502432 PG 10 WC Immunology SC Immunology GA DY3NB UT WOS:000384999100037 PM 27430720 ER PT J AU Deruaz, M Moldt, B Le, KM Power, KA Vrbanac, VD Tanno, S Ghehremichael, MS Allen, TM Tager, AM Burton, DR Luster, AD AF Deruaz, Maud Moldt, Brian Le, Khoa M. Power, Karen A. Vrbanac, Vladimir D. Tanno, Serah Ghehremichael, Musie S. Allen, Todd M. Tager, Andrew M. Burton, Dennis R. Luster, Andrew D. TI Protection of Humanized Mice From Repeated Intravaginal HIV Challenge by Passive Immunization: A Model for Studying the Efficacy of Neutralizing Antibodies In Vivo SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE humanized mice; neutralizing antibodies; HIV transmission; mucosal infection ID MUCOSAL SHIV CHALLENGE; MONOCLONAL-ANTIBODY; MOUSE MODEL; BLT MICE; TRANSMISSION; THERAPY AB Humanized mice reconstituted with a human immune system can be mucosally infected with human immunodeficiency virus (HIV), opening up the possibility of studying HIV transmission in a small-animal model. Here we report that passive immunization with the broadly neutralizing antibody b12 protected humanized mice against repetitive intravaginal infection in a dose-dependent manner. In addition, treatment with the antibody PGT126, which is more potent in vitro, was more efficacious in vivo and provided sterilizing protection. Our results demonstrate that humanized mice can be used as a small-animal model to study the efficacy and mechanism of broadly neutralizing antibody protection against HIV acquisition. C1 [Deruaz, Maud; Vrbanac, Vladimir D.; Tanno, Serah; Tager, Andrew M.; Luster, Andrew D.] Harvard Med Sch, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Power, Karen A.; Vrbanac, Vladimir D.; Tanno, Serah; Ghehremichael, Musie S.; Allen, Todd M.; Tager, Andrew M.; Burton, Dennis R.] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Moldt, Brian; Le, Khoa M.; Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Moldt, Brian; Le, Khoa M.; Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. RP Luster, AD (reprint author), Massachusetts Gen Hosp, 149 Thirteenth St, Charlestown, MA 02129 USA. EM aluster@mgh.harvard.edu FU National Institutes of Health [P01-AI078897, P01-AI104715, R01-AI33292]; Center for Human Immunodeficiency Virus/AIDS Vaccine Immunology and Immunogen Discovery [UM1-AI100663]; Harvard Center for AIDS Research [P30-AI060354]; Ragon Institute of MGH, MIT and Harvard; International AIDS Vaccine Initiative through the Neutralizing Antibody Consortium; Lundbeck Foundation FX This work was supported by the National Institutes of Health (grants P01-AI078897, P01-AI104715, and R01-AI33292), the Center for Human Immunodeficiency Virus/AIDS Vaccine Immunology and Immunogen Discovery (grant UM1-AI100663), the Harvard Center for AIDS Research (grant P30-AI060354), the Ragon Institute of MGH, MIT and Harvard, and the International AIDS Vaccine Initiative through the Neutralizing Antibody Consortium and the Lundbeck Foundation. NR 15 TC 2 Z9 2 U1 5 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2016 VL 214 IS 4 BP 612 EP 616 DI 10.1093/infdis/jiw203 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DY1JB UT WOS:000384849600015 PM 27357340 ER PT J AU Herbst-Kralovetz, MM Pyles, RB Ratner, AJ Sycuro, LK Mitchell, C AF Herbst-Kralovetz, Melissa M. Pyles, Richard B. Ratner, Adam J. Sycuro, Laura K. Mitchell, Caroline TI New Systems for Studying Intercellular Interactions in Bacterial Vaginosis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE vaginal microbiome; in vitro vaginal epithelial cell culture models; animal models; microfluidics; biofilm ID EPITHELIAL-CELL MODEL; GARDNERELLA-VAGINALIS; GENITAL-TRACT; HAEMOPHILUS VAGINALIS; IN-VITRO; LACTOBACILLUS; EXPRESSION; INFECTION; IDENTIFICATION; MICROBIOME AB Bacterial vaginosis (BV) affects almost a quarter of US women, making it a condition of major public health relevance. Key questions remain regarding the etiology of BV, mechanisms for its association with poor reproductive health outcomes, and reasons for high rates of treatment failure. New model systems are required to answer these remaining questions, elucidate the complex host-microbe and microbe-microbe interactions, and develop new, effective interventions. In this review, we cover the strengths and limitations of in vitro and in vivo model systems to study these complex intercellular interactions. Furthermore, we discuss advancements needed to maximize the translational utility of the model systems. As no single model can recapitulate all of the complex physiological and environmental conditions of the human vaginal microenvironment, we conclude that combinatorial approaches using in vitro and in vivo model systems will be required to address the remaining fundamental questions surrounding the enigma that is BV. C1 [Herbst-Kralovetz, Melissa M.] Univ Arizona, Coll Med Phoenix, Dept Basic Med Sci, Bldg ABC 1,425 N 5th St, Phoenix, AZ 85004 USA. [Pyles, Richard B.] Univ Texas Med Branch, Dept Pediat, Galveston, TX 77555 USA. [Ratner, Adam J.] NYU, Dept Pediat, Sch Med, New York, NY 10016 USA. [Ratner, Adam J.] NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. [Sycuro, Laura K.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. [Mitchell, Caroline] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. RP Herbst-Kralovetz, MM (reprint author), Univ Arizona, Coll Med Phoenix, Dept Basic Med Sci, Bldg ABC 1,425 N 5th St, Phoenix, AZ 85004 USA. EM mherbst1@email.arizona.edu OI Herbst-Kralovetz, Melissa/0000-0002-8540-5917 FU Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases; University of Alabama at Birmingham Sexually Transmitted Infections Clinical Trials Group [HHSN272201300012I] FX This article appears as part of the supplement "Proceedings of the 2015 NIH/NIAID Bacterial Vaginosis Expert Consultation," sponsored by the Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases in partnership with the University of Alabama at Birmingham Sexually Transmitted Infections Clinical Trials Group; contract HHSN272201300012I. NR 45 TC 2 Z9 2 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2016 VL 214 SU 1 BP S6 EP S13 DI 10.1093/infdis/jiw130 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DY1JA UT WOS:000384849500002 PM 27449872 ER PT J AU Murphy, K Mitchell, CM AF Murphy, Kerry Mitchell, Caroline M. TI The Interplay of Host Immunity, Environment and the Risk of Bacterial Vaginosis and Associated Reproductive Health Outcomes SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE mucosal immunity; bacterial vaginosis; vaginal microbiota ID FEMALE GENITAL-TRACT; DEPOT MEDROXYPROGESTERONE ACETATE; CHLAMYDIA-TRACHOMATIS INFECTION; PEROXIDE-PRODUCING LACTOBACILLI; RECEPTOR GENE VARIANTS; VAGINAL MICROBIOME; HORMONAL CONTRACEPTION; PREGNANT-WOMEN; PRETERM BIRTH; CYTOKINE CONCENTRATIONS AB Bacterial vaginosis (BV) is one of the most common causes of vaginal symptoms in US women, but its causal mechanism has not yet been defined. BV is more prevalent in women who are immunosuppressed, and several risk factors for the development of BV are associated with lower quantities of immune mediators in vaginal fluid. In contrast, the poor reproductive health outcomes associated with BV, such as preterm birth and human immunodeficiency virus type 1 acquisition, are associated with increased levels of proinflammatory immune mediators in the genital tract. In this article, we discuss how variations in the host immune profile and environmental effects on host immunity may influence the risk of BV, as well as the risk of complications associated with BV. C1 [Murphy, Kerry] Albert Einstein Coll Med, Div Infect Dis, Bronx, NY 10467 USA. [Mitchell, Caroline M.] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, 55 Fruit St, Boston, MA 02114 USA. RP Mitchell, CM (reprint author), Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, 55 Fruit St, Boston, MA 02114 USA. EM caroline.mitchell@mgh.harvard.edu FU Einstein-Montefiore Institutional Mentored Clinical and Translational Research Career Development Award, through the National Institutes of Health/National Center for Advancing Translational Sciences Clinical and Translational Science Award; Doris Duke Foundation FX This work was supported by Einstein-Montefiore Institutional Mentored Clinical and Translational Research Career Development Award, through the National Institutes of Health/National Center for Advancing Translational Sciences Clinical and Translational Science Award (KL2 award to K. M.); and the Doris Duke Foundation. Clinical Scientist Development Award (to C. M. M.). NR 66 TC 1 Z9 1 U1 7 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2016 VL 214 SU 1 BP S29 EP S35 DI 10.1093/infdis/jiw140 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DY1JA UT WOS:000384849500005 PM 27056955 ER PT J AU Charidimou, A Boulouis, G AF Charidimou, Andreas Boulouis, Gregoire TI Intracerebral haemorrhage recurrence in cerebral amyloid angiopathy: Time to look beyond microbleeds? SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Editorial Material DE Cerebral microbleeds; Cerebral amyloid angiopathy; Intracerebral haemorrhage; Cortical superficial siderosis; Antithrombotics; Enlarged perivascular spaces ID CORTICAL SUPERFICIAL SIDEROSIS; PATHOPHYSIOLOGY C1 [Charidimou, Andreas; Boulouis, Gregoire] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Stroke Res, Dept Neurol, Boston, MA 02115 USA. RP Charidimou, A (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Stroke Res, Dept Neurol, Boston, MA 02115 USA. EM andreas.charidimou.09@ucl.ac.uk OI Boulouis, Gregoire/0000-0001-8422-9205 NR 11 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X EI 1878-5883 J9 J NEUROL SCI JI J. Neurol. Sci. PD AUG 15 PY 2016 VL 367 BP 213 EP 214 DI 10.1016/j.jns.2016.06.014 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DT0IQ UT WOS:000381167600039 PM 27423589 ER PT J AU Zeng, X Jedrychowski, MP Chen, Y Serag, S Lavery, GG Gygi, SP Spiegehnan, BM AF Zeng, Xing Jedrychowski, Mark P. Chen, Yi Serag, Sara Lavery, Gareth G. Gygi, Steve P. Spiegehnan, Bruce M. TI Lysine-specific demethylase 1 promotes brown adipose tissue thermogenesis via repressing glucocorticoid activation SO GENES & DEVELOPMENT LA English DT Article DE LSD1; PRDM16; HSD11B1; brown adipose tissue; thermogenesis; mitochondria ID SYMPATHETIC DENERVATION; UCP1 TRANSCRIPTION; METABOLIC SYNDROME; BEIGE ADIPOCYTES; WHITE FAT; PRDM16; OBESITY; COMPLEX; LSD1; PROGRAM AB Brown adipocytes display phenotypic plasticity, as they can switch between the active states of fatty acid oxidation and energy dissipation versus a more dormant state. Cold exposure or beta-adrenergic stimulation favors the active thermogenic state, whereas sympathetic denervation or glucocorticoid administration promotes more lipid accumulation. Our understanding of the molecular mechanisms underlying these switches is incomplete. Here we found that LSD1 (lysine-specific demethylase 1), a histone demethylase, regulates brown adipocyte metabolism in two ways. On the one hand, LSD1 associates with PRDM16 to repress expression of white fat-selective genes. On the other hand, LSD1 represses HSD11B1 (hydroxysteroid 11-beta-dehydrogenase isozyme 1), a key glucocorticoid-activating enzyme, independently from PRDM16. Adipose-specific ablation of LSD1 impaired mitochondrial fatty acid oxidation capacity of the brown adipose tissue, reduced whole-body energy expenditure, and increased fat deposition, which can be significantly alleviated by simultaneously deleting HSD11B1. These findings establish a novel regulatory pathway connecting histone modification and hormone activation with mitochondrial oxidative capacity and whole-body energy homeostasis. C1 [Zeng, Xing; Chen, Yi; Serag, Sara; Spiegehnan, Bruce M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Zeng, Xing; Jedrychowski, Mark P.; Chen, Yi; Gygi, Steve P.; Spiegehnan, Bruce M.] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. [Lavery, Gareth G.] Univ Birmingham, Inst Metab & Syst Res, Birmingham B15 2TT, W Midlands, England. RP Spiegehnan, BM (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA.; Spiegehnan, BM (reprint author), Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. EM bruce_spiegelman@dfci.harvard.edu FU National Institutes of Health [DK31405]; American Heart Association FX We thank Stuart Orkin and Marc Kerenyi for generously sharing the lsd1flox animals, Yang Shi and Benoit Laurent for providing the LSD1 constructs and experimental advice, Zachary Herbert and the Molecular Biology Core Facilities at Dana Farber Cancer Institute for sequencing studies, the Rodent Histology Core at Harvard Medical School for histology studies, and the Nikon Imaging Center at Harvard Medical School for immunofluorescence studies. This study was supported by National Institutes of Health grant DK31405 to B.M.S., and an American Heart Association post-doctoral fellowship to X.Z. NR 36 TC 3 Z9 3 U1 5 U2 5 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD AUG 15 PY 2016 VL 30 IS 16 BP 1822 EP 1836 DI 10.1101/gad.285312.116 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA DW6CJ UT WOS:000383733700005 PM 27566776 ER PT J AU Patterson, TF Thompson, GR Denning, DW Fishman, JA Hadley, S Herbrecht, R Kontoyiannis, DP Marr, KA Morrison, VA Nguyen, MH Segal, BH Steinbach, WJ Stevens, DA Walsh, TJ Wingard, JR Young, JAH Bennett, JE AF Patterson, Thomas F. Thompson, George R., III Denning, David W. Fishman, Jay A. Hadley, Susan Herbrecht, Raoul Kontoyiannis, Dimitrios P. Marr, Kieren A. Morrison, Vicki A. Nguyen, M. Hong Segal, Brahm H. Steinbach, William J. Stevens, David A. Walsh, Thomas J. Wingard, John R. Young, Jo-Anne H. Bennett, John E. TI Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE aspergillosis; invasive aspergillosis; allergic aspergillosis; chronic aspergillosis; fungal diagnostics; azoles; echniocandins; amphotericin AB It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances. C1 [Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Patterson, Thomas F.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Thompson, George R., III] Univ Calif Davis, Davis, CA 95616 USA. [Denning, David W.] Univ Manchester, Univ South Manchester Hosp, Natl Aspergillosis Ctr, Manchester M13 9PL, Lancs, England. [Fishman, Jay A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fishman, Jay A.] Harvard Med Sch, Boston, MA USA. [Hadley, Susan] Tufts Med Ctr, Boston, MA USA. [Herbrecht, Raoul] Univ Strasbourg, Strasbourg, France. [Kontoyiannis, Dimitrios P.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Marr, Kieren A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Marr, Kieren A.] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Morrison, Vicki A.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Morrison, Vicki A.; Young, Jo-Anne H.] Univ Minnesota, Minneapolis, MN USA. [Nguyen, M. Hong] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Segal, Brahm H.] SUNY Buffalo, Jacobs Sch Med & Biomed Sci, Buffalo, NY USA. [Segal, Brahm H.] Roswell Pk Canc Inst, New York, NY USA. [Steinbach, William J.] Duke Univ, Med Ctr, Durham, NC USA. [Stevens, David A.] Calif Inst Med Res, San Jose, CA 95128 USA. [Walsh, Thomas J.] New York Presbyterian Hosp, Weill Cornell Med Ctr, New York, NY USA. [Wingard, John R.] Univ Florida, Gainesville, FL USA. [Bennett, John E.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Patterson, TF (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Infect Dis, San Antonio Ctr Med Mycol, 7703 Floyd Curl Dr,MSC 7881, San Antonio, TX 78229 USA. EM patterson@uthscsa.edu FU IDSA FX Support for this guideline was provided by the IDSA. NR 1 TC 9 Z9 9 U1 6 U2 6 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 AUG 15 PY 2016 VL 63 IS 4 BP 433 EP 442 DI 10.1093/cid/ciw444 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DV8QU UT WOS:000383202400002 PM 27481947 ER PT J AU Patterson, TF Thompson, GR Denning, DW Fishman, JA Hadley, S Herbrecht, R Kontoyiannis, DP Marr, KA Morrison, VA Nguyen, MH Segal, BH Steinbach, WJ Stevens, DA Walsh, TJ Wingard, JR Young, JAH Bennett, JE AF Patterson, Thomas F. Thompson, George R., III Denning, David W. Fishman, Jay A. Hadley, Susan Herbrecht, Raoul Kontoyiannis, Dimitrios P. Marr, Kieren A. Morrison, Vicki A. Nguyen, M. Hong Segal, Brahm H. Steinbach, William J. Stevens, David A. Walsh, Thomas J. Wingard, John R. Young, Jo-Anne H. Bennett, John E. TI Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE aspergillosis; invasive aspergillosis; allergic aspergillosis; chronic aspergillosis; fungal diagnostics; azoles; echniocandins; amphotericin ID INVASIVE FUNGAL-INFECTIONS; CELL TRANSPLANT RECIPIENTS; LIPOSOMAL AMPHOTERICIN-B; CHRONIC PULMONARY ASPERGILLOSIS; ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS; CENTRAL-NERVOUS-SYSTEM; BRONCHOALVEOLAR LAVAGE FLUID; CHRONIC GRANULOMATOUS-DISEASE; RANDOMIZED CONTROLLED-TRIAL; SOLID-ORGAN TRANSPLANT AB It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances. C1 [Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Patterson, Thomas F.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Thompson, George R., III] Univ Calif Davis, Davis, CA 95616 USA. [Denning, David W.] Univ Manchester, Univ South Manchester Hosp, Natl Aspergillosis Ctr, Manchester M13 9PL, Lancs, England. [Fishman, Jay A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fishman, Jay A.] Harvard Med Sch, Boston, MA USA. [Hadley, Susan] Tufts Med Ctr, Boston, MA USA. [Herbrecht, Raoul] Univ Strasbourg, Strasbourg, France. [Kontoyiannis, Dimitrios P.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Marr, Kieren A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Marr, Kieren A.] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Morrison, Vicki A.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Morrison, Vicki A.; Young, Jo-Anne H.] Univ Minnesota, Minneapolis, MN USA. [Nguyen, M. Hong] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Segal, Brahm H.] SUNY Buffalo, Jacobs Sch Med & Biomed Sci, Buffalo, NY USA. [Segal, Brahm H.] Roswell Pk Canc Inst, New York, NY USA. [Steinbach, William J.] Duke Univ, Med Ctr, Durham, NC USA. [Stevens, David A.] Calif Inst Med Res, San Jose, CA 95128 USA. [Walsh, Thomas J.] New York Presbyterian Hosp, Weill Cornell Med Ctr, New York, NY USA. [Wingard, John R.] Univ Florida, Gainesville, FL USA. [Bennett, John E.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Patterson, TF (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Infect Dis, San Antonio Ctr Med Mycol, 7703 Floyd Curl Dr,MSC 7881, San Antonio, TX 78229 USA. EM patterson@uthscsa.edu OI Herbrecht, Raoul/0000-0002-9381-4876 FU IDSA FX Support for this guideline was provided by the IDSA. NR 657 TC 27 Z9 27 U1 10 U2 11 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 AUG 15 PY 2016 VL 63 IS 4 BP E1 EP E60 DI 10.1093/cid/ciw326 PG 60 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DV8QU UT WOS:000383202400001 PM 27365388 ER EF